Dietary Phytochemicals as Neurotherapeutics for Autism Spectrum Disorder: Plausible Mechanism and Evidence. Bhandari Ranjana,Paliwal Jyoti K,Kuhad Anurag Advances in neurobiology Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with symptoms ranging from lack of social interaction and communication deficits to rigid, repetitive, and stereotypic behavior. It has also been associated with comorbidities such as anxiety, aggression, epilepsy, deficit in sensory processing, as well as ADHD (attention deficit hyperactivity disorder). Apart from several behavioral and cognitive complications arising as a result of central nervous system dysfunction, there are various physiological comorbidities such as immune system deregulation, neuroinflammation, oxidative stress, mitochondrial dysfunction, and gastrointestinal complications which can worsen existing behavioral complications. There are no available treatments for these physiological comorbidities. The prevalence of gastrointestinal complications in ASD ranges from 9% to 70% and it correlates with behaviors consistent with the autistic endophenotype indicating that these are one of the major comorbidities associated with ASD. A strong connection of gut-brain cross talk occurs as a result of gut dysbiosis responsible for excessive production of short-chain fatty acids such as propanoic acid (PPA) by abnormal gut flora in ASD patients. This worsens behavioral, neurochemical, and mitochondrial dysfunction occurring in ASD. These physiological comorbidities are responsible for the generation of free radical species that cause immune system dysfunction leading to synthesis of various pro-inflammatory cytokines and chemokines. This in turn causes activation of microglia. Dietary phytochemicals are thought to be safer and useful as an alternative neurotherapeutic moiety. These compounds provide neuroprotection by modulating signaling pathways such as Nrf2, NF-κB, MAPK pathway or Sirtuin-FoxO pathway. There has been recent evidence in scientific literature regarding the modulation of gut-brain cross talk responsible for behavioral, biochemical, and mitochondrial dysfunction as well as cellular and behavioral sensory alterations by dietary phytochemicals such as curcumin, resveratrol, naringenin, and sulforaphane. These dietary phytochemicals can be formulated in novel brain-targeted delivery systems which overcome their limitation of low oral bioavailability and short half-life leading to prolonged action. Till date, not much work has been done on the development of brain-targeted neurotherapeutics for ASD. In this chapter we discuss plausible mechanisms and evidence from our own and other scientific research for the utilization of curcumin, resveratrol, naringenin, and sulforaphane as neurotherapeutics for ASD. 10.1007/978-3-030-30402-7_23
    Negative Effects of a High-Fat Diet on Intestinal Permeability: A Review. Rohr Michael W,Narasimhulu Chandrakala A,Rudeski-Rohr Trina A,Parthasarathy Sampath Advances in nutrition (Bethesda, Md.) The intestinal tract is the largest barrier between a person and the environment. In this role, the intestinal tract is responsible not only for absorbing essential dietary nutrients, but also for protecting the host from a variety of ingested toxins and microbes. The intestinal barrier system is composed of a mucus layer, intestinal epithelial cells (IECs), tight junctions (TJs), immune cells, and a gut microbiota, which are all susceptible to external factors such as dietary fats. When components of this barrier system are disrupted, intestinal permeability to luminal contents increases, which is implicated in intestinal pathologies such as inflammatory bowel disease, necrotizing enterocolitis, and celiac disease. Currently, there is mounting evidence that consumption of excess dietary fats can enhance intestinal permeability differentially. For example, dietary fat modulates the expression and distribution of TJs, stimulates a shift to barrier-disrupting hydrophobic bile acids, and even induces IEC oxidative stress and apoptosis. In addition, a high-fat diet (HFD) enhances intestinal permeability directly by stimulating proinflammatory signaling cascades and indirectly via increasing barrier-disrupting cytokines [TNFα, interleukin (IL) 1B, IL6, and interferon γ (IFNγ)] and decreasing barrier-forming cytokines (IL10, IL17, and IL22). Finally, an HFD negatively modulates the intestinal mucus composition and enriches the gut microflora with barrier-disrupting species. Although further research is necessary to understand the precise role HFDs play in intestinal permeability, current data suggest a stronger link between diet and intestinal disease than was first thought to exist. Therefore, this review seeks to highlight the various ways an HFD disrupts the gut barrier system and its many implications in human health. 10.1093/advances/nmz061
    The Alternate Consumption of Quercetin and Alliin in the Traditional Asian Diet Reshaped Microbiota and Altered Gene Expression of Colonic Epithelial Cells in Rats. Yu Juntong,Guo Hui,Xie Jinli,Luo Jianming,Li Yuetong,Liu Liu,Ou Shiyi,Zhang Guangwen,Peng Xichun Journal of food science The diet of traditional Asian is similar to the Mediterranean that was considered as a healthy dietary pattern. The report was scarce on whether different plant-derived components with similar anti-oxidative and anti-inflammatory function such as quercetin and alliin in traditional Asian diet consumed in an alternate style cooperatively affect health including the growth of host and the status of the gut microbiota and colonic epithelial immunity. In the present study, the effects of alternate consumption of quercetin and alliin on host health judging by the profile of gut microbiota and gene expression of colonic epithelial cells were investigated with the Illumina MiSeq sequencing (16S rRNA genes) and Illumina HiSeq (RNA-seq) technique, respectively. The results showed that the alternate consumption significantly increased the rat body weight and reshaped the gut microbiota composition. At the phylum level, it significantly increased the relative abundance of fecal Firmicutes and Cyanobacteria but decreased that of Bacteroidetes (P < 0.05) and increased the relative abundance of Candidatus Arthromitus, Lactococcus, Geobacillus, and Ruminococcus at the genus level that benefits the host's health. The alternate consumption of quercetin and alliin also altered 13 genes expression involved in the KEGG pathways of complement and coagulation cascades and hematopoietic cell lineage to improve the gut immunity. Therefore, the alternate consumption of quercetin and alliin in traditional Asian diet can contribute beneficial metabolic effects by optimizing gut microbiota and altering the immunologic function of colonic epithelial cells, resulting in its potential to improve the sub-health status. 10.1111/1750-3841.14473
    Inflammatory and oxidative and nitrosative stress pathways underpinning chronic fatigue, somatization and psychosomatic symptoms. Maes Michael Current opinion in psychiatry PURPOSE OF REVIEW:The aim of this paper is to review recent findings on inflammatory and oxidative and nitrosative stress (IO&NS) pathways in chronic fatigue and somatization disorder. RECENT FINDINGS:Activation of IO&NS pathways is the key phenomenon underpinning chronic fatigue syndrome (CFS): intracellular inflammation, with an increased production of nuclear factor kappa beta (NFkappabeta), cyclo-oxygenase-2 (COX-2) and inducible NO synthase (iNOS); and damage caused by O&NS to membrane fatty acids and functional proteins. These IO&NS pathways are induced by a number of trigger factors, for example psychological stress, strenuous exercise, viral infections and an increased translocation of LPS from gram-bacteria (leaky gut). The 'psychosomatic' symptoms experienced by CFS patients are caused by intracellular inflammation (aches and pain, muscular tension, fatigue, irritability, sadness, and the subjective feeling of infection); damage caused by O&NS (aches and pain, muscular tension and fatigue); and gut-derived inflammation (complaints of irritable bowel). Inflammatory pathways (monocytic activation) are also detected in somatizing disorder. SUMMARY:'Functional' symptoms, as occurring in CFS and somatization, have a genuine organic cause, that is activation of peripheral and central IO&NS pathways and gut-derived inflammation. The development of new drugs, aimed at treating those disorders, should target these IO&NS pathways. 10.1097/yco.0b013e32831a4728
    Redox signaling mediated by the gut microbiota. Neish Andrew S Free radical research The microbiota that occupies the mammalian intestine can modulate a range of physiological functions, including control over immune responses, epithelial barrier function, and cellular proliferation. While commensal prokaryotic organisms are well known to stimulate inflammatory signaling networks, less is known about control over homeostatic pathways. Recent work has shown that gut epithelia contacted by enteric commensal bacteria rapidly generate reactive oxygen species (ROS). While the induced production of ROS in professional phagocytes via stimulation of formyl peptide receptors (FPRs) and activation of NADPH oxidase 2 (Nox2) is a well-studied process, ROS are also similarly elicited in other cell types, including intestinal epithelia, in response to microbial signals via FPRs and the epithelial NADPH oxidase 1 (Nox1). ROS generated by Nox enzymes have been shown to function as critical second messengers in multiple signal transduction pathways via the rapid and transient oxidative inactivation of a distinct class of sensor proteins bearing oxidant-sensitive thiol groups. These redox-sensitive proteins include tyrosine phosphatases that serve as regulators of MAP kinase pathways, focal adhesion kinase, as well as components involved in NF-κB activation. As microbe-elicited ROS has been shown to stimulate cellular proliferation and motility, and to modulate innate immune signaling, we hypothesize that many of the established effects of the normal microbiota on intestinal physiology may be at least partially mediated by this ROS-dependent mechanism. 10.3109/10715762.2013.833331
    Zingerone regulates intestinal transit, attenuates behavioral and oxidative perturbations in irritable bowel disorder in rats. Banji David,Banji Otilia J F,Pavani Bandlapalli,Kranthi Kumar Ch,Annamalai A R Phytomedicine : international journal of phytotherapy and phytopharmacology Stress can lead to the manifestation of functional gastrointestinal disorders, the most prominent being irritable bowel disorder. The present study investigated the impact zingerone in ameliorating chronic water stress induced irritable bowel disorder, brain gut axis dysfunction and dysregulation of the intestinal barrier due to oxidative stress. Rats were randomly allocated to groups and subjected to chronic water stress for a period of 21 days for 1h and the fecal pellet output was measured. At the end of chronic stress, behavioral assessment for anxiety like behavior was recorded and plasma corticosterone levels were measured 60min after water stress. The colonic transit was determined, levels of oxidative and antioxidant biomarkers were measured in the colon homogenate. Myeloperoxidase activity was determined as an indirect index of neutrophil infiltration. Chronic water stress increased the rate of colonic transit, fecal output, induced behavioral changes, and decreased antioxidant levels. An increase in lipid peroxide levels, catalase and corticosterone was observed. Mast cell infiltration was evident in the stressed group. Zingerone significantly reduced colonic transit, fecal output, neutrophil infiltration, and lipid peroxide formation. The levels of catalase were not altered; however, a marginal increase in the levels of glutathione peroxidase was observed. Zingerone significantly enhanced the levels of superoxide dismutase, glutathione and decreased the levels of corticosterone. Zingerone produced marked improvement in stress induced irritable bowel disorder which could be attributed to the powerful antioxidant nature, direct effect on the intestinal smooth muscle and adaptogenic nature. 10.1016/j.phymed.2013.10.007
    Irisin reverses intestinal epithelial barrier dysfunction during intestinal injury via binding to the integrin αVβ5 receptor. Bi Jianbin,Zhang Jia,Ren Yifan,Du Zhaoqing,Li Teng,Wang Tao,Zhang Lin,Wang Mengzhou,Wu Zheng,Lv Yi,Wu Rongqian Journal of cellular and molecular medicine Disruption of the gut barrier results in severe clinical outcomes with no specific treatment. Metabolic disorders and destruction of enterocytes play key roles in gut barrier dysfunction. Irisin is a newly identified exercise hormone that regulates energy metabolism. However, the effect of irisin on gut barrier function remains unknown. The therapeutic effect of irisin on gut barrier dysfunction was evaluated in gut ischemia reperfusion (IR). The direct effect of irisin on gut barrier function was studied in Caco-2 cells. Here, we discovered that serum and gut irisin levels were decreased during gut IR and that treatment with exogenous irisin restored gut barrier function after gut IR in mice. Meanwhile, irisin decreased oxidative stress, calcium influx and endoplasmic reticulum (ER) stress after gut IR. Moreover, irisin protected mitochondrial function and reduced enterocyte apoptosis. The neutralizing antibody against irisin significantly aggravated gut injury, oxidative stress and enterocyte apoptosis after gut IR. Further studies revealed that irisin activated the AMPK-UCP 2 pathway via binding to the integrin αVβ5 receptor. Inhibition of integrin αVβ5, AMPK or UCP 2 abolished the protective role of irisin in gut barrier function. In conclusion, exogenous irisin restores gut barrier function after gut IR via the integrin αVβ5-AMPK-UCP 2 pathway. 10.1111/jcmm.14811
    Suppression of AMPK/aak-2 by NRF2/SKN-1 down-regulates autophagy during prolonged oxidative stress. Kosztelnik Monika,Kurucz Anita,Papp Diana,Jones Emily,Sigmond Timea,Barna Janos,Traka Maria H,Lorincz Tamas,Szarka Andras,Banhegyi Gabor,Vellai Tibor,Korcsmaros Tamas,Kapuy Orsolya FASEB journal : official publication of the Federation of American Societies for Experimental Biology NF-E2-related factor 2 (NRF2) transcription factor has a fundamental role in cell homeostasis maintenance as one of the master regulators of oxidative and electrophilic stress responses. Previous studies have shown that a regulatory connection exists between NRF2 and autophagy during reactive oxygen species-generated oxidative stress. The aim of the present study was to investigate how autophagy is turned off during prolonged oxidative stress, to avoid overeating and destruction of essential cellular components. AMPK is a key cellular energy sensor highly conserved in eukaryotic organisms, and it has an essential role in autophagy activation at various stress events. Here the role of human AMPK and its Caenorhabditis elegans counterpart AAK-2 was explored upon oxidative stress. We investigated the regulatory connection between NRF2 and AMPK during oxidative stress induced by tert-butyl hydroperoxide (TBHP) in HEK293T cells and C. elegans. Putative conserved NRF2/protein skinhead-1 binding sites were found in AMPK/aak-2 genes by in silico analysis and were later confirmed experimentally by using EMSA. After addition of TBHP, NRF2 and AMPK showed a quick activation; AMPK was later down-regulated, however, while NRF2 level remained high. Autophagosome formation and Unc-51-like autophagy activating kinase 1 phosphorylation were initially stimulated, but they returned to basal values after 4 h of TBHP treatment. The silencing of NRF2 resulted in a constant activation of AMPK leading to hyperactivation of autophagy during oxidative stress. We observed the same effects in C. elegans demonstrating the conservation of this self-defense mechanism to save cells from hyperactivated autophagy upon prolonged oxidative stress. We conclude that NRF2 negatively regulates autophagy through delayed down-regulation of the expression of AMPK upon prolonged oxidative stress. This regulatory connection between NRF2 and AMPK may have an important role in understanding how autophagy is regulated in chronic human morbidities characterized by oxidative stress, such as neurodegenerative diseases, certain cancer types, and in metabolic diseases.-Kosztelnik, M., Kurucz, A., Papp, D., Jones, E., Sigmond, T., Barna, J., Traka, M. H., Lorincz, T., Szarka, A., Banhegyi, G., Vellai, T., Korcsmaros, T., Kapuy, O. Suppression of AMPK/aak-2 by NRF2/SKN-1 down-regulates autophagy during prolonged oxidative stress. 10.1096/fj.201800565RR
    Evolution of the gut microbiota and the influence of diet. Rothe M,Blaut M Beneficial microbes Diet is a major force that shapes the composition and activity of the gut microbiota. This is evident from alterations in gut microbiota composition after weaning or drastic dietary changes. Owing to the complexity of the microbiota, interactions of intestinal bacteria with the host are difficult to study. Gnotobiotic animal models offer the opportunity to reduce the complexity and the interindividual variability of the intestinal microbiota. Germ-free animals were associated with a simplified microbial community consisting of eight bacterial species, that are found in the human gut. These microbes were selected because their genome sequences are available, and they mimic to some extent the metabolic activity of the human gut microbiota. The microbiota responded to dietary modifications by changes in the relative proportions of the community members. This model offers the chance to better define the role of intestinal bacteria in obesity development, but little is known on how diet affects intestinal bacteria at the cellular level. Mice monoassociated with Escherichia coli were used as a simplified model to investigate the influence of dietary factors on bacterial protein expression in the intestine. The mice were fed three different diets: a carbohydrate (lactose)-rich diet, a protein-rich diet and a diet rich in starch. The lactose-rich diet led to an induction of proteins involved in E. coli's oxidative stress response (Fur, AhpF, Dps). The corresponding genes are under control of the OxyR transcriptional regulator which is activated by oxidative stress. Further experiments demonstrated that osmotic stress exerted by various carbohydrates leads to an upregulation of proteins belonging to the oxyR regulon. The data suggest that the upregulated proteins enable intestinal E. coli to better cope with diet-induced osmotic stress. These examples demonstrate that gnotobiotic animal models are a valuable tool for studying diet-induced changes at the community and the cell level. 10.3920/BM2012.0029
    Heme oxygenase-1 and gut ischemia/reperfusion injury: A short review. Liao Yu-Feng,Zhu Wei,Li Dong-Pei,Zhu Xiao World journal of gastroenterology Ischemia/reperfusion (I/R) injury of the gut is a significant problem in a variety of clinical settings and is associated with a high morbidity and mortality. Although the mechanisms involved in the pathogenesis of gut I/R injury have not been fully elucidated, it is generally believed that oxidative stress with subsequent inflammatory injury plays an important role. Heme oxygenase (HO) is the rate-limiting enzyme in the catabolism of heme, followed by production of CO, biliverdin, and free iron. The HO system is believed to confer cytoprotection by inhibiting inflammation, oxidation, and apoptosis, and maintaining microcirculation. HO-1, an inducible form of HO, serves a vital metabolic function as the rate-limiting step in the heme degradation pathway, and affords protection in models of intestinal I/R injury. HO-1 system is an important player in intestinal I/R injury condition, and may offer new targets for the management of this condition. 10.3748/wjg.v19.i23.3555
    Honey Bee Gut Microbiome Is Altered by In-Hive Pesticide Exposures. Kakumanu Madhavi L,Reeves Alison M,Anderson Troy D,Rodrigues Richard R,Williams Mark A Frontiers in microbiology Honey bees (Apis mellifera) are the primary pollinators of major horticultural crops. Over the last few decades, a substantial decline in honey bees and their colonies have been reported. While a plethora of factors could contribute to the putative decline, pathogens, and pesticides are common concerns that draw attention. In addition to potential direct effects on honey bees, indirect pesticide effects could include alteration of essential gut microbial communities and symbionts that are important to honey bee health (e.g., immune system). The primary objective of this study was to determine the microbiome associated with honey bees exposed to commonly used in-hive pesticides: coumaphos, tau-fluvalinate, and chlorothalonil. Treatments were replicated at three independent locations near Blacksburg Virginia, and included a no-pesticide amended control at each location. The microbiome was characterized through pyrosequencing of V2-V3 regions of the bacterial 16S rRNA gene and fungal ITS region. Pesticide exposure significantly affected the structure of bacterial but not fungal communities. The bee bacteriome, similar to other studies, was dominated by sequences derived from Bacilli, Actinobacteria, α-, β-, γ-proteobacteria. The fungal community sequences were dominated by Ascomycetes and Basidiomycetes. The Multi-response permutation procedures (MRPP) and subsequent Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) analysis indicated that chlorothalonil caused significant change to the structure and functional potential of the honey bee gut bacterial community relative to control. Putative genes for oxidative phosphorylation, for example, increased while sugar metabolism and peptidase potential declined in the microbiome of chlorothalonil exposed bees. The results of this field-based study suggest the potential for pesticide induced changes to the honey bee gut microbiome that warrant further investigation. 10.3389/fmicb.2016.01255
    Murine gut microbiota and transcriptome are diet dependent. Carlisle Erica M,Poroyko Valeriy,Caplan Michael S,Alverdy John,Morowitz Michael J,Liu Donald Annals of surgery OBJECTIVE:Here, we determine how formula feeding impacts the gut microbiota and host transcriptome. BACKGROUND:Formula-fed (FF) infants are at risk for diseases that involve complex interactions between microbes and host immune elements such as necrotizing enterocolitis. The aims of this study were to simultaneously examine the microbiota and host transcriptional profiles of FF and maternal-fed (MF) mice to evaluate how diet impacts gut colonization and host genes. METHODS:After 72 hours of FF or MF, colonic tissue was collected. 16S ribosomal RNA was sequenced with Roche GS-FLX (Genome Sequencer-FLX) pyrosequencing. Operational taxonomical unit clustering, diversity analysis, and principal coordinate analysis (PCA) were performed. Complementary DNA libraries were sequenced by Solexa. Reads were annotated by BLAST (Basic Local Alignment Search Tool) search against mouse RNA database [National Center for Biotechnology Information (NCBI) build-37] and functionally classified using the KOG (Eukaryotic Orthologous Groups) database (NCBI). RESULTS:Firmicutes (P < 0.001) was the dominant phylum in MF pups, whereas Proteobacteria (P < 0.001) and Bacteroidetes (P < 0.05) were dominant in FF mice. On the genus level, FF mice had increased Serratia (P < 0.001) and Lactococcus (P < 0.05) whereas MF mice had increased Lactobacillus (P < 0.001). PCA confirmed clustering by diet. Solexa sequencing demonstrated different (P < 0.05) messenger RNA transcript levels in 148 genes. Heme oxygenase 1 (P < 0.01), an oxidative stress marker, was increased 25-fold in FF mice. In addition, decreased vinculin (P < 0.05), a cytoskeletal protein associated with adherens junctions in FF pups suggested impaired gut structural integrity. Diet also impacted immune regulation, cell cycle control/gene expression, cell motility, and vascular function genes. CONCLUSIONS:FF shifted gut microbiota and structural integrity, oxidative stress, and immune function genes, presumably increasing vulnerability to disease in FF mice. Interrogation of microbial and host gene expression in FF neonates may offer new insight on how diet affects disease pathogenesis. 10.1097/SLA.0b013e318262a6a6
    The Role of Oxidative Stress and Hormones in Controlling Obesity. Di Domenico Marina,Pinto Federica,Quagliuolo Lucio,Contaldo Maria,Settembre Giuliana,Romano Antonio,Coppola Mario,Ferati Kenan,Bexheti-Ferati Arbëresha,Sciarra Antonella,Nicoletti Giovanni Francesco,Ferraro Giuseppe Andrea,Boccellino Mariarosaria Frontiers in endocrinology The accumulation of adipose tissue in the body occurs because the energy introduced with food and drink exceeds that expense, but to understand why this imbalance is established and why it is maintained over time, it is important to consider the main causes and risk factors of excess weight. In this review, we will refer to the main factors linked to obesity, starting from oxidative stress to hormonal factors including the role of obesity in breast cancer. Among the many hypotheses formulated on the etiopathology of obesity, a key role can be attributed to the relationship between stress oxidative and intestinal microbiota. Multiple evidences tend to show that genetic, epigenetic, and lifestyle factors contribute to determine in the obese an imbalance of the redox balance correlated with the alteration of the intestinal microbial flora. Obesity acts negatively on the wound healing, in fact several studies indicate morbid obesity significantly increased the risk of a post-operative wound complication and infection. Currently, in the treatment of obesity, medical interventions are aimed not only at modifying caloric intake, but also to modulate and improve the composition of diet with the aim of rebalancing the microbiota-redox state axis. 10.3389/fendo.2019.00540
    Oxidative stress, antioxidants and intestinal calcium absorption. Diaz de Barboza Gabriela,Guizzardi Solange,Moine Luciana,Tolosa de Talamoni Nori World journal of gastroenterology The disequilibrium between the production of reactive oxygen (ROS) and nitrogen (RNS) species and their elimination by protective mechanisms leads to oxidative stress. Mitochondria are the main source of ROS as by-products of electron transport chain. Most of the time the intestine responds adequately against the oxidative stress, but with aging or under conditions that exacerbate the ROS and/or RNS production, the defenses are not enough and contribute to developing intestinal pathologies. The endogenous antioxidant defense system in gut includes glutathione (GSH) and GSH-dependent enzymes as major components. When the ROS and/or RNS production is exacerbated, oxidative stress occurs and the intestinal Ca absorption is inhibited. GSH depleting drugs such as DL-buthionine-S,R-sulfoximine, menadione and sodium deoxycholate inhibit the Ca transport from lumen to blood by alteration in the protein expression and/or activity of molecules involved in the Ca transcellular and paracellular pathways through mechanisms of oxidative stress, apoptosis and/or autophagy. Quercetin, melatonin, lithocholic and ursodeoxycholic acids block the effect of those drugs in experimental animals by their antioxidant, anti-apoptotic and/or anti-autophagic properties. Therefore, they may become drugs of choice for treatment of deteriorated intestinal Ca absorption under oxidant conditions such as aging, diabetes, gut inflammation and other intestinal disorders. 10.3748/wjg.v23.i16.2841
    Vegetarian diets and gut microbiota: important shifts in markers of metabolism and cardiovascular disease. do Rosario Vinicius A,Fernandes Ricardo,Trindade Erasmo B S de M Nutrition reviews Vegetarian diets have been associated with a lower incidence of several chronic diseases. The benefits of plant-based diets are related mainly to the improvement of metabolic parameters that can indicate risk for such diseases. Some metabolic factors, such as oxidative balance, lipid profile, and glucose homeostasis, can be improved directly by diet, but paradoxically, some characteristics of vegetarian diets may promote a negative scenario that increases the risk of certain chronic diseases. Additionally, many benefits of a vegetarian diet are mediated by the gut microbiota, members of which not only have taxonomic and functional differences but also produce diverse, specific metabolites that vary according to whether the host consumes an omnivorous or a vegetarian diet. This review examines the modulation of human metabolism and gut microbiota by vegetarian and omnivorous dietary patterns and explores how this modulation may affect the risk of cardiovascular disease. 10.1093/nutrit/nuw012
    Quercetin Protects Against Lipopolysaccharide-Induced Intestinal Oxidative Stress in Broiler Chickens through Activation of Nrf2 Pathway. Sun Lei,Xu Gaoqing,Dong Yangyunyi,Li Meng,Yang Lianyu,Lu Wenfa Molecules (Basel, Switzerland) We investigated the potential ability of quercetin to protect against lipopolysaccharide (LPS)-induced intestinal oxidative stress in broiler chickens and the potential role of the Nrf2 (nuclear factor erythroid 2-related factor 2) signaling pathway. One-day-old broiler chickens (n = 240) were randomized into four groups: saline-challenged broiler chickens fed a basal diet (Con), LPS-challenged broiler chickens on a basal diet (LPS), and LPS-treated broiler chickens on a basal diet containing either 200 or 500 mg/kg of quercetin (Que200+LPS or Que500+LPS). Quercetin (200 mg/kg) significantly alleviated LPS-induced decreased duodenal, jejunal, and illeal villus height and increased the crypt depth in these regions. Quercetin significantly inhibited LPS-induced jejunal oxidative stress, including downregulated reactive oxygen species (ROS), malondialdehyde (MDA), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels, and it upregulated superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels. Quercetin relieved LPS-induced jejunal mitochondria damage and upregulated mitochondrial DNA copy number-related gene expression, including cytochrome c oxidase subunit 1 (COX1), ATP synthase F0 subunit 6 (ATP6), and NADH dehydrogenase subunit 1 (ND1). Quercetin attenuated the LPS-induced inhibition of Nrf2 activation, translocation, and downstream gene expression, including heme oxygenase-1 (HO-1), NAD (P) H dehydrogenase quinone 1 (NQO1), and manganese superoxide dismutase (SOD2). Additionally, quercetin attenuated the LPS-inhibition of c-Jun N-terminal kinase (JNK), Extracellular Regulated protein Kinases (ERK), and p38MAPK (p38) phosphorylation in the MAPK pathway. Thus, quercetin attenuated LPS-induced oxidative stress in the intestines of broiler chickens via the MAPK/Nrf2 signaling pathway. 10.3390/molecules25051053
    The effects of antibiotics and melatonin on hepato-intestinal inflammation and gut microbial dysbiosis induced by a short-term high-fat diet consumption in rats. Yildirim Alper,Arabacı Tamer Sevil,Sahin Duran,Bagriacik Fatma,Kahraman Merve M,Onur Nilsu D,Cayirli Yusuf B,Cilingir Kaya Özlem T,Aksu Burak,Akdeniz Esra,Yuksel Meral,Çetinel Şule,Yeğen Berrak Ç The British journal of nutrition High-fat diet (HFD) consumption leads to metabolic disorders, gastrointestinal dysfunction and intestinal dysbiosis. Antibiotics also disrupt the composition of intestinal microbiota. The aim of the present study was to investigate the impact of a short-term feeding with HFD on oxidative status, enteric microbiota, intestinal motility and the effects of antibiotics and/or melatonin treatments on diet-induced hepato-intestinal dysfunction and inflammation. Male Sprague-Dawley rats were pair-fed with either standard chow or HFD (45 % fat) and were given tap water or melatonin (4 mg/kg per d) or melatonin plus antibiotics (ABX; neomycin, ampicillin, metronidazole; each 1 g/l) in drinking water for 2 weeks. On the 14th day, colonic motility was measured and the next day intestinal transit was assessed using charcoal propagation. Trunk blood, liver and intestine samples were removed for biochemical and histopathological evaluations, and faeces were collected for microbiota analysis. A 2-week HFD feeding increased blood glucose level and perirenal fat weight, induced low-level hepatic and intestinal inflammation, delayed intestinal transit, led to deterioration of epithelial tight junctions and overgrowth of colonic bacteria. Melatonin intake in HFD-fed rats reduced ileal inflammation, colonic motility and perirenal fat accumulation. ABX abolished increases in fat accumulation and blood glucose, reduced ileal oxidative damage, suppressed HFD-induced overgrowth in colonic bacteria, and reversed HFD-induced delay in intestinal transit; however, hepatic neutrophil accumulation, hepatic injury and dysfunction were further enhanced. In conclusion, the results demonstrate that even a short-term HFD ingestion results in hepato-intestinal inflammatory state and alterations in bacterial populations, which may be worsened with antibiotic intake, but alleviated by melatonin. 10.1017/S0007114519001466
    The Combination of Mulberry Extracts and Silk Amino Acids Alleviated High Fat Diet-Induced Nonalcoholic Hepatic Steatosis by Improving Hepatic Insulin Signaling and Normalizing Gut Microbiome Dysbiosis in Rats. Park Sunmin,Zhang Ting,Qiu Jing Yi,Wu Xuangao Evidence-based complementary and alternative medicine : eCAM Mulberry water extracts (MB) and silk amino acids (SA) are reported to improve oxidative stress and inflammation, respectively. We hypothesized whether the mixture of mulberry water extracts and silk amino acids can alleviate nonalcoholic fatty liver disease (NAFLD) induced by high fat diets. Male Sprague Dawley rats were orally provided with high fat diets containing different ratios of MB and SA (1:3, MS1:3, or 1:5, MS1:5) or cellulose (the disease-control) for 12 weeks. Rats had 200 or 600 mg/kg bw of MS1:3 and MS1:5 (MS1:3-L, MS1:3-H; MS1:5-L, and MS1:5-H). Rats in the normal-control group were fed the 20% fat diet with cellulose. Disease-control rats exhibited much greater triglyceride (TG) deposition in the liver than the normal-control rats along with increased body weight gain, visceral fat mass, serum concentrations of cholesterol, triglyceride and nonesterified fatty acid (NEFA), and insulin resistance. Disease-control rats also had liver damage with increased oxidative stress and inflammation compared to the normal-control rats. MS1:3-H and MS1:5-H were found to have greater hepatic glycogen accumulation and decreased hepatic TG, insulin resistance, and dyslipidemia, with MS1:5-H being similar to the normal-control. MS1:3-H alleviated oxidative stress with lower hepatic lipid peroxide compared to MS1:5-H whereas MS1:5-H ameliorated inflammation and hepatocyte damage better than MS1:3-H. Both MS1:3-H and MS1:5-H potentiated hepatic insulin signaling (pAktpACC) and reduced the mRNA expression of TG synthesis genes mRNA (FAS and SREBP-1c). In the gut microbiome MS1:3-H elevated the ratio of to in the cecum better than MS1:5-H but MS1:5-H reduced the proinflammatory . In conclusion, both MS1:3-H and MS1:5-H prevented liver damage induced by high fat diets, mainly by suppressing oxidative stress and inflammation, respectively. MS1:3 and MS1:5 might be used as therapeutic agent for NAFLD. 10.1155/2019/8063121
    In Vitro Gut Metabolism of [U- C]-Quinic Acid, The Other Hydrolysis Product of Chlorogenic Acid. Naranjo Pinta Martine,Montoliu Ivan,Aura Anna-Marja,Seppänen-Laakso Tuulikki,Barron Denis,Moco Sofia Molecular nutrition & food research SCOPE:Quinic acid in its free form is broadly abundant in plants, and can accumulate in copious amounts in coffee, tea, and certain fruits. However, it has been mostly studied as chlorogenic acid, an ester of caffeic and quinic acids. When chlorogenic acid reaches the colon, it is hydrolyzed by microbial esterases releasing caffeic and quinic acids. While biotransformation of chlorogenic and caffeic acids have been elucidated by in vitro and in vivo studies, the gut metabolism of quinic acid has been so far overlooked. METHODS AND RESULTS:[U- C]-Quinic acid is submitted to a colonic model using human fecal microbiota for assessing its metabolic fate. The metabolite profiles formed along microbial biotransformation are monitored by a combined metabolomics approach, using both 2D GC- and ultra-HPLC-MS. Six metabolic intermediates are identified by incorporation of isotopic label. CONCLUSION:Two parallel degradation pathways could be proposed: (1) an oxidative route, leading to aromatization and accumulation of protocatechuic acid, and a (2) reductive route, including dehydroxylation to cyclohexane carboxylic acid. Elucidating the biotransformation of food bioactives by the gut microbiota is of relevance for understanding nutrition, interindividual variability and potential effects on human metabolism. 10.1002/mnfr.201800396
    Gut microbiota drives the attenuation of dextran sulphate sodium-induced colitis by Huangqin decoction. Yang Yang,Chen Gang,Yang Qian,Ye Juan,Cai Xueting,Tsering Pamo,Cheng Xiaolan,Hu Chunping,Zhang Shuangquan,Cao Peng Oncotarget The gut microbiota, including probiotics and pathogenic microorganisms, is involved in ulcerative colitis (UC) by regulating pathogenic microorganisms and the production of intestinal mucosal antibodies. Huangqin decoction (HQD), a traditional Chinese formula chronicled in the Shanghan lun, has been recognized as an effective drug for UC, owing to its anti-inflammatory and anti-oxidative properties. In the present study, we investigated whether HQD ameliorates dextran sulphate sodium (DSS)-induced colitis through alteration of the gut microbiota. We found that HQD significantly inhibited colitis, alleviating the loss of body weight, disease activity index, colon shortening, tissue injury, and inflammatory cytokine changes induced by DSS treatment. Principal component analysis and principal co-ordinate analysis showed an obvious difference among the groups, with increased diversity in the DSS and DSS+HQD groups. Linear discriminant analysis effect size was used to determine differences between the groups. The relative abundance of Lactococcus was higher in the DSS+HQD group than in the DSS group, whereas Desulfovibrio and Helicobacter were decreased. Furthermore, the protective effect of HQD was attenuated only in antibiotic-treated mice. In conclusion, our results suggest that HQD could ameliorate DSS-induced inflammation through alteration of the gut microbiota. 10.18632/oncotarget.16458
    Camellia sinensis and Litsea coreana Ameliorate Intestinal Inflammation and Modulate Gut Microbiota in Dextran Sulfate Sodium-Induced Colitis Mice. Liu Yan,Wang Xinghua,Chen Qiubing,Luo Liyong,Ma Mengjun,Xiao Bo,Zeng Liang Molecular nutrition & food research SCOPE:Polyphenol-enriched herbal extracts have been proved as alternative therapeutic strategies for experimentally induced colitis. The in vivo and in vitro anti-inflammatory effects of Camellia sinensis (green, white, yellow, oolong, black, and dark tea) and Litsea coreana (hawk tea) are comparatively explored. METHODS AND RESULTS:HPLC analysis confirms dissimilarities among phytochemical compositions of these teas. The tea extracts (TEs) significantly decrease the production of pro-inflammatory cytokines (IL-6, IL-12, and tumor necrosis factor-α) and increase the anti-inflammatory cytokines (IL-10) in LPS-stimulated RAW 264.7 macrophages and a dextran sodium sulfate (DSS)-induced colitis mouse model. The treatment of TEs in colitis mice can ameliorate colon inflammation, pro-oxidative enzyme activity, colon integrity, and suppress the activation of nuclear factor-κB. Of note, green TE significantly attenuates the DSS-induced decrease in richness and diversity of gut microbiota. Moreover, TEs are capable of exerting a prebiotic effect on gut microbiota by increasing the abundance of potentially beneficial bacteria (e.g., Faecalibaculum, and Bifidobacterium), and decreasing the abundance of potentially harmful bacteria (e.g., Bacteroids, and Mucispirillum). TEs restore the decreased production of SCFAs in the feces of colitic mice. CONCLUSION:The treatment of seven types of tea can alleviate DSS-induced colitis in mice, and modulate the dysbiosis of gut microbiota in colitis mice. 10.1002/mnfr.201900943
    Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway. Singh Rajbir,Chandrashekharappa Sandeep,Bodduluri Sobha R,Baby Becca V,Hegde Bindu,Kotla Niranjan G,Hiwale Ankita A,Saiyed Taslimarif,Patel Paresh,Vijay-Kumar Matam,Langille Morgan G I,Douglas Gavin M,Cheng Xi,Rouchka Eric C,Waigel Sabine J,Dryden Gerald W,Alatassi Houda,Zhang Huang-Ge,Haribabu Bodduluri,Vemula Praveen K,Jala Venkatakrishna R Nature communications The importance of gut microbiota in human health and pathophysiology is undisputable. Despite the abundance of metagenomics data, the functional dynamics of gut microbiota in human health and disease remain elusive. Urolithin A (UroA), a major microbial metabolite derived from polyphenolics of berries and pomegranate fruits displays anti-inflammatory, anti-oxidative, and anti-ageing activities. Here, we show that UroA and its potent synthetic analogue (UAS03) significantly enhance gut barrier function and inhibit unwarranted inflammation. We demonstrate that UroA and UAS03 exert their barrier functions through activation of aryl hydrocarbon receptor (AhR)- nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent pathways to upregulate epithelial tight junction proteins. Importantly, treatment with these compounds attenuated colitis in pre-clinical models by remedying barrier dysfunction in addition to anti-inflammatory activities. Cumulatively, the results highlight how microbial metabolites provide two-pronged beneficial activities at gut epithelium by enhancing barrier functions and reducing inflammation to protect from colonic diseases. 10.1038/s41467-018-07859-7
    Pomegranate ellagitannin-gut microbial-derived metabolites, urolithins, inhibit neuroinflammation in vitro. DaSilva Nicholas A,Nahar Pragati P,Ma Hang,Eid Aseel,Wei Zhengxi,Meschwitz Susan,Zawia Nasser H,Slitt Angela L,Seeram Navindra P Nutritional neuroscience OBJECTIVES:Urolithins, ellagitannin-gut microbial-derived metabolites, have been reported to mediate pomegranate's neuroprotective effects against Alzheimer's disease (AD), but there are limited data on their effects against neuroinflammation. Herein, we: (1) evaluated whether urolithins (urolithins A and B and their methylated derivatives) attenuate neuroinflammation in murine BV-2 microglia and human SH-SY5Y neurons, and (2) evaluated hippocampus of transgenic AD (R1.40) mice administered a pomegranate extract (PE; 100 or 200 mg/kg/day for 3 weeks) for inflammatory biomarkers. METHODS:Effects of urolithins (10 μM) on inflammatory biomarkers were evaluated in lipopolysaccharide (LPS)-stimulated BV-2 microglia. In a non-contact co-culture cell model, SH-SY5Y cell viability was assessed after exposure to media collected from LPS-BV-2 cells treated with or without urolithins. Effects of urolithins on apoptosis and caspase 3/7 and 9 release from HO-induced oxidative stress of BV-2 and SH-SY5Y cells were assessed. Hippocampal tissues of vehicle and PE-treated transgenic R1.40 mice were evaluated for gene expression of inflammatory biomarkers by qRT-PCR. RESULTS:Urolithins decreased media levels of nitric oxide, interleukin 6 (IL-6), prostaglandin E, and tumor necrosis factor alpha from LPS-BV-2 microglia. In the co-culture cell model, media from LPS-BV-2 cells treated with urolithins preserved SH-SY5Y cell viability greater than media from cells treated without urolithins. Urolithins mitigated apoptosis and caspase 3/7 and 9 release from HO-induced oxidative stress of BV-2 and SH-SY5Y cells. While not statistically significant, inflammatory biomarkers (TNF-α, COX-2, IL-1, and IL-6) appeared to follow a decreasing trend in the hippocampus of high-dose PE-treated animals compared to controls. DISCUSSION:The attenuation of neuroinflammation by urolithins may contribute, in part, toward pomegranate's neuroprotective effects against AD. 10.1080/1028415X.2017.1360558
    Nopal (Opuntia ficus indica) protects from metabolic endotoxemia by modifying gut microbiota in obese rats fed high fat/sucrose diet. Sánchez-Tapia Mónica,Aguilar-López Miriam,Pérez-Cruz Claudia,Pichardo-Ontiveros Edgar,Wang Mei,Donovan Sharon M,Tovar Armando R,Torres Nimbe Scientific reports Current efforts are directed to reducing the gut dysbiosis and inflammation produced by obesity. The purpose of this study was to investigate whether consuming nopal, a vegetable rich in dietary fibre, vitamin C, and polyphenols can reduce the metabolic consequences of obesity by modifying the gut microbiota and preventing metabolic endotoxemia in rats fed a high fat and sucrose diet. With this aim, rats were fed a high fat diet with 5% sucrose in the drinking water (HFS) for 7 months and then were fed for 1 month with HFS + 5% nopal (HFS + N). The composition of gut microbiota was assessed by sequencing the 16S rRNA gene. Nopal modified gut microbiota and increased intestinal occludin-1 in the HFS + N group. This was associated with a decrease in metabolic endotoxemia, glucose insulinotropic peptide, glucose intolerance, lipogenesis, and metabolic inflexibility. These changes were accompanied by reduced hepatic steatosis and oxidative stress in adipose tissue and brain, and improved cognitive function, associated with an increase in B. fragilis. This study supports the use of nopal as a functional food and prebiotic for its ability to modify gut microbiota and to reduce metabolic endotoxemia and other obesity-related biochemical abnormalities. 10.1038/s41598-017-05096-4
    Impact of Cranberries on Gut Microbiota and Cardiometabolic Health: Proceedings of the Cranberry Health Research Conference 2015. Blumberg Jeffrey B,Basu Arpita,Krueger Christian G,Lila Mary Ann,Neto Catherine C,Novotny Janet A,Reed Jess D,Rodriguez-Mateos Ana,Toner Cheryl D Advances in nutrition (Bethesda, Md.) Recent advances in cranberry research have expanded the evidence for the role of this Vaccinium berry fruit in modulating gut microbiota function and cardiometabolic risk factors. The A-type structure of cranberry proanthocyanidins seems to be responsible for much of this fruit's efficacy as a natural antimicrobial. Cranberry proanthocyanidins interfere with colonization of the gut by extraintestinal pathogenic Escherichia coli in vitro and attenuate gut barrier dysfunction caused by dietary insults in vivo. Furthermore, new studies indicate synergy between these proanthocyanidins, other cranberry components such as isoprenoids and xyloglucans, and gut microbiota. Together, cranberry constituents and their bioactive catabolites have been found to contribute to mechanisms affecting bacterial adhesion, coaggregation, and biofilm formation that may underlie potential clinical benefits on gastrointestinal and urinary tract infections, as well as on systemic anti-inflammatory actions mediated via the gut microbiome. A limited but growing body of evidence from randomized clinical trials reveals favorable effects of cranberry consumption on measures of cardiometabolic health, including serum lipid profiles, blood pressure, endothelial function, glucoregulation, and a variety of biomarkers of inflammation and oxidative stress. These results warrant further research, particularly studies dedicated to the elucidation of dose-response relations, pharmacokinetic/metabolomics profiles, and relevant biomarkers of action with the use of fully characterized cranberry products. Freeze-dried whole cranberry powder and a matched placebo were recently made available to investigators to facilitate such work, including interlaboratory comparability. 10.3945/an.116.012583
    Cellular Stress Responses and Gut Microbiota in Inflammatory Bowel Disease. Cao Siyan Stewart Gastroenterology research and practice Progresses in the past two decades have greatly expanded our understanding of inflammatory bowel disease (IBD), an incurable disease with multifaceted and challenging clinical manifestations. The pathogenesis of IBD involves multiple processes on the cellular level, which include the stress response signaling such as endoplasmic reticulum (ER) stress, oxidative stress, and hypoxia. Under physiological conditions, the stress responses play key roles in cell survival, mucosal barrier integrity, and immunomodulation. However, they can also cause energy depletion, trigger cell death and tissue injury, promote inflammatory response, and drive the progression of clinical disease. In recent years, gut microflora has emerged as an essential pathogenic factor and therapeutic target for IBD. Altered compositional and metabolic profiles of gut microbiota, termed dysbiosis, are associated with IBD. Recent studies, although limited, have shed light on how ER stress, oxidative stress, and hypoxic stress interact with gut microorganisms, a potential source of stress in the microenvironment of gastrointestinal tract. Our knowledge of cellular stress responses in intestinal homeostasis as well as their cross-talks with gut microbiome will further our understanding of the pathogenesis of inflammatory bowel disease and probably open avenues for new therapies. 10.1155/2018/7192646
    Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease. Rotman Yaron,Sanyal Arun J Gut Given the high prevalence and rising incidence of non-alcoholic fatty liver disease (NAFLD), the absence of approved therapies is striking. Although the mainstay of treatment of NAFLD is weight loss, it is hard to maintain, prompting the need for pharmacotherapy as well. A greater understanding of disease pathogenesis in recent years was followed by development of new classes of medications, as well as potential repurposing of currently available agents. NAFLD therapies target four main pathways. The dominant approach is targeting hepatic fat accumulation and the resultant metabolic stress. Medications in this group include peroxisome proliferator-activator receptor agonists (eg, pioglitazone, elafibranor, saroglitazar), medications targeting the bile acid-farnesoid X receptor axis (obeticholic acid), inhibitors of de novo lipogenesis (aramchol, NDI-010976), incretins (liraglutide) and fibroblast growth factor (FGF)-21 or FGF-19 analogues. A second approach is targeting the oxidative stress, inflammation and injury that follow the metabolic stress. Medications from this group include antioxidants (vitamin E), medications with a target in the tumour necrosis factor α pathway (emricasan, pentoxifylline) and immune modulators (amlexanox, cenicriviroc). A third group has a target in the gut, including antiobesity agents such as orlistat or gut microbiome modulators (IMM-124e, faecal microbial transplant, solithromycin). Finally, as the ongoing injury leads to fibrosis, the harbinger of liver-related morbidity and mortality, antifibrotics (simtuzumab and GR-MD-02) will be an important element of therapy. It is very likely that in the next few years several medications will be available to clinicians treating patients with NAFLD across the entire spectrum of disease. 10.1136/gutjnl-2016-312431
    Curcumin ameliorates oxidative stress-induced intestinal barrier injury and mitochondrial damage by promoting Parkin dependent mitophagy through AMPK-TFEB signal pathway. Cao Shuting,Wang Chunchun,Yan Jintao,Li Xin,Wen Jiashu,Hu Caihong Free radical biology & medicine The gut epithelial is known as the most critical barrier for protection against harmful antigens and pathogens. Oxidative stress has been implicated in the dysfunction of the intestine barrier. Hence, effective and safe therapeutic approaches for maintaining intestinal redox balance are urgently needed. Curcumin has gained attention for its vast beneficial biological function via antioxidative stress. However, whether the curcumin can relief intestine damage and mitochondrial injury induced by oxidative stress is still unclear. In this study, we found that curcumin can effectively ameliorate hydrogen peroxide (HO)-induced oxidative stress, intestinal epithelial barrier injury and mitochondrial damage in porcine intestinal epithelial cells (IPEC-J2 cells) in a PTEN-induced putative kinase (PINK1)-Parkin mitophagy dependent way. Mechanistically, depletion of Parkin (a mitophagy related protein) abolished curcumin's protective action on anti-oxidative stress, improving intestinal barrier and mitochondrial function in porcine intestinal epithelial cells (IPEC-J2) induced by HO. Consistently, the protective effect of curcumin was not found in cells transfected with GFP-ParkinΔUBL, which encodes a mutant Parkin protein without the ubiquitin E3 ligase activity, indicating that the ubiquitin E3 ligase of Parkin is required for curcumin's protective effects. On the other hand, we also found that the protective function of curcumin was diminished when PRKAA1 was depleted in IPEC-J2 cells treated with HO. Immunofluorescence and luciferase assay showed that curcumin dramatically enhanced nuclear translocation and transcriptional activity of transcription factor EB (TFEB) in IPEC-J2 cells treated with HO, and it was ameliorated by co-treated with compound C, an Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) inhibitor, which means curcumin promotes TFEB transcript via AMPK signal pathway. Consistent with in vitro data, dietary curcumin protected intestinal barrier function, improved redox status, alleviated mitochondrial damage, triggered mitophagy and influenced AMPK-TFEB signal pathway in a well-established pig oxidative stress model by challenging with diquat. Taken together, these results unveil that curcumin ameliorates oxidative stress, enhances intestinal barrier function and mitochondrial function via the induction of Parkin dependent mitophagy through AMPK activation and subsequent TFEB nuclear translocation. 10.1016/j.freeradbiomed.2019.12.004
    Towards a comprehensive theory of obesity and a healthy diet: The causal role of oxidative stress in food addiction and obesity. Tobore Tobore Onojighofia Behavioural brain research BACKGROUND:Obesity is a major public health problem whose prevalence has been rapidly increasing in the United States (U.S), and globally. It is one of the leading causes of preventable deaths globally and contributes to the development of many diseases. METHODS:The search was limited to studies published in English and other languages involving both animal and human subjects. Articles selected included preclinical studies, randomized clinical trials RCTs, observational studies, meta-analyses, narrative and systemic reviews providing primary quantitative data with a measure of obesity or food addiction as an outcome. Over 5000 articles were found in the first round of search which was filtered to 506 articles. RESULTS:Oxidative stress plays a critical role in food addiction and is both a cause and mediator of obesity. Reactive oxygen species play a direct role in adipogenesis and oxidative stress modulates all factors involved in obesity including genetics, sleep, gut microbiome, insulin, ghrelin, inflammation, adipokines, leptin, stress, HPA axis, and the hypothalamus. CONCLUSIONS:The idea of thinking of combating obesity from the lens of calorie count, low carbohydrate, high or low-fat, vegetarian, vegan, plant-based, or animal-based diet is fundamentally wrong. The best way to look at obesity is through the framework of systemic redox homeostasis. Since redox homeostasis is tilted towards increased reactive oxygen species production, and excessive antioxidant intake can result in oxidative stress, an antioxidant and prooxidant food ratio of 2:3 per meal is the ideal nutritional ratio for good health and ideal weight. A ratio of 3:4 is ideal for obese individuals because of their state of chronic oxidative stress and inflammation. Physical activity, sleep quality, psychological stress, maternal prenatal diet and oxidative stress promoting disease conditions are important modulators of oxidative stress and obesity. 10.1016/j.bbr.2020.112560
    Metabolism of anthocyanins and consequent effects on the gut microbiota. Tian Lingmin,Tan Yisha,Chen Guowei,Wang Gang,Sun Jianxia,Ou Shiyi,Chen Wei,Bai Weibin Critical reviews in food science and nutrition Anthocyanins are natural water-soluble polyphenols present in fruits and vegetables. Health-promoting effects attributed to anthocyanins are mainly associated with oxidative stress inhibition and gut microbiota modulation. Dietary anthocyanins undergo a complex metabolism after ingestion and interact with endogenous and microbial enzymes, leading to the production of a large number of circulating and excreted anthocyanin metabolites and catabolic products. To date, the bioavailability and health benefits of anthocyanins have been widely documented. Although there are several papers that illustrated the metabolism of anthocyanins, the effects of dietary anthocyanins on the modulation of the gut microbial ecology and on the growth of certain microbial species are still poorly understood. The present paper summarizes the recent data on the absorption of anthocyanins in the upper gastrointestine and the metabolism of anthocyanins by gut microbiota. The modulatory effects of anthocyanins from different sources on gut microbiota are also discussed. 10.1080/10408398.2018.1533517
    Honey Polyphenols Ameliorate DSS-Induced Ulcerative Colitis via Modulating Gut Microbiota in Rats. Zhao Haoan,Cheng Ni,Zhou Wenqi,Chen Sinan,Wang Qian,Gao Hui,Xue Xiaofeng,Wu Liming,Cao Wei Molecular nutrition & food research SCOPE:Ulcerative colitis (UC) is a multifaceted and recurrent immune disorder that requires long-term potent pharmacological treatment. Honey, as a natural food of nourishment and pharmaceutical value, has been found to defend against colitis. METHODS AND RESULTS:The effects of different constituents in honey are investigated on DSS-induced colitis in rats. Rats are given DSS, sugars, honey, polyphenols, or SASP for a week, with blood and colon samples collected for the biochemical parameters and inflammation-related gene analysis and colon contents for gut microbiota. The results show that pretreatments with honey polyphenols significantly improve SOD, GSH-Px, NO, and MPO levels and reduce DSS-induced colonic apoptosis, the colonic inflammatory cytokines IL-6, TNF-α, and TGF-β1 accompanied by downregulation of IL-1β, IL-6, TNF-α, and IFN-γ gene and upregulation of IκB-α gene. Furthermore, honey polyphenols and SASP show similar microbial community structure shifts and selective enrichment of key species. At the genus level, honey polyphenols significantly reduce the population of Bacteroides, Corynebacterium, and Proteus species. The correlation analysis indicates that colonic gene expression regulated by honey polyphenols is relative to the key species of gut microbiota. CONCLUSIONS:Honey polyphenols improve intestinal inflammation and oxidative stress resistance via modulating gut microbiota, which is conducive to revealing the host-microbe interactions. 10.1002/mnfr.201900638
    Effect of a polyphenol-rich dietary pattern on intestinal permeability and gut and blood microbiomics in older subjects: study protocol of the MaPLE randomised controlled trial. Guglielmetti Simone,Bernardi Stefano,Del Bo' Cristian,Cherubini Antonio,Porrini Marisa,Gargari Giorgio,Hidalgo-Liberona Nicole,Gonzalez-Dominguez Raul,Peron Gregorio,Zamora-Ros Raul,Winterbone Mark S,Kirkup Benjamin,Kroon Paul A,Andres-Lacueva Cristina,Riso Patrizia BMC geriatrics BACKGROUND:During aging, alterations of the intestinal microbial ecosystem can occur contributing to immunosenescence, inflamm-aging and impairment of intestinal barrier function (increased intestinal permeability; IP). In the context of a diet-microbiota-IP axis in older subjects, food bioactives such as polyphenols may play a beneficial modulatory role. METHODS:MaPLE is a project centered on a randomized, controlled cross-over dietary intervention trial [polyphenol-rich diet (PR-diet) versus control diet (C-diet)] targeted to older people (≥ 60 y) living in a well-controlled setting (i.e. nursing home). The 8-week interventions are separated by an 8-week wash-out period. Three small portions per day of selected polyphenol-rich foods are consumed during intervention in substitution of other comparable products within the C-diet. Biological samples are collected before and after each treatment period to evaluate markers related to IP, inflammation, vascular function, oxidative stress, gut and blood microbiomics, metabolomics. A sample size of 50 subjects was defined based on IP as primary outcome. DISCUSSION:Evidence that increasing the consumption of polyphenol-rich food products can positively affect intestinal microbial ecosystem resulting in reduced IP and decreased translocation of inflammogenic bacterial factors into the bloodstream will be provided. The integration of data from gut and blood microbiomics, metabolomics and other IP-related markers will improve the understanding of the beneficial effect of the intervention in the context of polyphenols-microbiota-IP interactions. Finally, findings obtained will provide a proof of concept of the reliability of the dietary intervention, also contributing to future implementations of dietary guidelines directed to IP management in the older and other at risk subjects. TRIAL REGISTRATION:The trial is registered at (ISRCTN10214981); April 28, 2017. 10.1186/s12877-020-1472-9
    Rhubarb extract prevents hepatic inflammation induced by acute alcohol intake, an effect related to the modulation of the gut microbiota. Neyrinck Audrey M,Etxeberria Usune,Taminiau Bernard,Daube Georges,Van Hul Matthias,Everard Amandine,Cani Patrice D,Bindels Laure B,Delzenne Nathalie M Molecular nutrition & food research SCOPE:Binge consumption of alcohol is an alarming global health problem. Acute ethanol intoxication is characterized by hepatic inflammation and oxidative stress, which could be promoted by gut barrier function alterations. In this study, we have tested the hypothesis of the hepatoprotective effect of rhubarb extract in a mouse model of binge drinking and we explored the contribution of the gut microbiota in the related metabolic effects. METHODS AND RESULTS:Mice were fed a control diet supplemented with or without 0.3% rhubarb extract for 17 days and were necropsied 6 h after an alcohol challenge. Supplementation with rhubarb extract changed the microbial ecosystem (assessed by 16S rDNA pyrosequencing) in favor of Akkermansia muciniphila and Parabacteroides goldsteinii. Furthermore, it improved alcohol-induced hepatic injury, downregulated key markers of both inflammatory and oxidative stresses in the liver tissue, without affecting significantly steatosis. In the gut, rhubarb supplementation increased crypt depth, tissue weight, and the expression of antimicrobial peptides. CONCLUSIONS:These findings suggest that some bacterial genders involved in gut barrier function, are promoted by phytochemicals present in rhubarb extract, and could therefore be involved in the modulation of the susceptibility to hepatic diseases linked to acute alcohol consumption. 10.1002/mnfr.201500899
    The Good and the Bad Side of Heme-Oxygenase-1 in the Gut. Marelli Giulia,Allavena Paola Antioxidants & redox signaling Mucosal immunity in the gut has the important task of protecting an organism against potential danger, but at the same time of staying silent in response to harmless antigens present in the intestinal lumen. The delicate balance between immune activation and tolerance is referred to as gut homeostasis. It has become clear that different types of immune cells and several factors participate in the maintenance of gut homeostasis, having as a final goal the prevention of non-necessary inflammation. Immune cells of the myeloid lineage, such as macrophages located in the lamina propria, represent the most abundant leukocyte population in the intestine and play a critical role in keeping the immune system silent, the production of the anti-inflammatory cytokine interleukin-10. Gut macrophages are an important source of the oxidative enzyme heme-oxygenase-1 (HO-1), which has crucial immune-modulatory properties. The protective role of HO-1 in the control of the intestinal inflammation, and its connection with the enteric flora have been demonstrated in experimental settings as well as in human biological samples. Loss of the gut homeostasis gives rise to conditions of acute inflammation that may degenerate into chronic disease, eventually leading to carcinogenesis. Understanding the mechanisms that regulate this enzyme will disclose novel therapeutic approaches that are designed to control chronic inflammation in the intestine. 10.1089/ars.2019.7956
    Polyphenols in the management of brain disorders: Modulation of the microbiota-gut-brain axis. Serra Diana,Almeida Leonor M,Dinis Teresa C P Advances in food and nutrition research The modulation of the microbiota-gut-brain axis with a view to preventing and treating brain disorders became recently a hot topic for the scientific community. Dietary polyphenols are multifaceted compounds that have demonstrated to be highly advantageous to counteract inflammation, oxidative stress, and neurodegeneration, among other pathological conditions, being useful in the prevention and treatment of several chronic disorders. The potential of these compounds to prevent and treat brain disorders has not been only related to their capacity to reach the brain, depending on their chemical structure, and interact directly with brain cells, but also to their ability to modulate the communication between the brain and the gut, interfering with multiple branches of this axis. Preclinical studies have demonstrated the potential of these food bioactive compounds in brain diseases, namely, neurodevelopmental, such as Down's syndrome and Autism spectrum disorder, neurodegenerative, such as Parkinson's disease and Alzheimer's disease, and psychiatric disorders, such as depression and anxiety. Until now, dietary polyphenols have been recognized as promising nutraceuticals to combat brain disorders. However, the impact of these compounds on the gut-brain interconnection remains poorly elucidated. Also, clinical assays are crucial to further support the beneficial effects of these compounds as demonstrated in preclinical research. 10.1016/bs.afnr.2019.08.001
    Effect of dark sweet cherry powder consumption on the gut microbiota, short-chain fatty acids, and biomarkers of gut health in obese db/db mice. Garcia-Mazcorro Jose F,Lage Nara N,Mertens-Talcott Susanne,Talcott Stephen,Chew Boon,Dowd Scot E,Kawas Jorge R,Noratto Giuliana D PeerJ Cherries are fruits containing fiber and bioactive compounds (e.g., polyphenolics) with the potential of helping patients with diabetes and weight disorders, a phenomenon likely related to changes in the complex host-microbiota milieu. The objective of this study was to investigate the effect of cherry supplementation on the gut bacterial composition, concentrations of caecal short-chain fatty acids (SCFAs) and biomarkers of gut health using an model of obesity. Obese diabetic (db/db) mice received a supplemented diet with 10% cherry powder (supplemented mice,  = 12) for 12 weeks; obese ( = 10) and lean ( = 10) mice served as controls and received a standard diet without cherry. High-throughput sequencing of the 16S rRNA gene and quantitative real-time PCR (qPCR) were used to analyze the gut microbiota; SCFAs and biomarkers of gut health were also measured using standard techniques. According to 16S sequencing, supplemented mice harbored a distinct colonic microbiota characterized by a higher abundance of mucin-degraders (i.e., ) and fiber-degraders (the S24-7 family) as well as lower abundances of and Enterobacteriaceae. Overall this particular cherry-associated colonic microbiota did not resemble the microbiota in obese or lean controls based on the analysis of weighted and unweighted UniFrac distance metrics. qPCR confirmed some of the results observed in sequencing, thus supporting the notion that cherry supplementation can change the colonic microbiota. Moreover, the SCFAs detected in supplemented mice (caproate, methyl butyrate, propionate, acetate and valerate) exceeded those concentrations detected in obese and lean controls except for butyrate. Despite the changes in microbial composition and SCFAs, most of the assessed biomarkers of inflammation, oxidative stress, and intestinal health in colon tissues and mucosal cells were similar in all obese mice with and without supplementation. This paper shows that dietary supplementation with cherry powder for 12 weeks affects the microbiota and the concentrations of SCFAs in the lower intestinal tract of obese db/db diabetic mice. These effects occurred in absence of differences in most biomarkers of inflammation and other parameters of gut health. Our study prompts more research into the potential clinical implications of cherry consumption as a dietary supplement in diabetic and obese human patients. 10.7717/peerj.4195
    Breastfeeding and the gut-brain axis: is there a role for melatonin? Anderson George,Vaillancourt Cathy,Maes Michael,Reiter Russel J Biomolecular concepts The benefits of breastfeeding over formula feed are widely appreciated. However, for many mothers breastfeeding is not possible, highlighting the need for a significant improvement in the contents of formula feed. In this article, the overlooked role of melatonin and the melatonergic pathways in breast milk and in the regulation of wider breast milk components are reviewed. There is a growing appreciation that the benefits of breastfeeding are mediated by its effects in the infant gut, with consequences for the development of the gut-brain axis and the immune system. The melatonergic pathways are intimately associated with highly researched processes in the gut, gut microbiome and gut-brain axis. As the melatonergic pathways are dependent on the levels of serotonin availability as a necessary precursor, decreased melatonin is linked to depression and depression-associated disorders. The association of breastfeeding and the gut-brain axis with a host of medical conditions may be mediated by their regulation of processes that modulate depression susceptibility. The biological underpinnings of depression include increased levels of pro-inflammatory cytokines, oxidative stress, kynurenine pathway activity and dysregulation of the hypothalamic-pituitary adrenal axis, all of which can decrease melatonergic pathway activity. The inclusion of the melatonergic pathways in the biological interactions of breast milk and gut development has significant theoretical and treatment implications, as well as being important to the prevention of a host of infant-, child- and adult-onset medical conditions. 10.1515/bmc-2017-0009
    The Role of the Gut Microbiota in the Metabolism of Polyphenols as Characterized by Gnotobiotic Mice. Pasinetti Giulio Maria,Singh Risham,Westfall Susan,Herman Francis,Faith Jeremiah,Ho Lap Journal of Alzheimer's disease : JAD A growing body of experimental data suggests that microbes in the gut influence behavior and can alter brain physiology and neurochemistry. Although promising, researchers are only starting to understand the potential of the gut microbiota for use in neurological disease. Recent evidence demonstrated that gastrointestinal activities are linked to mood disorders such as anxiety, depression, and most recently, cognitive functions in age-related neurodegenerative disorders. Studies from our group and others are uncovering new evidence suggesting that the gut microbiota plays a crucial role in the metabolism and bioavailability of certain dietary compounds and synthetic drugs. Based on this evidence, this review article will discuss the implications of the gut microbiota in mechanisms of bioavailability and biotransformation with an emphasis on dietary polyphenol compounds. This will be followed by a survey of ongoing innovative research identifying the ability of individual gut bacteria to enhance the bioavailability of gut-derived, brain-penetrating, bioactive polyphenol metabolites that ultimately influence mechanisms associated with the promotion of resilience against psychological and cognitive impairment in response to stress. Lastly, current research initiatives aimed at promoting the generation of brain bioactive polyphenol metabolites by specialized gut microbes will be discussed, specifically the use of gnotobiotic mice to develop bioengineered second generation probiotics. We propose that leveraging the gut microbial ecosystem to generate brain targeted bioactive metabolites from dietary polyphenols can attenuate lifestyle risk factors and promote resilience against age-related cognitive decline. 10.3233/JAD-171151
    Rotundic Acid Protects against Metabolic Disturbance and Improves Gut Microbiota in Type 2 Diabetes Rats. Yan Zenghao,Wu Hao,Yao Hongliang,Pan Wenjun,Su Minmin,Chen Taobin,Su Weiwei,Wang Yonggang Nutrients Rotundic acid (RA) is a major triterpene constituent in the barks of Thunb, which have been widely used to make herbal tea for health care in southern China. RA has a variety of bioactivities such as anti-inflammation and lipid-lowering effect. However, little is known about the effects and mechanisms of RA on metabolic disturbance in type 2 diabetes (T2D) and its effect on gut microbiota. A T2D rat model induced by high fat diet (HFD) feeding and low-dose streptozotocin (STZ) injection was employed and RA showed multipronged effects on T2D and its complications, including improving glucolipid metabolism, lowering blood pressure, protecting against cardiovascular and hepatorenal injuries, and alleviating oxidative stress and inflammation. Furthermore, 16s rRNA gene sequencing was carried out on an Illumina HiSeq 2500 platform and RA treatment could restore the gut microbial dysbiosis in T2D rats to a certain extent. RA treatment significantly enhanced the richness and diversity of gut microbiota. At the genus level, beneficial or commensal bacteria , , and were significantly increased by RA treatment, while RA-treated rats had a lower abundance of opportunistic pathogen and . Spearman's correlation analysis showed that the abundances of these bacteria were strongly correlated with various biochemical parameters, suggesting that the improvement of gut microbiota might help to prevent or attenuate T2D and its complication. In conclusion, our findings support RA as a nutraceutical agent or plant foods rich in this compound might be helpful for the alleviation of T2D and its complications through improving gut microbiota. 10.3390/nu12010067
    Correlation Analysis of Intestinal Redox State with the Gut Microbiota Reveals the Positive Intervention of Tea Polyphenols on Hyperlipidemia in High Fat Diet Fed Mice. Ma Hui,Zhang Bowei,Hu Yaozhong,Wang Jin,Liu Jingmin,Qin Renbing,Lv Shiwen,Wang Shuo Journal of agricultural and food chemistry Tea polyphenols (TP) possess the ability to regulate dyslipidemia and gut microbiota dysbiosis. However, the underlying mechanism is still elusive. The present study explored the intervention of TP on high fat diet induced metabolic disorders, gut microbiota dysbiosis in mice, and the underlying intestinal mechanism. As a result, TP significantly ameliorated hyperlipidemia, improved the expression levels of hepatic lipid metabolism genes, and modulated gut microbiota. The underlying mechanism was supposed to rely on the maintaining of intestinal redox state by TP. Intestinal redox related indicators were significantly correlated with the distribution of gut microbiota. An unidentified genus of Lachnospiraceae, Bacteroides, Alistipes, and Faecalibaculum were identified as the biomarkers for intestinal redox state. Importantly, different dosages of TP modulated intestinal redox state and gut microbiota in varied patterns, and an overdose intake attenuated the beneficial effects on gut health. Our findings offered novel insights into the mechanism of TP on intestinal homeostasis. 10.1021/acs.jafc.9b02211
    Polyphenols-gut microbiota interplay and brain neuromodulation. Filosa Stefania,Di Meo Francesco,Crispi Stefania Neural regeneration research Increasing evidence suggests that food ingested polyphenols can have beneficial effects in neuronal protection acting against oxidative stress and inflammatory injury. Moreover, polyphenols have been reported to promote cognitive functions. Biotransformation of polyphenols is needed to obtain metabolites active in brain and it occurs through their processing by gut microbiota. Polyphenols metabolites could directly act as neurotransmitters crossing the blood-brain barrier or indirectly by modulating the cerebrovascular system. The microbiota-gut-brain axis is considered a neuroendocrine system that acts bidirectionally and plays an important role in stress responses. The metabolites produced by microbiota metabolism can modulate gut bacterial composition and brain biochemistry acting as neurotransmitters in the central nervous system. Gut microbiota composition can be influenced by dietary ingestion of natural bioactive molecules such as probiotics, prebiotics and polyphenol. Microbiota composition can be altered by dietary changes and gastrointestinal dysfunctions are observed in neurodegenerative diseases. In addition, several pieces of evidence support the idea that alterations in gut microbiota and enteric neuroimmune system could contribute to onset and progression of these age-related disorders. The impact of polyphenols on microbiota composition strengthens the idea that maintaining a healthy microbiome by modulating diet is essential for having a healthy brain across the lifespan. Moreover, it is emerging that they could be used as novel therapeutics to prevent brain from neurodegeneration. 10.4103/1673-5374.241429
    Dietary Pattern, Gut Microbiota, and Alzheimer's Disease. Zhang Miao,Zhao Di,Zhou Guanghong,Li Chunbao Journal of agricultural and food chemistry Alzheimer's disease is the most common neurodegenerative disease. Until now, there has been no specific medicine that can cure Alzheimer's disease or effectively reverse the disease process. A good dietary pattern is an efficient way to prevent or delay the progression of the disease. Evidence suggests that diet may affect β-amyloid production and tau processing or may regulate inflammation, metabolism, and oxidative stress associated with Alzheimer's disease, which can be exerted by gut microbiota. The gut microbiota is a complex microbial community that affects not only various digestive diseases but also neurodegenerative diseases. Studies have shown that gut microbial metabolites, such as pro-inflammatory factors, short-chain fatty acids, and neurotransmitters, can affect the pathogenesis of Alzheimer's disease. Clinical studies suggested that the gut microbial composition of patients with Alzheimer's disease is different, in particular to lower abundances of and , which have an anti-inflammatory activity. The purpose of this review is to summarize the neuropathological pathogenesis of Alzheimer's disease, and the modulation of dietary patterns rather than single dietary components on Alzheimer's disease through the gut-brain axis was discussed. 10.1021/acs.jafc.9b08309
    The Gut Microbiota Links Dietary Polyphenols With Management of Psychiatric Mood Disorders. Westfall Susan,Pasinetti Giulio Maria Frontiers in neuroscience The pathophysiology of depression is multifactorial yet generally aggravated by stress and its associated physiological consequences. To effectively treat these diverse risk factors, a broad acting strategy is required and is has been suggested that gut-brain-axis signaling may play a pinnacle role in promoting resilience to several of these stress-induced changes including pathogenic load, inflammation, HPA-axis activation, oxidative stress and neurotransmitter imbalances. The gut microbiota also manages the bioaccessibility of phenolic metabolites from dietary polyphenols whose multiple beneficial properties have known therapeutic efficacy against depression. Although several potential therapeutic mechanisms of dietary polyphenols toward establishing cognitive resilience to neuropsychiatric disorders have been established, only a handful of studies have systematically identified how the interaction of the gut microbiota with dietary polyphenols can synergistically alleviate the biological signatures of depression. The current review investigates several of these potential mechanisms and how synbiotics, that combine probiotics with dietary polyphenols, may provide a novel therapeutic strategy for depression. In particular, synbiotics have the potential to alleviate neuroinflammation by modulating microglial and inflammasome activation, reduce oxidative stress and balance serotonin metabolism therefore simultaneously targeting several of the major pathological risk factors of depression. Overall, synbiotics may act as a novel therapeutic paradigm for neuropsychiatric disorders and further understanding the fundamental mechanisms of gut-brain-axis signaling will allow full utilization of the gut microbiota's as a therapeutic tool. 10.3389/fnins.2019.01196
    Corrigendum to "Pomegranate prevents binge alcohol-induced gut leakiness and hepatic inflammation by suppressing oxidative and nitrative stress" [Redox Biol. 18 (2018) 266-278]. Cho Young-Eun,Song Byoung-Joon Redox biology 10.1016/j.redox.2018.08.019
    Age-related shifts in gut microbiota contribute to cognitive decline in aged rats. Li Yanli,Ning Li,Yin Yiru,Wang Rui,Zhang Zhiyong,Hao Lijun,Wang Bin,Zhao Xin,Yang Xiaorong,Yin Litian,Wu Shufen,Guo Dawei,Zhang Ce Aging Cognitive function declines during the aging process, meanwhile, gut microbiota of the elderly changed significantly. Although previous studies have reported the effect of gut microbiota on learning and memory, all the reports were based on various artificial interventions to change the gut microbiota without involvement of aging biological characteristics. Here, we investigated the effect of aged gut microbiota on cognitive function by using fecal microbiota transplantation (FMT) from aged to young rats. Results showed that FMT impaired cognitive behavior in young recipient rats; decreased the regional homogeneity in medial prefrontal cortex and hippocampus; changed synaptic structures and decreased dendritic spines; reduced expression of brain-derived neurotrophic factor (BDNF), N-methyl-D-aspartate receptor NR1 subunit, and synaptophysin; increased expression of advanced glycation end products (AGEs) and receptor for AGEs (RAGE). All these behavioral, brain structural and functional alterations induced by FMT reflected cognitive decline. In addition, FMT increased levels of pro-inflammatory cytokines and oxidative stress in young rats, indicating that inflammation and oxidative stress may underlie gut-related cognitive decline in aging. This study provides direct evidence for the contribution of gut microbiota to the cognitive decline during normal aging and suggests that restoring microbiota homeostasis in the elderly may improve cognitive function. 10.18632/aging.103093
    Comorbidity between depression and inflammatory bowel disease explained by immune-inflammatory, oxidative, and nitrosative stress; tryptophan catabolite; and gut-brain pathways. Martin-Subero Marta,Anderson George,Kanchanatawan Buranee,Berk Michael,Maes Michael CNS spectrums The nature of depression has recently been reconceptualized, being conceived as the clinical expression of activated immune-inflammatory, oxidative, and nitrosative stress (IO&NS) pathways, including tryptophan catabolite (TRYCAT), autoimmune, and gut-brain pathways. IO&NS pathways are similarly integral to the pathogenesis of inflammatory bowel disease (IBD). The increased depression prevalence in IBD associates with a lower quality of life and increased morbidity in IBD, highlighting the role of depression in modulating the pathophysiology of IBD.This review covers data within such a wider conceptualization that better explains the heightened co-occurrence of IBD and depression. Common IO&NS underpinning between both disorders is evidenced by increased pro-inflammatory cytokine levels, eg, interleukin-1 (IL-1) and tumor necrosis factor-α, IL-6 trans-signalling; Th-1- and Th-17-like responses; neopterin and soluble IL-2 receptor levels; positive acute phase reactants (haptoglobin and C-reactive protein); lowered levels of negative acute phase reactants (albumin, transferrin, zinc) and anti-inflammatory cytokines (IL-10 and transforming growth factor-β); increased O&NS with damage to lipids, proteinsm and DNA; increased production of nitric oxide (NO) and inducible NO synthase; lowered plasma tryptophan but increased TRYCAT levels; autoimmune responses; and increased bacterial translocation. As such, heightened IO&NS processes in depression overlap with the biological underpinnings of IBD, potentially explaining their increased co-occurrence. This supports the perspective that there is a spectrum of IO&NS disorders that includes depression, both as an emergent comorbidity and as a contributor to IO&NS processes. Such a frame of reference has treatment implications for IBD when "comorbid" with depression. 10.1017/S1092852915000449
    Nutrition, oxidative stress and intestinal dysbiosis: Influence of diet on gut microbiota in inflammatory bowel diseases. Tomasello Giovanni,Mazzola Margherita,Leone Angelo,Sinagra Emanuele,Zummo Giovanni,Farina Felicia,Damiani Provvidenza,Cappello Francesco,Gerges Geagea Alice,Jurjus Abdo,Bou Assi Tarek,Messina Massimiliano,Carini Francesco Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia BACKGROUND:Microbiota refers to the population of microorganisms (bacteria, viruses and fungi) that inhabit the entire gastrointestinal tract, more particularly the colon whose role is to maintain the integrity of the intestinal mucosa and control the proliferation of pathogenic bacteria. Alteration in the composition of the gut microbiota is called dysbiosis. Dysbiosis redisposes to inflammatory bowel diseases such as ulcerative colitis, Crohn disease and indeterminate colitis. METHODS:The purpose of this literature review is to elucidate the influence of diet on the composition of the gastrointestinal microbiota in the healthy gut and the role of diet in the development of dysbiosis. CONCLUSION:The "Western diet", in particular a low - fiber high fat/high carbohydrate diet is one factor that can lead to severe dysbiosis. In contrast, "mediterranean" and vegetarian diets that includes abundant fruits, vegetables, olive oil and oily fish are known for their anti-inflammatory effects and could prevent dysbiosis and subsequent inflammatory bowel disease. 10.5507/bp.2016.052
    Polyphenol-Rich Loquat Fruit Extract Prevents Fructose-Induced Nonalcoholic Fatty Liver Disease by Modulating Glycometabolism, Lipometabolism, Oxidative Stress, Inflammation, Intestinal Barrier, and Gut Microbiota in Mice. Li Wenfeng,Yang Hongyan,Zhao Qiang,Wang Xv,Zhang Jing,Zhao Xin Journal of agricultural and food chemistry Fructose as a daily sweetener is widely recognized as a risk catalyst for nonalcoholic fatty liver disease (NAFLD). The aim of current study is to evaluate the effects and molecular mechanism by which polyphenol-rich loquat fruit extract (LFP) prevents NAFLD in mice fed 30% fructose water (HF) for 8 weeks. Administration of LFP to HF-fed mice mitigated abnormal body weight, disordered lipid metabolism, oxidative stress, and inflammation through a mechanism regulated by the AKT, ChREBP/SREBP-1c, Nrf2, and TLR4/MyD88/TRIF pathways. LFP caused a significant decrease in the endotoxin content (16.67-12.7 EU/mL) in the liver of HF-fed mice. LFP not only improved HF-induced breakage of the intestinal barrier via interacting with tight junction proteins (ZO-1, occludin), mucin, and immunoreaction in the colon but also maintained normal colonic / ratios and the relative abundance of in HF-fed mice. Our results suggest that LFP may serve as a nutritional agent for protecting liver in HF-fed mice. 10.1021/acs.jafc.9b02523
    Oxidative Stress and the Microbiota-Gut-Brain Axis. Dumitrescu Laura,Popescu-Olaru Iulia,Cozma Liviu,Tulbă Delia,Hinescu Mihail Eugen,Ceafalan Laura Cristina,Gherghiceanu Mihaela,Popescu Bogdan Ovidiu Oxidative medicine and cellular longevity The gut-brain axis is increasingly recognized as an important pathway of communication and of physiological regulation, and gut microbiota seems to play a significant role in this mutual relationship. Oxidative stress is one of the most important pathogenic mechanisms for both neurodegenerative diseases, such as Alzheimer's or Parkinson's, and acute conditions, such as stroke or traumatic brain injury. A peculiar microbiota type might increase brain inflammation and reactive oxygen species levels and might favor abnormal aggregation of proteins. Reversely, brain lesions of various etiologies result in alteration of gut properties and microbiota. These recent hypotheses could open a door for new therapeutic approaches in various neurological diseases. 10.1155/2018/2406594
    Gut-Resident Lactobacilli Activate Hepatic Nrf2 and Protect Against Oxidative Liver Injury. Saeedi Bejan J,Liu Ken H,Owens Joshua A,Hunter-Chang Sarah,Camacho Mary C,Eboka Richard U,Chandrasekharan Bindu,Baker Nusaiba F,Darby Trevor M,Robinson Brian S,Jones Rheinallt M,Jones Dean P,Neish Andrew S Cell metabolism Many studies have suggested a role for gut-resident microbes (the "gut microbiome") in modulating host health; however, the mechanisms by which they impact systemic physiology remain largely unknown. In this study, metabolomic and transcriptional profiling of germ-free and conventionalized mouse liver revealed an upregulation of the Nrf2 antioxidant and xenobiotic response in microbiome-replete animals. Using a Drosophila-based screening assay, we identified members of the genus Lactobacillus capable of stimulating Nrf2. Indeed, the human commensal Lactobacillus rhamnosus GG (LGG) potently activated Nrf2 in the Drosophila liver analog and the murine liver. This activation was sufficient to protect against two models of oxidative liver injury, acetaminophen overdose and acute ethanol toxicity. Characterization of the portal circulation of LGG-treated mice by tandem mass spectrometry identified a small molecule activator of Nrf2, 5-methoxyindoleacetic acid, produced by LGG. Taken together, these data demonstrate a mechanism by which intestinal microbes modulate hepatic susceptibility to oxidative injury. 10.1016/j.cmet.2020.03.006
    Dietary Verbascoside Influences Gut Morphology and the Expression of α-Transducin and α-Gustducin in the Small Intestine of Weaned Piglets Exposed to n-6 Polyunsaturated Fatty Acids-Induced Oxidative Stress. Rossi Raffaella,Corino Carlo,Modina Silvia,Di Giancamillo Alessia Animals : an open access journal from MDPI Reducing oxidative stress is an important goal in post-weaning piglets; previous studies have reported that verbascoside decreases oxidative stress in piglets. The effect of verbascoside on gut morphology and α-transducin and α-gustducin expression in weaned piglets fed high dosages of sunflower oil, inducing oxidative stress, was evaluated. A diet with 9% sunflower oil (T1), the same diet supplemented with 5 mg of verbascoside/kg feed (T2) and a diet containing starch (control-CTR) were employed. Histology, histometry, histochemistry, immunofluorescence and Western blot analyses were performed on the piglets' small intestine. In the T1 group, apical erosion was observed and villi height was lower than in other groups. The mucin profile was acidic in goblet cells of both the T1 and T2 groups. However, it was both neutral and acidic in the CTR group. Dietary treatments did not affect α-gustducin expression. Otherwise, the expression of α-transducin in the duodenum was lower ( < 0.01) in the T1 groups than in the other groups. The colocalization of α-transducin with chromogranin A and ghrelin revealed that the endocrine cells were immunopositive for both ghrelin and α-transducin. Overall, these results provide new insights into gut sensory perception in piglets and contribute to understanding how feed ingredients such as fat and polyphenols may be involved in gustatory signal transduction. 10.3390/ani9010020
    Gut Microbiota in Alzheimer's Disease, Depression, and Type 2 Diabetes Mellitus: The Role of Oxidative Stress. Luca Maria,Di Mauro Maurizio,Di Mauro Marco,Luca Antonina Oxidative medicine and cellular longevity Gut microbiota consists of over 100 trillion microorganisms including at least 1000 different species of bacteria and is crucially involved in physiological and pathophysiological processes occurring in the host. An imbalanced gastrointestinal ecosystem (dysbiosis) seems to be a contributor to the development and maintenance of several diseases, such as Alzheimer's disease, depression, and type 2 diabetes mellitus. Interestingly, the three disorders are frequently associated as demonstrated by the high comorbidity rates. In this review, we introduce gut microbiota and its role in both normal and pathological processes; then, we discuss the importance of the gut-brain axis as well as the role of oxidative stress and inflammation as mediators of the pathological processes in which dysbiosis is involved. Specific sections pertain the role of the altered gut microbiota in the pathogenesis of Alzheimer's disease, depression, and type 2 diabetes mellitus. The therapeutic implications of microbiota manipulation are briefly discussed. Finally, a conclusion comments on the possible role of dysbiosis as a common pathogenetic contributor (via oxidative stress and inflammation) shared by the three disorders. 10.1155/2019/4730539
    A polyphenol-rich cranberry extract protects from diet-induced obesity, insulin resistance and intestinal inflammation in association with increased Akkermansia spp. population in the gut microbiota of mice. Anhê Fernando F,Roy Denis,Pilon Geneviève,Dudonné Stéphanie,Matamoros Sébastien,Varin Thibault V,Garofalo Carole,Moine Quentin,Desjardins Yves,Levy Emile,Marette André Gut OBJECTIVE:The increasing prevalence of obesity and type 2 diabetes (T2D) demonstrates the failure of conventional treatments to curb these diseases. The gut microbiota has been put forward as a key player in the pathophysiology of diet-induced T2D. Importantly, cranberry (Vaccinium macrocarpon Aiton) is associated with a number of beneficial health effects. We aimed to investigate the metabolic impact of a cranberry extract (CE) on high fat/high sucrose (HFHS)-fed mice and to determine whether its consequent antidiabetic effects are related to modulations in the gut microbiota. DESIGN:C57BL/6J mice were fed either a chow or a HFHS diet. HFHS-fed mice were gavaged daily either with vehicle (water) or CE (200 mg/kg) for 8 weeks. The composition of the gut microbiota was assessed by analysing 16S rRNA gene sequences with 454 pyrosequencing. RESULTS:CE treatment was found to reduce HFHS-induced weight gain and visceral obesity. CE treatment also decreased liver weight and triglyceride accumulation in association with blunted hepatic oxidative stress and inflammation. CE administration improved insulin sensitivity, as revealed by improved insulin tolerance, lower homeostasis model assessment of insulin resistance and decreased glucose-induced hyperinsulinaemia during an oral glucose tolerance test. CE treatment was found to lower intestinal triglyceride content and to alleviate intestinal inflammation and oxidative stress. Interestingly, CE treatment markedly increased the proportion of the mucin-degrading bacterium Akkermansia in our metagenomic samples. CONCLUSIONS:CE exerts beneficial metabolic effects through improving HFHS diet-induced features of the metabolic syndrome, which is associated with a proportional increase in Akkermansia spp. 10.1136/gutjnl-2014-307142
    Picroside II Improves Severe Acute Pancreatitis-Induced Intestinal Barrier Injury by Inactivating Oxidative and Inflammatory TLR4-Dependent PI3K/AKT/NF-B Signaling and Improving Gut Microbiota. Piao Xuehua,Liu Baohai,Sui Xiaodan,Li Shuangdi,Niu Wei,Zhang Qingyu,Shi Xuan,Cai Shusheng,Fan Ying Oxidative medicine and cellular longevity Background:Picroside II exerts anti-inflammatory and antidiarrheal effects for treating the diseases associated with oxidative injury. However, its function on pancreatitis-induced intestinal barrier injury remains unclear. . We hypothesized that picroside II will have protective effects against pancreatitis-induced intestinal barrier injury by affecting oxidative and inflammatory signaling (Toll-like receptor 4- (TLR4-) dependent phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and nuclear factor kappa B (NF-B)). . A Sprague-Dawley (SD) rat model with severe acute pancreatitis (SAP) was induced via the injection of sodium taurocholate (4% wt/vol; 1 mL/kg). All rats were divided into 3 groups: sham (CG), SAP-induced intestinal barrier injury (MG), and picroside II (PG) groups. Intestinal barrier injury was assessed by scanning electron microscopy (SEM), hematoxylin and eosin staining, and pathological scores. We measured the levels of pancreatitis biomarkers (amylase and lipase), oxidative and inflammatory signaling (TLR4-dependent PI3K/AKT/NF-B), oxidative stress marker (superoxidase dismutase (SOD), catalase (CAT), glutathione peroxidases (GPx), and malondialdehyde), and inflammatory markers (tumor necrosis factor (TNF), interleukin- (IL-) 1, IL-6, and IL-10) in serum and/or gut tissues. Gut microbiota composition in feces was measured by using 16S rRNA sequencing. Results:SEM showed that intestinal barrier injury was caused with the loss of intestinal villi and mitochondria destruction, and pathological scores were increased in the MG group. The levels of amylase, lipase, malondialdehyde, TNF, IL-1, IL-6, TLR4, PI3K, AKT, and NF-B were increased, and the levels of SOD, GPx, CAT, and IL-10 was reduced in the MG group when compared with CG group ( < 0.05). Picroside II treatment inhibited the symptoms in the MG group and showed antioxidant and anti-inflammatory activities. The serum levels of picroside II had strong correlation with the levels of inflammatory and oxidative stress biomarkers ( < 0.05). increased the proportion of and and decreased the proportion of and in the model. Conclusions:Picroside II improved the SAP-induced intestinal barrier injury in the rat model by inactivating oxidant and inflammatory signaling and improving gut microbiota. 10.1155/2020/3589497
    Resveratrol Prevents the Development of Hypertension Programmed by Maternal Plus Post-Weaning High-Fructose Consumption through Modulation of Oxidative Stress, Nutrient-Sensing Signals, and Gut Microbiota. Tain You-Lin,Lee Wei-Chia,Wu Kay L H,Leu Steve,Chan Julie Y H Molecular nutrition & food research SCOPE:High-fructose (HF) intake, oxidative stress, nutrient-sensing signals, and gut microbiota dysbiosis are closely related to the development of hypertension. It was investigated whether resveratrol can prevent hypertension induced by maternal plus post-weaning HF diets in adult offspring via the above-mentioned mechanisms. METHODS AND RESULTS:Female Sprague-Dawley rats received either a normal (ND) or 60% high-fructose (HF) diet during gestation and lactation. Male offspring were assigned to five groups (maternal diet/post-weaning diet; n = 8 per group): ND/ND, ND/HF, HF/ND, HF/HF, and HF/HF+ Resveratrol. Resveratrol (50 mg L ) was administered in drinking water from weaning to 3 months of age. It was found that HF/HF induced hypertension in adult offspring. Maternal HF diet altered gut microbiota composition in adult offspring, including decreasing the abundance of genera Bacteroides, Dysgonomonas, and Turicibacter, while increasing phylum Verrucomicrobia and Akkermansia muciniphila. Additionally, HF/HF diets increased oxidative stress and decreased renal mRNA expression of Prkaa2, Prkag2, Ppara, Pparb, Ppargc1a, and Sirt4. Resveratrol reduced renal oxidative stress, activated nutrient-sensing signals, modulated gut microbiota, and prevented associated HF/HF-induced programmed hypertension. CONCLUSION:Targeting oxidative stress, nutrient-sensing signals, and gut microbiota by resveratrol might be a useful therapeutic strategy for the treatment of hypertension induced by excessive consumption of fructose in the adult rat offspring. 10.1002/mnfr.201800066
    Suppression of the gut microbiome ameliorates age-related arterial dysfunction and oxidative stress in mice. Brunt Vienna E,Gioscia-Ryan Rachel A,Richey James J,Zigler Melanie C,Cuevas Lauren M,Gonzalez Antonio,Vázquez-Baeza Yoshiki,Battson Micah L,Smithson Andrew T,Gilley Andrew D,Ackermann Gail,Neilson Andrew P,Weir Tiffany,Davy Kevin P,Knight Rob,Seals Douglas R The Journal of physiology KEY POINTS:Age-related arterial dysfunction, characterized by oxidative stress- and inflammation-mediated endothelial dysfunction and arterial stiffening, is the primary risk factor for cardiovascular diseases. To investigate whether age-related changes in the gut microbiome may mediate arterial dysfunction, we suppressed gut microbiota in young and old mice with a cocktail of broad-spectrum, poorly-absorbed antibiotics in drinking water for 3-4 weeks. In old mice, antibiotic treatment reversed endothelial dysfunction and arterial stiffening and attenuated vascular oxidative stress and inflammation. To provide insight into age-related changes in gut microbiota that may underlie these observations, we show that ageing altered the abundance of microbial taxa associated with gut dysbiosis and increased plasma levels of the adverse gut-derived metabolite trimethylamine N-oxide. The results of the present study provide the first proof-of-concept evidence that the gut microbiome is an important mediator of age-related arterial dysfunction and therefore may be a promising therapeutic target for preserving arterial function with ageing, thereby reducing the risk of cardiovascular diseases. ABSTRACT:Oxidative stress-mediated arterial dysfunction (e.g. endothelial dysfunction and large elastic artery stiffening) is the primary mechanism driving age-related cardiovascular diseases. Accumulating evidence suggests the gut microbiome modulates host physiology because dysregulation ('gut dysbiosis') has systemic consequences, including promotion of oxidative stress. The present study aimed to determine whether the gut microbiome modulates arterial function with ageing. We measured arterial function in young and older mice after 3-4 weeks of treatment with broad-spectrum, poorly-absorbed antibiotics to suppress the gut microbiome. To identify potential mechanistic links between the gut microbiome and age-related arterial dysfunction, we sequenced microbiota from young and older mice and measured plasma levels of the adverse gut-derived metabolite trimethylamine N-oxide (TMAO). In old mice, antibiotics reversed endothelial dysfunction [area-under-the-curve carotid artery dilatation to acetylcholine in young: 345 ± 16 AU vs. old control (OC): 220 ± 34 AU, P < 0.01; vs. old antibiotic-treated (OA): 334 ± 15 AU; P < 0.01 vs. OC] and arterial stiffening (aortic pulse wave velocity in young: 3.62 ± 0.15 m s vs. OC: 4.43 ± 0.38 m s ; vs. OA: 3.52 ± 0.35 m s ; P = 0.03). These improvements were accompanied by lower oxidative stress and greater antioxidant enzyme expression. Ageing altered the abundance of gut microbial taxa associated with gut dysbiosis. Lastly, plasma TMAO was higher with ageing (young: 2.6 ± 0.4 μmol L   vs. OC: 7.2 ± 2.0 μmol L ; P < 0.0001) and suppressed by antibiotic treatment (OA: 1.2 ± 0.2 μmol L ; P < 0.0001 vs. OC). The results of the present study provide the first evidence for the gut microbiome being an important mediator of age-related arterial dysfunction and oxidative stress and suggest that therapeutic strategies targeting gut microbiome health may hold promise for preserving arterial function and reducing cardiovascular risk with ageing in humans. 10.1113/JP277336
    Gut microbiota, endotoxemia, inflammation, and oxidative stress in patients with heart failure, left ventricular assist device, and transplant. Yuzefpolskaya Melana,Bohn Bruno,Nasiri Mojdeh,Zuver Amelia M,Onat Drew D,Royzman Eugene A,Nwokocha Joseph,Mabasa Melissa,Pinsino Alberto,Brunjes Danielle,Gaudig Antonia,Clemons Autumn,Trinh Pauline,Stump Stephania,Giddins Marla J,Topkara Veli K,Garan A Reshad,Takeda Koji,Takayama Hiroo,Naka Yoshifumi,Farr Maryjane A,Nandakumar Renu,Uhlemann Anne-Catrin,Colombo Paolo C,Demmer Ryan T The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation BACKGROUND:Gut microbial imbalance may contribute to endotoxemia, inflammation, and oxidative stress in heart failure (HF). Changes occurring in the intestinal microbiota and inflammatory/oxidative milieu during HF progression and following left ventricular assist device (LVAD) or heart transplantation (HT) are unknown. We aimed to investigate variation in gut microbiota and circulating biomarkers of endotoxemia, inflammation, and oxidative stress in patients with HF (New York Heart Association, Class I-IV), LVAD, and HT. METHODS:We enrolled 452 patients. Biomarkers of endotoxemia (lipopolysaccharide and soluble [sCD14]), inflammation (C-reactive protein, interleukin-6, tumor necrosis factor-α, and endothelin-1 adiponectin), and oxidative stress (isoprostane) were measured in 644 blood samples. A total of 304 stool samples were analyzed using 16S rRNA sequencing. RESULTS:Gut microbial community measures of alpha diversity were progressively lower across worsening HF class and were similarly reduced in patients with LVAD and HT (p < 0.05). Inflammation and oxidative stress were elevated in patients with Class IV HF vs all other groups (all p < 0.05). Lipopolysaccharide was elevated in patients with Class IV HF (vs Class I-III) as well as in patients with LVAD and HT (p < 0.05). sCD14 was elevated in patients with Class IV HF and LVAD (vs Class I-III, p < 0.05) but not in patients with HT. CONCLUSIONS:Reduced gut microbial diversity and increased endotoxemia, inflammation, and oxidative stress are present in patients with Class IV HF. Inflammation and oxidative stress are lower among patients with LVAD and HT relative to patients with Class IV HF, whereas reduced gut diversity and endotoxemia persist in LVAD and HT. 10.1016/j.healun.2020.02.004
    Systems-Level Feedbacks of NRF2 Controlling Autophagy upon Oxidative Stress Response. Kapuy Orsolya,Papp Diána,Vellai Tibor,Bánhegyi Gábor,Korcsmáros Tamás Antioxidants (Basel, Switzerland) Although the primary role of autophagy-dependent cellular self-eating is cytoprotective upon various stress events (such as starvation, oxidative stress, and high temperatures), sustained autophagy might lead to cell death. A transcription factor called NRF2 (nuclear factor erythroid-related factor 2) seems to be essential in maintaining cellular homeostasis in the presence of either reactive oxygen or nitrogen species generated by internal metabolism or external exposure. Accumulating experimental evidence reveals that oxidative stress also influences the balance of the 5' AMP-activated protein kinase (AMPK)/rapamycin (mammalian kinase target of rapamycin or mTOR) signaling pathway, thereby inducing autophagy. Based on computational modeling here we propose that the regulatory triangle of AMPK, NRF2 and mTOR guaranties a precise oxidative stress response mechanism comprising of autophagy. We suggest that under conditions of oxidative stress, AMPK is crucial for autophagy induction via mTOR down-regulation, while NRF2 fine-tunes the process of autophagy according to the level of oxidative stress. We claim that the cellular oxidative stress response mechanism achieves an incoherently amplified negative feedback loop involving NRF2, mTOR and AMPK. The mTOR-NRF2 double negative feedback generates bistability, supporting the proper separation of two alternative steady states, called autophagy-dependent survival (at low stress) and cell death (at high stress). In addition, an AMPK-mTOR-NRF2 negative feedback loop suggests an oscillatory characteristic of autophagy upon prolonged intermediate levels of oxidative stress, resulting in new rounds of autophagy stimulation until the stress events cannot be dissolved. Our results indicate that AMPK-, NRF2- and mTOR-controlled autophagy induction provides a dynamic adaptation to altering environmental conditions, assuming their new frontier in biomedicine. 10.3390/antiox7030039
    Bioaccessibility of pistachio polyphenols, xanthophylls, and tocopherols during simulated human digestion. Mandalari Giuseppina,Bisignano Carlo,Filocamo Angela,Chessa Simona,Sarò Mariagiovanna,Torre Germana,Faulks Richard M,Dugo Paola Nutrition (Burbank, Los Angeles County, Calif.) OBJECTIVE:The bioaccessibility of bioactives from pistachios has not been previously evaluated. In the present study we quantified the release of polyphenols, xanthophylls (lutein), and tocopherols from pistachios (raw pistachios, roasted salted pistachios, and muffins made with raw pistachios) during simulated human digestion. METHODS:A dynamic gastric model of digestion that provides a realistic and predictive simulation of the physical and chemical processing and accurately mimics the residence time and the luminal environment within the human stomach was used for the digestion studies. RESULTS:More than 90% of the polyphenols were released in the gastric compartment, with virtually total release in the duodenal phase. No significant differences were observed between raw shelled and roasted salted pistachio. The presence of a food matrix (muffin) decreased the bioaccessibility of protocatechuic acid (78%) and luteolin (36%). Almost 100% bioaccessibility of lutein and tocopherols was found after duodenal digestion, with no difference among the three samples. CONCLUSION:The rapid release of the assayed bioactives in the stomach maximizes the potential for absorption in the duodenum and contributes to the beneficial relation between pistachio consumption and health-related outcomes. 10.1016/j.nut.2012.08.004
    Degradation of quercetin-3-glucoside in gnotobiotic rats associated with human intestinal bacteria. Schneider H,Simmering R,Hartmann L,Pforte H,Blaut M Journal of applied microbiology AIM:The two bacterial species, Eubacterium ramulus and Enterococcus casseliflavus, which had previously been isolated from human faeces using the flavonoid quercetin-3-glucoside as the growth substrate, were tested for their ability to utilize this compound in vivo. METHODS AND RESULTS:Germ-free rats were associated with Eu. ramulus and subsequently with Ent. casseliflavus and vice versa. Identification and enumeration of the bacterial cell counts in faeces and intestinal contents were performed by whole cell fluorescence in situ hybridization. Eubacterium ramulus and Ent. casseliflavus occurred in caecal and colonic contents at cell counts of up to 10(10) g(-1) dry weight. In the jejunum, only Ent. casseliflavus was found (10(9) g(-1) dry weight). Upon oral administration of 32 micromol quercetin-3-glucoside, quercetin was detected in the faeces and urine of germ-free rats (2.2 x 10(-1)-8.1 x 10(-1) micromol 24-h(-1) faeces collection and 1.0 x 10(-2)-2.8 x 10(-1) micromol 24-h(-1) urine collection, respectively) and of rats monoassociated with Ent. casseliflavus (7.9 x 10(-1)-2.7 micromol 24-h(-1) faeces and 1.0 x 10(-1)-5.9 x 10(-1) micromol 24-h(-1) urine, respectively). In contrast, the faeces and urine of rats associated with Eu. ramulus contained 3,4-dihydroxyphenylacetic acid (4.7 x 10(-2)-3.6 micromol 24-h(-1) faeces and 2.4 x 10(-2)-1.0 micromol 24-h(-1) urine, respectively) but only low, or undetectable, concentrations of faecal quercetin (up to 9.3 x 10(-2) micromol 24-h(-1) faeces; detection limit 2.5 x 10(-2) micromol). Urinary quercetin concentrations varied markedly from undetectable amounts up to 1.0 micromol 24-h(-1) urine (detection limit 1.0 x 10(-2) micromol). Isorhamnetin was found in the urine of all animals independent of their bacterial status. There were no significant differences between the groups (2.0 x 10(-2)-2.8 x 10(-1) micromol 24-h(-1) urine). In complete intestinal tissues of animals, associated with both species, quercetin-3-glucoside and its metabolites were detected by a more sensitive and selective method at concentrations that were two to three orders of magnitude lower than in faeces or urine. CONCLUSIONS:These results indicate that Eu. ramulus may be a key organism for the bacterial transformation of flavonoids in the gut.
    Baicalin, the predominant flavone glucuronide of scutellariae radix, is absorbed from the rat gastrointestinal tract as the aglycone and restored to its original form. Akao T,Kawabata K,Yanagisawa E,Ishihara K,Mizuhara Y,Wakui Y,Sakashita Y,Kobashi K The Journal of pharmacy and pharmacology When baicalin was orally administered to conventional rats, it was detected in their plasma for 24 h after administration, but baicalein, the aglycone of baicalin, was not detected. However, when baicalin was given to germ-free rats, only a small amount of baicalin was detected in their plasma within 2 h after the administration, its AUC0-lim (the area under the concentration-time curve from 0 to last determination time) being 12.0% of that in conventional rats. Subsequently, a considerable amount (55.1 +/- 6.2%) of baicalin was recovered from the gastrointestinal tract even 4 h after administration. When baicalein was orally administered to conventional rats, however, baicalin appeared rapidly in their plasma at an AUC0-lim value similar to that obtained after oral administration of baicalin, despite the absence of baicalein in plasma. When intestinal absorption was evaluated by the rat jejunal loop method, baicalein was absorbed readily, but only traces of baicalin were absorbed. Moreover, in conventional rats a small amount (13.4 +/- 3.1%) of baicalin and an appreciable amount (21.9 +/- 3.4%) of baicalein were recovered from the gastrointestinal tract even 4 h after oral administration of baicalin, but only a small amount (3.93 +/- 1.43%) of baicalein was detected in the intestinal tract 1 h after administration of baicalein. Baicalin was transformed to baicalein readily by the rat gastric and caecal contents. When baicalin was administered orally to conventional rats, an appreciable amount of baicalein was recovered in their gastrointestinal tracts. Moreover, baicalein was efficiently conjugated to baicalin in rat intestinal and hepatic microsomes. These results indicate that baicalin itself is poorly absorbed from the rat gut, but is hydrolysed to baicalein by intestinal bacteria and then restored to its original form from the absorbed baicalein in the body. 10.1211/0022357001777621
    Absorption/metabolism of sulforaphane and quercetin, and regulation of phase II enzymes, in human jejunum in vivo. Petri Niclas,Tannergren Christer,Holst Birgit,Mellon Fred A,Bao Yongping,Plumb Geoff W,Bacon Jim,O'Leary Karen A,Kroon Paul A,Knutson Lars,Forsell Patrik,Eriksson Thomas,Lennernas Hans,Williamson Gary Drug metabolism and disposition: the biological fate of chemicals For the first time the human intestinal effective permeability, estimated from the luminal disappearance and intestinal metabolism of phytochemicals, sulforaphane and quercetin-3,4'-glucoside, as well as the simultaneous changes in gene expression in vivo in enterocytes, has been studied in the human jejunum in vivo (Loc-I-Gut). Both compounds as components of an onion and broccoli extract could readily permeate the enterocytes in the perfused jejunal segment. At the physiologically relevant, dietary concentration tested, the average effective jejunal permeability (Peff) and percentage absorbed (+/- S.D.) were 18.7 +/- 12.6 x 10-4 cm/s and 74 +/- 29% for sulforaphane and 8.9 +/- 7.1 x 10-4 cm/s and 60 +/- 31% for quercetin-3,4'-diglucoside, respectively. Furthermore, a proportion of each compound was conjugated and excreted back into the lumen as sulforaphane-glutathione and quercetin-3'-glucuronide. The capacity of the isolated segment to deconjugate quercetin from quercetin-3,4'-diglucoside during the perfusion was much higher than the beta-glucosidase activity of the preperfusion jejunal contents, indicating that the majority (79-100%) of the beta-glucosidase capacity derives from the enterocytes in situ. Simultaneously, we determined short-term changes in gene expression in exfoliated enterocytes, which showed 2.0 +/- 0.4-fold induction of glutathione transferase A1 (GSTA1) mRNA (p < 0.002) and 2.4 +/- 1.2-fold induction of UDP-glucuronosyl transferase 1A1 (UGT1A1) mRNA (p < 0.02). The changes in gene expression were also seen in differentiated Caco-2 cells, where sulforaphane was responsible for induction of GSTA1 and quercetin for induction of UGT1A1. These results show that food components have the potential to modify drug metabolism in the human enterocyte in vivo very rapidly. 10.1124/dmd.31.6.805
    Oxidants, transcription factors, and intestinal inflammation. Jourd'heuil D,Morise Z,Conner E M,Grisham M B Journal of clinical gastroenterology It is now well appreciated that chronic gut inflammation is characterized by enhanced production of reactive metabolites of oxygen and nitrogen. Some of these oxidants are known to modulate the expression of a variety of genes that are involved in the immune and inflammatory responses. For example, certain oxidants are known to activate the nuclear transcription factor kappa B, which regulates the expression of a variety of different adhesion molecules, cytokines, and enzymes. Oxidants are also known to activate another transcription factor, activator protein-1. This transcription factor is composed of products from the fos and jun proto-oncogene family and is believed to be important in regulating cell growth and proliferation. Finally, oxidants are believed to promote intestinal epithelial cell apoptosis, and the B-cell lymphoma/leukemia-2 gene product is believed to inhibit this phenomenon in an antioxidant-dependent manner. Taken together, these observations suggest that nontoxic concentrations of reactive metabolites of oxygen and nitrogen play an important role in regulating the expression of genes involved in the inflammatory response and in modulating apoptosis.
    The bioavailability of polyphenols is highly governed by the capacity of the intestine and of the liver to secrete conjugated metabolites. Silberberg M,Morand C,Mathevon T,Besson C,Manach C,Scalbert A,Remesy C European journal of nutrition BACKGROUND:After ingestion of a complex meal containing foods and beverages of plant origin, different polyphenols are likely to be simultaneously present in the intestine. However, almost nothing is known about their interactions and possible consequences on their bioavailability. AIM OF THE STUDY:The present study deals with the intestinal absorption and splanchnic metabolism of three polyphenols, genistein, hesperetin and ferulic acid (FA),when perfused in the small intestine alone or in combination, at different doses (15 and 120 microM). METHODS:The fate of polyphenols in the small intestine was studied using a rat in situ intestinal perfusion model. Polyphenols were analysed in perfusate, bile and plasma by HPLC. RESULTS:Whatever the perfused dose, the efficiency of the net transfer towards the enterocyte was similar for the three polyphenols and not significantly modified by any association between these molecules. However, FA largely differed from the two flavonoids by its low intestinal secretion of conjugates. When perfused at 15 microM, the secretion of conjugates back to the lumen represented 6.2% of the net transfer into the enterocytes for FA compared to 25.5 and 20 % for genistein and hesperetin respectively. Intestinal conjugation and secretion of conjugates back to the gut lumen varied with the dose of flavonoids: saturation of conjugation was observed for the highest dose or when a high dose of a second flavonoid was perfused simultaneously. Intensity of the biliary secretion substantially differed among tested polyphenols: 7.7% of the net transfer for FA vs 50% for genistein or hesperetin. The extent of the enterohepatic cycling of these polyphenols was proportional to the perfused dose and unaffected by the simultaneous presence of different compounds in the intestine. CONCLUSION:Genistein and hesperetin appeared less available than FA for peripheral tissues because of a high intestinal and biliary secretion of their conjugates. Moreover, data suggest that a high polyphenol intake may improve their bioavailability due to saturation of the intestinal secretion of conjugates. 10.1007/s00394-005-0568-5
    Investigation of the absorption mechanisms of baicalin and baicalein in rats. Taiming Liu,Xuehua Jiang Journal of pharmaceutical sciences To characterize and compare the absorption mechanisms of baicalin (BG) and baicalein (B), either of them was perfused in situ in rats with ligation of the bile duct as well as without it. Two RP-HPLC methods were developed to determine the drugs' concentrations in the gastric and intestinal perfusates, respectively. The result showed that BG was moderately absorbed in stomach but poorly in small intestine and colon, while B was well absorbed in stomach and small intestine but relatively less in colon. It also indicated that bile could excrete BG and significantly promote the absorption of B. When BG or B was perfused alone in the small intestine after ligation of the bile duct, there came out to be increasing B or BG in the perfusate, respectively. In addition, when B was intravenously administered to rats after ligation of the bile duct, there came out to be BG in the intestinal perfusate. In conclusion, B was more suitable to be administered orally than BG, which was absorbed as B and then restored to BG in the body. Part of the BG formed from the absorbed or intravenously administered B could be excreted back into the gut. 10.1002/jps.20593
    Anti-inflammatory implications of the microbial transformation of dietary phenolic compounds. Russell Wendy R,Scobbie Lorraine,Chesson Andrew,Richardson Anthony J,Stewart Colin S,Duncan Sylvia H,Drew Janice E,Duthie Garry G Nutrition and cancer Due to the success of therapeutic anti-inflammatory compounds to inhibit, retard, and reverse the development of colon cancer, the identification of dietary compounds as chemopreventives is being vigorously pursued. However, an important factor often overlooked is the metabolic transformation of the food-derived compounds in the gut that may affect their bioactivity. Commonly consumed dietary phenolics (esterified ferulic acid and its 5-5'-linked dimer), which have the potential to undergo predominant microbial transformations (de-esterification, hydrogenation, demethylation, dehydroxylation, and dimer cleavage), were incubated with human microbiota. The metabolites were identified (high-performance liquid chromatography and nuclear magnetic resonance) and confirmed to be present in fresh fecal samples from 4 human volunteers. The potential anti-inflammatory properties were compared by measuring the ability of the parent compounds and their metabolites to modulate prostanoid production in a cell line in which the inflammatory pathways were stimulated following a cytokine-induced insult. The compounds were readily de-esterified and hydrogenated, but no dimer cleavage occurred. Only the monomer underwent demethylation and selective de-hydroxylation. The resultant metabolites had differing effects on prostanoid production ranging from a slight increase to a significant reduction in magnitude. This suggests that the microbial transformation of dietary compounds will have important inflammatory implications in the chemoprevention of colon cancer. 10.1080/01635580801987498
    The sugar moiety is a major determinant of the absorption of dietary flavonoid glycosides in man. Hollman P C,Bijsman M N,van Gameren Y,Cnossen E P,de Vries J H,Katan M B Free radical research Flavonoids are antioxidants present in plant foods. They occur mainly as glycosides, i.e. linked with various sugars. It is uncertain to what extent dietary flavonoid glycosides are absorbed from the gut. We investigated how the nature of the sugar group affected absorption of one major flavonoid, quercetin. Quercetin linked with glucose, i.e. quercetin glucoside and quercetin linked with rutinose, i.e. quercetin rutinoside, both occur widely in foods. When we fed these compounds to nine volunteers, the peak concentration of quercetin (Cmax) in plasma was 20 times higher and was reached (Tmax) more than ten times faster after intake of the glucoside (Cmax = 3.5+/-0.6 microM (mean +/- SE); Tmax < 0.5 h) than after the rutinoside (Cmax = 0.18+/-0.04 microM; Tmax = 6.0+/-1.2 h). The bioavailability of the rutinoside was only 20% of that of the glucoside. We suggest that quercetin glucoside is actively absorbed from the small intestine, whereas quercetin rutinoside is absorbed from the colon after deglycosylation. Absorption of other food components might also be enhanced by attachment of a glucose group.
    Coumarins permeability in Caco-2 cell model. Galkin Anna,Fallarero Adyary,Vuorela Pia M The Journal of pharmacy and pharmacology OBJECTIVES:The presence of coumarins in human diet, their multiple pharmacological properties and occurrence in various herbal remedies represent significant reasons to explore their membrane permeability, as a first event contributing to coumarins oral bioavailability. Thus, we evaluated the permeability and cytotoxicity of 18 coumarins, with different substitution patterns involving OH, OCH3 and CH3 groups. METHODS:A modified Caco-2 permeability model was used, in which the permeability test is performed with a robotic workstation and cells are grown on 96-well plates for 7 days. KEY FINDINGS:All studied coumarins were highly permeable, with calculated Papp values that varied within 4.1 x 10(-5) to 2.1 x 10(-4) in apical to basolateral studies and within 1.8 x 10(-5) to 7.0 x 10(-5) in basolateral to apical studies. The efflux ratio remained in all cases below 1. It was demonstrated that the type and position of substituents contributed more to the permeability than the number of substituents. CONCLUSIONS:The results allowed us to predict that these coumarins are well absorbed in the gut lumen and efflux is not limiting the absorption. Five coumarins had an influence on the mitochondrial function of Caco-2 cells (1 < 80%, 4 > 120%), according to the WST-1 cytotoxicity test, but this does not seem to affect the permeability of the compounds. 10.1211/jpp/61.02.0006
    Effect of a low dose of dietary resveratrol on colon microbiota, inflammation and tissue damage in a DSS-induced colitis rat model. Larrosa Mar,Yañéz-Gascón María Josefa,Selma María Victoria,González-Sarrías Antonio,Toti Simona,Cerón José Joaquín,Tomás-Barberán Francisco,Dolara Piero,Espín Juan Carlos Journal of agricultural and food chemistry The naturally occurring polyphenol resveratrol has been acknowledged with health-beneficial properties. Most of the studies dealing with its in vivo effects assay huge doses, not representative from a dietary point of view. Our aim was to ascertain whether resveratrol can exert anti-inflammatory activity in vivo at an attainable dietary dose. Rats were fed with 1 mg of resveratrol/kg/day (a human equivalent dose) for 25 days, and in the last 5 days, 5% dextran sulfate sodium (DSS) was administered to induce colitis. Effects on colon tissue damage, gut microbiota, reactive oxygen species, inflammatory markers and nitric oxide production as well as gene expression profile with microarrays were evaluated. Resveratrol increased lactobacilli and bifidobacteria as well as diminished the increase of enterobacteria upon DSS treatment. Resveratrol significantly protected the colonic mucosa architecture, reduced body weight loss, diminished the induced anemia and reduced systemic inflammation markers, colonic mucosa prostaglandin E(2), cycloxygenase-2, prostaglandin E synthase and nitric oxide levels. In addition, the expression of 2,655 genes in distal colon mucosa related to important pathways was varied. These results reinforce the concept of resveratrol as a dietary beneficial compound in intestinal inflammation at doses possibly attainable with resveratrol-enriched nutraceuticals. 10.1021/jf803638d
    Pharmacokinetics and modeling of quercetin and metabolites. Chen Xiao,Yin Ophelia Q P,Zuo Zhong,Chow Moses S S Pharmaceutical research PURPOSE:To determine the pharmacokinetics of quercetin and its glucuronide/sulfate conjugates and to develop a pharmacokinetic model to simultaneously describe their disposition after intravenous and oral administration in rats. METHODS:After oral, intraportal, and intravenous administration of quercetin, serial plasma, urine, and fecal concentrations of quercetin and its conjugates were determined by an HPLC method. Enterohepatic recirculation was evaluated in a linked-rat model as well as after oral administration of bile containing quercetin and its metabolites. Based on the experimental data, a specific compartmental model was developed and validated to describe and predict the plasma concentration-time profiles of quercetin and its conjugates after oral and intravenous administration. RESULTS:Only 5.3% of unchanged quercetin was bioavailable, although the total quercetin absorbed was as high as 59.1%. After oral administration, about 93.3% of quercetin was metabolized in the gut, with only 3.1% metabolized in the liver. No significant enterohepatic recirculation was observed for both quercetin and its conjugated metabolites. The pharmacokinetic model fitted well the observed data of quercetin and its conjugates. CONCLUSIONS:Our study clarifies the relative importance of the gut, liver, and bile in the metabolism and excretion of quercetin and its conjugates. The pharmacokinetic model appears to be suitable for describing the absorption and disposition of the quercetin and its conjugates and may be applicable to other flavonoids that undergo similar pharmacokinetic pathways. 10.1007/s11095-005-4584-1
    Anti-inflammatory effects of resveratrol, curcumin and simvastatin in acute small intestinal inflammation. Bereswill Stefan,Muñoz Melba,Fischer André,Plickert Rita,Haag Lea-Maxie,Otto Bettina,Kühl Anja A,Loddenkemper Christoph,Göbel Ulf B,Heimesaat Markus M PloS one BACKGROUND:The health beneficial effects of Resveratrol, Curcumin and Simvastatin have been demonstrated in various experimental models of inflammation. We investigated the potential anti-inflammatory and immunomodulatory mechanisms of the above mentioned compounds in a murine model of hyper-acute Th1-type ileitis following peroral infection with Toxoplasma gondii. METHODOLOGY/PRINCIPAL FINDINGS:Here we show that after peroral administration of Resveratrol, Curcumin or Simvastatin, mice were protected from ileitis development and survived the acute phase of inflammation whereas all Placebo treated controls died. In particular, Resveratrol treatment resulted in longer-term survival. Resveratrol, Curcumin or Simvastatin treated animals displayed significantly increased numbers of regulatory T cells and augmented intestinal epithelial cell proliferation/regeneration in the ileum mucosa compared to placebo control animals. In contrast, mucosal T lymphocyte and neutrophilic granulocyte numbers in treated mice were reduced. In addition, levels of the anti-inflammatory cytokine IL-10 in ileum, mesenteric lymph nodes and spleen were increased whereas pro-inflammatory cytokine expression (IL-23p19, IFN-γ, TNF-α, IL-6, MCP-1) was found to be significantly lower in the ileum of treated animals as compared to Placebo controls. Furthermore, treated animals displayed not only fewer pro-inflammatory enterobacteria and enterococci but also higher anti-inflammatory lactobacilli and bifidobacteria loads. Most importantly, treatment with all three compounds preserved intestinal barrier functions as indicated by reduced bacterial translocation rates into spleen, liver, kidney and blood. CONCLUSION/SIGNIFICANCE:Oral treatment with Resveratrol, Curcumin or Simvastatin ameliorates acute small intestinal inflammation by down-regulating Th1-type immune responses and prevents bacterial translocation by maintaining gut barrier function. These findings provide novel and potential prophylaxis and treatment options of patients with inflammatory bowel diseases. 10.1371/journal.pone.0015099
    Microbial metabolism of caffeic acid and its esters chlorogenic and caftaric acids by human faecal microbiota in vitro. Gonthier M-P,Remesy C,Scalbert A,Cheynier V,Souquet J-M,Poutanen K,Aura A-M Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Caffeic acid and its esters, chlorogenic and caftaric acids, are major dietary polyphenols present in various foods and beverages. Although caffeic acid is easily absorbed in the small intestine, its esterification with quinic acid, as in chlorogenic acid, decreases its gut absorption and increases the quantities reaching the colon and its microbiota. The microbial conversion of caftaric acid, the tartaric acid ester of caffeic acid, has not been studied earlier. In this work we compared the direct action of a human faecal microbiota on the metabolism of caffeic, chlorogenic and caftaric acids in an in vitro fermentation model. All substrates disappeared quickly and none of the free acids (caffeic, quinic or tartaric acids) were detected after 2 hours of incubation. Two major microbial metabolites were identified by HPLC-ESI-MS-MS as 3-hydroxyphenylpropionic (3-HPP) and benzoic acids (BA). Maximal levels of 3-HPP were reached after 2 h of fermentation and accounted for 9-24% of the dose of caffeic acid and its esters. BA was formed steadily throughout the incubation, accounting for 4-5% of the initial dose of the substrates after 24 h of incubation. The similarities in the metabolic patterns observed for caffeic, chlorogenic and caftaric acids suggest that esterification does not influence the metabolism of caffeic acid by the gut microbiota. 10.1016/j.biopha.2006.07.084
    Route of administration determines the anxiolytic activity of the flavonols kaempferol, quercetin and myricetin--are they prodrugs? Vissiennon Cica,Nieber Karen,Kelber Olaf,Butterweck Veronika The Journal of nutritional biochemistry Several in vivo and in vitro studies have confirmed that flavonols are metabolized by the intestinal microflora to their corresponding hydroxyphenylacetic acids. In this article, a comparison of the anxiolytic activity of the flavonols kaempferol, quercetin and myricetin in the elevated plus maze after oral (po) and intraperitoneal (ip) administration to mice in a dose range of 0.1 to 2.0 mg/kg is presented. In addition, their corresponding metabolites p-hydroxyphenylacetic acid (p-HPAA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were tested after intraperitoneal administration. Anxiolytic activity was detected for kaempferol and quercetin only after oral administration. No anxiolytic effects were observed when kaempferol and quercetin were given via the intraperitoneal administration route. The corresponding hydroxyphenylacetic metabolites p-HPAA and DOPAC showed anxiolytic effects after intraperitoneal application. In order to further test the hypothesis that flavonoids are possible prodrugs which require activation by intestinal bacteria, gut sterilization was performed using pretreatment with the antibiotic enrofloxacin (7.5 mg/day, po, for 4 days). After antibiotic treatment, the anxiolytic effect of kaempferol and quercetin disappeared, whereas it was still present for the positive control diazepam. Our results support the hypothesis that flavonoids act as prodrugs which are transformed into their active hydroxyphenylacetic acid metabolites by intestinal microflora. 10.1016/j.jnutbio.2011.03.017
    Food Matrix Effects of Polyphenol Bioaccessibility from Almond Skin during Simulated Human Digestion. Mandalari Giuseppina,Vardakou Maria,Faulks Richard,Bisignano Carlo,Martorana Maria,Smeriglio Antonella,Trombetta Domenico Nutrients The goal of the present study was to quantify the rate and extent of polyphenols released in the gastrointestinal tract (GIT) from natural (NS) and blanched (BS) almond skins. A dynamic gastric model of digestion which provides a realistic simulation of the human stomach was used. In order to establish the effect of a food matrix on polyphenols bioaccessibility, NS and BS were either digested in water (WT) or incorporated into home-made biscuits (HB), crisp-bread (CB) and full-fat milk (FM). Phenolic acids were the most bioaccessible class (68.5% release from NS and 64.7% from BS). WT increased the release of flavan-3-ols (p < 0.05) and flavonols (p < 0.05) from NS after gastric plus duodenal digestion, whereas CB and HB were better vehicles for BS. FM lowered the % recovery of polyphenols, the free total phenols and the antioxidant status in the digestion medium, indicating that phenolic compounds could bind protein present in the food matrix. The release of bioactives from almond skins could explain the beneficial effects associated with almond consumption. 10.3390/nu8090568
    Evaluation of the inhibitory effects of quercetin-related flavonoids and tea catechins on the monoamine oxidase-A reaction in mouse brain mitochondria. Bandaruk Yauhen,Mukai Rie,Kawamura Tomoyuki,Nemoto Hisao,Terao Junji Journal of agricultural and food chemistry Quercetin, a typical dietary flavonoid, is thought to exert antidepressant effects by inhibiting the monoamine oxidase-A (MAO-A) reaction, which is responsible for regulation of the metabolism of the neurotransmitter 5-hydroxytryptamine (5-HT) in the brain. This study compared the MAO-A inhibitory activity of quercetin with those of O-methylated quercetin (isorhamnetin, tamarixetin), luteolin, and green tea catechins ((-)-epicatechin, (-)-epicatechin gallate, (-)-epigallocatechin, and (-)-epigallocatechin gallate) by measuring the formation of the oxidative deamination product of 5-HT, 5-hydroxyindole aldehyde (5-HIAL), in mouse brain mitochondria. Quercetin was inferior to luteolin in the inhibition of MAO-A activity, whereas isorhamnetin, tamarixetin, and tea catechins scarcely exerted inhibitory activity. Quercetin did not affect MAO-A activity in mouse intestinal mitochondria, indicating that it does not evoke side effects on the metabolism of dietary monoamines in the gut. These data suggest that quercetin is a weak (but safe) MAO-A inhibitor in the modulation of 5-HT levels in the brain. 10.1021/jf303055b
    Pharmacokinetics of resveratrol metabolic profile in healthy humans after moderate consumption of red wine and grape extract tablets. Rotches-Ribalta Maria,Andres-Lacueva Cristina,Estruch Ramon,Escribano Elvira,Urpi-Sarda Mireia Pharmacological research A pharmacokinetic study of the metabolic profile of resveratrol has been performed in healthy men after moderate red wine (RW) consumption. The bioavailability of resveratrol is highly influenced by several factors such as the food matrix and, therefore, this study has been compared with a pilot study in which men ingested grape extract (GE) tablets as a nutraceutical, containing similar total amounts of resveratrol than RW. Blood and urine samples were taken before and at several time points after intervention and then analyzed by SPE and LC-ESI-MS/MS. Up to 17 resveratrol and piceid derivatives were identified, including those formed by the intestinal microbiota. Resveratrol glucosides were found in plasma as intact forms and reached the lowest maximum concentrations 1h after both interventions. Higher plasma concentrations and longer times (t(max)) were observed for resveratrol glucuronides due to phase II metabolism and even higher values for conjugates derived from microbiota, such as dihydroresveratrol-glucuronides. The same trend was observed for total excreted amounts in urine samples. When both treatments were compared, statistically significant differences for some metabolites were obtained, which may be due to the different composition of resveratrol and piceid in both sources. However, GE formulation seems to delay resveratrol absorption, staying longer in the gut where could be metabolized to a greater degree, since 2.1-3.6-fold higher urinary concentrations of microbial metabolites were observed after GE intervention at 12-24h urinary fraction. Therefore, supplement intake could be also a way to bring resveratrol benefits to human health. 10.1016/j.phrs.2012.08.001
    Resveratrol and diabetes. Vallianou Natalia G,Evangelopoulos Angelos,Kazazis Christos The review of diabetic studies : RDS Resveratrol is a stilbene compound, and a phytoalexin, synthesized by plants in response to stressful stimuli, usually caused by infection. It is abundantly present in red wine, ports and sherries, red grapes, blueberries, peanuts, itadori tea, as well as hops, pistachios, and in grape and cranberry juices. The anti-hyperglycemic effects of resveratrol seem to be the result of an increased action of the glucose transporter in the cytoplasmic membrane. Studies on rats with streptozotocin-induced diabetes have demonstrated that the expression of the insulin-dependent glucose transporter, GLUT4, is increased after resveratrol ingestion. Also, resveratrol enhances adiponectin levels, which could be one of the potential mechanisms by which it improves insulin sensitivity. Another important observation is that resveratrol induces the secretion of the gut incretin hormone, glucagon-like peptide-1. Resveratrol is also reported to activate Sir2 (silent information regulatory 2), a SIRT1 homolog, thus mimicking the benefits of calorie restriction. It produces a wide variety of effects in mammalian cells, including activation of AMP-activated protein kinase, which is involved in some of the same metabolic pathways as SIRT1, which may influence other mechanisms via the involvement of nuclear factor kappa B (NF-κB). In the near future, resveratrol-based therapies with either resveratrol or its analogs that have better bioavailability could be useful in the treatment of diabetes and its complications, either alone or in combination with other anti-diabetic drugs. 10.1900/RDS.2013.10.236
    Anti-inflammatory properties of fruit juices enriched with pine bark extract in an in vitro model of inflamed human intestinal epithelium: the effect of gastrointestinal digestion. Frontela-Saseta Carmen,López-Nicolás Rubén,González-Bermúdez Carlos A,Martínez-Graciá Carmen,Ros-Berruezo Gaspar Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association Enrichment of fruit juices with pine bark extract (PBE) could be a strategy to compensate for phenolic losses during the gastrointestinal digestion. A coculture system with Caco-2 cells and RAW 264.7 macrophages was established as an in vitro model of inflamed human intestinal epithelium for evaluating the anti-inflammatory capacity of fruit juices enriched with PBE (0.5 g L(-1)) before and after in vitro digestion. The digestion of both PBE-enriched pineapple and red fruit juice led to significant changes in most of the analysed phenolic compounds. The in vitro inflammatory state showed cell barrier dysfunction and overproduction of IL-8, nitric oxide (NO) and reactive oxygen species (ROS). In the inflamed cells, incubation with nondigested samples reduced (P<0.05) the production of IL-8 and NO compared with digested samples. ROS production increased in the inflamed cells exposed to digested commercial red fruit juice (86.8±1.3%) compared with fresh juice (77.4±0.8%) and increased in the inflamed cells exposed to digested enriched red fruit juice (82.6±1.6%) compared with the fresh enriched juice (55.8±6%). The anti-inflammatory properties of PBE-enriched fruit juices decreased after digestion; further research on the bioavailability of the assayed compounds is needed to properly assess their usefulness for the treatment of gut inflammation. 10.1016/j.fct.2012.11.024
    Alpha-tocopherol succinate-mobilized progenitors improve intestinal integrity after whole body irradiation. Singh Vijay K,Wise Stephen Y,Singh Pankaj K,Posarac Ana,Fatanmi Oluseyi O,Ducey Elizabeth J,Bolduc David L,Elliott Thomas B,Seed Thomas M International journal of radiation biology PURPOSE:The objective of this study was to elucidate the action of α-tocopherol succinate (TS)- and AMD3100-mobilized progenitors in mitigating radiation-induced injuries. MATERIAL AND METHODS:CD2F1 mice were exposed to a high dose of radiation and then transfused intravenously with 5 million peripheral blood mononuclear cells (PBMC) from TS- and AMD3100-injected mice after irradiation. Intestinal and splenic tissues were harvested after irradiation and cells of those tissues were analyzed for markers of apoptosis and mitosis. Bacterial translocation from gut to heart, spleen, and liver in TS-treated and irradiated mice was evaluated by bacterial culture. RESULTS:We observed that the infusion of PBMC from TS- and AMD3100-injected mice significantly inhibited apoptosis, increased cell proliferation in the analyzed tissues of recipient mice, and inhibited bacterial translocation to various organs compared to mice receiving cells from vehicle-mobilized cells. This study further supports our contention that the infusion of TS-mobilized progenitor-containing PBMC acts as a bridging therapy by inhibiting radiation-induced apoptosis, enhancing cell proliferation, and inhibiting bacterial translocation in irradiated mice. CONCLUSIONS:We suggest that this novel bridging therapeutic approach that involves the infusion of TS-mobilized hematopoietic progenitors following acute radiation injury might be applicable to humans as well. 10.3109/09553002.2013.762137
    Flavonols enhanced production of anti-inflammatory substance(s) by Bifidobacterium adolescentis: prebiotic actions of galangin, quercetin, and fisetin. Kawabata Kyuichi,Sugiyama Yuta,Sakano Taiken,Ohigashi Hajime BioFactors (Oxford, England) The gut microbiota is capable of the bioconversion of flavonoids whereas influences of probiotic anaerobes on the bioactivities of flavonoids and vice versa are still unclear. Here, we investigated functional interactions with respect to the anti-inflammatory activity between flavonols and probiotic bacteria. Ten enteric (6 probiotic and 4 indigenous) bacteria were incubated with flavonols (galangin, kaempferol, quercetin, myricetin, and fisetin) under anaerobic conditions, and the supernatants were assessed for their effects on nitric oxide (NO) production in lipopolysaccaride-stimulated RAW264 cells. Although the conditioned medium from the flavonol mono-culture and almost all of the tested co-cultures failed to inhibit NO production, the medium from the Bifidobacterium adolescentis/flavonols (galangin, quercetin, and fisetin) co-culture highly suppressed NO production. This activity increased during the 1-6 H incubation in a time-dependent manner and was not observed in the co-culture using heat-inactivated B. adolescentis. Interestingly, when the B. adolescentis cell number was increased, the supernatant from the mono-culture of the bacteria showed NO suppression, suggesting that B. adolescentis may produce NO suppressant(s), and flavonols may have a promoting effect. These findings indicate that flavonols have a prebiotic-like effect on the anti-inflammatory activity of B. adolescentis. 10.1002/biof.1081
    Bioavailability of the major bioactive diterpenoids in a rosemary extract: metabolic profile in the intestine, liver, plasma, and brain of Zucker rats. Romo Vaquero María,García Villalba Rocío,Larrosa Mar,Yáñez-Gascón María J,Fromentin Emilie,Flanagan John,Roller Marc,Tomás-Barberán Francisco A,Espín Juan C,García-Conesa María-Teresa Molecular nutrition & food research SCOPE:Carnosic acid (CA) and derived diterpenes abundant in rosemary extracts (REs) exert anti-obesity effects. The aim of this study was to investigate the bioavailability of these compounds in a rat model of obesity. METHODS AND RESULTS:A total of 26 compounds were tentatively identified based on accurate mass information and the isotopic pattern provided by TOF-MS analyzer. The main metabolites detected in the gut content, liver, and plasma were the glucuronide conjugates of CA, carnosol, and rosmanol. Two other metabolites were also identified: CA 12-methyl ether and 5,6,7,10-tetrahydro-7-hydroxyrosmariquinone. All the metabolites were detected as early as 25 min following oral administration. Most of the compounds remained in the intestine, liver, and (or) plasma at substantial concentrations for several hours supporting their potential health benefits in these tissues. We also corroborated the presence of small quantities of CA and detected trace quantities of the main CA metabolites in the brain. Notably, we did not find significant differences in the metabolic profile between lean and obese rats. CONCLUSION:We report for the first time a comprehensive profile of metabolites in various organs following the oral consumption of an RE enriched in CA and contribute to establish the potential bioactive molecules. 10.1002/mnfr.201300052
    Demethoxycurcumin from Curcuma longa rhizome suppresses iNOS induction in an in vitro inflamed human intestinal mucosa model. Somchit Mayura,Changtam Chatchawan,Kimseng Rungruedi,Utaipan Tanyarath,Lertcanawanichakul Monthon,Suksamrarn Apichart,Chunglok Warangkana Asian Pacific journal of cancer prevention : APJCP BACKGROUND:It is known that inducible nitric oxide synthase (iNOS)/nitric oxide (NO) plays an integral role during intestinal inflammation, an important factor for colon cancer development. Natural compounds from Curcuma longa L. (Zingiberaceae) have long been a potential source of bioactive materials with various beneficial biological functions. Among them, a major active curcuminoid, demethoxycurcumin (DMC) has been shown to possess anti-inflammatory properties in lipopolysaccharide (LPS)-activated macrophages or microglia cells. However, the role of DMC on iNOS expression and NO production in an in vitro inflamed human intestinal mucosa model has not yet been elucidated. This study concerned inhibitory effects on iNOS expression and NO production of DMC in inflamed human intestinal Caco-2 cells. An in vitro model was generated and inhibitory effects on NO production of DMC at 65 μM for 24-96 h were assessed by monitoring nitrite levels. Expression of iNOS mRNA and protein was also investigated. DMC significantly decreased NO secretion by 35-41% in our inflamed cell model. Decrease in NO production by DMC was concomitant with down-regulation of iNOS at mRNA and protein levels compared to proinflammatory cytokine cocktail and LPS-treated controls. Mechanism of action of DMC may be partly due to its potent inhibition of the iNOS pathway. Our findings suggest that DMC may have potential as a therapeutic agent against inflammation-related diseases, especially in the gut. 10.7314/apjcp.2014.15.4.1807
    A rosemary extract rich in carnosic acid selectively modulates caecum microbiota and inhibits β-glucosidase activity, altering fiber and short chain fatty acids fecal excretion in lean and obese female rats. Romo-Vaquero María,Selma María-Victoria,Larrosa Mar,Obiol María,García-Villalba Rocío,González-Barrio Rocío,Issaly Nicolas,Flanagan John,Roller Marc,Tomás-Barberán Francisco A,García-Conesa María-Teresa PloS one BACKGROUND:Carnosic acid (CA) and rosemary extracts (RE) show body-weight, energy metabolism and inflammation regulatory properties in animal models but the mechanisms are not yet understood. Gut microbiota plays an important role in the host metabolism and inflammatory status and is modulated by the diet. The aim of this research was to investigate whether a RE enriched in CA affected caecum microbiota composition and activity in a rat model of genetic obesity. METHODS AND PRINCIPAL FINDINGS:A RE (40% CA) was administered with the diet (0.5% w/w) to lean (fa/+) and obese (fa/fa) female Zucker rats for 64 days. Changes in the microbiota composition and β-glucosidase activity in the caecum and in the levels of macronutrients and short chain fatty acids (SCFA) in feces were examined. The RE increased the Blautia coccoides and Bacteroides/Prevotella groups and reduced the Lactobacillus/Leuconostoc/Pediococccus group in both types of animals. Clostridium leptum was significantly decreased and Bifidobacterium increased only in the lean rats. β-Glucosidase activity was significantly reduced and fecal fiber excretion increased in the two genotypes. The RE also increased the main SCFA excreted in the feces of the obese rats but decreased them in the lean rats reflecting important differences in the uptake and metabolism of these molecules between the two genotypes. CONCLUSIONS:Our results indicate that the consumption of a RE enriched in CA modifies microbiota composition and decreases β-glucosidase activity in the caecum of female Zucker rats while it increases fiber fecal elimination. These results may contribute to explain the body weight gain reducing effects of the RE. The mutated leptin receptor of the obese animals significantly affects the microbiota composition, the SCFA fecal excretion and the host response to the RE intake. 10.1371/journal.pone.0094687
    Resveratrol metabolic fingerprinting after acute and chronic intakes of a functional beverage in humans. Rotches-Ribalta Maria,Urpi-Sarda Mireia,Martí Mercè Mercader,Reglero Guillermo,Andres-Lacueva Cristina Electrophoresis The study of the bioavailability of active compounds in functional foods, such as polyphenol-rich beverages, is required before making nutritional claims. In this work, we aimed to study the urinary excretion of resveratrol (RV), taking into consideration its gut and microbial metabolites after consumption of a functional beverage (FB), applying a ultra performance liquid chromatography (UPLC)-MS/MS methodology. A randomized, crossover, placebo-controlled, double-blind intervention study was performed with 26 volunteers, who consumed 187 mL of a control placebo or a FB in an acute study, and twice a day during 15 days for a chronic consumption study. The whole profile of 21 RV metabolites increased after acute and chronic consumption of the FB with respect to the control-placebo beverage and to the baseline. Urinary excretion of RV and piceid phase II metabolites was similar after both consumption periods, but a later formation of microbial metabolites required urine sampling of up to 24 h after the consumption of the FB. In addition, the intervariability has been evaluated. This study allows the knowledge of the RV metabolites that reach target tissues where biological activity would be achieved in order to elucidate the beneficial effects of this grape extract FB. 10.1002/elps.201300262
    Natural compounds boldine and menthol are antagonists of human 5-HT3 receptors: implications for treating gastrointestinal disorders. Walstab J,Wohlfarth C,Hovius R,Schmitteckert S,Röth R,Lasitschka F,Wink M,Bönisch H,Niesler B Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society BACKGROUND:Impaired 5-HT3 receptor function is likely involved in the pathogenesis of functional gastrointestinal disorders (FGID) and 5-HT3 receptor antagonists are effective treatments for chemotherapy-induced nausea and vomiting (CINV) and irritable bowel syndrome (IBS). The monoterpene alcohol menthol and the aporphine alkaloid boldine combat symptoms of gastrointestinal diseases; both interact with other members of the Cys-loop ligand-gated ion channel family and may therefore also act on 5-HT3 receptors. METHODS:The impact of boldine and menthol on human recombinant homomeric 5-HT3 A- and heteromeric 5-HT3 AB receptors in HEK293 cells was determined by radioligand binding, a luminescence-based Ca(2+) assay, and a membrane potential assay. 5-HT3 protein and mRNA expression was assessed in human colon tissue. KEY RESULTS:Boldine and menthol inhibited the 5-HT-induced activation of 5-HT3 receptors in the low and middle micromolar range, respectively. Boldine was a competitive antagonist of both receptors being 6.5- to 10-fold more potent at 5-HT3 A- vs 5-HT3 AB receptors. Menthol non-competitively and stereoselectively inhibited both receptors: In contrast to (+)-menthol, (-)-menthol was significantly more potent toward 5-HT3 A- vs 5-HT3 AB receptors. We show co-expression of 5-HT3A and 5-HT3B subunits in the human gut epithelium, the lamina propria, the myenteric plexus, and the muscular cell layer. CONCLUSIONS & INFERENCES:The demonstrated 5-HT3 inhibitory effects may be relevant for boldine's and menthol's alleviating properties on FGID and may encourage clinical studies with the compounds or the plant extracts for CINV and IBS treatment. The found receptor-discriminative properties make boldine and (-)-menthol to potentially useful tools for analyzing structural differences between these receptor subtypes. 10.1111/nmo.12334
    Ginger in gastrointestinal disorders: A systematic review of clinical trials. Nikkhah Bodagh Mehrnaz,Maleki Iradj,Hekmatdoost Azita Food science & nutrition Ginger, the rhizome of Zingiber officinale, which is used as a spice globally has a long history of medicinal use that stimulates investigators to assess its potential roles as an adjuvant therapy or alternative medicine in a range of diseases. Anti-inflammatory, antioxidant, antitumor, and antiulcer effects of ginger have been proven in many scientific studies, and some of the ancient applications of ginger as a home remedy has been confirmed in human. In this review, we summarized the current evidence on the effects of ginger consumption on gastrointestinal disorders based on clinical trials. Our data indicate that divided lower daily dosage of 1500 mg ginger is beneficial for nausea relief. Because of limited number of studies on some other gastrointestinal disorders, the results may not be as much powered as to find significant results. Therefore, more extensive and well-controlled human studies of ginger or its standard extracts are required to demonstrate its efficacy as a gastroprotective agent. Dose-finding studies should be undertaken to accurately determine the effective dose and preparation of ginger in further clinical trials protocol. 10.1002/fsn3.807
    Identification of diet-derived constituents as potent inhibitors of intestinal glucuronidation. Gufford Brandon T,Chen Gang,Lazarus Philip,Graf Tyler N,Oberlies Nicholas H,Paine Mary F Drug metabolism and disposition: the biological fate of chemicals Drug-metabolizing enzymes within enterocytes constitute a key barrier to xenobiotic entry into the systemic circulation. Furanocoumarins in grapefruit juice are cornerstone examples of diet-derived xenobiotics that perpetrate interactions with drugs via mechanism-based inhibition of intestinal CYP3A4. Relative to intestinal CYP3A4-mediated inhibition, alternate mechanisms underlying dietary substance-drug interactions remain understudied. A working systematic framework was applied to a panel of structurally diverse diet-derived constituents/extracts (n = 15) as inhibitors of intestinal UDP-glucuronosyl transferases (UGTs) to identify and characterize additional perpetrators of dietary substance-drug interactions. Using a screening assay involving the nonspecific UGT probe substrate 4-methylumbelliferone, human intestinal microsomes, and human embryonic kidney cell lysates overexpressing gut-relevant UGT1A isoforms, 14 diet-derived constituents/extracts inhibited UGT activity by >50% in at least one enzyme source, prompting IC(50) determination. The IC(50) values of 13 constituents/extracts (≤10 μM with at least one enzyme source) were well below intestinal tissue concentrations or concentrations in relevant juices, suggesting that these diet-derived substances can inhibit intestinal UGTs at clinically achievable concentrations. Evaluation of the effect of inhibitor depletion on IC(50) determination demonstrated substantial impact (up to 2.8-fold shift) using silybin A and silybin B, two key flavonolignans from milk thistle (Silybum marianum) as exemplar inhibitors, highlighting an important consideration for interpretation of UGT inhibition in vitro. Results from this work will help refine a working systematic framework to identify dietary substance-drug interactions that warrant advanced modeling and simulation to inform clinical assessment. 10.1124/dmd.114.059451
    Grape seed extract improves epithelial structure and suppresses inflammation in ileum of IL-10-deficient mice. Yang Guan,Wang Hui,Kang Yifei,Zhu Mei-Jun Food & function Defect in intestinal epithelial structure is a critical etiological factor of several intestinal diseases such as inflammatory bowel disease. The objective of this study was to evaluate the effect of grape seed extract (GSE), which contains a mixture of polyphenols, on ileal mucosal structure and inflammation in interleukin (IL)-10-deficient mice, a common model for studying inflammatory bowel disease. Wild-type and IL-10-deficient mice were fed GSE at 0 or 1% (based on dry feed weight) for 16 weeks. GSE supplementation decreased crypt depth and increased (P < 0.05) the ratio of villus/crypt length in the terminal ileum. Consistently, the dietary GSE decreased (P < 0.05) proliferation and enhanced (P < 0.05) differentiation of epithelial cells. These changes in gut epithelium were associated with the suppression of nuclear factor kappa-light-chain-enhancer of activated B-cell (NF-κB) signaling. Furthermore, compared with WT mice, IL-10 deletion promoted beclin-1 and AMPK expression, both of which were decreased to normal by GSE supplementation. These changes were associated with alterations in epithelial barrier function as indicated by reduced pore forming claudin-2 protein expression and increased barrier forming claudin-1 protein expression in the ileum of GSE supplemented mice. In summary, our data indicates that GSE exerts protective effects to the ileal epithelial structure in IL-10-deficient mice possibly through the suppression of inflammatory response. 10.1039/c4fo00451e
    Isolation and characterization of rat intestinal bacteria involved in biotransformation of (-)-epigallocatechin. Takagaki Akiko,Kato Yuko,Nanjo Fumio Archives of microbiology Two intestinal bacterial strains MT4s-5 and MT42 involved in the degradation of (-)-epigallocatechin (EGC) were isolated from rat feces. Strain MT4s-5 was tentatively identified as Adlercreutzia equolifaciens. This strain converted EGC into not only 1-(3, 4, 5-trihydroxyphenyl)-3-(2, 4, 6-trihydroxyphenyl)propan-2-ol (1), but also 1-(3, 5-dihydroxyphenyl)-3-(2, 4, 6-trihydroxyphenyl)propan-2-ol (2), and 4'-dehydroxylated EGC (7). Type strain (JCM 9979) of Eggerthella lenta was also found to convert EGC into 1. Strain MT42 was identified as Flavonifractor plautii and converted 1 into 4-hydroxy-5-(3, 4, 5-trihydroxyphenyl)valeric acid (3) and 5-(3, 4, 5-trihydroxyphenyl)-γ-valerolactone (4) simultaneously. Strain MT42 also converted 2 into 4-hydroxy-5-(3, 5-dihydroxyphenyl)valeric acid (5), and 5-(3, 5-dihydroxyphenyl)-γ-valerolactone (6). Furthermore, F. plautii strains ATCC 29863 and ATCC 49531 were found to catalyze the same reactions as strain MT42. Interestingly, formation of 2 from EGC by strain MT4s-5 occurred rapidly in the presence of hydrogen supplied by syntrophic bacteria. Strain JCM 9979 also formed 2 in the presence of the hydrogen or formate. Strain MT4s-5 converted 1, 3, and 4 to 2, 5, and 6, respectively, and the conversion was stimulated by hydrogen, whereas strain JCM 9979 could catalyze the conversion only in the presence of hydrogen or formate. On the basis of the above results together with previous reports, the principal metabolic pathway of EGC and EGCg by catechin-degrading bacteria in gut tract is proposed. 10.1007/s00203-014-1006-y
    Inhibitory effects of hyssop (Hyssopus officinalis) extracts on intestinal alpha-glucosidase activity and postprandial hyperglycemia. Miyazaki Hiroyuki,Matsuura Hideyuki,Yanagiya Chikako,Mizutani Junya,Tsuji Masayoshi,Ishihara Chiaki Journal of nutritional science and vitaminology It has been known that Hyssopus officinalis (hyssop) is a herb that grows in the wild and is a source of natural antioxidants. We previously reported that a-glucosidase inhibitors, (2S, 3S)1-O-beta-D-6'-O-cinnamoylglucopyranosyl-3-(3", 5"-dimethoxy-4"-hydroxyphenyl)-1,2,3-propanetriol and (2S, 3S)1-O-beta-D-glucopranosyl-3-(3", 5"-dimethoxy-4"-hydroxyphenyl)-1,2,3-propanetriol, from the dry leaves of hyssop, were isolated. This study examined the alpha-glucosidase inhibitory effects of hyssop extracts on intestinal carbohydrate absorption in rat everted gut sac and carbohydrate-loaded hyperglycemia in mice. In the everted gut sac experiment, 10 mM sucrose- and 5 mM maltose-treated increases in glucose concentration in the serosal compartment were inhibited in the presence of 0.5 and 1.0 mg/ mL hyssop extracts, although a 10 mM glucose-induced increase in serosal glucose was not inhibited by the extracts. Additionally, hyperglycemia in sucrose- and maltose-loaded mice was significantly suppressed at an early stage, within 30 to 60 min by oral pre-administration of 300 and 100 mg/kg hyssop extracts, respectively. These findings suggest that hyssop extracts inhibited the digestion of complex carbohydrates, but not that of absorbable monosaccharide, and might be a useful supplemental food for hyperglycemia.
    Procyanidins and their healthy protective effects against type 2 diabetes. Gonzalez-Abuin Noemi,Pinent Montserrat,Casanova-Marti Angela,Arola Lluis,Blay Mayte,Ardevol Anna Current medicinal chemistry This review focuses on the role of procyanidins, the main group of flavonoids, on type 2 diabetes mellitus (T2DM) and insulin resistance. We compile the role of procyanidins on several animal models, and we evaluate their effects on target tissues and analyze the mechanisms involved. Procyanidin treatments in fructose or high-fat induced insulin resistant models were found to improve the damage induced by the diet, thus improving glycemia and insulin sensitivity. The same positive effects were also reported in models of late stage T2DM, in which pancreatic β-cells can no longer counteract hyperglycemia. More controversial results were found in genetically obese or cafeteria diet-induced insulin resistant models. Human studies, although limited, further support the hypoglycemic effect of procyanidins. Regarding their mechanisms, procyanidins have been found to target several tissues involved in glucose homeostasis, which is also discussed in the present review. In insulin-sensitive tissues, procyanidins modulate glucose uptake and lipogenesis and improve their oxidative/inflammatory state, the disruption of which is important in T2DM development. In the insulin-producing tissue, the pancreas, procyanidins modulate insulin secretion and production and β-cell mass, although the available results are divergent. Finally, the gut is another potential target for procyanidins. The available data suggest that modulation of the active glucagon-like peptide-1 (GLP-1) levels could partially explain the reported antihyperglycemic effect of these natural compounds.
    Role of bifidobacteria in the hydrolysis of chlorogenic acid. Raimondi Stefano,Anighoro Andrew,Quartieri Andrea,Amaretti Alberto,Tomás-Barberán Francisco A,Rastelli Giulio,Rossi Maddalena MicrobiologyOpen This study aimed to explore the capability of potentially probiotic bifidobacteria to hydrolyze chlorogenic acid into caffeic acid (CA), and to recognize the enzymes involved in this reaction. Bifidobacterium strains belonging to eight species occurring in the human gut were screened. The hydrolysis seemed peculiar of Bifidobacterium animalis, whereas the other species failed to release CA. Intracellular feruloyl esterase activity capable of hydrolyzing chlorogenic acid was detected only in B. animalis. In silico research among bifidobacteria esterases identified Balat_0669 as the cytosolic enzyme likely responsible of CA release in B. animalis. Comparative modeling of Balat_0669 and molecular docking studies support its role in chlorogenic acid hydrolysis. Expression, purification, and functional characterization of Balat_0669 in Escherichia coli were obtained as further validation. A possible role of B. animalis in the activation of hydroxycinnamic acids was demonstrated and new perspectives were opened in the development of new probiotics, specifically selected for the enhanced bioconversion of phytochemicals into bioactive compounds. 10.1002/mbo3.219
    Comparative biokinetics and metabolism of pure monomeric, dimeric, and polymeric flavan-3-ols: a randomized cross-over study in humans. Wiese Stefanie,Esatbeyoglu Tuba,Winterhalter Peter,Kruse Hans-Peter,Winkler Stephanie,Bub Achim,Kulling Sabine E Molecular nutrition & food research SCOPE:Flavan-3-ols are abundant polyphenols in human nutrition and are associated with beneficial health effects. The aim of this study was to comparatively investigate the metabolic fate of (-)-epicatechin, procyanidin B1, and polymeric procyanidins in a randomized cross-over study in humans. METHODS AND RESULTS:Parent compounds, conjugates, and microbial metabolites were determined in plasma, urine, and faeces by HPLC-MS and GC-MS/MS. Glucuronidated, sulfated, and methylated (-)-epicatechin and 5-(3',4'-dihydroxyphenyl)-valerolactone were the dominant metabolites in blood and urine. In addition, minor amounts of procyanidin B1 and 4-hydroxy-5-(3',4'-dihydroxyphenyl)valeric acid and their conjugated metabolites were detected. The formation of 5-(3',4'-dihydroxyphenyl)-valerolactone and 4-hydroxy-5-(3',4'-dihydroxyphenyl)valeric acid varied largely between individuals as well as with the degree of polymerization of flavan-3-ols. Monomer units were not detectable in plasma or urine after procyanidin B1 and polymeric procyanidin intake. No correlation was found between the intake of flavan-3-ols and the occurrence of phenolic acids in blood and urine or the phenolic compound profiles in faeces. CONCLUSION:In addition to conjugated metabolites derived from the absorption of monomeric flavan-3-ols, 5-(3',4'-dihydroxyphenyl)-valerolactone represents an important in vivo metabolite of (-)-epicatechin and procyanidin B1 produced by the gut microbiota. 10.1002/mnfr.201400422
    Flavonoids and Colorectal Cancer Prevention. Li Yanyan,Zhang Tao,Chen Grace Y Antioxidants (Basel, Switzerland) Colorectal cancer (CRC) is the third most common cancer, but despite advances in treatment, it remains the second most common cause of cancer-related mortality. Prevention may, therefore, be a key strategy in reducing colorectal cancer deaths. Given reports of an inverse association between fruit and vegetable consumption with colorectal cancer risk, there has been significant interest in understanding the metabolism and bioactivity of flavonoids, which are highly abundant in fruits and vegetables and account for their pigmentation. In this review, we discuss host and microbiota-mediated metabolism of flavonoids and the potential mechanisms by which flavonoids can exert protective effects against colon tumorigenesis, including regulation of signaling pathways involved in apoptosis, cellular proliferation, and inflammation and modulation of the gut microbiome. 10.3390/antiox7120187
    Cocoa procyanidins with different degrees of polymerization possess distinct activities in models of colonic inflammation. Bitzer Zachary T,Glisan Shannon L,Dorenkott Melanie R,Goodrich Katheryn M,Ye Liyun,O'Keefe Sean F,Lambert Joshua D,Neilson Andrew P The Journal of nutritional biochemistry Procyanidins are available in the diet from sources such as cocoa and grapes. Procyanidins are unique in that they are comprised of repeating monomeric units and can exist in various degrees of polymerization. The degree of polymerization plays a role in determining the biological activities of procyanidins. However, generalizations cannot be made regarding the correlation between procyanidin structure and bioactivity because the size-activity relationship appears to be system dependent. Our aim was to screen fractions of procyanidins with differing degrees of polymerization in vitro for anti-inflammatory activities in models of colonic inflammation. Monomeric, oligomeric and polymeric cocoa procyanidin fractions were screened using cell models of disrupted membrane integrity and inflammation in human colon cells. High-molecular-weight polymeric procyanidins were the most effective at preserving membrane integrity and reducing secretion of interleukin-8 in response to inflammatory stimuli. Conversely, oligomeric procyanidins appeared to be the least effective. These results suggest that polymeric cocoa procyanidins may be the most effective for preventing loss of gut barrier function and epithelial inflammation, which are critical steps in the pathogenesis of metabolic endotoxemia, inflammatory bowel disease and colon cancer. Therefore, further investigations of the potential health-protective benefits of cocoa procyanidins with distinct degrees of polymerization, particularly high-molecular-weight procyanidins, are warranted. 10.1016/j.jnutbio.2015.02.007
    Metabolic faecal fingerprinting of trans-resveratrol and quercetin following a high-fat sucrose dietary model using liquid chromatography coupled to high-resolution mass spectrometry. Etxeberria Usune,Arias Noemi,Boqué Noemí,Romo-Hualde Ana,Macarulla M Teresa,Portillo María P,Milagro Fermín I,Martínez J Alfredo Food & function Faecal non-targeted metabolomics deciphers metabolic end-products resulting from the interactions among food, host genetics, and gut microbiota. Faeces from Wistar rats fed a high-fat sucrose (HFS) diet supplemented with trans-resveratrol and quercetin (separately or combined) were analysed by liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). Metabolomics in faeces are categorised into four clusters based on the type of treatment. Tentative identification of significantly differing metabolites highlighted the presence of carbohydrate derivatives or conjugates (3-phenylpropyl glucosinolate and dTDP-D-mycaminose) in the quercetin group. The trans-resveratrol group was differentiated by compounds related to nucleotides (uridine monophosphate and 2,4-dioxotetrahydropyrimidine D-ribonucleotide). Marked associations between bacterial species (Clostridium genus) and the amount of some metabolites were identified. Moreover, trans-resveratrol and resveratrol-derived microbial metabolites (dihydroresveratrol and lunularin) were also identified. Accordingly, this study confirms the usefulness of omics-based techniques to discriminate individuals depending on the physiological effect of food constituents and represents an interesting tool to assess the impact of future personalized therapies. 10.1039/c5fo00473j
    Bioavailability of ellagic acid in human plasma after consumption of ellagitannins from pomegranate (Punica granatum L.) juice. Seeram Navindra P,Lee Rupo,Heber David Clinica chimica acta; international journal of clinical chemistry BACKGROUND:Ellagic acid (EA) and hydrolyzable ellagitannins (ETs) are dietary polyphenols found in fruits and nuts and implicated with potent antioxidant, anticancer and antiatherosclerotic biological properties. Unfortunately, there are no reports on the bioavailability studies of EA or ETs in the human body. We conducted in vivo studies whereby a human subject consumed pomegranate juice (PJ) (180 ml) containing EA (25 mg) and ETs (318 mg, as punicalagins, the major fruit ellagitannin). METHODS:A rapid plasma extraction procedure utilizing acidic precipitation of proteins, followed by HPLC-UV analyses, was employed. RESULTS:EA was detected in human plasma at a maximum concentration (31.9 ng/ml) after 1 h post-ingestion but was rapidly eliminated by 4 h. The calibration curve for quantification of EA was linear (r2 = 0.9975) over the concentration range from 1000 to 15.6 ng/ml. CONCLUSIONS:Since EA has reportedly strong affinity for proteins and poor absorption in small animals, further studies to investigate whether the presence of free EA in human plasma may be due to its release from the hydrolysis of ETs, facilitated by physiological pH and/or gut microflora action, is warranted. EA can be considered as a biomarker for future human bioavailability studies involving consumption of ETs from food sources. 10.1016/j.cccn.2004.04.029
    Anti-hyperalgesic and anti-nociceptive potentials of standardized grape seed proanthocyanidin extract against CCI-induced neuropathic pain in rats. Kaur Gurmanpreet,Bedi Onkar,Sharma Nidhika,Singh Shamsher,Deshmukh Rahul,Kumar Puneet Journal of basic and clinical physiology and pharmacology BACKGROUND:Neuropathic pain is associated with severe chronic sensory disturbances characterized by spontaneous pain, increased responsiveness to painful stimuli (hyperalgesia) and pain perceived in response to non-noxious stimuli (allodynia). Morphine is effective treatment for neuropathic pain but produces tolerance on chronic use. The present study was designed to explore the anti-nociceptive and anti-hyperalgesic effect of grape seed extract using sciatic nerve ligation-induced neuropathic pain in rats. METHODS:Chronic constructive injury (CCI) was performed under anesthesia, on one side leg exposed by making a skin incision, and chromic gut ligatures were tied loosely around the sciatic nerve at 1 mm intervals. The treatment with grape seed proanthocyanidin extract (GSPE) (100 and 200 mg/kg, p.o.) was initiated on 7th day post-surgery and continued for next 14 days. Morphine (10 mg/kg, s.c.) alone and morphine in combination with GSPE (100 mg/kg, p.o.) were administered in CCI rats for 5 days starting from 7th day. On 3rd, 7th, 14th and 21st day, behavioral parameters (mechanical allodynia and thermal hyperalgesia) were assessed. Then the animals were killed on 22nd day and biochemical parameters [reduced glutathione (GSH), lipid peroxidation (LPO), catalase, nitrite, superoxide dismutase (SOD)] were assessed. RESULTS:Ligation of the sciatic nerve significantly induced mechanical allodynia and thermal hyperalgesia and induces oxidative stress (increase in LPO and nitrite) and decline of anti-oxidant enzyme levels (catalase, SOD, GSH) in sciatic nerve homogenate. GSPE (100 and 200 mg/kg, p.o.) attenuated all the behavioural and biochemical parameters. Morphine also significantly reversed the symptoms of neuropathic pain but produced tolerance after 5 days. Further, co-treatment of GSPE (100 mg/kg) with morphine (10 mg/kg, s.c.) in CCI rats significantly reversed the morphine tolerance and enhanced its anti-hyperalgesic effect as compared to the morphine-alone-treated group. CONCLUSIONS:In the present set of experiments, GSPE showed a significant anti-hyperalgesic and anti-nociceptive effect in rats. 10.1515/jbcpp-2015-0026
    (Anti)mutagenic and immunomodulatory properties of quercetin glycosides. Valentová Kateřina,Šíma Petr,Rybková Zuzana,Křížan Jiří,Malachová Kateřina,Křen Vladimír Journal of the science of food and agriculture BACKGROUND:Quercetin-3-O-β-D-glucopyranoside (isoquercitrin) and quercetin-3-O-rutinoside (rutin) are common components of a normal human diet and are increasingly used in food supplements. Here their effect on mutagenesis and immunity is shown. RESULTS:The in vitro (anti)mutagenic potential was compared with that of quercetin using the Ames test in Salmonella typhimurium His(-) strains TA100, TA98 and TA102. Isoquercitrin only slightly increased the number of revertants, while rutin was totally non-mutagenic. On the other hand, all compounds displayed dose-dependent protective activity against H2O2 - and tert-butyl hydroperoxide-induced oxidative damage to the TA102 strain and at 75 µmol L(-1) inhibited H2O2/Fe(2+)-induced formation of the open circular and linear forms of the DNA plasmid pBSIISK(-). In mice, none of the flavonols (0.86 µmol day(-1), 34 days) induced harmful effects. In immunized animals, all compounds enhanced ex vivo B cell proliferation; quercetin stimulated lymphocyte basal proliferation and increased the number of IgM-producing lymphocytes. Rutin promoted NK cytotoxic activity, supported T cells and enhanced gut epithelium renewal. No effect on IgG-forming cells was found. CONCLUSION:Isoquercitrin displayed negligible and rutin no mutagenicity, but both showed significant antimutagenic and DNA-protective effects against oxidative damage. In vivo, they supported the readiness of the immune system for specific humoral immune response. 10.1002/jsfa.7251
    Bioaccessibility of provitamin A carotenoids from fruits: application of a standardised static in vitro digestion method. Estévez-Santiago R,Olmedilla-Alonso B,Fernández-Jalao I Food & function Provitamin A carotenoids (β-carotene, α-carotene, and β-cryptoxanthin) contribute to the dietary intake of vitamin A and are associated with decreased risk of many chronic diseases. Besides their contents in foods, their bioaccessibility is of great interest since it represents the amount that will be absorbed in the gut. The aim of this study was to adopt, for the first time, the in vitro digestion model suitable for food, proposed in a consensus paper by Minekus et al. (2014), to assess the bioaccessibility of carotenoids from the fruits that are the major contributors to the intake of β-cryptoxanthin in Spain (orange, tangerine, red pepper, peach, watermelon, and persimmon) and loquat. The highest β-cryptoxanthin content and the lowest bioaccessibility was found in mandarin and loquat (13331.6 and 929.2 μg per 100 g respectively), whereas the highest contents of β-carotene and α-carotene were recorded in red pepper (1135.3 and 90.4 μg per 100 g respectively). The bioaccessibility of β-cryptoxanthin was similar to that of β-carotene (0.02-9.8% and 1-9.1%, respectively) and was higher than that of β-carotene in red pepper, watermelon and peach. α-Carotene bioaccessibility ranged between 0% and 4.6%. We discuss the critical factors for comparing our data: the form of the food being analyzed (raw/cooked/previously frozen, in the presence or absence of oil/fat) and the protocol for bioaccessibility assessment. Different food processing techniques may increase carotenoid bioaccessibility compared to raw food. However, given the difficulties encountered when comparing the results of studies on bioaccessibility, it seems logical to propose the application of the previously mentioned standardized in vitro protocol. 10.1039/c5fo01242b
    Melatonin and hydroxytyrosol-rich wines influence the generation of DNA oxidation catabolites linked to mutagenesis after the ingestion of three types of wine by healthy volunteers. Marhuenda Javier,Medina Sonia,Martínez-Hernández Pedro,Arina Simón,Zafrilla Pilar,Mulero Juana,Genieser Hans-Gottfried,Ferreres Federico,Gil-Izquierdo Ángel Food & function The Mediterranean Diet (MD) has been proved to exert benefits with respect to the maintenance of the redox balance, and wine is a representative component. Bioactive compounds such as polyphenols, melatonin and hydroxytyrosol act as radical scavengers and regulate the oxidation status of organisms. Oxidative damage to DNA yields a large range of end products. The repair of oxidized DNA entails the removal of the useless bases and/or nucleotides as well as the release of circulating nucleotides and nucleosides. The current research aims to elucidate, for the first time, the DNA protection against oxidative stress provided by three types of red wine - relating it to the intake of bioactive compounds - after the intake of a serving of red wine/must by 18 healthy female volunteers during a short term double-blind, crossover and placebo-controlled study. The novelty of our work is to describe the importance of melatonin and hydroxytyrosol and its metabolites (from gut microflora) in comparison with polyphenols in a red wine matrix (excluding colon derivatives). The results show that the intake of red wine and must secondarily reduces oxidative stress and carcinogenesis due to their content of homovanillic acid, as measured by decreases in the plasmatic concentration of 8-hydroxy-2'deoxyguanosine, 8-hydroxyguanine, and 8-nitroguanosine. Moreover, the intake of wine appears to exert vasodilatory effects, mediated by the action of nitric oxide and increased plasma guanosine-3'-5'-cyclic monophosphate plasmatic levels, owing to the intake of wines higher in melatonin and homovanillic acid. Therefore, the results obtained in the present study revealed that polyphenols, despite being the major compounds in the red wine matrix, are not the most effective compounds protecting DNA from oxidative attack. 10.1039/c6fo01246a
    Naringin protects viscera from ischemia/reperfusion injury by regulating the nitric oxide level in a rat model. Cerkezkayabekir A,Sanal F,Bakar E,Ulucam E,Inan M Biotechnic & histochemistry : official publication of the Biological Stain Commission We investigated the effects of naringin on small intestine, liver, kidney and lung recovery after ischemia/reperfusion (I/R) injury of the gut. Rats were divided randomly into four groups of eight. Group A was the sham control; group B was ischemic for 2 h; group C was ischemic for 2 h and re-perfused for 2 h (I/R); group D was treated with 50 mg/kg naringin after ischemia, then re-perfused for 2 h. Endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) expressions were detected by immunolabeling. We also measured arginase activity, amounts of nitric oxide (NO) and total protein. iNOS was increased significantly in the small intestine, liver and kidney in group C. iNOS was decreased significantly only in small intestine and lung in group D. eNOS was increased significantly in the small intestine, liver and lung in group C. eNOS was decreased in small intestine, liver and lung in group D; however, eNOS was decreased in the kidney in group C and increased in the kidney in group D. The amount of NO was decreased significantly in all tissues in group D, but arginase activity was decreased in the small intestine and lung, increased in the kidney and remained unchanged in the liver in group D. The total protein increased in the small intestine and liver in group D, but decreased significantly in the kidney and lung in group D. Naringin had significant, salutary effects on the biochemical parameters of I/R by decreasing the NO level, equilibrating iNOS and eNOS expressions, and decreasing arginase activity. 10.1080/10520295.2017.1305499
    Aloe Metabolites Prevent LPS-Induced Sepsis and Inflammatory Response by Inhibiting Mitogen-Activated Protein Kinase Activation. Li Chia-Yang,Suzuki Katsuhiko,Hung Yung-Li,Yang Meng-Syuan,Yu Chung-Ping,Lin Shiuan-Pey,Hou Yu-Chi,Fang Shih-Hua The American journal of Chinese medicine Aloe, a polyphenolic anthranoid-containing Aloe vera leaves, is a Chinese medicine and a popular dietary supplement worldwide. In in vivo situations, polyphenolic anthranoids are extensively broken down into glucuronides and sulfate metabolites by the gut and the liver. The anti-inflammatory potential of aloe metabolites has not been examined. The aim of this study was to investigate the anti-inflammatory effects of aloe metabolites from in vitro (lipopolysaccharides (LPS)-activated RAW264.7 macrophages) and ex vivo (LPS-activated peritoneal macrophages) to in vivo (LPS-induced septic mice). The production of proinflammatory cytokines (TNF-[Formula: see text] and IL-12) and NO was determined by ELISA and Griess reagents, respectively. The expression levels of iNOS and MAPKs were analyzed by Western blot. Our results showed that aloe metabolites inhibited the expression of iNOS, decreased the production of TNF-[Formula: see text], IL-12, and NO, and suppressed the phosphorylation of MAPKs by LPS-activated RAW264.7 macrophages. In addition, aloe metabolites reduced the production of NO, TNF-[Formula: see text] and IL-12 by murine peritoneal macrophages. Furthermore, aloe administration significantly reduced the NO level and exhibited protective effects against sepsis-related death in LPS-induced septic mice. These results suggest that aloe metabolites exerted anti-inflammatory effects in vivo, and that these effects were associated with the inhibition of inflammatory mediators. Therefore, aloe could be considered an effective therapeutic agent for the treatment of sepsis. 10.1142/S0192415X17500458
    In vitro investigation of intestinal transport mechanism of silicon, supplied as orthosilicic acid-vanillin complex. Sergent Thérèse,Croizet Karine,Schneider Yves-Jacques Molecular nutrition & food research SCOPE:Silicon (Si) is one of the most abundant trace elements in the body. Although pharmacokinetics data described its absorption from the diet and its body excretion, the mechanisms involved in the uptake and transport of Si across the gut wall have not been established. METHODS AND RESULTS:Caco-2 cells were used as a well-accepted in vitro model of the human intestinal epithelium to investigate the transport, across the intestinal barrier in both the absorption and excretion directions, of Si supplied as orthosilicic acid stabilized by vanillin complex (OSA-VC). The transport of this species was found proportional to the initial concentration and to the duration of incubation, with absorption and excretion mean rates similar to those of Lucifer yellow, a marker of paracellular diffusion, and increasing in the presence of EGTA, a chelator of divalents cations including calcium. A cellular accumulation of Si, polarized from the apical side of cells, was furthermore detected. CONCLUSION:These results provide evidence that Si, ingested as a food supplement containing OSA-VC, crosses the intestinal mucosa by passive diffusion via the paracellular pathway through the intercellular tight junctions and accumulates intracellularly, probably by an uptake mechanism of facilitated diffusion. This study can help to further understand the kinetic of absorption of Si. 10.1002/mnfr.201600602
    Enhancement of oral bioavailability of rivastigmine with quercetin nanoparticles by inhibiting CYP3A4 and esterases. Palle Suresh,Neerati Prasad Pharmacological reports : PR BACKGROUND:Quercetin is a well-known flavonoid, has pharmacokinetic interaction with ester drugs due to its capability of esterase inhibition in the gut and liver. However, the interaction between quercetin nanoparticles (NQC) and rivastigmine has not been reported. Hence, the present study was performed to evaluate the effect of quercetin alone and its nanoparticles on the pharmacokinetics of rivastigmine in rats. METHODS:NQC prepared by antisolvent precipitation method. The influence of quercetin on the pharmacokinetics of rivastigmine was evaluated by following methods i.e. in vitro inhibitory effect on esterase enzyme in rat liver microsomes and in vitro assessment of CYP3A activity using erythromycin-N-demethylase (EMD) assay. To confirm these findings, an in vivo pharmacokinetic study of orally administered rivastigmine in rats with quercetin and NQC pretreatments was performed. RESULTS:The size of NQC was observed below 300nm. Quercetin significantly (p<0.05) inhibited the esterase-mediated metabolism of rivastigmine. In in vitro assessment of CYP3A activity model the erythromycin-N-demethylation (EMD) levels in quercetin treated group were significantly reduced (p<0.05). C, AUC and AUC of rivastigmine were found to be increased in quercetin and NQC pretreated groups. Further, the CL/F and Vd/F of rivastigmine were significantly decreased. CONCLUSIONS:The results revealed that enhanced bioavailability of rivastigmine might be caused by the combination of their effects due to CYP3A and esterase inhibition, Therefore, concomitant administration of NQC influences the bioavailability of rivastigmine and also has synergetic effect in the treatment of Alzheimer's disease. 10.1016/j.pharep.2016.12.002
    Increasing dietary nitrate has no effect on cancellous bone loss or fecal microbiome in ovariectomized rats. Conley Melissa N,Roberts Cooper,Sharpton Thomas J,Iwaniec Urszula T,Hord Norman G Molecular nutrition & food research SCOPE:Studies suggest diets rich in fruit and vegetables reduce bone loss, although the specific compounds responsible are unknown. Substrates for endogenous nitric oxide (NO) production, including organic nitrates and dietary nitrate, may support NO production in age-related conditions, including osteoporosis. We investigated the capability of dietary nitrate to improve NO bioavailability, reduce bone turnover and loss. METHODS AND RESULTS:Six-month-old Sprague Dawley rats [30 ovariectomized (OVX) and 10 sham-operated (sham)] were randomized into three groups: (i) vehicle (water) control, (ii) low-dose nitrate (LDN, 0.1 mmol nitrate/kg bw/day), or (iii) high-dose nitrate (HDN, 1.0 mmol nitrate/kg bw/day) for three weeks. The sham received vehicle. Serum bone turnover markers; bone mass, mineral density, and quality; histomorphometric parameters; and fecal microbiome were examined. Three weeks of LDN or HDN improved NO bioavailability in a dose-dependent manner. OVX resulted in cancellous bone loss, increased bone turnover, and fecal microbiome changes. OVX increased relative abundances of Firmicutes and decreased Bacteroideceae and Alcaligenaceae. Nitrate did not affect the skeleton or fecal microbiome. CONCLUSION:These data indicate that OVX affects the fecal microbiome and that the gut microbiome is associated with bone mass. Three weeks of nitrate supplementation does not slow bone loss or alter the fecal microbiome in OVX. 10.1002/mnfr.201600372
    Endocrine disruption by dietary phyto-oestrogens: impact on dimorphic sexual systems and behaviours. Patisaul Heather B The Proceedings of the Nutrition Society A wide range of health benefits have been ascribed to soya intake including a lowered risk of osteoporosis, heart disease, breast cancer, and menopausal symptoms. Because it is a hormonally active diet, however, soya can also be endocrine disrupting, suggesting that intake has the potential to cause adverse health effects in certain circumstances, particularly when exposure occurs during development. Consequently, the question of whether or not soya phyto-oestrogens are beneficial or harmful to human health is neither straightforward nor universally applicable to all groups. Possible benefits and risks depend on age, health status, and even the presence or absence of specific gut microflora. As global consumption increases, greater awareness and consideration of the endocrine-disrupting properties of soya by nutrition specialists and other health practitioners is needed. Consumption by infants and small children is of particular concern because their hormone-sensitive organs, including the brain and reproductive system, are still undergoing sexual differentiation and maturation. Thus, their susceptibility to the endocrine-disrupting activities of soya phyto-oestrogens may be especially high. As oestrogen receptor partial agonists with molecular and cellular properties similar to anthropogenic endocrine disruptors such as bisphenol A, the soya phyto-oestrogens provide an interesting model for how attitudes about what is 'synthetic' v. what is 'natural,' shapes understanding and perception of what it means for a compound to be endocrine disrupting and/or potentially harmful. This review describes the endocrine-disrupting properties of soya phyto-oestrogens with a focus on neuroendocrine development and behaviour. 10.1017/S0029665116000677
    5-(3',4'-Dihydroxyphenyl-γ-valerolactone), a Major Microbial Metabolite of Proanthocyanidin, Attenuates THP-1 Monocyte-Endothelial Adhesion. Lee Charles C,Kim Jong Hun,Kim Ji Seung,Oh Yun Sil,Han Seung Min,Park Jung Han Yoon,Lee Ki Won,Lee Chang Yong International journal of molecular sciences Several metabolomics of polymeric flavan-3-ols have reported that proanthocyanidins are extensively metabolized by gut microbiota. 5-(3',4'-dihydroxyphenyl)-γ-valerolactone (DHPV) has been reported to be the major microbial metabolite of proanthocyanidins. We demonstrated that DHPV has stronger prevention effect on tumor necrosis factor (TNF)-α-stimulated adhesion of THP-1 human monocytic cells to human umbilical vein endothelial cells compared to its potential precursors such as procyanidin A1, A2, B1 and B2, (+)catechin, (-)epicatechin and its microbial metabolites such as 3-(3,4-dihydroxyphenyl)propionic acid and 2-(3,4-dihydroxyphenyl)acetic acid. Mechanism study showed that DHPV prevents THP-1 monocyte-endothelial cell adhesion by downregulating TNF-α-stimulated expressions of the two biomarkers of atherosclerosis such as vascular cell adhesion molecule-1 and monocyte chemotactic protein-1, activation of nuclear factor kappa B transcription and phosphorylation of I kappa-B kinase and IκBα. We suggested that DHPV has higher potentiality in prevention of atherosclerosis among the proanthocyanidin metabolites. 10.3390/ijms18071363
    Quercetin metabolism by fecal microbiota from healthy elderly human subjects. Tamura Motoi,Hoshi Chigusa,Kobori Masuko,Takahashi Shunsuke,Tomita Junko,Nishimura Mie,Nishihira Jun PloS one Quercetin is a polyphenol found in food that has numerous health benefits. This study investigated the relationship between quercetin metabolism, gut microbiota composition, and dietary intake in elderly Japanese subjects. A food frequency questionnaire was used to assess dietary intake during the week prior to stool sample collection. Fecal suspensions from 56 subjects were anaerobically incubated with quercetin and fecal microbiota composition was analyzed by next-generation sequencing. Inter-individual variations in quercetin concentration and fecal microbiota composition at family level suggested differences in microbial quercetin metabolism. The abundance of Sutterellaceae (r = -0.292) and Oscillospiraceae (r = -0.334) was negatively correlated whereas that of Fusobacteriaceae (r = 0.361) and Enterobacteriaceae (r = 0.321) was positively correlated with quercetin concentration. Niacin (r = -0.313), vitamin B6 (r = -0.297), vitamin B12 (r = -0.266), vitamin D (r = -0.301), and ratio of animal protein to total protein (r = -0.27) were also negatively correlated with quercetin concentration. Bacterial abundance was positively or negatively related to intake of food components. This is the first report describing the relationship between fecal quercetin metabolism, human microbiota, and dietary intake in the elderly. 10.1371/journal.pone.0188271
    Metabolism of dietary procyanidins in rats. Gonthier Marie-Paule,Donovan Jennifer L,Texier Odile,Felgines Catherine,Remesy Christian,Scalbert Augustin Free radical biology & medicine Procyanidins are major dietary polyphenols made of elementary flavan-3-ol (epi)catechin units. They have antioxidant properties and may contribute to health benefits in humans, but little is known about their metabolic fate. We compared here the metabolism of procyanidin dimer B3, trimer C2, and polymer isolated from willow tree catkins to that of catechin monomer in rats. These compounds were administered in the rat diet (0.1%, w/w) for 5 d and their metabolites estimated in 24 h urine. In rats fed procyanidins, neither parent compound nor catechin derivatives could be detected in contrast to animals fed catechin monomer, which excreted large amounts of catechin and its 3'-O-methylated form (25.7 +/- 0.6%). On the other hand, 16 metabolites of microbial origin were detected and identified as phenylvaleric, phenylpropionic, phenylacetic, and benzoic acid derivatives. Their total yields significantly decreased from the catechin monomer (10.6 +/- 1.1%) to the procyanidin dimer (6.5 +/- 0.2%), trimer (0.7 +/- 0.1%), and polymer (0.5 +/- 0.1%). Therefore, the degree of procyanidin polymerization has a major impact on their fate in the body characterized by a poor absorption through the gut barrier and a limited metabolism by the intestinal microflora as compared to catechin. This will have to be considered to explain the health effects of procyanidins. The contribution of their microbial metabolites should also be further investigated.
    Brown rice and retrograded brown rice alleviate inflammatory response in dextran sulfate sodium (DSS)-induced colitis mice. Praengam Kemika,Sahasakul Yuraporn,Kupradinun Piengchai,Sakarin Siriwan,Sanitchua Wanwisa,Rungsipipat Anudep,Rattanapinyopituk Kasem,Angkasekwinai Pornpimon,Changsri Khaimuk,Mhuantong Wuttichai,Tangphatsornruang Sithichoke,Tuntipopipat Siriporn Food & function The present study was aimed to investigate the impacts of brown rice (BR) and retrograded brown rice (R-BR) consumption on colonic health and gut microbiota in dextran sulfate sodium (DSS) induced colitis mice. Thirty two female C57Bl/6Mlac mice were fed with modified AIN 93G diets by replacing cornstarch in the original composition with white rice (WR), BR and R-BR powder. The mice were divided into 4 groups and fed with the following experimental diets for 4 weeks: (1) negative control (WR: diet with WR), (2) positive control (DSS_WR: DSS and diet with WR), (3) DSS_BR: DSS and diet with BR, and (4) DSS_R-BR: DSS and diet with R-BR. BR and R-BR had a greater content of fat, dietary fiber, GABA, γ-oryzanol, γ-tocotrienol, ferulic acid and p-coumaric acid than WR (p < 0.05). No significant difference in the level of these bioactive compounds was noted between BR and R-BR. Nevertheless, R-BR had a 1.8 fold resistant starch (RS) content of BR (p < 0.05). The DSS_BR and DSS_R-BR groups showed a lower ratio of colonic weight to length, and a lower content of iNOS, COX-2, MPO, IL-6 and INF-γ in colonic homogenates than the DSS_WR group. However, the DSS treated mice fed with the R-BR diet had significantly milder histopathological inflammatory injury and lower colonic iNOS expression than the DSS_BR and DSS_WR groups. The percentage of mesenteric regulatory T cells significantly increased in the DSS_R-BR group compared to that in the DSS_WR group. The DSS treated mice fed with the R-BR diet showed a significant increase in cecal bacterial diversity and abundance of genera Prevotella, Ruminococcus, Dorea, Coprococcus and Dehalobacterium but a significant decrease in pathogenic bacteria including Bacteroides and Enterococcus compared to the DSS_WR group. Thus, the present data indicate that BR and R-BR ameliorate colonic inflammation in experimental colitis induced by DSS in mice by suppressing inflammatory mediators and modulating regulatory T cell responses as well as bacterial diversity in the cecum. 10.1039/c7fo00305f
    Metabolomics Reveals that Dietary Ferulic Acid and Quercetin Modulate Metabolic Homeostasis in Rats. Zhang Limin,Dong Manyuan,Guangyong Xu ,Yuan Tian ,Tang Huiru,Wang Yulan Journal of agricultural and food chemistry Phenolic compounds ingestion has been shown to have potential preventive and therapeutic effects against various metabolic diseases such as obesity and cancer. To provide a better understanding of these potential benefit effects, we investigated the metabolic alterations in urine and feces of rat ingested ferulic acid (FA) and quercetin (Qu) using NMR-based metabolomics approach. Our results suggested that dietary FA and/or Qu significantly decreased short chain fatty acids and elevated oligosaccharides in the feces, implying that dietary FA and Qu may modulate gut microbial community with inhibition of bacterial fermentation of dietary fibers. We also found that dietary FA and/or Qu regulated several host metabolic pathways including TCA cycle and energy metabolism, bile acid, amino acid, and nucleic acid metabolism. These biological effects suggest that FA and Qu display outstanding bioavailability and bioactivity and could be used for treatment of some metabolic syndromes, such as inflammatory bowel diseases and obesity. 10.1021/acs.jafc.8b00054
    Effect of piperine on the bioavailability and pharmacokinetics of rosmarinic acid in rat plasma using UPLC-MS/MS. Yang Jun-Hui,Mao Kun-Jun,Huang Ping,Ye Yin-Jun,Guo Hua-Shan,Cai Bao-Chang Xenobiotica; the fate of foreign compounds in biological systems 1. The purpose of the present study was to investigate the effect of piperine (PP) on the pharmacokinetics of rosmarinic acid (RA) in rat plasma and to determine whether PP could enhance the oral bioavailability of RA via inhibition of its glucuronidation. 2. The pharmacokinetic profiles of RA between oral administration of RA (50 mg/kg) alone and in combination with different oral dose PP (20, 40, 60, and 80 mg/kg) to rats were investigated via a validated UPLC/MS/MS method. 3. The AUC and C of RA were significantly increased in combination with different dose PP dose dependently, especially in the presence of 60 and 80 mg/kg PP (p < 0.01). The relative bioavailability of RA in the presence of 20, 40, 60, and 80 mg/kg PP was 1.24-, 1.32-, 2.02-, and 2.26-folds higher, respectively, compared with the control group given RA alone. Compared with RA, the pharmacokinetic modulations of RA glucuronide were even more apparent, and the glucuronidation of RA was remarkedly inhibited. 4. This study demonstrated that PP significantly improved the in vivo bioavailability of RA partly attributing to the inhibition of gut and hepatic metabolism enzymes of RA. 10.1080/00498254.2017.1292564
    Resveratrol increases phagocytosis and lipopolysaccharide-induced interleukin-1β production, but decreases surface expression of Toll-like receptor 2 in THP-1 monocytes. Zunino Susan J,Hwang Daniel H,Huang Shurong,Storms David H Cytokine THP-1 monocytes were used to evaluate the effects of physiological levels of resveratrol aglycone, resveratrol-3-O-glucuronide, resveratrol-4'-O-glucuronide, and resveratrol-3-O-sulfate on phagocytosis, IL-1β, IL-1α, and IL-18 production, viability, and TLR2 and TLR4 expression. THP-1 cells were treated with 1, 5, 10, and 15μM resveratrol or metabolites. Resveratrol-3-O-glucuronide, resveratrol-4'-O-glucuronide, and resveratrol-3-O-sulfate had no effect on the functional parameters tested. Resveratrol aglycone increased phagocytosis at concentrations of 5, 10, and 15μM and LPS-induced IL-1β production at concentrations of 10 and 15μM. Expression of TLR4 increased slightly after resveratrol treatment, but surface expression of TLR2 was reduced as resveratrol concentrations increased. Our data suggest that resveratrol may be effective in modulating monocyte function in an environment where there is direct exposure to the aglycone, such as at the gut epithelium. 10.1016/j.cyto.2017.07.023
    Curcumin and dietary polyphenol research: beyond drug discovery. Jin Tian-Ru Acta pharmacologica Sinica Numerous natural products available over the counter are commonly consumed by healthy, sub-healthy or ill people for the treatment and prevention of various chronic diseases. Among them, a few dietary polyphenols, including the curry compound curcumin, have been attracting the most attention from biomedical researchers and drug developers. Unlike many so-called "good drug candidates", curcumin and several other dietary polyphenols do not have a single known therapeutic target or defined receptor. In addition, the bioavailability of these polyphenols is usually very low due to their poor absorption in the gut. These recently debated features have created enormous difficulties for drug developers. In this review, I do not discuss how to develop curcumin, other dietary polyphenols or their derivatives into pharmaceutical agents. Instead, I comment on how curcumin and dietary polyphenol research has enriched our knowledge of insulin signaling, including the presentation of my perspectives on how these studies will add to our understanding of the famous hepatic insulin function paradox. 10.1038/aps.2017.179
    Repurposing ebselen for decolonization of vancomycin-resistant enterococci (VRE). AbdelKhalek Ahmed,Abutaleb Nader S,Mohammad Haroon,Seleem Mohamed N PloS one Enterococci represent one of the microbial world's most challenging enigmas. Colonization of the gastrointestinal tract (GIT) of high-risk/immunocompromised patients by enterococci exhibiting resistance to vancomycin (VRE) can lead to life-threating infections, including bloodstream infections and endocarditis. Decolonization of VRE from the GIT of high-risk patients represents an alternative method to suppress the risk of the infection. It could be considered as a preventative measure to protect against VRE infections in high-risk individuals. Though multiple agents (ramoplanin and bacitracin) have been evaluated clinically, no drugs are currently approved for use in VRE decolonization of the GIT. The present study evaluates ebselen, a clinical molecule, for use as a decolonizing agent against VRE. When evaluated against a broad array of enterococcal isolates in vitro, ebselen was found to be as potent as linezolid (minimum inhibitory concentration against 90% of clinical isolates tested was 2 μg/ml). Though VRE has a remarkable ability to develop resistance to antibacterial agents, no resistance to ebselen emerged after a clinical isolate of vancomycin-resistant E. faecium was serially-passaged with ebselen for 14 days. Against VRE biofilm, a virulence factor that enables the bacteria to colonize the gut, ebselen demonstrated the ability to both inhibit biofilm formation and disrupt mature biofilm. Furthermore, in a murine VRE colonization reduction model, ebselen proved as effective as ramoplanin in reducing the bacterial shedding and burden of VRE present in the fecal content (by > 99.99%), cecum, and ileum of mice. Based on the promising results obtained, ebselen warrants further investigation as a novel decolonizing agent to quell VRE infection. 10.1371/journal.pone.0199710
    Therapeutic effect of the natural compounds baicalein and baicalin on autoimmune diseases. Xu Jian,Liu Jinlong,Yue Guolin,Sun Mingqiang,Li Jinliang,Xiu Xia,Gao Zhenzhong Molecular medicine reports A series of natural compounds have been implicated to be useful in regulating the pathogenesis of various autoimmune diseases. The present study demonstrated that the Scutellariae radix compounds baicalein and baicalin may serve as drugs for the treatment of autoimmune diseases, including rheumatoid arthritis and inflammatory bowel disease. Following the administration of baicalein and baicalin in vivo, T cell‑mediated autoimmune diseases in the mouse model were profoundly ameliorated: In the collagen‑induced arthritis model (CIA), the severity of the disease was reduced by baicalein and, consistently, baicalein was demonstrated to suppress T cell proliferation in CIA mice. In the dextran sodium sulfate (DSS)‑induced colitis model, the disease was attenuated by baicalin, and baicalin promoted colon epithelial cell (CEC) proliferation in vitro. The present study further revealed that the mRNA expression of signal transducer and activator of transcription (STAT)3 and STAT4 in the tyrosine‑protein kinase JAK‑STAT signaling pathway in T cells was downregulated by baicalein, contributing to its regulation of T cell proliferation. However, in the DSS model, the STAT4 transcription in CECs, which are the target cells of activated T cells in the gut, was downregulated by baicalin, suggesting that baicalein and baicalin mediated similar STAT expression in different cell types in autoimmune diseases. In conclusion, the similarly structured compounds baicalein and baicalin selectively exhibited therapeutic effects on autoimmune diseases by regulating cell proliferation and STAT gene expression, albeit in different cell types. 10.3892/mmr.2018.9054
    Melatonin in Prevention of the Sequence from Reflux Esophagitis to Barrett's Esophagus and Esophageal Adenocarcinoma: Experimental and Clinical Perspectives. Majka Jolanta,Wierdak Mateusz,Brzozowska Iwona,Magierowski Marcin,Szlachcic Aleksandra,Wojcik Dagmara,Kwiecien Slawomir,Magierowska Katarzyna,Zagajewski Jacek,Brzozowski Tomasz International journal of molecular sciences Melatonin is a tryptophan-derived molecule with pleiotropic activities which is produced in all living organisms. This "sleep" hormone is a free radical scavenger, which activates several anti-oxidative enzymes and mechanisms. Melatonin, a highly lipophilic hormone, can reach body target cells rapidly, acting as the circadian signal to alter numerous physiological functions in the body. This indoleamine can protect the organs against a variety of damaging agents via multiple signaling. This review focused on the role played by melatonin in the mechanism of esophagoprotection, starting with its short-term protection against acute reflux esophagitis and then investigating the long-term prevention of chronic inflammation that leads to gastroesophageal reflux disease (GERD) and Barrett's esophagus. Since both of these condition are also identified as major risk factors for esophageal carcinoma, we provide some experimental and clinical evidence that supplementation therapy with melatonin could be useful in esophageal injury by protecting various animal models and patients with GERD from erosions, Barrett's esophagus and neoplasia. The physiological aspects of the synthesis and release of this indoleamine in the gut, including its release into portal circulation and liver uptake is examined. The beneficial influence of melatonin in preventing esophageal injury from acid-pepsin and acid-pepsin-bile exposure in animals as well as the usefulness of melatonin and its precursor, L-tryptophan in prophylactic and supplementary therapy against esophageal disorders in humans, are also discussed. 10.3390/ijms19072033
    Comparative analysis of fecal phenolic content between normal and obese rats after oral administration of tea polyphenols. Chen Bo,Zhou Jie,Meng Qilu,Zhang Yang,Zhang Shihua,Zhang Liang Food & function Tea polyphenols (TP) have many health benefits, but most are metabolized into low molecular-weight phenolic acids after oral administration. In the present study, the absorption, metabolism, and excretion of catechins in rats fed a normal chow diet and in obese rats fed a high-fat and high-sugar (HFHS) diet were compared. After a ten-day oral administration of TP (500 mg per kg bw), the plasma levels of (-)-epigallocatechin gallate (EGCG) and (-)-gallocatechin gallate (GCG) in obese rats were significantly lower than those in the normal group. In obese rats, the fecal levels of EGCG, (-)-epicatechin gallate (ECG) and GCG were significantly enhanced. Ten phenolic metabolites of TP were quantitatively analyzed, and the results showed that 4-hydroxyphenylacetic acid was the primary metabolite in feces and plasma. The plasma and fecal concentrations of 4-hydroxyphenylacetic acid in the obese group were significantly lower than those in normal rats, but the levels of 4-hydroxyphenylpropionic acid in plasma and feces were increased. The content of other phenolic acids was also dramatically changed. These results suggested that a HFHS diet might influence the excretion of tea catechins, leading to insufficient metabolism of catechins by the gut microflora. 10.1039/c8fo00609a
    Faecal microbial metabolism of olive oil phenolic compounds: in vitro and in vivo approaches. Mosele Juana I,Martín-Peláez Sandra,Macià Alba,Farràs Marta,Valls Rosa-Maria,Catalán Úrsula,Motilva María-José Molecular nutrition & food research SCOPE:In the present study, the individual colonic metabolism of the main components of the virgin olive oil phenolic fraction was evaluated by an in vitro model using human faecal microbiota. To assess differences in metabolism related to the molecular structure, four phenolic standards were selected, tyrosol, hydroxytyrosol, hydroxytyrosol acetate and oleuropein. After studying the in vitro colonic metabolism pathways of the individual phenols, the presence of their colonic metabolites was investigated in human faecal samples obtained before and after the sustained intake (3 weeks) of a daily dose of 25 mL of a phenol-enriched olive oil. METHODS AND RESULTS:The in vitro colon fermentation of the four individual phenolic compounds revealed (i) an increase in phenolic acids, (ii) the stability of hydroxytyrosol and tyrosol and (iii) the high degradation of hydroxytyrosol acetate and oleuropein. Additionally, a moderate intake of a phenol-rich olive oil raised the concentration in human faeces of free hydroxytyrosol and phenylacetic and phenylpropionic acids. CONCLUSION:The products of colonic catabolism of olive oil phenolic compounds could be good candidates for novel preventive strategies and open a promising line of research into the preventive action of olive oil phenols in colon and other bowel diseases. 10.1002/mnfr.201400124
    Flavan-3-ol/Procyanidin Metabolomics in Rat Urine Using HPLC-Quadrupole TOF/MS. Masumoto Saeko,Aoki Shiori,Miura Tomisato,Shoji Toshihiko Molecular nutrition & food research SCOPE:Several studies have demonstrated that flavan-3-ol/procyanidins are associated with biological functions in the prevention of various chronic diseases, including obesity and diabetes. Knowledge of their mechanisms, including bioavailability, has significantly progressed in the last decade. However, the differences of the metabolic signatures among flavan-3-ol/procyanidins remain ambiguous. METHODS AND RESULTS:The metabolites in urine over time after acute administration of three typical flavan-3-ol/procyanidins ((epi)catechin [EPC], epigallocatechin gallate [EGCG], and procyanidin dimer [PC]) in view of the chemical structure were analyzed by HPLC-quadrupole TOF/MS. Several bile acid and amino acid derivatives including tryptophan and tyrosine, as well as flavan-3-ol/procyanidin conjugates and phenolic acid degradation products generated by the gut microbiota were observed in rat urine. CONCLUSION:Multivariate statistical analyses suggest that the exogenous and endogenous metabolites of flavan-3-ol/procyanidins greatly differ, although the chemical structures of three typical flavan-3-ol/procyanidins-EPC, EGCG, and PC-are similar. Thus, metabolomic differences likely affect their biological functions and health benefits. 10.1002/mnfr.201700867
    Baicalin, Baicalein, and Lactobacillus Rhamnosus JB3 Alleviated Helicobacter pylori Infections in Vitro and in Vivo. Chen Mu-En,Su Chiu-Hsian,Yang Jai-Sing,Lu Chi-Cheng,Hou Yu-Chi,Wu Jin-Bin,Hsu Yuan-Man Journal of food science Helicobacter pylori infection is associated with chronic gastritis, peptic ulcers, and gastric cancer. The flavonoid compounds baicalin and baicalein found in many medicinal plants exhibit an anti-inflammatory effect. The administration of Lactobacillus strains reducing the risk of H. pylori infection is well accepted. In this study, the therapeutic effects against H. pylori infection of baicalin, baicalein, and L. rhamnosus JB3 (LR-JB3), isolated from a dairy product, were investigated. Compared to baicalin, baicalein exhibited stronger anti-H. pylori activity and cytotoxicity on human gastric cancer epithelial AGS cells. Baicalin and baicalein both suppressed the vacA gene expression of H. pylori and interfered with the adhesion and invasion ability of H. pylori to AGS cells, as well as decreased H. pylori-induced interleukin (IL)-8 expression. In the mice infection model, high dosages of baicalin and baicalein inhibited H. pylori growth in the mice stomachs. Serum IL-1β levels and H. pylori-specific serum IgM and IgA levels in mice treated with baicalin and baicalein were decreased. Moreover, a synergistic therapeutic effect of baicalein and LR-JB3 on eradicating H. pylori infections was observed. Thus, administrating baicalin, baicalein, or LR-JB3 for an H. pylori infection could offer similar therapeutic effects to administering antibiotics while not disturbing the balance of gut microbiota. This study revealed the effects of baicalin, baicalein, and LR-JB3 on attenuating the virulence of H. pylori. The synergistic effect with baicalein and LR-JB3 provides the experimental rationale for testing the reliability, safety, and efficacy of this approach in higher animals and perhaps ultimately in humans to eradicate H. pylori infections. PRACTICAL APPLICATION: Baicalin and baicalein exert health promotion and avoidance of H. pylori infections by interfering with H. pylori growth and virulence. Lactobacillus rhamnosus JB3 was used to reduce the gastric inflammation caused by H. pylori infection. 10.1111/1750-3841.14372
    Aging, melatonin biosynthesis, and circadian clockworks in the gastrointestinal system of the laboratory mouse. Paulose Jiffin K,Cassone Charles V,Cassone Vincent M Physiological genomics The gastrointestinal (GI) system is vital in its capacities for nutrient and water uptake, immune function, metabolism and detoxification, and stem-cell derived regeneration. Of significance to human health are a myriad of GI disorders associated with aging that integrate with the circadian clock. Here we present data from three groups of mice: young (3 mo old), middle aged (12 mo old), and old aged (24 mo old). Small intestine and colon samples taken every 4 h under light-dark (LD) conditions were assayed for gene expression related to molecular circadian rhythmicity, transcription, cell signaling, and immune function. Transcripts related to melatonin biosynthesis and signaling, as well as melatonin content from stool, were also included, as GI melatonin and aging have been associated in contexts outside of the circadian clock. With respect to circadian genes, the data here are congruent with data from other peripheral tissues: age does not affect the rhythmic expression of core clock genes in the gut. The same can be said for several clock-controlled transcripts. In contrast, diurnal patterns in the expression of nitric oxide synthase 1 and of immune factors irak4 and interleukin-8 were observed in the colon of young mice that were lost in middle-aged and aged animals. Furthermore, the diurnal pattern of melatonin synthesis genes was altered by age, and stool melatonin levels showed significant decline between young mice and aged cohorts. These data expand the evidence for the persistence of the circadian clock throughout the aging process and highlight its importance to health. 10.1152/physiolgenomics.00095.2018
    Review of the factors affecting bioavailability of soy isoflavones in humans. Nielsen Inge Lise Finné,Williamson Gary Nutrition and cancer Soy isoflavones have anticarcinogenic, antioxidant, and antiatherosclerotic activities. They also interact with the estrogen receptor, which makes them weak or moderate phytoestrogens. Because of their bioactivity, isoflavone bioavailability has been extensively studied in humans. This review summarizes data from intervention studies in humans, focusing on the factors that affect bioavailability. Summarizing data from 16 studies shows that the maximum concentration in plasma normalized to a constant dose of genistin is approximately 1.6 times that of genistein, and daidzin is approximately 1.8-fold higher than daidzein, whereas the half-life is not significantly different for aglycone and glucoside. There is a wide variation in the reported percentage urinary excretion that is not dependent on dose. Bioavailability is increased by a rapid gut transit time and by low fecal digestion rates and is decreased by a fiber-rich diet. There is no difference in bioavailability between pre- and postmenopausal women. The daily ingestion of soymilk for 1 wk does not affect bioavailability, but daily ingestion for a month increases excretion of equol in women. The factors or habitual diet characteristics that influence equol production are not clear, but equol production is limited with an immature flora. There is no consensus on which source of isoflavones results in the highest isoflavone bioavailability, and published studies present different results, although bioavailability is affected by whether the dose is given as food or drink. In conclusion, it is important to consider the factors affecting bioavailability of isoflavones when designing intervention studies. 10.1080/01635580701267677
    High intake of orange juice and cola differently affects metabolic risk in healthy subjects. Büsing Franziska,Hägele Franziska A,Nas Alessa,Döbert Laura-Verena,Fricker Alena,Dörner Elisabeth,Podlesny Daniel,Aschoff Julian,Pöhnl Tobias,Schweiggert Ralf,Fricke W Florian,Carle Reinhold,Bosy-Westphal Anja Clinical nutrition (Edinburgh, Scotland) BACKGROUND:Higher consumption of sugar-containing beverages has been associated with an elevated risk of type 2 diabetes and gout. Whether this equally applies to cola with an unhealthy image and orange juice (OJ) having a healthy image remains unknown. METHODS:In order to investigate whether OJ and cola differently affect metabolic risk 26 healthy adults (24.7 ± 3.2 y; BMI 23.2 ± 3.3 kg/m) participated in a 2 × 2-wk intervention and consumed either OJ or caffeine-free cola (20% Ereq as sugar from beverages) in-between 3 meals/d at ad libitum energy intake. Glycemic control, uric acid metabolism and gut microbiota were assessed as outcome parameters. RESULTS:Fecal microbiota, body weight, basal and OGTT-derived insulin sensitivity remained unchanged in both intervention periods. Levels of uric acid were normal at baseline and did not change with 2-wk cola consumption (-0.03 ± 0.67 mg/dL; p > 0.05), whereas they decreased with OJ intervention (-0.43 ± 0.56 mg/dL; p < 0.01) due to increased uric acid excretion (+130.2 ± 130.0 mg/d; p < 0.001). Compared to OJ, consumption of cola led to a higher daylong glycemia (ΔiAUC: 36.9 ± 83.2; p < 0.05), an increase in glucose variability (ΔMAGE-Index: 0.29 ± 0.44; p < 0.05), and a lower 24 h-insulin secretion (ΔC-peptide excretion: -31.76 ± 38.61 μg/d; p < 0.001), which may be explained by a decrease in serum potassium levels (-0.11 ± 0.24 mmol/L; p < 0.05). CONCLUSION:Despite its sugar content, regular consumption of large amounts of OJ do not increase the risk of gout but may even contribute to lower uric acid levels. The etiology of impaired insulin secretion with cola consumption needs to be further investigated. 10.1016/j.clnu.2018.02.028
    In vitro colonic catabolism of orange juice (poly)phenols. Pereira-Caro Gema,Borges Gina,Ky Isabelle,Ribas Aleix,Calani Luca,Del Rio Daniele,Clifford Michael N,Roberts Susan A,Crozier Alan Molecular nutrition & food research SCOPE:The role of colonic microbiota in the breakdown of hesperetin, naringenin, and ferulic acid, compounds found as glycosides in orange juice, was investigated using an in vitro fermentation model. METHODS AND RESULTS:Test compounds were incubated with human fecal slurries cultured under anaerobic conditions, and the production of phenolic acid catabolites were monitored by GC-MS and HPLC-MS(2) . Hesperetin was converted to 3-(3'-hydroxy-4'-methoxyphenyl)propionic acid, 3-(3',4'-dihydroxyphenyl)propionic acid, and 3-(3'-hydroxyphenyl)propionic acid while 3-(phenyl)propionic acid was the major end product derived from naringenin. The data obtained are compared to our previously published data on urinary excretion of phenolic and aromatic acids after acute orange juice consumption (Pereira-Caro et al. Am. J. Clin. Nutr. 2014, 100, 1385-1391). Catabolism pathways are proposed for events occurring in the colon and those taking place postabsorption into the circulatory system with particular reference to the excretion of 3-(3'-hydroxy-4'-methoxyphenyl)hydracrylic acid, which is not formed in fecal incubations. Ferulic acid was also degraded by the colonic microflora being converted principally to 3-(3'-methoxy-4'-hydroxyphenyl)propionic acid, a phenolic acid that appears in urine after orange juice consumption. CONCLUSION:The study provides novel information on the potential involvement of the colonic microbiota in the overall bioavailability of orange juice (poly)phenols through the production of phenylpropionic acids and subsequent hepatic conversions that lead to hippuric acid and its hydroxylated analogues. 10.1002/mnfr.201400779
    Turmeric Extract: Potential Use as a Prebiotic and Anti-Inflammatory Compound? Ghiamati Yazdi Fariba,Soleimanian-Zad Sabihe,van den Worm Edwin,Folkerts Gert Plant foods for human nutrition (Dordrecht, Netherlands) Prebiotics are regarded as the non-digestible food constituents that are selectively consumed by health-promoting bacteria (probiotics). In fact, a number of active metabolites is released due to intensive interaction between prebiotics and probiotics in the gut which exert local and systemic beneficial effects including regulation of intestinal disorders and modulation of host immunity. Turmeric is one of the most important medicinal herbaceous that is derived from Curcuma longa rhizome. Curcumin is a well-recognized component of turmeric which contributes to the prevention of multiple inflammatory diseases. Despite curcumin as a well-known compound, few researches have focused on the turmeric extract (TE) and its potential as prebiotic and anti-inflammatory compound. The aim of this study was to evaluate the prebiotic potential and some functional-structural properties of TE. The Fourier-transform-infrared spectroscopy (FTIR) spectrum of TE showed identical peaks that belonged to β configuration in pyranose and glycosidic bonds. High performance liquid chromatography (HPLC) analysis revealed the presence of potent phenolic and flavonoid anti-oxidants and curcuminoids, and some functional monosaccharides. TE demonstrated excellent resistance to artificial human gastric and intestine juice compared to the standard prebiotic (inulin) (p ≤ 0.05). Interestingly, our time course experiment showed that TE not only is digested by probiotics including Lactobacillus rhamnosus GG (LGG) and Bifidobacterium animalis BB12, but also supports the growth of these bacteria even after 72 h (p ≤ 0.05). To our knowledge, this is the first report evaluating prebiotic potential of TE and exploring its suppressive effects on LPS induced IL-8 production in HT29-19A cell line. 10.1007/s11130-019-00733-x
    Stability and Fermentability of Green Tea Flavonols in In-Vitro-Simulated Gastrointestinal Digestion and Human Fecal Fermentation. Rha Chan-Su,Seong Hyunbin,Jung Young Sung,Jang Davin,Kwak Jun-Gu,Kim Dae-Ok,Han Nam Soo International journal of molecular sciences Flavonols, the second most abundant flavonoids in green tea, exist mainly in the form of glycosides. Flavonols are known to have a variety of beneficial health effects; however, limited information is available on their fate in the digestive system. We investigated the digestive stability of flavonol aglycones and glycosides from green tea under simulated digestion and anaerobic human fecal fermentation. Green tea fractions rich in flavonol glycosides and aglycones, termed flavonol-glycoside-rich fraction (FLG) and flavonol-aglycone-rich fraction (FLA) hereafter, were obtained after treatment with cellulase and tannase, respectively. Kaempferol and its glycosides were found to be more stable in simulated gastric and intestinal fluids than the derivatives of quercetin and myricetin. Anaerobic human fecal fermentation with FLG and FLA increased the populations of spp. and spp. and generated various organic acids, such as acetate, butyrate, propionate, and lactate, among which butyrate was produced in the highest amount. Our findings indicate that some stable polyphenols have higher bioaccessibilities in the gastrointestinal tract and that their health-modulating effects result from their interactions with microbes in the gut. 10.3390/ijms20235890
    The effects of dietary oxidized konjac glucomannan and its acidolysis products on the immune response, expression of immune related genes and disease resistance of Schizothorax prenanti. Zheng Qiaoran,Wu Yinglong,Xu Huailiang,Yao Yongfang,Xia Xiaojie,Feng Jiao,Tang Haolan,Wang Hongjie Fish & shellfish immunology In the present study, KGM was degraded by H2O2 and HCl to obtain two products with different molecular weights: oxidized konjac glucomannan (OKGM, 4.7 × 10(5) Da) and low-molecular-weight oxidized konjac glucomannan (L-OKGM, 9.2 × 10(3) Da). The effects of the two OKGM products on IL-1β, TNF-α, and TLR22 gene expression, and immune parameters and the resistance to Aeromonas hydrophila of Schizothorax prenanti were determined. The results showed that the lysozyme activity was significantly enhanced by the L-OKGM diets. The SOD activity was significantly increased by both OKGM and L-OKGM diets. The MDA level of fish fed the OKGM and L-OKGM diets was significantly lower than the control group. IL-1β mRNA level in the spleen significantly increased in all L-OKGM fed groups. The 8.0 g kg(-1) L-OKGM diet also significantly up-regulated IL-1β gene expression in the head kidney. In the gut, IL-1β mRNA levels were significantly higher in fish fed with the 8.0 g kg(-1) OKGM and 16.0 g kg(-1) L-OKGM diets. The TNF-α mRNA level of L-OKGM group significantly increased in the spleen, head kidney and gut. High dosing of OKGM significantly up-regulated TNF-α transcription in the head kidney, while only the 8.0 g kg(-1) OKGM group showed significantly higher TNF-α mRNA expression in the mesonephros. Fish fed the L-OKGM diets showed significantly higher expression of TLR22 in the spleen, head kidney and mesonephros. After the injection of A. hydrophila, the 8.0 g kg(-1) L-OKGM group showed a significantly higher survival rate than did the control group. Present study suggests that OKGM and L-OKGM can up-regulate immune-related gene expression and enhance disease resistance in S. prenanti, and L-OKGM exhibits higher immunomodulatory activity. 10.1016/j.fsi.2015.05.016
    A comparison of the absorption and metabolism of the major quercetin in brassica, quercetin-3-O-sophoroside, to that of quercetin aglycone, in rats. Wang Yanling,Berhow Mark A,Black Molly,Jeffery Elizabeth H Food chemistry Although flavonoid sophorosides are common glycosides in brassica vegetables, red raspberries and other food plants, there is a lack of studies of absorption and metabolism of any sophoroside. The aim of this study was to characterize the absorption, phase II metabolism and microbial catabolism of quercetin-3-O-sophoroside, compared to that of quercetin aglycone. Quercetin-3-O-sophoroside was purified from Apocynum venetum and characterized by MS, H and C NMR. Using an in situ rat gut model, we found intact, methylated, sulfated and both methylated and sulfated quercetin sophoroside in the plasma following jejunal introduction of the sophoroside; we found derivatives of benzoic acid, phenylacetic acid, and phenyl propionic acid in the cecal contents following cecal introduction. This novel finding, that quercetin sophoroside was absorbed intact, without deglycosylation, points to a possible role for the terminal sugar and/or the type of linkage among glycosidic moieties in the mechanism of absorption of flavonoid glycosides. 10.1016/j.foodchem.2019.125880
    FA-97, a New Synthetic Caffeic Acid Phenethyl Ester Derivative, Protects against Oxidative Stress-Mediated Neuronal Cell Apoptosis and Scopolamine-Induced Cognitive Impairment by Activating Nrf2/HO-1 Signaling. Wan Ting,Wang Zihao,Luo Yi,Zhang Yifan,He Wei,Mei Yu,Xue Jincheng,Li Min,Pan Huafeng,Li Weirong,Wang Qi,Huang Yujie Oxidative medicine and cellular longevity Alzheimer's disease (AD) is an age-related neurodegenerative disorder with cognitive deficits, which is becoming markedly more common in the world. Currently, the exact cause of AD is still unclear, and no curative therapy is available for preventing or mitigating the disease progression. Caffeic acid phenethyl ester (CAPE), a natural phenolic compound derived from honeybee hive propolis, has been reported as a potential therapeutic agent against AD, while its application is limited due to the low water solubility and poor bioavailability. Here, caffeic acid phenethyl ester 4--glucoside (FA-97) is synthesized. We validate that FA-97 attenuates HO-induced apoptosis in SH-SY5Y and PC12 cells and suppresses HO-induced oxidative stress by inhibiting the ROS level, malondialdehyde (MDA) level, and protein carbonylation level, as well as induces cellular glutathione (GSH) and superoxide dismutase (SOD). Mechanistically, FA-97 promotes the nuclear translocation and transcriptional activity of Nrf2 associated with the upregulated expression of HO-1 and NQO-1. The prime importance of Nrf2 activation in the neuroprotective and antioxidant effects of FA-97 is verified by Nrf2 siRNA transfection. In addition, FA-97 prevents scopolamine- (SCOP-) induced learning and memory impairments via reducing neuronal apoptosis and protecting against cholinergic system dysfunction in the hippocampus and cortex. Moreover, the increased MDA level and low total antioxidant capacity in SCOP-treated mouse brains are reversed by FA-97, with the increased expression of HO-1, NQO-1, and nuclear Nrf2. In conclusion, FA-97 protects against oxidative stress-mediated neuronal cell apoptosis and SCOP-induced cognitive impairment by activating Nrf2/HO-1 signaling, which might be developed as a therapeutic drug for AD. 10.1155/2019/8239642
    Multitargeted therapy of cancer by ellagitannins. Heber David Cancer letters Ellagitannins are bioactive polyphenols that have antioxidant and anti-inflammatory bioactivities. Pomegranate juice has the highest concentration of ellagitannins of any commonly consumed juice and contains the unique ellagitannin, punicalagin. Punicalagin is the largest molecular weight polyphenol known. Ellagitannins are not absorbed intact into the blood stream but are hydrolyzed to ellagic acid. They are also metabolized by gut flora into urolithins which are conjugated in the liver and excreted in the urine. These urolithins are also bioactive and inhibit prostate cancer cell growth. Inhibition of Nuclear Factor Kappa-B activation has been shown in prostate cancer cells and in human prostate cancer xenografts in mice. In clinical studies, pomegranate juice administration led to a decrease in the rate of rise of Prostate Specific Antigen after primary treatment with surgery or radiation. Continued translational research on the chemopreventive potential of pomegranate ellagitannins is ongoing. 10.1016/j.canlet.2008.03.043
    FA-97, a New Synthetic Caffeic Acid Phenethyl Ester Derivative, Ameliorates DSS-Induced Colitis Against Oxidative Stress by Activating Nrf2/HO-1 Pathway. Mei Yu,Wang Zihao,Zhang Yifan,Wan Ting,Xue Jincheng,He Wei,Luo Yi,Xu Yijun,Bai Xue,Wang Qi,Huang Yujie Frontiers in immunology Inflammatory bowel disease (IBD) is a chronic idiopathic inflammatory disorder of gastro-intestinal tract, lacking effective drug targets and medications. Caffeic acid phenethyl ester (CAPE), a phenolic constituent derived from propolis, has been reported to be a potential therapeutic agent for IBD with low water solubility and poor bioavailability. In this study, we synthesized a new CAPE derivative (FA-97) and aimed to investigate the effect of FA-97 on DSS-induced colitis. Here, we found that FA-97 attenuated body weight loss, colon length shortening and colonic pathological damage in colitis mice, as well as inhibited inflammatory cell infiltration and expression of pro-inflammatory cytokines in colons. In addition, FA-97 reduced ROS production and MDA generation, while total antioxidant capacity both in DSS-induced colitis mice and LPS-stimulated primary BMDMs and RAW 264.7 cells were enhanced. Mechanically, FA-97 activated Nrf2 followed by increased HO-1 and NQO-1 and down-regulated nuclear levels of p65 and c-Jun, to suppress DSS-induced colonic oxidative stress. Moreover, FA-97 decreased pro-inflammatory cytokine expression and increased the antioxidant defenses in RAW 264.7 via Nrf2 activation. In general, this study reveals that FA-97 activates Nrf2/HO-1 pathway to eventually alleviate DSS-induced colitis against oxidative stress, which has potential activity and may serve as a candidate for IBD therapy. 10.3389/fimmu.2019.02969
    Chronic supplementation with dietary proanthocyanidins protects from diet-induced intestinal alterations in obese rats. Gil-Cardoso Katherine,Ginés Iris,Pinent Montserrat,Ardévol Anna,Arola Lluís,Blay Mayte,Terra Ximena Molecular nutrition & food research SCOPE:Increased attention has been paid to the link between altered intestinal function and elevated incidence of metabolic disorders, such as in obesity. This study investigated in obese rats the role of grape seed proanthocyanidin extract (GSPE) chronic treatment, taken in a low, moderate, or high dose, on obesity-associated intestinal alterations in response to a cafeteria diet (CAF). METHODS AND RESULTS:To evaluate the degree of intestinal inflammation, reactive oxygen species (ROS) production and myeloperoxidase (MPO) activity were measured as well as the expression of inflammatory-related genes. The barrier integrity was assessed by quantifying the gene expression of tight-junction components and measuring the plasma LPS. GSPE decreased the ROS levels and MPO activity, without substantial differences among the doses. The supplementation with moderate and high GSPE doses significantly decreased iNOS expression compared to the CAF group, and the same pattern was observed in the low-dose animals with respect to IL-1β expression. Moreover, the results show that GSPE significantly increases zonulin-1 expression with respect to the CAF animals. CONCLUSION:This study provides evidence for the ameliorative effect of a proanthocyanidin extract on high-fat/high-carbohydrate diet-induced intestinal alterations, specifically reducing intestinal inflammation and oxidative stress and suggesting a protection against a barrier defect. 10.1002/mnfr.201601039
    Ingestion of black chokeberry fruit extract leads to intestinal and systemic changes in a rat model of prediabetes and hyperlipidemia. Jurgoński Adam,Juśkiewicz Jerzy,Zduńczyk Zenon Plant foods for human nutrition (Dordrecht, Netherlands) This report presents a complex analysis of changes proceeding in the gut, blood and internal organs of rats with induced oxidative stress, glucose intolerance and hyperlipidemia after dietary supplementation with an extract from black chokeberry (Aronia melanocarpa) fruit, that is a condensed source of polyphenols (714 mg/g), especially anthocyanin glycosides (56.6%). The disturbances mimicking those observed in metabolic syndrome were induced by a high-fructose diet and simultaneous single injection of streptozotocin (20 mg/kg). Dietary supplementation with the chokeberry fruit extract (0.2%) decreased activity of maltase and sucrase as well as increased activity of lactase in the mucosa of the small intestine. Its ingestion led also to the improvement of antioxidant status, especially, the concentration of a lipid peroxidation indicator (TBARS) in organ tissues (liver, kidney and lung) was normalized; some cholesterol-lowering and distinct hypoglycemic actions were also observed. The mechanism of glucose reduction is likely to be multifactorial, and we suggest the factors related with the decreased activity of mucosal disaccharidases important for further investigation. In conclusion, chokeberry fruit derivatives may act as a promising supplementary therapeutic option in the prevention and treatment of disorders occurring in metabolic syndrome, as well as their complications. 10.1007/s11130-008-0087-7
    Spent coffee grounds, an innovative source of colonic fermentable compounds, inhibit inflammatory mediators in vitro. López-Barrera Dunia Maria,Vázquez-Sánchez Kenia,Loarca-Piña Ma Guadalupe Flavia,Campos-Vega Rocio Food chemistry Spent coffee grounds (SCG), rich in dietary fiber can be fermented by colon microbiota producing short-chain fatty acids (SCFAs) with the ability to prevent inflammation. We investigated SCG anti-inflammatory effects by evaluating its composition, phenolic compounds, and fermentability by the human gut flora, SCFAs production, nitric oxide and cytokine expression of the human gut fermented-unabsorbed-SCG (hgf-NDSCG) fraction in LPS-stimulated RAW 264.7 macrophages. SCG had higher total fiber content compared with coffee beans. Roasting level/intensity reduced total phenolic contents of SCG that influenced its colonic fermentation. Medium roasted hgf-NDSCG produced elevated SCFAs (61:22:17, acetate, propionate and butyrate) after prolonged (24h) fermentation, suppressed NO production (55%) in macrophages primarily by modulating IL-10, CCL-17, CXCL9, IL-1β, and IL-5 cytokines. SCG exerts anti-inflammatory activity, mediated by SCFAs production from its dietary fiber, by reducing the release of inflammatory mediators, providing the basis for SCG use in the control/regulation of inflammatory disorders. The results support the use of SGC in the food industry as dietary fiber source with health benefits. 10.1016/j.foodchem.2016.05.175
    Transport and metabolism of equol by Caco-2 human intestinal cells. Walsh Kelly R,Failla Mark L Journal of agricultural and food chemistry Equol is a metabolite of daidzein with greater estrogenic activity and antioxidant capacity than its precursor. Although it is known that equol is produced by the gut microflora, information regarding its transport and metabolism in the intestine is lacking. This study investigated transepithelial transport, bioconversion, and efflux of equol using differentiated cultures of Caco-2 cells to characterize its bioavailability. Uptake was directly proportional to the initial concentration in the apical compartment with maximal intracellular concentrations being reached and 20% of the total added to the apical compartment present in the basolateral compartment as free equol after 1 h. By 4 h, 73% of equol was present as beta-glucuronidase/sulfatase sensitive conjugates with approximately 47 and 26% of initial equol distributed in apical and basolateral compartments, respectively. Free equol in the basolateral compartment appeared to be retrotransported, largely conjugated, and effluxed across the apical membrane. These results suggest that differences in the synthesis and efflux of equol conjugates may contribute to the marked variance in the bioavailability of equol in "producer" phenotype. 10.1021/jf9011906
    Metabolic fate of tea polyphenols in humans. Xie Guoxiang,Zhao Aihua,Zhao Linjing,Chen Tianlu,Chen Huiyuan,Qi Xin,Zheng Xiaojiao,Ni Yan,Cheng Yu,Lan Ke,Yao Chun,Qiu Mingfeng,Jia Wei Journal of proteome research Polyphenols, a ubiquitous group of secondary plant metabolites sharing at least one aromatic ring structure with one or more hydroxyl groups, represent a large group of natural antioxidants abundant in fruits, vegetables, and beverages, such as grape juice, wine, and tea, and are widely considered to contribute to health benefits in humans. However, little is yet known concerning their bioactive forms in vivo and the mechanisms by which they may alter our metabolome, which ultimately contribute toward disease prevention. Here we report a study to determine the metabolic fate of polyphenolic components in a Chinese tea (Pu-erh) in human subjects using a metabonomic profiling approach coupled with multivariate and univariate statistical analysis. Urine samples were collected at 0 h, 1 h, 3 h, 6 h, 9 h, 12 h, and 24 h within the first 24 h and once a day during a 6 week period including a 2 week baseline phase, a 2 week daily Pu-erh tea ingestion phase, and a 2 week "wash-out" phase, and they were analyzed by gas chromatography mass spectrometry and liquid chromatography mass spectrometry. The dynamic concentration profile of bioavailable plant molecules (due to in vivo absorption and the hepatic and gut bacterial metabolism) and the human metabolic response profile were measured and correlated with each other. This study demonstrates that the metabonomic strategy will enable us to integrate the overwhelming amount of metabolic end points as a systems' response to the absorption, metabolism, and disposition of a multicomponent botanical intervention system, leading to a direct elucidation of their mechanisms of action. 10.1021/pr300318m
    The co-administration of proanthocyanidins and an obesogenic diet prevents the increase in intestinal permeability and metabolic endotoxemia derived to the diet. Gil-Cardoso Katherine,Ginés Iris,Pinent Montserrat,Ardévol Anna,Blay Mayte,Terra Ximena The Journal of nutritional biochemistry The consumption of Westernized diets leads to hyperphagia and obesity, as well as intestinal alterations. In the present study, we evaluated the effect of the administration of a grape seed proanthocyanidin extract (GSPE) at different time points on the modulation of intestinal barrier function (intestinal permeability and metabolic endotoxemia), in rats with high-fat/high-carbohydrate diet-induced obesity. Animals were fed a cafeteria diet (CAF) supplemented with a preventive (PRE-CAF) or simultaneously intermittent (SIT-CAF) GSPE treatment (500 mg/kg bw). Changes in the plasma levels of an orally administered marker of intestinal permeability (ovalbumin, OVA), lipopolysaccharide (LPS) and tumor necrosis factor-α (TNF-α) were analyzed after animals were fed the obesogenic diet for 8, 12 and 17 weeks. In addition, ex vivo variations in transepithelial electrical resistance (TEER), the expression of tight junction (TJ) genes and the activity of myeloperoxidase (MPO) in the small and large intestines were monitored at the end of the experiment. The CAF diet increased OVA, LPS, MPO and TNF-α levels, accompanied by decreased TEER values in the small and large intestines. Interestingly, both GSPE treatments prevented these detrimental effects of the CAF diet, being the SIT-CAF group the most effective after 17 weeks of diet intervention. For the first time, this study provides evidence of the ameliorative effect of a proanthocyanidin extract, administered before or together with an obesogenic diet, on barrier dysfunction, as measured by intestinal permeability and metabolic endotoxemia. 10.1016/j.jnutbio.2018.07.012
    Curcumin inhibits cholesterol uptake in Caco-2 cells by down-regulation of NPC1L1 expression. Feng Dan,Ohlsson Lena,Duan Rui-Dong Lipids in health and disease BACKGROUND:Curcumin is a polyphenol and the one of the principle curcuminoids of the spice turmeric. Its antioxidant, anti-cancer and anti-inflammatory effects have been intensively studied. Previous in vivo studies showed that administration of curcumin also decreased cholesterol levels in the blood, and the effects were considered to be related to upregulation of LDL receptor. However, since plasma cholesterol levels are also influenced by the uptake of cholesterol in the gut, which is mediated by a specific transporter Niemann-Pick Cl-like 1 (NPC1L1) protein, the present study is to investigate whether curcumin affects cholesterol uptake in the intestinal Caco-2 cells. METHODS:Caco-2 cells were cultured to confluence. The micelles composed of bile salt, monoolein, and 14C-cholesterol were prepared. We first incubated the cells with the micelles in the presence and absence of ezetimibe, the specific inhibitor of NPC1L1, to see whether the uptake of the cholesterol in the cells was mediated by NPC1L1. We then pretreated the cells with curcumin at different concentrations for 24 h followed by examination of the changes of cholesterol uptake in these curcumin-treated cells. Finally we determined whether curcumin affects the expression of NPC1L1 by both Western blot analysis and qPCR quantification. RESULTS:We found that the uptake of radioactive cholesterol in Caco-2 cells was inhibited by ezetimibe in a dose-dependent manner. The results indicate that the uptake of cholesterol in this study was mediated by NPC1L1. We then pretreated the cells with 25-100 muM curcumin for 24 h and found that such a treatment dose-dependently inhibited cholesterol uptake with 40% inhibition obtained by 100 muM curcumin. In addition, we found that the curcumin-induced inhibition of cholesterol uptake was associated with significant decrease in the levels of NPC1L1 protein and NPC1L1 mRNA, as analyzed by Western blot and qPCR, respectively. CONCLUSION:Curcumin inhibits cholesterol uptake through suppression of NPC1L1 expression in the intestinal cells. 10.1186/1476-511X-9-40
    Ascorbic acid and total vitamin C concentrations in plasma, gastric juice, and gastrointestinal mucosa: effects of gastritis and oral supplementation. Waring A J,Drake I M,Schorah C J,White K L,Lynch D A,Axon A T,Dixon M F Gut Epidemiological evidence suggests that high dietary ascorbic acid reduces gastric cancer risk. It may do this by either reducing N-nitroso compound formation in gastric juice, or by scavenging reactive oxygen species in gastric mucosa. The aim of this study was to discover if potential ascorbic acid protection might be increased by supplementation. Thirty two patients were supplemented with ascorbic acid, 500 mg twice daily for two weeks. Gastric juice, plasma, and upper gastrointestinal biopsy ascorbate concentrations were measured and compared with values in 48 unsupplemented patients. It was found that ascorbic acid and total vitamin C concentrations were considerably higher in biopsy specimens from oesophagus, body, antrum, duodenum, and rectum, compared with values in plasma or gastric juice. Plasma and mucosal concentrations were unaffected by the presence of chronic gastritis but gastric juice concentrations were substantially lower in patients with chronic gastritis than in patients with normal histological assessment (p < 0.01). Patients receiving ascorbic acid supplements had higher ascorbic acid concentrations in plasma (p < 0.001), gastric juice (p < 0.001), and at all biopsy sites in the upper gastrointestinal tract (p < 0.05). Gastric juice ascorbic acid and total vitamin C concentrations in gastritic patients, however, were still less after supplementation than in normal subjects (p < 0.01). These data suggest that high ascorbic acid intake could reduce gastric cancer risk, but its protective effect might be greater if gastritis is treated (for example, by Helicobacter pylori eradication). 10.1136/gut.38.2.171
    Flavonoids and age-related disease: risk, benefits and critical windows. Prasain J K,Carlson S H,Wyss J M Maturitas Plant derived products are consumed by a large percentage of the population to prevent, delay and ameliorate disease burden; however, relatively little is known about the efficacy, safety and underlying mechanisms of these traditional health products, especially when taken in concert with pharmaceutical agents. The flavonoids are a group of plant metabolites that are common in the diet and appear to provide some health benefits. While flavonoids are primarily derived from soy, many are found in fruits, nuts and more exotic sources, e.g., kudzu. Perhaps the strongest evidence for the benefits of flavonoids in diseases of aging relates to their effect on components of the metabolic syndrome. Flavonoids from soy, grape seed, kudzu and other sources all lower arterial pressure in hypertensive animal models and in a limited number of tests in humans. They also decrease the plasma concentration of lipids and buffer plasma glucose. The underlying mechanisms appear to include antioxidant actions, central nervous system effects, gut transport alterations, fatty acid sequestration and processing, PPAR activation and increases in insulin sensitivity. In animal models of disease, dietary flavonoids also demonstrate a protective effect against cognitive decline, cancer and metabolic disease. However, research also indicates that the flavonoids can be detrimental in some settings and, therefore, are not universally safe. Thus, as the population ages, it is important to determine the impact of these agents on prevention/attenuation of disease, including optimal exposure (intake, timing/duration) and potential contraindications. 10.1016/j.maturitas.2010.01.010
    Antiobesity molecular mechanisms of action: Resveratrol and pterostilbene. Pan Min-Hsiung,Wu Jia-Ching,Ho Chi-Tang,Lai Ching-Shu BioFactors (Oxford, England) Obesity is a current global epidemic that has led to a marked increase in metabolic diseases. However, its treatment remains a challenge. Obesity is a multifactorial disease, which involves the dysfunction of neuropeptides, hormones, and inflammatory adipokines from the brain, gut, and adipose tissue. An understanding of the mechanisms and signal interactions in the crosstalk between organs and tissue in the coordination of whole-body energy metabolism would be helpful to provide therapeutic and putative approaches to the treatment and prevention of obesity and related complications. Resveratrol and pterostilbene are well-known stilbenes that provide various potential benefits to human health. In particular, their potential anti-obesity effects have been proven in numerous cell culture and animal studies. Both compounds act to regulate energy intake, adipocyte life cycle and function, white adipose tissue (WAT) inflammation, energy expenditure, and gut microbiota by targeting multiple molecules and signaling pathways as an intervention for obesity. Although the efficacy of both compounds in humans requires further investigation with respect to their oral bioavailability, promising scientific findings have highlighted their potential as candidates for the treatment of obesity and the improvement of obesity-related metabolic diseases. © 2018 BioFactors, 44(1):50-60, 2018. 10.1002/biof.1409
    Protective effect of rosmarinic acid and carnosic acid against streptozotocin-induced oxidation, glycation, inflammation and microbiota imbalance in diabetic rats. Ou Juanying,Huang Junqing,Zhao Danyue,Du Bin,Wang Mingfu Food & function This study evaluated the protective effects of two rosemary components, rosmarinic acid (RA) and carnosic acid (CA), against hypoglycemia, hyperlipidemia, oxidative stress and an imbalanced gut microbiota architecture in diabetic rats. Treatment with RA and CA (30 mg kg) decreased the levels of fasting plasma glucose (23.7%, 15.6%), total cholesterol (30.4%, 14.1%) and triglyceride (65.7%, 47.8%) at 15 weeks. RA and CA also exhibited an anti-oxidative and anti-glycative effect by lowering the formation of malondialdehyde and advanced glycation end products. In addition, they showed protective effects against tissue damage and inflammation in the abdominal aorta, based on microscopic observations and the analysis of protein expression. Finally, the prebiotic effects of RA and CA on gut microbiota were demonstrated by increasing the population of diabetes-resistant bacteria and decreasing the amounts of diabetes-sensitive bacteria. Overall, RA showed a stronger protective effect than CA in mitigating diabetic symptoms in rats. 10.1039/c7fo01508a
    Anti-inflammatory properties of a pomegranate extract and its metabolite urolithin-A in a colitis rat model and the effect of colon inflammation on phenolic metabolism. Larrosa Mar,González-Sarrías Antonio,Yáñez-Gascón María J,Selma María V,Azorín-Ortuño María,Toti Simona,Tomás-Barberán Francisco,Dolara Piero,Espín Juan Carlos The Journal of nutritional biochemistry Whether the beneficial effects of pomegranate are due to the ellagitannins or to their microbiota-derived urolithins is not known. Our objectives were to evaluate the effects of pomegranate intake and its main microbiota-derived metabolite urolithin-A (UROA) on colon inflammation and to assess whether UROA is the main anti-inflammatory compound. In addition, the effect of the inflammation on the phenolic metabolism was also explored. Male Fisher rats were fed with 250 mg kg(-1) day(-1) pomegranate extract (PE) or 15 mg kg(-1) day(-1) UROA for 25 days. Dextran sodium sulfate (5%) (DSS) was administered for the five last days and then rats were euthanized. DSS is a well-known model of inflammatory bowel disease. Colon tissue damage, microbiota changes, antioxidant status, prostaglandin E(2) (PGE(2)), nitric oxide production, inducible nitric oxide synthase (iNOS), prostaglandin E synthase (PTGES), gene expression (microarrays and RT-PCR) and polyphenol metabolism (LC-MS-MS) were evaluated. Both PE and UROA decreased inflammation markers (iNOS, cycloxygenase-2, PTGES and PGE(2) in colonic mucosa) and modulated favorably the gut microbiota. The G(1) to S cell cycle pathway was up-regulated in both groups. UROA group showed various down-regulated pathways, including that of the inflammatory response. PE, but not UROA, decreased oxidative stress in plasma and colon mucosa. Only UROA preserved colonic architecture. The normal formation of urolithins in PE-fed rats was prevented during inflammation. Our results suggest that UROA could be the most active anti-inflammatory compound derived from pomegranate ingestion in healthy subjects, whereas in colon inflammation, the effects could be due to the nonmetabolized ellagitannin-related fraction. 10.1016/j.jnutbio.2009.04.012
    Absorption of quercetin and rutin in rat small intestine. Carbonaro Marina,Grant George Annals of nutrition & metabolism BACKGROUND/AIMS:Dietary antioxidant flavonoids, especially flavonols, are ubiquitous constituents of plant foods with potential health-promoting effects. However, the actual bioavailability of these compounds in vivo, especially in the prevalent glycosidic form, remains a controversial point in making an assessment of their biological importance. Thus, absorption of quercetin and rutin in the small intestine has been determined. METHODS:The bioavailability of quercetin and rutin (quercetin-3-rutinoside) was assessed in vivo, with single-meal experiments with rats and by an in vitro method with ligated loops of rat small intestine. The amount of quercetin or rutin in the plasma of rats or in the lumen of each intestinal segment was assayed by maximum absorption in the UV/VIS optical spectrum as was the amount of compound that had crossed the gut wall into the incubation buffer. In addition, uptake of [14C]quercetin was tested in vitro. RESULTS:Absorption of both quercetin and rutin from the small intestine of rat was evident. However, rutin appeared to be absorbed more slowly than quercetin. Experiments with [14C]quercetin showed that only 1.5% quercetin crossed the gut wall in vitro and more than half of the total quercetin was bound to the small intestinal tissue. CONCLUSIONS:Both quercetin and rutin can attach to and traverse the small intestine of the rat. Binding of flavonoids to the intestinal wall components may however greatly limit their absorption from the small intestine. 10.1159/000086882
    Effects of Baicalein on Cortical Proinflammatory Cytokines and the Intestinal Microbiome in Senescence Accelerated Mouse Prone 8. Gao Li,Li Jiaqi,Zhou Yuzhi,Huang Xudong,Qin Xuemei,Du Guanhua ACS chemical neuroscience Baicalein, a flavonoid derived from the roots of Scutellariae baicalensis Georgi, has shown health benefits for an array of human diseases including dementia. The senescence-accelerated mouse prone 8 (SAMP8) strain is extensively used as a senile dementia model. To further investigate the effects of baicalein in SAMP8 mice, behavioral testing, biochemical detection, and gut microbiota analysis were performed. The results demonstrated that treatment with baicalein ameliorated the senescence status of the SAMP8 mice, as manifested by reducing the grading score of senescence. Additionally, baicalein improved the cognitive functions of the SAMP8 mice, including spatial learning and memory abilities, object recognition memory, and olfactory memory. Furthermore, baicalein significantly inhibited the release of proinflammatory cytokines such as interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and tumor necrosis factor-α (TNF-α) in the brain cortex of SAMP8 mice. Gut microbiota analysis revealed that treatment with baicalein markedly altered the abundance of six genera in SAMP8 mice. Correlation analysis indicated that the abundances of Mucispirillum, Bacteroides, and Sutterella were negatively correlated with cognitive abilities and that Christensenellaceae was positively correlated with cognition. Furthermore, the abundance of Christensenellaceae was negatively correlated with the levels of IL-6 and TNF-α, while [ Prevotella] was positively correlated with the levels of IL-1β and IL-6. In addition, Mucispirillum and Bacteroides were positively correlated with the level of IL-6 in the brain cortex. These data indicated that baicalein ameliorates senescence status and improves cognitive function in SAMP8 mice and that this effect might be attributable to suppression of cortical proinflammatory cytokines and modulation of the intestinal microbiome. 10.1021/acschemneuro.8b00074
    Insights into the metabolism and microbial biotransformation of dietary flavan-3-ols and the bioactivity of their metabolites. Monagas Maria,Urpi-Sarda Mireia,Sánchez-Patán Fernando,Llorach Rafael,Garrido Ignacio,Gómez-Cordovés Carmen,Andres-Lacueva Cristina,Bartolomé Begoña Food & function Flavan-3-ols, occurring in monomeric, as well as in oligomeric and polymeric forms (also known as condensed tannins or proanthocyanidins), are among the most abundant and bioactive dietary polyphenols, but their in vivo health effects in humans may be limited because of their recognition as xenobiotics. Bioavailability of flavan-3-ols is largely influenced by their degree of polymerization; while monomers are readily absorbed in the small intestine, oligomers and polymers need to be biotransformed by the colonic microbiota before absorption. Therefore, phenolic metabolites, rather than the original high molecular weight compounds found in foods, may be responsible for the health effects derived from flavan-3-ol consumption. Flavan-3-ol phenolic metabolites differ in structure, amount and excretion site. Phase II or tissular metabolites derived from the small intestine and hepatic metabolism are presented as conjugated derivatives (glucuronic acid or sulfate esters, methyl ether, or their combined forms) of monomeric flavan-3-ols and are preferentially eliminated in the bile, whereas microbial metabolites are rather simple conjugated lactones and phenolic acids that are largely excreted in urine. Although the colon is seen as an important organ for the metabolism of flavan-3-ols, the microbial catabolic pathways of these compounds are still under consideration, partly due to the lack of identification of bacteria with such capacity. Studies performed with synthesized or isolated phase II conjugated metabolites have revealed that they could have an effect beyond their antioxidant properties, by interacting with signalling pathways implicated in important processes involved in the development of diseases, among other bioactivities. However, the biological properties of microbe-derived metabolites in their actual conjugated forms remain largely unknown. Currently, there is an increasing interest in their effects on intestinal infections, inflammatory intestinal diseases and overall gut health. The present review will give an insight into the metabolism and microbial biotransformation of flavan-3-ols, including tentative catabolic pathways and aspects related to the identification of bacteria with the ability to catabolize these kinds of polyphenols. Also, the in vitro bioactivities of phase II and microbial phenolic metabolites will be covered in detail. 10.1039/c0fo00132e
    Favourable effects of grape seed extract on intestinal epithelial differentiation and barrier function in IL10-deficient mice. Yang Guan,Xue Yansong,Zhang Hanying,Du Min,Zhu Mei-Jun The British journal of nutrition The impairment in the rate of cell proliferation and differentiation leads to a negative consequence on the renewal of the intestinal epithelium, which is the aetiological factor of a number of digestive diseases. Grape seed extract (GSE), a rich source of proanthocyanidins, is known for its beneficial health effects. The present study evaluated the beneficial effects of GSE on colonic cell differentiation and barrier function in IL10-deficient mice. Female mice aged 6 weeks were randomised into two groups and given drinking-water containing 0 or 0.1 % GSE (w/v) for 12 weeks. GSE supplementation decreased serum TNF-α level and intestinal permeability, and increased the colonic goblet cell density that was associated with increased mRNA expression of mucin (Muc)-2. Immunohistochemical analyses showed lower accumulation of β-catenin in the crypts of colon tissues of the GSE-supplemented mice, which was associated with a decreased mRNA expression of two downstream effectors of Wingless and Int (Wnt)/catenin signalling, myelocytomatosis oncogene protein (Myc) and cyclin D1 (Ccnd1). Consistently, GSE supplementation decreased the number of colonic proliferating cell nuclear antigen-positive cells, a well-known cell proliferation marker, and a weakened extracellular signal-regulated kinases 1 and 2 (ERK1/2) signalling. In summary, these data indicate that supplementation of 0.1 % GSE for 12 weeks improved gut barrier function and colonic cell differentiation in the IL10-deficient mice probably via inhibiting Wnt/β-catenin pathway. 10.1017/S0007114515001415
    The Relationship Between Daytime Salivary Melatonin and Gastrointestinal Symptoms in Young Adults Seeking Psychiatric Care. Söderquist Fanny,Sundberg Isak,Ramklint Mia,Widerström Rebecka,Hellström Per M,Cunningham Janet L Psychosomatic medicine OBJECTIVE:The pathophysiology of irritable bowel syndrome (IBS) is not completely understood, although we do know that patients with IBS have a high prevalence of psychiatric comorbidity (mainly depression and anxiety disorders). Melatonin, produced in the gastrointestinal tract, influences gut motility. Psychiatric conditions are associated with circadian disturbances in peripheral melatonin levels. This study aimed to investigate associations between daytime salivary melatonin and gastrointestinal symptoms in young adult psychiatric patients. METHODS:Ninety-six patients (86% women), aged 18-25 years (M (SD) = 21 (2)), seeking psychiatric care with primarily anxiety disorders, affective disorders, or both were included in the study. Total scores from the Gastrointestinal Symptoms Rating Scale - IBS were compared with salivary melatonin measured at three time points (30 minutes after waking up, at 11:00 hours and 30 minutes after lunch) during the waking hours of 1 day. RESULTS:After adjustment for potential confounders, melatonin levels in saliva 30 minutes after lunch remained significantly correlated to the total Gastrointestinal Symptoms Rating Scale - IBS score after correction for multiple testing (B = 0.016, SE = 0.006, p = .015, q = 0.045). In a post hoc analysis, symptoms of gastrointestinal pain and bloating contributed most to this association. CONCLUSIONS:In young adult psychiatric patients, salivary melatonin levels after lunch are associated with gastrointestinal symptoms, which is consistent with the proposed effect of elevated levels of gastrointestinal melatonin on gut motility. This result suggests a link between IBS symptoms and regulation of melatonin in patients with psychiatric disorders. 10.1097/PSY.0000000000000644
    Metabolites in contact with the rat digestive tract after ingestion of a phenolic-rich dietary fiber matrix. Touriño Sonia,Pérez-Jiménez Jara,Mateos-Martín María Luisa,Fuguet Elisabet,Vinardell María Pilar,Cascante Marta,Torres Josep Lluís Journal of agricultural and food chemistry Grape antioxidant dietary fiber (GADF) is a phenolic-rich dietary fiber matrix. The aim of this work was to determine which phenolic compounds come into contact with colonic epithelial tissue after the ingestion of GADF. By use of HPLC-ESI-MS/MS techniques phenolic metabolites were detected in feces, cecal content, and colonic tissue from rats. Free (epi)catechin (EC) was detected in all three sources, and more than 20 conjugated metabolites of EC were also detected in feces. Fourteen microbially derived phenolic metabolites were also identified in feces, cecal content, and/or colonic tissue. These results show that during transit along the digestive tract, proanthocyanidin oligomers and polymers are depolymerized into EC units. After ingestion of GADF, free EC and its conjugates, as well as free and conjugated microbially derived phenolic metabolites, come into contact with the intestine epithelium for more than 24 h and may be partly responsible for the positive influence of GADF on gut health. 10.1021/jf200159f
    Curcuma longa extract associated with white pepper lessens high fat diet-induced inflammation in subcutaneous adipose tissue. Neyrinck Audrey M,Alligier Maud,Memvanga Patrick B,Névraumont Elodie,Larondelle Yvan,Préat Véronique,Cani Patrice D,Delzenne Nathalie M PloS one BACKGROUND:Supra-nutritional doses of curcumin, derived from the spice Curcuma longa, have been proposed as a potential treatment of inflammation and metabolic disorders related to obesity. The aim of the present study was to test whether Curcuma longa extract rich in curcumin and associated with white pepper (Curcuma-P®), at doses compatible with human use, could modulate systemic inflammation in diet-induced obese mice. We questioned the potential relevance of changes in adiposity and gut microbiota in the effect of Curcuma-P® in obesity. METHODOLOGY/PRINCIPAL FINDINGS:Mice were fed either a control diet (CT), a high fat (HF) diet or a HF diet containing Curcuma longa extract (0.1 % of curcumin in the HF diet) associated with white pepper (0.01 %) for four weeks. Curcumin has been usually combined with white pepper, which contain piperine, in order to improve its bioavailability. This combination did not significantly modify body weight gain, glycemia, insulinemia, serum lipids and intestinal inflammatory markers. Tetrahydrocurcumin, but not curcumin accumulated in the subcutaneous adipose tissue. Importantly, the co-supplementation in curcuma extract and white pepper decreased HF-induced pro-inflammatory cytokines expression in the subcutaneous adipose tissue, an effect independent of adiposity, immune cells recruitment, angiogenesis, or modulation of gut bacteria controlling inflammation. CONCLUSIONS/SIGNIFICANCE:These findings support that nutritional doses of Curcuma longa, associated with white pepper, is able to decrease inflammatory cytokines expression in the adipose tissue and this effect could be rather linked to a direct effect of bioactive metabolites reaching the adipose tissue, than from changes in the gut microbiota composition. 10.1371/journal.pone.0081252
    Multi-targeted prevention and therapy of cancer by proanthocyanidins. Nandakumar Vijayalakshmi,Singh Tripti,Katiyar Santosh K Cancer letters In recent years, a considerable emphasis has been focused on the importance of the naturally available botanicals that can be consumed in an individual's everyday diet and that can also be useful as a chemopreventive or chemotherapeutic agent for certain diseases, including cancers. A wide variety of botanicals, mostly dietary flavonoids or polyphenolic substances, have been reported to possess substantial anti-carcinogenic and antimutagenic activities because of their antioxidant and anti-inflammatory properties. Proanthocyanidins are considered as one of them, and are abundantly available in various parts of the plants, such as fruits, berries, bark and seeds. Their modes of action were evaluated through a number of in vitro and in vivo studies which showed their potential role as anti-carcinogenic agent. We summarize and highlight the latest developments on anti-carcinogenic activities of proanthocyanidins from different sources, specifically from grape seeds, and their molecular targets, such as NF-kappaB, mitogen-activated protein kinases, PI3K/Akt, caspases, cytokines, angiogenesis and cell cycle regulatory proteins and other check points, etc. Although the bioavailability and metabolism data on proanthocyanidins is still largely unavailable, certain reports indicate that at least monomers and smaller oligomeric procyanidins are absorbed in the gut. The modulation of various molecular targets by proanthocyanidins in vitro and in vivo tumor models suggests their importance, contribution and mechanism of action to the prevention of cancers of different organs. 10.1016/j.canlet.2008.03.049
    Bioactivity of dietary polyphenols: The role of metabolites. Luca Simon Vlad,Macovei Irina,Bujor Alexandra,Miron Anca,Skalicka-Woźniak Krystyna,Aprotosoaie Ana Clara,Trifan Adriana Critical reviews in food science and nutrition A polyphenol-rich diet protects against chronic pathologies by modulating numerous physiological processes, such as cellular redox potential, enzymatic activity, cell proliferation and signaling transduction pathways. However, polyphenols have a low oral bioavailability mainly due to an extensive biotransformation mediated by phase I and phase II reactions in enterocytes and liver but also by gut microbiota. Despite low oral bioavailability, most polyphenols proved significant biological effects which brought into attention . In recent years, polyphenol metabolites have attracted great interest as many of them showed similar or higher intrinsic biological effects in comparison to the parent compounds. There is a huge body of literature reporting on the biological functions of polyphenol metabolites generated by phase I and phase II metabolic reactions and gut microbiota-mediated biotransformation. In this respect, the review highlights the pharmacokinetic fate of the major dietary polyphenols (resveratrol, curcumin, quercetin, rutin, genistein, daidzein, ellagitannins, proanthocyanidins) in order to further address the efficacy of biometabolites as compared to parent molecules. The present work strongly supports the contribution of metabolites to the health benefits of polyphenols, thus offering a better perspective in understanding the role played by dietary polyphenols in human health. 10.1080/10408398.2018.1546669
    Identification of Novel Nitrosative Stress Inhibitors through Virtual Screening and Experimental Evaluation. Sirimulla Suman,Pal Rituraj,Raparla Mrudula,Bailey Jake B,Duran Rene,Altamirano Alvin M,Herndon William C,Narayan Mahesh Molecular informatics Nitrosative and oxidative stress, associated with the generation of excessive reactive nitrogen and oxygen radical species respectively, are thought to contribute to protein misfolding diseases which represent a group of neurodegenerative disorders that are characterized by protein aggregation and plaque formation. Curcumin, a polyphenolic compound, possesses diverse anti-inflammatory, antitumor, and antioxidant properties. Several studies have revealed that curcumin can reduce the oxidative/nitrosative stress and thereby decrease the neuronal attrition. However, curcumin has poor bioavailability and has raised several concerns focused on its limited clinical impact. The aim of this study was to find other compounds which can assist in decreasing nitrosative stress and possess enhanced bioavailability. Here, use of β-lactoglobulin was examined as a vehicle to transport molecules to the gut. The Zinc database was searched using curcumin as reference and 6457 compounds were selected for the study. These compounds were docked to β-lactoglobulin using Glide to find the best fit ligands. Our studies identified four compounds that bind to β-lactoglobulin and scavenge NOx (free radicals) efficiently. 10.1002/minf.201100044
    Benefits of whole ginger extract in prostate cancer. Karna Prasanthi,Chagani Sharmeen,Gundala Sushma R,Rida Padmashree C G,Asif Ghazia,Sharma Vibhuti,Gupta Meenakshi V,Aneja Ritu The British journal of nutrition It is appreciated far and wide that increased and regular consumption of fruits and vegetables is linked with noteworthy anticancer benefits. Extensively consumed as a spice in foods and beverages worldwide, ginger (Zingiber officinale Roscoe) is an excellent source of several bioactive phenolics, including non-volatile pungent compounds such as gingerols, paradols, shogaols and gingerones. Ginger has been known to display anti-inflammatory, antioxidant and antiproliferative activities, indicating its promising role as a chemopreventive agent. Here, we show that whole ginger extract (GE) exerts significant growth-inhibitory and death-inductory effects in a spectrum of prostate cancer cells. Comprehensive studies have confirmed that GE perturbed cell-cycle progression, impaired reproductive capacity, modulated cell-cycle and apoptosis regulatory molecules and induced a caspase-driven, mitochondrially mediated apoptosis in human prostate cancer cells. Remarkably, daily oral feeding of 100 mg/kg body weight of GE inhibited growth and progression of PC-3 xenografts by approximately 56 % in nude mice, as shown by measurements of tumour volume. Tumour tissue from GE-treated mice showed reduced proliferation index and widespread apoptosis compared with controls, as determined by immunoblotting and immunohistochemical methods. Most importantly, GE did not exert any detectable toxicity in normal, rapidly dividing tissues such as gut and bone marrow. To the best of our knowledge, this is the first report to demonstrate the in vitro and in vivo anticancer activity of whole GE for the management of prostate cancer. 10.1017/S0007114511003308
    Genistein and gut inflammation: role of nitric oxide. Sadowska-Krowicka H,Mannick E E,Oliver P D,Sandoval M,Zhang X J,Eloby-Childess S,Clark D A,Miller M J Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.) Genistein, a principal soy isoflavone, has been identified as a protein kinase inhibitor that possesses immunosuppressive and anti-inflammatory properties. The aim of the study was to determine if genistein modified chronic ileitis in guinea pigs induced by the hapten trinitrobenzene sulfonic acid (TNBS), and the activity index of cultured macrophages (RAW 264.7 cells) stimulated with lipopolysaccharide (LPS). Genistein at low doses (0.1 mg/kg, s.c.) had mild anti-inflammatory effects in TNBS ileitis. Therapeutic benefit included a reduction in nitric oxide production, granulocyte infiltration and improved mucosal architecture. Genistein, at low doses, also appeared to attenuate immunohistochemical staining for inducible nitric oxide synthase (iNOS) and nitrotyrosine. The beneficial effects of genistein were not apparent at doses above 0.1 mg/kg. We found that genistein also inhibited LPS-induced nitrite production by cultured macrophages and protected against LPS-induced necrosis despite its ability to cause apoptosis. These results indicate that genistein displayed mild anti-inflammatory properties which may, in part, involve an attenuation of nitric oxide release via inducible nitric oxide synthase, and the formation of peroxynitrite. 10.3181/00379727-217-44244
    Metabolic profiles of the Flos Abelmoschus manihot extract by intestinal bacteria from the normal and CKD model rats based on UPLC-Q-TOF/MS. Du Le-Yue,Tao Jin-Hua,Jiang Shu,Qian Da-Wei,Guo Jian-Ming,Duan Jin-Ao Biomedical chromatography : BMC Flos Abelmoschus manihot is a traditional herbal medicine widely used in clinical practice to tackle chronic kidney disease (CKD) for thousands of years. Nowadays, many studies indicate that gut bacteria are closely related to the progression of CKD and CKD-related complications. In this study, a UPLC-Q-TOF/MS method coupled with the MetaboLynx™ software was established and successfully applied to investigate the metabolites and metabolic profile of Flos A. manihot extract by intestinal bacteria from normal and CKD rats. Eight parent components and eight metabolites were characterized by their protonated ions. Among these compounds, 15 were detected in the two group samples while M16 was only determined in the CKD model samples. Compared with the quercetin-type glycosides, fewer myricetin-type and gossypetin-type metabolites were obtained in the two group samples. These metabolites suggested that deglycosylation and methylation are the major metabolic pathways of Flos A. manihot extract. Few differences of metabolite classes were observed in the two group samples. However, the concentrations of aglycones such as quercetin, myricetin and gossypetin in the normal samples were notably higher than those in the CKD model samples. The results are important in unravelling the pharmacological effects of A. manihot and clarifying its mechanism of action in vivo. 10.1002/bmc.3795
    Metabolomics Elucidates Dose-Dependent Molecular Beneficial Effects of Hesperidin Supplementation in Rats Fed an Obesogenic Diet. Guirro Maria,Gual-Grau Andreu,Gibert-Ramos Albert,Alcaide-Hidalgo Juan Maria,Canela Núria,Arola Lluís,Mayneris-Perxachs Jordi Antioxidants (Basel, Switzerland) Metabolic syndrome (MetS) is a global epidemic concern. Polyphenols are proposed as good candidates for its prevention, although their mechanisms are not fully understood. The gut microbiota seems to play a key role in polyphenol beneficial effects. Here, we assessed the effects of the citrus polyphenol hesperidin combining an untargeted metabolomics approach, which has an inherent potential to elucidate the host-microbiome interplay, with extensive anthropometric and biochemical characterizations and integrating metabolomics results with our previous 16S rRNA bacterial sequencing data. The rats were fed either a standard or an obesogenic cafeteria diet (CAF) for 17 weeks. After nine weeks, rats were supplemented with vehicle; low- (H1), or high- (H2) hesperidin doses. CAF animals developed MetS features. Hesperidin supplementation in CAF rats decreased the total cholesterol, LDL-C, and free fatty acids. The highest hesperidin dose also ameliorated blood pressure, insulin sensitivity, and decreased markers of arterial stiffness and inflammation. Metabolomics revealed an improvement of the lipidomic profile, decreases in circulating amino acids, and lower excretions of inflammation- and oxidative stress-related metabolites. increases in the CAF-H2 group paralleled higher excretions of microbial-derived metabolites. Overall, our results provide detailed insights into the molecular effects of hesperidin on MetS and suggest that it is a promising prebiotic for the treatment of MetS and related conditions. 10.3390/antiox9010079
    Coexisted components of Salvia miltiorrhiza enhance intestinal absorption of cryptotanshinone via inhibition of the intestinal P-gp. Dai Haixue,Li Xiaorong,Li Xiaoli,Bai Lu,Li Yuhang,Xue Ming Phytomedicine : international journal of phytotherapy and phytopharmacology Cryptotanshinone, derived from the roots of Salvia miltiorrhiza Bge and Salvia przewalskii Maxim, is the major active component and possesses significant antibacterial, antidermatophytic, antioxidant, anti-inflammatory and anticancer activities. The objective of this study was to investigate the intestinal absorptive characteristics of cryptotanshinone as well as the absorptive behavior influenced by co-administration of the diterpenoid tanshinones and danxingfang using an in vitro everted rat gut sac model. The results showed a good linear correlation between cryptotanshinone of absorption and the incubation time from 10 to 70min. The concentration dependence showed that a non-linear correlation existed between the cryptotanshinone absorption and the concentration at 100 μg/ml. Coexisting diterpenoid tanshinones and danxingfang could significantly enhance the absorption of cryptotanshinone. Coexisting diterpenoid tanshinones and danxingfang, which influenced cryptotanshinone's absorption, manifested as similar to that of the P-glycoprotein inhibitor. The underlying mechanism of the improvement of oral bioavailability was proposed that coexisting diterpenoid tanshinones and danxingfang could decrease the efflux transport of cryptotanshinone by P-glycoprotein. 10.1016/j.phymed.2012.08.007
    Decreased melatonin secretion is associated with increased intestinal permeability and marker of endotoxemia in alcoholics. Swanson Garth R,Gorenz Annika,Shaikh Maliha,Desai Vishal,Forsyth Christopher,Fogg Louis,Burgess Helen J,Keshavarzian Ali American journal of physiology. Gastrointestinal and liver physiology Chronic heavy alcohol use is known to cause gut leakiness and alcoholic liver disease (ALD), but only 30% of heavy drinkers develop increased intestinal permeability and ALD. The hypothesis of this study was that disruption of circadian rhythms is a potential risk factor in actively drinking alcoholics for gut leakiness and endotoxemia. We studied 20 subjects with alcohol use disorder (AD) and 17 healthy controls (HC, 6 day workers, 11 night workers). Subjects wore a wrist actiwatch for 7 days and underwent a 24-h dim light phase assessment and urine collection for intestinal permeability. The AD group had significantly less total sleep time and increased fragmentation of sleep (P < 0.05). AD also had significantly lower plasma melatonin levels compared with the HC [mean area under the curve (AUC) 322.78 ± 228.21 vs. 568.75 ± 304.26 pg/ml, P = 0.03]. In the AD group, AUC of melatonin was inversely correlated with small bowel and colonic intestinal permeability (lactulose-to-mannitol ratio, r = -0.39, P = 0.03; urinary sucralose, r = -0.47, P = 0.01). Cosinor analysis of lipopolysaccharide-binding protein (marker of endotoxemia) and lipopolysaccharide every 4 h for 24 h in HC and AD subjects had a midline estimating statistic of rhythm of 5,026.15 ± 409.56 vs. 6,818.02 ± 628.78 ng/ml (P < 0.01) and 0.09 ± 0.03 vs. 0.15 ± 0.19 EU/ml (P < 0.05), respectively. We found plasma melatonin was significantly lower in the AD group, and lower melatonin levels correlated with increased intestinal permeability and a marker of endotoxemia. Our study suggests the suppression of melatonin in AD may promote gut leakiness and endotoxemia. 10.1152/ajpgi.00002.2015
    Formation of short-chain Fatty acids, excretion of anthocyanins, and microbial diversity in rats fed blackcurrants, blackberries, and raspberries. Jakobsdottir Greta,Blanco Narda,Xu Jie,Ahrné Siv,Molin Göran,Sterner Olov,Nyman Margareta Journal of nutrition and metabolism Introduction. Berries contain high amounts of dietary fibre and flavonoids and have been associated with improved metabolic health. The mechanisms are not clear but the formation of SCFAs, especially propionic and butyric acids, could be important. The potent antioxidant and antimicrobial properties of flavonoids could also be a factor, but little is known about their fate in the gastrointestinal tract. Aim. To compare how blackcurrants, blackberries, raspberries, and Lactobacillus plantarum HEAL19 affect formation of SCFAs, inflammatory status, caecal microbial diversity, and flavonoids. Results and Conclusions. Degradation of the dietary fibre, formation of SCFAs including propionic and butyric acids, the weight of the caecal content and tissue, and the faecal wet and dry weight were all higher in rats fed blackcurrants rather than blackberries or raspberries. However, the microbial diversity of the gut microbiota was higher in rats fed raspberries. The high content of soluble fibre in blackcurrants and the high proportion of mannose-containing polymers might explain these effects. Anthocyanins could only be detected in urine of rats fed blackcurrants, and the excretion was lower with HEAL19. No anthocyanins or anthocyanidins were detected in caecal content or blood. This may indicate uptake in the stomach or small intestine. 10.1155/2013/202534
    An integrated plasma and urinary metabonomic study using UHPLC-MS: intervention effects of Epimedium koreanum on 'Kidney-Yang Deficiency syndrome' rats. Huang Danxue,Yang Jie,Lu Xiumei,Deng Ying,Xiong Zhili,Li Famei Journal of pharmaceutical and biomedical analysis A metabonomic strategy based on UHPLC-MS with principal component analysis was developed to investigate the intervention effects of Epimedium koreanum on metabolism characters of 'Kidney-Yang Deficiency syndrome' rats. The rats were injected intraperitoneally hydrocortisone once daily for 15 days to simulate 'Kidney-Yang Deficiency syndrome' and then administered orally E. koreanum extract once daily for the following 15 days. Plasma and urine samples before hydrocortisone injection, on day 15 of hydrocortisone injection and on days 3, 6, 9, 12, 15 exposed to E. koreanum extract were collected. Significant metabolic disorders were observed in 'Kidney-Yang Deficiency syndrome' rats and sixteen potential biomarkers were identified. The disturbed plasma levels of phenylalanine, tryptophan, cholic acid, lysophosphatidylcholines and urinary levels of phenylalanine, hippurate, phenylacetylglycine, N(2)-succinyl-l-ornithine, creatinine, α-ketoglutarate, citrate, phenol sulfate, indoxyl sulfate, cresol sulfate in model rats were gradually restored to normal after administration of E. koreanum extract, which indicated that E. koreanum had time-dependent recovering effects via regulating oxidant-antioxidant balance, amino acid metabolism, lipid metabolism, energy metabolism, and gut microflora. This work highlights that metabonomics is a promising tool for studying the essence of Chinese medicine's syndrome theory and the action mechanism of traditional Chinese medicine, and provides scientific and reasonable information on safety and efficacy of traditional Chinese medicine. 10.1016/j.jpba.2012.12.022
    The bioavailability of non-nutrient plant factors: dietary flavonoids and phyto-oestrogens. Wiseman H The Proceedings of the Nutrition Society The bioavailability in human subjects of non-nutrient plant factors, including dietary flavonoids and phyto-oestrogens, is of great importance relative to their reported health protective effects. These effects include protection against heart disease, and also in the case of the phyto-oestrogens, hormone-dependent cancers. Epidemiological studies have shown flavonoid intake (mostly quercetin) to be inversely associated with mortality from CHD. Quercetin is a potent antioxidant in vitro, and protection against the oxidative damage to LDL implicated in atherogenesis has been suggested as a possible mechanism. Human subjects can absorb significant amounts of quercetin (particularly in the glucoside form) and it would appear to be sufficiently bioavailable to act as an antioxidant in vivo; however, following our recent study (J O'Reilly, TAB Sanders and H Wiseman, unpublished results), it is currently less clear whether quercetin really can act as an antioxidant in vivo. The isoflavone phyto-oestrogens genistein and daidzein are much less effective antioxidants than quercetin in vitro, however, they are well-absorbed by human subjects and appear to be sufficiently bioavailable to act as antioxidants in vivo. In our recent study (O'Reilly et al. 1998) lower plasma isoprostane concentrations and increased resistance of LDL to oxidation were observed following the high-isoflavone dietary phase compared with the low-isoflavone dietary phase. Considerable inter-individual variation in isoflavone metabolite excretion has been observed, in particular the production of equol (the gut bacterial metabolite of daidzein; a more potent antioxidant and more oestrogenic than daidzein), and this appears to be influenced by habitual diet. Further studies on the bioavailability of these non-nutrient plant factors and related influencing factors are clearly still required.
    Absorption, metabolism, anti-cancer effect and molecular targets of epigallocatechin gallate (EGCG): An updated review. Gan Ren-You,Li Hua-Bin,Sui Zhong-Quan,Corke Harold Critical reviews in food science and nutrition Green tea is one of the most popular beverages in the world, especially in Asian countries. Consumption of green tea has been demonstrated to possess many health benefits, which mainly attributed to the main bioactive compound epigallocatechin gallate (EGCG), a flavone-3-ol polyphenol, in green tea. EGCG is mainly absorbed in the intestine, and gut microbiota play a critical role in its metabolism prior to absorption. EGCG exhibits versatile bioactivities, with its anti-cancer effect most attracting due to the cancer preventive effect of green tea consumption, and a great number of studies intensively investigated its anti-cancer effect. In this review, we therefore, first stated the absorption and metabolism process of EGCG, and then summarized its anti-cancer effect in vitro and in vivo, including its manifold anti-cancer actions and mechanisms, especially its anti-cancer stem cell effect, and next highlighted its various molecular targets involved in cancer inhibition. Finally, the anti-cancer effect of EGCG analogs and nanoparticles, as well as the potential cancer promoting effect of EGCG were also discussed. Understanding of the absorption, metabolism, anti-cancer effect and molecular targets of EGCG can be of importance to better utilize it as a chemopreventive and chemotherapeutic agent. 10.1080/10408398.2016.1231168
    Gastroprotective Effects of Grape Seed Proanthocyanidin Extracts against Nonsteroid Anti-Inflammatory Drug-Induced Gastric Injury in Rats. Kim Tae Ho,Jeon Eun Jeong,Cheung Dae Young,Kim Chang Whan,Kim Sung Soo,Park Soo-Heon,Han Sok Won,Kim Myung Jun,Lee Youn Soo,Cho Mi-La,Chang Jae Hyuck,Min Jun Ki,Kim Jin Il Gut and liver BACKGROUND/AIMS:To investigate the gastroprotective effects of grape seed proanthocyanidin extracts (GSPEs) against nonsteroid anti-inflammatory drug (NSAID)-induced gastric mucosal injury in rats. METHODS:Sprague-Dawley rats were randomly allocated to the normal control, indomethacin, low-dose GSPE, high-dose GSPE and misoprostol groups. All groups except the normal control group received pretreatment drugs for 6 consecutive days. On the 5th and 6th day, indomethacin was administered orally to all groups except for normal control group. The microscopic features of injury were analyzed. The levels of gastric mucosal glutathione, gastric mucosal prostaglandin E2 (PGE2), and proinflammatory cytokines were investigated. RESULTS:The total areas of ulceration in the GSPE and misoprostol groups were significantly decreased compared with the indomethacin group (p<0.05). However, a difference in ulcer formation among the drug treatment groups was not observed. Meanwhile, the glutathione levels in the high-dose GSPE group were higher than those of both the indomethacin and misoprostol groups (p<0.05) and were similar to those of the normal control group. Additionally, there was no difference among the groups in the levels of gastric mucosal PGE2 and proinflammatory cytokines. CONCLUSIONS:High-dose GSPE has a strong protective effect against NSAID-induced gastric mucosal injury, which may be associated with the antioxidant effects of GSPE. 10.5009/gnl.2013.7.3.282
    Grape proanthocyanidin-induced intestinal bloom of Akkermansia muciniphila is dependent on its baseline abundance and precedes activation of host genes related to metabolic health. Zhang Li,Carmody Rachel N,Kalariya Hetal M,Duran Rocio M,Moskal Kristin,Poulev Alexander,Kuhn Peter,Tveter Kevin M,Turnbaugh Peter J,Raskin Ilya,Roopchand Diana E The Journal of nutritional biochemistry We previously showed that C57BL/6J mice fed high-fat diet (HFD) supplemented with 1% grape polyphenols (GP) for 12 weeks developed a bloom of Akkermansia muciniphila with attenuated metabolic syndrome symptoms. Here we investigated early timing of GP-induced effects and the responsible class of grape polyphenols. Mice were fed HFD, low-fat diet (LFD) or formulations supplemented with GP (HFD-GP, LFD-GP) for 14 days. Mice fed HFD-GP, but not LFD-GP, showed improved oral glucose tolerance compared to controls. A. muciniphila bloom occurred earlier in mice fed LFD-GP than HFD-GP; however, timing was dependent on baseline A. muciniphila levels rather than dietary fat. Mice gavaged for 10 days with GP extract (GPE) or grape proanthocyanidins (PACs), each delivering 360 mg PACs/kg body weight, induced a bloom of fecal and cecal A. muciniphila, the rate of which depended on initial A. muciniphila abundance. Grape PACs were sufficient to induce a bloom of A. muciniphila independent of specific intestinal gene expression changes. Gut microbial community analysis and in vitro inhibition of A. muciniphila by GPE or PACs suggest that the A. muciniphila bloom in vivo occurs via indirect mechanisms. 10.1016/j.jnutbio.2018.02.009
    The gastrointestinal microbiome and musculoskeletal diseases: a beneficial role for probiotics and prebiotics. Vitetta Luis,Coulson Samantha,Linnane Anthony W,Butt Henry Pathogens (Basel, Switzerland) Natural medicines are an attractive option for patients diagnosed with common and debilitating musculoskeletal diseases such as Osteoarthritis (OA) or Rheumatoid Arthritis (RA). The high rate of self-medication with natural products is due to (1) lack of an available cure and (2) serious adverse events associated with chronic use of pharmaceutical medications in particular non-steroidal anti-inflammatory drugs (NSAIDs) and high dose paracetamol. Pharmaceuticals to treat pain may disrupt gastrointestinal (GIT) barrier integrity inducing GIT inflammation and a state of and hyper-permeability. Probiotics and prebiotics may comprise plausible therapeutic options that can restore GIT barrier functionality and down regulate pro-inflammatory mediators by modulating the activity of, for example, Clostridia species known to induce pro-inflammatory mediators. The effect may comprise the rescue of gut barrier physiological function. A postulated requirement has been the abrogation of free radical formation by numerous natural antioxidant molecules in order to improve musculoskeletal health outcomes, this notion in our view, is in error. The production of reactive oxygen species (ROS) in different anatomical environments including the GIT by the epithelial lining and the commensal microbe cohort is a regulated process, leading to the formation of hydrogen peroxide which is now well recognized as an essential second messenger required for normal cellular homeostasis and physiological function. The GIT commensal profile that tolerates the host does so by regulating pro-inflammatory and anti-inflammatory GIT mucosal actions through the activity of ROS signaling thereby controlling the activity of pathogenic bacterial species. 10.3390/pathogens2040606
    Comparative absorption of curcumin formulations. Jäger Ralf,Lowery Ryan P,Calvanese Allison V,Joy Jordan M,Purpura Martin,Wilson Jacob M Nutrition journal BACKGROUND:The potential health benefits of curcumin are limited by its poor solubility, low absorption from the gut, rapid metabolism and rapid systemic elimination. The purpose of this study was the comparative measurement of the increases in levels of curcuminoids (curcumin, demethoxycurcumin, bisdemethoxycurcumin) and the metabolite tetrahydrocurcumin after oral administration of three different curcumin formulations in comparison to unformulated standard. METHODS:The relative absorption of a curcumin phytosome formulation (CP), a formulation with volatile oils of turmeric rhizome (CTR) and a formulation of curcumin with a combination of hydrophilic carrier, cellulosic derivatives and natural antioxidants (CHC) in comparison to a standardized curcumin mixture (CS) was investigated in a randomized, double-blind, crossover human study in healthy volunteers. Samples were analyzed by HPLC-MS/MS. RESULTS:Total curcuminoids appearance in the blood was 1.3-fold higher for CTR and 7.9-fold higher for CP in comparison to unformulated CS. CHC showed a 45.9-fold higher absorption over CS and significantly improved absorption over CP (5.8-fold) and CTR (34.9-fold, all p < 0.001). CONCLUSION:A formulation of curcumin with a combination of hydrophilic carrier, cellulosic derivatives and natural antioxidants significantly increases curcuminoid appearance in the blood in comparison to unformulated standard curcumin CS, CTR and CP. 10.1186/1475-2891-13-11
    1 - 1. The chemistry and pharmacology of indole-3-carbinol (indole-3-methanol) and 3-(methoxymethyl)indole. [Part I]. Broadbent T A,Broadbent H S Current medicinal chemistry Indole-3-carbinol (I3C) (2) is produced endogenously from naturally occurring glucosinolates contained in a wide variety of plant food substances including members of the family Cruciferae, and particularly members of the genus Brassica, whenever they are crushed or cooked. The acid environment of the gut very facilely converts it into a range of polyaromatic indolic compounds, e.g. (3, 4,5), which appear to be responsible for many of the physiological effects observed following the ingestion of these foods. 3-(Methoxymethyl)indole (6) is formed with great ease whenever 2 contacts methylating agents, including methanol, and it is often found as a contaminant of 2. This contamination is often not recognized or easily removed because of the great similarities of the two in melting points and solubilities. However, their biological properties are essentially identical. These so-called chemopreventive compounds are important because of their enzyme induction and suppression, mutagenic, carcinogenic and, particularly, antimutagenic and anticarcinogenic properties. The natural occurrence, formation, preparation, identification, separation, quantification, chemical transformations and general toxicological properties of these substances are critically reviewed in detail in this paper of 146 references, the first of two parts. The enzyme induction and suppression, mutagenic, antimutagenic, mutagenic, anticarcinogenic and carcinogenic effects will be published later as Part II. At the present time it appears that these have considerable potential as natural prophylactic anticancer agents against certain common neoplasms, especially inasmuch modern diets are increasingly deficient in these vegetable-derived substances.
    The Importance of the Gastrointestinal Tract in Controlling Food Intake and Regulating Energy Balance. Monteiro Mariana P,Batterham Rachel L Gastroenterology The gastrointestinal tract, the key interface between ingested nutrients and the body, plays a critical role in regulating energy homeostasis. Gut-derived signals convey information regarding incoming nutrients to the brain, initiating changes in eating behavior and energy expenditure, to maintain energy balance. Here we review hormonal, neural, and nutrient signals emanating from the gastrointestinal tract and evidence for their role in controlling feeding behavior. Mechanistic studies that have utilized pharmacologic and/or transgenic approaches targeting an individual hormone/mediator have yielded somewhat disappointing body weight changes, often leading to the hormone/mediator in question being dismissed as a potential obesity therapy. However, the recent finding of sustained weight reduction in response to systemic administration of a long-acting analog of the gut-hormone glucagon-like peptide-1 highlights the therapeutic potential of gut-derived signals acting via nonphysiologic mechanisms. Thus, we also review therapeutics strategies being utilized or developed to leverage gastrointestinal signals in order to treat obesity. 10.1053/j.gastro.2017.01.053
    Bioavailability of olive oil phenolic compounds in humans. de la Torre R Inflammopharmacology Olive oil is a functional food, which in addition to having a high level of monounsaturated fatty acids (MUFA), also contains multiple minor components, among them several phenolic compounds. Oleuropeine and its glycoside are the main sources of a simple phenol hydroxytyrosol with a strong antioxidant activity. Hydroxytyrosol is well absorbed in the gastrointestinal tract but its bioavailability is poor because an important first past metabolism both in gut and liver, leading to the formation of sulphate and glucuronide conjugates, to the extent that concentrations in body fluids of its free form are almost undetectable. This is a major drawback in our understanding of the antioxidant activity of this compound in vivo and the potential health benefits derived from its consumption. The picture is further compounded by the fact that hydroxytyrosol is also a dopamine metabolite and body fluids concentrations combine exogenous and endogenous sources. 10.1007/s10787-008-8029-4
    Gold kiwifruit ( Actinidia chinensis 'Hort16A') for immune support. Skinner Margot A,Loh Jacelyn M S,Hunter Denise C,Zhang Jingli The Proceedings of the Nutrition Society Kiwifruit is a good source of several vitamins and minerals and dietary fibre, and contains a number of phytochemicals; so kiwifruit potentially provides health benefits beyond basic nutrition. Consumption of green kiwifruit can have positive effects on cardiovascular health through antioxidant activity, inhibition of platelet aggregation and lowered TAG levels, and gut health through improving laxation, aiding digestion and promoting a healthy gut microflora. The importance of nutrition on immune function is well recognised, with deficiencies in vitamins A, C, E, B6 and B12, folic acid, Zn, Cu, Fe and Se being associated with impaired immune function and increased susceptibility to diseases. Evidence is growing that kiwifruit enhances immunity, with several small murine studies showing enhancement of innate and adaptive immune function. Few studies have examined the effect of kiwifruit on immune function in human subjects, but a recent study has revealed that kiwifruit up-regulates several 'immune' and 'DNA and repair'-related gene sets, and down-regulates one gene set related to Ig secretion. Taken together, the evidence from the literature provides supporting data for designing a human intervention trial to validate the ability of kiwifruit to support immune function in healthy and immunocompromised populations. 10.1017/S0029665111000048
    Grape Seed Extract Eliminates Visceral Allodynia and Colonic Hyperpermeability Induced by Repeated Water Avoidance Stress in Rats. Arie Hideyuki,Nozu Tsukasa,Miyagishi Saori,Ida Masayuki,Izumo Takayuki,Shibata Hiroshi Nutrients Grape seed extract (GSE) is rich in polyphenols composed mainly of proanthocyanidins, which are known to attenuate proinflammatory cytokine production. Repeated water avoidance stress (WAS) induces visceral allodynia and colonic hyperpermeability via toll-like receptor 4 (TLR4) and proinflammatory cytokine pathways, which is a rat irritable bowel syndrome (IBS) model. Thus, we explored the effects of GSE on repeated WAS (1 h for 3 days)-induced visceral allodynia and colonic hyperpermeability in Sprague-Dawley rats. Paracellular permeability, as evaluated by transepithelial electrical resistance and flux of carboxyfluorescein, was analyzed in Caco-2 cell monolayers treated with interleukin-6 (IL-6) and IL-1β. WAS caused visceral allodynia and colonic hyperpermeability, and intragastric administration of GSE (100 mg/kg, once daily for 11 days) inhibited these changes. Furthermore, GSE also suppressed the elevated colonic levels of IL-6, TLR4, and claudin-2 caused by WAS. Paracellular permeability was increased in Caco-2 cell monolayers in the presence of IL-6 and IL-1β, which was inhibited by GSE. Additionally, GSE suppressed the claudin-2 expression elevated by cytokine stimulation. The effects of GSE on visceral changes appear to be evoked by suppressing colonic TLR4-cytokine signaling and maintaining tight junction integrity. GSE may be useful for treating IBS. 10.3390/nu11112646
    The impact of polyphenols on Bifidobacterium growth. Gwiazdowska Daniela,Juś Krzysztof,Jasnowska-Małecka Joanna,Kluczyńska Katarzyna Acta biochimica Polonica Polyphenols are a common group of plant based bioactive compounds, that can affect human health because of their antioxidant and antimicrobial properties as well as free-radical scavenging activity. An increasing interest is observed in the interaction between polyphenols and microbiota occurring in food and the human gut. The aim of the work presented here, was to evaluate the effect of some polyphenolic compounds on the growth of two strains of Bifidobacterium: B. adolescentis and B. bifidum. The influence of some flavonoids: naringinin, hesperidin, rutin, quercetin as well as phenolic acids: gallic, caffeic, p-coumaric, ferulic, chlorogenic, vanillic and sinapic was determined by a 96-well microtiter plate assay. In the experiments the effect of three different concentrations of polyphenols: 2, 20 and 100 µg/ml on the growth of Bifidobacterium strains was investigated. All tested compounds influenced the growth of the examined bacteria. Both stimulatory and inhibitory effects were observed in comparison to the positive control. The strongest impact on the growth of bifidobacteria was observed during the first hours of incubation. The constant inhibitory effect was observed for hesperidin and quercetin addition and was dose-dependent. B. bifidum showed a stronger dependence on phenolic acids content in the medium than B. adolescentis during the first hours of incubation. 10.18388/abp.2015_1154
    Protective effect of melatonin on acute pancreatitis. Jaworek Jolanta,Szklarczyk Joanna,Jaworek Andrzej K,Nawrot-Porąbka Katarzyna,Leja-Szpak Anna,Bonior Joanna,Kot Michalina International journal of inflammation Melatonin, a product of the pineal gland, is released from the gut mucosa in response to food ingestion. Specific receptors for melatonin have been detected in many gastrointestinal tissues including the pancreas. Melatonin as well as its precursor, L-tryptophan, attenuates the severity of acute pancreatitis and protects the pancreatic tissue from the damage caused by acute inflammation. The beneficial effect of melatonin on acute pancreatitis, which has been reported in many experimental studies and supported by clinical observations, is related to: (1) enhancement of antioxidant defense of the pancreatic tissue, through direct scavenging of toxic radical oxygen (ROS) and nitrogen (RNS) species, (2) preservation of the activity of antioxidant enzymes; such as superoxide dismutase (SOD), catalase (CAT), or glutathione peroxidase (GPx), (3) the decline of pro-inflammatory cytokine tumor necrosis α (TNFα) production, accompanied by stimulation of an anti-inflammatory IL-10, (4) improvement of pancreatic blood flow and decrease of neutrophil infiltration, (5) reduction of apoptosis and necrosis in the inflamed pancreatic tissue, (6) increased production of chaperon protein (HSP60), and (7) promotion of regenerative process in the pancreas. Conclusion. Endogenous melatonin produced from L-tryptophan could be one of the native mechanisms protecting the pancreas from acute damage and accelerating regeneration of this gland. The beneficial effects of melatonin shown in experimental studies suggest that melatonin ought to be employed in the clinical trials as a supportive therapy in acute pancreatitis and could be used in people at high risk for acute pancreatitis to prevent the development of pancreatic inflammation. 10.1155/2012/173675
    Interactions between prebiotics, probiotics, polyunsaturated fatty acids and polyphenols: diet or supplementation for metabolic syndrome prevention? Peluso Ilaria,Romanelli Luca,Palmery Maura International journal of food sciences and nutrition The metabolic syndrome can be prevented by the Mediterranean diet, characterized by fiber, omega-3 polyunsaturated fatty acids and polyphenols. However, the composition of the Mediterranean diet, which can be viewed as a natural multiple supplement, is poorly controlled, and its beneficial effects poorly predictable. The metabolic syndrome is associated with intestinal dysbiosis and the gut microbioma seems to be the main target and player in the interactions occurring between probiotics, prebiotics, omega 3 polyunsaturated fatty acids, and polyphenols. From the reviewed evidence, it is reasonable to manage growth and metabolism of gut microflora with specific prebiotics and polyphenols. Even though the healthy properties of functional foods and nutraceuticals still need to be fully elucidated, available data suggest that well-designed supplements, containing the better ratio of omega-3 polyunsaturated fatty acids and antioxidants, specific probiotic strains, and selected polyphenols and prebiotics, could be useful in metabolic syndrome prevention and treatment. 10.3109/09637486.2014.880670
    Herbal plants and their derivatives as growth and health promoters in animal nutrition. Hashemi Seyed Reza,Davoodi Homa Veterinary research communications The purpose of this review is to summarize the effectiveness, modes of action and commercial application of herbal plants and their derivatives as growth promoters for animal. Feed supplements are a group of feed ingredients that can cause a desired animal response in a non-nutrient role such as pH shift, growth, or metabolic modifier (Hutjens, 1991). Common feed additives used in animal diets include immunostimulators, antimicrobials, antioxidants, pH control agents and enzymes. Herbal plants, are a new class of growth promoters and in recent years this feed additives have gained extensive attention in the feed industry. They are a wide variety of herbs, spices, and products derived thereof, and are mainly essential oils. Although numerous reports have demonstrated antioxidative and antimicrobial and immune stimulation efficacy in vitro, respective experimental in vivo evidence is still quite limited. A limited number of experimental comparisons of herbal plants feed additives with antibiotics or organic acid have suggested similar effects on the animal gut microflora. Gut microflora has significant effects on host nutrition, health, and growth performance by interacting with nutrient utilization and the development of gut system of the host. In addition, some phytogenic compounds seem to promote intestinal mucus production. However, the future of using herbs in animal feeding will in great measure depend on the knowledge of chemical structure, their value and characteristics of practical herbs or their extract physiological needs and well-being of animal, and, above all on consumer's preferences and expectations. 10.1007/s11259-010-9458-2
    Peroxynitrite-induced apoptosis in epithelial (T84) and macrophage (RAW 264.7) cell lines: effect of legume-derived polyphenols (phytolens). Sandoval M,Ronzio R A,Muanza D N,Clark D A,Miller M J Nitric oxide : biology and chemistry Peroxynitrite (ONOO-) has been proposed as a mediator of gut inflammation and as an inducer of cell death by apoptosis. Phytolens (PHY), a water-soluble extract of polyphenolic antioxidants from nonsoy legumes (Biotics Research Corp, patent pending), was evaluated as a cytoprotective agent in human colonic (T84) and murine macrophage (RAW 264.7) cell lines. In the antioxidant testing, PHY showed a significant free radical scavenging ability against 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) and superoxide (O2.) radicals with an IC50 of 4.44 and 5.87 microg/ml against DPPH and O2., respectively. Apoptosis (DNA fragmentation) was measured by an ELISA technique. Cells were exposed to oxidative stress by treating them with peroxynitrite (100-300 microM) for 4 h in the presence and absence of PHY. Peroxynitrite elicited a dose-dependent increase in DNA fragmentation in both cell lines compared to the control group receiving decomposed ONOO-. PHY (10, 30, or 50 microg/ml) significantly attenuated the degree of apoptosis in T84 cells induced by ONOO- (P < 0.05). PHY (10-100 microg/ml) did not directly affect T84 cell viability or induce apoptosis after 4 h or overnight exposure. RAW 264.7 cells exposed to PHY alone (>30 microg/ml) for 4 h displayed decreased cell viability (P < 0.05) and increased apoptosis (P < 0.05). Phytolens may have beneficial effects on inflammation by attenuating peroxynitrite-induced apoptosis. The sparing of epithelial cells while compromising the viability of macrophages suggests that PHY may be beneficial in autoimmune disorders. 10.1006/niox.1997.0160
    Melatonin is more effective than ascorbic acid and β-carotene in improvement of gastric mucosal damage induced by intensive stress. Akinci Aysin,Esrefoglu Mukaddes,Cetin Asli,Ates Burhan Archives of medical science : AMS INTRODUCTION:Oxidative stress has been considered to play a primary role in the pathogenesis of stress-induced gastric damage. The aim of this study was to investigate the effects of melatonin, ascorbic acid and β-carotene on stress-induced gastric mucosal damage. MATERIAL AND METHODS:Fifty-six male Wistar albino rats were divided into control, stress, stress + standard diet, stress + saline, stress + melatonin, stress + ascorbic acid and stress + β-carotene groups. The rats from stress groups were exposed to starvation, immobilization and cold by immobilizing for 8 h at +4°C following 72-hour food restriction. Following stress application, melatonin, ascorbic acid and β-carotene were administered for 7 days. Specimens of gastric tissue were prepared for microscopic and biochemical examinations. RESULTS:Mean histopathological damage scores and mean tissue malondialdehyde levels were significantly decreased but mean tissue glutathione levels and glutathione peroxidase and superoxide dismutase activities were increased in treatment groups vs. stress groups in general. Mean histopathological damage scores of the stress + Mel group was lower than those of stress + D, stress + S, stress + β-car (p < 0.05) and stress + Asc groups (p < 0.005). Additionally, mean tissue catalase activity of the stress + Mel group was higher than that of stress + S (p < 0.005), stress + D (p < 0.05) and stress + β-car groups (p < 0.05). CONCLUSIONS:Melatonin is more effective than ascorbic acid and β-carotene in improvement of gastric damage induced by intensive stress. We suggest that as well as the direct antioxidant and free radical scavenging potency of melatonin, its indirect effect via the brain-gut axis might account for its greater beneficial action against stress-induced gastric damage. 10.5114/aoms.2015.54870
    Nutrient interface with biology and aging. Cederholm Tommy,Morley John E Current opinion in clinical nutrition and metabolic care PURPOSE OF REVIEW:To highlight recent conundrums in the interface of nutrition, biology and aging. RECENT FINDINGS:A Mediterranean diet with extra virgin olive oil, or similar plant-based diets, including five helpings of fruit and vegetables, exercise and nonsmoking are the mainstays of aging successfully. Recent studies have questioned the utility of weight loss in older persons, the use of antioxidant vitamin supplements as well as the appropriate level of sodium intake. The understanding of the role of ethnicity in the levels of vitamin D-binding protein has questioned the measurement of 25(OH)vitamin D by itself. Gut microbiota may also appear important for aging. SUMMARY:Continuous scientific advances are leading us to question whether some of our nutrient beliefs need to be altered in older persons. 10.1097/MCO.0000000000000241
    NMR-based metabonomic approach reveals changes in the urinary and fecal metabolome caused by resveratrol. Torres Santiago Gabriela,Serrano Contreras José Iván,Meléndez Camargo María Estela,Zepeda Vallejo L Gerardo Journal of pharmaceutical and biomedical analysis An untargeted NMR-based metabonomics approach was used to evaluate the effects of pure resveratrol (RSV, 50 and 250 mg/kg per os) on the urinary and faecal metabolome of normal female Wistar rats. Multivariate data analysis on both the endogenous and xenobiotic metabotype of RSV provided an insight into its metabolic fate and influence on endogenous metabolites. The xenobiotic trajectory shows that RSV is highly metabolized within the first 12 h, the period of the most significant variation of endogenous metabolites. The results reveal alterations in gut microbiota co-metabolites, mainly at the high dose of RSV, such as hippurate, phenylacetyl glycine (PAG), p-cresyl glucuronide (p-CG), p-cresyl sulfate (p-CS) and 3-indoxylsulfate (3IS), as well as in osmolytes (creatine, creatinine, taurine and proline betaine). This metabolic variation could mean that RSV modulates the composition and/or function of the gut microbiota as well as its interaction with the host through the gut-microbiome-liver-kidney axis. For instance, RSV may interact with conjugating enzymes present in the intestine and liver. There were also modifications in metabolites of the tricarboxylic acid (TCA) cycle and energy metabolism (2-oxoglutarate, lactate and alanine), and diet-derived metabolites (pantothenate and trans-aconitate). These effects of RSV are perhaps related to its capacity to control energy homeostasis, provide renal protection, and downregulate some biomarkers of oxidative stress (e.g., glycoproteins). Such changes contribute to reduced oxidative stress and inflammation, which are associated with RSV-induced biological activity to improve various conditions, including metabolic disorders, obesity, and chronic and cardiovascular diseases. 10.1016/j.jpba.2018.09.025
    Rutin metabolites: novel inhibitors of nonoxidative advanced glycation end products. Pashikanti Srinath,de Alba David R,Boissonneault Gilbert A,Cervantes-Laurean Daniel Free radical biology & medicine Glycation is a nonenzymatic condensation reaction between reducing sugars and amino groups of proteins that undergo rearrangements to stable ketoamines, leading to the formation of advanced glycation end products (AGEs) including fluorescent (argpyrimidine) and nonfluorescent (N(epsilon)-carboxymethyllysine; CML) protein adducts and protein cross-links. AGEs are formed via protein glycation and correlate with processes resulting in aging and diabetes complications. Reactive carbonyl species such as glyoxal and methylglyoxal are ubiquitous by-products of cell metabolism that potently induce the formation of AGEs by nonenzymatic protein glycation and may achieve plasma concentrations of 0.3-1.5 micromol/L. In this in vitro study histone H1 glycation by glyoxal, methylglyoxal, or ADP-ribose was used to model nonoxidative protein glycation, permitting us to distinguish specific AGE inhibition from general antioxidant action. Rutin derivatives were tested as AGE inhibitors because rutin, a common dietary flavonoid that is consumed in fruits, vegetables, and plant-derived beverages, is metabolized by gut microflora to a range of phenolic compounds that are devoid of significant antioxidant activity and achieve blood concentrations in the mumol/L range. Our data show that in a 1:1 stoichiometry with glyoxal or methylglyoxal, 3,4-dihydroxyphenylacetic acid (DHPAA) and 3,4-dihydroxytoluene (DHT) are powerful inhibitors of CML and argpyrimidine histone H1 adduct formation, respectively. Furthermore, when DHPAA and DHT were tested as inhibitors of histone H1 glycation by the powerful glycating agent ADP-ribose, they inhibited glycation as effectively as aminoguanidine. These results suggest that dietary flavonoids may serve as effective AGE inhibitors and suggest mechanisms whereby fruit- and vegetable-rich diets contribute to the prevention of processes resulting in aging and diabetes complications. 10.1016/j.freeradbiomed.2009.11.019
    In nutrition, can we "see" what is good for us? Barnes Stephen,Prasain Jeevan,Kim Helen Advances in nutrition (Bethesda, Md.) The selection of foods to eat is a complex interplay of vision, taste, smell, and texture. In addition to micro- and macronutrients, plant-based foods also contain several classes of phytochemicals. In many cases, the phytochemicals account for the various colors of foods. Although aesthetically pleasing, the color of foods may mislead consumers as to their phytochemical content, which is particularly true with regard to polyphenols. Polyphenols are a broad class of compounds with antioxidant and other health benefits. Human vision is limited to a small window (390-765 nm) of the electromagnetic spectrum. Many important phytochemicals (e.g., vitamin C) have no absorbance in this range. Therefore, the human eye cannot directly judge the vitamin C content of foods. Being able to see in the ultraviolet range allows bees to locate the pollen-rich region of flowers, whereas pit vipers locate their prey by being able to "see" them in the infrared range. Assessing the impact of phytochemicals on human health depends on several factors. Colorless phytochemicals in unprocessed foods may be lost during the cooking process because no visual guide exists to ensure their retention. The molecular structures of phytochemicals influence the extent to which they are altered by cooking processes and the methods by which they are absorbed from the gastrointestinal tract. Extensive metabolism by phase I/II enzymes and by the gut microbiome may also create compounds that the eye is never allowed to appreciate. 10.3945/an.112.003558
    Addition of grape pomace extract to probiotic fermented goat milk: the effect on phenolic content, probiotic viability and sensory acceptability. Dos Santos Karina Mo,de Oliveira Isabel C,Lopes Marcos Ac,Cruz Ana Paula Gil,Buriti Flávia Ca,Cabral Lourdes M Journal of the science of food and agriculture BACKGROUND:Grape pomace is a source of phenolic compounds, which are associated with health benefits in humans. Additionally, fermented dairy foods with probiotics can be good vehicles to deliver these bioactive compounds. The effects of the addition of grape pomace extract (GPE) on the total phenolic (TP) content, physico-chemical characteristics and viability of Lactobacillus acidophilus LA-5 or Lactobacillus rhamnosus HN001 in fermented goat milks prepared with grape juice were investigated. RESULTS:The TP concentration increased significantly in fermented milks with the addition of GPE. A protective effect of GPE on the viability of L. acidophilus was observed. However, after 14 days of storage, the populations of L. acidophilus were significantly lower when compared with those of L. rhamnosus, and only the last probiotic maintained its viability above 7 log CFU mL throughout the period investigated. The sensory scores of flavor, color and overall acceptability of the fermented milk containing L. rhamnosus HN001 were significantly increased when GPE was added. CONCLUSION:The use of GPE might increase the functionality of probiotic fermented goat milk processed with L. rhamnosus HN001 and grape juice because grape polyphenols are known for their antioxidant properties and positive effect on the modulation of gut microbiota. © 2016 Society of Chemical Industry. 10.1002/jsfa.7836
    Pentoxifylline increases gut ketogenesis following trauma and hemorrhagic shock. Wang W,Wang P,Chaudry I H Critical care medicine OBJECTIVES:Although pentoxifylline produces various beneficial effects following adverse circulatory conditions, it is not known whether this agent has any effects on gut lipid metabolism after trauma-hemorrhage and resuscitation. The aim of this study, therefore, was to determine whether or not administration of pentoxifylline after trauma-hemorrhagic shock has any salutary effects on gut ketogenesis. DESIGN:A prospective, controlled animal study. SETTING:A university research laboratory. SUBJECTS:Fifty-six male Sprague-Dawley rats. INTERVENTIONS:Rats underwent a midline laparotomy (i.e., trauma-induced) and were bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of the shed blood volume was returned in the form of lactated Ringer's solution. The animals were then resuscitated with four times the volume of maximal bleedout with lactated Ringer's solution over 60 mins. Pentoxifylline (50 mg/kg body weight) or an equivalent volume of normal saline was infused intravenously over 100 mins during and after resuscitation. For in vivo lipid loading, one milliliter of olive oil was given intraduodenally on the completion of resuscitation. Blood samples from portal vein and carotid artery, as well as enterocytes from proximal small intestine, were obtained at 1.5 hrs after fat feeding. MEASUREMENTS AND MAIN RESULTS:Mitochondrial fatty acid beta-oxidation enzyme (i.e., palmitoyl-coenzyme A dehydrogenase) activity, as well as portal and arterial plasma beta-hydroxybutyrate values, were determined. Palmitoyl-coenzyme A dehydrogenase activity in villus tip cells and plasma beta-hydroxybutyrate values in portal vein and carotid artery were significantly reduced after trauma-hemorrhage and resuscitation. Pentoxifylline administration, however, significantly increased mitochondrial fatty acid beta-oxidation enzyme activity and portal plasma beta-hydroxybutyrate concentration without significantly affecting arterial concentrations under such conditions. CONCLUSION:Pentoxifylline promotes gut ketogenesis following trauma-hemorrhage and resuscitation. 10.1097/00003246-199801000-00023
    Polyphenols, food and pharma. Current knowledge and directions for future research. Tresserra-Rimbau Anna,Lamuela-Raventos Rosa M,Moreno Juan J Biochemical pharmacology Polyphenols are a large family of phytochemicals with great chemical diversity, known to be bioactive compounds of foods, species, medicinal plants and nutraceuticals. These compounds are ingested through the diet in significant amounts, around 1 g per day, an amount that be may be increased through supplements. The in vitro action of many representative polyphenols has been reported. However, their beneficial effects and their role in modulating the risk of high-prevalence diseases are difficult to demonstrate due to the wide variability of polyphenol structures and bioactive actions; the complexity of estimating the polyphenol content of food as a result of their variability in foods and cooked dishes; the potential modulation of the effects of polyphenols by food matrices; the addition of polyphenols and their synergistic interactions with each other and with other dietary bioactive components; the modulation of polyphenol bioavailability as a consequence of food composition and culinary techniques; their metabolism by the human body and the polyphenol gut microbiota metabolism in each metabotypes. Computational strategies, including virtual screening, shape-similarity-screening and molecular docking, were recently used to identify potential targets of polyphenols and thus gain a better understanding of the therapeutic effects exerted of polyphenols and modify natural polyphenol structures to potentiate specific activities. Here, we present the most relevant current knowledge and propose directions for future research in these fields, from the culinary world to the clinical setting. We hope this commentary will prompt scientists and clinicians to consider the therapeutic value of bioactive polyphenols and help shed some light on how much scientific truth lies in Hippocrates' famous quote: "Let your food be your medicine". 10.1016/j.bcp.2018.07.050
    Health benefits of walnut polyphenols: An exploration beyond their lipid profile. Sánchez-González Claudia,Ciudad Carlos J,Noé Véronique,Izquierdo-Pulido Maria Critical reviews in food science and nutrition Walnuts are commonly found in our diet and have been recognized for their nutritious properties for a long time. Traditionally, walnuts have been known for their lipid profile, which has been linked to a wide array of biological properties and health-promoting effects. In addition to essential fatty acids, walnuts contain a variety of other bioactive compounds, such as vitamin E and polyphenols. Among common foods and beverages, walnuts represent one of the most important sources of polyphenols, hence their effect over human health warrants attention. The main polyphenol in walnuts is pedunculagin, an ellagitannin. After consumption, ellagitannins are hydrolyzed to release ellagic acid, which is converted by gut microflora to urolithin A and other derivatives such as urolithins B, C, and D. Ellagitannins possess well known antioxidant and anti-inflammatory bioactivity, and several studies have assessed the potential role of ellagitannins against disease initiation and progression, including cancer, cardiovascular, and neurodegenerative diseases. The purpose of this review is to summarize current available information relating to the potential effect of walnut polyphenols in health maintenance and disease prevention. 10.1080/10408398.2015.1126218
    The Problem of Curcumin and Its Bioavailability: Could Its Gastrointestinal Influence Contribute to Its Overall Health-Enhancing Effects? Lopresti Adrian L Advances in nutrition (Bethesda, Md.) Curcumin, from the spice turmeric, exhibits anti-inflammatory, antioxidant, anticancer, antiviral, and neurotrophic activity and therefore holds promise as a therapeutic agent to prevent and treat several disorders. However, a major barrier to curcumin's clinical efficacy is its poor bioavailability. Efforts have therefore been dedicated to developing curcumin formulations with greater bioavailability and systemic tissue distribution. However, it is proposed in this review that curcumin's potential as a therapeutic agent may not solely rely on its bioavailability, but rather its medicinal benefits may also arise from its positive influence on gastrointestinal health and function. In this review, in vitro, animal, and human studies investigating the effects of curcumin on intestinal microbiota, intestinal permeability, gut inflammation and oxidative stress, anaphylactic response, and bacterial, parasitic, and fungal infections are summarized. It is argued that positive changes in these areas can have wide-ranging influences on both intestinal and extraintestinal diseases, and therefore presents as a possible mechanism behind curcumin's therapeutic efficacy. 10.1093/advances/nmx011
    Inhibitory activity of gut bacteria against Escherichia coli O157 mediated by dietary plant metabolites. Duncan S H,Flint H J,Stewart C S FEMS microbiology letters Under both aerobic and anaerobic conditions, the growth of Escherichia coli O157 strain NCTC 12,900 was inhibited by the coumarins esculetin, umbelliferone and scopoletin, but not by the coumarin glycoside esculin. Esculin-hydrolysing bacteria from the rumen, the pig gut and the human gut inhibited growth of E. coli in an overlay-plate assay in the presence of esculin. The combined effect of esculetin and volatile fatty acids was greater than the effect of either factor alone suggesting that coumarin glycosides in the diet might reduce the growth or survival of E. coli O157 in the gut. Adding esculin to incubations of mixed rumen contents significantly reduced the survival of E. coli O157. 10.1111/j.1574-6968.1998.tb13099.x
    Polyphenol Health Effects on Cardiovascular and Neurodegenerative Disorders: A Review and Meta-Analysis. Potì Francesco,Santi Daniele,Spaggiari Giorgia,Zimetti Francesca,Zanotti Ilaria International journal of molecular sciences Several studies have demonstrated that polyphenol-enriched diets may have beneficial effects against the development of degenerative diseases, including atherosclerosis and disorders affecting the central nervous system. This activity has been associated not only with antioxidant and anti-inflammatory properties, but also with additional mechanisms, such as the modulation of lipid metabolism and gut microbiota function. However, long-term studies on humans provided controversial results, making the prediction of polyphenol impact on health uncertain. The aim of this review is to provide an overview and critical analysis of the literature related to the effects of the principal dietary polyphenols on cardiovascular and neurodegenerative disorders. We critically considered and meta-analyzed randomized controlled clinical trials involving subjects taking polyphenol-based supplements. Although some polyphenols might improve specific markers of cardiovascular risk and cognitive status, many inconsistent data are present in literature. Therefore, definitive recommendations for the use of these compounds in the prevention of cardiovascular disease and cognitive decline are currently not applicable. Once pivotal aspects for the definition of polyphenol bioactivity, such as the characterization of pharmacokinetics and safety, are addressed, it will be possible to have a clear picture of the realistic potential of polyphenols for disease prevention. 10.3390/ijms20020351
    Curcumin utilizes the anti-inflammatory response pathway to protect the intestine against bacterial invasion. Cho Jin Ah,Park Eunmi Nutrition research and practice BACKGROUND/OBJECTIVES:Curcumin, a major component of the Curcuma species, contains antioxidant and anti-inflammatory properties. Although it was found to induce apoptosis in cancer cells, the functional role of curcumin as well as its molecular mechanism in anti-inflammatory response, particularly in intestinal cells, has been less investigated. The intestine epithelial barrier is the first barrier and the most important location for the substrate coming from the lumen of the gut. SUBJECTS/METHODS:We administered curcumin treatment in the human intestinal epithelial cell lines, T84 and Caco-2. We examined endoplasmic reticulum (ER) stress response by thapsigargin, qPCR of XBP1 and BiP, electrophysiology by wild-type cholera toxin in the cells. RESULTS:In this study, we showed that curcumin treatment reduces ER stress and thereby decreases inflammatory response in human intestinal epithelial cells. In addition, curcumin confers protection without damaging the membrane tight junction or actin skeleton change in intestine epithelial cells. Therefore, curcumin treatment protects the gut from bacterial invasion via reduction of ER stress and anti-inflammatory response in intestinal epithelial cells. CONCLUSIONS:Taken together, our data demonstrate the important role of curcumin in protecting the intestine by modulating ER stress and inflammatory response post intoxication. 10.4162/nrp.2015.9.2.117
    Cyanidin-3-O-glucoside: Physical-Chemistry, Foodomics and Health Effects. Olivas-Aguirre Francisco J,Rodrigo-García Joaquín,Martínez-Ruiz Nina Del R,Cárdenas-Robles Arely I,Mendoza-Díaz Sandra O,Álvarez-Parrilla Emilio,González-Aguilar Gustavo A,de la Rosa Laura A,Ramos-Jiménez Arnulfo,Wall-Medrano Abraham Molecules (Basel, Switzerland) Anthocyanins (ACNs) are plant secondary metabolites from the flavonoid family. Red to blue fruits are major dietary sources of ACNs (up to 1 g/100 g FW), being cyanidin-3--glucoside (Cy3G) one of the most widely distributed. Cy3G confers a red hue to fruits, but its content in raspberries and strawberries is low. It has a good radical scavenging capacity (RSC) against superoxide but not hydroxyl radicals, and its oxidative potential is pH-dependent (58 mV/pH unit). After intake, Cy3G can be metabolized (phases I, II) by oral epithelial cells, absorbed by the gastric epithelium (1%-10%) and it is gut-transformed (phase II &amp; microbial metabolism), reaching the bloodstream (<1%) and urine (about 0.02%) in low amounts. In humans and Caco-2 cells, Cy3G's major metabolites are protocatechuic acid and phloroglucinaldehyde which are also subjected to entero-hepatic recycling, although caffeic acid and peonidin-3-glucoside seem to be strictly produced in the large bowel and renal tissues. Solid evidence supports Cy3G's bioactivity as DNA-RSC, gastro protective, anti-inflammatory, anti-thrombotic chemo-preventive and as an epigenetic factor, exerting protection against infection, age-related diseases, type 2 diabetes, cardiovascular disease, metabolic syndrome and oral cancer. Most relevant mechanisms include RSC, epigenetic action, competitive protein-binding and enzyme inhibition. These and other novel aspects on Cy3G's physical-chemistry, foodomics, and health effects are discussed. 10.3390/molecules21091264
    Grinding levels of raspberry pomace affect intestinal microbial activity, lipid and glucose metabolism in Wistar rats. Fotschki Bartosz,Juśkiewicz Jerzy,Jurgoński Adam,Kosmala Monika,Milala Joanna,Zduńczyk Zenon,Markowski Jarosław Food research international (Ottawa, Ont.) This study presents the effect of raspberry pomace and its grinding level on microbial activity in the gastrointestinal tract as well as on the parameters involved in the regulation of lipid and glucose metabolism in Wistar rats. The nutritional experiment was performed using 24 male Wistar rats, which were divided into 3 groups of 8 animals each. The animals were fed a standard diet (C) or a modified diet containing 7% raspberry pomace subjected to standard (SG) or fine (FG) grinding. Finer grinding increased the concentration of polyphenols and altered the composition of the dietary fibre, thereby affecting the intestinal microbial activity and related mechanisms that regulate systemic parameters. The FG diet considerably increased the level of total ellagitannin metabolites in the colon (23.56 μg/g for SG and 79.54 μg/g for FG) and plasma (0.029 μg/mL for SG and 0.041 μg/mL for FG) and reduced β-glucuronidase and α-glucosidase activity (19.2 and 19.7 for SG and 13.3 and 8.7 μmol/h/g for FG, respectively) and short-chain fatty acid production (55.84 μmol/g for SG and 48.60 μmol/g for FG) in the caecum. Compared to the SG, the FG diet improved the antioxidant capacity of water-soluble substances in plasma (4.34 μg/mL for SG and 4.92 μg/mL for FG). Both diets with raspberry pomaces increased the plasma HDL cholesterol (0.48 mmol/L for C, 0.56 mmol/L for SG, 0.57 mmol/L for FG) and decreased the atherogenic index (AI = (TC-HDL)/HDL: 2.57 for C, 1.98 for SG, 2.00 for FG). The FG diet resulted in the lowest plasma glucose level (10.8 mmol/L for C, 8.2 mmol/L for SG, 7.3 mmol/L for FG). In conclusion, both diets with raspberry pomaces modulated intestinal microbial activity and related systemic parameters; however, FG pomace exhibited greater inhibitory effects than SG pomace in the lower gut environment and glucose metabolism. 10.1016/j.foodres.2019.03.014
    Synergistic anti-inflammatory effects and mechanisms of combined phytochemicals. Zhang Lijuan,Virgous Carlos,Si Hongwei The Journal of nutritional biochemistry The anti-inflammatory effects of phytochemicals, bioactive components from plants having health benefits, have been heavily investigated in the last several decades. However, the gap between the high dosage demands (μM) of phytochemicals in vitro studies and the low bioavailability (nM) of most phytochemicals after consuming relevant foods/supplements in humans undermines the application of these phytochemicals in the prevention of chronic inflammation and its related chronic diseases in humans. One of the approaches to bridging this gap is to combine two or more phytochemicals/foods to synergistically prevent chronic inflammation. While increasing combinations of phytochemicals on anti-inflammation studies have been reported, there is no report dedicating why combining two or more phytochemicals synergistically attenuates chronic inflammation. In the present review, we summarized different types of combinations exerting synergistic anti-inflammatory effects such as the combination of phytochemicals from the same foods, and the combination of phytochemicals from different foods/plants. Particularly, we proposed five mechanisms including enhancing the bioavailability of phytochemicals, increasing antioxidant capacity, interacting with gut microbiome and targeting same and different signaling pathways, to understand how the combination of phytochemicals exerts synergistic anti-inflammatory effects in cells, animals, and humans. This review provides clues to boost more studies to combine several phytochemicals/foods to reduce chronic inflammation and prevent chronic diseases in humans. 10.1016/j.jnutbio.2019.03.009
    Melatonin protects rats from radiotherapy-induced small intestine toxicity. Fernández-Gil Beatriz,Moneim Ahmed E Abdel,Ortiz Francisco,Shen Ying-Qiang,Soto-Mercado Viviana,Mendivil-Perez Miguel,Guerra-Librero Ana,Acuña-Castroviejo Darío,Molina-Navarro María M,García-Verdugo José M,Sayed Ramy K A,Florido Javier,Luna Juan D,López Luis Carlos,Escames Germaine PloS one Radiotherapy-induced gut toxicity is among the most prevalent dose-limiting toxicities following radiotherapy. Prevention of radiation enteropathy requires protection of the small intestine. However, despite the prevalence and burden of this pathology, there are currently no effective treatments for radiotherapy-induced gut toxicity, and this pathology remains unclear. The present study aimed to investigate the changes induced in the rat small intestine after external irradiation of the tongue, and to explore the potential radio-protective effects of melatonin gel. Male Wistar rats were subjected to irradiation of their tongues with an X-Ray YXLON Y.Tu 320-D03 irradiator, receiving a dose of 7.5 Gy/day for 5 days. For 21 days post-irradiation, rats were treated with 45 mg/day melatonin gel or vehicle, by local application into their mouths. Our results showed that mitochondrial oxidative stress, bioenergetic impairment, and subsequent NLRP3 inflammasome activation were involved in the development of radiotherapy-induced gut toxicity. Oral treatment with melatonin gel had a protective effect in the small intestine, which was associated with mitochondrial protection and, consequently, with a reduced inflammatory response, blunting the NF-κB/NLRP3 inflammasome signaling activation. Thus, rats treated with melatonin gel showed reduced intestinal apoptosis, relieving mucosal dysfunction and facilitating intestinal mucosa recovery. Our findings suggest that oral treatment with melatonin gel may be a potential preventive therapy for radiotherapy-induced gut toxicity in cancer patients. 10.1371/journal.pone.0174474
    Citrus aurantium L. var. amara Engl. inhibited lipid accumulation in 3T3-L1 cells and Caenorhabditis elegans and prevented obesity in high-fat diet-fed mice. Shen Chun-Yan,Wan Lin,Wang Tian-Xing,Jiang Jian-Guo Pharmacological research Natural products with anti-obesity effects and few side effects have attracted great attention recently. Citrus aurantium L. var. amara Engl. (CAVA) is popularly consumed as an edible and medicinal resource in China. However, its anti-obesity effects were poorly understood. The anti-obesity effects of CAVA extracts were systematically evaluated using 3T3-L1 cells, Caenorhabditis elegans (C. elegans) and high fat diet (HFD)-fed mice. Flavonoid-rich (EA) extracts with neohesperidin, hesperidin and naringin comprising 32.15%, were isolated from CAVA. EA extracts treatment significantly inhibited differentiation of 3T3-L1 preadipocytes by modulating lipid metabolism-related mediators. EA extracts supplementation also inhibited antioxidant responses in C. elegans by decreasing reactive oxygen species generation and malonaldehyde value, and increasing superoxide dismutase content. EA extracts feeding markedly decreased triglyceride (TG) content, and affected expression of genes involved in lipid and glucose metabolism in wild type C. elegans. TG content in mdt-15 (XA7702) mutants was not decreased by EA extracts administration, suggesting that EA extracts treatment might inhibit lipid accumulation in C. elegans dependent on mdt-15. EA extracts intervention further reduced body weight gain and modulated plasma biochemical parameters in HFD-fed mice. EA extracts treatment prevented HFD-induced epididymal adipose hypertrophy, liver oxidative injuries and steatosis. EA extracts administration also strongly prevented HFD-induced reduction of gut microbial diversity, decreased the Firmicutes-to-Bacteroidetes ratio and the Erysipelotrichaceae abundance, and enhanced the Bifidobacteriace abundance in HFD-fed mice. EA extracts from blossoms of CAVA were excellent antiobesogenic candidates that acted through multiple mechanisms that acted simultaneously. 10.1016/j.phrs.2019.104347
    Caffeine and its main targets of colorectal cancer. Cui Wen-Qi,Wang Shi-Tong,Pan Dan,Chang Bing,Sang Li-Xuan World journal of gastrointestinal oncology Caffeine is a purine alkaloid and is widely consumed in coffee, soda, tea, chocolate and energy drinks. To date, a growing number of studies have indicated that caffeine is associated with many diseases including colorectal cancer. Caffeine exerts its biological activity through binding to adenosine receptors, inhibiting phosphodiesterases, sensitizing calcium channels, antagonizing gamma-aminobutyric acid receptors and stimulating adrenal hormones. Some studies have indicated that caffeine can interact with signaling pathways such as transforming growth factor β, phosphoinositide-3-kinase/AKT/mammalian target of rapamycin and mitogen-activated protein kinase pathways through which caffeine can play an important role in colorectal cancer pathogenesis, metastasis and prognosis. Moreover, caffeine can act as a general antioxidant that protects cells from oxidative stress and also as a regulatory factor of the cell cycle that modulates the DNA repair system. Additionally, as for intestinal homeostasis, through the interaction with receptors and cytokines, caffeine can modulate the immune system mediating its effects on T lymphocytes, B lymphocytes, natural killer cells and macrophages. Furthermore, caffeine can not only directly inhibit species in the gut microbiome, such as and but also can indirectly exert inhibition by increasing the effects of other antimicrobial drugs. This review summarizes the association between colorectal cancer and caffeine that is being currently studied. 10.4251/wjgo.v12.i2.149
    The role of diet in preventing and reducing cognitive decline. Angeloni Cristina,Businaro Rita,Vauzour David Current opinion in psychiatry PURPOSE OF REVIEW:This review summarises the most recent evidence regarding the effects of diet in preventing and reducing age-related cognitive decline and neurodegenerative diseases. RECENT FINDINGS:Recent evidence indicates that nutraceuticals and whole diet approaches may protect against the development of age-related cognitive decline and pathological neurodegeneration. The neuroprotective effects are diverse depending on the nutrient employed and may involve a reduction of neuroinflammation, an activation of the endogenous antioxidant defence system and a modulation of the gut microbiota structure and function. SUMMARY:This review summarises the existing evidence in favour of diet as a viable alternative approach to directly impact cognitive decline and neurodegenerative diseases. The single nutrient (polyphenols, B vitamins, long-chain polyunsaturated fatty acids) versus whole diet approach (Mediterranean diet, Dietary Approaches to Stop Hypertension, MIND, Nordic, ketogenic) is presented and discussed. Potential mechanisms of action underlying the beneficial effects of these diets are also described. Implementation of large-scale preventive interventions based on dietary patterns identified as being beneficial to brain health should be a research and public health priority, ideally in conjunction with other health-promoting lifestyle factors. 10.1097/YCO.0000000000000605
    Dietary Habits and Nutrition in Rheumatoid Arthritis: Can Diet Influence Disease Development and Clinical Manifestations? Gioia Chiara,Lucchino Bruno,Tarsitano Maria Grazia,Iannuccelli Cristina,Di Franco Manuela Nutrients Rheumatoid arthritis (RA) is a systemic, autoimmune disease characterized by joint involvement, with progressive cartilage and bone destruction. Genetic and environmental factors determine RA susceptibility. In recent years, an increasing number of studies suggested that diet has a central role in disease risk and progression. Several nutrients, such as polyunsaturated fatty acids, present anti-inflammatory and antioxidant properties, featuring a protective role for RA development, while others such as red meat and salt have a harmful effect. Gut microbiota alteration and body composition modifications are indirect mechanisms of how diet influences RA onset and progression. Possible protective effects of some dietary patterns and supplements, such as the Mediterranean Diet (MD), vitamin D and probiotics, could be a possible future adjunctive therapy to standard RA treatment. Therefore, a healthy lifestyle and nutrition have to be encouraged in patients with RA. 10.3390/nu12051456
    Bioavailability and Bioactivity of Encapsulated Phenolics and Carotenoids Isolated from Red Pepper Waste. Vulić Jelena,Šeregelj Vanja,Kalušević Ana,Lević Steva,Nedović Viktor,Tumbas Šaponjac Vesna,Čanadanović-Brunet Jasna,Ćetković Gordana Molecules (Basel, Switzerland) In order to deactivate the health properties of bioactive compounds, they need to withstand the effects of food processing, their potential release from the food matrix, and remain bio-accessible in the gastrointestinal tract. Bio-actives from different plants are prone to oxidative degradation, and encapsulation is an effective method in improving their stability. In the present study, red pepper waste (RPW), a by-product of vegetable processing industry, was encapsulated in whey protein using spray and freeze-drying techniques. The aim was to evaluate the effects of in vitro gastrointestinal digestion on the release and bioactivity of encapsulated bio-actives, after each digestion step. The results showed that the release of phenolics and carotenoids, as well as antioxidants, anti-hyperglycemic, and anti-inflammatory activities are influenced by pH and intestinal fluid, with pH 7.5 exhibited at higher levels. There was a rapid initial release of carotenoids from whey protein matrices, while a more gradual increase of phenolics was observed, reaching around 50% for both encapsulates first at 6 h and 37 °C, and small intestine conditions. The encapsulation of RPW demonstrated a protective effect against pH changes and enzymatic activities along digestion, and contributed to the increase in bio-accessibility in the gut. Also, the results suggest that encapsulation is an efficient method for valorization of bio-actives from RPW, with improvements in nutrition, color, and bioactive properties. 10.3390/molecules24152837
    Resveratrol Anti-Obesity Effects: Rapid Inhibition of Adipocyte Glucose Utilization. Carpéné Christian,Les Francisco,Cásedas Guillermo,Peiro Cécile,Fontaine Jessica,Chaplin Alice,Mercader Josep,López Víctor Antioxidants (Basel, Switzerland) Studies in animal models of diabetes and obesity have shown that resveratrol mitigates complications of metabolic diseases, beyond those resulting from oxidative stress. Furthermore, results obtained with cultured preadipocytes have also revealed that prolonged resveratrol treatment impairs adipogenesis. Considering the role of adipocytes in the hypertrophy of fat stores, and keeping in mind that insulin is the main trigger of excessive energy storage during post-prandial periods, the present study aimed to investigate how short-term effects of resveratrol can limit glucose disposal in a gut-adipose tissue axis. We found that resveratrol exhibits a more potent inhibitory capacity towards α-glucosidase than pancreatic lipase activity. Resveratrol also rapidly blunts glucose transport in mature fat cells by counteracting the effect of insulin and insulin-like lipogenic agents. Within two hours, resveratrol also inhibited the incorporation of glucose into lipids of adipocytes, which was unaffected by membrane cholesterol depletion. Moreover, the comparison between adipocytes with invalidated semicarbazide-sensitive amine oxidase activity and their control, or between resveratrol and several inhibitors, did not indicate that the recently described interaction of resveratrol with amine oxidases was involved in its antilipogenic effect. Caffeine and piceatannol, previously said to interact with glucose carriers, also inhibit lipogenesis in adipocytes, whereas other antioxidant phytochemicals do not reproduce such an antilipogenic effect. This study highlights the diverse first steps by which resveratrol impairs excessive fat accumulation, indicating that this natural molecule and its derivatives deserve further studies to develop their potential anti-obesity properties. 10.3390/antiox8030074
    Effects of combination dietary conjugated linoleic acid with vitamin A (retinol) and selenium on the response of the immunoglobulin production in mice. Kim Jin-young,Chung Byung-hyun Journal of veterinary science The dietary effect of conjugated linoleic acid (CLA) on the response of the immunoglobulin (serum and tissue) production in Balb/C mice was examined at three doses: 0 %(control), 0.5% and 1.5%. The combination effects of CLA with vitamin ADE or selenium also were investigated. CLA at 0.5% increased serum immunoglobulin A, G, mesenteric lymph node (MHN) and gut luminal IgA (secretory IgA) levels. However, 1.5% CLA decreased SIgG slightly. CLA both alone and combined with vitamin ADE and selenium did not affect serum IgE. The levels of immunoglobulin concentration in the 0.5% CLA group were higher than those in the 1.5% CLA group. The level of serum IgG in 1.5% CLA combined with selenium was maintained at the same level as that of control. It is considered that over- doses of CLA (1.5%) even depressed the production of immunoglobulin but selenium and/or vitamin inhibited this activity to a certain extent. In this study, dietary CLA increased immunoglobulin production in a dose-dependent manner. Vitamin ADE and Selenium combined with CLA also increased the immunoglobulin production response except serum IgE.
    The Promising Pharmacological Effects and Therapeutic/Medicinal Applications of Punica Granatum L. (Pomegranate) as a Functional Food in Humans and Animals. Saeed Muhammad,Naveed Muhammad,BiBi Jannat,Kamboh Asghar A,Arain Muhammad A,Shah Qurban A,Alagawany Mahmoud,El-Hack Mohamed E A,Abdel-Latif Mervat A,Yatoo Mohd I,Tiwari Ruchi,Chakraborty Sandip,Dhama Kuldeep Recent patents on inflammation & allergy drug discovery BACKGROUND:Punica granatum L. (pomegranate), is a shrub mostly available in the Mediterranean Sea region. The fruits have gained the substantial attention among researchers due to their promising biological activities including anti-inflammatory, antibacterial, antidiarrheal, immune modulatory, antitumor, wound healing and antifungal that have been attributed to various constituents of seeds, bark, juice, pericarp, and leaf of this tree across the globe. The phenolic compounds of pomegranate have been documented to possess numbers of prophylactic and therapeutic utilities against various pathological infections as well as non-infectious disorders. OBJECTIVE:The current review expedites the pharmacological role of Punica granatum L. in curing elements related to infectious and non-infectious disorders. METHODS:The current review is based on literature and patents already available on various scientific databases highlighting the role of Punica granatum along with its therapeutic potentials against infectious and non-infectious disorders. The databases included under study were PubMed, Med line, PubMed Central, Science Direct and few other scientific databases. The information obtained through these diverse databases is compiled, critically interpreted and presented in the current study. RESULTS:Multi-dimensional beneficial application of pomegranate plant is recorded. The pomegranate seed oil has phytoestrogenic compounds and the fruit is rich in phenolic compounds with strong antioxidant activity. The fruit and bark of pomegranate are used against intestinal parasites, dysentery, and diarrhea in different animals and human models. Since the ancient time the juice and seeds had considered the best therapy for throat and heart disorders. Ellagic acid is one of the main components of pomegranate with potent antioxidant activity. Results from different studies reported that Punica granatum L or its byproducts can be used as natural food additives in human and animal nutrition in order to boost immunity, microbial safety and provide the housing environment without affecting body weight gain. In addition, Punica granatum L. byproducts can modulate immune function and gut microbiota of broiler chickens as well as reduce the odorous gas emissions from excreta. Naturally occurring polyphenols in a pomegranate can be a potential alternative medicine for the prevention of avian Colibacillosis diseases and can also be used as an intestine astringent to relieve diarrhea and enteritis in chickens. CONCLUSION:The present review gives the insight towards major components of pomegranate as well as their pharmacological activities against pathological disorders. In spite of many beneficial properties of Punica granatum L., more research evidence on a molecular basis is needed to find out the molecular mechanism of action in various animals and human models to validate the usefulness of Punica granatum L. as a potent therapeutic agent. 10.2174/1872213X12666180221154713
    Effect of synbiotic pomegranate juice on glycemic, sex hormone profile and anthropometric indices in PCOS: A randomized, triple blind, controlled trial. Esmaeilinezhad Z,Babajafari S,Sohrabi Z,Eskandari M-H,Amooee S,Barati-Boldaji R Nutrition, metabolism, and cardiovascular diseases : NMCD BACKGROUND AND AIMS:Polycystic Ovarian Syndrome is a common reproductive, endocrine, and metabolic disease in women. Pomegranate juice, known as a rich source of phytochemicals with high antioxidant activity, enriched with probiotic may improve PCOS. METHODS AND RESULTS:A randomized, controlled, triple-blinded, parallel trial study was performed in PCOS patients (n = 92). Three treatment groups (23 patients each) received 2 L of synbiotic pomegranate juice (SPJ), pomegranate juice (PJ), and synbiotic beverage (SB) weekly. The control group (23 patients) received 2 L of placebo beverage weekly. Primary outcome was any change in insulin resistance and secondary outcomes were fasting blood sugar (FBS), insulin sensitivity, testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), body mass index (BMI), waist and hip circumference, from baseline to the end of the trial. At the end of the study, 86 patients were analyzed. There was significant change in insulin resistance in the SPJ and SB groups. Insulin sensitivity increased significantly in the SPJ and SB groups. Insulin also changed significantly in the SPJ and SB groups. BMI, weight and waist circumference decreased significantly in the SPJ and SB groups. Testosterone level also decreased significantly in the SPJ and SB groups. There was no significant change in FPG, LH and FSH in any of the groups. CONCLUSION:SPJ in the form of a new beverage can improve insulin resistance, insulin, testosterone level, BMI, weight and waist circumference in PCOS. This trial was registered in Iranian Registry of Clinical Trials, with number: 25272. 10.1016/j.numecd.2018.07.002
    Polyphenolic Nutraceuticals to Combat Oxidative Stress Through Microbiota Modulation. Vamanu Emanuel Frontiers in pharmacology Due to their direct relationship with the activity of the gut microbiota, nutraceuticals are, at present, an effective alternative for the mitigation and alleviation of the dysfunctions governed by oxidative stress. The escalation in the number of the target group patients (diabetes, cardiovascular dysfunction, cancer, etc.) has spurred the quest for alternative action methods. The therapeutic value is determined through and methods, and involves the analysis of the therapeutic index. As the adverse outcomes are decreased, the pharmacological potential is assessed by the mechanisms, including biotransformation and the identification of the relevant biomarkers. Inflammatory action is among the principal effects that need to be reduced because it favors the presence of free radicals and dysbiosis. This article aimed at highlighting the action of the nutraceuticals in minimizing the oxidative stress by directly influencing the microbiota and slowing down the inflammatory progression. The pharmacological aspects as a therapeutic indicator of the use of nutraceuticals in improving the population health. 10.3389/fphar.2019.00492
    Dietary quercetin ameliorates experimental colitis in mouse by remodeling the function of colonic macrophages via a heme oxygenase-1-dependent pathway. Ju Songwen,Ge Yan,Li Ping,Tian Xinxin,Wang Haiyan,Zheng Xiaocui,Ju Songguang Cell cycle (Georgetown, Tex.) Inflammatory bowel disease (IBD) results from a chronic intestinal inflammation and tissue destruction via an aberrant immune-driven inflammatory response towards an altered gut microbiota. Dietary intervention is becoming an attractive avenue for the therapy of colitis because diet is a key determinant of the mucosal immune response. Quercetin (QCN) is the most common in nature and the major representative of dietary antioxidant flavonoids, which has been demonstrated to influence the progression of colitis. However, the underlying mechanism of QCN on intestinal immunomodulation remains unclear. Here, our study demonstrated dietary QCN could ameliorate experimental colitis in part by modulating the anti-inflammatory effects and bactericidal capacity of macrophages via Heme oxygenase-1 (Hmox1, HO-1) dependent pathway. It suggested that QCN might restore the proper intestinal host-microbe relationship to ameliorate the colitis via rebalancing the pro-inflammatory, anti-inflammatory and bactericidal function of enteric macrophages. Hence, modulating the function of intestinal macrophages with dietary administration of QCN to restore the immunological hemostasis and rebalance the enteric commensal flora is a potential and promising strategy for IBD therapy. 10.1080/15384101.2017.1387701
    Iron Transport Tocopheryl Polyethylene Glycol Succinate in Animal Health and Diseases. Srivastava Ajay,Lall Rajiv,Talukder Jamil,DuBourdieu Dan,Gupta Ramesh C Molecules (Basel, Switzerland) Gut health is the starting place for maintaining the overall health of an animal. Strategies to maintain gut health are, thus, an important part in achieving the goal of improving animal health. A new strategy to do this involves two molecules: the iron transport protein ovotransferrin (IT) and α-tocopheryl polyethylene glycol succinate (TPGS), which result in the novel formulation of ITPGS. These molecules help reduce gut pathogens, while enhancing the absorption and bioavailability of therapeutic drugs, phytomedicines, and nanomedicines. This, in turn, helps to maintain normal health in animals. Maintaining the gastrointestinal tract (GIT) in its normal condition is key for successful absorption and efficacy of any nutrient. A compromised GIT, due to an imbalance (dysbiosis) in the GIT microbiome, can lead to an impaired GI barrier system with impaired absorption and overall health of the animal. The molecules in ITPGS may address the issue of poor absorption by keeping the GI system healthy by maintaining the normal microbiome and improving the absorption of nutrients through multiple mechanisms involving antioxidative, anti-inflammatory, immunomodulatory, and antimicrobial activities. The ITPGS technology can allow the dose of active pharmaceutical or herbal medicine to be significantly reduced in order to attain equal or better efficacy. With complimentary actions between IT and TPGS, ITPGS presents a novel approach to increase the bioavailability of drugs, phytoconstituents, nutrients, and nanomedicines by enhanced transport to the tissues at the site of action, while reducing gut pathogen load. The ITPGS approach appears to be a novel strategy for maintaining the health of animals by manipulation of microbiota. 10.3390/molecules24234289
    Chia flour (Salvia hispanica L.) did not improve the deleterious aspects of hyperlipidic diet ingestion on glucose metabolism, but worsened glycaemia in mice. de Miranda Danielle Araujo,Pinheiro da Silva Fernanda,Carnier Marcela,Mennitti Laís Vales,Figuerêdo Raquel Galvão,Hachul Ana Claudia Losinskas,Boldarine Valter Tadeu,Neto Nelson Inácio Pinto,Seelaender Marília,Ribeiro Eliane Beraldi,Oller do Nascimento Claudia Maria,Carnier June,Oyama Lila Missae Food research international (Ottawa, Ont.) Obesity is mainly caused by intake of a high-fat diet and sedentarism, and is considered a public health issue worldwide. Increased intestinal permeability may favour endotoxaemia generated by lipopolysaccharides, a substance present in the cell membrane of Gram-negative bacteria, and, consequently, an increase in systemic inflammation and metabolic diseases. In contrast (On the other hand), consumption of a healthy diet can help in the prevention and treatment of metabolic syndrome. In this way, chia seeds (Salvia hispanica L.), rich in polyunsaturated fatty acids, may present an anti-inflammatory role. In addition, chia is rich in antioxidants like caffeic and gallic acid and fiber. However, few studies have investigated the relationship between chia seeds, inflammatory mechanisms and intestinal permeability. Therefore, the aim of this study was to analyse the effects of chia administration on metabolism in obese mice. Swiss mice were fed a hyperlipidic diet either supplemented with or without 3% chia flour for 16 weeks. The results showed that supplementation could not reduce the deleterious effects of the lipid-rich diet in terms of body composition, glucose intolerance and activity of antioxidants enzymes in the liver. In addition, supplementation with chia in the control diet decreased the amount of occludin in the intestinal colon. In conclusion, although chia did not improve metabolic parameters it seemed to restore the intestinal barriers integrity. The beneficial effects of chia seem to be dependent of the quantity used, since our data conflict with those in the literature; however, it is important to note that other studies, unlike our protocol, used chia in the form of seeds or oil, and not flour. 10.1016/j.foodres.2018.12.033
    Colonic fermentation of polyphenolics from Sea buckthorn (Hippophae rhamnoides) berries: Assessment of effects on microbial diversity by Principal Component Analysis. Attri Sampan,Sharma Kavita,Raigond Pinky,Goel Gunjan Food research international (Ottawa, Ont.) The present study investigates the stability of polyphenolic in Sea buckthorn berries juice (SBJ) during different phases of digestion and its effect on colonic microbial diversity. At each stage, the Total polyphenolic content (TPC), Total antioxidant activity (TAA) and polyphenolic profile was determined. A 1.64 and 2.20 folds increase in TPC with 4.88 and 9.61 folds increase in TAA were observed during gastric and small intestine digestion (p<0.05) with the release of quercetin from food matrix. The digestion resulted in deformation of intact crystalline structure as indicated by scanning electron micrographs. The colonic fermentation resulted in an increase in quercetin, caffeic acid with decrease in rutin and chlorogenic acid after 36h of fermentation (p<0.05). The Shannon diversity index (H) of beneficial groups including Lactic acid bacteria (LAB), Bacteroides/Prevotella and Bifidobacteria was increased by 35%, 71% and 17%, respectively (p<0.05). The PCA analysis indicated that the presence and digestion of polyphenolics promote the proliferation of Bacteroides/Prevotella group as well as Lactic acid bacteria and Bifidobacteria. The results suggest that SBJ is good source of prebiotic substrate in terms of the proliferation of beneficial gut microbiota. 10.1016/j.foodres.2017.11.032
    Diet and Mental Health: Review of the Recent Updates on Molecular Mechanisms. Godos Justyna,Currenti Walter,Angelino Donato,Mena Pedro,Castellano Sabrina,Caraci Filippo,Galvano Fabio,Del Rio Daniele,Ferri Raffaele,Grosso Giuseppe Antioxidants (Basel, Switzerland) Over the last decades, there has been a substantial increase in the prevalence of mental health disorders, including an increased prevalence of depression, anxiety, cognitive, and sleep disorders. Diet and its bioactive components have been recognized among the modifiable risk factors, possibly influencing their pathogenesis. This review aimed to summarize molecular mechanisms underlying the putative beneficial effects toward brain health of different dietary factors, such as micro- and macronutrient intake and habits, such as feeding time and circadian rhythm. The role of hormonal homeostasis in the context of glucose metabolism and adiponectin regulation and its impact on systemic and neuro-inflammation has also been considered and deepened. In addition, the effect of individual bioactive molecules exerting antioxidant activities and acting as anti-inflammatory agents, such as omega-3 fatty acids and polyphenols, considered beneficial for the central nervous system via modulation of adult neurogenesis, synaptic and neuronal plasticity, and microglia activation has been summarized. An overview of the regulation of the gut-brain axis and its effect on the modulation of systemic inflammation and oxidative stress has been provided. Finally, the impact of bioactive molecules on inflammation and oxidative stress and its association with brain health has been summarized. 10.3390/antiox9040346
    Chemical composition and health properties of coffee and coffee by-products. de Melo Pereira Gilberto V,de Carvalho Neto Dão Pedro,Magalhães Júnior Antonio I,do Prado Fernanda Guilherme,Pagnoncelli Maria Giovana B,Karp Susan Grace,Soccol Carlos Ricardo Advances in food and nutrition research Coffee can be an ally in the fight against diseases such as type 2 diabetes, cancer, hepatic injury, cirrhosis, depression, suicidal behavior, and neurological and cardiovascular disorders. The properties of coffee also favor gastrointestinal tract and gut microbiota establishment. Coffee bioactive components include phenolic compounds (chlorogenic acids, cafestol and kahweol), alkaloids (caffeine and trigonelin), diterpenes (cafestol and kahweol) and other secondary metabolites. The image of coffee as a super functional food has helped to increase coffee consumption across the globe. This chapter addresses the main health promotion mechanisms associated with coffee consumption. Related topics on coffee production chain, world consumption and reuse of coffee by-products in the production of high-value-adding molecules with potential applications in the food industry are addressed and discussed. 10.1016/bs.afnr.2019.10.002
    Transport of proanthocyanidin dimer, trimer, and polymer across monolayers of human intestinal epithelial Caco-2 cells. Deprez S,Mila I,Huneau J F,Tome D,Scalbert A Antioxidants & redox signaling The gut absorption of proanthocyanidins (PAs) and of the related (+)-catechin monomer was investigated with colonic carcinoma (Caco-2) cells of a human origin, grown in monolayers on permeable filters. Permeability of various radiolabeled PAs differing in their molecular weight was compared with that of the radiolabeled (+)-catechin. No toxicity was observed at PA concentrations up to the physiological concentration of 1 mM. (+)-Catechin and PA dimer and trimer had similar permeability coefficients (P(app) = 0.9-2.0 x 10(-6) cm s(-1)) close to that of mannitol, a marker of paracellular transport. Paracellular transport was also indicated by the increase of absorption after reduction of the transepithelial electric resistance through calcium ion removal. In contrast, permeability of a PA polymer with an average polymerization degree of 6 (molecular weight 1,740) was approximately 10 times lower (P(app) = 0.10 +/- 0.04 x 10(-6) cm s(-1)). PAs, particularly the most astringent PA polymer, were also adsorbed on the epithelial cells. These results suggest that PA dimers and trimers could be absorbed in vivo and that polymer bioavailability is limited to the gut lumen. 10.1089/152308601317203503
    SOD1 deficiency alters gastrointestinal microbiota and metabolites in mice. Sagi Haruka,Shibuya Shuichi,Kato Tamotsu,Nakanishi Yumiko,Tsuboi Arisa,Moriya Shigeharu,Ohno Hiroshi,Miyamoto Hirokuni,Kodama Hiroaki,Shimizu Takahiko Experimental gerontology Redox imbalance induces oxidative damage and causes age-related pathologies. Mice lacking the antioxidant enzyme SOD1 (Sod1) exhibit various aging-like phenotypes throughout the body and are used as aging model mice. Recent reports suggested that age-related changes in the intestinal environment are involved in various diseases. We investigated cecal microbiota profiles and gastrointestinal metabolites in wild-type (Sod1) and Sod1 mice. Firmicutes and Bacteroidetes were dominant in Sod1 mice, and most of the detected bacterial species belong to these two phyla. Meanwhile, the Sod1 mice had an altered Firmicutes and Bacteroidetes ratio compared to Sod1 mice. Among the identified genera, Paraprevotella, Prevotella, Ruminococcus, and Bacteroides were significantly increased, but Lactobacillus was significantly decreased in Sod1 mice compared to Sod1 mice. The correlation analyses between cecal microbiota and liver metabolites showed that Bacteroides and Prevotella spp. were grouped into the same cluster, and Paraprevotella and Ruminococcus spp. were also grouped as another cluster. These four genera showed a positive and a negative correlation with increased and decreased liver metabolites in Sod1 mice, respectively. In contrast, Lactobacillus spp. showed a negative correlation with increased liver metabolites and a positive correlation with decreased liver metabolites in Sod1 mice. These results suggest that the redox imbalance induced by Sod1 loss alters gastrointestinal microflora and metabolites. 10.1016/j.exger.2019.110795
    Colonic Bacteria-Transformed Catechin Metabolite Response to Cytokine Production by Human Peripheral Blood Mononuclear Cells. Krishnamoorthy Rajapandiyan,Adisa Abdulraheem R,Periasamy Vaiyapuri Subbarayan,Athinarayanan Jegan,Pandurangan Subash-Babu,Alshatwi Ali A Biomolecules Human gut microbes are a profitable tool for the modification of food compounds into biologically active metabolites. The biological properties of catechins have been extensively investigated. However, the bioavailability of catechin in human blood plasma is very low. This study aimed to determine the biotransformed catechin metabolites and their bioactive potentials for modulating the immune response of human peripheral blood mononuclear cells (PBMCs). Biotransformation of catechin was carried out using in-vitro gut microbial biotransformation method, the transformed metabolites were identified and confirmed by gas chromatography-mass spectrometry (GC-MS) and high-performance liquid chromatography-mass spectrometry (HPLC-MS). Present observations confirmed that the catechin was biotransformed into 11 metabolites upon microbial dehydroxylation and C ring cleavage. Further, immunomodulatory potential of catechin metabolites was analyzed in peripheral blood mononuclear cells (PBMCs). We found up-regulation of anti-inflammatory cytokine (IL-4, IL-10) and down-regulation of pro-inflammatory (IL-16, IL-12B) cytokine may be due to Th2 immune response. In conclusion, biotransformed catechin metabolites enhance anti-inflammatory cytokines which is beneficial for overcoming inflammatory disorders. 10.3390/biom9120830
    [Recent progress of potential effects and mechanisms of chlorogenic acid and its intestinal metabolites on central nervous system diseases]. Xing Li-na,Zhou Ming-mei,Li Yun,Shi Xiao-wen,Jia Wei Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica Chlorogenic acid displays several important roles in the therapeutic properties of many herbs, such as antioxidant activity, antibacterial, antiviral, scavenging free radicals and exciting central nervous system. Only about one-third of chlorogenic acid was absorbed in its prototype, therefore, its gut metabolites play a more important role in the therapeutic properties of chlorogenic acid. It is necessary to consider not only the bioactivities of chlorogenic acid but also its gut metabolites. This review focuses on the potential activities and mechanisms of chlorogenic acid and its gut metabolites on central nervous system diseases.
    Preparation and characterization of standardized pomegranate extract-phospholipid complex as an effective drug delivery tool. Vora Amisha Kamlesh,Londhe Vaishali Y,Pandita Nancy S Journal of advanced pharmaceutical technology & research Punicalagins, a pair of anomeric ellagitannins, present in Punica granatum (Pomegranates) are known to possess excellent antioxidant activity in vitro, but poor oral bioavailability. The reasons cited for poor bioavailability are their large molecular size, poor lipophilicity, and degradation by colonic microflora into less active metabolites. The objective of the present research work was to complex the standardized pomegranate extract (SPE) with phospholipid to formulate standardized pomegranate extract-phospholipid complex (SPEPC), characterize it and check its permeability through an ex vivo everted gut sac experiment. SPEPC was prepared by mixing SPE (30% punicalagins) and soya phosphatidylcholine (PC) in 1:1 v/v mixture of methanol and dioxane and spray-drying the mixture. The complex was characterized by infrared spectroscopy, differential scanning calorimetry, X-ray diffraction, and scanning electron microscopy. It was evaluated for its octanol solubility, dissolution, and permeability by everted the gut sac technique. The characterization methods confirmed the formation of complex. Increased n-octanol solubility of the complex proved its increased lipophilicity. Dissolution studies revealed that the phospholipid covering may prevent the punicalagins to be released in gastro-intestinal tract, thus preventing their colonic microbial degradation. SPEPC showed better apparent permeability than SPE in an everted gut sac technique. Hence, it could be concluded that phospholipid complex of SPE may be of potential use in increasing the permeability and hence the bioavailability of punicalagins. 10.4103/2231-4040.154542
    Quercetin and kaempferol increase the intestinal absorption of isorhamnetin coexisting in Elaeagnus rhamnoides (L.) A. Nelson (Elaeagnaceae) extracts via regulating multidrug resistance-associated protein 2. Xiao Yi,Xin Lei,Li Lujia,Li Guowen,Shi Xiufeng,Ji Guang,Mi Jinxia,Xie Yan Phytomedicine : international journal of phytotherapy and phytopharmacology BACKGROUND:Isorhamnetin (IS) is a flavonoid component with many biological activities such as antioxidant, anti-inflammatory, and anticancer, which is also the main active component in total flavones of Elaeagnus rhamnoides (L.) A. Nelson (Elaeagnaceae) (TFH); however, the interaction between IS and other components in TFH is unclear. PURPOSE:The aim of the present study was to investigate the enhancement of quercetin (QU) or kaempferol (KA) on the intestinal absorption of IS coexisting in TFH, and then preliminarily illuminate the related mechanisms. METHODS:Firstly, the intestinal absorption of IS in the presence or absence of QU or KA was conducted by in vivo pharmacokinetics model, in situ single-pass intestinal perfusion model (SPIP), and MDCK II-MRP2 monolayer cell model to confirm the enhancement of QU or KA on IS absorption. Secondly, the effects of multidrug resistance-associated protein 2 (MRP2) inhibitors on the IS intestinal absorption were investigated to ascertain the mediation of MRP2 on IS absorption. Finally, the effects of QU or KA on MRP2 activity, protein expression, and mRNA level were performed by SPIP, everted-gut sacs, western blotting, and real-time polymerase chain reaction experiments to elucidate the related mechanisms. RESULTS:QU or KA increased IS intestinal absorption according to the increased AUC, C, and P of IS after co-administrated with QU or KA to rats; the oral absorption of IS was mediated by MRP2 based on the facts that the average plasma concentration, AUC, and P of IS were increased when co-administrated with PR or MK571 (MRP2 inhibitors) as well as the P(BL/AP) of IS was decreased by MK571 in MDCK II-MRP2 cell monolayer; the activity, protein expression, and mRNA level of MRP2 were inhibited or down-regulated by QU or KA because of the increased P of MRP2 substrate calcein (CA) and the down-regulated relative protein and mRNA intensity after co-treated with QU or KA. CONCLUSION:QU and KA increased the intestinal absorption of IS in TFH by regulating the activity and expression of MRP2, which provides useful information for the investigation of the transporter-mediated interaction of flavonoid components in herbal extracts. 10.1016/j.phymed.2018.09.028
    Olive Tree Biophenols in Inflammatory Bowel Disease: When Bitter is Better. Larussa Tiziana,Imeneo Maria,Luzza Francesco International journal of molecular sciences The current therapeutic scenario for inflammatory bowel diseases (IBD) involves aminosalicylates, corticosteroids, and immunomodulators, but concerns regarding their safety profiles and high costs heavily impact their widespread use. In recent years, the beneficial effects thatbiophenols-from fruit and vegetables-have on human health have been investigated. The antioxidant and anti-inflammatory properties of phenolic fraction, from olive leaves and fruits, have been suggested, and a potential application in gut inflammation has been supported by in vitro and IBD-animal models studies. In the present review, we first introduced the potential therapeutic role of olive tree biophenolsin chronic inflammatory disease. Then, we aimed to describe their most interesting application for gut inflammation, as the results of basic science studies and animal experimental models. Finally, the potential role of olive tree biophenols in the setting of human IBD is discussed. 10.3390/ijms20061390
    Supplementation of a grape seed and grape marc meal extract decreases activities of the oxidative stress-responsive transcription factors NF-κB and Nrf2 in the duodenal mucosa of pigs. Gessner Denise K,Fiesel Anja,Most Erika,Dinges Jennifer,Wen Gaiping,Ringseis Robert,Eder Klaus Acta veterinaria Scandinavica BACKGROUND:In pigs, enteric infections and the development of gut disorders such as diarrhoea are commonly observed, particularly after weaning. The present study investigated the hypothesis that feeding a grape seed and grape marc extract (GSGME) as a dietary supplement has the potential to suppress the inflammatory process in the small intestine of pigs by modulating the activities of NF-κB and Nrf2 due to its high content of flavonoids. METHODS:Twenty-four crossbred, 6 weeks old pigs were randomly assigned to 2 groups of 12 animals each and fed nutritionally adequate diets without or with 1% GSGME for 4 weeks. RESULTS:Pigs administered GSGME had a lower transactivation of NF-κB and Nrf2 and a lower expression of various target genes of these transcription factors in the duodenal mucosa than control pigs (P < 0.05). Concentrations of α-tocopherol and thiobarbituric acid reactive substances (TBARS) in liver and plasma and total antioxidant capacity of plasma and relative mRNA abundances of NF-κB and Nrf2 target genes in the liver did not differ between the two groups. However, the ratio of villus height:crypt depth and the gain:feed ratio was higher in the pigs fed GSGME than in control pigs (P < 0.05). CONCLUSIONS:This study shows that dietary supplementation of a polyphenol rich GSGME suppresses the activity of NF-κB in the duodenal mucosa of pigs and thus might provide a useful dietary strategy to inhibit inflammation in the gut frequently occurring in pigs. Feeding GSGME did not influence vitamin E status and the antioxidant system of the pigs but improved the gain:feed ratio. In overall, the study suggests that polyphenol-rich plant extracts such GSGME could be useful feed supplements in pig nutrition, in order to maintain animal health and improve performance. 10.1186/1751-0147-55-18
    Effect of physiological concentrations of vitamin C on gastric cancer cells and Helicobacter pylori. Zhang Z-W,Abdullahi M,Farthing M J G Gut BACKGROUND:Gastric juice vitamin C may be protective against gastric carcinogenesis but concentrations are significantly reduced by Helicobacter pylori infection. We investigated the in vitro effects of vitamin C at concentrations comparable with those found in gastric juice on gastric cancer cells and H pylori. METHODS:Gastric cancer cell lines and various H pylori strains were treated with L-ascorbic acid for up to 72 hours. Cell viability, and protein and DNA synthesis were determined. Flow cytometry was used for assessment of H pylori adherence, cell cycle distribution, and apoptosis. H pylori growth and its haemagglutination activity were determined using viability count and microtitration assay. RESULTS:Vitamin C induced a significant dose dependent growth inhibition of gastric AGS and MKN45 cells but this effect was significantly reduced at levels similar to those in gastric juice of H pylori infected patients (<50 microM). Although vitamin C had no obvious effect on H pylori growth, haemagglutination activity, or adherence ability to gastric AGS cells compared with untreated controls, it significantly enhanced H pylori associated apoptosis and induced cell cycle arrest in these cells. CONCLUSION:Vitamin C may inhibit gastric cancer cell growth and alter H pylori induced cell cycle events at concentrations comparable with those in gastric juice, but has no effect on H pylori growth or pathogenicity. However, the inhibitory effect on gastric cancer cells was lost at vitamin C concentrations found in patients with H pylori infection. 10.1136/gut.50.2.165
    Interactions of tea polyphenols with intestinal microbiota and their implication for cellular signal conditioning mechanism. Li Yongyong,Gao Xing,Lou Yongjiang Journal of food biochemistry Tea polyphenols (TP) is the main functional substances in tea. It has been reported that TP can modulate the composition of gut microbes in the human body, in addition, after the bio-transformation by intestinal flora, the metabolites of TP also have positive effects on the health of the host. Lots of researches have shown that TP have possible therapeutic effect against high fat diet induced obesity, which is closely related to the gut flora of the host. Therefore, this review focused on the interactions of TP with intestinal microbiota and their implication for cellular signal conditioning mechanism that will enable us to better study the two-way effects of TP and intestinal microbiota on host health improvement. PRACTICAL APPLICATIONS: TP have been widely concerned for their health care properties. As the functional food components, TP have strong antioxidant and physiological activities for human body. A better understanding on the interactions of TP with intestinal microbiota and their implication for cellular signal conditioning mechanism will lead us to better evaluate the contribution of the microbial metabolites of TP, as well as the regulation of intestinal bacterial diversity and abundance for host health. 10.1111/jfbc.12953
    Simulated digestion of an olive pomace water-soluble ingredient: relationship between the bioaccessibility of compounds and their potential health benefits. Ribeiro Tânia B,Oliveira Ana,Campos Débora,Nunes João,Vicente António A,Pintado Manuela Food & function Olive pomace is a semisolid by-product with great potential as a source of bioactive compounds. Using its soluble fraction, a liquid-enriched powder (LOPP) was obtained, exhibiting a rich composition in sugars, polyphenols and minerals, with potential antioxidant, antihypertensive and antidiabetic health benefits. To validate the potential of LOPP as a functional ingredient the effect of the gastrointestinal tract on its bioactive composition and bioactivities was examined. Polyphenols and minerals were the most affected compounds; however, a significant bioaccessibility of potassium and hydroxytyrosol was verified (≥57%). As a consequence, the LOPP bioactivities were only moderately affected (losses around 50%). For example, 57.82 ± 1.27% of the recovered antioxidant activity by ORAC was serum-available. From an initial α-glucosidase inhibition activity of 87.11 ± 1.04%, at least 50% of the initial potential was retained (43.82 ± 1.14%). Regarding the initial ACE inhibitory activity (91.98 ± 3.24%), after gastrointestinal tract losses, significant antihypertensive activity was retained in the serum-available fraction (43.4 ± 3.65%). The colon-available fraction also exhibited an abundant composition in phenolics and minerals. LOPP showed to be a potential functional ingredient not only with potential benefits in preventing cardiovascular diseases but also in gut health. 10.1039/c9fo03000j
    Resveratrol-Induced White Adipose Tissue Browning in Obese Mice by Remodeling Fecal Microbiota. Liao Weiyao,Yin Xiaohan,Li Qingrong,Zhang Hongmin,Liu Zihui,Zheng Xinjie,Zheng Lin,Feng Xiang Molecules (Basel, Switzerland) Promoting the browning of white fat may be a potential means of combating obesity. Therefore, in this study, we investigated the effect of resveratrol (RES) on the body weight and browning of white fat in high-fat diet (HFD)-induced obese mice and the potential associated mechanism in vivo. Eight-week-old male mice were randomized to receive different treatments: (1), chow without any additional treatment (chow); (2), chow plus 0.4% resveratrol (chow-RES); (3), HFD without any additional treatment (HFD); and (4), HFD plus 0.4% resveratrol (HFD-RES). After 4 weeks of feeding, additional 8-week-old male recipient mice were randomly allocated to the following 4 treatments: (5), HFD and received feces from chow-fed mice; (6), HFD and received feces from chow-RES-fed mice; (7), HFD and received feces from HFD-fed mice; and (8), HFD and received feces from HFD-RES-fed mice. RES treatment significantly inhibited increases in fat accumulation, promoted the browning of white adipose tissue (WAT) and alleviated gut microbiota dysbiosis in HFD-fed mice. Subsequent analyses showed that the gut microbiota remodeling induced by resveratrol had a positive role in WAT browning, and sirtuin-1 (Sirt1) signaling appears to be a key component of this process. Overall, the results show that RES may serve as a potential intervention to reduce obesity by alleviating dysbiosis of the gut microbiota. 10.3390/molecules23123356
    Where do health benefits of flavonoids come from? Insights from flavonoid targets and their evolutionary history. Lu Ming-Feng,Xiao Zheng-Tao,Zhang Hong-Yu Biochemical and biophysical research communications Flavonoid intake is negatively correlated with the incidence of some chronic diseases including cardiovascular diseases, type II diabetes, neurodegenerative diseases, and cancers. Thus, the molecular mechanisms underlying this correlation are of great interest. Although ample attention has been given to the free radical-scavenging potential of flavonoids, the poor bioavailability of exogenous flavonoids suggests that the direct antioxidant activity is unlikely responsible for their favorable effects. This study comprehensively analyzed flavonoid targets. The results show that the main functions of these targets are associated with cancers and cardiovascular and metabolic diseases. Moreover, evolutionary analysis of these targets showed that ~1000 of the targets have homologues in human gut bacterial metagenomes. Clusters of orthologous groups of proteins (COG) analysis indicated that most of these bacterial targets are associated with bacterial metabolism. Given that the metabolism of gut microbiota is coupled with the metabolism of the host, this finding implies that flavonoids exert their benefits by regulating gut microbes. Therefore, the health benefits of flavonoids are well explained by their targets rather than their direct antioxidant potential. 10.1016/j.bbrc.2013.04.035
    Optimal Dietary Ferulic Acid for Suppressing the Obesity-Related Disorders in Leptin-Deficient Obese C57BL/6J -ob/ob Mice. Wang Weiwei,Pan Yiou,Wang Li,Zhou Hang,Song Ge,Wang Yongwei,Liu Jianxue,Li Aike Journal of agricultural and food chemistry Ferulic acid (FA) is a major polyphenolic compound and has been shown to improve the glucose and lipid homeostasis in high-fat diet-induced obese mice. Here, we found the optimal level of dietary FA to ameliorate obesity and obesity-correlated disorders, and identified the responses of gut microbiota to dietary FA in genetic leptin-deficient obese ( ob/ob) mice. The ob/ob mice exhibited persistent higher body weights, feed efficiency, white adipose tissue weights, and hepatic lipid accumulation, compared to those of the wild-type mice. However, 0.5% dietary FA suppressed these symptoms in ob/ob mice. The diversity of gut microbiota and the total abundance of obesity- and anti-obesity-related genera were not influenced after FA intervention in ob/ob mice. These data suggest that sufficient intake of FA (0.5%) could be useful for treating obesity or obesity-related diseases, and this weight-control effect is possibly not correlated with the gut-brain axis. 10.1021/acs.jafc.8b06760
    Phytochemicals as Prebiotics and Biological Stress Inducers. Martel Jan,Ojcius David M,Ko Yun-Fei,Young John D Trends in biochemical sciences Phytochemicals in fruits and vegetables produce health benefits, but questions remain regarding their bioavailability, molecular targets, and mechanism of action. Here, we address these issues by considering the prebiotic and biological properties of phytochemicals. A fraction of phytochemicals consumed orally passes through the gut lumen, where it modulates the composition of the gut microbiota and maintains intestinal integrity. Phytochemicals and microbiota-derived metabolites that are absorbed by the organism comprise compounds that, at low doses, induce stress resistance mechanisms, including autophagy, DNA repair, and expression of detoxifying and antioxidant enzymes. We propose that these mechanisms improve cellular and organ function and can account for the promiscuous bioactivities of phytochemicals, despite their limited bioavailability and extremely varied chemical structures. 10.1016/j.tibs.2020.02.008
    Hydroxycinnamic acids and human health: recent advances. Coman Vasile,Vodnar Dan C Journal of the science of food and agriculture There is an urgent need to improve human diet globally. Compelling evidence gathered over the past several decades suggests that a suboptimal diet is associated with many chronic diseases and may be responsible for more deaths than any other risks worldwide. The main components in our diet that need higher intake are whole grains, fruit and vegetables, and nuts and seeds; all of these are important sources of dietary fiber and polyphenols. The health benefits of dietary fiber and polyphenols are also supported by several decades of valuable research. However, the conclusions drawn from interventional human trials are not straightforward and the action mechanisms in improving human health are not fully understood. Moreover, there is a great inter-individual variation caused by different individual capabilities of processing, absorbing and using these compounds effectively. Data on the bioavailability and bioefficacy of hydroxycinnamic acids (HCAs) are limited when compared to other classes of polyphenols (e.g. anthocyanins). This review aims to summarize the latest research advances related to HCA bioavailability and their biological effects revealed by epidemiological data, pre-clinical and clinical studies. Moreover, we aim to review the effects of HCAs on gut microbiota diversity and function and its respective influence on host health. © 2019 Society of Chemical Industry. 10.1002/jsfa.10010
    First-Pass Metabolism of Polyphenols from Selected Berries: A High-Throughput Bioanalytical Approach. Olivas-Aguirre Francisco J,Mendoza Sandra,Alvarez-Parrilla Emilio,Gonzalez-Aguilar Gustavo A,Villegas-Ochoa Monica A,Quintero-Vargas Jael T J,Wall-Medrano Abraham Antioxidants (Basel, Switzerland) Small berries are rich in polyphenols whose first-pass metabolism may alter their ultimate physiological effects. The antioxidant capacity and polyphenol profile of three freeze-dried berries (blackberry, raspberry, Red Globe grape) were measured and their apparent permeability (Papp) and first-pass biotransformation were tracked with an ex vivo bioanalytical system [everted gut sac (rat) + three detection methods: spectrophotometry, HPLC-ESI-QTOF-MS, differential pulse voltammetry (DPV)]. Total polyphenol (ratio 0.07-0.14-1.0) and molecular diversity (anthocyanins>flavan-3-ols), antioxidant capacity (DPPH, FRAP), anodic current and Papp (efflux> uptake) were in the following order: blackberry > raspberry > Red Globe grape. Epicatechin, pelargonidin & cyanin (all), callistephin (raspberry/blackberry), catechin (grape), cyanidin glycosides (blackberry) and their derived metabolites [quinic acid, epicatechin, cyanidin/malvidin glucosides, and chlorogenic/caffeic acids] were fruit-specific and concentration-dependent. Time-trend DPV kinetic data revealed concurrent epithelial permeability & biotransformation processes. Regular permeability and high-biotransformation of berry polyphenols suggest fruit-specific health effects apparently at the intestinal level. 10.3390/antiox9040311
    Is Eating Raisins Healthy? Olmo-Cunillera Alexandra,Escobar-Avello Danilo,Pérez Andy J,Marhuenda-Muñoz María,Lamuela-Raventós Rosa Mª,Vallverdú-Queralt Anna Nutrients Raisins are dried grapes consumed worldwide that contain beneficial components for human health. They are rich in fiber and phytochemicals such as phenolic compounds. Despite a 60% sugar content, several studies have reported health-promoting properties for raisins and this review compiles the intervention studies, as well as the cell line and animal model studies carried out to date. It has been demonstrated that raisins possess a low-to-moderate glycemic index, which makes them a healthy snack. They seem to contribute to a better diet quality and may reduce appetite. Their antioxidant capacity has been correlated to the phenolic content and this may be involved in the improvement of cardiovascular health. In addition, raisins maintain a good oral health due to their antibacterial activity, low adherence to teeth and an optimum oral pH. Raisin consumption also seems to be favorable for colon function, although more studies should be done to conclude this benefit. Moreover, gut microbiota could be affected by the prebiotic content of raisins. Cell line and animal model studies show other potential benefits in specific diseases, such as cancer and Alzheimer's disease. However, deeper research is required and future intervention studies with humans are needed. Overall, incorporating an 80-90 g portion of raisins (half a cup) into the daily diet may be favorable for human health. 10.3390/nu12010054
    The effects of cocoa on the immune system. Pérez-Cano Francisco J,Massot-Cladera Malen,Franch Angels,Castellote Cristina,Castell Margarida Frontiers in pharmacology Cocoa is a food relatively rich in polyphenols, which makes it a potent antioxidant. Due to its activity as an antioxidant, as well as through other mechanisms, cocoa consumption has been reported to be beneficial for cardiovascular health, brain functions, and cancer prevention. Furthermore, cocoa influences the immune system, in particular the inflammatory innate response and the systemic and intestinal adaptive immune response. Preclinical studies have demonstrated that a cocoa-enriched diet modifies T cell functions that conduce to a modulation of the synthesis of systemic and gut antibodies. In this regard, it seems that a cocoa diet in rats produces changes in the lymphocyte composition of secondary lymphoid tissues and the cytokines secreted by T cells. These results suggest that it is possible that cocoa could inhibit the function of T helper type 2 cells, and in line with this, the preventive effect of cocoa on IgE synthesis in a rat allergy model has been reported, which opens up new perspectives when considering the beneficial effects of cocoa compounds. On the other hand, cocoa intake modifies the functionality of gut-associated lymphoid tissue by means of modulating IgA secretion and intestinal microbiota. The mechanisms involved in these influences are discussed here. Further research may elucidate the cocoa compounds involved in such an effect and also the possible medical approaches to these repercussions. 10.3389/fphar.2013.00071
    A single supplement of a standardised bilberry (Vaccinium myrtillus L.) extract (36 % wet weight anthocyanins) modifies glycaemic response in individuals with type 2 diabetes controlled by diet and lifestyle. Hoggard Nigel,Cruickshank Morven,Moar Kim-Marie,Bestwick Charles,Holst Jens J,Russell Wendy,Horgan Graham Journal of nutritional science Dietary strategies for alleviating health complications associated with type 2 diabetes (T2D) are being pursued as alternatives to pharmaceutical interventions. Berries such as bilberries (Vaccinium myrtillus L.) that are rich in polyphenols may influence carbohydrate digestion and absorption and thus postprandial glycaemia. In addition, berries have been reported to alter incretins as well as to have antioxidant and anti-inflammatory properties that may also affect postprandial glycaemia. The present study investigated the acute effect of a standardised bilberry extract on glucose metabolism in T2D. Male volunteers with T2D (n 8; BMI 30 (sd 4) kg/m(2)) controlling their diabetes by diet and lifestyle alone were given a single oral capsule of either 0·47 g standardised bilberry extract (36 % (w/w) anthocyanins) which equates to about 50 g of fresh bilberries or placebo followed by a polysaccharide drink (equivalent to 75 g glucose) in a double-blinded cross-over intervention with a 2-week washout period. The ingestion of the bilberry extract resulted in a significant decrease in the incremental AUC for both glucose (P = 0·003) and insulin (P = 0·03) compared with the placebo. There was no change in the gut (glucagon-like peptide-1, gastric inhibitory polypeptide), pancreatic (glucagon, amylin) or anti-inflammatory (monocyte chemotactic protein-1) peptides. In addition there was no change in the antioxidant (Trolox equivalent antioxidant capacity, ferric-reducing ability of plasma) responses measured between the volunteers receiving the bilberry extract and the placebo. In conclusion the present study demonstrates for the first time that the ingestion of a concentrated bilberry extract reduces postprandial glycaemia and insulin in volunteers with T2D. The most likely mechanism for the lower glycaemic response involves reduced rates of carbohydrate digestion and/or absorption. 10.1017/jns.2013.16
    Role of melatonin in sleep deprivation-induced intestinal barrier dysfunction in mice. Gao Ting,Wang Zixu,Dong Yulan,Cao Jing,Lin Rutao,Wang Xintong,Yu Zhengquan,Chen Yaoxing Journal of pineal research Intestinal diseases caused by sleep deprivation (SD) are severe public health threats worldwide. This study focuses on the effect of melatonin on intestinal mucosal injury and microbiota dysbiosis in sleep-deprived mice. Mice subjected to SD had significantly elevated norepinephrine levels and decreased melatonin content in plasma. Consistent with the decrease in melatonin levels, we observed a decrease of antioxidant ability, down-regulation of anti-inflammatory cytokines and up-regulation of pro-inflammatory cytokines in sleep-deprived mice, which resulted in colonic mucosal injury, including a reduced number of goblet cells, proliferating cell nuclear antigen-positive cells, expression of MUC2 and tight junction proteins and elevated expression of ATG5, Beclin1, p-P65 and p-IκB. High-throughput pyrosequencing of 16S rRNA demonstrated that the diversity and richness of the colonic microbiota were decreased in sleep-deprived mice, especially in probiotics, including Akkermansia, Bacteroides and Faecalibacterium. However, the pathogen Aeromonas was markedly increased. By contrast, supplementation with 20 and 40 mg/kg melatonin reversed these SD-induced changes and improved the mucosal injury and dysbiosis of the microbiota in the colon. Our results suggest that the effect of SD on intestinal barrier dysfunction might be an outcome of melatonin suppression rather than a loss of sleep per se. SD-induced intestinal barrier dysfunction involved the suppression of melatonin production and activation of the NF-κB pathway by oxidative stress. 10.1111/jpi.12574
    Equol: A Bacterial Metabolite from The Daidzein Isoflavone and Its Presumed Beneficial Health Effects. Mayo Baltasar,Vázquez Lucía,Flórez Ana Belén Nutrients Epidemiological data suggest that regular intake of isoflavones from soy reduces the incidence of estrogen-dependent and aging-associated disorders, such as menopause symptoms in women, osteoporosis, cardiovascular diseases and cancer. Equol, produced from daidzein, is the isoflavone-derived metabolite with the greatest estrogenic and antioxidant activity. Consequently, equol has been endorsed as having many beneficial effects on human health. The conversion of daidzein into equol takes place in the intestine via the action of reductase enzymes belonging to incompletely characterized members of the gut microbiota. While all animal species analyzed so far produce equol, only between one third and one half of human subjects (depending on the community) are able to do so, ostensibly those that harbor equol-producing microbes. Conceivably, these subjects might be the only ones who can fully benefit from soy or isoflavone consumption. This review summarizes current knowledge on the microorganisms involved in, the genetic background to, and the biochemical pathways of, equol biosynthesis. It also outlines the results of recent clinical trials and meta-analyses on the effects of equol on different areas of human health and discusses briefly its presumptive mode of action. 10.3390/nu11092231
    Phytochemical Properties and Nutrigenomic Implications of Yacon as a Potential Source of Prebiotic: Current Evidence and Future Directions. Cao Yang,Ma Zheng Feei,Zhang Hongxia,Jin Yifan,Zhang Yihe,Hayford Frank Foods (Basel, Switzerland) The human gut is densely populated with diverse microbial communities that are essential to health. Prebiotics and fiber have been shown to possess the ability to modulate the gut microbiota. One of the plants being considered as a potential source of prebiotic is yacon. Yacon is an underutilized plant consumed as a traditional root-based fruit in South America. Yacon mainly contains fructooligosaccharides (FOS) and inulin. Therefore, it has bifidogenic benefits for gut health, because FOS are not easily broken down by digestive enzymes. Bioactive chemical compounds and extracts isolated from yacon have been studied for their various nutrigenomic properties, including as a prebiotic for intestinal health and their antimicrobial and antioxidant effects. This article reviewed scientific studies regarding the bioactive chemical compounds and nutrigenomic properties of extracts and isolated compounds from yacon. These findings may help in further research to investigate yacon-based nutritional products. Yacon can be considered a potential prebiotic source and a novel functional food. However, more detailed epidemiological, animal, and human clinical studies, particularly mechanism-based and phytopharmacological studies, are lacking for the development of evidence-based functional food products. 10.3390/foods7040059
    Proanthocyanidin-Rich Grape Seed Extract Reduces Inflammation and Oxidative Stress and Restores Tight Junction Barrier Function in Caco-2 Colon Cells. Nallathambi Rameshprabu,Poulev Alexander,Zuk Joshua B,Raskin Ilya Nutrients Grape polyphenols have previously been shown to improve gut health and attenuate the symptoms of metabolic syndrome; however, the mechanism of these beneficial effects is still debated. In this study, we investigated the protective effect of proanthocyanidin-rich grape seed extract (GSE) on bacterial lipopolysaccharide (LPS)-induced oxidative stress, inflammation, and barrier integrity of human Caco-2 colon cells. GSE significantly reduced the LPS-induced intracellular reactive oxygen species (ROS) production and mitochondrial superoxide production, and upregulated the expression of antioxidant enzyme genes. GSE also restored the LPS-damaged mitochondrial function by increasing mitochondrial membrane potential. In addition, GSE increased the expression of tight junction proteins in the LPS-treated Caco-2 cells, increased the expression of anti-inflammatory cytokines, and decreased pro-inflammatory cytokine gene expression. Our findings suggest that GSE exerts its beneficial effects on metabolic syndrome by scavenging intestinal ROS, thus reducing oxidative stress, increasing epithelial barrier integrity, and decreasing intestinal inflammation. 10.3390/nu12061623
    Polyphenolic compounds: interactions with the gut and implications for human health. Gee J M,Johnson I T Current medicinal chemistry Polyphenolic compounds are abundant throughout the plant kingdom and are found in a wide variety of human foods. The flavonoids, which are the best defined group of polyphenols in the human diet, themselves comprise a large and complex group, all of which contain a three-ring structure with two aromatic centres and a central oxygenated heterocycle. Recent evidence suggests that significant quantities of quercetin and possibly myricetin and kaempferol are absorbed in the gut. A larger fraction probably remains in the lumen, and thus a substantial proportion of the gastrointestinal mucosa is exposed to biologically significant concentrations of these compounds. A substantial body of experimental work has established that flavonoids can suppress carcinogenesis in animal models and there is considerable interest in the biological effects of these compounds at the cellular level. Flavonoids interact with cellular signal pathways controlling the cell cycle, differentiation and apoptosis. Their potentially antineoplastic effects include antioxidant activity, induction of Phase II enzyme activity, inhibition of protein kinases and interactions with Type II estrogen binding sites. Naturally occurring polyphenolic compounds may play a role in the protective effects of fruits and vegetables against cancers in general, and they appear to have considerable potential for pharmaceutical uses as chemopreventive agents against neoplastic changes in the alimentary tract. Future research should therefore focus on the biological effects of flavonoids in the human body, using biomarkers to define their effects at each stage in the onset of neoplasia.
    Melatonin reduces inflammatory response in human intestinal epithelial cells stimulated by interleukin-1β. Mannino Giuseppe,Caradonna Fabio,Cruciata Ilenia,Lauria Antonino,Perrone Anna,Gentile Carla Journal of pineal research Melatonin is the main secretory product of the pineal gland, and it is involved in the regulation of periodic events. A melatonin production independent of the photoperiod is typical of the gut. However, the local physiological role of melatonin at the intestinal tract is poorly characterized. In this study, we evaluated the anti-inflammatory activities of melatonin in an in vitro model of inflamed intestinal epithelium. To this purpose, we assessed different parameters usually associated with intestinal inflammation using IL-1β-stimulated Caco-2 cells. Differentiated monolayers of Caco-2 cells were preincubated with melatonin (1 nmol/L-50 μmol/L) and then exposed to IL-1β. After each treatment, different inflammatory mediators, DNA-breakage, and global DNA methylation status were assayed. To evaluate the involvement of melatonin membrane receptors, we also exposed differentiated monolayers to melatonin in the presence of luzindole, a MT1 and MT2 antagonist. Our results showed that melatonin, at concentrations similar to those obtained in the lumen gut after ingestion of dietary supplements for the treatment of sleep disorders, was able to attenuate the inflammatory response induced by IL-1β. Anti-inflammatory effects were expressed as both a decrease of the levels of inflammatory mediators, including IL-6, IL-8, COX-2, and NO, and a reduced increase in paracellular permeability. Moreover, the protection was associated with a reduced NF-κB activation and a prevention of DNA demethylation. Conversely, luzindole did not reverse the melatonin inhibition of stimulated-IL-6 release. In conclusion, our findings suggest that melatonin, through a local action, can modulate inflammatory processes at the intestinal level, offering new opportunities for a multimodal management of IBD. 10.1111/jpi.12598
    Bioactive Polyphenols and Neuromodulation: Molecular Mechanisms in Neurodegeneration. Di Meo Francesco,Valentino Anna,Petillo Orsolina,Peluso Gianfranco,Filosa Stefania,Crispi Stefania International journal of molecular sciences The interest in dietary polyphenols in recent years has greatly increased due to their antioxidant bioactivity with preventive properties against chronic diseases. Polyphenols, by modulating different cellular functions, play an important role in neuroprotection and are able to neutralize the effects of oxidative stress, inflammation, and apoptosis. Interestingly, all these mechanisms are involved in neurodegeneration. Although polyphenols display differences in their effectiveness due to interindividual variability, recent studies indicated that bioactive polyphenols in food and beverages promote health and prevent age-related cognitive decline. Polyphenols have a poor bioavailability and their digestion by gut microbiota produces active metabolites. In fact, dietary bioactive polyphenols need to be modified by microbiota present in the intestine before being absorbed, and to exert health preventive effects by interacting with cellular signalling pathways. This literature review includes an evaluation of the literature in English up to December 2019 in PubMed and Web of Science databases. A total of 307 studies, consisting of research reports, review articles and articles were examined and 146 were included. The review highlights the role of bioactive polyphenols in neurodegeneration, with a particular emphasis on the cellular and molecular mechanisms that are modulated by polyphenols involved in protection from oxidative stress and apoptosis prevention. 10.3390/ijms21072564
    Dietary Hemp Seeds More Effectively Attenuate Disorders in Genetically Obese Rats than Their Lipid Fraction. Opyd Paulina M,Jurgoński Adam,Fotschki Bartosz,Juśkiewicz Jerzy The Journal of nutrition BACKGROUND:Hemp seeds are rich in PUFAs and other bioactives that can attenuate the development of obesity-related disorders; however, the extent to which their lipid fraction is responsible for this effect is unknown. OBJECTIVE:We hypothesized that hemp seed or hemp oil supplementation can attenuate genetically determined disorders and that the former are more effective in doing so. METHODS:Lean and obese male Zucker rats, aged 8 wk, weighing 174 ± 4.2 g and 223 ± 3.8 g, respectively, were allocated to 4 groups. The lean (LC) and obese controls (OC) were fed a standard diet, whereas the other 2 obese groups were fed a modified diet in which hemp oil (4% diet; O + HO) or hemp seeds (12% diet; O + HS) were included. All diets had the same proportions of protein (18%), fat (8%), and fiber (5%) and a similar carbohydrate proportion (∼52%). Diets fed to O + HO and O + HS had similar fatty acid profiles. After 4 wk, markers of gut and liver function, antioxidant status, and lipid metabolism were measured. RESULTS:The total SCFA concentration in the cecal digesta was lower in OC (64.8 ± 4.21 µmol/g) compared with LC (78.1 ± 2.83 µmol/g) (P ≤ 0.05), whereas it was greater in O + HS (89 ± 4.41 µmol/g) compared with LC, OC, and O + HO (69.7 ± 2.68 µmol/g) (P ≤ 0.05). Plasma total cholesterol was greater in OC (6.20 ± 0.198 mmol/L) and O + HO (5.60 ± 0.084 mmol/L) compared with LC (2.71 ± 0.094 mmol/L) (P ≤ 0.05); in O + HS, the concentration did not differ from the other groups (5.16 ± 0.278 mmol/L). The liver cholesterol concentration was greater in OC (1.79 ± 0.379 mg/g) compared with the other groups (1.28-1.43 mg/g) (P ≤ 0.05). Hepatic expression of peroxisome proliferator-activated receptor γ was lower in OC (11.9 ± 0.93 units) compared with LC (17.3 ± 1.3 units) (P ≤ 0.05), whereas it was greater in O + HS (19.2 ± 1.04 units) compared with OC and O + HO (14.0 ± 1.33 units) (P ≤ 0.05). CONCLUSIONS:Dietary hemp seeds more effectively attenuate metabolic disorders in genetically obese rats than the oil extracted from them, which suggests that the lipid fraction is only partly responsible for these effects. 10.1093/jn/nxaa081
    Berberine in the treatment of metabolism-related chronic diseases: A drug cloud (dCloud) effect to target multifactorial disorders. Kong Wei-Jia,Vernieri Claudio,Foiani Marco,Jiang Jian-Dong Pharmacology & therapeutics Berberine (BBR) is a multi-target drug (MTD) that has proven effective in the treatment of metabolism-related chronic diseases (CDs). However, the mode of action (MOA) of BBR remains to be clarified. At a cellular level, the inhibitory effect of BBR on mitochondrial enzymes is probably responsible for many of its biological activities, including the activation of low-density lipoprotein receptor (LDLR), AMP-activated protein kinase (AMPK) and insulin receptor (InsR); these biological activities contribute to ameliorate peripheral blood metabolic profiles, e.g. by reducing plasma lipids and glucose levels, thus improving signs and symptoms of metabolic disorders. In this perspective, BBR acts as a targeted therapy. However, it also exerts pleiotropic systemic activities on some root causes of CDs that include antioxidant / anti-inflammatory effects and modifications of gut microbiota composition and metabolism, which may also contribute to its disease-modifying effects. After reviewing the different MOA of BBR, here we propose that BBR acts through a drug-cloud (dCloud) mechanism, as different to a drug-target effect. The dCloud here is defined as a group of terminal molecular events induced by the drug (or/and related metabolites), as well as the network connections among them. In this scenario, the therapeutic efficacy of BBR is the result of its dCloud effect acting on symptoms/signs as well as on root causes of the diseases. The dCloud concept is applicable to other established MTDs, such as aspirin, metformin, statins as well as to nutrient starvation, thus providing a novel instrument for the design of effective therapies against multifactorial metabolism-related CDs. 10.1016/j.pharmthera.2020.107496
    Maqui berry exhibited therapeutic effects against DSS-induced ulcerative colitis in C57BL/6 mice. Zhou Gao,Chen Ling,Sun Qing,Mo Qi-Gui,Sun Wan-Chun,Wang You-Wei Food & function Maqui berry (Aristotelia chilensis) is an edible berry. The study aimed to explore the therapeutic effect of maqui berry on inflammatory bowel disease. Maqui berry water extract was separated by multiple solvents extraction. The chemical bases, antioxidant and anti-inflammatory properties of different extract fractions were then compared. Dextran sodium sulfate (DSS)-induced ulcerative colitis mice were used for the pharmacological activity test in vivo. Experimental results showed that the ethyl acetate fraction of maqui berry water extract (MWE) was rich in phenols and exhibited good antioxidant and anti-inflammatory activities. MWE considerably reduced the expression of COX2 and IL-6 in LPS-stimulated RAW 264.7 cells. Inflammatory bowel disease index, MDA, NO, i-NOS, and COX2 in colon tissues and MPO, TNF-α, and IL-1β in blood serums were remarkably decreased in the treatment group compared to in the model group (p < 0.05). Intestinal histopathological damage was significantly alleviated in the treatment group, and the expression of occludin was increased (p < 0.05). MWE treatment alleviated the imbalance of gut microbiota caused by DSS injury. Overall, MWE plays a therapeutic role in ulcerative colitis through its anti-inflammatory effect, reduces immune stress, and regulates gut microbiota. 10.1039/c9fo00663j
    Comparative metabolism of genistin by human and rat gut microflora: detection and identification of the end-products of metabolism. Coldham N G,Darby C,Hows M,King L J,Zhang A Q,Sauer M J Xenobiotica; the fate of foreign compounds in biological systems 1. Biotransformations by gut microflora play a pivotal role in determining the biological activity of isoflavones that occur in soya-based foods predominantly as betaglycosyl conjugates. Microflora prepared from rat caecae and human faeces were used to investigate the metabolic fate of genistein beta-glycosides extracted from soya flour. The end-products of such metabolism were determined by parallel incubations of microflora with [2',3,5',6'-3H] and [4-14C]-labelled genistein. 2. Quantitative analysis by LC-MS/IS indicated very rapid and complete degradation of genistin, which was associated with a transient increase in genistein. Qualitative studies indicated that the malonyl and acetyl glycosides of genistein were also degraded by the microflora. 3. Incubation of caecal and faecal microflora with [3H] and [14C]genistein yielded similar radiolabelled metabolites, which were identified by radio-LC-MS(n) as the intermediates dihydrogenistein and 6'-hydroxy-O-desmethylangolensin and end-product 4-hydroxyphenyl-2-propionic acid. This profile of genistein metabolites indicated selective hydrolysis of 6'-hydroxy-O-desmethylangolensin between carbon atoms 1' and 1 to yield the end-products 4-hydroxyphenyl-2-propionic acid and 1,3,5-trihydroxybenzene. 4. The biological significance of the products of genistein metabolism warrant further investigation since they may play an important role in mediating the beneficial antioxidant health effects associated with the consumption of isoflavones in food. 10.1080/00498250110085809
    Microbiota facilitates the formation of the aminated metabolite of green tea polyphenol (-)-epigallocatechin-3-gallate which trap deleterious reactive endogenous metabolites. Zhang Shuwei,Zhao Yantao,Ohland Christina,Jobin Christian,Sang Shengmin Free radical biology & medicine The in vivo mechanism of tea polyphenol-mediated prevention of many chronic diseases is still largely unknown. Studies have shown that accumulation of toxic reactive cellular metabolites, such as ammonia and reactive carbonyl species (RCS), is one of the causing factors to the development of many chronic diseases. In this study, we investigated the in vivo interaction between (-)-epigallocatechin-3-gallate (EGCG), the most abundant polyphenol in tea leaves, and ammonia and RCS. We found that EGCG could be oxidized to EGCG quinone in mice, and then rapidly react with ammonia to generate the aminated EGCG metabolite, 4'-NH-EGCG. Both EGCG and its aminated metabolite could further scavenge RCS, such as methylglyoxal (MGO), malondialdehyde (MDA), and trans-4-hydroxy-2-nonenal (4-HNE), to produce the RCS conjugates of EGCG and the aminated EGCG. Both the aminated and the RCS conjugated metabolites of EGCG were detected in human after drinking four cups of green tea per day. By comparing the levels of the aminated and the RCS conjugated metabolites in EGCG exposed germ-free (GF) mice and specific-pathogen-free (SPF) mice, we demonstrated that gut microbiota facilitate the formation of the aminated metabolite of EGCG, the RCS conjugates of EGCG, and the RCS conjugates of the aminated EGCG. By comparing the trapping capacities of EGCG and its aminated metabolite under aerobic and anaerobic conditions, we found that oxygen is not essential for the trapping of reactive species by EGCG and 4'-NH-EGCG suggesting that EGCG and its aminated metabolite could scavenge RCS in the GI track and in the circulation system. Altogether, this study provides in vivo evidences that EGCG has the capacity to scavenge toxic reactive metabolic wastes. This finding opens a new window to understand the underlying mechanisms by which drinking tea could prevent the development of chronic diseases. 10.1016/j.freeradbiomed.2018.12.023
    The Effects and Mechanisms of Cyanidin-3-Glucoside and Its Phenolic Metabolites in Maintaining Intestinal Integrity. Tan Jijun,Li Yanli,Hou De-Xing,Wu Shusong Antioxidants (Basel, Switzerland) Cyanidin-3-glucoside (C3G) is a well-known natural anthocyanin and possesses antioxidant and anti-inflammatory properties. The catabolism of C3G in the gastrointestinal tract could produce bioactive phenolic metabolites, such as protocatechuic acid, phloroglucinaldehyde, vanillic acid, and ferulic acid, which enhance C3G bioavailability and contribute to both mucosal barrier and microbiota. To get an overview of the function and mechanisms of C3G and its phenolic metabolites, we review the accumulated data of the absorption and catabolism of C3G in the gastrointestine, and attempt to give crosstalk between the phenolic metabolites, gut microbiota, and mucosal innate immune signaling pathways. 10.3390/antiox8100479
    Anthocyanins and Human Health-A Focus on Oxidative Stress, Inflammation and Disease. Speer Hollie,D'Cunha Nathan M,Alexopoulos Natalie I,McKune Andrew J,Naumovski Nenad Antioxidants (Basel, Switzerland) Consumption of anthocyanins (ACNs), due to their antioxidant, anti-inflammatory and anti-apoptotic effects, has been proposed for the prevention and treatment of several different diseases and conditions. ACNs are recognized as one of the leading nutraceuticals for prolonging health benefits through the attenuation of oxidative stress, and inflammatory or age-related diseases. Increased consumption of ACNs has the potential to attenuate the damage ensuing from oxidative stress, inflammation, enhance cardiometabolic health, and delay symptoms in predisposed neuropathology. A myriad of evidence supports ACN consumption as complementary or standalone treatment strategies for non-communicable diseases (NCDs) including obesity, diabetes, cardiovascular disease (CVD), neurodegenerative diseases, as well as, more recently, for the modulation of gut bacteria and bone metabolism. While these findings indicate the beneficial effects of ACN consumption, their food sources differ vastly in ACN composition and thus potentially in their physiological effects. Consumption of foods high in ACNs can be recommended for their potential beneficial health effects due to their relatively easy and accessible addition to the everyday diet. 10.3390/antiox9050366
    Comparison of metabolic pharmacokinetics of naringin and naringenin in rabbits. Hsiu Su-Lan,Huang Tang-Yen,Hou Yu-Chi,Chin Der-Hang,Chao Pei-Dawn Lee Life sciences Naringin and naringenin are antioxidant constituents of many Citrus fruits. Naringenin is the aglycone and a metabolite of naringin. In order to characterize and compare the metabolic pharmacokinetics of naringenin and naringin, naringenin was administered intravenously and orally to rabbits, and naringin was administered orally. The concentration of naringenin in serum prior to and after enzymatic hydrolysis was determined by HPLC method. The pharmacokinetic parameters were calculated by using WINNONLIN. The results showed that the absolute bioavailability of oral naringenin was only 4%, whereas after taking the conjugated naringenin into account, it increased to 8%. When naringin was administered orally, only little naringenin and predominantly its glucuronides/sulfates were circulating in the plasma. The ratio of AUC of naringenin conjugates to the total naringenin absorbed into the systemic circulation after oral naringenin was much higher when compared to that after i.v. bolus of naringenin, indicating that extensive glucuronidation/sulfation of naringenin occurred during the first pass at gut wall. Oral dosing of naringin resulted in even higher ratio of AUC of naringenin conjugates to the total naringenin than that after oral naringenin. Our results also showed that there were great differences in pharmacokinetics of naringin and naringenin. Oral naringin resulted in latter Tmax, lower Cmax and longer MRT (mean residence time) for both naringenin and its conjugated metabolites than those after oral naringenin. 10.1016/s0024-3205(01)01491-6
    Stability and biotransformation of various dietary anthocyanins in vitro. Fleschhut Jens,Kratzer Frank,Rechkemmer Gerhard,Kulling Sabine E European journal of nutrition BACKGROUND:Anthocyanins, which are found in high concentrations in fruit and vegetable, may play a beneficial role in retarding or reversing the course of chronic degenerative diseases. However, little is known about the biotransformation and the metabolism of anthocyanins so far. AIM OF THE STUDY:The aim of the study was to investigate possible transformation pathways of anthocyanins by human faecal microflora and by rat liver microsomes as a source of cytochrome P450 enzymes as well as of glucuronyltransferases. METHODS:Pure anthocyanins, an aqueous extract of red radish as well as the assumed degradation products were incubated with human faecal suspension. The incubation mixtures were purified by solid-phase extraction and analysed by HPLC/DAD/MS and GC/MS. Quantification was done by the external standard method. Furthermore the biotransformation of anthocyanins by incubation with rat liver microsomes in the presence of the cofactor NADPH (as a model for the phase I oxidation) and in the presence of activated glucuronic acid (as a model for the phase II glucuronidation) was investigated. RESULTS:Glycosylated and acylated anthocyanins were rapidly degraded by the intestinal microflora after anaerobic incubation with a human faecal suspension. The major stable products of anthocyanin degradation are the corresponding phenolic acids derived from the B-ring of the anthocyanin skeleton. Anthocyanins were not metabolised by cytochrome P450 enzymes, neither hydroxylated nor demethylated. However they were glucuronidated by rat liver microsomes to several products. CONCLUSIONS:The gut microflora seem to play an important role in the biotransformation of anthocyanins. A rapid degradation could be one major reason for the poor bioavailability of anthocyanins in pharmacokinetic studies described so far in the literature. The formation of phenolic acids as the major stable degradation products gives an important hint to the fate of anthocyanins in vivo. 10.1007/s00394-005-0557-8
    The Efficacy and Safety of GCWB104 (<i>Flos</i> Lonicera Extract) in Functional Dyspepsia: A Single-Center, Randomized, Double-Blind, Placebo-Controlled Study. Choi Yonghoon,Kim Nayoung,Noh Gi Tark,Lee Ju Yup,Lee Dong Ho Gut and liver <b>Background/Aims:</b> The <i>Flos Lonicera</i> extract GCWB104 has been shown to have significant protective effects against gastritis and gastric ulcers <i>in vivo</i>. The aim of this study was to investigate the efficacy and safety of GCWB104 in subjects with functional dyspepsia (FD). <b>Methods:</b> In this single-center, double-blind, randomized clinical trial, 92 subjects diagnosed with FD using the Rome III criteria were allocated to either the test group (300 mg of GCWB104, containing 125 mg of <i>Flos Lonicera</i> extract, twice daily) or the placebo group (300 mg placebo, twice daily). The total score improvement on the Gastrointestinal Symptom Rating Scale (GSRS) for individual symptoms, changes in antioxidant levels, changes in dyspepsia-related quality of life according to the Nepean Dyspepsia Index (NDI), and adverse effects were compared before and after 8 weeks of treatment. <b>Results:</b> The differences in total GSRS scores and score improvements after 8 weeks of treatment were significant between the GCWB104 and control groups (p=0.0452 and p=0.0486, respectively). Thirteen of 15 individual symptoms on the GSRS improved in the GCWB104 group, while six symptoms improved in the control group. In addition, statistically significant changes in rumbling, loose stool, and stool urgency were observed in the GCWB104 group. Blood 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels, known as antioxidants, showed significant reductions after 8 weeks of administration of GCWB104. There were no adverse events related to treatment with GCWB104. <b>Conclusions:</b> GCWB104 safely contributed to improvements in mild to moderate FD and irritable bowel syndrome symptoms. Antioxidant effects of GCWB104 were also suggested (Clinicaltrials.gov number NCT04008901). 10.5009/gnl19283
    Management of food allergy: vitamins, fatty acids or probiotics? Laitinen Kirsi,Isolauri Erika European journal of gastroenterology & hepatology The dietary approach to allergic disease in infancy is evolving from passive allergen avoidance to active stimulation of the immature immune system, the aim of which is to support the establishment of tolerance. This may include probiotics providing maturational signals for the gut-associated lymphoid tissue and by balancing the generation of pro and anti-inflammatory cytokines in addition to their capacity to reduce the dietary antigen load by degrading and modifying macromolecules. Probiotics have also been shown to reverse the increased intestinal permeability characteristic of children with food allergy and to enhance specific IgA responses frequently defective in children with food allergy. The promotion of gut barrier functions by probiotics also includes the normalization of the gut microecology, alterations in which have been demonstrated in allergic individuals. Dietary lipids, especially long-chain polyunsaturated fatty acids, regulate immune function and may modify the adherence of microbes in the mucosa thereby contributing to host-microbe interactions. The properties of specific dietary compounds in optimal combinations and the joint effects of nutrients can be exploited in the development of specific prophylactic and therapeutic interventions. To meet these targets, rigorous scientific effort is required to elucidate how the food matrix and the dietary content impacts on the complex cascade of interrelated immunological mechanisms in food allergy.
    Effect of intestinal microbiota on exercise performance in mice. Hsu Yi Ju,Chiu Chien Chao,Li Yen Peng,Huang Wen Ching,Huang Yen Te,Huang Chi Chang,Chuang Hsiao Li Journal of strength and conditioning research The antioxidant enzyme system helps protect against intense exercise-induced oxidative damage and is related to the physical status of athletes. Evidence suggests that intestinal microbiota may be an important environmental factor associated with host metabolism, physiology, and antioxidant endogenous defense. However, evidence of the effect of gut microbiota status on exercise performance and physical fatigue is limited. We investigated the association of intestinal bacteria and exercise performance in specific pathogen-free (SPF), germ-free (GF), and Bacteroides fragilis (BF) gnotobiotic mice. Endurance swimming time was longer for SPF and BF than GF mice, and the weight of liver, muscle, brown adipose, and epididymal fat pads was higher for SPF and BF than GF mice. The serum levels of glutathione peroxidase (GPx) and catalase were greater in SPF than GF mice. Serum superoxide dismutase activity was lower in BF than SPF and GF mice. In addition, hepatic GPx level was higher in SPF than GF and BF mice. Gut microbial status could be crucial for exercise performance and its potential action linked with the antioxidant enzyme system in athletes. 10.1519/JSC.0000000000000644
    A Review of Plant-based Diets to Prevent and Treat Heart Failure. Kerley Conor P Cardiac failure review Evidence supporting the role of nutrition in heart failure (HF) incidence and severity is growing. A comprehensive search of online databases was conducted using relevant keywords to identify human studies including diet and HF. Several plant-based diets have consistently been associated with decreased HF incidence and severity, notably the Dietary Approaches to Stop Hypertension (DASH) and Mediterranean diets. Several other plant-based dietary patterns, including low-fat diets and the rice diet, also show promise. Higher dietary quality, as assessed using different scores, seems to provide protective qualities. Fruit, vegetables, legumes and wholegrains appear to be beneficial, whereas red/processed meats, eggs and refined carbohydrates appear harmful. Some evidence suggests detrimental effects of dairy products and poultry, but more research is needed. There is observational and interventional evidence that a plant-based diet high in antioxidants, micronutrients, nitrate and fibre but low in saturated/trans fats may decrease the incidence and severity of HF. Potential mechanisms for this include decreased oxidative stress, homocysteine and inflammation levels, as well as higher antioxidant defence and nitric oxide bioavailability with gut microbiome modulation. Well-designed randomised, controlled nutrition intervention trials specific to HF are urgently required. 10.15420/cfr.2018:1:1
    Melatonin improves abdominal pain in irritable bowel syndrome patients who have sleep disturbances: a randomised, double blind, placebo controlled study. Song G H,Leng P H,Gwee K A,Moochhala S M,Ho K Y Gut BACKGROUND AND AIMS:Melatonin, a sleep promoting agent, is involved in the regulation of gastrointestinal motility and sensation. We aimed to determine if melatonin was effective in improving bowel symptoms and sleep disturbances in irritable bowel syndrome (IBS) patients with sleep disturbance. METHODS:Forty IBS patients (aged 20-64 years; 24 female) with sleep disturbances were randomly assigned to receive either melatonin 3 mg (n = 20) or matching placebo (n = 20) at bedtime for two weeks. Immediately before and after the treatment, subjects completed bowel, sleep, and psychological questionnaires, and underwent rectal manometry and overnight polysomnography. RESULTS:Compared with placebo, melatonin taken for two weeks significantly decreased mean abdominal pain score (2.35 v 0.70; p<0.001) and increased mean rectal pain threshold (8.9 v -1.2 mm Hg; p<0.01). Bloating, stool type, stool frequency, and anxiety and depression scores did not significantly differ after treatment in both groups. Data from sleep questionnaires and polysomnography showed that the two week course of melatonin did not influence sleep parameters, including total sleep time, sleep latency, sleep efficiency, sleep onset latency, arousals, duration of stages 1-4, rapid eye movement (REM) sleep, and REM onset latency. CONCLUSIONS:Administration of melatonin 3 mg at bedtime for two weeks significantly attenuated abdominal pain and reduced rectal pain sensitivity without improvements in sleep disturbance or psychological distress. The findings suggest that the beneficial effects of melatonin on abdominal pain in IBS patients with sleep disturbances are independent of its action on sleep disturbances or psychological profiles. 10.1136/gut.2004.062034
    Melatonin: a novel treatment for IBS? Elsenbruch S Gut 10.1136/gut.2005.074377
    Dietary patterns and components to prevent and treat heart failure: a comprehensive review of human studies. Kerley Conor P Nutrition research reviews Growing evidence has emerged about the role of dietary patterns and components in heart failure (HF) incidence and severity. The objective here is to provide a comprehensive summary of the current evidence regarding dietary patterns/components and HF. A comprehensive search of online databases was conducted using multiple relevant keywords to identify relevant human studies. The Dietary Approaches to Stop Hypertension (DASH) and Mediterranean diets have consistently been associated with decreased HF incidence and severity. Regarding specific dietary components, fruit, vegetables, legumes and whole grains appear beneficial. Current evidence suggests that red/processed meats, eggs and refined carbohydrates are harmful, while fish, dairy products and poultry remain controversial. However, there is a notable lack of human intervention trials. The existing but limited observational and interventional evidence from human studies suggests that a plant-based dietary pattern high in antioxidants, micronutrients, nitrate and fibre but low in saturated/trans-fat and Na may decrease HF incidence/severity. Potential mechanisms include decreased oxidative stress, homocysteine and inflammation but higher antioxidant defence and NO bioavailability and gut microbiome modulation. Randomised, controlled trials are urgently required. 10.1017/S0954422418000148
    Antiinflammatory activity of melatonin in central nervous system. Esposito Emanuela,Cuzzocrea Salvatore Current neuropharmacology Melatonin is mainly produced in the mammalian pineal gland during the dark phase. Its secretion from the pineal gland has been classically associated with circadian and circanual rhythm regulation. However, melatonin production is not confined exclusively to the pineal gland, but other tissues including retina, Harderian glands, gut, ovary, testes, bone marrow and lens also produce it. Several studies have shown that melatonin reduces chronic and acute inflammation. The immunomodulatory properties of melatonin are well known; it acts on the immune system by regulating cytokine production of immunocompetent cells. Experimental and clinical data showing that melatonin reduces adhesion molecules and pro-inflammatory cytokines and modifies serum inflammatory parameters. As a consequence, melatonin improves the clinical course of illnesses which have an inflammatory etiology. Moreover, experimental evidence supports its actions as a direct and indirect antioxidant, scavenging free radicals, stimulating antioxidant enzymes, enhancing the activities of other antioxidants or protecting other antioxidant enzymes from oxidative damage. Several encouraging clinical studies suggest that melatonin is a neuroprotective molecule in neurodegenerative disorders where brain oxidative damage has been implicated as a common link. In this review, the authors examine the effect of melatonin on several neurological diseases with inflammatory components, including dementia, Alzheimer disease, Parkinson disease, multiple sclerosis, stroke, and brain ischemia/reperfusion but also in traumatic CNS injuries (traumatic brain and spinal cord injury). 10.2174/157015910792246155
    Effect of Hesperidin on Cardiovascular Disease Risk Factors: The Role of Intestinal Microbiota on Hesperidin Bioavailability. Mas-Capdevila Anna,Teichenne Joan,Domenech-Coca Cristina,Caimari Antoni,Del Bas Josep M,Escoté Xavier,Crescenti Anna Nutrients Recently, hesperidin, a flavonone mainly present in citrus fruits, has emerged as a new potential therapeutic agent able to modulate several cardiovascular diseases (CVDs) risk factors. Animal and in vitro studies demonstrate beneficial effects of hesperidin and its derived compounds on CVD risk factors. Thus, hesperidin has shown glucose-lowering and anti-inflammatory properties in diabetic models, dyslipidemia-, atherosclerosis-, and obesity-preventing effects in CVDs and obese models, and antihypertensive and antioxidant effects in hypertensive models. However, there is still controversy about whether hesperidin could contribute to ameliorate glucose homeostasis, lipid profile, adiposity, and blood pressure in humans, as evidenced by several clinical trials reporting no effects of treatments with this flavanone or with orange juice on these cardiovascular parameters. In this review, we focus on hesperidin's beneficial effects on CVD risk factors, paying special attention to the high interindividual variability in response to hesperidin-based acute and chronic interventions, which can be partly attributed to differences in gut microbiota. Based on the current evidence, we suggest that some of hesperidin's contradictory effects in human trials are partly due to the interindividual hesperidin variability in its bioavailability, which in turn is highly dependent on the α-rhamnosidase activity and gut microbiota composition. 10.3390/nu12051488
    The relationship between phenolic compounds from diet and microbiota: impact on human health. Valdés L,Cuervo A,Salazar N,Ruas-Madiedo P,Gueimonde M,González S Food & function The human intestinal tract is home to a complex microbial community called microbiota. This gut microbiota, whilst playing essential roles in the maintenance of the health of the host, is exposed to the impact of external factors such as the use of medication or dietary patterns. Alterations in the composition and/or function of the microbiota have been described in several disease states, underlining the role of the gut microbiota in keeping the health status. Among the different dietary compounds, polyphenols constitute a very interesting group as some of them have been found to possess important biological activities, including antioxidant, anticarcinogenic or antimicrobial activities. The term polyphenol comprises thousands of molecules presenting a phenol ring and are widely distributed in plant foods. The bioactivity of these compounds is highly dependent on their intestinal absorption and often they are ingested as non-absorbable precursors that are transformed into bioactive forms by specific microorganisms in the intestine. Some of these microorganisms have been identified and the enzymatic steps involved have been elucidated. However, little is known about the impact of these ingested polyphenols upon the human gut microbiota. The heterogeneity of the polyphenol compounds and their food sources, as well as their coexistence with other bioactive compounds within a normal diet, together with the complexity of the human gut microbiota make difficult the understanding of the interactions between dietary polyphenols and gut microbes. This is, however, an important area of research which promises to expand our knowledge on the food functionality area through understanding the microbiota-food component interaction. 10.1039/c5fo00322a
    Preventive effect of Coptis chinensis and berberine on intestinal injury in rats challenged with lipopolysaccharides. Zhang Qian,Piao Xiang-Lan,Piao Xiang-Shu,Lu Ting,Wang Ding,Kim Sung Woo Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association Coptis chinensis has been used in traditional Chinese medicine to treat inflammatory symptoms. Berberine is the main alkaloid compound of C. chinensis. This study utilized a typical lipopolysaccharide (LPS) injured model to investigate the effects of C. chinensis aqueous extract (CCAE) and berberine (major active ingredient in CCAE) in the gut-derived sepsis. In rats, pretreatment with different doses of berberine (30 or 120 mg/kg bw, i.g.; BBR30 or BBR120) or CCAE (containing 9.9% berberine; 300 mg/kg bw, i.g.; CCAE300) prior to the administration of LPS (20 mg/kg bw, i.p.) significantly suppressed the increased tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and nitrite oxide (NO) in plasma as well as the activation of toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) in ileum. In addition, CCAE300 and BBR30 markedly elevated the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px); significantly prevented the increased malondialdehyde (MDA), NO and villi injury in ileum compared with the negative control. Collectively, CCAE300 and BBR30 reduced the LPS-induced intestinal damage by elevating the activities of SOD and GSH-Px and by suppressing the activation of TLR4 and NF-κB in ileum. These results indicate that CCAE and berberine are promising agents for preventing sepsis and its complications. 10.1016/j.fct.2010.09.032
    Prebiotic evaluation of cocoa-derived flavanols in healthy humans by using a randomized, controlled, double-blind, crossover intervention study. Tzounis Xenofon,Rodriguez-Mateos Ana,Vulevic Jelena,Gibson Glenn R,Kwik-Uribe Catherine,Spencer Jeremy P E The American journal of clinical nutrition BACKGROUND:The absorption of cocoa flavanols in the small intestine is limited, and the majority of the flavanols reach the large intestine where they may be metabolized by resident microbiota. OBJECTIVE:We assessed the prebiotic potential of cocoa flavanols in a randomized, double-blind, crossover, controlled intervention study. DESIGN:Twenty-two healthy human volunteers were randomly assigned to either a high-cocoa flavanol (HCF) group (494 mg cocoa flavanols/d) or a low-cocoa flavanol (LCF) group (23 mg cocoa flavanols/d) for 4 wk. This was followed by a 4-wk washout period before volunteers crossed to the alternant arm. Fecal samples were recovered before and after each intervention, and bacterial numbers were measured by fluorescence in situ hybridization. A number of other biochemical and physiologic markers were measured. RESULTS:Compared with the consumption of the LCF drink, the daily consumption of the HCF drink for 4 wk significantly increased the bifidobacterial (P < 0.01) and lactobacilli (P < 0.001) populations but significantly decreased clostridia counts (P < 0.001). These microbial changes were paralleled by significant reductions in plasma triacylglycerol (P < 0.05) and C-reactive protein (P < 0.05) concentrations. Furthermore, changes in C-reactive protein concentrations were linked to changes in lactobacilli counts (P < 0.05, R(2) = -0.33 for the model). These in vivo changes were closely paralleled by cocoa flavanol-induced bacterial changes in mixed-batch culture experiments. CONCLUSION:This study shows, for the first time to our knowledge, that consumption of cocoa flavanols can significantly affect the growth of select gut microflora in humans, which suggests the potential prebiotic benefits associated with the dietary inclusion of flavanol-rich foods. This trial was registered at clinicaltrials.gov as NCT01091922. 10.3945/ajcn.110.000075
    Flavanol monomer-induced changes to the human faecal microflora. Tzounis Xenofon,Vulevic Jelena,Kuhnle Gunter G C,George Trevor,Leonczak Jadwiga,Gibson Glenn R,Kwik-Uribe Catherine,Spencer Jeremy P E The British journal of nutrition We have investigated the bacterial-dependent metabolism of ( - )-epicatechin and (+)-catechin using a pH-controlled, stirred, batch-culture fermentation system reflective of the distal region of the human large intestine. Incubation of ( - )-epicatechin or (+)-catechin (150 mg/l or 1000 mg/l) with faecal bacteria, led to the generation of 5-(3',4'-dihydroxyphenyl)-gamma-valerolactone, 5-phenyl-gamma-valerolactone and phenylpropionic acid. However, the formation of these metabolites from (+)-catechin required its initial conversion to (+)-epicatechin. The metabolism of both flavanols occurred in the presence of favourable carbon sources, notably sucrose and the prebiotic fructo-oligosaccharides, indicating that bacterial utilisation of flavanols also occurs when preferential energy sources are available. (+)-Catechin incubation affected the growth of select microflora, resulting in a statistically significant increase in the growth of the Clostridium coccoides-Eubacterium rectale group, Bifidobacterium spp. and Escherichia coli, as well as a significant inhibitory effect on the growth of the C. histolyticum group. In contrast, the effect of ( - )-epicatechin was less profound, only significantly increasing the growth of the C. coccoides-Eubacterium rectale group. These potential prebiotic effects for both (+)-catechin and ( - )-epicatechin were most notable at the lower concentration of 150 mg/l. As both ( - )-epicatechin and (+)-catechin were converted to the same metabolites, the more dramatic change in the growth of distinct microfloral populations produced by (+)-catechin incubation may be linked to the bacterial conversion of (+)-catechin to (+)-epicatechin. Together these data suggest that the consumption of flavanol-rich foods may support gut health through their ability to exert prebiotic actions. 10.1017/S0007114507853384
    Dietary polyphenols can modulate the intestinal inflammatory response. Romier Béatrice,Schneider Yves-Jacques,Larondelle Yvan,During Alexandrine Nutrition reviews Inflammatory bowel diseases (IBD) arise from multiple causes, including environmental factors, gut microflora, immunity, and genetic predispositions. In the course of IBD, immune homeostasis and intestinal mucosa barrier integrity are impaired. Among natural preventive treatments that have been identified to date, polyphenols appear as promising candidates. They have been shown to protect against several diseases, including cardiovascular diseases and cancers, and they have anti-inflammatory properties in non-intestinal models. This paper will review the literature that has described to date some effects of polyphenols on intestinal inflammation. Studies, conducted using in vivo and in vitro models, provide evidence that pure polyphenolic compounds and natural polyphenolic plant extracts can modulate intestinal inflammation. 10.1111/j.1753-4887.2009.00210.x
    Aqueous Extract of Brazilian Berry () Peel Improves Inflammatory Parameters and Modulates and in Rats with Induced-Colitis. da Silva-Maia Juliana Kelly,Batista Ângela Giovana,Cazarin Cinthia Baú Betim,Soares Edilene Siqueira,Bogusz Junior Stanislau,Leal Raquel Franco,da Cruz-Höfling Maria Alice,Maróstica Junior Mário Roberto Nutrients Natural compounds could be a complementary alternative to inflammatory bowel disease (IBD) management. This study determined the effects of an aqueous extract of peel (EJP) (50 g L) on 2,4,6-trinitrobenzenesulfonic acid-induced colitis. Wistar rats were randomized into five groups: HC-healthy control, CC-colitis control, DC-drug control, SJ-short-term treatment with EJP, and LJ-long-term treatment with EJP. The EJP treatments reduced body weight loss, stool consistency score, and spleen enlargement. Gut microbiota was modulated through increased and counts after EJP treatment. Short-chain fatty acids were also higher in the EJP treatment groups. The antioxidant enzyme activities were greater than CC or DC controls. Myeloperoxidase activity (LJ), inducible nitric oxide synthase (LJ/SJ), and intercellular adhesion molecule (SJ) levels were lower than in the CC group. EJP decreased histological scoring, mucosal thickness, and preserved the crypts and histological structure. Therefore, EJP showed beneficial effects and could be potentially used as an adjuvant in IBD treatment. 10.3390/nu11112776
    Effects of several wine polyphenols on lipid peroxidation and oxygen activation in rat liver microsomes. Matejková S,Gut I Advances in experimental medicine and biology 10.1007/978-1-4615-0667-6_44
    Role of active oxygen, lipid peroxidation, and antioxidants in the pathogenesis of gastric mucosal injury induced by indomethacin in rats. Yoshikawa T,Naito Y,Kishi A,Tomii T,Kaneko T,Iinuma S,Ichikawa H,Yasuda M,Takahashi S,Kondo M Gut The roles of active oxygen, lipid peroxidation, and the antioxidative defence mechanism in gastric mucosal injury induced by treatment with indomethacin in rats were investigated. The total area of gastric erosions and concentration of lipid peroxides in the gastric mucosa increased with time after administration of indomethacin (20 mg/kg, orally). The alpha-tocopherol:total cholesterol ratio in serum was significantly decreased and the activity of glutathione peroxidase, an important enzyme to scavenger of lipid peroxides, was inhibited by the administration of indomethacin. Treatments with superoxide dismutase and catalase inhibited the increases in gastric mucosal erosions and lipid peroxides in the gastric mucosa, and the reduction of serum alpha-tocopherol. Treatment with these scavengers did not improve the decreased glutathione peroxidase activity. These findings suggest that active oxygen species and lipid peroxidation play an important part in the pathogenesis of gastric mucosal injury induced by indomethacin, and that the decreased glutathione peroxidase activity aggravated the injury due to accelerated accumulation of hydrogen peroxide and lipid peroxides in the gastric mucosal cell. 10.1136/gut.34.6.732
    Aqueous extracts of husks of Plantago ovata reduce hyperglycaemia in type 1 and type 2 diabetes by inhibition of intestinal glucose absorption. Hannan J M A,Ali L,Khaleque J,Akhter M,Flatt P R,Abdel-Wahab Y H A The British journal of nutrition Plantago ovata has been reported to reduce postprandial glucose concentrations in diabetic patients. In the present study, the efficacy and possible modes of action of hot-water extracts of husk of P. ovata were evaluated. The administration of P. ovata (0.5 g/kg body weight) significantly improved glucose tolerance in normal, type 1 and type 2 diabetic rat models. When the extract was administered orally with sucrose solution, it suppressed postprandial blood glucose and retarded small intestinal absorption without inducing the influx of sucrose into the large intestine. The extract significantly reduced glucose absorption in the gut during in situ perfusion of small intestine in non-diabetic rats. In 28 d chronic feeding studies in type 2 diabetic rat models, the extract reduced serum atherogenic lipids and NEFA but had no effect on plasma insulin and total antioxidant status. No effect of the extract was evident on intestinal disaccharidase activity. Furthermore, the extract did not stimulate insulin secretion in perfused rat pancreas, isolated rat islets or clonal beta cells. Neither did the extract affect glucose transport in 3T3 adipocytes. In conclusion, aqueous extracts of P. ovata reduce hyperglycaemia in diabetes via inhibition of intestinal glucose absorption and enhancement of motility. These attributes indicate that P. ovata may be a useful source of active components to provide new opportunities for diabetes therapy. 10.1079/bjn20061819
    Why whole grains are protective: biological mechanisms. Slavin Joanne The Proceedings of the Nutrition Society Epidemiological studies find that whole-grain intake is protective against cancer, cardiovascular disease, diabetes and obesity. Potential mechanisms for this protection are diverse since whole grains are rich in nutrients and phytochemicals. First, whole grains are concentrated sources of dietary fibre, resistant starch and oligosaccharides, carbohydrates that escape digestion in the small intestine and are fermented in the gut, producing short-chain fatty acids (SCFA). SCFA lower colonic pH, serve as an energy source for the colonocytes and may alter blood lipids. These improvements in the gut environment may provide immune protection beyond the gut. Second, whole grains are rich in antioxidants, including trace minerals and phenolic compounds, and these compounds have been linked to disease prevention. Additionally, whole grains mediate insulin and glucose responses. Although lower glycaemic load and glycaemic index have been linked to diabetes and obesity, risk of cancers such as colon and breast cancer have also been linked to high intake of readily-available carbohydrate. Finally, whole grains contain many other compounds that may protect against chronic disease. These compounds include phytate, phyto-oestrogens such as lignan, plant stanols and sterols, and vitamins and minerals. As a consequence of the traditional models of conducting nutrition studies on isolated nutrients, few studies exist on the biological effects of increased whole-grain intake. The few whole-grain feeding studies that are available show improvements in biomarkers with whole-grain consumption, such as weight loss, blood lipid improvement and antioxidant protection. 10.1079/PNS2002221
    Procyanidin B2 protects against d-galactose-induced mimetic aging in mice: Metabolites and microbiome analysis. Xiao Ying,Dong Jialin,Yin Zhiting,Wu Qiguo,Zhou Yiming,Zhou Xiaoli Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association To elucidate the possible mechanisms for the preventive effect of procyanidin B2 on aging, a combined analysis of metabolic profile and gut microbiome was carried out in the present study. The mimetic aged mice induced by d-galactose injection (500 mg/kg, sc daily), and the preventive group was fed with the diet plus 0.2% procyanidin B2. After 7 weeks of treatment, the spatial memory was assayed using the Morris water maze test. Procyanidin B2 significantly ameliorated the impaired memory and antioxidant abilities induced by d-galactose. Furthermore, metabolomics analysis of plasma based on LC/Q-TOF-MS demonstrated that phosphatidyl cholines, oleic acid, linoleic acid, carnitine, pantothenic acid, and taurocholic acid were significantly increased in the mice treated with procyanidin B2, and pyruvic acid, hydroxybutyric acid, hippuric acid, and cholic acid were decreased significantly. Together, gut microbiome analysis using Illumina sequencing showed that there were significant differences in the Firmicutes/Bacteroidetes ratio and abundance of Roseburia, Lachnospiraceae, and Bifidobacterium between the aging and supplemental procyanidin B2 groups. In summary, procyanidin B2 possessed potential prevention of the cognitive and oxidative impairment via the metabolic pathway regulation related to citrate cycle, fatty acid, and bile acid in the aged mice, accompanied by remodeling the gut flora. 10.1016/j.fct.2018.05.017
    The role of natural polyphenols in cell signaling and cytoprotection against cancer development. Lewandowska Hanna,Kalinowska Monika,Lewandowski Włodzimierz,Stępkowski Tomasz M,Brzóska Kamil The Journal of nutritional biochemistry The cytoprotective and anticancer action of dietary in-taken natural polyphenols has for long been attributed only to their direct radical scavenging activities. Currently it is well supported that those compounds display a broad spectrum of biological and pharmacological outcomes mediated by their complex metabolism, interaction with gut microbiota as well as direct interactions of their metabolites with key cellular signaling proteins. The beneficial effects of natural polyphenols and their synthetic derivatives are extensively studied in context of cancer prophylaxis and therapy. Herein we focus on cell signaling to explain the beneficial role of polyphenols at the three stages of cancer development: we review the recent proceedings about the impact of polyphenols on the cytoprotective antioxidant response and their proapoptotic action at the premalignant stage, and finally we present data showing how phenolic acids (e.g., caffeic, chlorogenic acids) and flavonols (e.g., quercetin) hamper the development of metastatic cancer. 10.1016/j.jnutbio.2015.11.006
    Absorption and metabolism of polyphenols in the gut and impact on health. Scalbert Augustin,Morand Christine,Manach Claudine,Rémésy Christian Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Polyphenols are the most abundant antioxidants in the human diet. They show a considerable structural diversity, which largely influences their bioavailability. Phenolic acids like caffeic acid are easily absorbed through the gut barrier, whereas large molecular weight polyphenols such as proanthocyanidins are very poorly absorbed. Once absorbed, polyphenols are conjugated to glucuronide, sulphate and methyl groups in the gut mucosa and inner tissues. Non-conjugated polyphenols are virtually absent in plasma. Such reactions facilitate their excretion and limit their potential toxicity. The polyphenols reaching the colon are extensively metabolised by the microflora into a wide array of low molecular weight phenolic acids. The biological properties of both conjugated derivatives and microbial metabolites have rarely been examined. Their study will be essential to better assess the health effects of dietary polyphenols. Alternatively, some health effects of polyphenols may not require their absorption through the gut barrier. Their role as iron chelators in the gut lumen is briefly discussed. 10.1016/s0753-3322(02)00205-6
    Selenium affects the activity of black tea in preventing metabolic syndrome in high-fat diet-fed Sprague-Dawley rats. Gao Ying,Xu Yongquan,Ruan Jianyun,Yin Junfeng Journal of the science of food and agriculture BACKGROUND:Metabolic syndrome, a group of factors that increase the risk of health problems, is becoming increasingly common. Strategies to prevent metabolic syndrome have received substantial attention. Black tea consumption and selenium (Se) intake have been reported to be associated negatively with the prevalence of metabolic syndrome. We therefore sought to investigate whether Se-rich black tea might have a stronger effect than Se-deficient black tea in the prevention of metabolic syndrome. RESULTS:Sprague-Dawley rats were divided into four groups and fed a normal rodent diet, high-fat diet, high-fat diet containing 3% Se-rich black tea, or a high-fat diet containing 3% Se-deficient black tea for 4 weeks. Blood and tissue samples were tested at the end of the experiment. The results suggested that both types of black tea ameliorated high-fat diet-induced body-weight gain, lowered serum triglycerides and attenuated intestinal barrier dysfunction. Selenium-rich black tea showed stronger activity in decreasing fasting serum glucose and increasing insulin sensitivity, as well as stronger hepatoprotection, owing to higher total antioxidant capacity and activated hepatic antioxidant enzymes. However, it did not exhibit better effects in preventing fat accumulation. The different effects of Se-rich and Se-deficient black tea on the gut microbiota might have been partially responsible for the results. CONCLUSION:Compared with Se-deficient black tea, Se-rich black tea displayed stronger activity in preventing high-fat diet-induced hyperglycemia and liver damage but was not better at preventing fat accumulation and attenuating dysbiosis. More experiments are needed to understand the underlying mechanisms further. © 2019 Society of Chemical Industry. 10.1002/jsfa.10027
    Effect of proanthocyanidin, arginine and glutamine supplementation on methotrexate-induced gastrointestinal toxicity in rats. Gulgun M,Karaoglu A,Kesik V,Kurt B,Erdem O,Tok D,Kismet E,Koseoglu V,Ozcan O Methods and findings in experimental and clinical pharmacology Methotrexate is a folate antagonist that is commonly used as an antitumor and antiarthritic drug. The aim of this study was to investigate the possible roles of exogenous glutamine (Glu), arginine (Arg) and proanthocyanidin (PA) on gut protection from methotrexate-induced intestinal damage in rats. Experimental rats were separated into eight groups. The first (sham) group received a 0.9% NaCl solution alone. The second group received intraperitoneal injections of methotrexate (20 mg/kg/day) administered on day 4 of the experiment and continued for 5 days. Rats in the other six groups were administered PA, Glu, Arg, Glu+PA, Arg+PA or Glu+Arg orally by gavage together with methotrexate and animals were sacrificed on day 8 of the experiment. All animals were sacrificed 4 days after methotrexate injection for histopathological analysis, tissue glutathione peroxidase, malondialdehyde and superoxide dismutase assays. Proanthocyanidin and Glu decreased the severity of intestinal injury and oxidant injury as evident by histopathology and changes in malondialdehyde levels. Histological analysis confirmed that PA and to a lesser extent Glu supplementation were more favorable than Arg for the protection of the small intestine from methotrexate-induced injury. 10.1358/mf.2010.32.9.1516694
    Oxidative stress: an important phenomenon with pathogenetic significance in the progression of acute pancreatitis. Tsai K,Wang S S,Chen T S,Kong C W,Chang F Y,Lee S D,Lu F J Gut BACKGROUND:Reactive oxygen species and related oxidative damage have been implicated in the initiation of acute pancreatitis. Changes in these parameters during disease progression merit further investigation. AIMS:To evaluate changes and the clinical relevance of superoxide radicals, endogenous antioxidants, and lipid peroxidation during the course of acute pancreatitis. PATIENTS AND METHODS:Superoxide radicals (measured as lucigenin amplified chemiluminescence), ascorbic acid, dehydroascorbic acid, alpha tocopherol, and lipid peroxidation (measured as thiobarbiturate reactive substances) were analysed in blood samples from 56 healthy subjects, 30 patients with mild acute pancreatitis, and 23 patients with severe acute pancreatitis. The association with grades of disease severity was analysed. Measurements were repeated one and two weeks after onset of pancreatitis. RESULTS:In the blood from patients with acute pancreatitis, there were increased levels of the superoxide radical as well as lipid peroxides. There was notable depletion of ascorbic acid and an increased fraction of dehydroascorbic acid. Changes in alpha tocopherol were not great except in one case with poor prognosis. Differences between severe and mild acute pancreatitis were significant (p < 0.01). Variable but significant correlations with disease severity scores were found for most of these markers. The normalisation of these indexes postdated clinical recovery one or two weeks after onset of disease. CONCLUSIONS:Heightened oxidative stress appears early in the course of acute pancreatitis and lasts longer than the clinical manifestations. The dependence of disease severity on the imbalance between oxidants and natural defences suggests that oxidative stress may have a pivotal role in the progression of pancreatitis and may provide a target for treatment. 10.1136/gut.42.6.850
    A Review on the Weight-Loss Effects of Oxidized Tea Polyphenols. Rothenberg Dylan O'Neill,Zhou Caibi,Zhang Lingyun Molecules (Basel, Switzerland) The mechanistic systems in the body through which tea causes weight loss are complex and multi-dimensional. Additionally, the bioactive components in tea such as catechins, caffeine, and products of tea polyphenol oxidation vary greatly from one major tea type to the next. Green tea has been the primary subject of consideration for investigation into the preventative health effects of tea because it contains the highest levels of phenolic compounds and retains the highest antioxidant capabilities of any major tea type. However, recent research suggests decreasing body fat accumulation has little to do with antioxidant activity and more to do with enzyme inhibition, and gut microbiota interactions. This paper reviews several different tea polyphenol-induced weight-loss mechanisms, and purposes a way in which these mechanisms may be interrelated. Our original 'short-chain fatty acid (SCFA) hypothesis' suggests that the weight-loss efficacy of a given tea is determined by a combination of carbohydrate digestive enzyme inhibition and subsequent reactions of undigested carbohydrates with gut microbiota. These reactions among residual carbohydrates, tea polyphenols, and gut microbiota within the colon produce short-chain fatty acids, which enhance lipid metabolism through AMP-activated protein kinase (AMPK) activation. Some evidence suggests the mechanisms involved in SCFA generation may be triggered more strongly by teas that have undergone fermentation (black, oolong, and dark) than by non-fermented (green) teas. We discussed the mechanistic differences among fermented and non-fermented teas in terms of enzyme inhibition, interactions with gut microbiota, SCFA generation, and lipid metabolism. The inconsistent results and possible causes behind them are also discussed. 10.3390/molecules23051176
    Intestinal cell culture models and their potential to study the effect of food components on intestinal inflammation. Ponce de León-Rodríguez Maria Del Carmen,Guyot Jean-Pierre,Laurent-Babot Caroline Critical reviews in food science and nutrition Cell cultures are widely used in pharmaceutical, medical, food/nutrition and biological sciences. In food and nutrition science, intestinal cell culture models of human origin are attracting increasing interest but are still rarely used in investigations of the effects of bioactive food compounds on intestinal inflammation. However, such models would, among other benefits, limit the use of models and could provide new molecular data.This review is an overview of two-dimensional (2D) and three-dimensional (3D) intestinal cell culture models and their potential use in gut inflammation studies. After describing the features of healthy and inflamed intestinal barriers, we describe the main intestinal cell lines (Caco2, HT29, T84) and their use in investigations of the transport and antioxidant/anti-inflammatory potential of some bioactive food compounds. Finally, different co-culture models of gut inflammation, in association with immune cells (PBMC, THP1 and RAW 264.7 cell lines) in both 2D and 3D models are presented. 3D models called organs-on-chips or biochips are the most recent and very promising approach made possible by bioengineering and biotechnological improvements and more accurately mimic the gut microenvironment. 10.1080/10408398.2018.1506734
    The effect of flavonoid derivatives on doxorubicin transport and metabolism. Václavíková Radka,Kondrová Eliska,Ehrlichová Marie,Boumendjel Ahcene,Kovár Jan,Stopka Pavel,Soucek Pavel,Gut Ivan Bioorganic & medicinal chemistry This study investigated the effect of naturally occurring flavonoids and synthetic aurone derivatives on the formation of cardiotoxic doxorubicinol and transport of doxorubicin in breast cancer cells. Quercetin significantly inhibited the formation of doxorubicinol. Quercetin and aurones did not significantly affect transport of [14C]doxorubicin in human resistant breast cancer cells. In conclusion, quercetin should be further tested for its potency to decrease doxorubicin-mediated toxicity. 10.1016/j.bmc.2007.10.093
    Polyphenol supplementation as a complementary medicinal approach to treating inflammatory bowel disease. Biasi F,Astegiano M,Maina M,Leonarduzzi G,Poli G Current medicinal chemistry Inflammatory bowel disease (IBD) comprises a group of idiopathic chronic intestinal inflammation syndromes that are very common in developed countries. It is characterized by intermittent episodes of clinical remission and relapse, with recurrent inflammatory injury that can lead to structural damage of the intestine. The uncontrolled intestinal immune response to bacterial antigens leads to the production of abundant cytokines and chemokines, by activated leukocytes and epithelial cells, which trigger inflammatory and oxidative reactions. The current treatment of IBD consists in long-term anti-inflammatory therapy that, however, does not exclude relapses and side effects, frequently resulting in surgical intervention. Polyphenols have been acknowledged to be anti-oxidant and anti-inflammatory and therefore, have been proposed as an alternative natural approach to prevent or treat chronic inflammatory diseases. Most studies have been in animal models of colitis, using chemical inducers or mice defective in anti-inflammatory mediators and in intestinal cell lines treated with pro-inflammatory cytokines or lipid oxidation products. These studies provide evidence that polyphenols can effectively modulate intestinal inflammation. They exert their effects by modulating cell signaling pathways, mainly activated in response to oxidative and inflammatory stimuli, and NF-kB is the principal downstream effector. Polyphenols may thus be considered able to prevent or delay the progression of IBD, especially because they reach higher concentrations in the gut than in other tissues. However, knowledge of the use of polyphenols in managing human IBD is still scanty, and further clinical studies should afford more solid evidence of their beneficial effects.
    Dietary fiber reduces the antioxidative effect of a carotenoid and alpha-tocopherol mixture on LDL oxidation ex vivo in humans. Hoffmann J,Linseisen J,Riedl J,Wolfram G European journal of nutrition BACKGROUND:Antioxidant concentrations in low density lipoproteins (LDL) are an important determinant for their susceptibility to oxidation and can be modulated by dietary intake. AIM OF THE STUDY:In the present study, the influence of dietary fiber on the antioxidant enrichment and the oxidation resistance of LDL after antioxidant supplementation is investigated. METHOD:An antioxidant supplement consisting of beta-carotene, lycopene, lutein, canthaxanthin and alpha-tocopherol was given to six young women together with a standard meal. Using a cross-over study design, each subject received the standard meal without additional dietary fiber and enriched with pectin, guar, or cellulose in a random order. To determine the resistance of LDL against copper ion-induced oxidation, the formation of conjugated dienes was measured. RESULTS:Eight, 10, and 24 hours after antioxidant supplementation the isolated LDL revealed significantly (p < 0.05) increased antioxidant concentrations; addition of pectin, guar, or cellulose to the meal depressed this increase. Concomitantly, the observed increase in the resistance of LDL against oxidation (measured as lag phase) was lower with dietary fiber supplementation than that found without. On average, pectin, guar, and cellulose reduced the increase of the lag phase (measured without addition of dietary fiber) by 38%, 22%, and 18%, respectively. CONCLUSIONS:These results indicate that dietary fiber supplementation decreases the antioxidative effect of a supplement consisting of carotenoids and alpha-tocopherol in LDL, an effect that is likely to be mediated by a reduced bioavailability of these antioxidants in the gut. 10.1007/s003940050078
    Chlorogenic acid bioavailability largely depends on its metabolism by the gut microflora in rats. Gonthier Marie-Paule,Verny Marie-Anne,Besson Catherine,Rémésy Christian,Scalbert Augustin The Journal of nutrition Chlorogenic acid, the ester of caffeic acid with quinic acid, is one of the most abundant polyphenols in the human diet with coffee, fruits and vegetables as its major sources. Its antioxidant and anticarcinogenic properties have been well established in animal studies. However, little is known about its gut absorption and metabolism. In the present work, four groups of rats (n = 8) were fed a diet supplemented with chlorogenic, caffeic or quinic acids (250 micromol/d) or an unsupplemented diet for 8 d. Parent compounds and their metabolites were estimated in urine (24-h collection) and plasma by HPLC-electrospray ionization-tandem mass spectrometry. Significant differences in their levels were observed among the groups. The recovery of chlorogenic acid in urine was low (0.8%, mol/mol), and the total urinary excretion of caffeic acid liberated by hydrolysis of chlorogenic acid and its tissular methylated metabolites (ferulic and isoferulic acids) did not account for >0.5% (mol/mol) of the dose ingested. On the other hand, the metabolites of microbial origin, namely, m-coumaric acid and derivatives of phenylpropionic, benzoic and hippuric acids, represented the major compounds in both urine and plasma. Hippuric acid largely originated from the transformation of the quinic acid moiety, and all other metabolites from the caffeic acid moiety. These microbial metabolites accounted for 57.4% (mol/mol) of the chlorogenic acid intake. Such a high abundance of microbial metabolites shows that the bioavailability of chlorogenic acid depends largely on its metabolism by the gut microflora. Their potential importance in explaining the biological effects of dietary polyphenols is emphasized. 10.1093/jn/133.6.1853
    Metabolic aspects of phenolic compounds from seeds in the management of oxidative stress. Lopes Neto José Joaquim,de Almeida Thiago Silva,Gonçalves de Lima Rita de Cássia,Dos Santos Nunes Ricardo Gomes,de Lima Silva Jailson Renato,de Almeida Lécio Leone,Kamdem Jean Paul,Carvalho Ana Fontenele Urano Drug development and industrial pharmacy Considering the limited number of studies that analyze the behavior of plant preparations in human body, this study aimed to characterize the phenolic compounds from extract (EETg) in terms of antioxidant and metabolic aspects, integrating , and strategies. EETg was analyzed in relation to polyphenols release from the plant matrix under digestion, as well as the pharmacokinetic prediction of their major compounds by simulation and understanding of its antioxidant effect in an alternative animal model. About 35.22% of polyphenols from EETg proved to be accessible after enzymatic hydrolysis. A kinetics study showed that 40% of the total content of these phytochemicals was released from the extract accompanied by increased antioxidant capacity after 180 min of gastrointestinal simulation. A computational approach revealed that 7 out of 9 major phenolic compounds of EETg showed good pharmacokinetic parameters such as intestinal absorption and bioavailability score. In addition, the extract showed a protective effect on copper-induced oxidative stress in , evidenced by the restoration of basal levels of thiol and malondialdehyde contents. These biochemical observations were supported by the examination of histological features of . brain. It was demonstrated that the oral administration of EETg would provide phenolic compounds partially absorbable by the human gut and capable of providing health benefits associated with the inhibition of oxidative stress. Additionally, the results highlight the need to implement new approaches for the rational development of plant-based medicines. 10.1080/03639045.2020.1767126
    Relative bioavailability of the antioxidant flavonoid quercetin from various foods in man. Hollman P C,van Trijp J M,Buysman M N,van der Gaag M S,Mengelers M J,de Vries J H,Katan M B FEBS letters Quercetin is a strong antioxidant and a major dietary flavonoid. Epidemiological studies suggest that consumption of quercetin protects against cardiovascular disease, but its absorption in man is controversial. We fed nine subjects a single large dose of onions, which contain glucose conjugates of quercetin, apples, which contain both glucose and non-glucose quercetin glycosides, or pure quercetin-3-rutinoside, the major quercetin glycoside in tea. Plasma levels were then measured over 36 h. Bioavailability of quercetin from apples and of pure quercetin rutinoside was both 30% relative to onions. Peak levels were achieved less than 0.7 h after ingestion of onions, 2.5 h after apples and 9 h after the rutinoside. Half-lives of elimination were 28 h for onions and 23 h for apples. We conclude that conjugation with glucose enhances absorption from the small gut. Because of the long half-lives of elimination, repeated consumption of quercetin-containing foods will cause accumulation of quercetin in blood. 10.1016/s0014-5793(97)01367-7
    Possible effects of dietary polyphenols on sugar absorption and digestion. Williamson Gary Molecular nutrition & food research Excessive post-prandial glucose excursions are a risk factor for developing diabetes, associated with impaired glucose tolerance. One way to limit the excursion is to inhibit the activity of digestive enzymes for glucose production and of the transporters responsible for glucose absorption. Flavonols, theaflavins, gallate esters, 5-caffeoylqunic acid and proanthocyanidins inhibit α-amylase activity. Anthocyanidins and catechin oxidation products, such as theaflavins and theasinsensins, inhibit maltase; sucrase is less strongly inhibited but anthocyanidins seem somewhat effective. Lactase is inhibited by green tea catechins. Once produced in the gut by digestion, glucose is absorbed by SGLT1 and GLUT2 transporters, inhibited by flavonols and flavonol glycosides, phlorizin and green tea catechins. These in vitro data are supported by oral glucose tolerance tests on animals, and by a limited number of human intervention studies on polyphenol-rich foods. Acarbose is a drug whose mechanism of action is only through inhibition of α-amylases and α-glucosidases, and in intervention studies gives a 6% reduction in diabetes risk over 3 years. A lifetime intake of dietary polyphenols, assuming the same mechanism, has therefore a comparable potential to reduce diabetes risk, but more in vivo studies are required to fully test the effect of modulating post-prandial blood glucose in humans. 10.1002/mnfr.201200511
    Nitroxide radical attenuates ischaemia/reperfusion injury to the rat small intestine. Udassin R,Haskel Y,Samuni A Gut BACKGROUND:Free radicals are associated with post-ischaemic intestinal injury and contribute to major clinical problems primarily in premature infants. Various antioxidative means and modes of intervention, previously tested, have demonstrated only limited efficacy. AIMS:To study the protective activity of the stable nitroxide radical 4-OH, 2,2,6,6-tetramethylpiperidine-1-oxyl (TPL) and its respective hydroxylamine (TPL-H) against ischaemia/reperfusion (I/R) injury. METHODS:An isolated loop of ileum was created in laboratory male Sabra rats and constantly perfused with warmed normal saline. Intestinal injury was elicited through clamping of the superior mesenteric rat artery followed by reperfusion. Either TPL or TPL-H was given intravenously immediately before ischaemia or reperfusion and continuously afterwards. The rate of mucosal to lumen clearance of para-aminohippurate (PAH) was used to evaluate intestinal mucosal injury. Serum and perfusate levels of both TPL and TPL-H were measured using electron paramagnetic resonance spectrometry. RESULTS:The increase in intestinal permeability induced by I/R was significantly inhibited by both TPL and TPL-H. The nitroxide was effective also when given immediately before reperfusion. CONCLUSIONS:Through a continuous exchange, TPL and TPL-H act as self-replenishing antioxidants and thus protect from intestinal injury. This demonstrates the potential of the family of nitroxide antioxidants against oxidative stress in general and I/R injury in particular. 10.1136/gut.42.5.623
    Physicochemical Properties and Health Benefits of Pistachio Nuts. Esmaeili Nadimi Ali,Ahmadi Zahra,Falahati-Pour Soudeh Khanamani,Mohamadi Maryam,Nazari Alireza,Hassanshahi Gholamhossein,Ekramzadeh Maryam International journal for vitamin and nutrition research. Internationale Zeitschrift fur Vitamin- und Ernahrungsforschung. Journal international de vitaminologie et de nutrition The genus of Pistacia plant systematically fits into the family of Anacardiaceae. Pistachios contain protein, carbohydrate, dietary fibers, fat, folic acid, vitamin K, magnesium and potassium, gama-tocopherols, phytochemicals, and polyphenols. Collectively, these constituents have been shown to possess antioxidant and anti-inflammatory functions to improve overall health when consumed as a healthy diet. We searched the following keywords within the literature databases: pistachio, heart disorders, lipids, weight, antioxidants, and allergy. Further searching theses keywords, we have found 50 articles in PubMed, 40 articles in ISI web of knowledge and 30 articles in Google Scholar. We have selected 100 articles, among them 80 articles were used as the references of this review. In the current article, we have discussed the most recent data published regarding the regulatory effects of pistachios on several clinical states such as heart related disorders, hyperlipidemia, hypertension, vascular stiffness and endothelial and gut functions, weight management, glucose metabolism, kidney function and finally allergies. 10.1024/0300-9831/a000529
    Diet-derived phenols in plasma and tissues and their implications for health. Clifford M N Planta medica This paper seeks to catalyse a reappraisal of the nature, fate and biological significance in humans of phenols, polyphenols and tannins (PPT) consumed in normal diets, and in particular questions the primacy of PPT radical-scavenging mechanisms for the supposed health benefits of diets rich in fruits and vegetables. PPT are classified by structure and function. Arguments are presented to show that cinnamates and derived polyphenols make significantly larger contributions to the total PPT intake than the flavonols and flavones upon which the vast majority of attention has been focussed previously. Daily intakes of total PPT may range from less than 100 mg to in excess of 2 g, and the critical importance of coffee and black tea as the major dietary sources is shown. Only some 5% of the dietary PPT is absorbed in the duodenum, and of this only some 5%, mainly flavanols, reaches the plasma unchanged, the balance being mammalian conjugates. Over 95% of the intake passes to the colon and is fermented by the gut microflora. A fraction of the resulting microbial metabolites is absorbed and appears in the plasma primarily as mammalian conjugates. Even following high intakes of PPT, the plasma metabolites collectively make a very small (less than 5%) and transient contribution to the total concentration of redox active substances in plasma. This explains the failure of most studies that sought to detect an increase in plasma antioxidant power after consuming a PPT-rich meal or supplement. The powerfully antioxidant PPT aglycones, much used in in vitro studies, do not reach the plasma. The redox potential of those unchanged PPT and PPT metabolites that reach the plasma enables them to scavenge damaging radicals, but the endogenous plasma antioxidants, especially ascorbate, are required for disposal of the resultant phenoxyl radicals. Black tea and coffee, the major sources of PPT, are poor sources of ascorbate. It is suggested that if diets rich in fruits and vegetables are health-promoting, and if these effects are due to PPT, then alternatives to radical-scavenging mechanisms must be sought. Evidence is presented to show that some mammalian metabolites of PPT may indeed be able to protect the vascular endothelium and that diets rich in PPT may in humans at normal dietary levels have the ability to protect against Type II diabetes and the metabolic syndrome through effects on glucose absorption and associated hormones. Such effects are recommended for further investigation. 10.1055/s-2004-835835
    Effects of an onion by-product on bioactivity and safety markers in healthy rats. Roldán-Marín Eduvigis,Krath Britta N,Poulsen Morten,Binderup Mona-Lise,Nielsen Tom H,Hansen Max,Barri Thaer,Langkilde Søren,Cano M Pilar,Sánchez-Moreno Concepción,Dragsted Lars O The British journal of nutrition Onions are excellent sources of bioactive compounds including fructo-oligosaccharides (FOS) and polyphenols. An onion by-product was characterised in order to be developed as a potentially bioactive food ingredient. Our main aim was to investigate whether the potential health and safety effects of this onion by-product were shared by either of two derived fractions, an extract containing the onion FOS and polyphenols and a residue fraction containing mainly cell wall materials. We report here on the effects of feeding these products on markers of potential toxicity, protective enzymes and gut environment in healthy rats. Rats were fed during 4 weeks with a diet containing the products or a control feed balanced in carbohydrate. The onion by-product and the extract caused anaemia as expected in rodents for Allium products. No other toxicity was observed, including genotoxicity. Glutathione reductase (GR) and glutathione peroxidase (GPx1) activities in erythrocytes increased when rats were fed with the onion extract. Hepatic gene expression of Gr, Gpx1, catalase, 5-aminolevulinate synthase and NAD(P)H:quinone oxidoreductase was not altered in any group of the onion fed rats. By contrast, gamma-glutamate cysteine ligase catalytic subunit gene expression was upregulated but only in rats given the onion residue. The onion by-products as well as the soluble and insoluble fractions had prebiotic effects as evidenced by decreased pH, increased butyrate production and altered gut microbiota enzyme activities. In conclusion, the onion by-products have no in vivo genotoxicity, may support in vivo antioxidative defence and alter the functionality of the rat gut microbiota. 10.1017/S0007114509990870
    The Influence of Polyphenol Compounds on Human Gastrointestinal Tract Microbiota. Wiciński Michał,Gębalski Jakub,Mazurek Ewelina,Podhorecka Marta,Śniegocki Maciej,Szychta Paweł,Sawicka Ewelina,Malinowski Bartosz Nutrients Polyphenols form a diverse group of compounds containing at least two hydroxyl groups in their chemical structure. Because of the common presence in plant kingdom, polyphenols are considered a significant component of food and an important group of compounds with antioxidant properties. The absorption of polyphenols present in food depends mostly on the activity of intestinal microflora. However, little is known about the processes and interactions responsible for such phenomenon in guts ecosystem. There are only few available publications that examine the effect on polyphenols on intestinal microbiota. Therefore, this work will focus on describing the relationship between polyphenol compounds present in food and bacteria colonizing the intestines, their mechanism, and impact on human's health. 10.3390/nu12020350
    Isoflavones, equol and cardiovascular disease: pharmacological and therapeutic insights. Jackman Katherine A,Woodman Owen L,Sobey Christopher G Current medicinal chemistry Isoflavones are an important class of phytoestrogens that are found at extrememly high levels in soy. Up until recently, daidzein and genistein were considered to be the most important and hence most studied isoflavones, however more recently attention has shifted to isoflavone metabolies. Equol represents the main active product of daidzein metabolism, produced via specific microflora in the gut. It has a longer half life and greater biological activity, including superior antioxidant activity. Yet, whilst the majority of animals produce equol following soy consumption, as much as 30-50 % of the adult human population cannot. This inability to produce equol in as much as half the population is thought to provide some explanation for the failure of soy to reveal any substantial health benefits in clinical studies. This article will comprehensively review literature investigating the potential cardiovascular benefits of daidzein and its metabolites, paying particular attention to equol. It will focus on the relative vasorelaxant activity, effects on nitric oxide synthase (NOS), antioxidant activity and potential for the treatment and prevention of hypertension and stroke. Findings obtained in both animal and human studies will be reviewed with the hope of gaining an insight into the experimental and clinical importance of equol to the cardiovascular benefits of soy.
    Natural mood foods: the actions of polyphenols against psychiatric and cognitive disorders. Gomez-Pinilla Fernando,Nguyen Trang T J Nutritional neuroscience OBJECTIVES:Polyphenols, natural compounds found in plant-based foods, possess special properties that can battle oxidative stress and stimulate the activation of molecules that aid in synaptic plasticity, a process that underlies cognitive function. Unlike many traditional treatments, polyphenols affect a broad range of mechanisms in the brain that can assist in the maintenance of cognitive and mental health, as well as the recovery from neurodegenerative diseases. Examining the molecular basis underlying the link between food intake and brain function has presented the exciting possibility of using diet as a viable method to battle cognitive and psychiatric disorders. METHODS:We will discuss the molecular systems that link polyphenols, the gut, and the brain, as well as introduce published human and animal studies demonstrating the effects of polyphenol consumption on brain plasticity and cognition. RESULTS:By influencing cellular energy metabolism and modulating the signaling pathways of molecules involved with brain plasticity, dietary factors--formerly recognized for just their effects on bodily systems--have emerged as affecters of the brain. CONCLUSION:Thus, the consumption of diets enriched with polyphenols may present the potential of dietary manipulation as a non-invasive, natural, and inexpensive therapeutic means to support a healthy brain. 10.1179/1476830511Y.0000000035
    Proanthocyanidins and human health: systemic effects and local effects in the gut. Scalbert A,Déprez S,Mila I,Albrecht A M,Huneau J F,Rabot S BioFactors (Oxford, England) Proanthocyanidins share common properties with other polyphenols, in particular their reducing capacity and ability to chelate metal ions. However, their polymeric nature clearly makes them different. They have a high affinity for proteins and their absorption through the gut barrier is likely limited to the molecules of low polymerization degree and to the metabolites formed by the colonic microflora, as suggested by in vitro experiments. The nutritional significance of proanthocyanidins is discussed in relation to their physico-chemical properties and bioavailability. 10.1002/biof.5520130119
    Dietary advanced lipid oxidation endproducts are risk factors to human health. Kanner Joseph Molecular nutrition & food research Lipid oxidation in foods is one of the major degradative processes responsible for losses in food quality. The oxidation of unsaturated fatty acids results in significant generation of dietary advanced lipid oxidation endproducts (ALEs) which are in part cytotoxic and genotoxic compounds. The gastrointestinal tract is constantly exposed to dietary oxidized food compounds, after digestion a part of them are absorbed into the lymph or directly into the blood stream. After ingestion of oxidized fats animals and human have been shown to excrete in urine increase amounts of malondialdehyde but also lipophilic carbonyl compounds. Oxidized cholesterol in the diet was found to be a source of oxidized lipoproteins in human serum. Some of the dietary ALEs, which are absorbed from the gut to the circulatory system, seems to act as injurious chemicals that activate an inflammatory response which affects not only circulatory system but also organs such as liver, kidney, lung, and the gut itself. We believe that repeated consumption of oxidized fat in the diet poses a chronic threat to human health. High concentration of dietary antioxidants could prevent lipid oxidation and ALEs generation not only in foods but also in stomach condition and thereby potentially decrease absorption of ALEs from the gut. This could explains the health benefit of diets containing large amounts of dietary antioxidants such those present in fruits and vegetables, or products such as red-wine or tea consuming during the meal. 10.1002/mnfr.200600303
    Colon cancer chemopreventive efficacy of silibinin through perturbation of xenobiotic metabolizing enzymes in experimental rats. Sangeetha Nagarajan,Viswanathan Periyaswamy,Balasubramanian Thangavel,Nalini Namasivayam European journal of pharmacology Our findings reported so far demonstrate that silibinin modulates gut microbial enzymes, colonic oxidative stress and Wnt/β-catenin signaling, to exert its antiproliferative effect against 1,2 di-methylhydrazine (DMH) induced colon carcinogenesis. Since xenobiotic metabolizing enzymes play a crucial role in carcinogen activation and metabolism, we aimed to explore the effect of silibinin on xenobiotic metabolizing enzymes during DMH induced colon carcinogenesis. Male albino rats were randomly divided into six groups. Group 1 served as control and group 2 rats received 50mg/kg body weight of silibinin p.o. every day. Groups 3-6 rats were given DMH at a dose of (20mg/kg body weight subcutaneously) once a week for 15 weeks to induce colonic tumors. In addition to DMH, group 4 (initiation), group 5 (post-initiation) and group 6 (entire period) rats received silibinin (50mg/kg body weight, p.o., everyday) at different time points during the experimental period of 32 weeks. Rats exposed to DMH alone showed increased activities of phase I enzymes (cytochrome b5, cytochrome b5 reductase, cytochromeP450, cytochromeP450 reductase, cytochromP4502E1) and decreased activities of phase II enzymes (Uridine diphospho glucuronyl transferase, Glutathione-S-transferase and DT-Diaphorase) in the liver and colonic mucosa as compared to control rats. Silibinin supplementation modulates the xenobiotic metabolizing enzymes favoring carcinogen detoxification. Evaluation of lipid peroxidation and antioxidants status showed that silibinin supplementation counteracts DMH induced hepatic and circulatory oxidative stress. Tumor burden in experimental animals was assessed both macroscopically and microscopically in the colon tissues. Our findings emphasize the potential chemopreventive action of silibinin against DMH induced colon carcinogenesis. 10.1016/j.ejphar.2011.11.008
    Lignan transformation by gut bacteria lowers tumor burden in a gnotobiotic rat model of breast cancer. Mabrok Hoda B,Klopfleisch Robert,Ghanem Kadry Z,Clavel Thomas,Blaut Michael,Loh Gunnar Carcinogenesis High dietary lignan exposure is implicated in a reduced breast cancer risk in women. The bacterial transformation of plant lignans to enterolignans is thought to be essential for this effect. To provide evidence for this assumption, gnotobiotic rats were colonized with the lignan-converting bacteria Clostridium saccharogumia, Eggerthella lenta, Blautia producta and Lactonifactor longoviformis (LCC rats). Germ-free rats were used as the control. All animals were fed a lignan-rich flaxseed diet and breast cancer was induced with 7,12-dimethylbenz(a)anthracene. The lignan secoisolariciresinol diglucoside was converted into the enterolignans enterodiol and enterolactone in the LCC but not in the germ-free rats. This transformation did not influence cancer incidence at the end of the 13 weeks experimental period but significantly decreased tumor numbers per tumor-bearing rat, tumor size, tumor cell proliferation and increased tumor cell apoptosis in LCC rats. No differences between LCC and control rats were observed in the expression of the genes encoding the estrogen receptors (ERs) α, ERβ and G-coupled protein 30. The same was true for IGF-1 and EGFR involved in tumor growth. The activity of selected enzymes involved in the degradation of oxidants in plasma and liver was significantly increased in the LCC rats. However, plasma and liver concentrations of reduced glutathione and malondialdehyde, considered as oxidative stress markers, did not differ between the groups. In conclusion, our results show that the bacterial conversion of plant lignans to enterolignans beneficially influences their anticancer effects. 10.1093/carcin/bgr256
    Metabolizes Dietary Plant Glucosides and Externalizes Their Bioactive Phytochemicals. Theilmann Mia C,Goh Yong Jun,Nielsen Kristian Fog,Klaenhammer Todd R,Barrangou Rodolphe,Abou Hachem Maher mBio Therapeutically active glycosylated phytochemicals are ubiquitous in the human diet. The human gut microbiota (HGM) modulates the bioactivities of these compounds, which consequently affect host physiology and microbiota composition. Despite a significant impact on human health, the key players and the underpinning mechanisms of this interplay remain uncharacterized. Here, we demonstrate the growth of on mono- and diglucosyl dietary plant glycosides (PGs) possessing small aromatic aglycones. Transcriptional analysis revealed the upregulation of host interaction genes and identified two loci that encode phosphotransferase system (PTS) transporters and phospho-β-glucosidases, which mediate the uptake and deglucosylation of these compounds, respectively. Inactivating these transport and hydrolysis genes abolished or severely reduced growth on PG, establishing the specificity of the loci to distinct groups of PGs. Following intracellular deglucosylation, the aglycones of PGs are externalized, rendering them available for absorption by the host or for further modification by other microbiota taxa. The PG utilization loci are conserved in and closely related lactobacilli, in correlation with versatile growth on these compounds. Growth on the tested PG appeared more common among human gut lactobacilli than among counterparts from other ecologic niches. The PGs that supported the growth of were utilized poorly or not at all by other common HGM strains, underscoring the metabolic specialization of These findings highlight the role of human gut and select lactobacilli in the bioconversion of glycoconjugated phytochemicals, which is likely to have an important impact on the HGM and human host. Thousands of therapeutically active plant-derived compounds are widely present in berries, fruits, nuts, and beverages like tea and wine. The bioactivity and bioavailability of these compounds, which are typically glycosylated, are altered by microbial bioconversions in the human gut. Remarkably, little is known about the bioconversion of PGs by the gut microbial community, despite the significance of this metabolic facet to human health. Our work provides the first molecular insights into the metabolic routes of diet relevant and therapeutically active PGs by and related human gut lactobacilli. This taxonomic group is adept at metabolizing the glucoside moieties of select PG and externalizes their aglycones. The study highlights an important role of lactobacilli in the bioconversion of dietary PG and presents a framework from which to derive molecular insights into their metabolism by members of the human gut microbiota. 10.1128/mBio.01421-17
    Reactive oxygen species and the hypomotility of the gall bladder as targets for the treatment of gallstones with melatonin: a review. Koppisetti Sreedevi,Jenigiri Bharat,Terron M Pilar,Tengattini Sandra,Tamura Hiroshi,Flores Luis J,Tan Dun-Xian,Reiter Russel J Digestive diseases and sciences Free radical-mediated damage of the gall bladder epithelium predisposes to the development of both gall bladder inflammation and gallstone formation, which often coexist. Melatonin, a pineal and gut secretory product, due to its antioxidant activity along with its effect on the aging gall bladder myocytes, inhibits gallstone formation. Melatonin reduces the biliary levels of cholesterol by inhibiting cholesterol absorption across the intestinal epithelium and by increasing the conversion of cholesterol to bile acids. The incidence of gallstones is increasing and is expected to rise dramatically with the increase in the longevity and the risk factors such as obesity. The change in the prevalence of cholelithiasis is associated with a proportionate rise in the incidence of cholangiocarcinoma. In an attempt to improve the quality of life of the rapidly increasing aging population, this article reviews up-to-date information on the pathophysiology of the gall bladder function and discusses the development of new therapies with potential good patient compliance and lower cost than the current treatments. 10.1007/s10620-007-0195-5
    Effects of Dietary Fibre from the Traditional Indonesian Food, Green Cincau ( Merr.) on Preneoplastic Lesions and Short Chain Fatty Acid Production in an Azoxymethane Rat Model of Colon Cancer. Nurdin Samsu U,Le Leu Richard K,Aburto-Medina Arturo,Young Graeme P,Stangoulis James C R,Ball Andy S,Abbott Catherine A International journal of molecular sciences Green cincau ( Merr.) is a traditional food of Indonesia and provides a natural source of dietary fibre and antioxidants. This study evaluated the ability of green cincau, and other dietary fibres with or without the addition of anti-oxidant, epigallocatechin-3-gallate (EGCG), to prevent colorectal cancer in a 12 week azoxymethane (AOM) rat model. While all dietary treatments stimulated short chain fatty acid production (SCFA) in the digesta and faeces, no one treatment was able to significantly protect against aberrant crypt formation (ACF), when compared to the control diet. However, feeding green cincau leaves or extracts did not result in an increase in ACF compared to the control diet. Unexpectedly, when the dietary fibre source was pectin, 0.1% EGCG increased proliferative activity and liver lipid peroxidation when compared to the control diet containing cellulose. Examination of faecal microbial communities identified the presence of short chain acid producing bacteria, but a distinct community profile was not observed from any individual diet group. Overall, this research implies that combining dietary fibre with an antioxidant does not automatically equate to a beneficial response. Further work is required to investigate the health-promoting properties of green cincau. 10.3390/ijms19092593
    Stability of oleuropein in the human proximal gut. Markopoulos Constantinos,Vertzoni Maria,Agalias Apostolos,Magiatis Prokopios,Reppas Christos The Journal of pharmacy and pharmacology OBJECTIVES:We aimed to assess the intralumenal stability of oleuropein in human gastric and small intestinal contents. We additionally aimed to assess the stability characteristics of oleuropein in media simulating the intralumenal conditions. METHODS:The intralumenal stability of oleuropein was assessed in aspirates from the stomach and the upper small intestine of healthy volunteers collected under both fasted and fed state conditions and in media simulating the intralumenal environment. KEY FINDINGS:Oleuropein degraded in aspirates collected in the fasted state. When the initial concentration was about 50 microg/ml (close to expected intragastric concentration after single dose of commercially available products of oleuropein) the mean zero-order half-life of oleuropein in aspirates collected from the fasted small intestine was estimated to be 3.14 +/- 0.08 h at 37 degrees C (i.e. after oral administration in the fasted state, a substantial fraction of oleuropein degrades before reaching the intestinal mucosa). In contrast, oleuropein was stable in aspirates collected from the fed stomach; in small intestinal contents aspirated in the fed state the estimated zero-order degradation half-life was at least 12 h. CONCLUSIONS:These data suggest that oleuropein should not have substantial intralumenal stability problems when administered in the fed state. Data collected in media simulating the intragastric and intraintestinal environment suggest that pH affects the stability of oleuropein only at low pH values (of about 2). At higher pHs degradation characteristics are at least partly affected by the presence of other scavengers of reactive oxygen species in the medium. 10.1211/jpp/61.02.0002
    Protective effect of p-coumaric acid against 1,2 dimethylhydrazine induced colonic preneoplastic lesions in experimental rats. Sharma Sharada H,Chellappan David Raj,Chinnaswamy Prabu,Nagarajan Sangeetha Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Oxidative stress and gut microbial enzymes are intricately linked to the onset of colon carcinogenesis. Phytochemicals that modulate these two factors hold promise for the development of such agents as anticancer drugs. The present study evaluates the chemopreventive potential of p-coumaric acid (p-CA) - a phenolic acid in rats challenged with the colon specific procarcinogen DMH (1,2 di-methyl hydrazine). Rats were randomized into six groups (n=7/group). Group 1 (control); Group 2 (p-CA 200mg/kg b.w.); Group 3 (DMH 40mg/kg b.w.); Groups 4 (DMH+p-CA 50mg/kg b.w.) and Group 5 (DMH+p-CA 100mg/kg b.w.) and Group 6 (DMH+p-CA 200mg/kg b.w.). After the experimental duration of 15 weeks' rats were subjected to necropsy and tissues were collected for the histological and biochemical investigations. DMH induced colonic preneoplastic lesions viz., aberrant crypt foci (ACF), dysplastic ACF (DACF), mucin depleted foci (MDF) and beta catenin accumulated crypts (BCAC) were significantly suppressed by p-CA supplementation. Glucuronide conjugation of DMH in liver and its subsequent deconjugation mediated by microbes in the colon induced the formation of colonic preneoplastic lesions. p-CA inhibited these lesions and protected the rat colon against genotoxic insult by scavenging the free radicals via its strong antioxidant response and detoxification mechanism as measured by TBARS and enzymic antioxidants in control and experimental rats. Of the three tested doses, p-CA at a dose of 100mg/kg body weight is found to exhibit a significant optimum effect compared to the other two doses 50mg/kg body weight and 200mg/kg body weight. 10.1016/j.biopha.2017.07.146
    Resveratrol activates duodenal Sirt1 to reverse insulin resistance in rats through a neuronal network. Côté Clémence D,Rasmussen Brittany A,Duca Frank A,Zadeh-Tahmasebi Melika,Baur Joseph A,Daljeet Mira,Breen Danna M,Filippi Beatrice M,Lam Tony K T Nature medicine Resveratrol improves insulin sensitivity and lowers hepatic glucose production (HGP) in rat models of obesity and diabetes, but the underlying mechanisms for these antidiabetic effects remain elusive. One process that is considered a key feature of resveratrol action is the activation of the nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase sirtuin 1 (SIRT1) in various tissues. However, the low bioavailability of resveratrol raises questions about whether the antidiabetic effects of oral resveratrol can act directly on these tissues. We show here that acute intraduodenal infusion of resveratrol reversed a 3 d high fat diet (HFD)-induced reduction in duodenal-mucosal Sirt1 protein levels while also enhancing insulin sensitivity and lowering HGP. Further, we found that duodenum-specific knockdown of Sirt1 expression for 14 d was sufficient to induce hepatic insulin resistance in rats fed normal chow. We also found that the glucoregulatory role of duodenally acting resveratrol required activation of Sirt1 and AMP-activated protein kinase (Ampk) in this tissue to initiate a gut-brain-liver neuronal axis that improved hypothalamic insulin sensitivity and in turn, reduced HGP. In addition to the effects of duodenally acting resveratrol in an acute 3 d HFD-fed model of insulin resistance, we also found that short-term infusion of resveratrol into the duodenum lowered HGP in two other rat models of insulin resistance--a 28 d HFD-induced model of obesity and a nicotinamide (NA)-streptozotocin (STZ)-HFD-induced model of mild type 2 diabetes. Together, these studies highlight the therapeutic relevance of targeting duodenal SIRT1 to reverse insulin resistance and improve glucose homeostasis in obesity and diabetes. 10.1038/nm.3821
    Effects of vitamin antioxidant supplementation on cell kinetics of patients with adenomatous polyps. Cahill R J,O'Sullivan K R,Mathias P M,Beattie S,Hamilton H,O'Morain C Gut Colonic crypt cell proliferation is used as an indicator of risk of colorectal carcinoma. Subjects with adenomatous polyps and cancer have an increased cell proliferation and a shift of the proliferative zone towards the apex of the crypt. Epidemiological and in vitro studies have confirmed a link between vitamins A, E, C, beta-carotene, and colorectal cancer. In vitro bromodeoxyuridine immunohistochemical technique was used to assess the effect of daily oral supplementation with vitamin E (160 mg), vitamin C (750 mg), or beta-carotene (9 mg) on the colonic crypt cell proliferation in patients with adenomatous polyps (n = 40) compared with normal subjects with no colonic disease (n = 20). The patients were given supplementation for one month and colonic biopsy specimens were taken before and at the end of the trial. Patients with adenomatous polyps had a significantly higher mean labelling index per cent than controls (p < 0.001). Vitamin C or beta-carotene supplementation, however, significantly reduced the total proliferation (p < 0.005) whereas vitamin E supplementation had no effect on the colonic crypt cell proliferation. beta-carotene reduced cell proliferation at the base of the crypt only. Vitamin C reduced cell proliferation in all the crypt compartments from the apex to the base to those values seen in age and sex matched controls. These findings indicate that prolonged supplementation with vitamin C may reduce the recurrence of adenomatous polyps. 10.1136/gut.34.7.963
    Nutrients, foods, and colorectal cancer prevention. Song Mingyang,Garrett Wendy S,Chan Andrew T Gastroenterology Diet has an important role in the development of colorectal cancer. In the past few decades, findings from extensive epidemiologic and experimental investigations have linked consumption of several foods and nutrients to the risk of colorectal neoplasia. Calcium, fiber, milk, and whole grains have been associated with a lower risk of colorectal cancer, and red meat and processed meat have been associated with an increased risk. There is substantial evidence for the potential chemopreventive effects of vitamin D, folate, fruits, and vegetables. Nutrients and foods also may interact, as a dietary pattern, to influence colorectal cancer risk. Diet likely influences colorectal carcinogenesis through several interacting mechanisms. These include the direct effects on immune responsiveness and inflammation, and the indirect effects of overnutrition and obesity-risk factors for colorectal cancer. Emerging evidence also implicates the gut microbiota as an important effector in the relationship between diet and cancer. Dietary modification therefore has the promise of reducing colorectal cancer incidence. 10.1053/j.gastro.2014.12.035
    The photoperiod, circadian regulation and chronodisruption: the requisite interplay between the suprachiasmatic nuclei and the pineal and gut melatonin. Reiter R J,Rosales-Corral S,Coto-Montes A,Boga J A,Tan D-X,Davis J M,Konturek P C,Konturek S J,Brzozowski T Journal of physiology and pharmacology : an official journal of the Polish Physiological Society The current scientific literature is replete with investigations providing information on the molecular mechanisms governing the regulation of circadian rhythms by neurons in the suprachiasmatic nucleus (SCN), the master circadian generator. Virtually every function in an organism changes in a highly regular manner during every 24-hour period. These rhythms are believed to be a consequence of the SCN, via neural and humoral means, regulating the intrinsic clocks that perhaps all cells in organisms possess. These rhythms optimize the functions of cells and thereby prevent or lower the incidence of pathologies. Since these cyclic events are essential for improved cellular physiology, it is imperative that the SCN provide the peripheral cellular oscillators with the appropriate time cues. Inasmuch as the 24-hour light:dark cycle is a primary input to the central circadian clock, it is obvious that disturbances in the photoperiodic environment, e.g., light exposure at night, would cause disruption in the function of the SCN which would then pass this inappropriate information to cells in the periphery. One circadian rhythm that transfers time of day information to the organism is the melatonin cycle which is always at low levels in the blood during the day and at high levels during darkness. With light exposure at night the amount of melatonin produced is compromised and this important rhythm is disturbed. Another important source of melatonin is the gastrointestinal tract (GIT) that also influences the circulating melatonin is the generation of this hormone by the entero-endocrine (EE) cells in the gut following ingestion of tryptophan-containing meal. The consequences of the altered melatonin cycle with the chronodisruption as well as the alterations of GIT melatonin that have been linked to a variety of pathologies, including those of the gastrointestinal tract.
    Thirty days of resveratrol supplementation does not affect postprandial incretin hormone responses, but suppresses postprandial glucagon in obese subjects. Knop F K,Konings E,Timmers S,Schrauwen P,Holst J J,Blaak E E Diabetic medicine : a journal of the British Diabetic Association AIMS:Resveratrol, a natural polyphenolic compound produced by various plants (e.g. red grapes) and found in red wine, has glucose-lowering effects in humans and rodent models of obesity and/or diabetes. The mechanisms behind these effects have been suggested to include resveratrol-induced secretion of the gut incretin hormone glucagon-like peptide-1. We investigated postprandial incretin hormone and glucagon responses in obese human subjects before and after 30 days of resveratrol supplementation. METHODS:Postprandial plasma responses of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide and glucagon were evaluated in 10 obese men [subjects characteristics (mean ± standard error of the mean): age 52 ± 2 years; BMI 32 ± 1 kg/m(2), fasting plasma glucose 5.5 ± 0.1 mmol/l] who had been given a dietary supplement of resveratrol (Resvida(®) 150 mg/day) or placebo for 30 days in a randomized, double-blind, crossover design with a 4-week washout period. At the end of each intervention period a standardized meal test (without co-administration of resveratrol) was performed. RESULTS:Resveratrol supplementation had no impact on fasting plasma concentrations or postprandial plasma responses (area under curve values) of glucose-dependent insulinotropic polypeptide (11.2 ± 2.1 vs. 11.8 ± 2.2 pmol/l, P = 0.87; 17.0 ± 2.2 vs. 14.8 ± 1.6 min × nmol/l, P = 0.20) or glucagon-like peptide-1 (15.4 ± 1.0 vs. 15.2 ± 0.9 pmol/l, P = 0.84; 5.6 ± 0.4 vs. 5.7 ± 0.3 min × nmol/l, P = 0.73). Resveratrol supplementation significantly suppressed postprandial glucagon responses (4.4 ± 0.4 vs. 3.9 ± 0.4 min × nmol/l, P = 0.01) without affecting fasting glucagon levels (15.2 ± 2.2 vs. 14.5 ± 1.5 pmol/l, P = 0.56). CONCLUSIONS:Our data suggest that 30 days of resveratrol supplementation does not affect fasting or postprandial incretin hormone plasma levels in obese humans, but suppresses postprandial glucagon responses. 10.1111/dme.12231
    From oxidative stress to inflammation: redox balance and immune system. Lauridsen Charlotte Poultry science Important intestinal diseases in young pigs and chickens, such as diarrhea and enteritis, may be associated with oxidative stress and inflammatory reactions. Especially enteric infectious diseases of weaned pigs and broiler chickens are responsible for a high antibiotic consumption, and there is a major request for alternative strategies to enhance animal disease resistance and robustness. The aim of this presentation was to address the role of oxidative stress and inflammation to combat infectious pathogens, and to elucidate how the reactive processes will contribute to normal immune defense mechanisms of the animal. Furthermore, factors that can enhance oxidative stress (e.g., intensive production, heat stress, polyunsaturated fatty acids, and impaired fat quality), uncontrolled inflammatory reactions (e.g., high ratio of n-6 and n-3 in cellular membranes), and limited immune development (such as micronutrient deficiency) are addressed. In addition, the presentation reviews how micronutrient supplementation during critical phases can support a normal immune system and modulate resistance to infectious diseases of pigs and poultry. The mechanisms concern especially modulation of signal transduction in leukocytes (fat-soluble vitamins and fatty acids) and protection against immunopathology, as exerted by the antioxidative vitamins and selenium. Substantial advances in optimized gut health could be expected by increasing our understanding on how to foster or inhibit production of reactive oxygen species and inflammatory reaction; the relation to enteric pathogens, and how to monitor the effect of disease prevention in farm animals by the use of antioxidant therapy and antibacterial feed components. 10.3382/ps/pey407
    Identification of Cabernet Sauvignon anthocyanin gut microflora metabolites. Forester Sarah C,Waterhouse Andrew L Journal of agricultural and food chemistry Anthocyanins are polyphenol antioxidants that have been shown to prevent many chronic diseases, including colon cancer. The compounds are largely metabolized by various enzymes and bacteria in the large intestine, and the health benefits of consuming foods rich in anthocyanins could be due mostly to the effects of these metabolites. In this study, the contents of the large intestine of pigs were used to model anthocyanin metabolism because pig and human intestinal microflora are similar. An anthocyanin extract from Cabernet Sauvignon grapes that contained delphinidin-3-glucoside, petunidin-3-glucoside, peonidin-3-glucoside, and malvidin-3-glucoside was employed. The extract was incubated anaerobically in the contents of the large intestine of freshly slaughtered pigs for 0, 0.5, and 6 h (final concentrations of 20.9, 28.2, 61.4, and 298.0 microM of the above anthocyanin compounds, respectively, at t = 0 h). Anthocyanins and their metabolites were measured by LC-ESI-MS. After 6 h, anthocyanins were no longer detected, and three metabolites were identified as 3-O-methylgallic acid, syringic acid, and 2,4,6-trihydroxybenzaldehyde. Results from this study suggest that consumption of Cabernet Sauvignon grape anthocyanins could lead to the formation of specific metabolites in the human gut, and it is possible that these metabolites offer the protective effect against colon cancer attributed to anthocyanin consumption. 10.1021/jf801309n
    Absorption and metabolism of caffeic acid and chlorogenic acid in the small intestine of rats. Lafay Sophie,Morand Christine,Manach Claudine,Besson Catherine,Scalbert Augustin The British journal of nutrition The absorption and metabolism in the small intestine of chlorogenic acid (5-O-caffeoylquinic acid), the main phenolic acid in the human diet, and of caffeic acid were studied in rats in order to determine whether chlorogenic acid is directly absorbed or hydrolysed in the small intestine. Chlorogenic and caffeic acids were perfused into a segment of ileum plus jejunum during 45 min (50 microm, 0.75 ml/min) using an in situ intestinal perfusion rat model with cannulation of the biliary duct, and were quantified together with their metabolites in perfusion effluent, bile and plasma. The net absorption (influent flux minus effluent flux of phenolic acids and their metabolites) accounted for 19.5 % and 8 % of the perfused caffeic and chlorogenic acids, respectively. A minor fraction of the perfused caffeic acid was metabolized in the intestinal wall and secreted back into the gut lumen in the form of ferulic acid (0.5 % of the perfused flux). Part of the chlorogenic acid (1.2 % of the perfused flux) was recovered in the gut effluent as caffeic acid, showing the presence of trace esterase activity in the gut mucosa. No chlorogenic acid was detected in either plasma or bile, and only low amounts of phenolic acids (less than 0.4 %) were secreted in the bile. The present results show that chlorogenic acid is absorbed and hydrolysed in the small intestine. In contrast to numerous flavonoids, absorbed phenolic acids are poorly excreted in the bile or gut lumen. Their bioavailability therefore appears to be governed largely by their uptake into the gut mucosa. 10.1079/bjn20061714
    LPS-Enhanced Glucose-Stimulated Insulin Secretion Is Normalized by Resveratrol. Nøhr Mark K,Dudele Anete,Poulsen Morten M,Ebbesen Lene H,Radko Yulia,Christensen Lars P,Jessen Niels,Richelsen Bjørn,Lund Sten,Pedersen Steen B PloS one UNLABELLED:Low-grade inflammation is seen with obesity and is suggested to be a mediator of insulin resistance. The eliciting factor of low-grade inflammation is unknown but increased permeability of gut bacteria-derived lipopolysaccharides (LPS) resulting in endotoxemia could be a candidate. Here we test the effect of LPS and the anti-inflammatory compound resveratrol on glucose homeostasis, insulin levels and inflammation. Mice were subcutaneously implanted with osmotic mini pumps infusing either low-dose LPS or saline for 28 days. Half of the mice were treated with resveratrol delivered through the diet. LPS caused increased inflammation of the liver and adipose tissue (epididymal and subcutaneous) together with enlarged spleens and increased number of leukocytes in the blood. Resveratrol specifically reduced the inflammatory status in epididymal fat (reduced expression of TNFa and Il1b, whereas the increased macrophage infiltration was unaltered) without affecting the other tissues investigated. By LC-MS, we were able to quantitate resveratrol metabolites in epididymal but not subcutaneous adipose tissue. LPS induced insulin resistance as the glucose-stimulated insulin secretion during an oral glucose tolerance test was increased despite similar plasma glucose level resulting in an increase in the insulinogenic index (IGI; delta0-15insulin/delta0-15glucose) from 13.73 to 22.40 pmol/mmol (P < 0.001). This aberration in insulin and glucose homeostasis was normalized by resveratrol. IN CONCLUSION:Low-dose LPS enhanced the glucose-stimulated insulin secretion without affecting the blood glucose suggesting increased insulin resistance. Resveratrol restored LPS-induced alteration of the insulin secretion and demonstrated anti-inflammatory effects specifically in epididymal adipose tissue possibly due to preferential accumulation of resveratrol metabolites pointing towards a possible important involvement of this tissue for the effects on insulin resistance and insulin secretion. 10.1371/journal.pone.0146840
    Astragalus membranaceus: A Review of its Protection Against Inflammation and Gastrointestinal Cancers. Auyeung Kathy K,Han Quan-Bin,Ko Joshua K The American journal of Chinese medicine Astragalus membranaceus is a major medicinal herb commonly used in many herbal formulations in the practice of traditional Chinese medicine (TCM) to treat a wide variety of diseases and body disorders. Among its diversified clinical applications, the potential use of this herb and its chemical constituents in treatments of inflammatory diseases and cancers has been actively investigated in recent years. Astragalus-based treatments have demonstrated significant amelioration of the toxicity induced by other concurrently administered orthodox drugs (e.g., immunosuppressants and cancer chemotherapeutics). The major components of Astragalus membranaceus are polysaccharides, flavonoids, and saponins. Contemporary use of Astragalus membranaceus mainly focuses on its immunomodulating, anti-oxidant, and anti-inflammatory, as well as anticancer effects. In this paper, we summarize the properties of Astragalus membranaceus and its major constituents in the biological system based on experimental and clinical studies. The antitumorigenic mechanisms of a novel Astragalus saponins extract called AST in treating various gastrointestinal cancers are highlighted. We discuss in detail how the Astragalus herb and AST influence the immune system, modulate various cancer signaling pathways, and interact with specific transcription molecules during protection against gastrointestinal inflammation and cancers. This information could help clinicians and scientists develop novel target-specific and effective therapeutic agents that are deprived of major systemic side effects, so as to establish a better treatment regimen in the battle against inflammatory diseases and cancers of the gut. 10.1142/S0192415X16500014
    Low molecular weight procyanidins from grape seeds enhance the impact of 5-Fluorouracil chemotherapy on Caco-2 human colon cancer cells. Cheah Ker Y,Howarth Gordon S,Bindon Keren A,Kennedy James A,Bastian Susan E P PloS one OBJECTIVE:Grape seed procyanidins (PC) are flavan-3-ol oligomers and polymers known for their biological activity in the gut. Grape seed extract (GSE) have been reported to reduce intestinal injury in a rat model of mucositis. We sought to investigate effects of purified PC fractions differing in mean degree of polymerization (mDP) combined with 5-Fluorouracil (5-FU) chemotherapy on the viability of colon cancer cells (Caco-2). DESIGN:SixPC fractions (F1-F6) were isolated from Cabernet Sauvignon seeds at two ripeness stages: pre-veraison unripe (immature) and ripe (mature), utilizing step gradient, low-pressure chromatography on a Sephadex LH-20 resin. Fractions were tested on Caco-2 cells, alone and in combination with 5-FU. Eluted fractions were characterized by phloroglucinolysis and gel permeation chromatography. Cell viability was determined by the 3-(4,5-Dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide) (MTT) assay. RESULTS:All isolated fractions significantly reduced Caco-2 cell viability compared to the control (P<0.05), but F2 and F3 (mDP 2-6) were the most active fractions (immature F2 = 32% mDP 2.4, F3 = 35% mDP 5.8 and mature F2 = 13% mDP 3.6 and F3 = 17% mDP 5.9; percentage of viable cells remaining) on Caco-2 cells. When combined with 5-FU, immature fractions F1-F3 enhanced the cell toxicity effects of 5-FU by 27-73% (P<0.05). Mature seed PC fractions (F1-F4) significantly enhanced the toxicity of 5-FU by 60-83% against Caco-2 cells (P<0.05). Moreover, some fractions alone were more potent at decreasing viability in Caco-2 cells (P<0.05; immature fractions = 65-68% and mature fractions = 83-87%) compared to 5-FU alone (37%). CONCLUSIONS:PCs of mDP 2-6 (immature F1-F3 and mature F1 and F4)not only enhanced the impact of 5-FU in killing Caco-2 cells, but also surpassed standard 5-FU chemotherapy as an anti-cancer agent.The bioactivity of PC is therefore attributed primarily to lower molecular weight PCs. 10.1371/journal.pone.0098921
    Luteolin and luteolin-7-O-glucoside strengthen antioxidative potential through the modulation of Nrf2/MAPK mediated HO-1 signaling cascade in RAW 264.7 cells. Song Young Sun,Park Chung Mu Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association It has been understood that glycosidic forms of flavonoids were hydrolyzed by gut bacteria and absorbed as aglycones. However, several reports suggested that glycosides were partly absorbed without hydrolysis and remained biologically active. In this study, we evaluated the antioxidative potential of luteolin and luteolin-7-O-glucoside, glycosidic form of luteolin, against the oxidative damage and compared their antioxidative mechanisms in RAW 264.7 cells. Heme oxygenase-1 (HO-1), one of the phase II enzymes showing an antioxidative activity, was potently induced by luteolin and luteolin-7-O-glucoside treatment, which was in accordance with the translocated nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) into nucleus. Moreover, luteolin and the luteolin-7-O-glucoside activated HO-1 expression by p38 and c-Jun NH2-terminal kinase (JNK) regulation. In order to identify the antioxidation potential by HO-1, tert-butyl hydroperoxide (t-BHP)-induced oxidative damage was applied and ameliorated by luteolin and the luteolin-7-O-glucoside treatment in a dose dependent manner, which was confirmed by HO-1 selective inhibitor and inducer, tin protoporphyrin (SnPP) and cobalt protoporphyrin (CoPP), respectively. Consequently, luteolin and luteolin-7-O-glucoside potently strengthen the HO-1-mediated antioxidative potential through the modulation of the Nrf2/MAPK signaling pathways. 10.1016/j.fct.2013.12.017
    Influence of Diet and Nutrition on Prostate Cancer. Matsushita Makoto,Fujita Kazutoshi,Nonomura Norio International journal of molecular sciences The incidence of prostate cancer (PCa) displays widespread regional differences, probably owing to differences in dietary habits. Nutrients, including fat, protein, carbohydrates, vitamins (vitamin A, D, and E), and polyphenols, potentially affect PCa pathogenesis and progression, as previously reported using animal models; however, clinical studies have reported controversial results for almost all nutrients. The effects of these nutrients may be manifested through various mechanisms including inflammation, antioxidant effects, and the action of sex hormones. Dietary patterns including the Western and Prudent patterns also influence the risk of PCa. Recent studies reported that the gut microbiota contribute to tumorigenesis in some organs. Diet composition and lifestyle have a direct and profound effect on the gut bacteria. Human studies reported an increase in the abundance of specific gut bacteria in PCa patients. Although there are few studies concerning their relationship, diet and nutrition could influence PCa, and this could be mediated by gut microbiota. An intervention of dietary patterns could contribute to the prevention of PCa. An intervention targeting dietary patterns may thus help prevent PCa. 10.3390/ijms21041447
    Melatonin-synthesizing enzymes in pineal, retina, liver, and gut of the goldfish (Carassius): mRNA expression pattern and regulation of daily rhythms by lighting conditions. Velarde Elena,Cerdá-Reverter Jose Miguel,Alonso-Gómez Angel Luis,Sánchez Elisa,Isorna Esther,Delgado María Jesús Chronobiology international It has been suggested that melatonin is synthesized in nonphotosensitive organs of vertebrates in addition to the well-known sites of the pineal gland and retina. However, very few studies have demonstrated the gene expression of melatonin-synthesizing enzymes in extrapineal and extraretinal locations. This study focuses on the circadian expression of the two key enzymes of the melatoninergic pathway, arylalkylamine N-acetyltransferase (AANAT) and hydroxyindole-O-methyltransferase (HIOMT), in central and peripheral locations of a teleost fish, the goldfish (Carassius auratus). First, the full-length cDNA sequences corresponding to the goldfish AANAT-2 (gAanat-2) and HIOMT-2 (gHiomt-2) were cloned, showing high similarity with other teleost sequences. Two forms of AANAT exist in teleosts. Here, for the first time, two isoforms of HIOMT are deduced from phylogenetic analysis. Moreover, both HIOMT and AANAT were detected in several peripheral locations, including liver and gut, the present results being the first to find HIOMT in nonphotosensitive structures of a fish species. Second, quantitative real-time polymerase chain reaction (PCR) studies were performed to investigate regulation of gAanat-2 in pineal and peripheral locations of goldfish maintained under different lighting conditions. The current results show circadian rhythms in Aanat-2 and Hiomt-2 transcripts in liver and hindgut, suggesting a local melatonin synthesis in goldfish. Moreover, the analysis of daily expression of gAanat-2 under different lighting conditions, including continuous light (24L) and darkness (24D) revealed light-dependent rhythms in the pineal and retina, as expected, but also in liver and hindgut. The persistence in hindgut of these gAanat-2 rhythms under both constant conditions, 24L and 24D, suggests expression of this transcript is governed by a circadian clock and entrained by nonphotic cues. Finally, the current results support the existence of melatonin synthesis in gut and liver of the goldfish. 10.3109/07420528.2010.496911
    Quantification of microbial uptake of quercetin and its derivatives using an UHPLC-ESI-QTOF mass spectrometry assay. Said Inamullah Hakeem,Shah Rohan Lakshmidas,Ullrich Matthias S,Kuhnert Nikolai Food & function A liquid chromatography-mass spectrometry-based method for the quantification of intracellular concentrations of dietary phenolics in bacteria was developed. Using this assay, the time-dependent uptake of quercetin and two of its glycosides into gut microbiota model organisms (Escherichia coli and Bifidobacterium bifidum) under aerobic and anaerobic conditions was studied. For the first time, quantitative data on the uptake of dietary phenols were obtained indicating a time-dependent differential uptake of the dietary compounds. The shape of the uptake curve and the comparative use of bacterial mutants lacking porins OmpFC or the multi-drug efflux pump AcrAB, respectively, along with the identification and quantification of selected bacterial metabolites provided a mechanistic insight into the uptake process. 10.1039/c6fo00652c
    Cocrystals of quercetin with improved solubility and oral bioavailability. Smith Adam J,Kavuru Padmini,Wojtas Lukasz,Zaworotko Michael J,Shytle R Douglas Molecular pharmaceutics Flavonoids have been studied extensively due to the observation that diets rich in these compounds are associated with lower incidences of many diseases. One of the most studied flavonoids, quercetin, is also the most abundant of these compounds in the plant kingdom. Numerous therapeutic bioactivities have been identified in vitro. However, its in vivo efficacy in pure form is limited by poor bioavailability, primarily due to its low solubility and consequent low absorption in the gut. Cocrystallization has gained attention recently as a means for improving the physicochemical characteristics of a compound. Here, we synthesized and evaluated four new cocrystals of quercetin (QUE): quercetin:caffeine (QUECAF), quercetin:caffeine:methanol (QUECAF·MeOH), quercetin:isonicotinamide (QUEINM), and quercetin:theobromine dihydrate (QUETBR · 2H(2)O). Each of these cocrystals exhibited pharmacokinetic properties that are vastly superior to those of quercetin alone. Cocrystallization was able to overcome the water insolubility of quercetin, with all four cocrystals exhibiting some degree of solubility. The QUECAF and QUECAF·MeOH cocrystals increased the solubility of QUE by 14- and 8-fold when compared to QUE dihydrate. We hypothesized that this improved solubility would translate into enhanced systemic absorption of QUE. This hypothesis was supported in our pharmacokinetic study. The cocrystals outperformed QUE dihydrate with increases in bioavailability up to nearly 10-fold. 10.1021/mp200209j
    Antioxidative protection of dietary bilberry, chokeberry and Lactobacillus plantarum HEAL19 in mice subjected to intestinal oxidative stress by ischemia-reperfusion. Jakesevic Maja,Aaby Kjersti,Borge Grethe-Iren A,Jeppsson Bengt,Ahrné Siv,Molin Göran BMC complementary and alternative medicine BACKGROUND:Ischemia-reperfusion (I/R) in the intestines is an inflammatory condition which activates leukocytes and reactive oxygen species (ROS) and leads to lipid peroxidation and DNA damage. Bilberry and chokeberry fruits are rich sources of polyphenols which may act as antioxidants and prevent lipid peroxidation. Lactic acid bacteria (LAB) may improve microbial status in the intestines and increase the metabolic activity towards polyphenolic degradation. The aim of the study was to clarify antioxidative effects of bilberry and chokeberry fruits alone and with addition of a LAB-strain, Lactobacillus plantarum HEAL19, in an I/R-model in mice. METHODS:Male BALB/cJ mice were fed the experimental diets for 10 days. Diets consisted of standard chow supplemented with either bilberry (Vaccinium myrtillus) or chokeberry (Aronia × prunifolia) powder alone or in combination with the LAB-strain Lactobacillus plantarum HEAL19. I/R-injury was induced by holding superior mesenteric artery clamped for 30 minutes followed by reperfusion for 240 minutes. Thereafter, colonic and caecal tissues and contents were collected. Malondialdehyde (MDA) was used as indicator of lipid peroxidation and was measured by a calorimetric assay, lactobacilli were cultured on Rogosa agar plates and Enterobacteriaceae on VRBG agar plates, anthocyanins and phenolic acids were analysed by HPLC-DAD-ESI-MSn. RESULTS:MDA was significantly decreased in the colon of groups fed bilberry alone (p = 0.030) and in combination with L. plantarum HEAL19 (p = 0.021) compared to the IR-control but not in chokeberry-fed groups. Supplementation with bilberry or chokeberry alone reduced the total number of lactobacilli on the mucosa. Higher concentrations of anthocyanins were found in the colon than in the caecum content of mice. A more varied composition of different anthocyanins was also observed in the colon content compared to the caecum of bilberry-fed mice. Phenolic acids formed by microbial degradation of the dietary polyphenols in the gut could be detected. More phenolic metabolites were found in the intestines of bilberry-fed mice than in the chokeberry-fed ones. CONCLUSIONS:Bilberry alone and in combination with L. plantarum HEAL19 exerts a better protection against lipid peroxidation than chokeberry. These dietary supplements may be used to prevent or suppress oxidative stress. 10.1186/1472-6882-11-8
    Pharmacological and biological screening of ascorbigen: protection against glucose-induced endothelial cell toxicity. Joshi Mandar S,Bauer John A,Werbovetz Karl A,Barszcz Todd,Patil Popat N Phytotherapy research : PTR Cruciferous vegetables contain significant amounts of ascorbigen and related substances with known molecular structures. This study tested the hypothesis that ascorbigen demonstrates antioxidant properties and protects human umbilical cord endothelial cells against hyperglycemic toxicity in vitro. It was observed that ascorbigen, in micromolar concentrations, protected against endothelial cell death from glucose toxicity. Additionally, ascorbigen at 3.0 mm shifted the concentration response curve of l-phenylephrine to the right, with a reduction in the maximal contractile effects of the agonist. This action was not related to alpha-adrenoceptor blockade. Ascorbigen also relaxed the vascular tone induced by l-phenylephrine, which is not mediated by an endothelial cell nitric oxide-dependent mechanism. On the guinea-pig ileum, the spasmogenic effects of carbachol, histamine and serotonin were reduced in the presence of 3 mM ascorbigen. Spasm of the gut induced by the acetylcholinesterase inhibitor, physostigmine, was antagonized by ascorbigen with an IC50 of 286 microM. This natural product also has a weak antiparasitic activity. The cytoprotective effects of ascorbigen may be highly relevant in the optimum physiological regulation of the function and the therapeutic value of this substance in disease settings needs to be further investigated. 10.1002/ptr.2494
    Phytochemistry and Pharmacological Activities of the Genus Swertia (Gentianaceae): A Review. Li Jie,Zhao Yan-Li,Huang Heng-Yu,Wang Yuan-Zhong The American journal of Chinese medicine Swertia plants have been considered to be medicinal plants useful for the treatment of various ailments for thousands of years, especially in Asian countries. This is due to the broad variety of chemical compounds that provide multiple ligands for bonding to different endogenous biomacromolecules for patients. Chemical constituents and pharmacological activities of Swertia plants are summarized in this paper. Approximately 419 metabolites and 40 bioactive compounds have been reported from 30 Swertia species, including xanthones, flavonoids, seco-iridiods, iridiods, triterpenoids, alkaloids, volatiles, and other secondary metabolites. The bioactivities of Swertia plants include anticarcinogenic, hepatoprotective, anti-oxidant, hypoglycemic, anthelmintic, antibacterial, antifungal, anti-diabetic, gut, and airways modulatory, metabolizing isozymes inhibitory, neuroprotective, HIV-I reverse transcriptases inhibitory, anticholinergic, and CNS-depressant activities, etc. In addition, biosynthetic pathways of xanthones, and seco-iridiods, two most important secondary metabolites for Swertia, are elucidated. The xanthones biosynthetic pathway is a mixed biosynthetic pathway involved the shikimate and the malonate routes, and the seco-iridoid pathway starts with geraniol derived from IPP which is produced either via the MEP or the MVA pathway. This review will offer a reference for future researches on the protection of natural resources, the investigation of therapeutic basis, new drug development, and so forth. Metabolic pathways of some crucial active compounds were also discussed in this review. 10.1142/S0192415X17500380
    Characterization of high molecular weight coffee fractions and their fermentation by human intestinal microbiota. Reichardt Nicole,Gniechwitz Diana,Steinhart Hans,Bunzel Mirko,Blaut Michael Molecular nutrition & food research To investigate the structure and fermentability of high M(r) components of coffee brews by human gut bacteria Arabica coffee samples of three different degrees of roast (light, medium, and dark) were used for drip brew preparations and fractionation by ultrafiltration with different M(r) cut-offs. Total carbohydrates of the fractions ranged from 28.6 g/100 g to 56.7 g/100 g. Galactomannans and arabinogalactans were the main polysaccharides and made up between one-fourth and one-half of the respective coffee fraction. After 24 h of incubation with a human fecal suspension the polysaccharides of all fractions were extensively degraded. A decrease in the absorbance values at 405 and 280 nm, respectively, indicated that also chemically noncharacterized UV-active components such as Maillard reaction products, had been partially degraded or modified by the human gut bacteria. The remainder after 24 h of fermentation still showed antioxidant activity. Bacterial cells belonging to the Bacteroides-Prevotella group increased 2- to 40-fold during fermentation depending on the M(r) range of the fraction and the degree of roast. The production of high amounts of acetate and propionate is in accordance with a role of these bacteria in the degradation of high M(r) components from coffee. 10.1002/mnfr.200700509
    Health benefit of vegetable/fruit juice-based diet: Role of microbiome. Henning Susanne M,Yang Jieping,Shao Paul,Lee Ru-Po,Huang Jianjun,Ly Austin,Hsu Mark,Lu Qing-Yi,Thames Gail,Heber David,Li Zhaoping Scientific reports The gut microbiota is an important contributor to human health. Vegetable/fruit juices provide polyphenols, oligosaccharides, fiber and nitrate (beet juice), which may induce a prebiotic-like effect. Juice-based diets are becoming popular. However, there is a lack of scientific evidence of their health benefits. It was our hypothesis that changes in the intestinal microbiota induced by a juice-based diet play an important role in their health benefits. Twenty healthy adults consumed only vegetable/fruit juices for 3 days followed by 14 days of customary diet. On day 4 we observed a significant decrease in weight and body mass index (p = 2.0E), which was maintained until day 17 (p = 3.0E). On day 4 the proportion of the phylum Firmicutes and Proteobacteria in stool was significantly decreased and Bacteroidetes and Cyanobacteria was increased compared to baseline and was partially reversed on day 17. On day 4 plasma and urine nitric oxide was increased by 244 ± 89% and 450 ± 360%, respectively, and urinary lipid peroxidation marker malondialdehyde was decreased by 32 ± 21% compared to baseline. General well-being score was increased at the end of the study. In summary a 3-day juice-based diet altered the intestinal microbiota associated with weight loss, increase in the vasodilator NO, and decrease in lipid oxidation. 10.1038/s41598-017-02200-6
    No influence of supplemental dietary calcium intake on the bioavailability of spinach carotenoids in humans. Corte-Real Joana,Guignard Cédric,Gantenbein Manon,Weber Bernard,Burgard Kim,Hoffmann Lucien,Richling Elke,Bohn Torsten The British journal of nutrition Dietary carotenoid intake, especially from fruits and vegetables, has been associated with a reduced incidence of several chronic diseases. However, its bioavailability can vary, depending on the food matrix and host factors. Recently, it has been suggested that divalent minerals negatively impinge on carotenoid bioavailability by reducing bile-salt and non-esterified fatty-acid levels in the gut, which normally aid in emulsifying carotenoids. The aim of the present study was to investigate whether supplemental Ca would negatively influence carotenoid absorption in humans. A total of twenty-five healthy, non-obese men (age: 20-46 years, BMI<30 kg/m2) were recruited for this postprandial, randomised, crossover, double-blinded trial. Following a randomised block design, each participant received (after 2-week washout periods), on three occasions separated by 1 week, 270 g of spinach-based meals (8·61 (sd 1·08) mg carotenoids/100 g fresh weight), supplemented with 0, 500 or 1000 mg of Ca (as calcium carbonate), with each participant acting as his or her own control. Blood samples were collected at regular postprandial intervals for up to 10 h following test meal intake, and standardised lunches were served. TAG-rich lipoprotein fractions were separated and carotenoid concentrations determined. AUC for meals without supplemented Ca were 22·72 (sem 2·78) nmol×h/l (lutein), 0·19 (sem 3·90) nmol×h/l (β-carotene) and 2·80 (sem 1·75) nmol×h/l (β-cryptoxanthin). No significant influence of supplementation with either 500 or 1000 mg of supplemental Ca was found. In conclusion, Ca - the most abundant divalent mineral in the diet - given at high but physiological concentrations, does not appear to have repercussions on the bioavailability of carotenoids from a spinach-based meal. 10.1017/S0007114517001532
    Beneficial action of resveratrol: How and why? Diaz-Gerevini Gustavo Tomas,Repossi Gaston,Dain Alejandro,Tarres María Cristina,Das Undurti Narasimha,Eynard Aldo Renato Nutrition (Burbank, Los Angeles County, Calif.) Flavonoid resveratrol modulates the transcription factor NF-κB; inhibits the cytochrome P450 isoenzyme CYP1 A1; suppresses the expression and activity of cyclooxygenase enzymes; and modulates Fas/Fas-ligand-mediated apoptosis, p53, mammalian target of rapamycin, and cyclins and various phosphodiesterases. This increases the cytosolic cAMP that activates Epac1/CaMKKβ/AMPK/SIRT1/PGC-1α pathway, which in turn facilitates increased oxidation of fatty acids, mitochondrial biogenesis, mitochondrial respiration, and gluconeogenesis. Resveratrol triggers apoptosis of activated T cells and suppresses tumor necrosis factor-α, interluekin-17 (IL-17), and other proinflammatory molecules, and thus is of benefit in autoimmune diseases. In addition, resveratrol inhibits expression of hypoxia-inducible factor-1α and vascular endothelial growth factor, explaining its effective action against cancer. Brain-derived neurotrophic factor (BDNF) that is involved in the pathogenesis of obesity, type 2 diabetes mellitus, and metabolic syndrome is also altered in depression, schizophrenia, bipolar disorder, and autism. We noted that BDNF protects against cytotoxic actions of alloxan, streptozotocin, and benzo(a)pyrene. Resveratrol prevents bisphenol A-induced autism, type 2 diabetes mellitus, and metabolic syndrome, suggesting that it may augment BDNF synthesis and action. We also observed that BDNF levels are low in type 2 diabetes mellitus and that BDNF enhances production of antiinflammatory lipid, lipoxin A4, whose levels are low in diabetes mellitus. Thus, resveratrol may augment production of lipoxin A4. Resveratrol alters gut microbiota and influences stem cell proliferation and differentiation. These pleiotropic actions of resveratrol may explain the multitude of its actions and benefits. 10.1016/j.nut.2015.08.017
    The Effects of Broccoli Sprout Extract Containing Sulforaphane on Lipid Peroxidation and Helicobacter pylori Infection in the Gastric Mucosa. Chang Young Woon,Jang Jae Young,Kim Yong Ho,Kim Jung-Wook,Shim Jae-Jun Gut and liver BACKGROUND/AIMS:The aims of this study were to investigate whether a broccoli sprout extract containing sulforaphane (BSES) inhibited the Helicobacter pylori infection density and exerted an antioxidative effect on gastric mucosal damage. METHODS:The enrolled subjects were randomized in a double-blinded manner into three groups. Finally, 33 H. pylori (+) BSES treatment subjects (group A), 28 H. pylori (+) placebo subjects (group B), and 28 H. pylori (-) BSES treatment subjects (group C) were studied. H. pylori infection density was indirectly quantified by a (13)C-urea breath test (UBT), and the ammonia concentration in gastric juice aspirates was measured through gastroscopic examination. Malondialdehyde (MDA), an oxidative damage biomarker, and reduced glutathione (GSH), an antioxidant biomarker, were measured in the gastric mucosa by an enzyme-linked immunosorbent assay. RESULTS:BSES treatment did not significantly affect the UBT values or ammonia concentration in group A (p=0.634 and p=0.505, respectively). BSES treatment did significantly reduce mucosal MDA concentrations in group A (p<0.05) and group C (p<0.001), whereas the gastric mucosal GSH concentrations did not differ before and after treatment in any of the groups. CONCLUSIONS:BSES did not inhibit the H. pylori infection density. However, BSES prevented lipid peroxidation in the gastric mucosa and may play a cytoprotective role in H. pylori-induced gastritis. 10.5009/gnl14040
    Synthesis, analytical features, and biological relevance of 5-(3',4'-dihydroxyphenyl)-γ-valerolactone, a microbial metabolite derived from the catabolism of dietary flavan-3-ols. Sanchez-Patan Fernando,Chioua Mourad,Garrido Ignacio,Cueva Carolina,Samadi Abdelouahid,Marco-Contelles Jose,Moreno-Arribas M Victoria,Bartolome Begona,Monagas Maria Journal of agricultural and food chemistry The physiological significance of 5-(3',4'-dihydroxyphenyl)-γ-valerolactone, an important metabolite derived from the catabolism of flavan-3-ols by gut microbiota, has been often overlooked due to the lack of the commercial standard. In the present work, this metabolite has been chemically synthesized, and its analytical parameters and antioxidant capacity have been determined in comparison to other chemical analogues [isomer 3-(3',4'-dihydroxyphenyl)-δ-valerolactone and γ-valerolactone] and other structurally related compounds [(+)-catechin, (-)-epicatechin, and 3-(3,4-dihydroxyphenyl)-propionic acid]. The synthesized compound was also used to perform a targeted analysis in samples collected during the in vitro fermentation of a grape seed flavan-3-ol extract with human fecal microbiota from three healthy volunteers. The time-course formation of 5-(3',4'-dihydroxyphenyl)-γ-valerolactone revealed large interindividual differences among volunteers, with concentrations ranging from 3.31 to 77.54 μM at 10 h of fermentation. These results are further discussed in view of the scarce reports quantifying 5-(3',4'-dihydroxyphenyl)-γ-valerolactone in in vitro fermentation studies, and pharmacokinetic and intervention studies. 10.1021/jf2020182
    Subchronic treatment with grape-seed phenolics inhibits ghrelin production despite a short-term stimulation of ghrelin secretion produced by bitter-sensing flavanols. Serrano Joan,Casanova-Martí Àngela,Depoortere Inge,Blay Maria Teresa,Terra Ximena,Pinent Montserrat,Ardévol Anna Molecular nutrition & food research SCOPE:Grape-seed phenolic compounds have recently been described as satiating agents in rats when administered as a whole phenolic extract (GSPE). This satiating effect may involve the release of satiating gut hormones such as GLP-1, although a short-term increase in the orexigenic hormone ghrelin was also reported. In this study, we investigated the short- and long-term effects of GSPE in rats, focusing on the role of the main grape-seed phenolics in ghrelin secretion. METHODS AND RESULTS:GSPE produced a short-term increase in plasma ghrelin in rats after an acute treatment. A mouse ghrelinoma cell line was used to test the effects of the main pure grape-seed phenolic compounds on ghrelin release. Monomeric flavanols stimulated ghrelin secretion by activating bitter taste receptors. In contrast, gallic acid (GA) and oligomeric flavanols inhibited ghrelin release. The ghrelin-inhibiting effects of GA were confirmed in rats and in rat duodenal segments. One day after the last dose of a subchronic treatment, GSPE decreased plasma ghrelin in rats, ghrelin secretion in intestinal segments, and ghrelin mRNA expression in stomach. CONCLUSION:The sustained satiating effects of GSPE are related to a long-term decrease in ghrelin expression. GA and oligomeric flavanols play a ghrelin-inhibiting role in this process. 10.1002/mnfr.201600242
    Nuts and Cardiovascular Disease Prevention. Coates A M,Hill A M,Tan S Y Current atherosclerosis reports PURPOSE OF REVIEW:We review recent epidemiological and clinical studies investigating the consumption of tree nuts and peanuts and cardiovascular disease (CVD) mortality as well as CVD risk factors. RECENT FINDINGS:A greater consumption of tree nuts and peanuts is associated with a reduced risk of CVD mortality, as well as lower CVD events. Furthermore, risk factors associated with the development of CVD such as dyslipidemia, impaired vascular function, and hypertension are improved with regular tree nut and peanut consumption through a range of mechanism associated with their nutrient-rich profiles. There is weak inconsistent evidence for an effect of nut consumption on inflammation. There is emerging evidence that consuming tree nuts reduces the incidence of non-alcoholic fatty liver disease (NAFLD) and promotes diversity of gut microbiota, which in turn may improve CVD outcomes. Evidence for CVD prevention is strong for some varieties of tree nuts, particularly walnuts, and length of supplementation and dose are important factors for consideration with recommendations. 10.1007/s11883-018-0749-3
    Multiple Immune-Inflammatory and Oxidative and Nitrosative Stress Pathways Explain the Frequent Presence of Depression in Multiple Sclerosis. Morris Gerwyn,Reiche Edna Maria Vissoci,Murru Andrea,Carvalho André F,Maes Michael,Berk Michael,Puri Basant K Molecular neurobiology Patients with a diagnosis of multiple sclerosis (MS) or major depressive disorder (MDD) share a wide array of biological abnormalities which are increasingly considered to play a contributory role in the pathogenesis and pathophysiology of both illnesses. Shared abnormalities include peripheral inflammation, neuroinflammation, chronic oxidative and nitrosative stress, mitochondrial dysfunction, gut dysbiosis, increased intestinal barrier permeability with bacterial translocation into the systemic circulation, neuroendocrine abnormalities and microglial pathology. Patients with MS and MDD also display a wide range of neuroimaging abnormalities and patients with MS who display symptoms of depression present with different neuroimaging profiles compared with MS patients who are depression-free. The precise details of such pathology are markedly different however. The recruitment of activated encephalitogenic Th17 T cells and subsequent bidirectional interaction leading to classically activated microglia is now considered to lie at the core of MS-specific pathology. The presence of activated microglia is common to both illnesses although the pattern of such action throughout the brain appears to be different. Upregulation of miRNAs also appears to be involved in microglial neurotoxicity and indeed T cell pathology in MS but does not appear to play a major role in MDD. It is suggested that the antidepressant lofepramine, and in particular its active metabolite desipramine, may be beneficial not only for depressive symptomatology but also for the neurological symptoms of MS. One clinical trial has been carried out thus far with, in particular, promising MRI findings. 10.1007/s12035-017-0843-5
    Extracts from Epilobium sp. herbs, their components and gut microbiota metabolites of Epilobium ellagitannins, urolithins, inhibit hormone-dependent prostate cancer cells-(LNCaP) proliferation and PSA secretion. Stolarczyk Magdalena,Piwowarski Jakub P,Granica Sebastian,Stefańska Joanna,Naruszewicz Marek,Kiss Anna K Phytotherapy research : PTR Extracts from Epilobium sp. herbs have been traditionally used in the treatment of prostate-associated ailments. Our studies demonstrated that the extracts from Epilobium angustifolium, Epilobium parviflorum and Epilobium hirsutum herbs are potent prostate cancer cells (LNCaP) proliferation inhibitors with IC50 values around 35 µg/ml. The tested extracts reduced prostate specific antigen (PSA) secretion (from 325.6 ± 25.3 ng/ml to ~90 ng/ml) and inhibited arginase activity (from 65.2 ± 1.1 mUnits of urea/mg of protein to ~40 mUnits of urea/mg protein). Selected constituents of extracts (oenothein B, quercetin-3-O-glucuronide, myricetin-3-O-rhamnoside) were proven to be active in relation to LNCaP cells. However, oenothein B was the strongest inhibitor of cells proliferation (IC50  = 7.8 ± 0.8 μM), PSA secretion (IC50  = 21.9 ± 3.2 μM) and arginase activity (IC50 = 19.2 ± 2.0 μM). Additionally, ellagitannins from E. hirustum extract were proven to be transformed by human gut microbiota into urolithins. Urolithin C showed the strongest activity in the inhibition of cell proliferation (IC50  = 35.2 ± 3.7 μM), PSA secretion (reduced PSA secretion to the level of 100.7 ± 31.0 ng/ml) and arginase activity (reduced to the level of 27.9 ± 3.3 mUnits of urea/mg of protein). Results of the work offer an explanation of the activity of Epilobium extracts and support the use of Epilobium preparations in the treatment of prostate diseases. 10.1002/ptr.4941
    Profiling a gut microbiota-generated catechin metabolite's fate in human blood cells using a metabolomic approach. Mülek Melanie,Fekete Agnes,Wiest Johannes,Holzgrabe Ulrike,Mueller Martin J,Högger Petra Journal of pharmaceutical and biomedical analysis The microbial catechin metabolite δ-(3,4-dihydroxy-phenyl)-γ-valerolactone (M1) has been found in human plasma samples after intake of maritime pine bark extract (Pycnogenol). M1 has been previously shown to accumulate in endothelial and blood cells in vitro after facilitated uptake and to exhibit anti-inflammatory activity. The purpose of the present research approach was to systematically and comprehensively analyze the metabolism of M1 in human blood cells in vitro and in vivo. A metabolomic approach that had been successfully applied for drug metabolite profiling was chosen to detect 19 metabolite peaks of M1 which were subsequently further analyzed and validated. The metabolites were categorized into three levels of identification according to the Metabolomics Standards Initiative with six compounds each confirmed at levels 1 and 2 and seven putative metabolites at level 3. The predominant metabolites were glutathione conjugates which were rapidly formed and revealed prolonged presence within the cells. Although a formation of an intracellular conjugate of M1 and glutathione (M1-GSH) was already known two GSH conjugate isomers, M1-S-GSH and M1-N-GSH were observed in the current study. Additionally detected organosulfur metabolites were conjugates with oxidized glutathione and cysteine. Other biotransformation products constituted the open-chained ester form of M1 and a methylated M1. Six of the metabolites determined in in vitro assays were also detected in blood cells in vivo after ingestion of the pine bark extract by two volunteers. The present study provides the first evidence that multiple and structurally heterogeneous polyphenol metabolites can be generated in human blood cells. The bioactivity of the M1 metabolites and their contribution to the previously determined anti-inflammatory effects of M1 now need to be elucidated. 10.1016/j.jpba.2015.04.042
    PH-dependent forms of red wine anthocyanins as antioxidants. Lapidot T,Harel S,Akiri B,Granit R,Kanner J Journal of agricultural and food chemistry Anthocyanins are one of the main classes of flavonoids in red wines, and they appear to contribute significantly to the powerful antioxidant properties of the flavonoids. In grapes and wines the anthocyanins are in the flavylium form. However, during digestion they may reach higher pH values, forming the carbinol pseudo-base, quinoidal-base, or the chalcone, and these compounds appear to be absorbed from the gut into the blood system. The antioxidant activity of these compounds, in several metal-catalyzed lipid oxidation model systems, was evaluated in comparison with other antioxidants. The pseudo-base and quinoidal-base malvidin 3-glucoside significantly inhibited the peroxidation of linoleate by myoglobin. Both compounds were found to work better than catechin, a well-known antioxidant. In a membrane lipid peroxidation system, the effectiveness of the antioxidant was dependent on the catalyst: In the presence of H(2)O(2)-activated myoglobin, the inhibition efficiency of the antioxidant was malvidin 3-glucoside > catechin > malvidin > resveratrol. However, in the presence of an iron redox cycle catalyzer, the order of effectiveness was resveratrol > malvidin 3-glucoside = malvidin > catechin. The pH-transformed forms of the anthocyanins remained effective antioxidants in these systems, and their I(50) values were between 0.5 and 6.2 microM. 10.1021/jf980704g
    Absorption and bioavailability of glucosamine in the rat. Ibrahim Alyaa,Gilzad-kohan Mohammad H,Aghazadeh-Habashi Ali,Jamali Fakhreddin Journal of pharmaceutical sciences The objective of this study was to determine reasons behind the low oral (p.o.) bioavailability of glucosamine. By using male Sprague-Dawley rats, the movement of glucosamine through everted gut, the effect of dose and glucose, and inhibition of a glucose transporter (GLUT2) by quercetin were studied. Glucosamine pharmacokinetics and the effect of dosing, route of administration, food and antibiotic to eradicate gut microflora was also studied. Both in vitro and in vivo studies demonstrated linear absorption kinetics for glucosamine. Absorption from duodenum was the greatest. Glucose had no effect on the transport, whereas quercetin significantly reduced the extent of glucosamine transport. Intraperitoneal doses were completely absorbed, whereas p.o. doses demonstrated low bioavailability, indicating the gut as the site of presystemic loss. Food had no significant effect on glucosamine pharmacokinetics. Antibiotic treatment resulted in strong trends towards increased bioavailability with significant increase in fecal recovery. Incubation of glucosamine with faeces resulted in a significant loss. Glucosamine's low bioavailability is, at least in part, due to its dependence on a transport-facilitated absorption and presystemic loss brought about by the gut microflora. 10.1002/jps.23145
    Interfacial dilational properties of tea polyphenols and milk proteins with gut epithelia and the role of mucus in nutrient adsorption. Guri Anilda,Li Yang,Corredig Milena Food & function By interacting with nutrients, the mucus layer covering the intestinal epithelium may mediate absorption. This study aimed to determine possible interactions between epigallocatechin-3-gallate (EGCG), skim milk proteins or their complexes with human intestinal mucin films. The films were extracted from postconfluent monolayers of HT29-MTX, a human intestinal cell line, and a model system was created using drop shape tensiometry. The EGCG uptake tested in vitro on postconfluent Caco-2 cells or co-cultures of Caco-2/HT29-MTX (mucus producing) showed recovery of bioavailable EGCG only for Caco-2 cell monolayers, suggesting an effect of mucus on absorption. Interfacial dilational rheology was employed to characterize the properties of the interface mixed with mucus dispersion. Adsorption of polyphenols greatly enhanced the viscoelastic modulus of the mucus film, showing the presence of interactions between the nutrient molecules and mucus films. On the other hand, in situ digestion of milk proteins using trypsin showed higher surface activities as a result of protein unfolding and competitive adsorption of the hydrolyzed products. There was an increase of viscoelastic modulus over the drop ageing time for the mixed interfaces, indicating the formation of a stiffer interfacial network. These results bring new insights into the role of the mucus layer in nutrient absorption and the interactions of mucus and dairy products. 10.1039/c5fo00654f
    Resveratrol Protects Oxidative Stress-Induced Intestinal Epithelial Barrier Dysfunction by Upregulating Heme Oxygenase-1 Expression. Wang Na,Han Qing,Wang Gai,Ma Wei-Ping,Wang Jia,Wu Wen-Xin,Guo Yu,Liu Li,Jiang Xiao-Yu,Xie Xiao-Li,Jiang Hui-Qing Digestive diseases and sciences BACKGROUND/AIM:Obstructive jaundice (OJ) is frequently complicated by infections and has been associated with increased bacterial translocation, intestinal epithelial hyperpermeability, and oxidative stress, but the mechanism remains unclear. The potential effect of resveratrol (Res) on modifying intestinal epithelial dysfunction was evaluated both in vitro and in vivo. METHODS:Caco-2 cells (in vitro) and male Wistar rats (n = 60; in vivo) were used to evaluate the role of Res on intestinal epithelial dysfunction. Hydrogen peroxide was used to induce oxidative stress in the Caco-2 cells. In bile duct-ligated group, OJ was successfully established on Day 7 after bile duct ligation, whereas sham-operated and vehicle-treated rats served as controls. Western blot and RT-qPCR were performed to analyze TJ proteins expression in epithelium isolated from rat intestine. RESULTS:Intestinal hyperpermeability was associated with decreased expression and phosphorylation of occludin and zonula occluden (ZO-1), but increased oxidation in Caco-2 cells and the intestinal epithelium. Res treatment increased the epithelial expression and phosphorylation of occludin and ZO-1 in a concentration-dependent manner. Moreover, Res which protected Caco-2 cells from H2O2-induced oxidative damage clearly reduced malondialdehyde level and intracellular reactive oxygen species accumulation, but increased the expression levels of superoxide dismutase and heme oxygenase-1 (HO-1). Further studies showed that Res also inhibited H2O2-induced protein kinase C activity and p38 phosphorylation. Interestingly, these effects of Res were abolished by the HO-1 inhibitor zinc protoporphyrin or knockdown of HO-1 by siRNA. CONCLUSIONS:Res protected gut barrier function possibly by initiating HO-1-dependent signaling which is essential for common expression of key tight junction proteins. It also provides a rationale to develop Res clinical applications of intestinal disorders. 10.1007/s10620-016-4184-4
    Human Gut Bacteria Are Sensitive to Melatonin and Express Endogenous Circadian Rhythmicity. Paulose Jiffin K,Wright John M,Patel Akruti G,Cassone Vincent M PloS one Circadian rhythms are fundamental properties of most eukaryotes, but evidence of biological clocks that drive these rhythms in prokaryotes has been restricted to Cyanobacteria. In vertebrates, the gastrointestinal system expresses circadian patterns of gene expression, motility and secretion in vivo and in vitro, and recent studies suggest that the enteric microbiome is regulated by the host's circadian clock. However, it is not clear how the host's clock regulates the microbiome. Here, we demonstrate at least one species of commensal bacterium from the human gastrointestinal system, Enterobacter aerogenes, is sensitive to the neurohormone melatonin, which is secreted into the gastrointestinal lumen, and expresses circadian patterns of swarming and motility. Melatonin specifically increases the magnitude of swarming in cultures of E. aerogenes, but not in Escherichia coli or Klebsiella pneumoniae. The swarming appears to occur daily, and transformation of E. aerogenes with a flagellar motor-protein driven lux plasmid confirms a temperature-compensated circadian rhythm of luciferase activity, which is synchronized in the presence of melatonin. Altogether, these data demonstrate a circadian clock in a non-cyanobacterial prokaryote and suggest the human circadian system may regulate its microbiome through the entrainment of bacterial clocks. 10.1371/journal.pone.0146643
    Bioavailability of dietary doses of 3H-labelled tea antioxidants (+)-catechin and (-)-epicatechin in rat. Catterall F,King L J,Clifford M N,Ioannides C Xenobiotica; the fate of foreign compounds in biological systems 1. The bioavailability and pharmacokinetic characteristics of the tea antioxidants (+)-catechin and (-)-epicatechin were investigated in the rat following intake of dietary doses. 2. To achieve this objective, tritiated derivatives (tritium was incorporated at the 3-position of the heterocyclic ring) of these compounds were administered to rats orally and intravenously at dose levels equivalent to human dietary levels of intake. 3. Following intravenous administration of both compounds, about one-third of the dose was excreted in the urine and two-thirds in the faeces, indicating extensive biliary excretion. When the same doses were administered orally, only about 5% of the dose of each compound was recovered in the urine. 4. Comparison of the areas under the curve following oral and intravenous administration revealed that the bioavailability of both compounds was less than 5%. 5. Exchange of tritium with water in the blood occurred 3 h after oral, but not after intravenous, administration of the flavanols to rat. This is believed to represent microbial degradation of the compounds by the gut flora. 6. It was established that the bioavailability of the tea antioxidants (+)-catechin and (-)-epicatechin in the rat following intake of dietary doses was poor. 10.1080/0049825031000108315
    Effects of dietary Corinthian currants (Vitis vinifera L., var. Apyrena) on atherosclerosis and plasma phenolic compounds during prolonged hypercholesterolemia in New Zealand White rabbits. Yanni Amalia E,Efthymiou Vissarion,Lelovas Pavlos,Agrogiannis George,Kostomitsopoulos Nikolaos,Karathanos Vaios T Food & function Corinthian currants are a rich source of phenolic compounds, which are known to exert beneficial effects on cardiovascular disease. The hypothesis tested is whether dietary supplementation with currants attenuates atherosclerosis and affects plasma phenolics during prolonged hypercholesterolemia in rabbits. Thirty New Zealand White rabbits were fed one of four diets (normal and supplemented with 10% currants, with 0.5% cholesterol, and with 0.5% cholesterol plus 10% currants) for eight weeks. Plasma lipids, glucose and hepatic enzymes were determined. Individual phenolic compounds were identified and quantified in plasma during the dietary intervention. At the end of the study, histological examinations of aorta and liver were performed. The high-cholesterol diet resulted in hypercholesterolemia and oxidative stress, increased aspartate aminotransferase (AST) activity and induced aortic and hepatic lesion formation. Corinthian currant supplementation attenuated atherosclerotic lesions, maintained AST within the normal range and reduced oxidative stress without affecting glucose concentrations. The p-OH-benzoic and p-OH-phenylacetic acids predominated at high concentrations in plasma and remained almost constant during the study in the group that received the normal rabbit chow and the groups given food with added cholesterol either alone or supplemented with currants. Currant supplementation to the normal diet resulted in the reduced absorption of phenolic compounds, as revealed by the measurement of their plasma metabolites, suggesting a regulatory mechanism at the gut level under normal conditions. 10.1039/c4fo01106f
    Biotransformation of aesculin by human gut bacteria and identification of its metabolites in rat urine. Ding Wei-Jun,Deng Yun,Feng Hao,Liu Wei-Wei,Hu Rong,Li Xiang,Gu Zhe-Ming,Dong Xiao-Ping World journal of gastroenterology AIM:To observe the biotransformation process of a Chinese compound, aesculin, by human gut bacteria, and to identify its metabolites in rat urine. METHODS:Representative human gut bacteria were collected from 20 healthy volunteers, and then utilized in vitro to biotransform aesculin under anaerobic conditions. At 0, 2, 4, 8, 12, 16, 24, 48 and 72 h post-incubation, 10 mL of culture medium was collected. Metabolites of aesculin were extracted 3 x from rat urine with methanol and analyzed by HPLC. For in vivo metabolite analysis, aesculetin (100 mg/kg) was administered to rats via stomach gavage, rat urine was collected from 6 to 48 h post-administration, and metabolite analysis was performed by LC/ESI-MS and MS/MS in the positive and negative modes. RESULTS:Human gut bacteria could completely convert aesculin into aesculetin in vitro. The biotransformation process occurred from 8 to 24 h post-incubation, with its highest activity was seen from 8 to 12 h. The in vitro process was much slower than the in vivo process. In contrast to the in vitro model, six aesculetin metabolites were identified in rat urine, including 6-hydroxy-7-gluco-coumarin (M1), 6-hydroxy-7-sulf-coumarin (M2), 6, 7-di-gluco-coumarin (M3), 6-glc-7-gluco-coumarin (M4), 6-O-methyl-7-gluco-coumarin (M5) and 6-O-methyl-7-sulf-coumarin (M6). Of which, M2 and M6 were novel metabolites. CONCLUSION:Aesculin can be transferred into aesculetin by human gut bacteria and is further modified by the host in vivo. The diverse metabolites of aesculin may explain its pleiotropic pharmaceutical effects. 10.3748/wjg.15.1518
    Ratio of "A-type" to "B-type" proanthocyanidin interflavan bonds affects extra-intestinal pathogenic Escherichia coli invasion of gut epithelial cells. Feliciano Rodrigo P,Meudt Jennifer J,Shanmuganayagam Dhanansayan,Krueger Christian G,Reed Jess D Journal of agricultural and food chemistry Gut colonization by extra-intestinal pathogenic Escherichia coli (ExPEC) increases the risk of subsequent infections, including urinary tract infection and septicemia. Previous work suggests that cranberry proanthocyanidins (PAC) interact with bacterial surface factors, altering bacterial interaction with host cells. Methods were developed to determine if ratios of "A-type" to "B-type" interflavan bonds in PAC affect ExPEC agglutination and invasion of enterocytes. In cranberries, 94.5% of PAC contain one or more "A-type" bonds, whereas in apples, 88.3% of PAC contain exclusively "B-type" bonds. Results show that cranberry "A-type" PAC have greater bioactivity than apple "B-type" PAC for increasing ExPEC agglutination and decreasing ExPEC epithelial cell invasion. 10.1021/jf403839a
    Caffeic acid ameliorates colitis in association with increased Akkermansia population in the gut microbiota of mice. Zhang Zhan,Wu Xinyue,Cao Shuyuan,Wang Li,Wang Di,Yang Hui,Feng Yiming,Wang Shoulin,Li Lei Oncotarget Emerging evidence shows that dietary agents and phytochemicals contribute to the prevention and treatment of ulcerative colitis (UC). We first reported the effects of dietary caffeic acid (CaA) on murine experimental colitis and on fecal microbiota. Colitis was induced in C57BL/6 mice by administration of 2.5% dextran sulfate sodium (DSS). Mice were fed a control diet or diet with CaA (1 mM). Our results showed that dietary CaA exerted anti-inflammatory effects in DSS colitis mice. Moreover, CaA could significantly suppress the secretion of IL-6, TNFα, and IFNγ and the colonic infiltration of CD3+ T cells, CD177+ neutrophils and F4/80+ macrophages via inhibition of the activation of NF-κB signaling pathway. Analysis of fecal microbiota showed that CaA could restore the reduction of richness and inhibit the increase of the ratio of Firmicute to Bacteroidetes in DSS colitis mice. And CaA could dramatically increase the proportion of the mucin-degrading bacterium Akkermansia in DSS colitis mice. Thus, CaA could ameliorate colonic pathology and inflammation in DSS colitis mice, and it might be associated with a proportional increase in Akkermansia. 10.18632/oncotarget.9306
    Hydroxytyrosol in the Prevention of the Metabolic Syndrome and Related Disorders. Peyrol Julien,Riva Catherine,Amiot Marie Josèphe Nutrients Virgin olive oil (VOO) constitutes the main source of fat in the Mediterranean diet. VOO is rich in oleic acid, displaying health-promoting properties, but also contains minor bioactive components, especially phenolic compounds. Hydroxytyrosol (HT), the main polyphenol of olive oil, has been reported to be the most bioactive component. This review aims to compile the results of clinical, animal and cell culture studies evaluating the effects of HT on the features of Metabolic Syndrome (MetS) (body weight/adiposity, dyslipidemia, hypertension, and hyperglycemia/insulin resistance) and associated complications (oxidative stress and inflammation). HT was able to improve the lipid profile, glycaemia, and insulin sensitivity, and counteract oxidative and inflammatory processes. Experimental studies identified multiple molecular targets for HT conferring its beneficial effect on health in spite of its low bioavailability. However, rodent experiments and clinical trials with pure HT at biologically relevant concentrations are still lacking. Moreover, the roles of intestine and its gut microbiota have not been elucidated. 10.3390/nu9030306
    A comprehensive review of agrimoniin. Grochowski Daniel M,Skalicka-Woźniak Krystyna,Orhan Ilkay Erdogan,Xiao Jianbo,Locatelli Marcello,Piwowarski Jakub P,Granica Sebastian,Tomczyk Michał Annals of the New York Academy of Sciences Plant tannins are a unique class of polyphenols with relatively high molecular weights. Within the ellagitannins group, agrimoniin--dimeric ellagitannin--is one of the most representative compounds found in many plant materials belonging to the Rosaceae family. Agrimoniin was first isolated in 1982 from roots of Agrimonia pilosa Ledeb. (Rosaceae), a plant traditionally used in Japan and China as an antidiarrheal, hemostatic, and antiparasitic agent. Agrimoniin is a constituent of medicinal plants, which are often applied orally in the form of infusions, decoctions, or tinctures. It is also present in commonly consumed food products, such as strawberries and raspberries. It is metabolized by human gut microbiota into a series of low-molecular-weight urolithins with proven anti-inflammatory and anticancer in vivo and in vitro bioactivities. The compound has received widespread interest owing to some interesting biological effects and therapeutic activities, which we elaborate in the present review. Additionally, we present an overview of the techniques used for the analysis, isolation, and separation of agrimoniin from the practical perspective. 10.1111/nyas.13421
    Chronic administration of dietary grape seed extract increases colonic expression of gut tight junction protein occludin and reduces fecal calprotectin: a secondary analysis of healthy Wistar Furth rats. Goodrich Katheryn M,Fundaro Gabrielle,Griffin Laura E,Grant Ar'quette,Hulver Matthew W,Ponder Monica A,Neilson Andrew P Nutrition research (New York, N.Y.) Animal studies have demonstrated the potential of grape seed extract (GSE) to prevent metabolic syndrome, obesity, and type 2 diabetes. Recently, metabolic endotoxemia induced by bacterial endotoxins produced in the colon has emerged as a possible factor in the etiology of metabolic syndrome. Improving colonic barrier function may control endotoxemia by reducing endotoxin uptake. However, the impact of GSE on colonic barrier integrity and endotoxin uptake has not been evaluated. We performed a secondary analysis of samples collected from a chronic GSE feeding study with pharmacokinetic end points to examine potential modulation of biomarkers of colonic integrity and endotoxin uptake. We hypothesized that a secondary analysis would indicate that chronic GSE administration increases colonic expression of intestinal tight junction proteins and reduces circulating endotoxin levels, even in the absence of an obesity-promoting stimulus. Wistar Furth rats were administered drinking water containing 0.1% GSE for 21 days. Grape seed extract significantly increased the expression of gut junction protein occludin in the proximal colon and reduced fecal levels of the neutrophil protein calprotectin, compared with control. Grape seed extract did not significantly reduce serum or fecal endotoxin levels compared with control, although the variability in serum levels was widely increased by GSE. These data suggest that the improvement of gut barrier integrity and potential modulation of endotoxemia warrant investigation as a possible mechanism by which GSE prevents metabolic syndrome and associated diseases. Further investigation of this mechanism in high-fat feeding metabolic syndrome and obesity models is therefore justified. 10.1016/j.nutres.2012.09.004
    Gut and microbial resveratrol metabolite profiling after moderate long-term consumption of red wine versus dealcoholized red wine in humans by an optimized ultra-high-pressure liquid chromatography tandem mass spectrometry method. Rotches-Ribalta Maria,Urpi-Sarda Mireia,Llorach Rafa,Boto-Ordoñez Maria,Jauregui Olga,Chiva-Blanch Gemma,Perez-Garcia Lluïsa,Jaeger Walter,Guillen Marisa,Corella Dolores,Tinahones Francisco J,Estruch Ramon,Andres-Lacueva Cristina Journal of chromatography. A Resveratrol exerts a variety of biological and pharmacological activities, which are observed despite its extremely low bioavailability and rapid clearance from the circulation due to extensive sulfation and glucuronidation in the intestine and liver. In order to more accurately quantify all known resveratrol metabolites, a sensitive and optimized analytical assay was developed and validated by pure standards. Methodology improvements aimed to the chromatographic detection of disulfates and sulfoglucuronides, improving resolution of sulfates, by using a buffered solution, with recovery values of resveratrol and its metabolites, even of sulfates, of 99%. The adapted methodology was then applied to a clinical study with high cardiovascular risk subjects, after the moderate consumption of red wine (RW) or dealcoholized red wine (DRW) for 28 days. Up to 21 resveratrol metabolites, including those formed by gut and microbial metabolism, were identified in 24-h urine samples. Interestingly, after long-term consumption of RW and DRW, resveratrol metabolite concentration significantly increased in urine with no differences between the two interventions, indicating that bioavailability and biotransformation of resveratrol is not affected by the alcoholic matrix of wine. In summary, we established a sensitive analytical assay for the quantification of a wide resveratrol metabolic profile in human urine, also regarding gut microbial-derived metabolites, which may also be applied to blood and tissue samples. The resveratrol metabolic pattern might therefore act as an excellent marker for the efficacy of resveratrol in clinical and epidemiological studies for the study of the beneficial effects of grape product consumption. In this sense, having a more precise concentration value of all the resveratrol metabolites in target tissues would finally lead to a better interpretation of the obtained results. 10.1016/j.chroma.2012.09.093
    Effects on Nitric Oxide Production of Urolithins, Gut-Derived Ellagitannin Metabolites, in Human Aortic Endothelial Cells. Spigoni Valentina,Mena Pedro,Cito Monia,Fantuzzi Federica,Bonadonna Riccardo C,Brighenti Furio,Dei Cas Alessandra,Del Rio Daniele Molecules (Basel, Switzerland) The consumption of foodstuffs yielding circulating compounds able to maintain endothelial function by improving nitric oxide (NO) bioavailability can be considered as an effective strategy for cardiovascular disease prevention. This work assessed the in vitro effects of urolithin A, urolithin B, and urolithin B-glucuronide, ellagitannin-derived metabolites of colonic origin, on NO release and endothelial NO synthase (eNOS) activation in primary human aortic endothelial cells (HAECs). Urolithins were tested both individually at 15 μM and as a mixture of 5 μM each, at different time points. The biotransformation of these molecules in cell media due to cell metabolism was also evaluated by UHPLC-MS(n). The mix of urolithins at 5 μM significantly increased nitrite/nitrate levels following 24 h of incubation, while single urolithins at 15 μM did not modify NO bioavailability. Both the mix of urolithins at 5 μM and urolithin B-glucuronide at 15 μM activated eNOS expression. All urolithins underwent metabolic reactions, but these were limited to conjugation with sulfate moieties. This study represents a step forward in the understanding of cardiovascular health benefits of ellagitannin-rich foodstuffs and backs the idea that peripheral cells may contribute to urolithin metabolism. 10.3390/molecules21081009
    Metabolomic approach with LC-QTOF to study the effect of a nutraceutical treatment on urine of diabetic rats. Godzien Joanna,Ciborowski Michal,Angulo Santiago,Ruperez Francisco J,Martínez Ma Paz,Señorans Francisco J,Cifuentes Alejandro,Ibañez Elena,Barbas Coral Journal of proteome research The rat treated with streptozotocin has been proposed as the most appropriate model of systemic oxidative stress for studying antioxidant therapies. In that sense, rosemary extracts have long been recognized as having antioxidant properties, and folic acid may be able to improve endothelial progenitor cell function. A mixture containing both has been tested as a possible nutraceutical to improve health complications in diabetes. We have developed the methodology to evaluate metabolic changes in the urine of streptozotocin-induced diabetic rats after supplementing their diet with rosemary extract obtained with supercritical fluids (SFE) containing 10% folic acid in an acute but short-term study. It has been done with a metabolomics approach using LC-QTOF as an analytical tool. About 20 endogenous metabolites have been identified by databases and MS/MS showing statistically significant changes. Among them, several amino acids and their metabolites point to changes due to the effect of the gut microbiota. In addition, the comparison between control and streptozotocin-diabetic rats has permitted the showing of some metabolic coincidences between type 1 diabetes and other (possible) autoimmune diseases such as autism and/or Crohn's disease, and the nutraceutical intervention has succeeded in inducing changes in such biomarkers. 10.1021/pr100993x
    Black tea extract and its thearubigins relieve the sildenafil-induced delayed gut motility in mice: a possible role of nitric oxide. Murad Hussam A S,Abdallah Hossam M Phytotherapy research : PTR In this study we hypothesize that a standardized black tea aqueous extract (BTE) and thearubigins, its main polyphenolic pigments, will improve sildenafil-induced delay in gastric emptying (GE) and small intestinal transit (SIT) in mice. Twenty groups of mice (n = 8) were given a phenol red meal, and three sets of experiments were performed. In the first and second sets, effects of different concentrations of BTE, thearubigins (TRs), and sildenafil (SLD), alone and in combinations, on GE and SIT were measured. In the third set, influence of nω -Nitro-l-arginine methyl ester hydrochloride (l-NAME) pretreatment on effects of these treatments was tested. Black tea extract (3% and 4.5%) and thearubigins (50 and 60 mg/kg) dose-dependently increased GE and SIT, whereas BTE 6% and thearubigins 70 mg/kg did not affect them. Sildenafil dose-dependently reduced both GE and SIT. Combination of metoclopramide, BTE 4.5%, thearubigins 60, or l-NAME with sildenafil (5 mg/kg) reversed its motility-delaying effects. Pretreatment with l-NAME followed by BTE 4.5%, thearubigins 60, BTE 4.5% + sildenafil 5, or thearubigins 60 + sildenafil 5 only partially affected the accelerating effects of BTE 4.5% and thearubigins 60. In conclusion, a standardized BTE and its thearubigins improve the sildenafil-induced delayed gut motility in mice. This improvement was partially blocked by l-NAME suggesting a possible role of nitric oxide. Thus, BTE 4.5% or TRs 60 mg/kg solution could be considered a reliever therapy for the sildenafil-induced dyspepsia. 10.1002/ptr.5183
    Flavonoids in Inflammatory Bowel Disease: A Review. Vezza Teresa,Rodríguez-Nogales Alba,Algieri Francesca,Utrilla Maria Pilar,Rodriguez-Cabezas Maria Elena,Galvez Julio Nutrients Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the intestine that compromises the patients' life quality and requires sustained pharmacological and surgical treatments. Since their etiology is not completely understood, non-fully-efficient drugs have been developed and those that have shown effectiveness are not devoid of quite important adverse effects that impair their long-term use. In this regard, a growing body of evidence confirms the health benefits of flavonoids. Flavonoids are compounds with low molecular weight that are widely distributed throughout the vegetable kingdom, including in edible plants. They may be of great utility in conditions of acute or chronic intestinal inflammation through different mechanisms including protection against oxidative stress, and preservation of epithelial barrier function and immunomodulatory properties in the gut. In this review we have revised the main flavonoid classes that have been assessed in different experimental models of colitis as well as the proposed mechanisms that support their beneficial effects. 10.3390/nu8040211
    Procyanidin B2 induces Nrf2 translocation and glutathione S-transferase P1 expression via ERKs and p38-MAPK pathways and protect human colonic cells against oxidative stress. Rodríguez-Ramiro Ildefonso,Ramos Sonia,Bravo Laura,Goya Luis,Martín Maria Ángeles European journal of nutrition PURPOSE:Procyanidin B2 (PB2) is a naturally occurring flavonoid widely found in cocoa, red wine and grape juice. Recent studies have suggested that PB2 could protect against oxidative stress- and chemical-induced injury in colonic cells by modulating the endogenous cellular defence. However, the precise mechanism for this protection is not fully understood. Herein, we examined the effect of PB2 on the expression of one of the major antioxidant/detoxificant enzymes related to intestinal protection, the glutathione S-transferase P1 (GSTP1), and the molecular mechanisms involved. METHODS:Human colonic Caco-2 cells were treated with PB2 at different times and enzymatic activity, and mRNA and protein levels of GSTP1 were evaluated. The nuclear translocation of the transcription factor NF-erythroid 2-related factor (Nrf2) and the phosphorylation states of specific proteins central to intracellular signalling cascades were also investigated. RESULTS:PB2 induced the expression and activity of GSTP1 and the nuclear translocation of Nrf2. Interestingly, two important signalling proteins involved in Nrf2 translocation, the extracellular signal-regulated protein kinases (ERKs) and the p38 mitogen-activated protein kinase (MAPK) were also activated. Further experiments with specific inhibitors of both pathways confirmed their critical role in the beneficial effects induced by PB2. CONCLUSIONS:The present results show that PB2 protects against oxidative injury in colonic cells and up-regulate the expression of GSTP1 via a mechanism that involves ERK and p38 MAPK activation and Nrf2 translocation. These results provide a molecular basis for the potential contribution of PB2 in the prevention of oxidative stress-related intestinal injury and gut pathologies. 10.1007/s00394-011-0269-1
    Equol, a Dietary Daidzein Gut Metabolite Attenuates Microglial Activation and Potentiates Neuroprotection In Vitro. Subedi Lalita,Ji Eunhee,Shin Dongyun,Jin Jongsik,Yeo Joo Hong,Kim Sun Yeou Nutrients Estrogen deficiency has been well characterized in inflammatory disorders including neuroinflammation. Daidzein, a dietary alternative phytoestrogen found in soy (Glycine max) as primary isoflavones, possess anti-inflammatory activity, but the effect of its active metabolite Equol (7-hydroxy-3-(4'-hydroxyphenyl)-chroman) has not been well established. In this study, we investigated the anti-neuroinflammatory and neuroprotective effect of Equol in vitro. To evaluate the potential effects of Equol, three major types of central nervous system (CNS) cells, including microglia (BV-2), astrocytes (C6), and neurons (N2a), were used. Effects of Equol on the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2), Mitogen activated protein kinase (MAPK) signaling proteins, and apoptosis-related proteins were measured by western blot analysis. Equol inhibited the lipopolysaccharide (LPS)-induced TLR4 activation, MAPK activation, NF-kB-mediated transcription of inflammatory mediators, production of nitric oxide (NO), release of prostaglandin E2 (PGE-2), secretion of tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6), in Lipopolysaccharide (LPS)-activated murine microglia cells. Additionally, Equol protects neurons from neuroinflammatory injury mediated by LPS-activated microglia through downregulation of neuronal apoptosis, increased neurite outgrowth in N2a cell and neurotrophins like nerve growth factor (NGF) production through astrocytes further supporting its neuroprotective potential. These findings provide novel insight into the anti-neuroinflammatory effects of Equol on microglial cells, which may have clinical significance in cases of neurodegeneration. 10.3390/nu9030207
    Nutritional therapy for cancer cachexia. Grimble R F Gut 10.1136/gut.52.10.1391
    Flavonoids as detoxifying and pro-survival agents: What's new? Bjørklund Geir,Dadar Maryam,Chirumbolo Salvatore,Lysiuk Roman Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association The role of flavonoids in the survival machinery of cells has come in the spotlight due to the recent evidence of their effect on the relationship mitochondria-ER stress-proteasome, including the intracellular mechanisms of autophagy and apoptosis. Numerous experimental animal investigations and even human clinical studies have highlighted the major role of these natural compounds in the economy of life and their deep relationship with autotrophic organisms in the evolutionary space. Their role as anti-oxidant and oxidative stress preventive molecules has to date been investigated extensively in the literature. Despite this great amount of promising evidence, many concerns, however, remain, most of which dealing with biochemistry, bioavailability, pharmacokinetics, and interaction of flavonoids with gut microbiome, issues that make difficult any good attempt to introduce these molecules in the human healthcare systems as possible, encouraging therapeutic substances. This review tries to address and elucidate these items. 10.1016/j.fct.2017.10.039
    Effect of nutritional interventions with quercetin, oat hulls, β-glucans, lysozyme and fish oil on performance and health status related parameters of broilers chickens. Torki M,Schokker D,Duijster-Lensing M,Van Krimpen M M British poultry science 1. An experiment was conducted to evaluate the effects of technical feed ingredients between 14 and 28 d of age on performance and health status of broilers (d 14-35) fed diets with a high inclusion rate of rapeseed meal as a nutritional challenge. It was hypothesized that the feed ingredients would improve health status related parameters. 2. A total of 1008 one-day-old male Ross 308 chicks were distributed over 36 floor pens and allocated to one of six iso-caloric (AME 13 MJ/kg) growing diets (d 15-28): a control and five test diets supplemented with quercetin (400 mg/kg), oat hulls (50 g/kg), β-glucan (100 mg/kg), lysozyme (40 mg/kg) or fish oil ω-3 fatty acids (40 g/kg), with six replicate pens per treatment. 3. Dietary inclusion of oat hulls and lysozyme resulted in a reduction in broiler performance during the first week after providing the experimental diets. 4. No effect of interventions on the microbiota diversity in the jejunum and ileum was observed. Ileal microbiota composition of birds fed oat hulls differed from the other groups, as shown by a higher abundance of the genus Enterococcus, mainly at the expense of the genus Lactobacillus. 5. In the jejunum, villus height and crypt depth of lysozyme-fed birds at d 28 were decreased compared to the control group. Higher total surface area of villi occupied by goblet cells and total villi surface area in jejunum (d 21 and 28) were observed in chickens fed oat hulls compared to other groups. 6. Genes related to the growth-factor-activity pathway were more highly expressed in birds fed β-glucan compared to the control group, while the genes related to anion-transmembrane-transporter-activity pathway in the quercetin- and oat hull-fed birds were less expressed. The genes differently expressed between dietary interventions did not seem to be directly involved in immune related processes. 7. It was concluded that the tested nutritional interventions in the current experiment only marginally effected health status related parameters. 10.1080/00071668.2018.1496402
    Coffee, glucose homeostasis, and insulin resistance: physiological mechanisms and mediators. Tunnicliffe Jasmine M,Shearer Jane Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme Epidemiological studies show coffee consumption to be correlated to large risk reductions in the prevalence of type 2 diabetes (T2D). Such correlations are seen with decaffeinated and caffeinated coffee, and occur regardless of gender, method of brewing, or geography. They also exist despite clear evidence showing that caffeine causes acute postprandial hyperglycemia and lower whole-body insulin sensitivity. As the beneficial effects of coffee consumption exist for both decaffeinated and caffeinated coffee, a component of coffee other than caffeine must be responsible. This review examines the specific coffee compounds responsible for coffee's effects on T2D, and their potential physiological mechanisms of action. Being plant-derived, coffee contains many beneficial compounds found in fruits and vegetables, including antioxidants. In fact, coffee is the largest source of dietary antioxidants in industrialized nations. When green coffee is roasted at high temperatures, Maillard reactions create a number of unique compounds. Roasting causes a portion of the antioxidant, chlorogenic acid, to be transformed into quinides, compounds known to alter blood glucose levels. Coffee consumption may also mediate levels of gut peptides (glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1), hormones intimately involved in the regulation of satiety and insulin secretion. Finally, coffee may have prebiotic-like properties, altering gut flora and ultimately digestion. In summary, it is evident that a better understanding of the role of coffee in the development and prevention of T2D has the potential to uncover novel therapeutic targets and nutraceutical formulations for the disease. 10.1139/H08-123
    Organic food and the impact on human health. Hurtado-Barroso Sara,Tresserra-Rimbau Anna,Vallverdú-Queralt Anna,Lamuela-Raventós Rosa María Critical reviews in food science and nutrition In the last decade, the production and consumption of organic food have increased steadily worldwide, despite the lower productivity of organic crops. Indeed, the population attributes healthier properties to organic food. Although scientific evidence is still scarce, organic agriculture seems to contribute to maintaining an optimal health status and decreases the risk of developing chronic diseases. This may be due to the higher content of bioactive compounds and lower content of unhealthy substances such as cadmium and synthetic fertilizers and pesticides in organic foods of plant origin compared to conventional agricultural products. Thus, large long-term intervention studies are needed to determine whether an organic diet is healthier than a diet including conventionally grown food products. This review provides an update of the present knowledge of the impact of an organic versus a conventional food diet on health. 10.1080/10408398.2017.1394815
    Effect of ginger (Zingiber officinale Roscoe) on growth performance, nutrient digestibility, serum metabolites, gut morphology, and microflora of growing guinea fowl. Oso Abimbola Oladele,Awe Abdul Wahab,Awosoga Fiyinfunjesu Gedion,Bello Foyeke A,Akinfenwa Taiwo A,Ogunremi Emmanuel Babatunde Tropical animal health and production A 56-day feeding trial was conducted to investigate the effect of dietary supplementation of dried ginger meal (DGM) on the growth performance, nutrient digestibility, serum parameters, gut morphology, and microflora of growing helmeted guinea fowl (Numidia meleagris). One hundred sixty 28-day-old male keets were assigned to four dietary treatments. There were 40 birds per treatment replicated four times with 10 keets each. The experimental diets consisted of the basal diet (control), ginger-supplemented diets containing 20, 40, and 60 g/kg DGM, respectively. Guinea fowls fed diet supplemented with DGM had higher (P <0.05) final body weight, body weight gain and lower (P <0.05) feed intake. Optimum weight gain was obtained with supplementation level of 36.15-g DGM (R (2) = 0.923). Guinea fowls fed diet supplemented with 40 g/kg DGM recorded the highest (P <0.05) coefficient of total tract apparent digestibility of dry matter, ether extract and longest (P <0.05) duodenal and ileal villus heights. The crypt depth of the duodenum and ileum reduced (P <0.05) with increasing level of dietary supplementation of DGM. Dietary supplementation of DGM resulted in increased (P <0.05) total serum protein, serum albumin and low (P <0.05) serum cholesterol concentration. Ileum content of birds fed diet supplemented with 40 g/kg DGM recorded the highest (P <0.05) lactobacillus count. In conclusion, dietary inclusion of 40-g DGM per kilogram diet is hereby recommended for improved growth, apparent nutrient digestibility, gut morphology, serum chemistry, and stimulation of balanced intestinal microflora in growing guinea fowl. 10.1007/s11250-013-0430-3
    Interaction of tea polyphenols and food constituents with model gut epithelia: the protective role of the mucus gel layer. D'Agostino Eleanor M,Rossetti Damiano,Atkins Derek,Ferdinando Dudley,Yakubov Gleb E Journal of agricultural and food chemistry The luminal surface of the gastrointestinal tract is covered by a mucus gel layer that acts to protect gut epithelial cells from the harsh luminal environment. This study investigated the use of two human colonic adenocarcinoma cell lines, HT29-MTX-E12 and HT29, as a model to mimic gut epithelium with and without a mucus gel layer. The effect of adding the tea polyphenols epigallocatechin gallate (EGCG) and epicatechin (EC) to the cells with subsequent examination of cell morphology and viability was assessed. EGCG, at the concentrations tested, was very toxic to the HT29 cells, but less toxic to the HT29-MTX-E12 cells, suggesting that the mucus gel layer on the HT29-MTX-E12 cells can protect the cells against EGCG toxicity. In contrast, EC had no effect on the viability of either the HT29 or HT29-MTX-E12 cells, suggesting that proteins within the mucus gel layer on the apical surface of gut epithelial cells may bind to the galloyl ring of EGCG. The effect of adding food-related ingredients with the ability to complex with EGCG, β-casein and maltodextrin, on cell viability was also examined. The presence of β-casein was very effective in protecting the cells against the toxicity effect of EGCG, but maltodextrin, at the concentration tested, was less effective in protecting against this toxicity. In conclusion, the results demonstrate that the mucus gel layer on HT29 human colonic adenocarcinoma cells may protect these cells against EGCG toxicity. In addition, the data showing reduced toxicity of EC compared to that of EGCG suggest that the cytotoxic effects of high polyphenol levels may be associated with the ability of polyphenols to interact with cellular proteins and mucins. 10.1021/jf205111k
    Pharmacological effects of nanoencapsulation of human-based dosing of probucol on ratio of secondary to primary bile acids in gut, during induction and progression of type 1 diabetes. Mooranian Armin,Zamani Nassim,Takechi Ryu,Al-Sallami Hesham,Mikov Momir,Goločorbin-Kon Svetlana,Kovacevic Bozica,Arfuso Frank,Al-Salami Hani Artificial cells, nanomedicine, and biotechnology INTRODUCTION:The ratio of secondary to primary bile acids changes during Type 1 Diabetes (T1D) development and these effects might be ameliorated by using cholesterol lowering drugs or hydrophilic bile acids. Probucol is a cholesterol-lowering drug, while ursodeoxycholic acid is a hydrophilic bile acid. This study investigated whether nanoencapsulated probucol with ursodeoxycholic acid altered bile acid ratios and the development of diabetes. METHODS:Balb/c mice were divided into three groups and gavaged daily with either free probucol, nanoencapsulated probucol or nanoencapsulated probucol with ursodeoxycholic acid for seven days. Alloxan was injected and once T1D was confirmed the mice continued to receive daily gavages until euthanasia. Blood, tissues, faeces and urine were collected for analysis of insulin and bile acids. RESULTS AND CONCLUSIONS:Nanoencapsulated probucol-ursodeoxycholic acid resulted in significant levels of insulin in the blood, lower levels of secondary bile acids in liver and lower levels of primary bile acids in brain, while ratio of secondary to primary bile acids remains similar among all groups, except in the faeces. Findings suggests that nanoencapsulated probucol-ursodeoxycholic acid may exert a protective effect on pancreatic β-cells and reserve systemic insulin load via modulation of bile acid concentrations in the liver and brain. 10.1080/21691401.2018.1511572
    Effect of diet and gut environment on the gastrointestinal formation of N-nitroso compounds: A review. Kobayashi Jun Nitric oxide : biology and chemistry Diet is associated with the development of cancer in the gastrointestinal (GI) tract, because dietary nitrate and nitrite are the main nitrosating agents that are responsible for the formation of carcinogenic N-nitroso compounds (NOCs) when nitrosatable substrates, such as amine and amide, are present in the GI tract. However, whether the nitroso compounds become beneficial S-nitroso compounds or carcinogenic NOCs might depend on dietary and environmental factors including food stuffs, gastric acidity, microbial flora, and the mean transit time of digesta. This review focused on GI NOC formation and environmental risk factors affecting its formation to provide appropriate nutritional strategies to prevent the development of GI cancer. 10.1016/j.niox.2017.06.001
    Is equol production beneficial to health? Magee Pamela J The Proceedings of the Nutrition Society The health benefits associated with soya food consumption have been widely studied, with soya isoflavones and soya protein implicated in the protection of CVD, osteoporosis and cancers such as those of the breast and prostate. Equol (7-hydroxy-3-(4'-hydroxyphenyl)-chroman), a metabolite of the soya isoflavone daidzein, is produced via the formation of the intermediate dihydrodaidzein, by human intestinal bacteria, with only approximately 30-40% of the adult population having the ability to perform this transformation following a soya challenge. Inter-individual variation in conversion of daidzein to equol has been attributed, in part, to differences in the diet and in gut microflora composition, although the specific bacteria responsible for the colonic biotransformation of daidzein to equol are yet to be identified. Equol is a unique compound in that it can exert oestrogenic effects, but is also a potent antagonist of dihydrotestosterone in vivo. Furthermore, in vitro studies suggest that equol is more biologically active than its parent compound, daidzein, with a higher affinity for the oestrogen receptor and a more potent antioxidant activity. Although some observational and intervention studies suggest that the ability to produce equol is associated with reduced risk of breast and prostate cancer, CVD, improved bone health and reduced incidence of hot flushes, others have reported null or adverse effects. Studies to date have been limited and well-designed studies that are sufficiently powered to investigate the relationship between equol production and disease risk are warranted before the clinical relevance of the equol phenotype can be fully elucidated. 10.1017/S0029665110003940
    Orally administered rutin inhibits the gene expression of Th2 cytokines in the gut and lung in aged mice. Morimoto Motoko,Takagi Yasuhiro,Higashi Natsumi,Suzuki Tateo The Journal of veterinary medical science Rutin is one of the flavonoids derived from plants such as buckwheat and is well known as a powerful antioxidant. To determine whether dietary rutin could modulate mucosal immunity, we examined the gene expression of Th1/Th2 cytokines and the receptors in the gut and lung. Aged (18 months old, 18 M) C3H/HeN female mice were orally administered rutin for 10 days. The small intestine and lung were taken and analyzed by real-time PCR for gene expression. Interleukin (IL)-13 and IL-13Rα2 gene expression was significantly low (P<0.05 respectively) in the small intestine of aged rutin-fed mice. Meanwhile, there was no change in interferon γ gene expression between control and rutin-fed mice. IL-13 gene expression was also downregulated in the lung. To examine the mechanism of the inhibitory effect of rutin on Th2 cytokines in aged mice, intestinal nitric oxide synthase (NOS) expression was evaluated. Rutin inhibited inducible NOS (NOS2) gene expression, but not neuronal NOS and endothelial NOS. Gene analysis of cells collected from the small intestine by laser capture dissection revealed that NOS2 expression was significantly inhibited in crypt regions. Thus, rutin might be effective against a Th2-dominant profile through NOS2 inhibition in aged mice. 10.1292/jvms.10-0480
    Metabolic perturbance in autism spectrum disorders: a metabolomics study. Ming Xue,Stein T Peter,Barnes Virginia,Rhodes Nelson,Guo Lining Journal of proteome research Autism spectrum disorders (ASD) are a group of biological disorders with associated metabolic derangement. This study aimed to identify a pattern of metabolic perturbance in ASD using metabolomics in urinary specimens from 48 children with ASD and 53 age matched controls. Using a combination of liquid- and gas-chromatography-based mass spectrometry, we detected the levels of 82 metabolites (53 of which were increased) that were significantly altered between the ASD and the control groups using osmolality normalized data. Pattern analysis showed that the levels of several amino acids such as glycine, serine, threonine, alanine, histidine, glutamyl amino acids and the organic acid, taurine were significantly (p≤0.05) lower in ASD children. The levels of antioxidants such as carnosine were also reduced in ASD (p=0.054). Furthermore, several gut bacterial metabolites were significantly altered in ASD children who had gastrointestinal dysfunction. Overall, this study detected abnormal amino acid metabolism, increased oxidative stress, and altered gut microbiomes in ASD. The relationship of altered gut microbial co-metabolism and the disrupted metabolisms requires further investigation. 10.1021/pr300910n
    Grape seed proanthocyanidins influence gut microbiota and enteroendocrine secretions in female rats. Casanova-Martí Àngela,Serrano Joan,Portune Kevin J,Sanz Yolanda,Blay M Teresa,Terra Ximena,Ardévol Anna,Pinent Montserrat Food & function Grape seed proanthocyanidin extract (GSPE) modulates several parameters involved in metabolic syndrome. GSPE is a mixture of compounds, some which are rapidly absorbed, while others remain in the lumen where they might have effects that are translated to the whole organism. Our aim was to decipher if the 8-day treatment of GSPE, previously shown to reduce food intake, induces changes in the microbiota and enterohormone secretion. The ratio of Firmicutes : Bacteroidetes was lower in the microbiota of GSPE-treated rats compared to controls, and differences in several taxonomic families and genera were observed. Such modulation led to a reduction in cecal butyrate content. GSPE also increased plasma glucagon-like-peptide-1 (GLP-1). Gallic acid did not induce major changes in the microbiota profile nor in GLP-1 secretion. Correlations between several microbiota taxa and plasma triacylglycerol, adiposity, and enterohormones were observed. Modulation of microbiota may be one of the mechanism by which GSPE impacts metabolic health. 10.1039/c7fo02028g
    Selenium and vitamin E together improve intestinal epithelial barrier function and alleviate oxidative stress in heat-stressed pigs. Liu Fan,Cottrell Jeremy J,Furness John B,Rivera Leni R,Kelly Fletcher W,Wijesiriwardana Udani,Pustovit Ruslan V,Fothergill Linda J,Bravo David M,Celi Pietro,Leury Brian J,Gabler Nicholas K,Dunshea Frank R Experimental physiology What is the central question of this study? Oxidative stress may play a role in compromising intestinal epithelial barrier integrity in pigs subjected to heat stress, but it is unknown whether an increase of dietary antioxidants (selenium and vitamin E) could alleviate gut leakiness in heat-stressed pigs. What is the main finding and its importance? Levels of dietary selenium (1.0 p.p.m.) and vitamin E (200 IU kg(-1) ) greater than those usually recommended for pigs reduced intestinal leakiness caused by heat stress. This finding suggests that oxidative stress plays a role in compromising intestinal epithelial barrier integrity in heat-stressed pigs and also provides a nutritional strategy for mitigating these effects. Heat stress compromises the intestinal epithelial barrier integrity of mammals through mechanisms that may include oxidative stress. Our objective was to test whether dietary supplementation with antioxidants, selenium (Se) and vitamin E (VE), protects intestinal epithelial barrier integrity in heat-stressed pigs. Female growing pigs (n = 48) were randomly assigned to four diets containing from 0.2 p.p.m. Se and 17 IU kg(-1) VE (control, National Research Council recommended) to 1.0 p.p.m. Se and 200 IU kg(-1) VE for 14 days. Six pigs from each dietary treatment were then exposed to either thermoneutral (20°C) or heat-stress conditions (35°C 09.00-17.00 h and 28°C overnight) for 2 days. Transepithelial electrical resistance and fluorescein isothiocyanate-dextran (4 kDa; FD4) permeability were measured in isolated jejunum and ileum using Ussing chambers. Rectal temperature, respiratory rate and intestinal HSP70 mRNA abundance increased (all P < 0.001), and respiratory alkalosis occurred, suggesting that pigs were heat stressed. Heat stress also increased FD4 permeability and decreased transepithelial electrical resistance (both P < 0.01). These changes were associated with changes indicative of oxidative stress, a decreased glutathione peroxidase (GPX) activity and an increased glutathione disulfide (GSSG)-to-glutathione (GSH) ratio (both P < 0.05). With increasing dosage of Se and VE, GPX-2 mRNA (P = 0.003) and GPX activity (P = 0.049) increased linearly, the GSSG:GSH ratio decreased linearly (P = 0.037), and the impacts of heat stress on intestinal barrier function were reduced (P < 0.05 for both transepithelial electrical resistance and FD4 permeability). In conclusion, in pigs an increase of dietary Se and VE mitigated the impacts of heat stress on intestinal barrier integrity, associated with a reduction in oxidative stress. 10.1113/EP085746
    Nano- and micro-particles for delivery of catechins: Physical and biological performance. Ye Jian-Hui,Augustin Mary Ann Critical reviews in food science and nutrition Catechins, present in many fruits and vegetables, have many health benefits, but they are prone to degradation. Nano- and micro-particle systems have been used to stabilise catechins when exposed to adverse environments and to improve their bioavailability after ingestion. This review discusses the inherent properties of various catechins, the design of delivery formulations and the properties of catechin-loaded nano- and micro-particles. The protection afforded to catechins during exposure to harsh environmental conditions and gastrointestinal tract transit is reviewed. The bioavailability and efficacy of encapsulated catechins, as assessed by various and conditions, are discussed. Bioavailability based on uptake in the upper gut alone underestimates the bioavailability as polyphenols. The caveats with interpretation of bioavailability based on various tests are discussed, when taking into consideration the pathways of catechin metabolism including the role of the gut microflora. However, taken together, the weight of the evidence suggests that there are potentially improved health benefits with the use of appropriately designed nano- and micro-particles for delivery of catechins. Further systematic studies on the metabolism and physiological effects of encapsulated catechins and clinical trials are needed to validate the bioefficacy of the encapsulated catechins. 10.1080/10408398.2017.1422110
    Oral Supplementation of Tocotrienol-Rich Fraction Alleviates Severity of Ulcerative Colitis in Mice. Saw Tzuen Yih,Malik Najib Abdul,Lim Kee Pah,Teo Cheryl Wei Ling,Wong Esther Sook Miin,Kong San Choon,Fong Chee Wai,Petkov Jordan,Yap Wei Ney Journal of nutritional science and vitaminology Ulcerative colitis (UC) is characterized by damaged colonic mucosa and submucosa layers that are caused by excessive inflammatory reactions and oxidative stress. This study aimed to examine the use of tocotrienol-rich fraction (TRF) in mitigating damages caused by UC on the colon epithelium. Dextran sulfate sodium (DSS)-induced UC mice were treated with vehicle control, TRF, alpha-tocopherol (αTP) and 5-aminosalicylic acid (5-ASA). Observable clinical signs, quality of stool, histopathological scoring, inflammatory and oxidative markers were assessed. Vitamin E levels of colons and plasma were quantified. Oral supplementation of TRF significantly reduced the severity of DSS-induced UC by lowering the disease activity index (DAI) and histopathological inflammatory scoring. TRF also attenuated the DSS-induced enlargement of spleen and shortening of the colon. TRF has demonstrated marked anti-inflammatory and antioxidative properties indicated by the attenuation of DSS-induced upregulation of inflammation and oxidative stress markers including interleukin (IL)-6, IL-17, tumor necrosis factor (TNF)-α, myeloperoxidase (MPO), cyclooxygenase-2 (COX-2), nitric oxide (NO), malondialdehyde (MDA) and pNF-κB. These improvements were similar to that of 5-aminosalicylic acid (5-ASA) treatment. In contrast, αTP did not demonstrate evident clinical and histopathological improvements. The superior protective effect of TRF may be ascribed to the preferential absorption of TRF by the gut mucosa. TRF alleviated the signs and symptoms of acute UC in murine model via the reduction of local inflammatory reactions and oxidative stress. These effects suggested that TRF could serve as a gut health supplement for preventive measures for UC condition in patients. 10.3177/jnsv.65.318
    Flavonoid metabolism: the interaction of metabolites and gut microbiota. Murota Kaeko,Nakamura Yoshimasa,Uehara Mariko Bioscience, biotechnology, and biochemistry Several dietary flavonoids exhibit anti-oxidative, anti-inflammatory, and anti-osteoporotic activities relevant to prevention of chronic diseases, including lifestyle-related diseases. Dietary flavonoids (glycoside forms) are enzymatically hydrolyzed and absorbed in the intestine, and are conjugated to their glucuronide/sulfate forms by phase II enzymes in epithelial cells and the liver. The intestinal microbiota plays an important role in the metabolism of flavonoids found in foods. Some specific products of bacterial transformation, such as ring-fission products and reduced metabolites, exhibit enhanced properties. Studies on the metabolism of flavonoids by the intestinal microbiota are crucial for understanding the role of these compounds and their impact on our health. This review focused on the metabolic pathways, bioavailability, and physiological role of flavonoids, especially metabolites of quercetin and isoflavone produced by the intestinal microbiota. 10.1080/09168451.2018.1444467
    Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Mathurin Philippe,O'Grady John,Carithers Robert L,Phillips Martin,Louvet Alexandre,Mendenhall Charles L,Ramond Marie-José,Naveau Sylvie,Maddrey Willis C,Morgan Timothy R Gut INTRODUCTION:A meta-analysis was performed using individual patient data from the five most recent randomised controlled trials (RCTs) which evaluated corticosteroids in severe alcoholic hepatitis (Maddrey discriminant function (DF) ≥ 32 or encephalopathy). This approach overcomes limitations associated with the use of literature data and improves the relevance of the study and estimates of effect size. AIMS:To compare 28-day survival between corticosteroid- and non-corticosteroid-treated patients and to analyse the response to treatment using the Lille model. METHODS:Individual patient data were obtained from five RCTs comparing corticosteroid treatment with placebo (n=3), enteral nutrition (n=1) or an antioxidant cocktail (n=1). RESULTS:221 patients allocated to corticosteroid treatment and 197 allocated to non-corticosteroid treatment were analysed. The two groups were similar at baseline. 28-day survival was higher in corticosteroid-treated patients than in non-corticosteroid-treated patients (79.97±2.8% vs 65.7±3.4%, p=0.0005). In multivariate analysis, corticosteroids (p=0.005), DF (p=0.006), leucocytes (p=0.004), Lille score (p<0.00001) and encephalopathy (p=0.003) were independently predictive of 28-day survival. A subgroup analysis was performed according to the percentile distribution of the Lille score. Patients were classified as complete responders (Lille score ≤ 0.16; ≤ 35th percentile), partial responders (Lille score 0.16-0.56; 35th-70th percentile) and null responders (Lille ≥ 0.56; ≥ 70th percentile). 28-day survival was strongly associated with these groupings (91.1±2.7% vs 79.4±3.8% vs 53.3±5.1%, p<0.0001). Corticosteroids had a significant effect on 28-day survival in complete responders (HR 0.18, p=0.006) and in partial responders (HR 0.38, p=0.04) but not in null responders. CONCLUSION:Analysis of individual data from five RCTs showed that corticosteroids significantly improve 28-day survival in patients with severe alcoholic hepatitis. The survival benefit is mainly observed in patients classified as responders by the Lille model. 10.1136/gut.2010.224097
    Gut microbiota: a new way to take your vitamins. Gomes-Neto João Carlos,Round June L Nature reviews. Gastroenterology & hepatology 10.1038/s41575-018-0044-3
    Antioxidant action and potential antidiabetic properties of an isoflavonoid-containing soyabean phytochemical extract (SPE). Vedavanam K,Srijayanta S,O'Reilly J,Raman A,Wiseman H Phytotherapy research : PTR The potential role of oestrogenic agents, antioxidants and intestinal glucose-uptake inhibitors in the treatment of diabetes is briefly reviewed. Reports in the literature suggest that oestrogen replacement therapy may favourably modulate glucose homeostasis. A soya phytochemical extract (SPE) containing the isoflavone phytoestrogens genistein and daidzein (mostly in their glycone forms as genistin and daidzin) was investigated as an antioxidant and modulator of intestinal glucose-transport. In the present study, SPE was found to protect against glucose-induced oxidation of human low density lipoproteins (LDL) in vitro. Equol (a gut bacterial metabolite of daidzein) was a more effective antioxidant than daidzein or genistein in this system and was of similar antioxidant potency to the dietary flavonols quercetin and kaempferol and to the endogenous antioxidant 17beta-oestradiol. SPE was found to be an inhibitor of glucose uptake into rabbit intestinal brush border membrane vesicles in vitro, though of weaker potency than the classical sodium dependent glucose transporter (SGLT) inhibitor, phlorizin. Thus SPE displays a range of properties which may be of benefit in diabetes, namely as an oestrogenic agent, an inhibitor of intestinal glucose-uptake and a preventive agent for glucose-induced lipid peroxidation. 10.1002/(sici)1099-1573(199911)13:7<601::aid-ptr550>3.0.co;2-o
    Effect of Quercetin Monoglycosides on Oxidative Stress and Gut Microbiota Diversity in Mice with Dextran Sodium Sulphate-Induced Colitis. Hong Zhu,Piao Meiyu BioMed research international The pathogenesis of inflammatory bowel disease (IBD) is linked to an intricate association of environmental, microbial, and host-related factors. This study examined the potential effects of dietary addition of two preparations from onion, one comprising quercetin aglycone alone (Q: 0.15% polyphenols, quercetin aglycone:quercetin monoglycosides, 98:2) and another comprising quercetin aglycone with monoglycosides (Q+MQ: 0.15% total polyphenols, quercetin aglycone:quercetin monoglycosides, 69:31), on dextran sodium sulphate- (DSS-) induced colitis in mice. The results revealed a significant decrease in the body weight gain of the mice with DSS-induced colitis, which was counteracted by the dietary Q or Q+MQ supplementation. Meanwhile, the oxidative stress indicated by myeloperoxidase (MPO), reduced glutathione (GSH), malondialdehyde (MDA), and serum nitrate (NO) concentrations was higher in mice with DSS-induced colitis than in the control group mice, but dietary Q or Q+MQ supplementation counteracted this trend. The colitis mice demonstrated reduced Chao1, angiotensin-converting enzyme (ACE), and Shannon indices and an increased Simpson index, but the colitis mice receiving dietary Q or Q+MQ exhibited higher Chao1, ACE, and Shannon indices and a reduced Simpson index. In conclusion, this research showed that even at a low dose, dietary Q or Q+MQ supplementation counteracts DSS-induced colitis in mice, indicating that Q or Q+MQ may be used as an adjuvant therapy for IBD patients. 10.1155/2018/8343052
    Resveratrol Suppresses Gut-Derived NLRP3 Inflammasome Partly through Stabilizing Mast Cells in a Rat Model. Zhao Weicheng,Huang Xiaolei,Han Xue,Hu Dan,Hu Xiaohuai,Li Yuantao,Huang Pinjie,Yao Weifeng Mediators of inflammation Background:Inflammatory responses induced by intestinal ischemia-reperfusion (IIR) lead to serious systemic organ dysfunction and pose a challenge for current treatment. This study aimed at investigating the effects of resveratrol on IIR-induced intestinal injury and its influence on mast cells (MCs) in rats. Methods:Rats subjected to intestinal ischemia for 60 min and 4 h of IIR were investigated. Animals were randomly divided into five groups ( = 8 per group): sham, IIR, resveratrol (RESV, 15 mg/kg/day for 5 days before operation) + IIR, cromolyn sodium (CS, MC membrane stabilizer) + IIR, and RESV + compound 48/80 (CP, MC agonist) + IIR. Results:Intestinal injury and increased proinflammatory cytokines including tumor necrosis factor-, interleukin-1, and interleukin-18 were observed in the IIR group. Intestinal MC-related tryptase and -hexosaminidase levels were also increased after rats were subjected to IIR accompanied by activation of NLRP3 inflammasomes. Interestingly, pretreatment with resveratrol significantly suppressed the activities of proinflammatory cytokines and attenuated intestinal injury. Resveratrol also reduced MC and NLRP3 inflammasome activation, which was consistent with the effects of cromolyn sodium. However, the protective effects of resveratrol were reversed by the MC agonist compound 48/80. Conclusions:In summary, these findings reveal that resveratrol suppressed IIR injury by stabilizing MCs, preventing them from degranulation, accompanied with intestinal mucosa NLRP3 inflammasome inhibition and intestinal epithelial cell apoptosis reduction. 10.1155/2018/6158671
    Digestion and absorption of phenolic compounds assessed by in vitro simulation methods. A review. Tarko Tomasz,Duda-Chodak Aleksandra,Zajac Natalia Roczniki Panstwowego Zakladu Higieny Phenolic compounds are a group of key plant metabolites found abundantly in fruit and vegetables. Because of their antioxidant properties, they play a significant role in preventing various degenerative illnesses, tumours or cardiovascular disease. In nature, they are present in foods mainly as esters, glycosides and polymers which need to undergo enzymatic hydrolysis in the digestive tract or by the gut microflora before becoming absorbed. The biological properties of these phenolic compounds undergoing this degradation, are thus governed by their absorption as well as metabolism. Many methods are used to assess the rates and the degrees to which these substances are digested and absorbed, both in vivo and in vitro ones, where the former are the most reliable, although they suffer from various limitations. For this reason, many in vitro models have now arisen to simulate the function of human digestion in the attempt to faithfully re-create real-life conditions. Mechanisms of polyphenols absorption have been principally studied by intestinal epithelial cell models, in particular, those using the Caco-2 cell line.
    Zingiber officinale and oxidative stress in patients with ulcerative colitis: A randomized, placebo-controlled, clinical trial. Nikkhah-Bodaghi Mehrnaz,Maleki Iradj,Agah Shahram,Hekmatdoost Azita Complementary therapies in medicine OBJECTIVES:Oxidative stress plays an essential role in ulcerative colitis (UC) initiation and severity. We aimed to investigate the effect of ginger as a well-known antioxidant agent on the quality of life, disease activity index and oxidative stress in patients with UC. METHODS:Forty six patients with active mild to moderate UC randomly assigned to consume 2000 mg/day dried ginger powder in 4 capsules or similar placebo capsules for 12 weeks. Disease activity index, quality of life and some oxidative stress factors were measured before, at the middle and at the end of the intervention through valid and reliable questionnaires and blood sampling. RESULTS:Ginger reduced Malondialdehyde (MDA) significantly after 6 weeks (p = 0.003) and 12 weeks (p < 0.001) of intervention, whereas it did not affect serum total anti-oxidant capacity (TAC). The scores of severity of disease activity at 12th week was significantly improved in ginger group in comparison to placebo (p = 0.017). Moreover, ginger increased patients quality of life significantly at 12 week (p = 0.039). CONCLUSION:Our data indicate that ginger supplementation can improve treatment of patients with UC. Further clinical trials with different dosages and duration of ginger or its standard extract supplementation are needed to obtain firm conclusion. 10.1016/j.ctim.2018.12.021
    Oxidant/Antioxidant Balance in Animal Nutrition and Health: The Role of Protein Oxidation. Celi Pietro,Gabai Gianfranco Frontiers in veterinary science This review examines the role that oxidative stress (OS), and protein oxidation in particular, plays in nutrition, metabolism, and health of farm animals. The route by which redox homeostasis is involved in some important physiological functions and the implications of the impairment of oxidative status on animal health and diseases is also examined. Proteins have various and, at the same time, unique biological functions and their oxidation can result in structural changes and various functional modifications. Protein oxidation seems to be involved in pathological conditions, such as respiratory diseases and parasitic infection; however, some studies also suggest that protein oxidation plays a crucial role in the regulation of important physiological functions, such as reproduction, nutrition, metabolism, lactation, gut health, and neonatal physiology. As the characterization of the mechanisms by which OS may influence metabolism and health is attracting considerable scientific interest, the aim of this review is to present veterinary scientists and clinicians with various aspects of oxidative damage to proteins. 10.3389/fvets.2015.00048
    Characterization of chemical composition and prebiotic effect of a dietary medicinal plant Penthorum chinense Pursh. Yin Jianhua,Ren Wei,Wei Bin,Huang Huimin,Li Mingxing,Wu Xiaoxiao,Wang Anqi,Xiao Zhangang,Shen Jing,Zhao Yueshui,Du Fukuan,Ji Huijiao,Kaboli Parham Jabbarzadeh,Ma Yongshun,Zhang Zhuo,Cho Chi Hin,Wang Shengpeng,Wu Xu,Wang Yitao Food chemistry Penthorum chinense Pursh is a dietary medicinal plant widely distributed in Asia-Pacific countries. The present study aims to profile the chemical constituents of P. chinense and investigate its prebiotic role in modulating gut microbiota. Fifty polyphenolic compounds were rapidly identified using UPLC-HR-MS. Total flavonoid and phenolic contents of P. chinense were 46.6% and 61.3% (w/w), respectively. Thirteen individual polyphenols were quantified, which accounted for 33.1% (w/w). P. chinense induced structural arrangement of microbial community in mice, showing increased microbiota diversity, elevated Bacteroidetes/Firmicutes ratio and enriched gut health-promoting bacteria. After a one-week drug-free wash, most of these changes were recovered, but the abundance of some beneficial bacteria was further increased. The altered composition of gut microbiota enriched several metabolic pathways. Moreover, P. chinense increased antioxidant capacity in vivo. The results suggest that polyphenol-enriched P. chinense modulates gut microbiota and enhances antioxidant capacity in mice toward a beneficial environment for host health. 10.1016/j.foodchem.2020.126568
    Isolation and identification of quercetin degrading bacteria from human fecal microbes. Zhang Zhichao,Peng Xichun,Li Shaoting,Zhang Ning,Wang Yong,Wei Hua PloS one Quercetin has a wide range of biological properties. The gut microflora can often modulate its biological activity and their potential health effects. There still is a lack of information about gut bacteria involving in this process. The strains of gut microbes from human feces that can transform quercetin were isolated and identified by in vitro fermentation. The results showed that Escherichia coli, Stretococcus lutetiensis, Lactobacillus acidophilus, Weissella confusa, Enterococcus gilvus, Clostridium perfringens and Bacteroides fragilis have the various ability of degrading quercetin. Among them, C. perfringens and B. fragilis were discovered to have the strongest ability of degrading quercetin. Additionally, quercetin can't inhibit the growth of C. perfringens. In conclusion, many species of gut microbiota can degrade quercetin, but their ability are different. 10.1371/journal.pone.0090531
    The gut: a regulatory hall governing fat-soluble micronutrient absorption. Reboul Emmanuelle The American journal of clinical nutrition 10.1093/ajcn/nqz199
    Gastric emptying, glucose metabolism and gut hormones: evaluation of a common preoperative carbohydrate beverage. Vermeulen Mechteld A R,Richir Milan C,Garretsen Martijn K,van Schie Annelies,Ghatei Mohammed A,Holst Jens J,Heijboer Annemieke C,Uitdehaag Bernard M J,Diamant Michaela,Eekhoff E Marelise W,van Leeuwen Paul A M,Ligthart-Melis Gerdien C Nutrition (Burbank, Los Angeles County, Calif.) OBJECTIVE:To study the gastric-emptying rate and gut hormonal response of two carbohydrate-rich beverages. A specifically designed carbohydrate-rich beverage is currently used to support the surgical patient metabolically. Fruit-based beverages may also promote recovery, due to natural antioxidant and carbohydrate content. However, gastric emptying of fluids is influenced by its nutrient composition; hence, safety of preoperative carbohydrate loading should be confirmed. Because gut hormones link carbohydrate metabolism and gastric emptying, hormonal responses were studied. METHODS:In eight volunteers, gastric emptying rates of both 400 mL of a ready-to-use beverage (A: Nutricia preOp; 50.4 g carbohydrates-mainly polysaccharides; 260 mOsm/kg) and 400 mL over-the-counter fruit-based lemonade (B: Roosvicee Original; 48 g carbohydrates--mainly fruit-associated saccharides; 805 mOsm/kg) were determined scintigraphically (using hepatate Tc-99(m)) according to a crossover design. Plasma glucose, insulin, C-peptide, glucagon-like peptide (GLP-1), peptide YY, total glucagon, and ghrelin were studied. RESULTS:Gastric emptying showed no differences in residual volumes. Earlier onset in emptying for beverage A versus B was observed (trend), with significantly higher glucose, insulin, C-peptide, and glucagon responses at 15-90 min. GLP-1 was inversely related to residual volume. CONCLUSION:Fruit-based lemonade is a safe alternative for preoperative purposes. It induces a more limited glucose, insulin, and C-peptide response. Later onset in gastric emptying (B versus A: trend), lower glucagon release, and differences in beverage content and osmolarity may have contributed to those differences. Efficient emptying was reflected by early GLP-1 levels. 10.1016/j.nut.2010.10.001
    Better Management of Alcohol Liver Disease Using a 'Microstructured Synbox' System Comprising L. plantarum and EGCG. Rishi Praveen,Arora Sumeha,Kaur Ujjwal Jit,Chopra Kanwaljit,Kaur Indu Pal PloS one Synergistic combination of probiotics with carbohydrate based prebiotics is widely employed for the treatment of various gut related disorders. However, such carbohydrate based prebiotics encourage the growth of pathogens and probiotics, equally. Aim of the study was (i) to explore the possibility of using epigallocatechin gallate (EGCG) a phenolic compound, as a prebiotic for L.plantarum; (ii) to develop and evaluate a microstructured synbox (microencapsulating both probiotic and EGCG together) in rat model of alcohol liver disease (ALD); and, (iii) to confirm whether the combination can address issues of EGCG bioavailability and probiotic survivability in adverse gut conditions. Growth enhancing effect of EGCG on L. plantarum (12.8±0.5 log 10 units) was significantly (p≤0.05) better than inulin (11.4±0.38 log 10 units), a natural storage carbohydrate. The formulated synbox significantly modulated the levels of alcohol, endotoxin, hepatic enzymes and restored the hepatoarchitecture in comparison to simultaneous administration of free agents. Additionally, using a battery of techniques, levels of various cellular and molecular markers viz. NF-kB/p50, TNF-α, IL12/p40, and signalling molecules TLR4, CD14, MD2, MyD88 and COX-2 were observed to be suppressed. Developed microbead synbox, as a single delivery system for both the agents showed synergism and hence, holds promise as a therapeutic option for ALD management. 10.1371/journal.pone.0168459
    Flos Lonicera ameliorates obesity and associated endotoxemia in rats through modulation of gut permeability and intestinal microbiota. Wang Jing-Hua,Bose Shambhunath,Kim Gi-Cheol,Hong Seung-Ug,Kim Ji-Hun,Kim Jai-Eun,Kim Hojun PloS one BACKGROUND AND AIM:Increasing evidence has indicated a close association of host-gut flora metabolic interaction with obesity. Flos Lonicera, a traditional herbal medicine, is used widely in eastern Asia for the treatment of various disorders. The aim of this study was to evaluate whether unfermented or fermented formulations of Flos Lonicera could exert a beneficial impact to combat obesity and related metabolic endotoxemia. METHODS:Obesity and metabolic endotoxemia were induced separately or together in rats through feeding a eight-week high fat diet either alone (HFD control group) or in combination with a single LPS stimulation (intraperitoneal injection, 0.75 mg/kg) (LPS control group). While, the mechanism of action of the Lonicera formulations was explored in vitro using RAW 264.7 and HCT 116 cell lines as models. RESULTS:In cell-based studies, treatment with both unfermented Flos Lonicera (UFL) and fermented Flos Lonicera (FFL) formulations resulted in suppression of LPS-induced NO production and gene expression of vital proinflammatory cytokines (TNF-α, COX-2, and IL-6) in RAW 264.7 cells, reduced the gene expression of zonula occludens (ZO)-1 and claudin-1, and normalized trans epithelial electric resistance (TEER) and horseradish peroxidase (HRP) flux in LPS-treated HCT-116 cells. In an animal study, treatment of HFD as well as HFD+LPS groups with UFL or FFL resulted in a notable decrease in body and adipose tissue weights, ameliorated total cholesterol, HDL, triglyceride, aspartate transaminase and endotoxin levels in serum, reduced the urinary lactulose/mannitol ratio, and markedly alleviated lipid accumulation in liver. In addition, exposure of HFD as well as HFD+LPS groups with UFL or FFL resulted in significant alteration of the distribution of intestinal flora, especially affecting the population of Akkermansia spp. and ratio of Bacteroidetes and Firmicutes. CONCLUSION:This evidence collectively demonstrates that Flos Lonicera ameliorates obesity and related metabolic endotoxemia via regulating distribution of gut flora and gut permeability. 10.1371/journal.pone.0086117
    Effect of dietary supplementation of (-)-epigallocatechin gallate on gut microbiota and biomarkers of colonic fermentation in rats. Unno Tomonori,Sakuma Mina,Mitsuhashi Shiho Journal of nutritional science and vitaminology Alterations in gut microbiota composition offer insights that may be relevant for several chronic conditions, including obesity. This study aimed to evaluate the effect of (-)-epigallocatechin gallate (EGCG) on the modulation of gut microbiota and biomarkers of colonic fermentation end-products in rats. Rats were fed an assigned diet of either a control diet, a 0.3% (w/w) EGCG diet, or a 0.6% (w/w) EGCG diet for 4 wk. Compared to the control group, the addition of 0.6% EGCG to the diet brought about a significant increase in the starch and protein contents in the feces collected in the fourth week of feeding, but the relative weights of abdominal adipose tissues of rats were inversely suppressed. Host-specific bacterial community composition, as determined by terminal restriction fragment length polymorphism (T-RFLP) patterns for fecal 16S ribosomal RNA, showed a significant response in the reduced occupation of Clostridium spp. and an increased trend of Bacteroides by dietary supplementation with EGCG. The 0.6% EGCG diet also influenced the status of Bifidobacterium and Prevotella to a lesser extent. Interestingly, the cecum of rats fed the 0.6% EGCG diet contained lower levels of acetic and butyric acids, whereas EGCG had little influence on the cecal level of propionic acid. EGCG also reduced the cecal p-cresol concentration in a dose-dependent fashion. In conclusion, dietary EGCG affects the growth of certain species of gut microbiota in rats and is associated with the cecal pattern of short chain fatty acids which could be responsible for regulating energy metabolism in the body.
    Fecal transplant from resveratrol-fed donors improves glycaemia and cardiovascular features of the metabolic syndrome in mice. Kim Ty T,Parajuli Nirmal,Sung Miranda M,Bairwa Suresh C,Levasseur Jody,Soltys Carrie-Lynn M,Wishart David S,Madsen Karen,Schertzer Jonathan D,Dyck Jason R B American journal of physiology. Endocrinology and metabolism Oral administration of resveratrol attenuates several symptoms associated with the metabolic syndrome, such as impaired glucose homeostasis and hypertension. Recent work has shown that resveratrol can improve glucose homeostasis in obesity via changes in the gut microbiota. Studies involving fecal microbiome transplants (FMTs) suggest that either live gut microbiota or bacterial-derived metabolites from resveratrol ingestion are responsible for producing the observed benefits in recipients. Herein, we show that obese mice receiving FMTs from healthy resveratrol-fed mice have improved glucose homeostasis within 11 days of the first transplant, and that resveratrol-FMTs is more efficacious than oral supplementation of resveratrol for the same duration. The effects of FMTs from resveratrol-fed mice are also associated with decreased inflammation in the colon of obese recipient mice. Furthermore, we show that sterile fecal filtrates from resveratrol-fed mice are sufficient to improve glucose homeostasis in obese mice, demonstrating that nonliving bacterial, metabolites, or other components within the feces of resveratrol-fed mice are sufficient to reduce intestinal inflammation. These postbiotics may be an integral mechanism by which resveratrol improves hyperglycemia in obesity. Resveratrol-FMTs also reduced the systolic blood pressure of hypertensive mice within 2 wk of the first transplant, indicating that the beneficial effects of resveratrol-FMTs may also assist with improving cardiovascular conditions associated with the metabolic syndrome. 10.1152/ajpendo.00471.2017
    Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Wikoff William R,Anfora Andrew T,Liu Jun,Schultz Peter G,Lesley Scott A,Peters Eric C,Siuzdak Gary Proceedings of the National Academy of Sciences of the United States of America Although it has long been recognized that the enteric community of bacteria that inhabit the human distal intestinal track broadly impacts human health, the biochemical details that underlie these effects remain largely undefined. Here, we report a broad MS-based metabolomics study that demonstrates a surprisingly large effect of the gut "microbiome" on mammalian blood metabolites. Plasma extracts from germ-free mice were compared with samples from conventional (conv) animals by using various MS-based methods. Hundreds of features were detected in only 1 sample set, with the majority of these being unique to the conv animals, whereas approximately 10% of all features observed in both sample sets showed significant changes in their relative signal intensity. Amino acid metabolites were particularly affected. For example, the bacterial-mediated production of bioactive indole-containing metabolites derived from tryptophan such as indoxyl sulfate and the antioxidant indole-3-propionic acid (IPA) was impacted. Production of IPA was shown to be completely dependent on the presence of gut microflora and could be established by colonization with the bacterium Clostridium sporogenes. Multiple organic acids containing phenyl groups were also greatly increased in the presence of gut microbes. A broad, drug-like phase II metabolic response of the host to metabolites generated by the microbiome was observed, suggesting that the gut microflora has a direct impact on the drug metabolism capacity of the host. Together, these results suggest a significant interplay between bacterial and mammalian metabolism. 10.1073/pnas.0812874106
    Ascorbic acid: chemistry, biology and the treatment of cancer. Du Juan,Cullen Joseph J,Buettner Garry R Biochimica et biophysica acta Since the discovery of vitamin C, the number of its known biological functions is continually expanding. Both the names ascorbic acid and vitamin C reflect its antiscorbutic properties due to its role in the synthesis of collagen in connective tissues. Ascorbate acts as an electron-donor keeping iron in the ferrous state thereby maintaining the full activity of collagen hydroxylases; parallel reactions with a variety of dioxygenases affect the expression of a wide array of genes, for example via the HIF system, as well as via the epigenetic landscape of cells and tissues. In fact, all known physiological and biochemical functions of ascorbate are due to its action as an electron donor. The ability to donate one or two electrons makes AscH(-) an excellent reducing agent and antioxidant. Ascorbate readily undergoes pH-dependent autoxidation producing hydrogen peroxide (H(2)O(2)). In the presence of catalytic metals this oxidation is accelerated. In this review, we show that the chemical and biochemical nature of ascorbate contribute to its antioxidant as well as its prooxidant properties. Recent pharmacokinetic data indicate that intravenous (i.v.) administration of ascorbate bypasses the tight control of the gut producing highly elevated plasma levels; ascorbate at very high levels can act as prodrug to deliver a significant flux of H(2)O(2) to tumors. This new knowledge has rekindled interest and spurred new research into the clinical potential of pharmacological ascorbate. Knowledge and understanding of the mechanisms of action of pharmacological ascorbate bring a rationale to its use to treat disease especially the use of i.v. delivery of pharmacological ascorbate as an adjuvant in the treatment of cancer. 10.1016/j.bbcan.2012.06.003
    Bound phytophenols from ready-to-eat cereals: comparison with other plant-based foods. Neacsu M,McMonagle J,Fletcher R J,Scobbie L,Duncan G J,Cantlay L,de Roos B,Duthie G G,Russell W R Food chemistry Whole-grain diets are linked to reduced risk of several chronic diseases (heart disease, cancer, diabetes, metabolic syndrome) and all-cause mortality. There is increasing evidence that these benefits are associated with the gut microbiota and that release of fibre-related phenolic metabolites in the gut is a contributing factor. Additional sources of these metabolites include fruits and vegetables, but the evidence for their protective effects is less well established. With respect to the availability of bound phytophenols, ready-to-eat cereals are compared with soft fruits (considered rich in antioxidants) and other commonly consumed fruits and vegetables. The results demonstrated that when compared with an equivalent serving of fruits or vegetables, a recommended portion of whole-grain cereals deliver substantially higher amounts of bound phytophenols, which are available for metabolism in the colon. The increased amount of these phenolic metabolites may, in part, explain the evidence for the protective effects of whole-grain cereals. 10.1016/j.foodchem.2013.05.023
    Influence of gut microbiota-derived ellagitannins' metabolites urolithins on pro-inflammatory activities of human neutrophils. Piwowarski Jakub P,Granica Sebastian,Kiss Anna K Planta medica Ellagitannin-rich products exhibit beneficial influence in the case of inflammation-associated diseases. Urolithins, metabolites of ellagitannins produced by gut microbiota, in contrary to high molecular weight hydrophilic parental polyphenols, possess well established bioavailability. Because of the important role of neutrophils in progression of inflammation, the influence of urolithins on their pro-inflammatory functions was tested. Urolithin B at a concentration of 20 µM showed significant inhibition of interleukin 8 and extracellular matrix-degrading enzyme MMP-9 production. It was also significantly active in prevention of cytochalasin A/formyl-met-leu-phenylalanine-triggered selectin CD62L shedding. Urolithin C was the only active compound towards inhibition of elastase release from cytochalasin A/formyl-met-leu-phenylalanine-stimulated neutrophils with 39.0 ± 15.9% inhibition at a concentration of 5 µM. Myeloperoxidase release was inhibited by urolithins A and C (at 20 µM by 46.7 ± 16.1 and 63.8 ± 8.6%, respectively). Urolithin A was the most potent reactive oxygen species release inhibitor both in formyl-met-leu-phenylalanine and 4β-phorbol-12β-myristate-R13-acetate-stimulated neutrophils. At the concentration of 1 µM, it caused reactive oxygen species level decrease by 42.6 ± 26.6 and 53.7 ± 16.0%, respectively. Urolithins can specifically modulate inflammatory functions of neutrophils, and thus could contribute to the beneficial health effects of ellagitannin-rich medicinal plant materials and food products. 10.1055/s-0034-1368615
    Chronic Repression of mTOR Complex 2 Induces Changes in the Gut Microbiota of Diet-induced Obese Mice. Jung Mi-Ja,Lee Jina,Shin Na-Ri,Kim Min-Soo,Hyun Dong-Wook,Yun Ji-Hyun,Kim Pil Soo,Whon Tae Woong,Bae Jin-Woo Scientific reports Alterations in the gut microbiota play a crucial role in host physiology and metabolism; however, the molecular pathways underlying these changes in diet-induced obesity are unclear. Mechanistic target of rapamycin (mTOR) signaling pathway is associated with metabolic disorders such as obesity and type 2 diabetes (T2D). Therefore, we examined whether changes in the regulation of mTOR signaling induced by diet (a high-fat diet [HFD] or normal-chow diet) and/or therapeutics (resveratrol [a specific inhibitor of mTOR complex 1] or rapamycin [an inhibitor of both mTOR complex 1 and 2]) altered the composition of the gut microbiota in mice. Oral administration of resveratrol prevented glucose intolerance and fat accumulation in HFD-fed mice, whereas rapamycin significantly impaired glucose tolerance and exacerbated intestinal inflammation. The abundance of Lactococcus, Clostridium XI, Oscillibacter, and Hydrogenoanaerobacterium increased under the HFD condition; however, the abundance of these species declined after resveratrol treatment. Conversely, the abundance of unclassified Marinilabiliaceae and Turicibacter decreased in response to a HFD or rapamycin. Taken together, these results demonstrated that changes in the composition of intestinal microbiota induced by changes in mTOR activity correlate with obese and diabetic phenotypes. 10.1038/srep30887
    Drug-induced liver injury: recent advances in diagnosis and risk assessment. Kullak-Ublick Gerd A,Andrade Raul J,Merz Michael,End Peter,Benesic Andreas,Gerbes Alexander L,Aithal Guruprasad P Gut Idiosyncratic drug-induced liver injury (IDILI) is a rare but potentially severe adverse drug reaction that should be considered in patients who develop laboratory criteria for liver injury secondary to the administration of a potentially hepatotoxic drug. Although currently used liver parameters are sensitive in detecting DILI, they are neither specific nor able to predict the patient's subsequent clinical course. Genetic risk assessment is useful mainly due to its high negative predictive value, with several human leucocyte antigen alleles being associated with DILI. New emerging biomarkers which could be useful in assessing DILI include total keratin18 (K18) and caspase-cleaved keratin18 (ccK18), macrophage colony-stimulating factor receptor 1, high mobility group box 1 and microRNA-122. From the numerous in vitro test systems that are available, monocyte-derived hepatocytes generated from patients with DILI show promise in identifying the DILI-causing agent from among a panel of coprescribed drugs. Several computer-based algorithms are available that rely on cumulative scores of known risk factors such as the administered dose or potential liabilities such as mitochondrial toxicity, inhibition of the bile salt export pump or the formation of reactive metabolites. A novel DILI cluster score is being developed which predicts DILI from multiple complimentary cluster and classification models using absorption-distribution-metabolism-elimination-related as well as physicochemical properties, diverse substructural descriptors and known structural liabilities. The provision of more advanced scientific and regulatory guidance for liver safety assessment will depend on validating the new diagnostic markers in the ongoing DILI registries, biobanks and public-private partnerships. 10.1136/gutjnl-2016-313369
    Toxins and the gut: role in human disease. Fasano A Gut Bacterial enteric infections exact a heavy toll on the human population, particularly among children. Despite the explosion of knowledge on the pathogenesis of enteric diseases experienced during the past decade, the number of diarrhoeal episodes and human deaths reported worldwide remains of apocalyptic dimensions. However, our better understanding of the pathogenic mechanisms involved in the onset of diarrhoea is finally leading to preventive interventions, such as the development of enteric vaccines, that may have a significant impact on the magnitude of this human plague. The application of a multidisciplinary approach to study bacterial pathogenesis, along with the recent sequencing of entire microbial genomes, have made possible discoveries that are changing the way scientists view the bacterium-host interaction. Today, research on the molecular basis of the pathogenesis of infective diarrhoeal diseases of necessity transcends established boundaries between microbiology, cell biology, intestinal pathophysiology, and immunology. This review focuses on the most recent outcomes of this multidisciplinary effort. 10.1136/gut.50.suppl_3.iii9
    [The immunomodulatory role of plant polyphenols]. Paszkiewicz Małgorzata,Budzyńska Aleksandra,Różalska Barbara,Sadowska Beata Postepy higieny i medycyny doswiadczalnej (Online) Polyphenols, plant secondary metabolites, are present in human diet and have been widely used for medical and cosmetic purposes. They possess beneficial features such as antioxidant, immunomodulatory, anti-cancer and antibacterial activity. There is some evidence that these phytochemicals can improve wound healing. However, more and more data suggest that, under certain conditions, they can act in a different, often unpredictable way. Some investigations indicate that polyphenols, generally known as antioxidants, can exhibit pro-oxidant, and therefore cytotoxic, activity. Hence, the ability of phytochemicals to induce apoptosis of cancer cells and bacterial cell damage may be, at least partly, due to their prooxidant properties. Phytocompounds enter the body through the digestive system where they undergo metabolic processes that often change their chemical features. The gastrointestinal microbiome interacts with phytochemicals and influences their bioavailability and absorption in the gut. Except for biochemical changes of plant polyphenols in the host, the achievement of therapeutic concentration in vivo may be the main problem in the determination of their real efficacy. Ambiguous results of some studies demonstrate the need for the development of more accurate and standardized methods for the evaluation of polyphenols' properties. Better understanding of human body-polyphenol interactions is crucial for more effective use of these phytochemicals in disease prevention and therapy.  10.5604/17322693.1009908
    Aminoguanidine and curcumin attenuated tumor necrosis factor (TNF)-α-induced oxidative stress, colitis and hepatotoxicity in mice. Mouzaoui Souad,Rahim Ibtissem,Djerdjouri Bahia International immunopharmacology The up regulation of gut mucosal cytokines such as tumor necrosis factor (TNF)-α and oxidative stress have been related to inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn's disease (CD). This study investigated an immune-mediated model of colitis. TNF-α injected intraperitonally to mice induced a dose-dependent recruitment of neutrophils into abdominal mesentery. The leukocytes influx induced by TNF-α (10 μg kg(-1) body weight) increased by 3 fold liver and colon damage scores. TNF-α-colitis was characterized by hemorrhagic edemas and crypt abscesses massively infiltrated by inflammatory cells, namely neutrophils. Moreover, TNF-α-toxicity resulted in liver steatosis and foci of necrosis infiltrated by Kupffer cells and neutrophils in parenchyma and around the centrilobular veins. The involvement of oxidative stress was evaluated using aminoguanidine (AG) as selective inhibitor of inducible NO synthase (iNOS) and curcumin (Cur), the polyphenolic antioxidant of turmeric (Curcuma longa L.). TNF-α-toxicity led to significant increase in myeloperoxidase (MPO, an index of neutrophils infiltration), nitrites (stable nitric oxide metabolites) and malondialdehyde (MDA, a marker of lipid peroxides) levels and cell apoptosis in liver and colon. AG and Cur treatments significantly attenuated the hallmarks of oxidative stress, neutrophils influx and ROS-related cellular and histological damages, in TNF-α-treated mice. Taken together, our results provide insights into the role of phagocytes-derived oxidants in TNF-α-colitis in mice. Cur and AG, by inhibiting neutrophils priming and iNOsynthase could be effective against oxidative bowel damages induced in IBD by imbalanced gut immune response. 10.1016/j.intimp.2011.10.010
    Ageing skin: oestrogen receptor β agonists offer an approach to change the outcome. Jackson Richard L,Greiwe Jeffrey S,Schwen Richard J Experimental dermatology Oestrogen (17β estradiol) and the dietary antioxidants resveratrol, genistein and S-equol, an isoflavone produced from the gut biotransformation of soy daidzein, are effective agents to reduce ageing in skin. It is widely held that these antioxidants scavenge free radicals to prevent skin damage. However, the evidence to date suggests that the primary mechanism of action of these antioxidants is to activate oestrogen receptor β (ERβ), which in turn enhances the expression of antioxidant enzymes and inhibits the expression of snail, a transcription factor that regulates keratinocyte cell proliferation and migration. Based on their selectivity, ERβ agents provide a treatment option for ageing skin without the potential safety issues associated with oestrogen therapy. 10.1111/j.1600-0625.2011.01362.x
    In vivo and in vitro metabolism of trans-resveratrol by human gut microbiota. Bode Lisa M,Bunzel Diana,Huch Melanie,Cho Gyu-Sung,Ruhland Denise,Bunzel Mirko,Bub Achim,Franz Charles M A P,Kulling Sabine E The American journal of clinical nutrition BACKGROUND:Strong interindividual differences in the microbial conversion of some dietary polyphenols have been reported. In-depth studies of trans-resveratrol metabolism by human gut microbiota, however, are lacking, and only one bacterial metabolite, namely dihydroresveratrol, has been described. OBJECTIVE:The aim of this study was to elucidate interindividual differences in trans-resveratrol metabolism by human gut microbiota and to identify bacterial strains involved. DESIGN:In the first part of the study, in vitro fermentation experiments were performed with feces samples from 7 healthy volunteers, and metabolite formation was measured by liquid chromatography-ultraviolet/visible (UV/Vis)-mass spectrometry (MS)/MS detection. Microbial diversities in 3 feces samples were analyzed by high-throughput pyrosequencing and quantitative real-time polymerase chain reaction. In addition, trans-resveratrol conversion experiments were conducted with selected fecal bacterial strains in pure culture. The second part of the study was a controlled intervention study with 12 healthy volunteers. After a washout period, all of the subjects received a one-time oral dose of 0.5 mg trans-resveratrol/kg body weight in the form of a grapevine-shoot supplement, and 24-h urine samples were analyzed by liquid chromatography-UV/Vis-MS/MS. RESULTS:Besides dihydroresveratrol, 2 previously unknown bacterial trans-resveratrol metabolites were identified in vitro and in vivo: 3,4'-dihydroxy-trans-stilbene and 3,4'-dihydroxybibenzyl (lunularin). Their formation, however, varied among the volunteers. Two strains, Slackia equolifaciens and Adlercreutzia equolifaciens, were identified as dihydroresveratrol producers. Gut bacteria able to produce dehydroxylated metabolites could, however, not be identified. CONCLUSIONS:trans-Resveratrol metabolism by human gut microbiota shows pronounced interindividual differences, which should be taken into account during investigation of health-related effects of this stilbene. This trial was registered at the German Clinical Trials Register as DRKS00004311, Universal Trial Number (WHO) UTN: U1111-1133-4621. 10.3945/ajcn.112.049379
    Cranberries and wild blueberries treated with gastrointestinal enzymes positively modify glutathione mechanisms in Caco-2 cells in vitro. Slemmer Jennifer E,Livingston-Thomas Jessica M,Gottschall-Pass Katherine T,Sweeney Marva I Journal of food science Beneficial health effects of cranberries (CBs) and wild blueberries (BBs), such as reduced levels of oxidative stress, have been demonstrated in feeding studies. These Vaccinium berries contain high levels of flavonoids; however, the bioavailability of flavonoids is generally low. We investigated the in vitro effects of these berries on intestinal cells, focusing on mitigating oxidative stress and associated reactive oxygen species (ROS). First, we simulated the passage of CB and BB through the gastrointestinal (GI) tract by treating berry homogenates to a battery of digestive enzymes. Then, Caco-2 cells, a model of small intestine epithelial uptake, were exposed to these homogenates for 60 min. Using a cell-free assay, we found that the antioxidant activity in CB homogenates was not affected by these enzymes, but that BB homogenates treated with gut enzymes had 43% lower free-radical quenching activity (P < 0.05). However, both of the enzyme-treated homogenates were still able to counteract the ROS-generating ability of H2O2 added exogenously to Caco-2 cells. Berry homogenates also increased mitochondrial metabolic rates at 60 min posttreatment, as measured by MTT assays. Enzyme-treated CB (but not BB) homogenates increased the levels of reduced glutathione (GSH) relative to oxidized glutathione (GSSG), a critical indicator of the cellular redox state (P < 0.05). Our data suggest that CBs do not lose their antioxidant ability when passing through the GI tract, and specifically, digested CB may serve to enhance cytoprotective effects in intestinal cells by reducing potential damage caused by free radicals and ROS derived from other food sources. 10.1111/1750-3841.12136
    Polyphenols and Sesquiterpene Lactones from Artichoke Heads: Modulation of Starch Digestion, Gut Bioaccessibility, and Bioavailability following In Vitro Digestion and Large Intestine Fermentation. Rocchetti Gabriele,Giuberti Gianluca,Lucchini Franco,Lucini Luigi Antioxidants (Basel, Switzerland) Artichoke is a relevant source of health-promoting compounds such as polyphenols and sesquiterpene lactones. In this study, the bioaccessibility and gut bioavailability of artichoke constituents were evaluated by combining in vitro digestion and large intestine fermentation, metabolomics, and Caco-2 human intestinal cells model. Moreover, the ability of artichoke polyphenols to modulate the in vitro starch digestibility was also explored. An untargeted metabolomic approach based on liquid chromatography quadrupole-time-of-flight (UHPLC/QTOF) mass spectrometry coupled with multivariate statistics was used to comprehensively screen the phytochemical composition of raw, digested, and fermented artichoke. Overall, a large abundance of phenolic acids and sesquiterpene lactones was detected, being 13.77 and 11.99 mg·g, respectively. After 20 h of in vitro large intestine fermentation, a decrease in polyphenols and sesquiterpene lactones content was observed. The most abundant compounds characterizing the raw material (i.e., chlorogenic acid and cynaropicrin equivalents) showed an average % bioaccessibility of 1.6%. The highest % bioaccessibility values were recorded for flavonoids such as anthocyanin and flavone equivalents (on average, 13.6%). However, the relatively high bioavailability values recorded for flavonols, phenolic acids, and sesquiterpene lactones (from 71.6% up to 82.4%) demonstrated that these compounds are able to be transported through the Caco-2 monolayer. The phenolic compounds having the highest permeation rates through the Caco-2 model included low molecular weight phenolics such as tyrosol and 4-ethylcatechol; the isoflavonoids 3'--methylviolanone, equol 4'--glucuronide, and hydroxyisoflavone; together with the methyl and acetyl derivatives of glycosylated anthocyanins. Therefore, although human in vivo confirmatory trials are deemed possible, current findings provide insights into the mechanistic effects underlying artichoke polyphenols and sesquiterpenoids bioavailability following gastrointestinal and large intestine processes. 10.3390/antiox9040306
    More Flavor for Flavonoid-Based Interventions? Kaakoush Nadeem O,Morris Margaret J Trends in molecular medicine Poor diets are associated with obesity and a decline in cognitive function. Flavonoids are plant compounds that have been associated with improved metabolic parameters in obesity and reversal of cognitive decline. Given that microbial flavonoid conversion is important for bioactivity, flavonoid-derived neuroactive compounds may be functionally crucial in the gut microbiome-brain axis. 10.1016/j.molmed.2017.02.008
    Proanthocyanidin-chitosan composite nanoparticles prevent bacterial invasion and colonization of gut epithelial cells by extra-intestinal pathogenic Escherichia coli. Alfaro-Viquez Emilia,Esquivel-Alvarado Daniel,Madrigal-Carballo Sergio,Krueger Christian G,Reed Jess D International journal of biological macromolecules Cranberry proanthocyanidin-chitosan composite nanoparticles (PAC-CHT NPs) were formulated using 2:1, 5:1, 10:1, 15:1 20:1, 25:1, and 30:1 PAC to CHT weight ratio to form round shaped particles. The PAC-CHT NPs were characterized by size, polydispersity, surface charge, morphology, and PAC content. PAC-CHT NPs bioactivity was measured by agglutination of extra-intestinal pathogenic Escherichia coli (ExPEC) and inhibition of gut epithelial cell invasion by ExPEC. Results indicate that by increasing the PAC to CHT ratio 10:1 to 30:1 formed stable nanoparticles with diameters of 122.8 to 618.7 nm, a polydispersity index of approximated 0.4 to 0.5, and a zeta potential of 34.5 to 54.4 mV. PAC-CHT NPs ratio 30:1 agglutinated ExPEC and decreased the ability of ExPEC to invade epithelial cells in a dose-dependent manner. PAC-CHT NPs ratio 10:1 to 30:1 form stable, round-shaped, and bioactive nanoparticles for potential applications in the treatment of ExPEC bacterial infections. 10.1016/j.ijbiomac.2019.04.170
    Polyphenol-rich extract of pomegranate peel alleviates tissue inflammation and hypercholesterolaemia in high-fat diet-induced obese mice: potential implication of the gut microbiota. Neyrinck Audrey M,Van Hée Vincent F,Bindels Laure B,De Backer Fabienne,Cani Patrice D,Delzenne Nathalie M The British journal of nutrition Pomegranate extracts have been used for centuries in traditional medicine to confer health benefits in a number of inflammatory diseases, microbial infections and cancer. Peel fruit are rich in polyphenols that exhibit antioxidant and anti-inflammatory capacities in vitro. Recent studies strongly suggest that the gut microbiota is an environmental factor to be taken into account when assessing the risk factors related to obesity. The aim of the present study was to test the prebiotic potency of a pomegranate peel extract (PPE) rich in polyphenols in a nutritional model of obesity associated with hypercholesterolaemia and inflammatory disorders. Balb/c mice were fed either a control diet or a high-fat (HF) diet with or without PPE (6 mg/d per mouse) over a period of 4 weeks. Interestingly, PPE supplementation increased caecal content weight and caecal pool of bifidobacteria. It did not significantly modify body weight gain, glycaemia, glucose tolerance and inflammatory markers measured in the serum. However, it reduced the serum level of cholesterol (total and LDL) induced by HF feeding. Furthermore, it counteracted the HF-induced expression of inflammatory markers both in the colon and the visceral adipose tissue. Together, these findings support that pomegranate constitutes a promising food in the control of atherogenic and inflammatory disorders associated with diet-induced obesity. Knowing the poor bioavailability of pomegranate polyphenols, its bifidogenic effect observed after PPE consumption suggests the involvement of the gut microbiota in the management of host metabolism by polyphenolic compounds present in pomegranate. 10.1017/S0007114512002206
    Melatonin attenuates Co γ-ray-induced hematopoietic, immunological and gastrointestinal injuries in C57BL/6 male mice. Khan Shahanshah,Adhikari Jawahar Singh,Rizvi Moshahid Alam,Chaudhury Nabo Kumar Environmental toxicology Protection of hematopoietic, immunological, and gastrointestinal injuries from deleterious effects of ionizing radiation is prime rational for developing radioprotector. The objective of this study, therefore, was to evaluate the radioprotective potential of melatonin against damaging effects of radiation-induced hematopoietic, immunological, and gastrointestinal injuries in mice. C57BL/6 male mice were intraperitoneally administered with melatonin (50-150 mg/kg) 30 min prior to whole-body radiation exposure of 5 and 7.5 Gy using Co-teletherapy unit. Thirty-day survival against 7.5 Gy was monitored. Melatonin (100 mg/kg) pretreatment showed 100% survival against 7.5 Gy radiation dose. Melatonin pretreatment expanded femoral HPSCs, and inhibited spleenocyte DNA strands breaks and apoptosis in irradiated mice. At this time, it also protected radiation-induced loss of T cell sub-populations in spleen. In addition, melatonin pretreatment enhanced crypts regeneration and increased villi number and length in irradiated mice. Translocation of gut bacteria to spleen, liver and kidney were controlled in irradiated mice pretreated with melatonin. Radiation-induced gastrointestinal DNA strand breaks, lipid peroxidation, and expression of proapoptotic-p53, Bax, and antiapoptotic-Bcl-xL proteins were reversed in melatonin pretreated mice. This increase of Bcl-xL was associated with the decrease of Bax/Bcl-xL ratio. ABTS and DPPH radical assays revealed that melatonin treatment alleviated total antioxidant capacity in hematopoietic and gastrointestinal tissues. Present study demonstrated that melatonin pretreatment was able to prevent hematopoietic, immunological, and gastrointestinal radiation-induced injury, therefore, overcoming lethality in mice. These results suggest potential of melatonin in developing radioprotector for protection of bone marrow, spleen, and gastrointestine in planned radiation exposure scenarios including radiotherapy. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 501-518, 2017. 10.1002/tox.22254
    Gut microbiota composition in relation to the metabolic response to 12-week combined polyphenol supplementation in overweight men and women. Most J,Penders J,Lucchesi M,Goossens G H,Blaak E E European journal of clinical nutrition BACKGROUND/OBJECTIVES:The intestinal microbiota may have a profound impact on host metabolism. As evidence suggests that polyphenols affect substrate utilization, the present study aimed to investigate the effects of polyphenol supplementation on intestinal microbiota composition in humans. Furthermore, we examined whether (changes in) gut microbiota composition may determine the metabolic response to polyphenol supplementation. SUBJECTS/METHODS:In this randomized, double-blind, placebo (PLA)-controlled trial, 37 overweight and obese men and women (18 males/19 females, 37.8±1.6 years, body mass index: 29.6±0.5 kg/m) received either epigallocatechin-3-gallate and resveratrol (EGCG+RES, 282 and 80 mg/day, respectively) or PLA for 12 weeks. Before and after intervention, feces samples were collected to determine microbiota composition. Fat oxidation was assessed by indirect calorimetry during a high-fat mixed meal test (2.6 MJ, 61 energy% fat) and skeletal muscle mitochondrial oxidative capacity by means of ex vivo respirometry on isolated skeletal muscle fibers. Body composition was measured by dual-energy X-ray absorptiometry. RESULTS:Fecal abundance of Bacteroidetes was higher in men as compared with women, whereas other assessed bacterial taxa were comparable. EGCG+RES supplementation significantly decreased Bacteroidetes and tended to reduce Faecalibacterium prausnitzii in men (P=0.05 and P=0.10, respectively) but not in women (P=0.15 and P=0.77, respectively). Strikingly, baseline Bacteroidetes abundance was predictive for the EGCG+RES-induced increase in fat oxidation in men but not in women. Other bacterial genera and species were not affected by EGCG+RES supplementation. CONCLUSIONS:We demonstrated that 12-week EGCG+RES supplementation affected the gut microbiota composition in men but not in women. Baseline microbiota composition determined the increase in fat oxidation after EGCG+RES supplementation in men. 10.1038/ejcn.2017.89
    Resveratrol improves exercise performance and skeletal muscle oxidative capacity in heart failure. Sung Miranda M,Byrne Nikole J,Robertson Ian M,Kim Ty T,Samokhvalov Victor,Levasseur Jody,Soltys Carrie-Lynn,Fung David,Tyreman Neil,Denou Emmanuel,Jones Kelvin E,Seubert John M,Schertzer Jonathan D,Dyck Jason R B American journal of physiology. Heart and circulatory physiology We investigated whether treatment of mice with established pressure overload-induced heart failure (HF) with the naturally occurring polyphenol resveratrol could improve functional symptoms of clinical HF such as fatigue and exercise intolerance. C57Bl/6N mice were subjected to either sham or transverse aortic constriction surgery to induce HF. Three weeks postsurgery, a cohort of mice with established HF (%ejection fraction <45) was administered resveratrol (~450 mg·kg·day) or vehicle for 2 wk. Although the percent ejection fraction was similar between both groups of HF mice, those mice treated with resveratrol had increased total physical activity levels and exercise capacity. Resveratrol treatment was associated with altered gut microbiota composition, increased skeletal muscle insulin sensitivity, a switch toward greater whole body glucose utilization, and increased basal metabolic rates. Although muscle mass and strength were not different between groups, mice with HF had significant declines in basal and ADP-stimulated O consumption in isolated skeletal muscle fibers compared with sham mice, which was completely normalized by resveratrol treatment. Overall, resveratrol treatment of mice with established HF enhances exercise performance, which is associated with alterations in whole body and skeletal muscle energy metabolism. Thus, our preclinical data suggest that resveratrol supplementation may effectively improve fatigue and exercise intolerance in HF patients. Resveratrol treatment of mice with heart failure leads to enhanced exercise performance that is associated with altered gut microbiota composition, increased whole body glucose utilization, and enhanced skeletal muscle metabolism and function. Together, these preclinical data suggest that resveratrol supplementation may effectively improve fatigue and exercise intolerance in heart failure via these mechanisms. 10.1152/ajpheart.00455.2016
    Urolithins, gut microbiota-derived metabolites of ellagitannins, inhibit LPS-induced inflammation in RAW 264.7 murine macrophages. Piwowarski Jakub P,Kiss Anna K,Granica Sebastian,Moeslinger Thomas Molecular nutrition & food research SCOPE:Ellagitannin-rich food products and medicinal plant materials were shown to have beneficial effects toward intestinal inflammation. Due to the questionable bioavailability of ellagitannins their gut microbiota metabolites-urolithins have come to be regarded as potential factors responsible for biological activities observed in vivo. The aim of the study was to determine the influence of the three most abundant bioavailable ellagitannin gut microbiota metabolites-urolithins A, B, and C on inflammatory responses in RAW 264.7 murine macrophages, which are involved in the pathogenesis of intestine inflammation. METHODS AND RESULTS:Urolithins A, B, and C decreased NO production via inhibition of the iNOS protein and mRNA expression. They decreased the expression of IL-1β, TNF-α, and IL-6 mRNA in LPS challenged RAW 264.7 murine macrophages. A clear inhibition of NF-κB p65 nuclear translocation and p50 DNA-binding activity was associated with the observed anti-inflammatory activities of urolithins. Among the tested compounds urolithin A had the strongest anti-inflammatory activity. CONCLUSION:The anti-inflammatory effects of urolithins at concentrations that are physiologically relevant for gut tissues (≥40 μM), as revealed in this study, support the data from in vivo studies showing the beneficial effects of ellagitannin-rich products toward intestinal inflammation. 10.1002/mnfr.201500264
    Evaluating the antioxidant potential of new treatments for inflammatory bowel disease using a rat model of colitis. Millar A D,Rampton D S,Chander C L,Claxson A W,Blades S,Coumbe A,Panetta J,Morris C J,Blake D R Gut BACKGROUND:Reactive oxygen species may mediate tissue injury in inflammatory bowel disease. Aminosalicylates have antioxidant activity and the antioxidants, superoxide dismutase and allopurinol, are of reported benefit in inflammatory bowel disease. AIM:To develop a convenient technique for testing the antioxidant potential of standard and novel therapeutic agents for use in inflammatory bowel disease. METHODS:Amplified chemiluminescence was used to measure reactive oxygen species production by colonic biopsy specimens from rats with acetic acid induced colitis and to assess the in vitro effect of conventional antioxidants, standard therapies and proposed novel therapies for inflammatory bowel disease. RESULTS:The model was validated by demonstrating that the profile of effects on chemiluminescence of acetic acid induced colitis biopsy specimens given by conventional antioxidants (sodium azide, catalase, copper-zinc superoxide dismutase, dimethyl sulphoxide, N-acetylcysteine and ascorbate) and standard therapies (5-aminosalicylate and hydrocortisone) resembled that previously reported using biopsy specimens from ulcerative colitis. Human recombinant manganese superoxide dismutase did not alter chemiluminescence. Two novel compounds, LY231617 (10 mM) and amflutizole (20 mM), reduced chemiluminescence by 98% (n = 5, p = 0.009) and 88% (n = 5, p = 0.03), respectively. CONCLUSIONS:The similarity of the chemiluminescence responses of colonic biopsy specimens from acetic acid induced colitis and ulcerative colitis to a range of conventional antioxidants and standard treatments suggests that this model is a useful method for testing the antioxidant potential of new therapies for inflammatory bowel disease. The antioxidant actions of dimethyl sulphoxide, ascorbate, and the novel compounds, amflutizole and LY231617 in this model suggest that these agents merit further assessment in the treatment of inflammatory bowel disease. 10.1136/gut.39.3.407
    Urolithins, the rescue of "old" metabolites to understand a "new" concept: Metabotypes as a nexus among phenolic metabolism, microbiota dysbiosis, and host health status. Tomás-Barberán Francisco A,González-Sarrías Antonio,García-Villalba Rocío,Núñez-Sánchez María A,Selma María V,García-Conesa María T,Espín Juan Carlos Molecular nutrition & food research Urolithins are dibenzo[b,d]pyran-6-one derivatives that are produced by the human gut microbiota from ellagitannins and ellagic acid (EA). These metabolites are much better absorbed than their precursors and have been suggested to be responsible for the health effects attributed to ellagitannins and EA that occur in food products as berries and nuts. In the present review, the role and potential of urolithins in human health are critically reviewed, and a perspective of the research approach needed to demonstrate these health effects is presented, based on the existing knowledge. The analytical methods available for urolithin analysis, their occurrence in different tissues and biological fluids, and their metabolism by human gut microbiota are considered. In addition, the interindividual variability observed for the production of urolithins (metabotypes) and its relationship with health status and dysbiosis are also reviewed. The potential mechanisms of action of urolithins are also critically discussed, paying attention to the concentration and the type of metabolites used in the in vitro and in vivo assays and the physiological significance of the results obtained. The gut microbiota metabolism of EA to urolithins and that of daidzein to equol, their individual variations, and the effects on health are also compared. 10.1002/mnfr.201500901
    Interactions of gut microbiota with functional food components and nutraceuticals. Laparra J M,Sanz Y Pharmacological research The human gut is populated by an array of bacterial species, which develop important metabolic and immune functions, with a marked effect on the nutritional and health status of the host. Dietary component also play beneficial roles beyond basic nutrition, leading to the development of the functional food concept and nutraceuticals. Prebiotics, polyunsaturated fatty acids (PUFAs) and phytochemicals are the most well characterized dietary bioactive compounds. The beneficial effects of prebiotics mainly relay on their influence on the gut microbiota composition and their ability to generate fermentation products (short-chain fatty acids) with diverse biological roles. PUFAs include the omega-3 and omega-6 fatty acids, whose balance may influence diverse aspects of immunity and metabolism. Moreover, interactions between PUFAs and components of the gut microbiota may also influence their biological roles. Phytochemicals are bioactive non-nutrient plant compounds, which have raised interest because of their potential effects as antioxidants, antiestrogenics, anti-inflammatory, immunomodulatory, and anticarcinogenics. However, the bioavailability and effects of polyphenols greatly depend on their transformation by components of the gut microbiota. Phytochemicals and their metabolic products may also inhibit pathogenic bacteria while stimulate the growth of beneficial bacteria, exerting prebiotic-like effects. Therefore, the intestinal microbiota is both a target for nutritional intervention and a factor influencing the biological activity of other food compounds acquired orally. This review focuses on the reciprocal interactions between the gut microbiota and functional food components, and the consequences of these interactions on human health. 10.1016/j.phrs.2009.11.001
    The beneficial and deleterious role of dietary polyphenols on chronic degenerative diseases by regulating gene expression. Qu Guojing,Chen Jinhua,Guo Xiuli Bioscience trends Dietary polyphenols, a natural component in many kinds of foods such as fruits and vegetables, play essential roles in a wide range of plant functions. Importantly, the discovery of the functions of polyphenols including anti-oxidant, anti-carcinogenic and anti-inflammatory has been appealing to researchers' attentions. Dietary polyphenols have shown protective effects on chronic degenerative diseases (CDD) such as cardiovascular diseases, cancers, and neurodegenerative diseases by regulating gene expression. Dietary polyphenols also affect the composition and activity of gut microbiota, in reverse, gut microbiota influences the bioavailability and physiological activity of dietary polyphenols. However, not all kinds of dietary polyphenols are beneficial for human health. The potential deleterious effects of several dietary polyphenols have been reported by inducing DNA damage and gene mutants. This review summarizes the potential therapeutic effects of dietary polyphenols on chronic degeneration diseases, the polyphenols-gut microbiota interactions, and the potential dangers of individual dietary polyphenols on human health. 10.5582/bst.2018.01172
    Research Advances of Purple Sweet Potato Anthocyanins: Extraction, Identification, Stability, Bioactivity, Application, and Biotransformation. Li Aoran,Xiao Ruoshi,He Sijia,An Xiaoyu,He Yi,Wang Chengtao,Yin Sheng,Wang Bin,Shi Xuewei,He Jingren Molecules (Basel, Switzerland) Purple sweet potato anthocyanins are kinds of natural anthocyanin red pigments extracted from the root or stem of purple sweet potato. They are stable and have the functions of anti-oxidation, anti-mutation, anti-tumor, liver protection, hypoglycemia, and anti-inflammation, which confer them a good application prospect. Nevertheless, there is not a comprehensive review of purple sweet potato anthocyanins so far. The extraction, structural characterization, stability, functional activity, application in the food, cosmetics, medicine, and other industries of anthocyanins from purple sweet potato, together with their biotransformation in vitro or by gut microorganism are reviewed in this paper, which provides a reference for further development and utilization of anthocyanins. 10.3390/molecules24213816
    PGC-1β promotes enterocyte lifespan and tumorigenesis in the intestine. Bellafante Elena,Morgano Annalisa,Salvatore Lorena,Murzilli Stefania,Di Tullio Giuseppe,D'Orazio Andria,Latorre Dominga,Villani Gaetano,Moschetta Antonio Proceedings of the National Academy of Sciences of the United States of America The mucosa of the small intestine is renewed completely every 3-5 d throughout the entire lifetime by small populations of adult stem cells that are believed to reside in the bottom of the crypts and to migrate and differentiate into all the different populations of intestinal cells. When the cells reach the apex of the villi and are fully differentiated, they undergo cell death and are shed into the lumen. Reactive oxygen species (ROS) production is proportional to the electron transfer activity of the mitochondrial respiration chain. ROS homeostasis is maintained to control cell death and is finely tuned by an inducible antioxidant program. Here we show that peroxisome proliferator-activated receptor-γ coactivator-1β (PGC-1β) is highly expressed in the intestinal epithelium and possesses dual activity, stimulating mitochondrial biogenesis and oxygen consumption while inducing antioxidant enzymes. To study the role of PGC-1β gain and loss of function in the gut, we generated both intestinal-specific PGC-1β transgenic and PGC-1β knockout mice. Mice overexpressing PGC-1β present a peculiar intestinal morphology with very long villi resulting from increased enterocyte lifespan and also demonstrate greater tumor susceptibility, with increased tumor number and size when exposed to carcinogens. PGC-1β knockout mice are protected from carcinogenesis. We show that PGC-1β triggers mitochondrial respiration while protecting enterocytes from ROS-driven macromolecule damage and consequent apoptosis in both normal and dysplastic mucosa. Therefore, PGC-1β in the gut acts as an adaptive self-point regulator, capable of providing a balance between enhanced mitochondrial activity and protection from increased ROS production. 10.1073/pnas.1415279111
    Distribution, function and physiological role of melatonin in the lower gut. Chen Chun-Qiu,Fichna Jakub,Bashashati Mohammad,Li Yong-Yu,Storr Martin World journal of gastroenterology Melatonin is a hormone with endocrine, paracrine and autocrine actions. It is involved in the regulation of multiple functions, including the control of the gastrointestinal (GI) system under physiological and pathophysiological conditions. Since the gut contains at least 400 times more melatonin than the pineal gland, a review of the functional importance of melatonin in the gut seems useful, especially in the context of recent clinical trials. Melatonin exerts its physiological effects through specific membrane receptors, named melatonin-1 receptor (MT1), MT2 and MT3. These receptors can be found in the gut and their involvement in the regulation of GI motility, inflammation and pain has been reported in numerous basic and clinical studies. Stable levels of melatonin in the lower gut that are unchanged following a pinealectomy suggest local synthesis and, furthermore, implicate physiological importance of endogenous melatonin in the GI tract. Presently, only a small number of human studies report possible beneficial and also possible harmful effects of melatonin in case reports and clinical trials. These human studies include patients with lower GI diseases, especially patients with irritable bowel syndrome, inflammatory bowel disease and colorectal cancer. In this review, we summarize the presently available information on melatonin effects in the lower gut and discuss available in vitro and in vivo data. We furthermore aim to evaluate whether melatonin may be useful in future treatment of symptoms or diseases involving the lower gut. 10.3748/wjg.v17.i34.3888
    Isoquercetin and inulin synergistically modulate the gut microbiome to prevent development of the metabolic syndrome in mice fed a high fat diet. Tan Si,Caparros-Martin Jose A,Matthews Vance B,Koch Henrietta,O'Gara Fergal,Croft Kevin D,Ward Natalie C Scientific reports Dietary fibre positively influences gut microbiome composition, enhancing the metabolism of dietary flavonoids to produce bioactive metabolites. These synergistic activities facilitate the beneficial effects of dietary flavonoids on cardiometabolic health parameters. The aims of this study were to investigate whether isoquercetin (a major dietary flavonoid) and inulin (soluble fibre), either alone or in combination could improve features of the metabolic syndrome. Following a 1 week acclimatization, male C57BL6 mice (6-8 weeks) were randomly assigned to; (i) normal chow diet (n = 10), (ii) high fat (HF) diet (n = 10), (iii) HF diet + 0.05% isoquercetin (n = 10), (iv) HF diet + 5% inulin, or (v) HF diet + 0.05% isoquercetin + 5% inulin (n = 10). Body weight and food intake were measured weekly. At 12 weeks, glucose and insulin tolerance tests were performed, and blood, faecal samples, liver, skeletal muscle and adipose tissue were collected. At 12 weeks, mice on the HF diet had significantly elevated body weights as well as impaired glucose tolerance and insulin sensitivity compared to the normal chow mice. Supplementation with either isoquercetin or inulin had no effect, however mice receiving the combination had attenuated weight gain, improved glucose tolerance and insulin sensitivity, reduced hepatic lipid accumulation, adipocyte hypertrophy, circulating leptin and adipose FGF21 levels, compared to mice receiving the HF diet. Additionally, mice on the combination diet had improvements in the composition and functionality of their gut microbiome as well as production of short chain fatty acids. In conclusion, long-term supplementation with the dietary flavonoid isoquercetin and the soluble fibre inulin can attenuate development of the metabolic syndrome in mice fed a high fat diet. This protective effect appears to be mediated, in part, through beneficial changes to the microbiome. 10.1038/s41598-018-28521-8
    Cytotoxicity comparison of quercetin and its metabolites from in vitro fermentation of several gut bacteria. Zhang Zhichao,Peng Xichun,Zhang Ning,Liu Liu,Wang Yong,Ou Shiyi Food & function Part of quercetin is coerced into the colon after ingestion and interacts with the gut microbiota. The interaction between quercetin and gut microbiota will influence human health. The cytotoxicity of quercetin and its metabolites from human gut bacteria in vitro fermentation was investigated in this study. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide) (MTT) and agar diffusion disc methods were individually applied in vitro to examine their inhibitory effect on three cultured human cancer cells and five pathogenic bacteria species. The results showed that the metabolites from Clostridium perfringens and Bacteroides fragilis exerted a strong inhibitory effect (P < 0.05) on HCT-116 cells and that of Weissella confusa was stronger (P < 0.01) on both A549 cells and HeLa cells than on the others. Most metabolites have similar or decreased inhibitory ability on human cancer cells compared to quercetin itself. This inhibitory effect had not been detected in quercetin and its metabolites in five common pathogenic bacteria species. Quercetin is a potential chemopreventive agent. However, this study reported that some gut bacteria can improve their function of inhibiting cancer cells after fermenting quercetin. 10.1039/c4fo00418c
    In vitro potential modulation of baicalin and baicalein on P-glycoprotein activity and expression in Caco-2 cells and rat gut sacs. Miao Qing,Wang Zhiyong,Zhang Yuanyuan,Miao Peipei,Zhao Yuanyuan,Zhang Yujie,Ma Shuangcheng Pharmaceutical biology Context Previous studies have shown that Scutellariae Radix, the dried root of Scutellaria baicalensis Georgi (Labiatae), has a certain inhibitory effect on P-glycoprotein (P-gp), but the effects of its main active constituents on P-gp are still ambiguous. Objectives In vitro studies were performed to investigate the effects of its main active constituents (baicalin and its aglycone, baicalein) on the activity and expression of P-gp in intestine using Caco-2 cells and rat gut sacs. Materials and methods In Caco-2 cell experiments, the effects of baicalin and baicalein on P-gp activity were investigated using a P-gp substrate, rhodamine 123 and non-substrate fluorescein Na, by determining their intracellular fluorescence accumulation, and their effects on P-gp expression were determined using flow cytometry. In addition, rat gut sac model was selected to investigate the effects of baicalin and baicalein on the transport of verapamil, a classical P-gp substrate. The gut sacs of male Sprague-Dawley rats were filled with 0.4 mL the test solution contained verapamil (0.2575 mg/mL) and the drugs [baicalin and baicalein, at concentrations of 1/8 IC50 (59.875, 41.5 μg/mL), 1/4 IC50 (119.75, 83 μg/mL) and 1/2 IC50 (239.5, 166 μg/mL)], and then incubated in Tyrode's solution for a period of time. After termination of the incubation, the incubated solution was processed for the subsequent detection. Results According to the results of MTT assay, the IC50 values of verapamil, baicalin and baicalein were 104, 479, 332 μg/mL, respectively. The obtained results from the two models were confirmed mutually. As a result, baicalin exhibited no obvious effect on intracellular accumulation of Rh-123, and almost had no effect on P-gp expression and verapamil transportation, while baicalein significantly increased intracellular accumulation of Rh-123 (p < 0.01), down-regulated P-gp expression (p < 0.01) and increased the transport of verapamil (p < 0.05). Discussion and conclusion The results indicated that baicalein may be a P-gp inhibitor, which presented obvious inhibitory effects on P-gp activity and expression level. A comparison of the structures of baicalin and baicalein indicates that the existence of glucosyl plays a decisive role in influencing the activity and expression of P-gp. 10.3109/13880209.2015.1107744
    Berberine and inflammatory bowel disease: A concise review. Habtemariam Solomon Pharmacological research Berberine is the principal component of many popular medicinal plants (e.g. the genus Berberis, Coptis and Hydrastis among others) with a history of thousands of years of usage in traditional medicine. The numerous pharmacological activities of berberine reported in the last two decades have been attracting high level interests both within the scientific community, clinicians and the public at large. Despite enormous amount of efforts have been placed to show its therapeutic value for inflammatory bowel diseases (IBD), however, comprehensive up-to-date review article in this field is not yet available. In this communication, literature data from in vitro and in vivo experiments were scrutinised and concisely presented to demonstrate its anti-IBD potential. Beyond the known general antioxidant and anti-inflammatory effects of berberine, IBD-specific effects including gut epithelial barrier pathology, T cells as emerging targets, antinociceptive and other effects are discussed. 10.1016/j.phrs.2016.09.041
    Mechanisms by which cocoa flavanols improve metabolic syndrome and related disorders. Strat Karen M,Rowley Thomas J,Smithson Andrew T,Tessem Jeffery S,Hulver Matthew W,Liu Dongmin,Davy Brenda M,Davy Kevin P,Neilson Andrew P The Journal of nutritional biochemistry Dietary administration of cocoa flavanols may be an effective complementary strategy for alleviation or prevention of metabolic syndrome, particularly glucose intolerance. The complex flavanol composition of cocoa provides the ability to interact with a variety of molecules, thus allowing numerous opportunities to ameliorate metabolic diseases. These interactions likely occur primarily in the gastrointestinal tract, where native cocoa flavanol concentration is high. Flavanols may antagonize digestive enzymes and glucose transporters, causing a reduction in glucose excursion, which helps patients with metabolic disorders maintain glucose homeostasis. Unabsorbed flavanols, and ones that undergo enterohepatic recycling, will proceed to the colon where they can exert prebiotic effects on the gut microbiota. Interactions with the gut microbiota may improve gut barrier function, resulting in attenuated endotoxin absorption. Cocoa may also positively influence insulin signaling, possibly by relieving insulin-signaling pathways from oxidative stress and inflammation and/or via a heightened incretin response. The purpose of this review is to explore the mechanisms that underlie these outcomes, critically review the current body of literature related to those mechanisms, explore the implications of these mechanisms for therapeutic utility, and identify emerging or needed areas of research that could advance our understanding of the mechanisms of action and therapeutic potential of cocoa flavanols. 10.1016/j.jnutbio.2015.12.008
    Phenolic Composition and Evaluation of the Antimicrobial Activity of Free and Bound Phenolic Fractions from a Peruvian Purple Corn (Zea mays L.) Accession. Gálvez Ranilla Lena,Christopher Ashish,Sarkar Dipayan,Shetty Kalidas,Chirinos Rosana,Campos David Journal of food science Beneficial effects on overall gut health by phenolic bioactives-rich foods are potentially due to their modulation of probiotic gut bacteria and antimicrobial activity against pathogenic bacteria. Based on this rationale, the effect of the free and bound phenolic fractions from a Peruvian purple corn accession AREQ-084 on probiotic lactic acid bacteria such as Lactobacillus helveticus and Bifidobacterium longum and the gastric cancer-related pathogen Helicobacter pylori was evaluated. The free and bound phenolic composition was also determined by ultra-performance liquid chromatography. Anthocyanins were the major phenolic compounds (310.04 mg cyanidin-3-glucoside equivalents/100 g dry weight, DW) in the free phenolic fraction along with hydroxycinnamic acids such as p-coumaric acid derivatives, followed by caffeic and ferulic acid derivatives. The bound phenolic form had only hydroxycinnamic acids such as ferulic acid, p-coumaric acid, and a ferulic acid derivative with ferulic acid being the major phenolic compound (156.30 mg/100 g DW). These phenolic compounds were compatible with beneficial probiotic lactic acid bacteria such as L. helveticus and B. longum as these bacteria were not inhibited by the free and bound phenolic fractions at 10 to 50 mg/mL and 10 mg/mL of sample doses, respectively. However, the pathogenic H. pylori was also not inhibited by both purple corn phenolic forms at same above sample doses. This study provides the preliminary base for the characterization of phenolic compounds of Peruvian purple corn biodiversity and its potential health benefits relevant to improving human gut health. PRACTICAL APPLICATION:This study provides insights that Peruvian purple corn accession AREQ-084 can be targeted as a potential source of health-relevant phenolic compounds such as anthocyanins along with hydroxycinnamic acids linked to its dietary fiber fraction. Additionally, these phenolic fractions did not affect the gut health associated beneficial bacteria nor the pathogenic H. pylori. Purple corn can be targeted for design of probiotic functional foods integrated with their anthocyanin linked-coloring properties. 10.1111/1750-3841.13973
    Ferulic acid may target MyD88-mediated pro-inflammatory signaling - Implications for the health protection afforded by whole grains, anthocyanins, and coffee. McCarty Mark F,Assanga Simon B Iloki Medical hypotheses Higher dietary intakes of anthocyanins have been linked epidemiologically to decreased risk for metabolic syndrome, type 2 diabetes and cardiovascular events; clinical trials and rodent studies evaluating ingestion of anthocyanin-rich extracts confirm favorable effects of these agents on endothelial function and metabolic syndrome. However, these benefits of anthocyanins are lost in rats whose gut microbiome has been eliminated with antibiotic treatment - pointing to bacterial metabolites of anthocyanins as the likely protective agents. A human pharmacokinetic assessment of orally administered cyanidin-3-O-glucoside, a prominent anthocyanin, has revealed that, whereas this compound is minimally absorbed, ferulic acid (FA) is one of its primary metabolites that appears in plasma. FA is a strong antioxidant and phase 2 inducer that has exerted marked anti-inflammatory effects in a number of rodent and cell culture studies; in particular, FA is highly protective in rodent models of diet-induced weight gain and metabolic syndrome. FA, a precursor for lignan synthesis, is widely distributed in plant-based whole foods, mostly in conjugated form; whole grains are a notable source. Coffee ingestion boosts plasma FA owing to gastrointestinal metabolism of chlorogenic acid. Hence, it is reasonable to suspect that FA mediates some of the broad health benefits that have been associated epidemiologically with frequent consumption of whole grains, anthocyanins, coffee, and unrefined plant-based foods. The molecular basis of the anti-inflammatory effects of FA may have been clarified by a recent study demonstrating that FA can target the adaptor protein MyD88; this plays an essential role in pro-inflammatory signaling by most toll-like receptors and interleukin-1β. If feasible oral intakes of FA can indeed down-regulate MyD88-dependent signaling, favorable effects of FA on neurodegeneration, hypothalamic inflammation, weight gain, adipocyte and beta cell function, adiponectin secretion, vascular health, and cartilage and bone integrity can be predicted. Since FA is well tolerated, safe, and natural, it may have great potential as a protective nutraceutical, and clinical trials evaluating its effects are needed. 10.1016/j.mehy.2018.06.032
    Improved Glucose Homeostasis in Obese Mice Treated With Resveratrol Is Associated With Alterations in the Gut Microbiome. Sung Miranda M,Kim Ty T,Denou Emmanuel,Soltys Carrie-Lynn M,Hamza Shereen M,Byrne Nikole J,Masson Grant,Park Heekuk,Wishart David S,Madsen Karen L,Schertzer Jonathan D,Dyck Jason R B Diabetes Oral administration of resveratrol is able to improve glucose homeostasis in obese individuals. Herein we show that resveratrol ingestion produces taxonomic and predicted functional changes in the gut microbiome of obese mice. In particular, changes in the gut microbiome were characterized by a decreased relative abundance of Turicibacteraceae, Moryella, Lachnospiraceae, and Akkermansia and an increased relative abundance of Bacteroides and Parabacteroides Moreover, fecal transplantation from healthy resveratrol-fed donor mice is sufficient to improve glucose homeostasis in obese mice, suggesting that the resveratrol-mediated changes in the gut microbiome may play an important role in the mechanism of action of resveratrol. 10.2337/db16-0680
    Anti-senescence compounds: A potential nutraceutical approach to healthy aging. Gurău Felicia,Baldoni Simone,Prattichizzo Francesco,Espinosa Emma,Amenta Francesco,Procopio Antonio Domenico,Albertini Maria Cristina,Bonafè Massimiliano,Olivieri Fabiola Ageing research reviews The desire of eternal youth seems to be as old as mankind. However, the increasing life expectancy experienced by populations in developed countries also involves a significantly increased incidence of the most common age-related diseases (ARDs). Senescent cells (SCs) have been identified as culprits of organismal aging. Their number rises with age and their senescence-associated secretory phenotype fuels the chronic, pro-inflammatory systemic state (inflammaging) that characterizes aging, impairing the regenerative ability of stem cells and increasing the risk of developing ARDs. A variegated class of molecules, including synthetic senolytic compounds and natural compounds contained in food, have been suggested to possess anti-senescence activity. Senolytics are attracting growing interest, and their safety and reliability as anti-senescence drugs are being assessed in human clinical trials. Notably, since SCs spread inflammation at the systemic level through pro-oxidant and pro-inflammatory signals, foods rich in polyphenols, which exert antioxidant and anti-inflammatory actions, have the potential to be harnessed as "anti-senescence foods" in a nutraceutical approach to healthier aging. We discuss the beneficial effects of polyphenol-rich foods in relation to the Mediterranean diet and the dietary habits of long-lived individuals, and examine their ability to modulate bacterial genera in the gut. 10.1016/j.arr.2018.05.001
    Green Tea Polyphenols Modify the Gut Microbiome in db/db Mice as Co-Abundance Groups Correlating with the Blood Glucose Lowering Effect. Chen Tingting,Liu Anna B,Sun Shili,Ajami Nadim J,Ross Matthew C,Wang Hong,Zhang Le,Reuhl Kenneth,Kobayashi Koichi,Onishi Janet C,Zhao Liping,Yang Chung S Molecular nutrition & food research SCOPE:The effects of green tea polyphenols, Polyphenon E (PPE), and black tea polyphenols, theaflavins (TFs), on gut microbiota and development of diabetes in db/db mice are investigated and compared. METHODS AND RESULTS:Supplementation of PPE (0.1%) in the diet of female db/db mice for 7 weeks decreases fasting blood glucose levels and mesenteric fat while increasing the serum level of insulin, possibly through protection against β-cell damage. However, TFs are less or not effective. Microbiome analysis through 16S rRNA gene sequencing shows that PPE and TFs treatments significantly alter the bacterial community structure in the cecum and colon, but not in the ileum. The key bacterial phylotypes responding to the treatments are then clustered into 11 co-abundance groups (CAGs). CAGs 6 and 7, significantly increased by PPE but not by TFs, are negatively associated with blood glucose levels. The operational taxonomic units in these CAGs are from two different phyla, Firmicutes and Bacteroidetes. CAG 10, decreased by PPE and TFs, is positively associated with blood glucose levels. CONCLUSION:Gut microbiota respond to tea polyphenol treatments as CAGs instead of taxa. Some of the CAGs associated with the blood glucose lowering effect are enriched by PPE, but not TFs. 10.1002/mnfr.201801064
    In vitro assessment of potential intestinal absorption of some phenolic families and carboxylic acids from commercial instant coffee samples. López-Froilán R,Ramírez-Moreno E,Podio N S,Pérez-Rodríguez M L,Cámara M,Baroni M V,Wunderlin D A,Sánchez-Mata M C Food & function Coffee is one of the most consumed beverages in the world, being a source of bioactive compounds as well as flavors. Hydroxycinnamic acids, flavonols, and carboxylic acids have been studied in the samples of instant coffee commercialized in Spain. The studies about contents of food components should be complemented with either in vitro or in vivo bioaccessibility studies to know the amount of food components effectively available for functions in the human body. In this sense, a widely used in vitro model has been applied to assess the potential intestinal absorption of phenolic compounds and organic acids. The contents of hydroxycinnamic acids and flavonols were higher in instant regular coffee samples than in the decaffeinated ones. Bioaccessible phenolic compounds in most analyzed samples account for 20-25% of hydroxycinnamic acids and 17-26% of flavonols. This could mean that a great part of them can remain in the gut, acting as potential in situ antioxidants. Quinic, acetic, pyroglutamic, citric and fumaric acids were identified in commercial instant coffee samples. Succinic acid was found in the coffee blend containing chicory. All carboxylic acids showed a very high bioaccessibility. Particularly, acetic acid and quinic acid were found in higher contents in the samples treated with the in vitro simulation of gastrointestinal processes, compared to the original ones, which can be explained by their cleavage from chlorogenic acid during digestion. This is considered as a positive effect, since quinic acid is considered as an antioxidant inducer. 10.1039/c6fo00315j
    Studies on Modulation of Gut Microbiota by Wine Polyphenols: From Isolated Cultures to Omic Approaches. Dueñas Montserrat,Cueva Carolina,Muñoz-González Irene,Jiménez-Girón Ana,Sánchez-Patán Fernando,Santos-Buelga Celestino,Moreno-Arribas M Victoria,Bartolomé Begoña Antioxidants (Basel, Switzerland) Moderate consumption of wine seems to produce positive health effects derived from the occurrence of bioactive polyphenols. The gut microbiota is involved in the metabolism of phenolic compounds, and these compounds and/or their metabolites may modulate gut microbiota through the stimulation of the growth of beneficial bacteria and the inhibition of pathogenic bacteria. The characterization of bacterial metabolites derived from polyphenols is essential in order to understand their effects, including microbial modulation, and therefore to associate dietary intake with particular health effects. This review aims to summarize the current information about the two-way "wine polyphenols-gut microbiota" interaction, from a perspective based on the experimental and analytical designs used. The availability of advanced methods for monitoring bacterial communities, along with the combination of in vitro and in vivo models, could help to assess the metabolism of polyphenols in the human body and to monitor total bacterial communities, and, therefore, to elucidate the implications of diet on the modulation of microbiota for delivering health benefits. 10.3390/antiox4010001
    Resveratrol modulates the gut microbiota to prevent murine colitis development through induction of Tregs and suppression of Th17 cells. Alrafas Haider Rasheed,Busbee Philip B,Nagarkatti Mitzi,Nagarkatti Prakash S Journal of leukocyte biology Inflammatory diseases of the gastrointestinal tract are often associated with microbial dysbiosis. Thus, dietary interactions with intestinal microbiota, to maintain homeostasis, play a crucial role in regulation of clinical disorders such as colitis. In the current study, we investigated if resveratrol, a polyphenol found in a variety of foods and beverages, would reverse microbial dysbiosis induced during colitis. Administration of resveratrol attenuated colonic inflammation and clinical symptoms in the murine model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis. Resveratrol treatment in mice with colitis led to an increase in CD4 FOXP3 and CD4 IL-10 T cells, and a decrease in CD4 IFN-γ and CD4 IL-17 T cells. 16S rRNA gene sequencing to investigate alterations in the gut microbiota revealed that TNBS caused significant dysbiosis, which was reversed following resveratrol treatment. Analysis of cecal flush revealed that TNBS administration led to an increase in species such as Bacteroides acidifaciens, but decrease in species such as Ruminococcus gnavus and Akkermansia mucinphilia, as well as a decrease in SCFA i-butyric acid. However, resveratrol treatment restored the gut bacteria back to homeostatic levels, and increased production of i-butyric acid. Fecal transfer experiments confirmed the protective role of resveratrol-induced microbiota against colitis inasmuch as such recipient mice were more resistant to TNBS-colitis and exhibited polarization toward CD4 FOXP3 T cells and decreases in CD4 IFN-γ and CD4 IL-17 T cells. Collectively, these data demonstrate that resveratrol-mediated attenuation of colitis results from reversal of microbial dysbiosis induced during colitis and such microbiota protect the host from colonic inflammation by inducing Tregs while suppressing inflammatory Th1/Th17 cells. 10.1002/JLB.3A1218-476RR
    Antioxidant and free radical scavenging activity of isoflavone metabolites. Rimbach G,De Pascual-Teresa S,Ewins B A,Matsugo S,Uchida Y,Minihane A M,Turner R,VafeiAdou K,Weinberg P D Xenobiotica; the fate of foreign compounds in biological systems 1. Soy isoflavones have been extensively studied because of their possible health-promoting effects. Genistein and daidzein, the major isoflavone aglycones, have received most attention; however, they undergo extensive metabolism in the gut and liver, which might affect their biological properties. 2. The antioxidant activity, free radical-scavenging properties and selected cellular effects of the isoflavone metabolites equol, 8-hydroxydaidzein, O-desmethylangiolensin, and 1,3,5 trihydroxybenzene were investigated in comparison with their parent aglycones, genistein and daidzein. 3. Electron spin resonance spectroscopy indicated that 8-hydroxydaidzein was the most potent scavenger of hydroxyl and superoxide anion radicals. Isoflavone metabolites also exhibited higher antioxidant activity than parent compounds in standard antioxidant (FRAP and TEAC) assays. However, for the suppression of nitric oxide production by activated macrophages, genistein showed the highest potency, followed by equol and daidzein. 4. The metabolism of isoflavones affects their free radical scavenging and antioxidant properties, and their cellular activity, but the effects are complex. 10.1080/0049825031000150444
    Different Flavonoids Can Shape Unique Gut Microbiota Profile In Vitro. Huang Jiacheng,Chen Long,Xue Bin,Liu Qianyue,Ou Shiyi,Wang Yong,Peng Xichun Journal of food science The impact of flavonoids has been discussed on the relative viability of bacterial groups in human microbiota. This study was aimed to compare the modulation of various flavonoids, including quercetin, catechin and puerarin, on gut microbiota culture in vitro, and analyze the interactions between bacterial species using fructo-oligosaccharide (FOS) as carbon source under the stress of flavonoids. Three plant flavonoids, quercetin, catechin, and puerarin, were added into multispecies culture to ferment for 24 h, respectively. The bacterial 16S rDNA amplicons were sequenced, and the composition of microbiota community was analyzed. The results revealed that the tested flavonoids, quercetin, catechin, and puerarin, presented different activities of regulating gut microbiota; flavonoid aglycones, but not glycosides, may inhibit growth of certain species. Quercetin and catechin shaped unique biological webs. Bifidobacterium spp. was the center of the biological web constructed in this study. 10.1111/1750-3841.13411
    Taurine and tea polyphenols combination ameliorate nonalcoholic steatohepatitis in rats. Zhu Wenhua,Chen Siwen,Chen Ronggui,Peng Zhiqing,Wan Jun,Wu Benyan BMC complementary and alternative medicine BACKGROUND:Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease, for which there is currently no safe and effective drug for therapy. In this study, we explored the effects of taurine, tea polyphenols (TPs), or a combination thereof, on NASH rats. METHODS:Rats were divided into a normal group, a high-fat diet induced model group and a treatment group (including taurine, TPs, or taurine + TPs treatment for 8 weeks). Twelve weeks later, all rats were sacrificed, and serum transaminase, lipid and lipopolysaccharide levels and hepatic oxidative stress levels were determined. Histological changes were evaluated. RESULTS:In NASH rats, hepatocyte damage, lipid disturbance, oxidative stress and elevated lipopolysaccharide levels were confirmed. Taurine treatment alleviated hepatocyte damage and oxidative stress. TPs treatment improved lipid metabolism and increased hepatic antioxidant activity. The therapeutic effects of taurine + TPs treatment on hepatocyte damage, lipid disturbance, and oxidative stress were superior to those of taurine and TPs treatment, respectively. Taurine, TPs and their combination all decreased serum lipopolysaccharide levels in NASH rats, but the combination of the compounds caused these levels to decrease more significantly than taurine or TPs treatment alone. CONCLUSION:Taurine combined with TPs treatment could relieve NASH by alleviating hepatocyte damage, decreasing oxidative stress and improving lipid metabolism and gut flora disturbance partly. Taurine and TPs combination may act as a new effective medicine for treating NASH patients. 10.1186/s12906-017-1961-3
    Gut Microbiota Dysbiosis in Obesity-Linked Metabolic Diseases and Prebiotic Potential of Polyphenol-Rich Extracts. Anhê Fernando F,Varin Thibault V,Le Barz Mélanie,Desjardins Yves,Levy Emile,Roy Denis,Marette André Current obesity reports Trillions of microorganisms inhabit the human body, strongly colonizing the gastro-intestinal tract and outnumbering our own cells. High-throughput sequencing techniques and new bioinformatic tools have enabled scientists to extend our knowledge on the relationship between the gut microbiota and host's physiology. Disruption of the ecological equilibrium in the gut (i.e., dysbiosis) has been associated with several pathological processes, including obesity and its related comorbidities, with diet being a strong determinant of gut microbial balance. In this review, we discuss the potential prebiotic effect of polyphenol-rich foods and extracts and how they can reshape the gut microbiota, emphasizing the novel role of the mucin-degrading bacterium Akkermansia muciniphila in their metabolic benefits. 10.1007/s13679-015-0172-9
    Dietary antioxidants protect gut epithelial cells from oxidant-induced apoptosis. Miller M J,Angeles F M,Reuter B K,Bobrowski P,Sandoval M BMC complementary and alternative medicine BACKGROUND:The potential of ascorbic acid and two botanical decoctions, green tea and cat's claw, to limit cell death in response to oxidants were evaluated in vitro. METHODS:Cultured human gastric epithelial cells (AGS) or murine small intestinal epithelial cells (IEC-18) were exposed to oxidants - DPPH (3 microM), H2O2 (50 microM), peroxynitrite (300 microM) - followed by incubation for 24 hours, with antioxidants (10 microg/ml) administered as a 1 hour pretreatment. Cell number (MTT assay) and death via apoptosis or necrosis (ELISA, LDH release) was determined. The direct interactions between antioxidants and DPPH (100 microM) or H2O2 (50 microM) were evaluated by spectroscopy. RESULTS:The decoctions did not interact with H2O2, but quenched DPPH although less effectively than vitamin C. In contrast, vitamin C was significantly less effective in protecting human gastric epithelial cells (AGS) from apoptosis induced by DPPH, peroxynitrite and H2O2 (P < 0.001). Green tea and cat's claw were equally protective against peroxynitrite and H2O2, but green tea was more effective than cat's claw in reducing DPPH-induced apoptosis (P < 0.01). Necrotic cell death was marginally evident at these low concentrations of peroxynitrite and H2O2, and was attenuated both by cat's claw and green tea (P < 0.01). In IEC-18 cells, all antioxidants were equally effective as anti-apoptotic agents. CONCLUSIONS:These results indicate that dietary antioxidants can limit epithelial cell death in response to oxidant stress. In the case of green tea and cat's claw, the cytoprotective response exceed their inherent ability to interact with the injurious oxidant, suggestive of actions on intracellular pathways regulating cell death. 10.1186/1472-6882-1-11
    Effects of resveratrol on gut microbiota and fat storage in a mouse model with high-fat-induced obesity. Qiao Yi,Sun Jin,Xia Shufang,Tang Xue,Shi Yonghui,Le Guowei Food & function Recent studies have investigated the anti-obesity effect of resveratrol, but the pathways through which resveratrol resists obesity are not clear. In the present study, we hypothesize that resveratrol exerts anti-obesity effects that are likely mediated by mechanisms of regulating gut microbes, and in turn, improving fat storage and metabolism. Gut microbes, glucose and lipid metabolism in high-fat diet (HF) mice in vivo are investigated after resveratrol treatment. Several biochemical markers are measured. Fluorescence in situ hybridization and flow cytometry are used to monitor and quantify the changes in gut microbiota. The key genes related to fat storage and metabolism in the liver and visceral adipose tissues are measured by real-time PCR. The results show that resveratrol (200 mg per kg per day) significantly lowers both body and visceral adipose weights, and reduces blood glucose and lipid levels in HF mice. Resveratrol improves the gut microbiota dysbiosis induced by the HF diet, including increasing the Bacteroidetes-to-Firmicutes ratios, significantly inhibiting the growth of Enterococcus faecalis, and increasing the growth of Lactobacillus and Bifidobacterium. Furthermore, resveratrol significantly increases the fasting-induced adipose factor (Fiaf, a key gene negatively regulated by intestinal microbes) expression in the intestine. Resveratrol significantly decreases mRNA expression of Lpl, Scd1, Ppar-γ, Acc1, and Fas related to fatty acids synthesis, adipogenesis and lipogenesis, which may be driven by increased Fiaf expression. The Pearson's correlation coefficient shows that there is a negative correlation between the body weight and the ratios of Bacteroidetes-to-Firmicutes. Therefore, resveratrol mediates the composition of gut microbes, and in turn, through the Fiaf signaling pathway, accelerates the development of obesity. 10.1039/c3fo60630a
    Rebelling against the (Insulin) Resistance: A Review of the Proposed Insulin-Sensitizing Actions of Soybeans, Chickpeas, and Their Bioactive Compounds. Clark Jaime L,Taylor Carla G,Zahradka Peter Nutrients Insulin resistance is a major risk factor for diseases such as type 2 diabetes and metabolic syndrome. Current methods for management of insulin resistance include pharmacological therapies and lifestyle modifications. Several clinical studies have shown that leguminous plants such as soybeans and pulses (dried beans, dried peas, chickpeas, lentils) are able to reduce insulin resistance and related type 2 diabetes parameters. However, to date, no one has summarized the evidence supporting a mechanism of action for soybeans and pulses that explains their ability to lower insulin resistance. While it is commonly assumed that the biological activities of soybeans and pulses are due to their antioxidant activities, these bioactive compounds may operate independent of their antioxidant properties and, thus, their ability to potentially improve insulin sensitivity via alternative mechanisms needs to be acknowledged. Based on published studies using in vivo and in vitro models representing insulin resistant states, the proposed mechanisms of action for insulin-sensitizing actions of soybeans, chickpeas, and their bioactive compounds include increasing glucose transporter-4 levels, inhibiting adipogenesis by down-regulating peroxisome proliferator-activated receptor-γ, reducing adiposity, positively affecting adipokines, and increasing short-chain fatty acid-producing bacteria in the gut. Therefore, this review will discuss the current evidence surrounding the proposed mechanisms of action for soybeans and certain pulses, and their bioactive compounds, to effectively reduce insulin resistance. 10.3390/nu10040434
    Long-Term Green Tea Supplementation Does Not Change the Human Gut Microbiota. Janssens Pilou L H R,Penders John,Hursel Rick,Budding Andries E,Savelkoul Paul H M,Westerterp-Plantenga Margriet S PloS one BACKGROUND:Green tea catechins may play a role in body weight regulation through interactions with the gut microbiota. AIM:We examined whether green tea supplementation for 12 weeks induces changes in composition of the human gut microbiota. METHODS:58 Caucasian men and women were included in a randomized, placebo-controlled design. For 12 weeks, subjects consumed either green tea (>0.56 g/d epigallocatechin-gallate + 0.28 ∼ 0.45 g/d caffeine) or placebo capsules. Fecal samples were collected twice (baseline, vs. week 12) for analyses of total bacterial profiles by means of IS-profiling, a 16S-23S interspacer region-based profiling method. RESULTS:No significant changes between baseline and week 12 in subjects receiving green tea or placebo capsules, and no significant interactions between treatment (green tea or placebo) and time (baseline and week 12) were observed for body composition. Analysis of the fecal samples in subjects receiving green tea and placebo showed similar bacterial diversity and community structures, indicating there were no significant changes in bacterial diversity between baseline and week 12 in subjects receiving green tea capsules or in subjects receiving placebo capsules. No significant interactions were observed between treatment (green tea or placebo) and time (baseline and week 12) for the gut microbial diversity. Although, there were no significant differences between normal weight and overweight subjects in response to green tea, we did observe a reduced bacterial alpha diversity in overweight as compared to normal weight subjects (p = 0.002). CONCLUSION:Green tea supplementation for 12 weeks did not have a significant effect on composition of the gut microbiota. TRIAL REGISTRATION:ClinicalTrials.gov NCT01556321. 10.1371/journal.pone.0153134
    Evolution of nitric oxide regulation of gut function. Yaguchi Junko,Yaguchi Shunsuke Proceedings of the National Academy of Sciences of the United States of America Although morphologies are diverse, the common pattern in bilaterians is for passage of food in the gut to be controlled by nerves and endodermally derived neuron-like cells. In vertebrates, nitric oxide (NO) derived from enteric nerves controls relaxation of the pyloric sphincter. Here, we show that in the larvae of sea urchins, there are endoderm-derived neuronal nitric oxide synthase (nNOS)-positive cells expressing pan-neural marker, Synaptotagmin-B (SynB), in sphincters and that NO regulates the relaxation of the pyloric sphincter. Our results indicate that NO-dependent pylorus regulation is a shared feature within the deuterostomes, and we speculate that it was a characteristic of stem deuterostomes. 10.1073/pnas.1816973116
    Effects of phytogenic feed additives on cellular oxidative stress and inflammatory reactions in intestinal porcine epithelial cells1. Kaschubek Theresa,Mayer Elisabeth,Rzesnik Sophia,Grenier Bertrand,Bachinger Diana,Schieder Carina,König Jürgen,Teichmann Klaus Journal of animal science Due to increasing concerns about the use of antibiotic growth promoters (AGP) in livestock production and their complete ban in the European Union in 2006, suitable alternatives are urgently needed. Among others, anti-inflammatory activities of AGP are discussed as their putative mode of action. As numerous phytochemicals are known to modulate the cellular antioxidant capacity and immune response, we studied the antioxidative and anti-inflammatory properties of a phytogenic (plant-derived) feed additive (PFA) in intestinal porcine epithelial cells (IPEC-J2). The effects of the PFA were compared with those of selected phytogenic ingredients (grape seed extract [GRS], licorice extract [LIC], menthol [MENT], methyl salicylate [MES], oak bark extract [OAK], oregano essential oil [ORE], and a plant powder mix [PLA]), and with the effects of the AGP tylosin (TYL). Oxidative or inflammatory stress was induced by stimulating IPEC-J2 with hydrogen peroxide (H2O2; 0.5 mM) or tumor necrosis factor alpha (TNF-α; 10 ng/mL), respectively. The antioxidative effects of feed additives were assessed with a reactive oxygen species (ROS)-sensitive probe and by measuring the expression of 6 antioxidative target genes via quantitative real-time PCR (RT-qPCR). Anti-inflammatory potential was analyzed using a nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) reporter gene assay. Moreover, the expression levels of 6 NF-κB target genes were measured using RT-qPCR analysis, and the release of IL-6 was analyzed via ELISA. Significant decreases in cellular ROS upon H2O2 treatment were observed for the PFA (P < 0.001), LIC (P < 0.001), ORE (P < 0.05), and GRS (P < 0.01). No significant changes in the expression of antioxidative genes were found. NF-κB activation upon TNF-α treatment was significantly inhibited by the PFA (P < 0.05) and by ORE (P < 0.001). Moreover, the PFA and ORE significantly reduced the gene expression of IL-6 (P < 0.001), IL-8 (P < 0.001), and C-C motif chemokine ligand 2 (CCL2; P < 0.05), as well as the release of IL-6 (P < 0.05). The other phytogenic compounds as well as the AGP TYL did not significantly affect any of the inflammatory parameters. In summary, we revealed the antioxidative properties of the PFA, LIC, ORE, and GRS, as well as anti-inflammatory properties of the PFA and ORE in IPEC-J2, providing a better understanding of the mode of action of this PFA under our experimental conditions. 10.1093/jas/sky263
    Plantago maxima leaves extract inhibits adipogenic action of a high-fat diet in female Wistar rats. Tinkov Alexey A,Nemereshina Olga N,Popova Elizaveta V,Polyakova Valentina S,Gritsenko Viktor A,Nikonorov Alexandr A European journal of nutrition PURPOSE:The primary objective of this study is to investigate the content of biologically active compounds producing an antioxidant effect in Plantago maxima and their influence on main mechanisms of dietary obesity development. METHODS:Biologically active compounds in P. maxima were tested using paper chromatography. In in vivo experiment, high-fat-fed Wistar rats obtained P. maxima water extract for 3 months. Morphometric parameters, weight gain, serum adipokines, and cytokines, as well as oxidative stress biomarkers in rats’ tissues were evaluated. Gut microflora was also examined. RESULTS:Plantago maxima leaves used in the experiment contained significant amount of flavonoids, iridoids, phenol carboxylic acids, and tannins and ascorbic acid. Our in vivo experiment data demonstrate that P. maxima water extract prevents excessive adiposity in a diet-induced model. P. maxima consumption reduced serum leptin (twofold), macrophage chemoattractant protein-1 (sevenfold), tumornecrosis factor-α (25%), and interleukine-6 (26%) levels. P. maxima water extract decreased adipose tissue oxidative stress biomarkers in rats fed a high-fat diet. In addition, increased bacterial growth in the diet-induced obesity model was reversed by the P. maxima extract treatment. CONCLUSION:Plantago maxima water extract possessed antiadipogenic, antidiabetic, antiinflammatory, antioxidant activity, and normalized gut microflora in a rat model of diet-induced excessive adiposity due to a high content of biologically active compounds. 10.1007/s00394-013-0587-6
    Neuroprotection of Resveratrol Against Focal Cerebral Ischemia/Reperfusion Injury in Mice Through a Mechanism Targeting Gut-Brain Axis. Dou Zhongci,Rong Xiongfei,Zhao Erxian,Zhang Lixia,Lv Yunqi Cellular and molecular neurobiology Increasing evidences have shown that resveratrol could protect the brain from ischemic injury; the mechanisms underlying its neuroprotective effects are multifactorial and not fully understood. It remains unclear whether resveratrol could exert neuroprotection through modulating gut-brain axis, which plays important roles in stroke pathology. In this study, C57BL/6 mice underwent middle cerebral artery occlusion (60 min) followed by reperfusion for 3 days. Resveratrol, when applied immediately after MCAO onset for 3 days, promoted Th1/Th2 balance towards Th2 polarization and skewed Treg/Th17 balance towards Treg in the small intestinal lamina propria (SI-LP), and decreased small intestinal pro-inflammatory cytokines expression through modulating intestinal flora at 3 days post-ischemia (dpi). Resveratrol attenuated cerebral ischemia-induced increase in the epithelial and vascular permeability of small intestine as evidenced by reduced evans blue extravasasion and decreased protein leakage by feces/plasma albumin ratio at 3 dpi. The blood levels of pro-inflammatory cytokines at 3 dpi were also attenuated by resveratrol due to inhibiting intestinal pro-inflammatory immunity and decreasing epithelial and vascular permeability. Resveratrol robustly protected against post-stroke inflammation-induced blood-brain barrier disruption not only in the cortex but also in the striatum at 3 dpi. Furthermore, resveratrol mediated smaller cerebral infarcts and less neurological deficits via decreasing the levels of pro-inflammatory cytokines in the peri-infarct area at 3 dpi. Our results for the first time demonstrated that resveratrol may inhibit systemic post-stroke inflammation and neuroinflammation via modulating intestinal flora-mediated Th17/Tregs and Th1/Th2 polarity shift in SI-LP, which may be one of the mechanisms underlying the neuroprotective effects of resveratrol. 10.1007/s10571-019-00687-3
    Melatonin: Pharmacology, Functions and Therapeutic Benefits. Tordjman Sylvie,Chokron Sylvie,Delorme Richard,Charrier Annaëlle,Bellissant Eric,Jaafari Nemat,Fougerou Claire Current neuropharmacology BACKGROUND:Melatonin synchronizes central but also peripheral oscillators (fetal adrenal gland, pancreas, liver, kidney, heart, lung, fat, gut, etc.), allowing temporal organization of biological functions through circadian rhythms (24-hour cycles) in relation to periodic environmental changes and therefore adaptation of the individual to his/her internal and external environment. Measures of melatonin are considered the best peripheral indices of human circadian timing based on an internal 24-hour clock. METHODS:First, the pharmacology of melatonin (biosynthesis and circadian rhythms, pharmacokinetics and mechanisms of action) is described, allowing a better understanding of the short and long term effects of melatonin following its immediate or prolonged release. Then, research related to the physiological effects of melatonin is reviewed. RESULTS:The physiological effects of melatonin are various and include detoxification of free radicals and antioxidant actions, bone formation and protection, reproduction, and cardiovascular, immune or body mass regulation. Also, protective and therapeutic effects of melatonin are reported, especially with regard to brain or gastrointestinal protection, psychiatric disorders, cardiovascular diseases and oncostatic effects. CONCLUSION:This review highlights the high number and diversity of major melatonin effects and opens important perspectives for measuring melatonin as a biomarker (biomarker of early identification of certain disorders and also biomarker of their follow-up) and using melatonin with clinical preventive and therapeutic applications in newborns, children and adults based on its physiological regulatory effects. 10.2174/1570159X14666161228122115
    Biological significance of urolithins, the gut microbial ellagic Acid-derived metabolites: the evidence so far. Espín Juan Carlos,Larrosa Mar,García-Conesa María Teresa,Tomás-Barberán Francisco Evidence-based complementary and alternative medicine : eCAM The health benefits attributed to pomegranate have been associated with its high content in polyphenols, particularly ellagitannins. This is also the case for other ellagitannin-containing fruits and nuts including strawberry, raspberry, blackberry, walnuts, and muscadine grapes. The bioavailability of ellagitannins and ellagic acid is however very low. These molecules suffer extensive metabolism by the gut microbiota to produce urolithins that are much better absorbed. Urolithins circulate in plasma as glucuronide and sulfate conjugates at concentrations in the range of 0.2-20  μ M. It is therefore conceivable that the health effects of ellagitannin-containing products can be associated with these gut-produced urolithins, and thus the evaluation of the biological effects of these metabolites is essential. Recent research, mostly based on in vitro testing, has shown preliminary evidence of the anti-inflammatory, anticarcinogenic, antiglycative, antioxidant, and antimicrobial effects of urolithins, supporting their potential contribution to the health effects attributed to pomegranate and ellagitannin-rich foods. The number of in vivo studies is still limited, but they show preventive effects of urolithins on gut and systemic inflammation that encourage further research. Both in vivo and mechanistic studies are necessary to clarify the health effects of these metabolites. Attention should be paid when designing these mechanistic studies in order to use the physiologically relevant metabolites (urolithins in gut models and their conjugated derivatives in systemic models) at concentrations that can be reached in vivo. 10.1155/2013/270418
    Dietary Tomato Powder Inhibits High-Fat Diet-Promoted Hepatocellular Carcinoma with Alteration of Gut Microbiota in Mice Lacking Carotenoid Cleavage Enzymes. Xia Hui,Liu Chun,Li Cheng-Chung,Fu Maobin,Takahashi Shingo,Hu Kang-Quan,Aizawa Koichi,Hiroyuki Suganuma,Wu Guojun,Zhao Liping,Wang Xiang-Dong Cancer prevention research (Philadelphia, Pa.) Both incidence and death rate due to liver cancer have increased in the United States. Higher consumption of lycopene-rich tomato and tomato products is associated with a decreased risk of cancers. β-Carotene-15, 15'-oxygenase (BCO1), and β-carotene-9', 10'-oxygenase (BCO2) cleave lycopene to produce bioactive apo-lycopenoids. Although BCO1/BCO2 polymorphisms affect human and animal lycopene levels, whether dietary tomato consumption can inhibit high-fat diet (HFD)-promoted hepatocellular carcinoma (HCC) development and affect gut microbiota in the absence of BCO1/BCO2 is unclear. BCO1/BCO2 double knockout mice were initiated with a hepatic carcinogen (diethylnitrosamine) at 2 weeks of age. At 6 weeks of age, the mice were randomly assigned to an HFD (60% of energy as fat) with or without tomato powder (TP) feeding for 24 weeks. Results showed that TP feeding significantly decreased HCC development (67%, 83%, and 95% reduction in incidence, multiplicity, and tumor volume, respectively, < 0.05). Protective effects of TP feeding were associated with (1) decreased hepatic inflammatory foci development and mRNA expression of proinflammatory biomarkers (IL1β, IL6, IL12α, monocyte chemoattractant protein-1, and inducible NO synthase); (2) increased mRNA expression of deacetylase sirtuin 1 and nicotinamide phosphoribosyltransferase involving NAD production; and (3) increased hepatic circadian clock genes (circadian locomotor output cycles kaput, period 2, and cryptochrome-2, Wee1). Furthermore, TP feeding increased gut microbial richness and diversity, and significantly decreased the relative abundance of the genus and , respectively. The present study demonstrates that dietary tomato feeding independent of carotenoid cleavage enzymes prevents HFD-induced inflammation with potential modulating gut microbiota and inhibits HFD-promoted HCC development. 10.1158/1940-6207.CAPR-18-0188
    Bioactivity of Polyphenols: Preventive and Adjuvant Strategies toward Reducing Inflammatory Bowel Diseases-Promises, Perspectives, and Pitfalls. Kaulmann Anouk,Bohn Torsten Oxidative medicine and cellular longevity Inflammatory bowel diseases (IBDs) are characterized by autoimmune and inflammation-related complications of the large intestine (ulcerative colitis) and additional parts of the digestive tract (Crohn's disease). Complications include pain, diarrhoea, chronic inflammation, and cancer. IBD prevalence has increased during the past decades, especially in Westernized countries, being as high as 1%. As prognosis is poor and medication often ineffective or causing side effects, additional preventive/adjuvant strategies are sought. A possible approach is via diets rich in protective constituents. Polyphenols, the most abundant phytochemicals, have been associated with anti-inflammatory, antioxidant, immunomodulatory, and apoptotic properties. Locally reducing oxidative stress, they can further act on cellular targets, altering gene expression related to inflammation, including NF-κB, Nrf-2, Jak/STAT, and MAPKs, suppressing downstream cytokine formation (e.g., IL-8, IL-1β, and TNF-α), and boosting the bodies' own antioxidant status (HO-1, SOD, and GPx). Moreover, they may promote, as prebiotics, healthy microbiota (e.g., Bifidobacteria, Akkermansia), short-chain fatty acid formation, and reduced gut permeability/improved tight junction stability. However, potential adverse effects such as acting as prooxidants, or perturbations of efflux transporters and phase I/II metabolizing enzymes, with increased uptake of undesired xenobiotics, should also be considered. In this review, we summarize current knowledge around preventive and arbitrary actions of polyphenols targeting IBD. 10.1155/2016/9346470
    Recent advances of resveratrol in nanostructured based delivery systems and in the management of HIV/AIDS. Singh Gurinder,Pai Roopa S Journal of controlled release : official journal of the Controlled Release Society Resveratrol, a natural polyphenolic compound present in trees, in peanuts, in grapevines and exhibited multiple pharmacological activities. Extensive research in last two decades suggested that resveratrol possesses anti-inflammatory, anti-cancer, anti-viral, anti-amyloid, anti-arthritic and antioxidant properties. Some clinical reports have proposed that resveratrol might be a potential candidate for the prevention and/or treatment of HIV/AIDS and synergistically enhances the anti-HIV-1 activity. Resveratrol is not toxic to cells, and by itself reduces viral replication by 20% to 30%. With almost 12% of the world population suffering from HIV/AIDS including its resurgence in the developed world, better management of this global threat is highly desired. Further, various studies demonstrated several issues associated with resveratrol which account for its poor systemic bioavailability (almost zero) due to rapid and extensive first pass metabolism and existence of enterohepatic recirculation. In order to improve bioavailability and cellular uptake of resveratrol, various strategies have been adopted to date which includes resveratrol prodrug and the development of nanostructured delivery systems. Besides, nanostructured delivery systems are also known to inhibit the P-glycoprotein (P-gp) efflux, reduced metabolism by gut cytochrome P-450 enzymes, and circumnavigate the hepatic first-pass effect, facilitating absorption of drugs via intestinal lymphatic pathways. This review paper provides an updated bird's-eye view account on the publications and patents study on the recent novel approaches to deliver resveratrol in order to enhance oral bioavailability, overcome first pass metabolism and trounce enterohepatic recirculation to make resveratrol a therapeutically potent drug. Providing a relatively pithy overview, this paper thus presents recent advances of resveratrol for the treatment and prevention of HIV/AIDS. 10.1016/j.jconrel.2014.09.002
    Phytoestrogen Metabolism by Adult Human Gut Microbiota. Gaya Pilar,Medina Margarita,Sánchez-Jiménez Abel,Landete José Mᵃ Molecules (Basel, Switzerland) Phytoestrogens are plant-derived polyphenols with a structure similar to human estrogens. The three main groups of phytoestrogens, isoflavones, ellagitannins, and lignans, are transformed into equol, urolithins, and enterolignans, respectively, by bacteria. These metabolites have more estrogenic/antiestrogenic and antioxidant activities than their precursors, and they are more bioavailable. The aim of this study was to analyze the metabolism of isoflavones, lignans and ellagitannins by gut microbiota, and to study the possible correlation in the metabolism of these three groups of phytoestrogens. In vitro fermentation experiments were performed with feces samples from 14 healthy adult volunteers, and metabolite formation was measured by HPLC-PAD and HPLC-ESI/MS. Only the microbiota of one subject produced equol, while most of them showed production of O-desmethylangolensin (O-DMA). Significant inter-subject differences were observed in the metabolism of dihydrodaidzein and dihydrogenistein, while the glucoside isoflavones and their aglycones showed less variability, except for glycitin. Most subjects produced urolithins M-5 and E. Urolithin D was not detected, while uroltithin B was found in half of the individuals analyzed, and urolithins A and C were detected in two and four subjects, respectively. Enterolactone was found in all subjects, while enterodiol only appeared in five. Isoflavone metabolism could be correlated with the metabolism of lignans and ellagitannins. However, the metabolism of ellagitannins and lignans could not be correlated. This the first study where the metabolism of the three groups together of phytoestrogen, isoflavones, lignans, and ellagitannins by gut microbiota is analyzed. 10.3390/molecules21081034
    Green tea polyphenol extract attenuates ischemia/reperfusion injury of the gut. Muià Carmelo,Mazzon Emanuela,Di Paola Rosanna,Genovese Tiziana,Menegazzi Marta,Caputi Achille P,Suzuki Hisanori,Cuzzocrea Salvatore Naunyn-Schmiedeberg's archives of pharmacology Various studies have clearly demonstrated that green tea catechins possess potent antioxidative properties, and the preventive effects against various oxidative diseases have been reported. The aim of this study was to investigate the effect of green tea extract on the tissue injury caused by ischemia/reperfusion (I/R) of the gut. I/R injury of the intestine was caused by clamping both the superior mesenteric artery and the celiac trunk for 45 min followed by release of the clamp allowing reperfusion for 1 h or 4 h. This procedure results in splanchnic artery occlusion (SAO) shock. Rats subjected to SAO developed a significant fall in mean arterial blood pressure, and only 10% of the animals survived for the entire 4-h reperfusion period. Surviving animals were sacrificed for histological examination and biochemical studies. Rats subjected to SAO displayed a significant increase in tissue myeloperoxidase (MPO) activity and malondialdehyde (MDA) levels, significant increases in plasma tumor necrosis factor (TNF)-alpha levels and marked injury to the distal ileum. Increased immunoreactivity to nitrotyrosine was observed in the ileum of rats subjected to SAO. Staining of sections of the ileum obtained from SAO rats with anti-intercellular adhesion molecule (ICAM-1) antibody and with anti-P-selectin antibody resulted in diffuse staining. Administration of green tea extract (20 and 10 mg kg(-1) i.v.) 15 min prior to the onset of gut reperfusion significantly reduced in a dose-dependent manner the fall in mean arterial blood pressure, the mortality rate, infiltration of the reperfused intestine with polymorphonuclear neutrophils (MPO activity), lipid peroxidation (MDA levels), production of TNF-alpha, and histological evidence of gut injury. Administration of green tea extract also markedly reduced nitrotyrosine formation and the up-regulation of ICAM-1 and P-selectin during reperfusion. In order to clarify that green tea extract might be useful in the therapy of I/R injury, we also investigated the effect of green tea extract (20 mg kg(-1) i.v.) when administered 5 min after the onset of gut reperfusion. Similar to the pretreatment approach, the post-treatment also significantly reduced the gut injury induced by I/R. These results demonstrate that green tea extract significantly reduces I/R injury of the intestine. 10.1007/s00210-005-1076-0
    Preventive Efficiency of Green Tea and Its Components on Nonalcoholic Fatty Liver Disease. Zhou Jie,Ho Chi-Tang,Long Piaopiao,Meng Qilu,Zhang Liang,Wan Xiaochun Journal of agricultural and food chemistry Nonalcoholic fatty liver disease (NAFLD) is a typical chronic liver disease highly correlated with metabolic syndrome. Growing prevalence of NAFLD is supposed to be linked with the unhealthy lifestyle, especially high-calorie diet and lacking enough exercise. Currently, there is no validated pharmacological therapy for NAFLD except for weight reduction. However, many dietary strategies had preventive effects on the development of liver steatosis or its progression. As one of the most common beverages, green tea contains abundant bioactive compounds possessing antioxidant, lipid-lowering, and anti-inflammatory effects, as well as improving insulin resistance and gut dysbiosis that can alleviate the risk of NAFLD. Hence, in this review, we summarized the studies of green tea and its components on NAFLD from animal experiments and human interventions and discussed the potential mechanisms. Available evidence suggested that tea consumption is promising to prevent NAFLD, and further mechanisms and clinical studies need to be investigated. 10.1021/acs.jafc.8b05032
    Targeting mitochondria-derived reactive oxygen species to reduce epithelial barrier dysfunction and colitis. Wang Arthur,Keita Åsa V,Phan Van,McKay Catherine M,Schoultz Ida,Lee Joshua,Murphy Michael P,Fernando Maria,Ronaghan Natalie,Balce Dale,Yates Robin,Dicay Michael,Beck Paul L,MacNaughton Wallace K,Söderholm Johan D,McKay Derek M The American journal of pathology Epithelial permeability is often increased in inflammatory bowel diseases. We hypothesized that perturbed mitochondrial function would cause barrier dysfunction and hence epithelial mitochondria could be targeted to treat intestinal inflammation. Mitochondrial dysfunction was induced in human colon-derived epithelial cell lines or colonic biopsy specimens using dinitrophenol, and barrier function was assessed by transepithelial flux of Escherichia coli with or without mitochondria-targeted antioxidant (MTA) cotreatment. The impact of mitochondria-targeted antioxidants on gut permeability and dextran sodium sulfate (DSS)-induced colitis in mice was tested. Mitochondrial superoxide evoked by dinitrophenol elicited significant internalization and translocation of E. coli across epithelia and control colonic biopsy specimens, which was more striking in Crohn's disease biopsy specimens; the mitochondria-targeted antioxidant, MitoTEMPO, inhibited these barrier defects. Increased gut permeability and reduced epithelial mitochondrial voltage-dependent anion channel expression were observed 3 days after DSS. These changes and the severity of DSS-colitis were reduced by MitoTEMPO treatment. In vitro DSS-stimulated IL-8 production by epithelia was reduced by MitoTEMPO. Metabolic stress evokes significant penetration of commensal bacteria across the epithelium, which is mediated by mitochondria-derived superoxide acting as a signaling, not a cytotoxic, molecule. MitoTEMPO inhibited this barrier dysfunction and suppressed colitis in DSS-colitis, likely via enhancing barrier function and inhibiting proinflammatory cytokine production. These novel findings support consideration of MTAs in the maintenance of epithelial barrier function and the management of inflammatory bowel diseases. 10.1016/j.ajpath.2014.05.019
    Sulfation of genistein alters its antioxidant properties and its effect on platelet aggregation and monocyte and endothelial function. Rimbach Gerald,Weinberg Peter D,de Pascual-Teresa Sonia,Alonso Maria Garcia,Ewins Ben A,Turner Rufus,Minihane Anne Marie,Botting Nigel,Fairley Brian,Matsugo Seiichi,Uchida Yuzo,Cassidy Aedin Biochimica et biophysica acta Soy isoflavones have been extensively studied because of their possible benefits to human health. Genistein, the major isoflavone aglycone, has received most attention; however, it undergoes extensive metabolism (e.g. conjugation with sulfuric acid) in the gut and liver, which may affect its biological properties. This study investigated the antioxidant activity and free radical-scavenging properties of genistein, genistein-4'-sulfate and genistein-4'-7-disulfate as well as their effect on platelet aggregation and monocyte and endothelial function. Electron spin resonance spectroscopy (ESR) and spin trapping data and other standard antioxidant assays indicated that genistein is a relatively weak antioxidant compared to quercetin and that its sulfated metabolites are even less effective. Furthermore, genistein-4'-sulfate was less potent than genistein, and genistein-4'-7-disulfate even less potent, at inhibiting collagen-induced platelet aggregation, nitric oxide (NO) production by macrophages, and secretion by primary human endothelial cells of monocyte chemoattractant protein 1 (MCP-1), intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1). The current data suggest that sulfation of genistein, with the associated loss of hydroxyl groups, decreases its antioxidant activity and its effect on platelet aggregation, inflammation, cell adhesion and chemotaxis. 10.1016/j.bbagen.2003.12.008
    Metabolic Syndrome as a Multifaceted Risk Factor for Oxidative Stress. Spahis Schohraya,Borys Jean-Michel,Levy Emile Antioxidants & redox signaling SIGNIFICANCE:Metabolic syndrome (MetS) is associated with a greater risk of diabetes and cardiovascular diseases. It is estimated that this multifactorial condition affects 20%-30% of the world's population. A detailed understanding of MetS mechanisms is crucial for the development of effective prevention strategies and adequate intervention tools that could curb its increasing prevalence and limit its comorbidities, particularly in younger age groups. With advances in basic redox biology, oxidative stress (OxS) involvement in the complex pathophysiology of MetS has become widely accepted. Nevertheless, its clear association with and causative effects on MetS require further elucidation. Recent Advances: Although a better understanding of the causes, risks, and effects of MetS is essential, studies suggest that oxidant/antioxidant imbalance is a key contributor to this condition. OxS is now understood to be a major underlying mechanism for mitochondrial dysfunction, ectopic lipid accumulation, and gut microbiota impairment. CRITICAL ISSUES:Further studies, particularly in the field of translational research, are clearly required to understand and control the production of reactive oxygen species (ROS) levels, especially in the mitochondria, since the various therapeutic trials conducted to date have not targeted this major ROS-generating system, aimed to delay MetS onset, or prevent its progression. FUTURE DIRECTIONS:Multiple relevant markers need to be identified to clarify the role of ROS in the etiology of MetS. Future clinical trials should provide important proof of concept for the effectiveness of antioxidants as useful therapeutic approaches to simultaneously counteract mitochondrial OxS, alleviate MetS symptoms, and prevent complications. Antioxid. Redox Signal. 26, 445-461. 10.1089/ars.2016.6756
    Gut Microbiota in a Rat Oral Sensitization Model: Effect of a Cocoa-Enriched Diet. Camps-Bossacoma Mariona,Pérez-Cano Francisco J,Franch Àngels,Castell Margarida Oxidative medicine and cellular longevity Increasing evidence is emerging suggesting a relation between dietary compounds, microbiota, and the susceptibility to allergic diseases, particularly food allergy. Cocoa, a source of antioxidant polyphenols, has shown effects on gut microbiota and the ability to promote tolerance in an oral sensitization model. Taking these facts into consideration, the aim of the present study was to establish the influence of an oral sensitization model, both alone and together with a cocoa-enriched diet, on gut microbiota. Lewis rats were orally sensitized and fed with either a standard or 10% cocoa diet. Faecal microbiota was analysed through metagenomics study. Intestinal IgA concentration was also determined. Oral sensitization produced few changes in intestinal microbiota, but in those rats fed a cocoa diet significant modifications appeared. Decreased bacteria from the Firmicutes and Proteobacteria phyla and a higher percentage of bacteria belonging to the Tenericutes and Cyanobacteria phyla were observed. In conclusion, a cocoa diet is able to modify the microbiota bacterial pattern in orally sensitized animals. As cocoa inhibits the synthesis of specific antibodies and also intestinal IgA, those changes in microbiota pattern, particularly those of the Proteobacteria phylum, might be partially responsible for the tolerogenic effect of cocoa. 10.1155/2017/7417505
    Dietary flavonoids from modified apple reduce inflammation markers and modulate gut microbiota in mice. Espley Richard V,Butts Christine A,Laing William A,Martell Sheridan,Smith Hannah,McGhie Tony K,Zhang Jingli,Paturi Gunaranjan,Hedderley Duncan,Bovy Arnaud,Schouten Henk J,Putterill Joanna,Allan Andrew C,Hellens Roger P The Journal of nutrition Apples are rich in polyphenols, which provide antioxidant properties, mediation of cellular processes such as inflammation, and modulation of gut microbiota. In this study we compared genetically engineered apples with increased flavonoids [myeloblastis transcription factor 10 (MYB10)] with nontransformed apples from the same genotype, "Royal Gala" (RG), and a control diet with no apple. Compared with the RG diet, the MYB10 diet contained elevated concentrations of the flavonoid subclasses anthocyanins, flavanol monomers (epicatechin) and oligomers (procyanidin B2), and flavonols (quercetin glycosides), but other plant secondary metabolites were largely unaltered. We used these apples to investigate the effects of dietary flavonoids on inflammation and gut microbiota in 2 mouse feeding trials. In trial 1, male mice were fed a control diet or diets supplemented with 20% MYB10 apple flesh and peel (MYB-FP) or RG apple flesh and peel (RG-FP) for 7 d. In trial 2, male mice were fed MYB-FP or RG-FP diets or diets supplemented with 20% MYB10 apple flesh or RG apple flesh for 7 or 21 d. In trial 1, the transcription levels of inflammation-linked genes in mice showed decreases of >2-fold for interleukin-2 receptor (Il2rb), chemokine receptor 2 (Ccr2), chemokine ligand 10 (Cxcl10), and chemokine receptor 10 (Ccr10) at 7 d for the MYB-FP diet compared with the RG-FP diet (P < 0.05). In trial 2, the inflammation marker prostaglandin E(2) (PGE(2)) in the plasma of mice fed the MYB-FP diet at 21 d was reduced by 10-fold (P < 0.01) compared with the RG-FP diet. In colonic microbiota, the number of total bacteria for mice fed the MYB-FP diet was 6% higher than for mice fed the control diet at 21 d (P = 0.01). In summary, high-flavonoid apple was associated with decreases in some inflammation markers and changes in gut microbiota when fed to healthy mice. 10.3945/jn.113.182659
    QUERCETIN SUPPLEMENTATION PREVENTS CHANGES IN THE SEROTONIN AND CASPASE-3 IMMUNOREACTIVE CELLS OF THE JEJUNUM OF DIABETIC RATS. Martins-Perles Juliana Vanessa Colombo,Zignani Isabela,Souza Sara Raquel Garcia de,Frez Flávia Cristina Vieira,Bossolani Gleison Daion Piovezana,Zanoni Jacqueline Nelisis Arquivos de gastroenterologia BACKGROUND:Serotonin (5-HT) is present in the epithelial enterochromaffin cells (EC), mast cells of the lamina propria and enteric neurons. The 5-HT is involved in regulating motility, secretion, gut sensation, immune system and inflammation. OBJECTIVE:Evaluate the effects of diabetes and quercetin supplementation on serotoninergic cells and its cell loss by apoptosis in jejunal mucosa of streptozotocin-induced diabetic rats (STZ-rats). METHODS:Twenty-four male Wistar rats were divided into four groups: normoglycemic (C), normoglycemic supplemented with 40 mg/day quercetin (Q), diabetic (D) and diabetic supplemented with 40 mg/day quercetin (DQ). After 120 days, the jejunum was collected and fixated in Zamboni's solution for 18 h. After obtaining cryosections, immunohistochemistry was performed to label 5-HT and caspase-3. Quantification of 5-HT and caspase-3 immunoreactive (IR) cells in the lamina propria, villi and crypts were performed. RESULTS:The diabetic condition displayed an increase of the number of 5-HT-IR cells in villi and crypts, while decreased number of these cells was observed in lamina propria in the jejunum of STZ-rats. In the diabetic animals, an increased density of apoptotic cells in epithelial villi and crypts of the jejunum was observed, whereas a decreased number of caspase-3-IR cells was observed in lamina propria. Possibly, quercetin supplementation slightly suppressed the apoptosis phenomena in the epithelial villi and crypts of the STZ-rats, however the opposite effect was observed on the 5-HT-IR cells of the lamina propria. Quercetin supplementation on healthy animals promoted few changes of serotoninergic function and apoptotic stimuli. CONCLUSION:These results suggest that quercetin supplementation mostly improved the serotonergic function affected by diabetes maybe due to antioxidant and anti-inflammatory properties of quercetin. 10.1590/S0004-2803.201900000-81
    The protective effect of procyanidin against LPS-induced acute gut injury by the regulations of oxidative state. Wu Qiu Jue,Wang Yu Qin,Qi Yan Xia SpringerPlus BACKGROUND:A 2 × 4 factorial arrangement of treatments was used to investigate the protective effect of procyanidin (PCA) against lipopolysaccharide (LPS)-induced acute gut injury by the regulations of oxidative state for a 21-days feeding trial. METHODS:A total of 384 1-days-old broiler chicks were assigned to 8 treatments with 8 replicate of 6 broiler chickens per pen. Broiler chickens fed diets based on 4 levels of dietary PCA (0, 0.05, 0.075 and 0.1 % of the requirements). Half of the birds from each treatment group were challenged with 0.9 % NaCl solution or LPS (250 μg/kg body weight, injection administered) at 16, 18 and 21 days of age. RESULTS:The results indicated that, prior to LPS challenge, there was no dietary effect on bird growth performance (P > 0.05). The injection of LPS were also not associated with any significant changes in poultry performance (P > 0.05). But LPS injection increased serum diamine oxidase (DAO) level and the malondialdehyde (MDA) content of intestinal mucosa (P < 0.05), cause adverse effects to the morphology of the small intestine (P < 0.05), decreased the glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activity of intestinal mucosa (P < 0.05). When LPS-challenged birds were pretreated with PCA, serum DAO concentration and MDA activity in jejunal and ileal mucosa were dramatically attenuated, and improved the morphology of the small intestine as well (P < 0.05). CONCLUSION:In conclusion, PCA is able to prevent LPS-induced oxidative stress response in vivo, improved the morphology of the small intestine. The beneficial effect of PCA may depend on increasing the activity of body's antioxidant enzymes and scavenging free radical activity. 10.1186/s40064-016-3306-y
    Resveratrol, Metabolic Syndrome, and Gut Microbiota. Chaplin Alice,Carpéné Christian,Mercader Josep Nutrients Resveratrol is a polyphenol which has been shown to have beneficial effects on metabolic syndrome-related alterations in experimental animals, including glucose and lipid homeostasis improvement and a reduction in fat mass, blood pressure, low-grade inflammation, and oxidative stress. Clinical trials have been carried out to address its potential; however, results are still inconclusive. Even though resveratrol is partly metabolized by gut microbiota, the relevance of this "forgotten organ" had not been widely considered. However, in the past few years, data has emerged suggesting that the therapeutic potential of this compound may be due to its interaction with gut microbiota, reporting changes in bacterial composition associated with beneficial metabolic outcomes. Even though data is still scarce and for the most part observational, it is promising nevertheless, suggesting that resveratrol supplementation could be a useful tool for the treatment of metabolic syndrome and its associated conditions. 10.3390/nu10111651
    Antioxidant effects of tea: evidence from human clinical trials. Rietveld Anton,Wiseman Sheila The Journal of nutrition Tea remains the most consumed drink in the world after water, well ahead of coffee, beer, wine and carbonated soft drinks. An accumulated number of population studies suggests that consumption of green and black tea beverages may bring positive health effects (1). One hypothesis explaining such effects is that the high levels of flavonoids in tea can protect cells and tissues from oxidative damage by scavenging oxygen-free radicals. Chemically, the flavonoids found in green and black tea are very effective radical scavengers. The tea flavonoids may therefore be active as antioxidants in the digestive tract or in other tissues after uptake. A substantial number of human intervention studies with green and black tea demonstrates a significant increase in plasma antioxidant capacity in humans approximately 1 h after consumption of moderate amounts of tea (1-6 cups/d). There are initial indications that the enhanced blood antioxidant potential leads to reduced oxidative damage to macromolecules such as DNA and lipids. However, the measurement of oxidative damage through biomarkers needs to be further established. In conclusion, tea flavonoids are potent antioxidants that are absorbed from the gut after consumption. Tea consumption consistently leads to a significant increase in the antioxidant capacity of the blood. Beneficial effects of increased antioxidant capacity in the body may be the reduction of oxidative damage to important biomolecules. The scientific support is strongest for the protection of DNA from oxidative damage after black or green tea consumption. However, the quality of the studies now available is insufficient to draw firm conclusions. Therefore, further evidence from human intervention studies is required. 10.1093/jn/133.10.3285S
    Curcumin, Cardiometabolic Health and Dementia. Kim Yoona,Clifton Peter International journal of environmental research and public health Current research indicates curcumin [diferuloylmethane; a polyphenolic compound isolated from the rhizomes of the dietary spice turmeric ()] exerts a beneficial effect on health which may be partly attributable to its anti-oxidative and anti-inflammatory properties. The aim of this review is to examine potential mechanisms of the actions of curcumin in both animal and human studies. Curcumin modulates relevant molecular target pathways to improve glucose and lipid metabolism, suppress inflammation, stimulate antioxidant enzymes, facilitate insulin signalling and reduce gut permeability. Curcumin also inhibits Aβ and tau accumulation in animal models and enhances mitochondria and synaptic function. In conclusion, in high-dose animal studies and in vitro, curcumin exerts a potential beneficial effect on cardiometabolic disease. However, human studies are relatively unconvincing. More intervention studies should be conducted with the new curcumin formulation with improved oral bioavailability. 10.3390/ijerph15102093
    Proanthocyanidins and hydrolysable tannins: occurrence, dietary intake and pharmacological effects. Smeriglio Antonella,Barreca Davide,Bellocco Ersilia,Trombetta Domenico British journal of pharmacology Tannins are a heterogeneous group of high MW, water-soluble, polyphenolic compounds, naturally present in cereals, leguminous seeds and, predominantly, in many fruits and vegetables, where they provide protection against a wide range of biotic and abiotic stressors. Tannins exert several pharmacological effects, including antioxidant and free radical scavenging activity as well as antimicrobial, anti-cancer, anti-nutritional and cardio-protective properties. They also seem to exert beneficial effects on metabolic disorders and prevent the onset of several oxidative stress-related diseases. Although the bioavailability and pharmacokinetic data for these phytochemicals are still sparse, gut absorption of these compounds seems to be inversely correlated with the degree of polymerization. Further studies are mandatory to better clarify how these molecules and their metabolites are able to cross the intestinal barrier in order to exert their biological properties. This review summarizes the current literature on tannins, focusing on the main, recently proposed mechanisms of action that underlie their pharmacological and disease-prevention properties, as well as their bioavailability, safety and toxicology. LINKED ARTICLES:This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc. 10.1111/bph.13630
    The vanillin derivative VND3207 protects intestine against radiation injury by modulating p53/NOXA signaling pathway and restoring the balance of gut microbiota. Li Ming,Gu Meng-Meng,Lang Yue,Shi Jianming,Chen Benjamin P C,Guan Hua,Yu Lan,Zhou Ping-Kun,Shang Zeng-Fu Free radical biology & medicine The intestine is a highly radiosensitive tissue that is susceptible to structural and functional damage due to systemic as well as localized radiation exposure. Unfortunately, no effective prophylactic or therapeutic agents are available at present to manage radiation-induced intestinal injuries. We observed that the vanillin derivative VND3207 improved the survival of lethally irradiated mice by promoting intestinal regeneration and increasing the number of surviving crypts. Pre-treatment with VND3207 significantly increased the number of Lgr5 intestinal stem cells (ISCs) and their daughter cells, the transient Ki67 proliferating cells. Mechanistically, VND3207 decreased oxidative DNA damage and lipid peroxidation and maintained endogenous antioxidant status by increasing the level of superoxide dismutase and total antioxidant capacity. In addition, VND3207 maintained appropriate levels of activated p53 that triggered cell cycle arrest but were not sufficient to induce NOXA-mediated apoptosis, thus ensuring DNA damage repair in the irradiated small intestinal crypt cells. Furthermore, VND3207 treatment restores the intestinal bacterial flora structures altered by TBI exposure. In conclusion, VND3207 promoted intestinal repair following radiation injury by reducing reactive oxygen species-induced DNA damage and modulating appropriate levels of activated p53 in intestinal epithelial cells. 10.1016/j.freeradbiomed.2019.09.035
    The Sasa quelpaertensis Leaf Extract Inhibits the Dextran Sulfate Sodium-induced Mouse Colitis Through Modulation of Antioxidant Enzyme Expression. Yeom Yiseul,Kim Yuri Journal of cancer prevention BACKGROUND:Oxidative stress plays an important role in the pathogenesis of inflammatory bowel disease. The objective of this study is to investigate the protective effect of Sasa quelpaertensis leaf extract (SQE) against oxidative stress in mice with dextran sulfate sodium (DSS)-induced colitis. METHODS:Mice were treated with SQE (100 mg/kg or 300 mg/kg body weight) by gavage in advance two weeks before inflammation was induced. Then, the mice were administered with 2.5% DSS in drinking water for 7 days and normal drinking water for 7 days between two DSS treatment. Disease activity index values, gut motility, and severity of the resulting oxidative DNA damage were analyzed. The antioxidant effect of SQE was evaluated by measuring malondialdehyde (MDA) and superoxide dismutase (SOD) activity in plasma samples. Catalase activity and expressions levels of glutathione peroxidase 1 (Gpx1), SOD1, and SOD2 were also detected in colon tissues. RESULTS:Administration of SQE significantly reduced the severity of DSS-induced colitis compared to the control (Ctrl) group. Levels of 8-oxo-dG, an oxidative DNA damage marker, were significantly lower in the SQE group compared to the untreated DSS Ctrl group. In the SQE (300 mg/kg) group, MDA levels were significantly lower, while SOD and catalase activity levels in the plasma samples were significantly higher compared with the DSS Ctrl group. The expression levels of the antioxidant enzymes, SOD2 and Gpx1, were significantly higher, while the levels of SOD 1 expression were lower, in the colon tissues of the DSS Ctrl group compared with those of the Ctrl group. In contrast, administration of SQE significantly down-regulated SOD2 and Gpx1 expressions and up-regulated SOD1 expression. CONCLUSIONS:These results indicate that SQE efficiently suppresses oxidative stress in DSS-induced colitis in mice, and its action is associated with the regulation of antioxidant enzymes. 10.15430/JCP.2015.20.2.136
    Apple polyphenol extracts prevent damage to human gastric epithelial cells in vitro and to rat gastric mucosa in vivo. Graziani G,D'Argenio G,Tuccillo C,Loguercio C,Ritieni A,Morisco F,Del Vecchio Blanco C,Fogliano V,Romano M Gut BACKGROUND:Fresh fruit and vegetables exert multiple biological effects on the gastrointestinal mucosa. AIM:To assess whether apple extracts counteract oxidative or indomethacin induced damage to gastric epithelial cells in vitro and to rat gastric mucosa in vivo. METHODS:Apple extracts were obtained from freeze dried apple flesh of the "Annurca" variety. Cell damage was induced by incubating MKN 28 cells with xanthine-xanthine oxidase or indomethacin and quantitated by MTT. In vivo gastric damage was induced by indomethacin 35 mg/kg. Intracellular antioxidant activity was determined using the (2,2'-azinobis (3-ethylbenzothiazolin-6-sulfonate) method. Malondialdehyde intracellular concentration, an index of lipid peroxidation, was determined by high pressure liquid chromatography with fluorometric detection. RESULTS:(1) Apple extracts decreased xanthine-xanthine oxidase or indomethacin induced injury to gastric epithelial cells by 50%; (2) catechin or chlorogenic acid (the main phenolic components of apple extracts) were equally effective as apple extracts in preventing oxidative injury to gastric cells; and (3) apple extracts (i) caused a fourfold increase in intracellular antioxidant activity, (ii) prevented its decrease induced by xanthine-xanthine oxidase, (iii) counteracted xanthine-xanthine oxidase induced lipid peroxidation, and (iv) decreased indomethacin injury to the rat gastric mucosa by 40%. CONCLUSIONS:Apple extracts prevent exogenous damage to human gastric epithelial cells in vitro and to the rat gastric mucosa in vivo. This effect seems to be associated with the antioxidant activity of apple phenolic compounds. A diet rich in apple antioxidants might exert a beneficial effect in the prevention of gastric diseases related to generation of reactive oxygen species. 10.1136/gut.2004.046292
    Effect of Flavonoid-Rich Extract of Glycyrrhiza glabra on Gut-Friendly Microorganisms, Commercial Probiotic Preparations, and Digestive Enzymes. Asha Mannanthendil Kumaran,Debraj Debnath,Dethe Shekhar,Bhaskar Anirban,Muruganantham Nithyanantham,Deepak Mundkinajeddu Journal of dietary supplements Flavonoid-rich extract prepared from Glycyrrhiza glabra has been found to be beneficial in patients with functional dyspepsia and was reported to possess some gut health-promoting properties such as antioxidant, anti-inflammatory and anti-Helicobacter pylori activities. In the present study, the flavonoid-rich extract of Glycyrrhiza glabra was evaluated for its compatibility with probiotic strains (Lactobacillus casei, Lactobacillus fermentum, Lactobacillus plantarum, and Streptococcus thermophilus), commercial probiotic drinks, and digestive enzymes (pancreatic α-amylase, α-glucosidase, phytase, xylanase, and pancreatic lipase). Results of this study indicated that the flavonoid-rich extract of Glycyrrhiza glabra is compatible with the tested probiotic strains, probiotic drinks and digestive enzymes. 10.1080/19390211.2016.1223257
    Gut microbiota: A player in aging and a target for anti-aging intervention. Vaiserman Alexander M,Koliada Alexander K,Marotta Francesco Ageing research reviews Aging-associated alterations in composition, diversity and functional features of intestinal microbiota are well-described in the modern literature. They are suggested to be caused by an age-related decline in immune system functioning (immunosenescence) and a low-grade chronic inflammation (inflammaging), which accompany many aging-associated pathologies. The microbiota-targeted dietary and probiotic interventions have been shown to favorably affect the host health and aging by an enhancement of antioxidant activity, improving immune homeostasis, suppression of chronic inflammation, regulation of fat deposition and metabolism and prevention of insulin resistance. Recently, a high effectiveness and safety of novel therapeutic application such as fecal microbiota transplantation in the prevention and treatment of age-related pathological conditions including atherosclerosis, type 2 diabetes and Parkinson's disease has been demonstrated. In this review, recent research findings are summarized on the role of gut micribiota in aging processes with emphasis on therapeutic potential of microbiome-targeted interventions in anti-aging medicine. 10.1016/j.arr.2017.01.001
    Wine consumption and intestinal redox homeostasis. Biasi Fiorella,Deiana Monica,Guina Tina,Gamba Paola,Leonarduzzi Gabriella,Poli Giuseppe Redox biology Regular consumption of moderate doses of wine is an integral part of the Mediterranean diet, which has long been considered to provide remarkable health benefits. Wine's beneficial effect has been attributed principally to its non-alcoholic portion, which has antioxidant properties, and contains a wide variety of phenolics, generally called polyphenols. Wine phenolics may prevent or delay the progression of intestinal diseases characterized by oxidative stress and inflammation, especially because they reach higher concentrations in the gut than in other tissues. They act as both free radical scavengers and modulators of specific inflammation-related genes involved in cellular redox signaling. In addition, the importance of wine polyphenols has recently been stressed for their ability to act as prebiotics and antimicrobial agents. Wine components have been proposed as an alternative natural approach to prevent or treat inflammatory bowel diseases. The difficulty remains to distinguish whether these positive properties are due only to polyphenols in wine or also to the alcohol intake, since many studies have reported ethanol to possess various beneficial effects. Our knowledge of the use of wine components in managing human intestinal inflammatory diseases is still quite limited, and further clinical studies may afford more solid evidence of their beneficial effects. 10.1016/j.redox.2014.06.008
    Dietary polyphenols increase fecal mucin and immunoglobulin A and ameliorate the disturbance in gut microbiota caused by a high fat diet. Taira Toshio,Yamaguchi Sayori,Takahashi Azusa,Okazaki Yukako,Yamaguchi Akihiro,Sakaguchi Hirohide,Chiji Hideyuki Journal of clinical biochemistry and nutrition The effects of dietary polyphenols on human health have mainly been discussed in the context of preventing degenerative diseases, particularly cardiovascular diseases and cancer. The antioxidant properties of polyphenols have been widely studied, but it has become clear that the mechanism of action of polyphenols extends beyond the modulation of oxidative stress, as they are poorly absorbed from the digestive tract. The purpose of this study was to clarify the effects of polyphenols on the colonic environment, intestinal barrier function, and gut microbiota. We demonstrated that dietary polyphenols derived from aronia, haskap, and bilberry, markedly elevated the amount of fecal mucin and immunoglobulin A (IgA) as an intestinal barrier function and ameliorated the disturbance in gut microbiota caused by a high fat diet in rats. These results suggest that dietary polyphenols play a significant role in the prevention of degenerative diseases through improvement of the colonic environment without any absorption from the digestive tract. 10.3164/jcbn.15-15
    Cardiometabolic risk and gut microbial phytoestrogen metabolite phenotypes. Frankenfeld Cara L Molecular nutrition & food research Recent evidence supports that the gut microbial community, independently and/or interactively with dietary intake, is a target for reducing cardiovascular disease risk through its effects on cardiometabolic risk factors. Dietary phytoestrogens may be a source for interactive effects. Phytoestrogens, such as isoflavones, lignans, and flavonoids, are compounds found in plants that have estrogenic or antiestrogenic activities, as well as antioxidant, antiproliferative, or apoptotic actions. Given these physiological activities, phytoestrogens may have a role in cardiometabolic health. Some phytoestrogens consumed in the diet undergo biotransformation through gut bacterial metabolism to other compounds that may exhibit similar or different physiological activity than the parent compound. There is interindividual variability in the capability to metabolize phytoestrogens to their metabolites, and there is a resulting phenotype that can be evaluated based on urinary metabolite excretion. Evidence suggests that phytoestrogen metabolites and/or phenotypes are associated with cardiometabolic risk factors, such as blood pressure, abdominal obesity, and serum lipids, triglycerides, glucose, and inflammatory markers. The objective of this review was to provide an overview of the observed associations between gut microbial phytoestrogen metabolites and metabolite phenotypes with cardiometabolic risk factors, with focus on the more extensively studied isoflavone metabolites. 10.1002/mnfr.201500900
    Crocin-I ameliorates the disruption of lipid metabolism and dysbiosis of the gut microbiota induced by chronic corticosterone in mice. Xie Xiaoxian,Xiao Qingfeng,Xiong Ze,Yu Chunan,Zhou Jiafeng,Fu Zhengwei Food & function Glucocorticoids (GCs) are widely used as anti-inflammatory and immunosuppressive drugs. However, chronic treatment with GCs in clinical settings has a series of side effects, such as metabolic disorders, gut microbiota dysbiosis and neurological impairment. Therefore, searching for a functional substance that can alleviate these side effects is greatly meaningful to clinical patients. Crocin is the main active ingredient of saffron, which has been reported to have numerous pharmacological activities. However, the action of crocin-I, one major member of the crocin family, on the physiological mediation in the individuals receiving GC treatment remains unclear. In this study, we aimed to evaluate the efficacy of crocin-I on lipid metabolism and the gut microbiota in a mouse model of chronic corticosterone (CORT) treatment. Our findings showed that crocin-I reduced the levels of triglycerides and total cholesterol and the ratio of low density lipoprotein to high density lipoprotein in the serum of CORT-treated mice. In addition, transcriptome analysis revealed that crocin-I was effective in mediating the amelioration of lipid metabolism, mainly in fatty acid metabolism and steroid biosynthesis in CORT-treated mice. Moreover, metabolome analysis demonstrated that crocin-I could restore the disturbed metabolites in the liver of CORT-treated mice, most of which are long-chain fatty acids. Furthermore, high-throughput sequencing of 16s rRNA revealed that crocin-I could mitigate the dysbiosis of the gut microbiota caused by CORT at a dose of 40 mg kg-1, by resulting in a significant increase in the alpha diversity of the microbes in the cecal contents and a significant reduction in the abundance of Firmicutes, whereas by increasing the abundance of Bacteroidetes. These results indicated that oral administration of crocin-I could modify the composition of the gut microbiota and alleviate hepatic lipid disorder in mice treated with a high dose of GCs. 10.1039/c9fo01533g
    A combination of quercetin and resveratrol reduces obesity in high-fat diet-fed rats by modulation of gut microbiota. Zhao Le,Zhang Qi,Ma Weini,Tian Feng,Shen Hongyi,Zhou Mingmei Food & function Resveratrol and quercetin, widely found in foods and vegetables, are plant polyphenols reported to have a wide range of biological activities. Despite their limited bioavailabilities, both resveratrol and quercetin are known to exhibit anti-inflammation and anti-obesity effects. We hypothesized that gut microbiota may be a potential target for resveratrol and quercetin to prevent the development of obesity. The aim of this research was to confirm whether a combination of quercetin and resveratrol (CQR) could restore the gut microbiota dysbiosis induced by a high-fat diet (HFD). In this study, Wistar rats were divided into three groups: a normal diet (ND) group, a HFD group and a CQR group. The CQR group was treated with a HFD and administered with a combination of quercetin [30 mg per kg body weight (BW) per day] and resveratrol [15 mg per kg body weight (BW) per day] by oral gavage. At the end of 10 weeks, CQR reduced the body weight gain and visceral (epididymal, perirenal) adipose tissue weight. Moreover, CQR also reduced serum lipids, attenuated serum inflammatory markers [interleukin (IL)-6, tumor necrosis factor (TNF)-α, monocyte chemotactic protein (MCP)-1] and reversed serum biochemical parameters (adiponectin, insulin, leptin, etc.). Importantly, our results demonstrated that CQR could modulate the gut microbiota composition. 16S rRNA gene sequencing revealed that CQR had an impact on gut microbiota, decreasing Firmicutes (P < 0.05) and the proportion of Firmicutes to Bacteroidetes (P = 0.052). CQR also significantly inhibited the relative abundance of Desulfovibrionaceae (P < 0.01), Acidaminococcaceae (P < 0.05), Coriobacteriaceae (P < 0.05), Bilophila (P < 0.05), Lachnospiraceae (P < 0.05) and its genus Lachnoclostridium (P < 0.001), which were reported to be potentially related to diet-induced obesity. Moreover, compared with the HFD group, the relative abundance of Bacteroidales_S24-7_group (P < 0.01), Christensenellaceae (P < 0.001), Akkermansia (P < 0.01), Ruminococcaceae (P < 0.01) and its genera Ruminococcaceae_UCG-014 (P < 0.01), and Ruminococcaceae_UCG-005 (P < 0.01), which were reported to have an effect of relieving HFD-induced obesity, was markedly increased in the CQR group. Overall, these results indicated that administration of CQR may have beneficial effects on ameliorating HFD-induced obesity and reducing HFD-induced gut microbiota dysbiosis. 10.1039/c7fo01383c
    Do interactions between gut ecology and environmental chemicals contribute to obesity and diabetes? Snedeker Suzanne M,Hay Anthony G Environmental health perspectives BACKGROUND:Gut microbiota are important factors in obesity and diabetes, yet little is known about their role in the toxicodynamics of environmental chemicals, including those recently found to be obesogenic and diabetogenic. OBJECTIVES:We integrated evidence that independently links gut ecology and environmental chemicals to obesity and diabetes, providing a framework for suggesting how these environmental factors may interact with these diseases, and identified future research needs. METHODS:We examined studies with germ-free or antibiotic-treated laboratory animals, and human studies that evaluated how dietary influences and microbial changes affected obesity and diabetes. Strengths and weaknesses of studies evaluating how environmental chemical exposures may affect obesity and diabetes were summarized, and research gaps on how gut ecology may affect the disposition of environmental chemicals were identified. RESULTS:Mounting evidence indicates that gut microbiota composition affects obesity and diabetes, as does exposure to environmental chemicals. The toxicology and pharmacology literature also suggests that interindividual variations in gut microbiota may affect chemical metabolism via direct activation of chemicals, depletion of metabolites needed for biotransformation, alteration of host biotransformation enzyme activities, changes in enterohepatic circulation, altered bioavailability of environmental chemicals and/or antioxidants from food, and alterations in gut motility and barrier function. CONCLUSIONS:Variations in gut microbiota are likely to affect human toxicodynamics and increase individual exposure to obesogenic and diabetogenic chemicals. Combating the global obesity and diabetes epidemics requires a multifaceted approach that should include greater emphasis on understanding and controlling the impact of interindividual gut microbe variability on the disposition of environmental chemicals in humans. 10.1289/ehp.1104204
    Histone chaperone FACT complex mediates oxidative stress response to promote liver cancer progression. Shen Jialing,Chen Mengnuo,Lee Derek,Law Cheuk-Ting,Wei Lai,Tsang Felice Ho-Ching,Chin Don Wai-Ching,Cheng Carol Lai-Hung,Lee Joyce Man-Fong,Ng Irene Oi-Lin,Wong Carmen Chak-Lui,Wong Chun-Ming Gut OBJECTIVE:Facilitates Chromatin Transcription (FACT) complex is a histone chaperone participating in DNA repair-related and transcription-related chromatin dynamics. In this study, we investigated its oncogenic functions, underlying mechanisms and therapeutic implications in human hepatocellular carcinoma (HCC). DESIGN:We obtained HCC and its corresponding non-tumorous liver samples from 16 patients and identified FACT complex as the most upregulated histone chaperone by RNA-Seq. We further used CRISPR-based gene activation and knockout systems to demonstrate the functions of FACT complex in HCC growth and metastasis. Functional roles and mechanistic insights of FACT complex in oxidative stress response were investigated by ChIP assay, flow cytometry, gene expression assays and 4sU-DRB transcription elongation assay. Therapeutic effect of FACT complex inhibitor, Curaxin, was tested in both in vitro and in vivo models. RESULTS:We showed that FACT complex was remarkably upregulated in HCC and contributed to HCC progression. Importantly, we unprecedentedly revealed an indispensable role of FACT complex in NRF2-driven oxidative stress response. Oxidative stress prevented NRF2 and FACT complex from KEAP1-mediated protein ubiquitination and degradation. Stabilised NRF2 and FACT complex form a positive feedback loop; NRF2 transcriptionally activates the FACT complex, while FACT complex promotes the transcription elongation of NRF2 and its downstream antioxidant genes through facilitating rapid nucleosome disassembly for the passage of RNA polymerase. Therapeutically, Curaxin effectively suppressed HCC growth and sensitised HCC cell to sorafenib. CONCLUSION:In conclusion, our findings demonstrated that FACT complex is essential for the expeditious HCC oxidative stress response and is a potential therapeutic target for HCC treatment. 10.1136/gutjnl-2019-318668
    The regulation effect of EGCG3''Me phospholipid complex on gut flora of a high-fat diet-induced obesity mouse model. Lin Yuhai,Zhang Xin,Cheng Lu,Yang Hua Journal of food biochemistry Despite the remarkable bioactivity, the potential of EGCG3''Me to be fully utilized has not yet been completely elucidated due to its low absorption. It has been reported that phospholipids can act as agents to improve the absorption of antioxidants. Therefore, EGCG3''Me phospholipid complex (EPC) was utilized in this study to investigate its activity on gut flora of an obesity mouse model. After the administration of the complex for 8 weeks, the relative abundance of Bacteroidetes was significantly increased (p < 0.05); meanwhile, the relative abundance of Firmicutes was decreased, suggesting the potential anti-obesity effect of the complex. Furthermore, the expression of Muc2 and Reg3g were directly upregulated by EPC intervention. PRACTICAL APPLICATIONS: Although EGCG3''Me has shown excellent biological benefits, the presence of multiple hydroxyl groups and high polar properties hindered its application. This study indicated the potential of phospholipids in promoting the bioavailability of EGCG3''Me and might contribute to the production of functional food with better tea catechins absorption. 10.1111/jfbc.12880
    Selenoproteins and oxidative stress-induced inflammatory tumorigenesis in the gut. Barrett Caitlyn W,Short Sarah P,Williams Christopher S Cellular and molecular life sciences : CMLS Selenium is an essential micronutrient that is incorporated into at least 25 selenoproteins encoded by the human genome, many of which serve antioxidant functions. Because patients with inflammatory bowel disease (IBD) demonstrate nutritional deficiencies and are at increased risk for colon cancer due to heightened inflammation and oxidative stress, selenoprotein dysfunction may contribute to disease progression. Over the years, numerous studies have analyzed the effects of selenoprotein loss and shown that they are important mediators of intestinal inflammation and carcinogenesis. In particular, recent work has focused on the role of selenoprotein P (SEPP1), a major selenium transport protein which also has endogenous antioxidant function. These experiments determined SEPP1 loss altered immune and epithelial cellular function in a murine model of colitis-associated carcinoma. Here, we discuss the current knowledge of SEPP1 and selenoprotein function in the setting of IBD, colitis, and inflammatory tumorigenesis. 10.1007/s00018-016-2339-2
    Characterization of gut microbiota composition and functions in patients with chronic alcohol overconsumption. Bjørkhaug Steinar Traae,Aanes Håvard,Neupane Sudan Prasad,Bramness Jørgen G,Malvik Stine,Henriksen Christine,Skar Viggo,Medhus Asle W,Valeur Jørgen Gut microbes Excessive alcohol intake can alter the gut microbiota, which may underlie the pathophysiology of alcohol-related diseases. We examined gut microbiota composition and functions in patients with alcohol overconsumption for >10 years, compared to a control group of patients with a history of no or low alcohol intake. Faecal microbiota composition was assessed by 16S rRNA sequencing. Gut microbiota functions were evaluated by quantification of short-chain fatty acids (SCFAs) and predictive metagenome profiling (PICRUSt). Twenty-four patients, mean age 64.8 years (19 males), with alcohol overconsumption, and 18 control patients, mean age 58.2 years (14 males) were included. The two groups were comparable regarding basic clinical variables. Nutritional assessment revealed lower total score on the screening tool Mini Nutritional Assessment, lower muscle mass as assessed by handgrip strength, and lower plasma vitamin C levels in the alcohol overconsumption group. Bacteria from phylum were found in higher relative abundance, while bacteria from genus were found in lower relative abundance in the group of alcohol overconsumers. The group also had higher levels of the genera and , and lower concentration and percentage of butyric acid. When applying PICRUSt to predict the metagenomic composition, we found that genes related to invasion of epithelial cells were more common in the group of alcohol overconsumers. We conclude that gut microbiota composition and functions in patients with alcohol overconsumption differ from patients with low consumption of alcohol, and seem to be skewed into a putative pro-inflammatory direction. 10.1080/19490976.2019.1580097
    Polyphenolic phytochemicals--just antioxidants or much more? Stevenson D E,Hurst R D Cellular and molecular life sciences : CMLS Polyphenolic phytochemicals are ubiquitous in plants, in which they function in various protective roles. A 'recommended' human diet contains significant quantities of polyphenolics, as they have long been assumed to be 'antioxidants' that scavenge excessive, damaging, free radicals arising from normal metabolic processes. There is recent evidence that polyphenolics also have 'indirect' antioxidant effects through induction of endogenous protective enzymes. There is also increasing evidence for many potential benefits through polyphenolic-mediated regulation of cellular processes such as inflammation. Inductive or signalling effects may occur at concentrations much lower than required for effective radical scavenging. Over the last 2-3 years, there have been many exciting new developments in the elucidation of the in vivo mechanisms of the health benefits of polyphenolics. We summarise the current knowledge of the intake, bio-availability and metabolism of polyphenolics, their antioxidant effects, regulatory effects on signalling pathways, neuro-protective effects and regulatory effects on energy metabolism and gut health. 10.1007/s00018-007-7237-1
    Prebiotic Potential and Chemical Composition of Seven Culinary Spice Extracts. Lu Qing-Yi,Summanen Paula H,Lee Ru-Po,Huang Jianjun,Henning Susanne M,Heber David,Finegold Sydney M,Li Zhaoping Journal of food science The objective of this study was to investigate prebiotic potential, chemical composition, and antioxidant capacity of spice extracts. Seven culinary spices including black pepper, cayenne pepper, cinnamon, ginger, Mediterranean oregano, rosemary, and turmeric were extracted with boiling water. Major chemical constituents were characterized by RP-HPLC-DAD method and antioxidant capacity was determined by measuring colorimetrically the extent to scavenge ABTS radical cations. Effects of spice extracts on the viability of 88 anaerobic and facultative isolates from intestinal microbiota were determined by using Brucella agar plates containing serial dilutions of extracts. A total of 14 phenolic compounds, a piperine, cinnamic acid, and cinnamaldehyde were identified and quantitated. Spice extracts exhibited high antioxidant capacity that correlated with the total amount of major chemicals. All spice extracts, with the exception of turmeric, enhanced the growth of Bifidobacterium spp. and Lactobacillus spp. All spices exhibited inhibitory activity against selected Ruminococcus species. Cinnamon, oregano, and rosemary were active against selected Fusobacterium strains and cinnamon, rosemary, and turmeric were active against selected Clostridium spp. Some spices displayed prebiotic-like activity by promoting the growth of beneficial bacteria and suppressing the growth of pathogenic bacteria, suggesting their potential role in the regulation of intestinal microbiota and the enhancement of gastrointestinal health. The identification and quantification of spice-specific phytochemicals provided insight into the potential influence of these chemicals on the gut microbial communities and activities. Future research on the connections between spice-induced changes in gut microbiota and host metabolism and disease preventive effect in animal models and humans is needed. 10.1111/1750-3841.13792
    Protective Effects of Anthocyanins in Obesity-Associated Inflammation and Changes in Gut Microbiome. Jayarathne Shasika,Stull April J,Park Oak-Hee,Kim Jung Han,Thompson Leslie,Moustaid-Moussa Naima Molecular nutrition & food research Obesity is a complex disease and a major public health epidemic. Chronic, low-grade inflammation is a common underlying feature of obesity and associated metabolic diseases; adipose tissue is a major contributor to this systemic inflammation. Evidence shows that obesity-associated inflammation may originate from gut dysfunction, including changes in intestinal bacteria or microbiome profiles. Increasingly, food and plant bioactive compounds with antioxidant and anti-inflammatory properties are proposed to ameliorate obesity-associated inflammation. Among these, the health-promoting effects of anthocyanin-rich foods are of interest here. Specifically, this review summarizes the reported benefits of anthocyanins in obesity-associated inflammation and underlying molecular mechanisms, including the role of gut microbiome and cell signaling pathways regulated by anthocyanins both in vivo and in vitro. 10.1002/mnfr.201900149
    An altered gut microbiome profile in a child affected by Crohn's disease normalized after nutritional therapy. D'Argenio Valeria,Precone Vincenza,Casaburi Giorgio,Miele Erasmo,Martinelli Massimo,Staiano Annamaria,Salvatore Francesco,Sacchetti Lucia The American journal of gastroenterology 10.1038/ajg.2013.46
    Polyphenolic Compounds and Gut Microbiome in Cardiovascular Diseases. McGrail Lindsay,Garelnabi Mahdi Current pharmaceutical biotechnology The onset of Cardiovascular Disease (CVD) is known to be associated with multiple risk factors related to exogenous exposures on predisposed genetic makeup. Diet and lifestyle have a cascade effect on microbiota biodiversity, thus impacting inflammation and heart health. Atherosclerosis is a type of CVD where chronic inflammation contributes to plaque buildup in the arteries resulting in narrowed blood vessels, which obstruct blood flow. Polyphenolic compounds, including flavonoids, most commonly consumed in the form of plants, have been identified to have various mechanisms of action to reduce the inflammatory response in the body. Flavonoids provide a variety of nutraceutical functions including antioxidant, antimicrobial, anti-inflammatory, antiangiogenic, antitumor, and improved pharmacokinetic properties. Therefore, the medicinal use of polyphenolic compounds as an intervention for the inflammatory response, especially relating to the gut microbiome, may significantly reduce the risk of atherosclerotic plaque development and disease onset. This review addresses the role of polyphenolic compounds and gut microbiome in cardiovascular disease. Research studies conducted in cells and animals were reviewed. These studies clearly illustrate that dietary polyphenolic compounds influence resident gut microbiota thus they are associated with the prevention of atherosclerosis progression. Further research in this field is warranted to identify potential gut microbiome mediated therapeutic approaches for CVD. 10.2174/1389201020666191111150239
    Identification of Phenolic Compounds-Rich Grape Pomace Extracts Urine Metabolites and Correlation with Gut Microbiota Modulation. Chacar Stéphanie,Tarighi Mehrad,Fares Nassim,Faivre Jean-François,Louka Nicolas,Maroun Richard G Antioxidants (Basel, Switzerland) The high diversity of phenolic compounds (PC) found in food matrices makes it challenging to analyze their bioavailability and their impact on health and functional metabolism. It is well recognized that PC do modulate the composition of the gut microbiota (GM), however, the literature still lacks significant data concerning the link between the metabolic fate of the ingested compounds and their bioactivity, mainly when considering the secondary metabolites produced. In this study, we assessed the metabolic fate of PC for a period covering 14 months of daily intake to identify the metabolites that could be responsible for the effects of PC on the GM observed in our previous work. Urinary analysis of polyphenol metabolites was performed using a high resolution mass spectrometry LC-QTOF-MS method. Among the sixteen metabolites identified, 3-hydroxyphenylacetic acid and 2-(4-hydroxyphenyl) propionic acid were detected simultaneously and, therefore, correlated with the growth of in the rat GM. In addition, Daidzedin, detected only at 14 months post-treatment, mostly interfered with the growth inhibition of (Cluster I). In conclusion, the impact of the long-term intake of PC on rat GM seems to be related to specific metabolites produced after ingestion of the parental compounds and this may also be due to their additional synergistic effects. 10.3390/antiox7060075
    Gut Microbiota Modulation and Anti-Inflammatory Properties of Dietary Polyphenols in IBD: New and Consolidated Perspectives. Santino Angelo,Scarano Aurelia,De Santis Stefania,De Benedictis Maria,Giovinazzo Giovanna,Chieppa Marcello Current pharmaceutical design BACKGROUND:Polyphenols represent a great variety of compounds occurring in fruits, vegetables and plant-derived products. Dietary polyphenols have been found displaying several biological properties, such as anti-inflammatory, antioxidant and anti-aging activities, cardiovascular and neuro-protection, and reduction of the risk of intestinal diseases. The bio-efficacy of polyphenols is tightly linked to their bioavailability, to structural complexity and composition of food matrix in which they are present. Since most of the polyphenols are naturally stored in food matrices as glycosylated and/or variously decorated forms, they need an intestinal bio-conversion in more absorbable forms. Recent findings are highlighting the polyphenols-gut microbiota interplay in the health benefits linked to these compounds. Furthermore, the prebiotic-like activities of polyphenols on microbiota and their potential use in preventive/therapeutic strategies for gastrointestinal disorders are recently emerging. CONCLUSION:In this review, we will focus on the dietary flavonols, anthocyanins and stilbenes, as widely occurring polyphenols in human diet, their metabolism mediated by gut microbiota and their protective effects on inflammatory bowel diseases (IBDs). 10.2174/1381612823666170207145420
    Melatonin plays a protective role in postburn rodent gut pathophysiology. Al-Ghoul Walid M,Abu-Shaqra Steven,Park Byeong Gyu,Fazal Nadeem International journal of biological sciences Melatonin is a possible protective agent in postburn gut pathophysiological dynamics. We investigated the role of endogenously-produced versus exogenously-administered melatonin in a major thermal injury rat model with well-characterized gut inflammatory complications. Our rationale is that understanding in vivo melatonin mechanisms in control and inflamed tissues will improve our understanding of its potential as a safe anti-inflammatory/antioxidant therapeutic alternative. Towards this end, we tested the hypothesis that the gut is both a source and a target for melatonin and that mesenteric melatonin plays an anti-inflammatory role following major thermal injury in rats with 3rd degree hot water scald over 30% TBSA. Our methods for assessing the gut as a source of melatonin included plasma melatonin ELISA measurements in systemic and mesenteric circulation as well as rtPCR measurement of jejunum and terminal ileum expression of the melatonin synthesizing enzymes arylalkylamine N-acetyltransferase (AA-NAT) and 5-hydroxyindole-O-methyltransferase (HIOMT) in sham versus day-3 postburn rats. Our melatonin ELISA results revealed that mesenteric circulation has much higher melatonin than systemic circulation and that both mesenteric and systemic melatonin levels are increased three days following major thermal injury. Our rtPCR results complemented the ELISA data in showing that the melatonin synthesizing enzymes AA-NAT and HIOMT are expressed in the ileum and jejunum and that this expression is increased three days following major thermal injury. Interestingly, the rtPCR data also revealed negative feedback by melatonin as exogenous melatonin supplementation at a dose of 7.43 mg (32 micromole/kg), but not 1.86 mg/kg (8 micromole/kg) drastically suppressed AA-NAT mRNA expression. Our methods also included an assessment of the gut as a target for melatonin utilizing computerized immunohistochemical measurements to quantify the effects of exogenous melatonin supplementation on postburn gut mucosa barrier inflammatory profiles. Here, our results revealed that daily postburn intraperitoneal melatonin administration at a dose of 1.86 mg/kg (8 micromole/kg) significantly suppressed both neutrophil infiltration and tyrosine nitrosylation as revealed by Gr-1 and nitrotyrosine immunohistochemistry, respectively. In conclusion, our results provide support for high mesenteric melatonin levels and dynamic de novo gut melatonin production, both of which increase endogenously in response to major thermal injury, but appear to fall short of abrogating the excessive postburn hyper-inflammation. Moreover, supplementation by exogenous melatonin significantly suppresses gut inflammation, thus confirming that melatonin is protective against postburn inflammation. 10.7150/ijbs.6.282
    Dietary Anthocyanins and Human Health. Blesso Christopher N Nutrients Anthocyanins may contribute to the inverse relationship between fruit and vegetable intake and chronic disease. Anthocyanins are pigments found in plant structures that consist of an anthocyanidin (aglycone) attached to sugar moieties. Anthocyanins may be beneficial for health through effects on cellular antioxidant status and inflammation; however, their underlying mechanisms of action in their protection of chronic diseases are likely complex and require further elucidation. This Special Issue comprises 8 peer-reviewed papers (including 6 original research articles) which highlight the diverse bioactivities of anthocyanins and anthocyanin-rich foods in the protection against chronic disease. 10.3390/nu11092107
    fruits and their flavonoids in inflammatory bowel disease: an overview. Musumeci Laura,Maugeri Alessandro,Cirmi Santa,Lombardo Giovanni Enrico,Russo Caterina,Gangemi Sebastiano,Calapai Gioacchino,Navarra Michele Natural product research Inflammatory bowel disease (IBD), with its major manifestations being Crohn's disease and ulcerative colitis, belongs to the gastrointestinal inflammatory disorders, whose main therapeutic approach is represented by synthetic anti-inflammatory drugs. However, they are often accompanied by many side effects that shifted the interest of the scientific community towards natural products. In this context, several studies asserted the anti-IBD effects of fruits and their flavonoids, thus the aim of the present review is to provide robust evidence favouring their role in the prevention and treatment of IBD. Key mechanisms relate to their anti-inflammatory and antioxidant properties, as well as their ability to modulate gut microbiota. All the findings collected in this review, lay the foundations for further studies in human with the aim of evaluating the concrete applicability as a novel preventive and therapeutic approach of fruits and their flavonoids.[Figure: see text]. 10.1080/14786419.2019.1601196
    Flavonoids and gut health. Pei Ruisong,Liu Xiaocao,Bolling Bradley Current opinion in biotechnology Flavonoids are dietary non-nutrient bioactives with antioxidant and anti-inflammatory properties. Fruits, vegetables, nuts, legumes, and tea are rich in flavonoids. After consumption, flavonoids are extensively metabolized by the gut microbiota and host tissues. Flavonoid metabolism exhibits extensive variation between individuals. It is plausible that inter-individual differences in flavonoid metabolism impact the immune system. Pre-clinical studies have characterized direct and indirect mechanisms by which flavonoids modulate intestinal immune function. This includes modulation of T cell differentiation, alteration of gut microbiota, and modulation of cytokines. Defining the importance of these mechanisms to human chronic disease will improve dietary recommendations for the anti-inflammatory uses of flavonoids. 10.1016/j.copbio.2019.12.018
    Deciphering the Role of Polyphenols in Sports Performance: From Nutritional Genomics to the Gut Microbiota toward Phytonutritional Epigenomics. Sorrenti Vincenzo,Fortinguerra Stefano,Caudullo Giada,Buriani Alessandro Nutrients The individual response to nutrients and non-nutrient molecules can be largely affected by three important biological layers. The gut microbiome can alter the bioavailability of nutrients and other substances, the genome can influence molecule kinetics and dynamics, while the epigenome can modulate or amplify the properties of the genome. Today the use of omic techniques and bioinformatics, allow the construction of individual multilayer networks and thus the identification of personalized strategies that have recently been considered in all medical fields, including sports medicine. The composition of each athlete's microbiome influences sports performance both directly by acting on energy metabolism and indirectly through the modulation of nutrient or non-nutrient molecule availability that ultimately affects the individual epigenome and the genome. Among non-nutrient molecules polyphenols can potentiate physical performances through different epigenetic mechanisms. Polyphenols interact with the gut microbiota, undergoing extensive metabolism to produce bioactive molecules, which act on transcription factors involved in mitochondrial biogenesis, antioxidant systems, glucose and lipid homeostasis, and DNA repair. This review focuses on polyphenols effects in sports performance considering the individual microbiota, epigenomic asset, and the genomic characteristics of athletes to understand how their supplementation could potentially help to modulate muscle inflammation and improve recovery. 10.3390/nu12051265
    The roles of gut microbiota and circadian rhythm in the cardiovascular protective effects of polyphenols. Man Andy W C,Xia Ning,Daiber Andreas,Li Huige British journal of pharmacology Polyphenols are secondary metabolites of plants that have been widely studied for their health benefits as antioxidants. In the last decade, several clinical trials and epidemiological studies have shown that long-term consumption of polyphenol-rich diet protects against chronic diseases such as cancers and cardiovascular diseases. Current cardiovascular studies have also suggested an important role of gut microbiota and circadian rhythm in the pathogenesis metabolic and cardiovascular diseases. It is known that polyphenols can modulate the composition of core gut microbiota and interact with circadian clocks. In this article, we summarize recent findings, review the molecular mechanisms and the potential of polyphenols as dietary supplements for regulating gut microbiota and circadian rhythms, and discuss future research directions. LINKED ARTICLES: This article is part of a themed section on The Pharmacology of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.6/issuetoc. 10.1111/bph.14850
    Gut Permeability and Microbiota in Parkinson's Disease: Role of Depression, Tryptophan Catabolites, Oxidative and Nitrosative Stress and Melatonergic Pathways. Anderson George,Seo Moonsang,Berk Michael,Carvalho Andre F,Maes Michael Current pharmaceutical design BACKGROUND:Increased gut permeability (leaky gut) and alterations in gut microbiota are now widely accepted as relevant to the etiology, course and treatment of many neuropsychiatric disorders, including Parkinson disease (PD). Although a wide array of data on the biological underpinnings of PD has not yet been linked to such gut-associated changes, increased gut permeability and dysregulated microbiota alter many pathways germane to PD. METHODS:In this article we review and integrate these wider biological changes in PD, including increased oxidative and nitrosative stress, immune-inflammatory processes, tryptophan catabolites and alterations in serotoninergic and melatoninergic pathways. RESULTS:These wider biological changes in PD are compatible with alterations in gut permeability and changes in gut microbiota. By driving tryptophan down the kynurenine pathway, pro-inflammatory cytokines and chronic stress-driven activation of the hypothalamic-pituitary-adrenal axis decrease the availability of serotonin as a precursor for activation of the melatonergic pathways. CONCLUSION:Decreased local melatonin synthesis in glia, gut, neuronal and immune cells is likely to be important to the etiology, course and management of PD.
    Sex-Specific Changes in Gut Microbiome Composition following Blueberry Consumption in C57BL/6J Mice. Wankhade Umesh D,Zhong Ying,Lazarenko Oxana P,Chintapalli Sree V,Piccolo Brian D,Chen Jin-Ran,Shankar Kartik Nutrients The antioxidant and anti-inflammatory properties of blueberries improve vascular function and insulin sensitivity. However, the bioavailability of the active compounds in blueberries is largely dependent on the gut microbiota, which may themselves be altered by blueberry components. The objective of the current study was to explore a possible sex-dependent modulation of the gut microbiota following supplementation with blueberries in adult mice. Eight-week-old C57BL/6J mice (n = 7⁻10/group) were provided with control or blueberry-containing diets (5% freeze-dried powder) for 4 weeks. Body weight, composition, and food intake were measured weekly. Genomic DNA was isolated from the cecal contents for 16S rRNA sequencing. Blueberry feeding decreased a-diversity (operational taxonomical unit &nbsp;abundance) and altered b-diversity (p < 0.05). At the phylum level, the Firmicutes to Bacteroidetes ratio was significantly lower in the blueberry-fed groups (p < 0.001), along with increased Tenericutes and decreased Deferribacteres. At the genus level, blueberry feeding led to sexually-dimorphic differences, which were associated with predicted metabolic pathways. Pathways such as fatty acid and lipid metabolism were significantly different and demonstrated a stronger association with microbes in the male. To summarize, blueberry supplementation led to sexually-dimorphic global changes in the gut microbiome, which could possibly contribute to physiological changes in mice. 10.3390/nu11020313
    The impact of exercise training and resveratrol supplementation on gut microbiota composition in high-fat diet fed mice. Brandt Nina,Kotowska Dorota,Kristensen Caroline M,Olesen Jesper,Lützhøft Ditte O,Halling Jens F,Hansen Martin,Al-Soud Waleed A,Hansen Lars,Kiilerich Pia,Pilegaard Henriette Physiological reports The aim of this study was to examine the effect of exercise training and dietary supplementation of resveratrol on the composition of gut microbiota and to test the hypothesis that exercise training and resveratrol can prevent high-fat diet (HFD)-induced changes in the gut microbiota. Mice fed a HFD supplemented with resveratrol (4 g/kg food) were protected against diet-induced obesity, while exercise trained HFD-fed animals (running on average 50 km/week) were not. Dietary resveratrol supplementation induced changes predominantly in the low-abundant bacteria, while exercise training induced changes in the high-abundant bacteria in the gut as analyzed by ADONIS test with Weighted UniFrac distances. Interestingly, the two interventions affected the gut microbiome independently of the inflammatory state of the HFD-fed animals as assessed by the systemic serum amyloid A levels. These results suggest that both resveratrol supplementation and regular physical activity modulate the composition of murine microbiota independently of the systemic inflammatory state. Moreover, the effects of exercise training on the microbiota seem to occur without changes in adiposity, while resveratrol-mediated alterations may relate to adipose tissue mass. 10.14814/phy2.13881
    Latitude, Vitamin D, Melatonin, and Gut Microbiota Act in Concert to Initiate Multiple Sclerosis: A New Mechanistic Pathway. Ghareghani Majid,Reiter Russel J,Zibara Kazem,Farhadi Naser Frontiers in immunology Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). While the etiology of MS is still largely unknown, scientists believe that the interaction of several endogenous and exogenous factors may be involved in this disease. Epidemiologists have seen an increased prevalence of MS in countries at high latitudes, where the sunlight is limited and where the populations have vitamin D deficiency and high melatonin levels. Although the functions and synthesis of vitamin D and melatonin are contrary to each other, both are involved in the immune system. While melatonin synthesis is affected by light, vitamin D deficiency may be involved in melatonin secretion. On the other hand, vitamin D deficiency reduces intestinal calcium absorption leading to gut stasis and subsequently increasing gut permeability. The latter allows gut microbiota to transfer more endotoxins such as lipopolysaccharides (LPS) into the blood. LPS stimulates the production of inflammatory cytokines within the CNS, especially the pineal gland. This review summarizes the current findings on the correlation between latitude, sunlight and vitamin D, and details their effects on intestinal calcium absorption, gut microbiota and neuroinflammatory mediators in MS. We also propose a new mechanistic pathway for the initiation of MS. 10.3389/fimmu.2018.02484
    Melatonin prevents obesity through modulation of gut microbiota in mice. Xu Pengfei,Wang Jialin,Hong Fan,Wang Sheng,Jin Xi,Xue Tingting,Jia Li,Zhai Yonggong Journal of pineal research Excess weight and obesity are severe public health threats worldwide. Recent evidence demonstrates that gut microbiota dysbiosis contributes to obesity and its comorbidities. The body weight-reducing and energy balancing effects of melatonin have been reported in several studies, but to date, no investigations toward examining whether the beneficial effects of melatonin are associated with gut microbiota have been carried out. In this study, we show that melatonin reduces body weight, liver steatosis, and low-grade inflammation as well as improving insulin resistance in high fat diet (HFD)-fed mice. High-throughput pyrosequencing of the 16S rRNA demonstrated that melatonin treatment significantly changed the composition of the gut microbiota in mice fed an HFD. The richness and diversity of gut microbiota were notably decreased by melatonin. HFD feeding altered 69 operational taxonomic units (OTUs) compare with a normal chow diet (NCD) group, and melatonin supplementation reversed 14 OTUs to the same configuration than those present in the NCD group, thereby impacting various functions, in particular through its ability to decrease the Firmicutes-to-Bacteroidetes ratio and increase the abundance of mucin-degrading bacteria Akkermansia, which is associated with healthy mucosa. Taken together, our results suggest that melatonin may be used as a probiotic agent to reverse HFD-induced gut microbiota dysbiosis and help us to gain a better understanding of the mechanisms governing the various melatonin beneficial effects. 10.1111/jpi.12399
    Resveratrol Attenuates Trimethylamine-N-Oxide (TMAO)-Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota. Chen Ming-liang,Yi Long,Zhang Yong,Zhou Xi,Ran Li,Yang Jining,Zhu Jun-dong,Zhang Qian-yong,Mi Man-tian mBio UNLABELLED:The gut microbiota is found to be strongly associated with atherosclerosis (AS). Resveratrol (RSV) is a natural phytoalexin with anti-AS effects; however, its mechanisms of action remain unclear. Therefore, we sought to determine whether the anti-AS effects of RSV were related to changes in the gut microbiota. We found that RSV attenuated trimethylamine-N-oxide (TMAO)-induced AS in ApoE(-/-) mice. Meanwhile, RSV decreased TMAO levels by inhibiting commensal microbial trimethylamine (TMA) production via gut microbiota remodeling in mice. Moreover, RSV increased levels of the genera Lactobacillus and Bifidobacterium, which increased the bile salt hydrolase activity, thereby enhancing bile acid (BA) deconjugation and fecal excretion in C57BL/6J and ApoE(-/-) mice. This was associated with a decrease in ileal BA content, repression of the enterohepatic farnesoid X receptor (FXR)-fibroblast growth factor 15 (FGF15) axis, and increased cholesterol 7a-hydroxylase (CYP7A1) expression and hepatic BA neosynthesis. An FXR antagonist had the same effect on FGF15 and CYP7A1 expression as RSV, while an FXR agonist abolished RSV-induced alterations in FGF15 and CYP7A1 expression. In mice treated with antibiotics, RSV neither decreased TMAO levels nor increased hepatic BA synthesis. Additionally, RSV-induced inhibition of TMAO-caused AS was also markedly abolished by antibiotics. In conclusion, RSV attenuated TMAO-induced AS by decreasing TMAO levels and increasing hepatic BA neosynthesis via gut microbiota remodeling, and the BA neosynthesis was partially mediated through the enterohepatic FXR-FGF15 axis. IMPORTANCE:Recently, trimethylamine-N-oxide (TMAO) has been identified as a novel and independent risk factor for promoting atherosclerosis (AS) partially through inhibiting hepatic bile acid (BA) synthesis. The gut microbiota plays a key role in the pathophysiology of TMAO-induced AS. Resveratrol (RSV) is a natural phytoalexin with prebiotic benefits. A growing body of evidence supports the hypothesis that phenolic phytochemicals with poor bioavailability are possibly acting primarily through remodeling of the gut microbiota. The current study showed that RSV attenuated TMAO-induced AS by decreasing TMAO levels and increasing hepatic BA neosynthesis via gut microbiota remodeling. And RSV-induced hepatic BA neosynthesis was partially mediated through downregulating the enterohepatic farnesoid X receptor-fibroblast growth factor 15 axis. These results offer new insights into the mechanisms responsible for RSV's anti-AS effects and indicate that the gut microbiota may become an interesting target for pharmacological or dietary interventions to decrease the risk of developing cardiovascular diseases. 10.1128/mBio.02210-15
    Bioactivity, Health Benefits, and Related Molecular Mechanisms of Curcumin: Current Progress, Challenges, and Perspectives. Xu Xiao-Yu,Meng Xiao,Li Sha,Gan Ren-You,Li Ya,Li Hua-Bin Nutrients Curcumin is a principal curcuminoid of turmeric (), which is commonly used as a spice in cooking and a yellow pigment in the food processing industry. Recent studies have demonstrated that curcumin has a variety of biological activities and pharmacological performances, providing protection and promotion of human health. In addition to presenting an overview of the gut metabolism of curcumin, this paper reviews the current research progress on its versatile bioactivity, such as antioxidant, anti-inflammatory, and immune-regulatory activities, and also intensively discusses its health benefits, including the protective or preventive effects on cancers and diabetes, as well as the liver, nervous system, and cardiovascular systems, highlighting the potential molecular mechanisms. Besides, the beneficial effects of curcumin on human are further stated based on clinical trials. Considering that there is still a debate on the beneficial effects of curcumin, we also discuss related challenges and prospects. Overall, curcumin is a promising ingredient of novel functional foods, with protective efficacy in preventing certain diseases. We hope this comprehensive and updated review will be helpful for promoting human-based studies to facilitate its use in human health and diseases in the future. 10.3390/nu10101553
    Reshaping faecal gut microbiota composition by the intake of trans-resveratrol and quercetin in high-fat sucrose diet-fed rats. Etxeberria U,Arias N,Boqué N,Macarulla M T,Portillo M P,Martínez J A,Milagro F I The Journal of nutritional biochemistry Diet-induced obesity is associated to an imbalance in the normal gut microbiota composition. Resveratrol and quercetin, widely known for their health beneficial properties, have low bioavailability, and when they reach the colon, they are targets of the gut microbial ecosystem. Hence, the use of these molecules in obesity might be considered as a potential strategy to modulate intestinal bacterial composition. The purpose of this study was to determine whether trans-resveratrol and quercetin administration could counteract gut microbiota dysbiosis produced by high-fat sucrose diet (HFS) and, in turn, improve gut health. Wistar rats were randomised into four groups fed an HFS diet supplemented or not with trans-resveratrol [15 mg/kg body weight (BW)/day], quercetin (30 mg/kg BW/day) or a combination of both polyphenols at those doses. Administration of both polyphenols together prevented body weight gain and reduced serum insulin levels. Moreover, individual supplementation of trans-resveratrol and quercetin effectively reduced serum insulin levels and insulin resistance. Quercetin supplementation generated a great impact on gut microbiota composition at different taxonomic levels, attenuating Firmicutes/Bacteroidetes ratio and inhibiting the growth of bacterial species previously associated to diet-induced obesity (Erysipelotrichaceae, Bacillus, Eubacterium cylindroides). Overall, the administration of quercetin was found to be effective in lessening HFS-diet-induced gut microbiota dysbiosis. In contrast, trans-resveratrol supplementation alone or in combination with quercetin scarcely modified the profile of gut bacteria but acted at the intestinal level, altering the mRNA expression of tight-junction proteins and inflammation-associated genes. 10.1016/j.jnutbio.2015.01.002
    Inadequate Production of H by Gut Microbiota and Parkinson Disease. Ostojic Sergej M Trends in endocrinology and metabolism: TEM Dysbiosis of the gut flora accompanies Parkinson disease (PD), yet no specific cause-effect link has been identified so far. The gut microbiota produce molecular hydrogen (H), a ubiquitous molecule recently recognized as a biologically active gas with antioxidant, antiapoptotic, anti-inflammatory, cytoprotective, and signaling properties. Here, we discuss an idea that an impaired production of endogenous H by intestinal microbiota might play a role in PD pathogenesis, with supplemental H debated as a possible therapy for this progressive neurodegenerative disease. 10.1016/j.tem.2018.02.006
    Coffee Silverskin Extract: Nutritional Value, Safety and Effect on Key Biological Functions. Iriondo-DeHond Amaia,Rios Maria Belen,Herrera Teresa,Rodriguez-Bertos Antonio,Nuñez Fernando,San Andres Manuel Ignacio,Sanchez-Fortun Sebastian,Del Castillo Maria Dolores Nutrients This study aimed to complete the scientific basis for the validation of a coffee silverskin extract (CSE) as a novel food ingredient according to European legislation. Nutritional value, safety, effects on biochemical biomarkers and excretion of short chain fatty acids (SCFAs) in vivo of CSE were assessed. Proteins, amino acids, fat, fatty acids, fiber, simple sugars and micronutrients were analyzed. For the first time, toxicological and physiological effects were evaluated in vivo by a repeated-dose study in healthy Wistar rats. Hormone secretion, antioxidant (enzymatic and no-enzymatic) and anti-inflammatory biomarkers, and dietary fiber fermentability of CSE (analysis of SCFAs in feces) were studied in biological samples. This unique research confirms the feasibility of CSE as a human dietary supplement with several nutrition claims: "source of proteins (16%), potassium, magnesium, calcium and vitamin C, low in fat (0.44%) and high in fiber (22%)". This is the first report demonstrating that its oral administration (1 g/kg) for 28 days is innocuous. Hormone secretion, antioxidant or anti-inflammatory biomarkers were not affected in heathy animals. Total SCFAs derived from CSE fiber fermentation were significantly higher ( < 0.05) in male treated rats compared to male control rats. All the new information pinpoints CSE as a natural, sustainable and safe food ingredient containing fermentable fiber able to produce SCFAs with beneficial effects on gut microbiota. 10.3390/nu11112693
    Metabolic and Microbial Modulation of the Large Intestine Ecosystem by Non-Absorbed Diet Phenolic Compounds: A Review. Mosele Juana I,Macià Alba,Motilva Maria-José Molecules (Basel, Switzerland) Phenolic compounds represent a diverse group of phytochemicals whose intake is associated with a wide spectrum of health benefits. As consequence of their low bioavailability, most of them reach the large intestine where, mediated by the action of local microbiota, a series of related microbial metabolites are accumulated. In the present review, gut microbial transformations of non-absorbed phenolic compounds are summarized. Several studies have reached a general consensus that unbalanced diets are associated with undesirable changes in gut metabolism that could be detrimental to intestinal health. In terms of explaining the possible effects of non-absorbed phenolic compounds, we have also gathered information regarded their influence on the local metabolism. For this purpose, a number of issues are discussed. Firstly, we consider the possible implications of phenolic compounds in the metabolism of colonic products, such as short chain fatty acids (SCFA), sterols (cholesterol and bile acids), and microbial products of non-absorbed proteins. Due to their being recognized as affective antioxidant and anti-inflammatory agents, the ability of phenolic compounds to counteract or suppress pro-oxidant and/or pro-inflammatory responses, triggered by bowel diseases, is also presented. The modulation of gut microbiota through dietetic maneuvers including phenolic compounds is also commented on. Although the available data seems to assume positive effects in terms of gut health protection, it is still insufficient for solid conclusions to be extracted, basically due to the lack of human trials to confirm the results obtained by the in vitro and animal studies. We consider that more emphasis should be focused on the study of phenolic compounds, particularly in their microbial metabolites, and their power to influence different aspects of gut health. 10.3390/molecules200917429
    Photo-activated synthesis and characterization of gold nanoparticles from Punica granatum L. seed oil: An assessment on antioxidant and anticancer properties for functional yoghurt nutraceuticals. Esther Lydia D,Khusro Ameer,Immanuel P,Esmail Galal Ali,Al-Dhabi Naif Abdullah,Arasu Mariadhas Valan Journal of photochemistry and photobiology. B, Biology Yoghurt is a fermenting milk-based dairy product that has high nutritional benefits. It exhibits not only protection against osteoporosis but also enhances gut microbiota and aids digestion. In order to improve health beneficial aspects of yoghurt, this study was aimed to synthesize gold nanoparticles (AuNPs) using seeds oil of pomegranate (Punica granatum L.) and to formulate functional yoghurt for its antioxidant and anticancer properties. The synthesized AuNPs were characterized using UV-Vis spectrophotometer, FT-IR, XRD, EDX, SEM, DLS, and Zeta potential analyzer. The photo-induced synthesis of AuNPs showed particle size and zeta potential of 70 nm and +34 mV, respectively, with unique peak at 525 nm as observed using UV-Vis spectrophotometer. The FT-IR spectrum of AuNPs showed shifts in the functional groups from 3632.27 to 541.899 cm, thereby indicating the presence of various functional groups in pomegranate seed oil (PSO) and PSO-capped AuNPs. The AuNPs were observed to be smooth, elongated, and rectangular in shape. The PSO-capped AuNPs based formulation of functional yoghurt revealed DPPH degradation (23.6 ± 1.5 to 62.5 ± 1.8%) and HO scavenging traits (21.6 ± 1.3 to 62.8 ± 1.8%) at varied concentrations. In addition, the PSO-capped AuNPs depicted strong anticancer attributes against lung and colon cancer with the cell viability ranging from 80.3 to 25% and 83.3 to 28.4.2%, respectively. Results concluded that the antioxidative components of PSO might have reduced and formulated AuNPs-based functional yoghurt. This functional yoghurt may reveal pivotal applications in food, nutraceuticals, and pharmaceuticals, especially as antioxidant and anticancer agents. 10.1016/j.jphotobiol.2020.111868
    Paclitaxel metabolism in rat and human liver microsomes is inhibited by phenolic antioxidants. Václavíková Radka,Horský Stanislav,Simek Petr,Gut Ivan Naunyn-Schmiedeberg's archives of pharmacology Paclitaxel is an important, recently introduced anti-neoplastic drug. Paclitaxel metabolites are virtually inactive in comparison with the parent drug. The study investigated whether phenolic antioxidants could inhibit metabolic inactivation sufficiently to increase paclitaxel effects. Cytochrome p450 (CYP)-catalysed metabolism of paclitaxel was investigated in rat and human liver microsomes. In rat microsomes, paclitaxel was metabolised mainly to C3'-hydroxypaclitaxel (C3'-OHP), less to C2-hydroxypaclitaxel (C2-OHP), di-hydroxypaclitaxel (di-OHP) and another monohydroxylated paclitaxel. In human liver microsomes, 6alpha-hydroxypaclitaxel (6alpha-OHP), formed by CYP2C8, was the main metabolite, while C3'-OHP, C2-OHP and another product different from di-OHP were minor metabolites, formed by CYP3A4. In individual human livers 6alpha-OHP was formed at 1.8-fold to 13-fold higher rates than C3'-OHP. Kinetic parameters (K(m) and V(max)) of production of various metabolites in rat and human liver microsomes revealed differences between species as well as human individual differences. Nine phenolic antioxidants ((+)-catechin, (-)-epicatechin, fisetin, gallic acid, morin, myricetin, naringenin, quercetin and resveratrol) were tested for inhibition of paclitaxel metabolism. In rat microsomes, resveratrol was more inhibitory than fisetin; the other phenolic antioxidants were without effect. In human microsomes, the inhibiting potency decreased in the order fisetin >quercetin >morin >resveratrol, while the other phenolic antioxidants were not inhibitory; the formation of 6alpha-OHP (CYP2C8) was generally more inhibited than that of C3'-OHP. The inhibition was mostly mixed-type. The results suggest that oral administration of some phenolic substances might increase paclitaxel blood concentrations during chemotherapy. 10.1007/s00210-003-0781-9
    A dietary isothiocyanate-enriched moringa () seed extract improves glucose tolerance in a high-fat-diet mouse model and modulates the gut microbiome. Jaja-Chimedza Asha,Zhang Li,Wolff Khea,Graf Brittany L,Kuhn Peter,Moskal Kristin,Carmouche Richard,Newman Susan,Salbaum J Michael,Raskin Ilya Journal of functional foods (moringa) has been traditionally used for the treatment of diabetes and in water purification. We previously showed that moringa seed extract (MSE), standardized to its primary bioactive isothiocyanate (MIC-1), modulated inflammatory and antioxidant signaling pathways . To understand the efficacy and mechanisms of action of MSE , we incorporated MSE into the diets of normal and obese C57Bl/6J male mice fed a standard low-fat diet or a very high-fat diet for 12 wk, respectively. MSE supplementation resulted in reduced body weight, decreased adiposity, improved glucose tolerance, reduced inflammatory gene expression, and increased antioxidant gene expression. 16S rRNA gene sequencing and quantitative PCR of fecal/cecal samples showed major modulation of the gut microbial community and a significantly reduced bacterial load, similar to an antibiotic response. This suggests that MSE improves metabolic health by its intracellular anti-inflammatory and antioxidant activities, and/or its antibiotic-like restructuring of the gut microbiota. 10.1016/j.jff.2018.05.056
    Ferulic acid ameliorates nonalcoholic fatty liver disease and modulates the gut microbiota composition in high-fat diet fed ApoE mice. Ma Yunci,Chen Kai,Lv Lin,Wu Shaoyu,Guo Zhijian Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie The objective of this study was to investigate the effects of ferulic acid (FA) on nonalcoholic fatty liver disease (NAFLD) and gut microbiota, and its regulation mechanism in ApoE mice fed on a high-fat diet (HFD). Liver morphology, blood lipids, gut microbiota and their metabolite indole-3-acetic acid (I3A) were determined in ApoE mice. We also examined the hepatic expression of aryl hydrocarbon receptor (AHR), which inhibits the expression of fatty acid synthase (FASN) and sterol regulatory element-binding protein 1c (SREBP-1c), and ultimately reduces the deposition of triglycerides (TG) and total cholesterol (TC) in the liver. The results of the animal experiment showed that oral administration of FA markedly alleviated the formation of NAFLD and decreased the levels of serum TC, TG and low-density lipoprotein cholesterol (LDL-C). Furthermore, FA supplementation altered the composition of gut microbiota, in particular, modulating the ratio of Firmicutes to Bacteroidetes, and decreased the generation of I3A. Additionally, FA could increase the expression of hepatic AHR and inhibit the expression of FASN and SREBP-1c in the liver. Finally, we found that FA did not have hepatorenal toxicity. The findings above illustrate that FA has the potential to ameliorate NAFLD, some of which are closely related to the modulation of specific gut microbiota and the regulation of genes involved in TG and TC metabolism. 10.1016/j.biopha.2019.108753
    Structural shift of gut microbiota during chemo-preventive effects of epigallocatechin gallate on colorectal carcinogenesis in mice. Wang Xin,Ye Tao,Chen Wen-Jie,Lv You,Hao Zong,Chen Jun,Zhao Jia-Ying,Wang Hui-Peng,Cai Yuan-Kun World journal of gastroenterology AIM:To investigate the effect of epigallocatechin gallate (EGCG) on structural changes of gut microbiota in colorectal carcinogenesis. METHODS:An azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis mouse model was established. Forty-two female FVB/N mice were randomly divided into the following three groups: group 1 (10 mice, negative control) was treated with vehicle, group 2 (16 mice, positive control) was treated with AOM plus vehicle, and group 3 (16 mice, EG) was treated with AOM plus EGCG. For aberrant crypt foci (ACF) evaluation, the colons were rapidly took out after sacrifice, rinsed with saline, opened longitudinally, laid flat on a polystyrene board, and fixed with 10% buffered formaldehyde solution before being stained with 0.2% methylene blue in saline. For tumor evaluation, the colon was macroscopically inspected and photographed, then the total number of tumors was enumerated and tumor size measured. For histological examination, the fixed tissues were paraffin-embedded and sectioned at 5 mm thickness. Microbial genomic DNA was extracted from fecal and intestinal content samples using a commercial kit. The V4 hypervariable regions of 16S rRNA were PCR-amplified with the barcoded fusion primers. Using the best hit classification option, the sequences from each sample were aligned to the RDP 16S rRNA training set to classify the taxonomic abundance in QIIME. Statistical analyses were then performed. RESULTS:Treatment of mice with 1% EGCG caused a significant decrease in the mean number of ACF per mouse, when compared with the model mice treated with AOM/DSS (5.38 ± 4.24 13.13 ± 3.02, < 0.01). Compared with the positive control group, 1% EGCG treatment dependently decreased tumor load per mouse by 85% (33.96 ± 6.10 2.96 ± 2.86, respectively, < 0.01). All revealed that EGCG could inhibit colon carcinogenesis by decreasing the number of precancerous lesions as well as solid tumors, with reduced tumor load and delayed histological progression of CRC. During the cancerization, the diversity of gut microbiota increased, potential carcinogenic bacteria such as were enriched, and the abundance of butyrate-producing bacteria (, , .) decreased continuously. In contrast, the structure of gut microbiota was relatively stable during the intervention of EGCG on colon carcinogenesis. Enrichment of probiotics (, , .) might be a potential mechanism for EGCG's effects on tumor suppression. bioinformatics analysis, principal coordinate analysis and cluster analysis of the tumor formation process, we found that the diversity of gut microbiota increased in the tumor model group while that in the EGCG interfered group (EG) remained relatively stable. CONCLUSION:Gut microbiota imbalance might be a potential mechanism for the prevention of malignant transformation by EGCG, which is significant for diagnosis, treatment, prognosis evaluation, and prevention of colorectal cancer. 10.3748/wjg.v23.i46.8128
    Effect of clarification techniques and rat intestinal extract incubation on phenolic composition and antioxidant activity of black currant juice. Pinelo Manuel,Landbo Anne-Katrine R,Vikbjerg Anders F,Meyer Anne S Journal of agricultural and food chemistry This study examined the phenolic composition and the antioxidant potencies of black currant juices that had been experimentally clarified with acidic proteases and pectinases to retain the phenolics and which had been subjected to rat intestinal mucosa extract incubation to mimic gut cell mediated biotransformation of phenolics. When compared at equimolar levels of 2.5 microM gallic acid equivalents, the black currant juice samples prolonged the induction time of human low-density lipoprotein oxidation in vitro by 2.6-3.6 times, and the order of antioxidant potency of differently clarified black currant juices was centrifuged juice > gelatin silica sol clarified juice > enzymatically clarified juice approximately raw juice. No immediate relationship between the, almost similar, phenolic profiles of the juice samples and their relative antioxidant activities could be established. Incubation of juices with a rat small intestine cell extract for 19 h promoted significant decreases in the contents of the anthocyanin 3-O-beta-glucosides (cyanidin 3-O-beta-glucoside and delphinidin 3-O-beta-glucoside), but did not affect the anthocyanin 3-O-beta-rutinosides (cyanidin 3-O-beta-rutinoside and delphinidin 3-O-beta-rutinoside) of the black currant juice. Black currant juice samples subjected to such intestinal cell extract incubation had approximately 30% decreased antioxidant capacity. Incubation of juices with the rat small intestine cell extracts at neutral pH appeared to decrease the levels of delphinidin glucosides more than the levels of cyanidin glucosides. The results provide an explanation for the predominant detection of anthocyanin rutinosides, and not anthocyanin glucosides, in plasma and urine in in vivo studies and provide important clues to better understand the complex mechanisms affecting dietary phenols in the gut. 10.1021/jf0600096
    Enzyme-assisted processing increases antimicrobial and antioxidant activity of bilberry. Puupponen-Pimiä Riitta,Nohynek Liisa,Ammann Sabine,Oksman-Caldentey Kirsi-Marja,Buchert Johanna Journal of agricultural and food chemistry The effects of nine cell wall-degrading enzymes on the antimicrobial and antioxidant activities of bilberry were studied. Antimicrobial activity was measured using the human pathogens Salmonella enterica sv. Typhimurium and Staphylococcus aureus as test strains. Enzyme treatments liberated phenolics from the cell wall matrix, which clearly increased the antimicrobial activity of berry juices, press cakes, and berry mashes on the basis of plate counts. Antibacterial effects were stronger against Salmonella than against Staphylococcus bacteria. In general, the increase in activity measured as colony-forming units per milliliter was 3-5 logarithmic units against Salmonella and 1-2 units against Staphylococcus bacteria. Increase in antimicrobial activity was observed only in acidic conditions, which is also the natural environment in various berry products, such as juices. The activity profile of the pectinase preparation affected the chemistry of the phenolics due to the presence of deglycosylating activities in some preparations. The difference in phenolic profiles was reflected in the antimicrobial effects. Bilberry mashes treated with Pectinex Ultra SP-L, Pectinex 3 XL, and Pectinex BE XXL were most efficient against Salmonella bacteria, whereas mashes treated with Pectinex Smash, Pectinex BE 3-L, and Biopectinase CCM showed the strongest antimicrobial activity against Staphylococcus bacteria. Due to the liberation of phenolics from the cell wall matrix the antioxidant activity measured as radical scavenging activity was also increased on average about 30% by the enzymatic treatments. The highest increase in phenolic compounds was about 40%. Highest increases in anthocyanins and in antioxidant activity were observed in berry mash treated with Pectinex Smash XXL enzyme, and the lowest increase was observed after treatment with Pectinex BE 3-L. Enzyme-assisted processing is traditionally used to improve berry and fruit juice yields. However, enzymatic treatments also have an impact on the functional properties of the products. The increased liberation of phenolics from the cell wall matrix can prolong the shelf life of berry products by limiting the growth of contaminants during processing or storage. The increased amount of phenolic compounds may also have a positive effect on gut well-being. 10.1021/jf072001h
    Health relevance of the modification of low grade inflammation in ageing (inflammageing) and the role of nutrition. Calder Philip C,Bosco Nabil,Bourdet-Sicard Raphaëlle,Capuron Lucile,Delzenne Nathalie,Doré Joel,Franceschi Claudio,Lehtinen Markus J,Recker Tobias,Salvioli Stefano,Visioli Francesco Ageing research reviews Ageing of the global population has become a public health concern with an important socio-economic dimension. Ageing is characterized by an increase in the concentration of inflammatory markers in the bloodstream, a phenomenon that has been termed "inflammageing". The inflammatory response is beneficial as an acute, transient reaction to harmful conditions, facilitating the defense, repair, turnover and adaptation of many tissues. However, chronic and low grade inflammation is likely to be detrimental for many tissues and for normal functions. We provide an overview of low grade inflammation (LGI) and determine the potential drivers and the effects of the "inflamed" phenotype observed in the elderly. We discuss the role of gut microbiota and immune system crosstalk and the gut-brain axis. Then, we focus on major health complications associated with LGI in the elderly, including mental health and wellbeing, metabolic abnormalities and infections. Finally, we discuss the possibility of manipulating LGI in the elderly by nutritional interventions. We provide an overview of the evidence that exists in the elderly for omega-3 fatty acid, probiotic, prebiotic, antioxidant and polyphenol interventions as a means to influence LGI. We conclude that slowing, controlling or reversing LGI is likely to be an important way to prevent, or reduce the severity of, age-related functional decline and the onset of conditions affecting health and well-being; that there is evidence to support specific dietary interventions as a strategy to control LGI; and that a continued research focus on this field is warranted. 10.1016/j.arr.2017.09.001
    Allicin Modifies the Composition and Function of the Gut Microbiota in Alcoholic Hepatic Steatosis Mice. Panyod Suraphan,Wu Wei-Kai,Lu Kuan-Hung,Liu Chun-Ting,Chu Yung-Lin,Ho Chi-Tang,Hsiao Wen-Luan Wendy,Lai Yi-Syuan,Chen Wei-Cheng,Lin Yu-En,Lin Shi-Hang,Wu Ming-Shiang,Sheen Lee-Yan Journal of agricultural and food chemistry The intestinal microbiome plays an important role in the pathogenesis of liver diseases. Alcohol intake induces gut microbiota dysbiosis and alters its function. This study investigated the antibiotic effect of allicin in mice with hepatic steatosis. Male C57BL/6 mice were administered an ethanol diet supplemented with allicin (5 and 20 mg/(kg bw day)) for 4 weeks. Allicin modified the gut microbiota composition. Cecal microbiota exhibited a positive correlation with alcohol and hepatic triacylglycerol, but were suppressed with allicin. Ethanol diet with 5 mg of allicin induced a lower intestinal permeability compared to the ethanol diet alone. Allicin mediated the lipopolysaccharide (LPS)-CD14-toll-like receptor 4 (TLR4)-induced hepatic inflammation pathway by reducing LPS, CD14, TLR4, and pro-inflammatory cytokines-tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. However, hepatic inflammation primarily resulted from alcohol toxicity rather than LPS production in the gut. The prediction of functional profiles from metagenomic 16S ribosomal RNA (rRNA) data revealed different functional profiles in each group. The predicted aldehyde dehydrogenase tended to increase in alcoholic mice administered allicin. The predicted LPS-related pathway and LPS biosynthesis protein results exhibited a similar trend as plasma LPS levels. Thus, alcohol and allicin intake shapes the gut microbiota and its functional profile and improves the CD14-TLR4 pathway to alleviate inflammation in the liver. 10.1021/acs.jafc.9b07555
    Rape bee pollen alleviates dextran sulfate sodium (DSS)-induced colitis by neutralizing IL-1β and regulating the gut microbiota in mice. Chen Sinan,Zhao Haoan,Cheng Ni,Cao Wei Food research international (Ottawa, Ont.) Colitis is a major chronic disease in today's society. Consumption of phenolic compounds can protect against colitis. We examined the phenolic compounds of rape bee pollen extract (RPE) and investigated its prevention of DSS-induced colitis in C57BL/6 mice. HPLC-DAD-ECD analysis showed that 7 phenolic compounds were tentatively identified in RPE, of which kaempferol had the highest content (19.87 mg/g), followed by sinapic acid and rosmarinic acid. RPE at 21.2 g/kg BW (HD - high-dose group) and 10.6 g/kg BW (LD - low-dose group) ameliorated colon shortening, spleen swelling and colon weight reduction, improved the structure of colonic villi, glandular structures and crypts, which was further confirmed by conventional histological assessment, and inhibited the activities of related inflammatory cytokines. In particular, IL-1β expression was downregulated by approximately 90% compared with that of the model group. Additionally, treatment with RPE altered the gut microbial structure of mice with colitis, showing that the abundances of Allobaculum and Bacteroides were significantly reduced and the abundance of Lactobacillus was markedly increased. This study indicated that RPE could protect the colon from DSS-induced colitis by increasing antioxidant capacity, alleviating inflammation and regulating the gut microbiota. This paper was conducted to investigate the potent protective effects of RPE treatments on a mouse model of colitis and provided new ideas for the application of rape bee pollen. 10.1016/j.foodres.2019.04.022
    Identification of urinary metabolites that correlate with clinical improvements in children with autism treated with sulforaphane from broccoli. Bent Stephen,Lawton Brittany,Warren Tracy,Widjaja Felicia,Dang Katherine,Fahey Jed W,Cornblatt Brian,Kinchen Jason M,Delucchi Kevin,Hendren Robert L Molecular autism Background:Children with autism spectrum disorder (ASD) have urinary metabolites suggesting impairments in several pathways, including oxidative stress, inflammation, mitochondrial dysfunction, and gut microbiome alterations. Sulforaphane, a supplement with indirect antioxidant effects that are derived from broccoli sprouts and seeds, was recently shown to lead to improvements in behavior and social responsiveness in children with ASD. We conducted the current open-label study to determine if we could identify changes in urinary metabolites that were associated with clinical improvements with the goal of identifying a potential mechanism of action. Methods:Children and young adults enrolled in a school for children with ASD and related neurodevelopmental disorders were recruited to participate in a 12-week, open-label study of sulforaphane. Fasting urinary metabolites and measures of behavior (Aberrant Behavior Checklist-ABC) and social responsiveness (Social Responsiveness Scale-SRS) were measured at baseline and at the end of the study. Pearson's correlation coefficient was calculated for the pre- to post-intervention change in each of the two clinical scales (ABS and SRS) versus the change in each metabolite. Results:Fifteen children completed the 12-week study. Mean scores on both symptom measures showed improvements (decreases) over the study period, but only the change in the SRS was significant. The ABC improved - 7.1 points (95% CI - 17.4 to 3.2), and the SRS improved - 9.7 points (95% CI - 18.7 to - 0.8). We identified 77 urinary metabolites that were correlated with changes in symptoms, and they clustered into pathways of oxidative stress, amino acid/gut microbiome, neurotransmitters, hormones, and sphingomyelin metabolism. Conclusions:Urinary metabolomics analysis is a useful tool to identify pathways that may be involved in the mechanism of action of treatments targeting abnormal physiology in ASD. Trial registration:This study was prospectively registered at clinicaltrials.gov (NCT02654743) on January 11, 2016. 10.1186/s13229-018-0218-4
    Effects of Turmeric and Curcumin Dietary Supplementation on Human Gut Microbiota: A Double-Blind, Randomized, Placebo-Controlled Pilot Study. Peterson Christine T,Vaughn Alexandra R,Sharma Vandana,Chopra Deepak,Mills Paul J,Peterson Scott N,Sivamani Raja K Journal of evidence-based integrative medicine BACKGROUND:Curcuma longa (common name: turmeric) and one of its biologically active constituents, curcumin, have received increased clinical attention. Insufficient data exist on the effects of curcumin and turmeric on the gut microbiota and such studies in humans are lacking. METHODS:Turmeric tablets with extract of piperine (Bioperine) (n = 6), curcumin with Bioperine tablets (n = 5), or placebo tablets (n = 3) were provided to healthy human subjects and subsequent changes in the gut microbiota were determined by 16S rDNA sequencing. RESULTS:The number of taxa detected ranged from 172 to 325 bacterial species. The placebo group displayed an overall reduction in species by 15%, whereas turmeric-treated subjects displayed a modest 7% increase in observed species posttreatment. Subjects taking curcumin displayed an average increase of 69% in detected species. The gut microbiota response to treatment was highly personalized, thus leading to responders and nonresponders displaying response concordance. These "responsive" subjects defined a signature involving uniform increases in most Clostridium spp., Bacteroides spp., Citrobacter spp., Cronobacter spp., Enterobacter spp., Enterococcus spp., Klebsiella spp., Parabacteroides spp., and Pseudomonas spp. Common to these subjects was the reduced relative abundance of several Blautia spp. and most Ruminococcus spp. CONCLUSIONS:All participants' microbiota displayed significant variation over time and individualized response to treatment. Among the responsive participants, both turmeric and curcumin altered the gut microbiota in a highly similar manner, suggesting that curcumin may drive the majority of observed changes observed in turmeric-treated subjects. 10.1177/2515690X18790725
    Melatonin reprogramming of gut microbiota improves lipid dysmetabolism in high-fat diet-fed mice. Yin Jie,Li Yuying,Han Hui,Chen Shuai,Gao Jing,Liu Gang,Wu Xin,Deng Jinping,Yu Qifang,Huang Xingguo,Fang Rejun,Li Tiejun,Reiter Russel J,Zhang Dong,Zhu Congrui,Zhu Guoqiang,Ren Wenkai,Yin Yulong Journal of pineal research Melatonin has been shown to improve lipid metabolism and gut microbiota communities in animals and humans; however, it remains to know whether melatonin prevents obesity through gut microbiota. Here, we found that high-fat diet promoted the lipid accumulation and intestinal microbiota dysbiosis in mice, while oral melatonin supplementation alleviated the lipid accumulation and reversed gut microbiota dysbiosis, including the diversity of intestinal microbiota, relative abundances of Bacteroides and Alistipes, and functional profiling of microbial communities, such as energy metabolism, lipid metabolism, and carbohydrate metabolism. Interestingly, melatonin failed to alleviate the high-fat-induced lipid accumulation in antibiotic-treated mice; however, microbiota transplantation from melatonin-treated mice alleviated high-fat diet-induced lipid metabolic disorders. Notably, short-chain fatty acids were decreased in high-fat diet-fed mice, while melatonin treatment improved the production of acetic acid. Correlation analysis found a marked correlation between production of acetic acid and relative abundances of Bacteroides and Alistipes. Importantly, sodium acetate treatment also alleviated high-fat diet-induced lipid metabolic disorders. Taken together, our results suggest that melatonin improves lipid metabolism in high-fat diet-fed mice, and the potential mechanisms may be associated with reprogramming gut microbiota, especially, Bacteroides and Alistipes-mediated acetic acid production. Future studies are needed for patients with metabolic syndrome to fully understand melatonin's effects on body weight and lipid profiles and the potential mechanism of gut microbiota. 10.1111/jpi.12524
    Cystine and Theanine Improve Survival after Gut Ischemia-Reperfusion. Miyakuni Taiki,Fukatsu Kazuhiko,Ri Motonari,Murakoshi Satoshi,Inoue Yoshiko,Kurihara Shigekazu,Takayama Tadatoshi,Yasuhara Hiroshi Annals of nutrition & metabolism BACKGROUND AND AIM:Oral administration of cystine and theanine (CT) may modulate antioxidant glutathione (GSH) metabolism, thereby improving outcomes after gut ischemia reperfusion. METHODS:Experiment 1: Institute of Cancer Research mice (n = 35) were assigned to a Vehicle (n = 11), a CT140 (n = 14), or a CT280 (n = 10) group. The CT140 and 280 groups were given CT at respective dosages of 140 and 280 mg/kg (cystine: theanine = 5: 2) once daily via gavage for 5 days. All mice underwent 75-min occlusion of the superior mesenteric artery (SMA). Survival after reperfusion was observed. Experiment 2: Mice (n = 67) were pretreated for 5 days (Vehicle: n = 24, CT280: n = 20, vehicle/sham: n = 23). The Vehicle and CT280 groups underwent 60-min SMA occlusion. Levels of GSH, the oxidized form of GSH, Glutathione-S-S-Glutathione (GSSG), and GSH-related amino acids (cysteine and glutamic acid) in the small intestine, and plasma cytokine (IL-6, IL-1β, TNFα) levels, were evaluated before (0 h), 3, 6, or 9 h after reperfusion. RESULTS:Experiment 1: The CT280 group showed significantly better survival than the Vehicle group. Experiment 2: Gut GSSG, cysteine, and glutamic acid levels were higher in the CT280 than in the Vehicle group after reperfusion. Plasma IL-6 and TNFα levels rose more rapidly in the CT280 than in the Vehicle group. CONCLUSION:Oral administration of CT improves survival after gut I/R, possibly through the modulation of the GSH-redox cycle and cytokine responses. 10.1159/000489825
    Grape seed proanthocyanidin extract ameliorates inflammation and adiposity by modulating gut microbiota in high-fat diet mice. Liu Wen,Zhao Shaoqian,Wang Jiqiu,Shi Juan,Sun Yingkai,Wang Weiqing,Ning Guang,Hong Jie,Liu Ruixin Molecular nutrition & food research SCOPE:Obesity and associated metabolic complications is a worldwide public health issue. Gut microbiota have been recently linked to obesity and its related inflammation. In this study, we have explored the anti-inflammatory effect of grape seed proanthocyanindin extract (GSPE) in the high-fat diet (HFD)-induced obesity and identified the contribution of the gut microbiota to GSPE effects on metabolism. METHODS AND RESULTS:Mice were fed a normal diet and a high-fat diet with or without GSPE (300 mg/kg body weight/day) by oral gavage for 7 weeks. Supplementation with GSPE significantly decreased plasma levels of inflammatory factors such as TNF-α, IL-6 and MCP-1, companied with ameliorated macrophage infiltration in epidydimal fat and liver tissues. Furthermore, GSPE also reduced epidydimal fat mass and improved insulin sensitivity. 16S rDNA analyses revealed that GSPE supplementation modulated the gut microbiota composition and certain bacteria including Clostridium XIVa, Roseburia and Prevotella. More importantly, depleting gut microbiota by antibiotics treatment abolished the beneficial effects of GSPE on inflammation and adiposity. CONCLUSION:Our study identifies the novel links between gut microbiota alterations and metabolic benefits by GSPE supplementation, providing possibilities for the prevention and treatment of metabolic disorders by targeting gut microbiota through a potential prebiotic agent GSPE. 10.1002/mnfr.201601082
    Red pitaya betacyanins protects from diet-induced obesity, liver steatosis and insulin resistance in association with modulation of gut microbiota in mice. Song Haizhao,Chu Qiang,Yan Fujie,Yang Yunyun,Han Wen,Zheng Xiaodong Journal of gastroenterology and hepatology BACKGROUND AND AIM:Growing evidence indicates that gut microbiota contributes to obesity and its related metabolic disorders. Betacyanins possess free radical scavenging and antioxidant activities, suggesting its potential beneficial effects on metabolic diseases. The present study aimed to investigate the metabolic effect of red pitaya (Hylocereus polyrhizus) fruit betacyanins (HPBN) on high-fat diet-fed mice and determine whether the beneficial effects of HPBN are associated with the modulation of gut microbiota. METHODS:Thirty-six male C57BL/6J mice were divided into three groups and fed low-fat diet (LFD), high-fat diet (HFD), or high-fat diet plus HPBN of 200 mg/kg for 14 weeks. Sixteen seconds rRNA sequencing was used to analyze the composition of gut microbiota. RESULTS:Our results indicated that administration of HPBN reduced HFD-induced body weight gain and visceral obesity and improved hepatic steatosis, adipose hypertrophy, and insulin resistance in mice. Sixteen seconds rRNA sequencing performed on the MiSeq Illumina platform (Illumina, Inc., San Diego, CA, USA) showed that HPBN supplement not only decreased the proportion of Firmicutes and increased the proportion of Bacteroidetes at the phylum level but also induced a dramatic increase in the relative abundance of Akkermansia at the genus level. CONCLUSIONS:Red pitaya betacyanins protect from diet-induced obesity and its related metabolic disorders, which is associated with improved inflammatory status and modulation of gut microbiota, especially its ability to decrease the ratio of Firmicutes and Bacteroidetes and increase the relative abundance of Akkermansia. The study suggested a clinical implication of HPBN in the management of obesity, non-alcoholic fatty liver disease, and type 2 diabetes. 10.1111/jgh.13278
    Cardiovascular and Antiobesity Effects of Resveratrol Mediated through the Gut Microbiota. Bird Julia K,Raederstorff Daniel,Weber Peter,Steinert Robert E Advances in nutrition (Bethesda, Md.) Encouraging scientific research into the health effects of dietary bioactive resveratrol has been confounded by its rapid first-pass metabolism, which leads to low in vivo bioavailability. Preliminary studies have shown that resveratrol can modulate gut microbiota composition, undergo biotransformation to active metabolites via the intestinal microbiota, or affect gut barrier function. In rodents, resveratrol can modify the relative Bacteroidetes:Firmicutes ratio and reverse the gut microbial dysbiosis caused by a high-fat diet. By upregulating the expression of genes involved in maintaining tight junctions between intestinal cells, resveratrol contributes to gut barrier integrity. The composition of the gut microbiome and rapid metabolism of resveratrol determines the production of resveratrol metabolites, which are found at greater concentrations in humans after ingestion than their parent molecule and can have similar biological effects. Resveratrol may affect cardiovascular risk factors such as elevated blood cholesterol or trimethylamine -oxide concentrations. Modulating the composition of the gut microbiota by resveratrol may affect central energy metabolism and modify concentrations of satiety hormones to produce antiobesity effects. Encouraging research from animal models could be tested in humans. 10.3945/an.117.016568
    Dietary Polyphenols Targeting Arterial Stiffness: Interplay of Contributing Mechanisms and Gut Microbiome-Related Metabolism. De Bruyne Tess,Steenput Bieke,Roth Lynn,De Meyer Guido R Y,Santos Claudia Nunes Dos,Valentová Kateřina,Dambrova Maija,Hermans Nina Nutrients Increased arterial stiffness is a degenerative vascular process, progressing with age that leads to a reduced capability of arteries to expand and contract in response to pressure changes. This progressive degeneration mainly affects the extracellular matrix of elastic arteries and causes loss of vascular elasticity. Recent studies point to significant interference of dietary polyphenols with mechanisms involved in the pathophysiology and progression of arterial stiffness. This review summarizes data from epidemiological and interventional studies on the effect of polyphenols on vascular stiffness as an illustration of current research and addresses possible etiological factors targeted by polyphenols, including pathways of vascular functionality, oxidative status, inflammation, glycation, and autophagy. Effects can either be inflicted directly by the dietary polyphenols or indirectly by metabolites originated from the host or microbial metabolic processes. The composition of the gut microbiome, therefore, determines the resulting metabolome and, as a consequence, the observed activity. On the other hand, polyphenols also influence the intestinal microbial composition, and therefore the metabolites available for interaction with relevant targets. As such, targeting the gut microbiome is another potential treatment option for arterial stiffness. 10.3390/nu11030578
    Obacunone Protects Against Ulcerative Colitis in Mice by Modulating Gut Microbiota, Attenuating TLR4/NF-κB Signaling Cascades, and Improving Disrupted Epithelial Barriers. Luo Xiaoping,Yue Bei,Yu Zhilun,Ren Yijing,Zhang Jing,Ren Junyu,Wang Zhengtao,Dou Wei Frontiers in microbiology Obacunone, a natural limonoid compound abundantly distributed in citrus fruits, possesses various biological properties, such as antitumor, antioxidant, and antiviral activities. Recent studies suggested an anti-inflammatory activity of obacunone , but its efficacy on intestinal inflammation remains unknown. This study was designed to evaluate the effects and mechanisms of obacunone in ameliorating intestinal inflammation in a mouse model of ulcerative colitis (UC). We found that obacunone efficiently alleviated the severity of dextran sulfate sodium (DSS)-induced mouse UC by modulating the abnormal composition of the gut microbiota and attenuating the excessive activation of toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling. The intestinal epithelial barrier was disrupted in DSS colitis mice, which was associated with activation of inflammatory signaling cascades. However, obacunone promoted the expression of tight junction proteins (TJP1 and occludin) and repressed the activation of inflammatory signaling cascades. In summary, our findings demonstrated that obacunone attenuated the symptoms of experimental UC in mice through modulation of the gut microbiota, attenuation of TLR4/NF-κB signaling cascades, and restoration of intestinal epithelial barrier integrity. 10.3389/fmicb.2020.00497
    Skin Antiageing and Systemic Redox Effects of Supplementation with Marine Collagen Peptides and Plant-Derived Antioxidants: A Single-Blind Case-Control Clinical Study. De Luca Chiara,Mikhal'chik Elena V,Suprun Maxim V,Papacharalambous Michael,Truhanov Arseniy I,Korkina Liudmila G Oxidative medicine and cellular longevity Recently, development and research of nutraceuticals based on marine collagen peptides (MCPs) have been growing due to their high homology with human collagens, safety, bioavailability through gut, and numerous bioactivities. The major concern regarding safety of MCPs intake relates to increased risk of oxidative stress connected with collagen synthesis (likewise in fibrosis) and to ROS production by MCPs-stimulated phagocytes. In this clinical-laboratory study, fish skin MCPs combined with plant-derived skin-targeting antioxidants (AO) (coenzyme Q10 + grape-skin extract + luteolin + selenium) were administered to volunteers (n = 41). Skin properties (moisture, elasticity, sebum production, and biological age) and ultrasonic markers (epidermal/dermal thickness and acoustic density) were measured thrice (2 months before treatment and before and after cessation of 2-month oral intake). The supplementation remarkably improved skin elasticity, sebum production, and dermal ultrasonic markers. Metabolic data showed significant increase of plasma hydroxyproline and ATP storage in erythrocytes. Redox parameters, GSH/coenzyme Q10 content, and GPx/GST activities were unchanged, while NO and MDA were moderately increased within, however, normal range of values. Conclusions. A combination of MCPs with skin-targeting AOs could be effective and safe supplement to improve skin properties without risk of oxidative damage. 10.1155/2016/4389410
    Dietary chlorogenic acid regulates gut microbiota, serum-free amino acids and colonic serotonin levels in growing pigs. Wu Yi,Liu Wenhui,Li Qi,Li Yafei,Yan Yali,Huang Fang,Wu Xin,Zhou Quancheng,Shu Xugang,Ruan Zheng International journal of food sciences and nutrition Chlorogenic acid (CGA) has many biological properties, including antibacterial, antioxidant and anti-inflammatory properties, and is one of the most abundant phenolic acids available in the human diet. The aim of this study was to investigate the effects of CGA on regulation of the gut microbiota, and on the levels of free amino acids and 5-hydroxytryptamine (5-HT, serotonin). Ninety-six healthy growing pigs were randomly assigned to two treatment groups: the Ctrl group (control group, standard feed) and the CGA group [standard feed plus 0.05% 3-caffeoylquinic acid (3-CQA)] for 60 days. The diversity of the gut microbiota was increased after CGA supplementation. Changes in these microbes were significantly associated with the serum free amino acid levels and colonic 5-HT level. Compared with the Ctrl group, the levels of serum aspartic acid, threonine, alanine, arginine, and colonic 5-HT were significantly increased (p < .05). These data suggest important roles for CGA in regulating the gut microbiota and increasing the serum free amino acid levels. 10.1080/09637486.2017.1394449
    Different antioxidant effects of polyphenols on lipid peroxidation and hydroxyl radicals in the NADPH-, Fe-ascorbate- and Fe-microsomal systems. Ozgová Sárka,Hermánek Josef,Gut Ivan Biochemical pharmacology Antioxidant and pro-oxidant effects of 14 naturally occurring polyphenols (PP) on rat liver microsomal lipid peroxidation (LP) and hydroxyl radical (*OH) production were studied in NADPH-dependent, 50 microM Fe(2+)-500 microM ascorbate (Fe-AA) or 50 microM Fe(2+) system, respectively. LP determined by the thiobarbituric acid method was inhibited in the NADPH system by flavonols and trans-resveratrol that were more effective than other flavonoids and derivatives of benzoic and cinnamic acid and were mostly more efficient than in the Fe-AA system. Inhibition of LP in the Fe system was higher by one order of magnitude than in the Fe-AA system. *OH production in the NADPH system, measured by formaldehyde production, was decreased by myricetin, fisetin and quercetin, but increased by kaempferol, morin and trans-resveratrol, indicating that z.rad;OH played a minor role in LP, which all of these PP inhibited. None of these PP at up to 40 microM concentration quenched *OH in the Fe-AA system. All tested PP, except trans-resveratrol and gentisic acid, spectrally interacted with Fe(2+) or Fe(3+), indicating formation of complexes or oxidation of PP. In contrast to the NADPH system we found no correlation between Fe(2+) chelation and inhibition of Fe-AA- or Fe-dependent LP indicating that iron chelation did not play a significant role in the two latter systems. It is concluded that the inhibition of LP by PP was apparently due to their hydrogen donating properties rather than chelation of iron. 10.1016/s0006-2952(03)00425-8
    Antioxidants counteract lipopolysaccharide-triggered alterations of human colonic smooth muscle cells. Matarrese Paola,Petitta Chiara,Scirocco Annunziata,Ascione Barbara,Ammoscato Francesca,Di Natale Giuseppe,Anastasi Emanuela,Marconi Matteo,Chirletti Piero,Malorni Walter,Severi Carola Free radical biology & medicine Gut dysmotility develops in individuals during and after recovering from infective acute gastroenteritis and it is apparently due to a