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Xylitol as a Hydrophilization Moiety for a Biocatalytically Synthesized Ibuprofen Prodrug. Zappaterra Federico,Tupini Chiara,Summa Daniela,Cristofori Virginia,Costa Stefania,Trapella Claudio,Lampronti Ilaria,Tamburini Elena International journal of molecular sciences Biocatalyzed synthesis can be exploited to produce high-value products, such as prodrugs. The replacement of chemical approaches with biocatalytic processes is advantageous in terms of environmental prevention, embracing the principles of green chemistry. In this work, we propose the covalent attachment of xylitol to ibuprofen to produce an IBU-xylitol ester prodrug. Xylitol was chosen as a hydrophilizer for the final prodrug, enhancing the water solubility of ibuprofen. Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) extensively used as an analgesic, anti-inflammatory, and antipyretic. Despite being the third-most-prescribed medicine in the world, the aqueous solubility of ibuprofen is just 21 mg/L. This poor water solubility greatly limits the bioavailability of ibuprofen. We aimed to functionalize ibuprofen with xylitol using the reusable immobilized N435 biocatalyst. Instead of a biphasic media, we proposed a monophasic reaction environment. The characterization of the IBU-xylitol ester was performed by H, C-NMR, DEPT, COSY, HMQC, HMBC, FTIR, and MS spectroscopy. Preliminary in vitro tests showed that this enzymatically synthesized prodrug of ibuprofen reduced the expression of the interleukin 8 genes in human bronchial epithelial cells (IB3-1) from cystic fibrosis (CF) patients. 10.3390/ijms23042026
The natural sweetener metabolite steviol inhibits the proliferation of human osteosarcoma U2OS cell line. Chen Jun-Ming,Zhang Jue,Xia Yong-Mei,Wang Xiao-Xia,Li Jian Oncology letters Steviol is the colonic metabolite of the natural sweetener steviol glycosides. It does not diffuse to the blood and the half maximal inhibitory concentration of steviol is longer compared with that of current chemotherapy agents, including 5-fluorouracil and doxorubicin. The present study demonstrated that steviol inhibits the proliferation of the human osteosarcoma U2OS cell line in a dose- and time-dependent manner, and that the inhibition rate is comparative with that of doxorubicin and 5-fluorouracil. The mechanism of this anticancer activity is also investigated. The results indicated that steviol inhibits U2OS cells through inducing G1 phase cell cycle arrest, downregulating the ability of colony formation via a mitochondrial apoptotic pathway, which was indicated by an increase of the Bax/Bcl-2 ratio and activation of cyclin-dependent kinase inhibitor 1, tumor protein 53 and cyclin-dependent kinase; whereas a Survivin and Caspase 3-independent mechanism was involved. Considering that steviol appears minimally in the plasma during metabolism, and possesses a median lethal dose of 100-fold greater compared with that of 5-fluorouracil, it may become a potential chemotherapy agent. 10.3892/ol.2018.7962
Effect of steviol, steviol glycosides and stevia extract on glucocorticoid receptor signaling in normal and cancer blood cells. Molecular and cellular endocrinology The use of steviol glycosides as non-caloric sweeteners has proven to be beneficial for patients with type 2 diabetes mellitus (T2D), obesity, and metabolic syndrome. However, recent data demonstrate that steviol and stevioside might act as glucocorticoid receptor (GR) agonists and thus correlate with adverse effects on metabolism. Herein, we evaluated the impact of steviol, steviol glycosides, and a Greek-derived stevia extract on a number of key steps of GR signaling cascade in peripheral blood mononuclear cells (PBMCs) and in Jurkat leukemia cells. Our results revealed that none of the tested compounds altered the expression of primary GR-target genes (GILZ, FKPB5), GR protein levels or GR subcellular localization in PBMCs; those compounds increased GILZ and FKPB5 mRNA levels as well as GRE-mediated luciferase activity, inducing in parallel GR nuclear translocation in Jurkat cells. The GR-modulatory activity demonstrated by stevia-compounds in Jurkat cells but not in PBMCs may be due to a cell-type specific effect. 10.1016/j.mce.2017.07.023
Lack of potential carcinogenicity for steviol glycosides - Systematic evaluation and integration of mechanistic data into the totality of evidence. Chappell G A,Heintz M M,Borghoff S J,Doepker C L,Wikoff D S Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association Steviol glycosides are present in the leaves of the Stevia rebaudiana plant, have a sweet taste, and have been used as a sweetener for centuries. To build on previous authoritative safety assessments of steviol glycosides, a systematic assessment of mechanistic data related to key characteristics of carcinogens (KCCs) was conducted. Over 900 KCC-relevant endpoints from peer-reviewed literature and high-throughput screening data (ToxCast/Tox21) were identified across individual steviol glycosides and derivatives, metabolites, and whole leaf extracts. Most data (both in vivo and in vitro, including human cells), showed inactivity. Studies were weighted according to quality and relevance. Although data were available for eight of the ten KCC, genotoxicity, oxidative stress, inflammation, and cell proliferation/cell death represent the KCCs with the most data. The data for these KCC primarily show beneficial activity (anti-inflammatory, antioxidant, and anti-proliferative). Following integration across all data, and accounting for study quality and relevance, the totality of the evidence demonstrated an overall lack of genotoxic and carcinogenic activity for steviol glycosides. This is in agreement with previous regulatory decisions, and is consistent with the lack of tumor response in two-year rodent cancer bioassays. The findings support prior conclusions that steviol glycosides are unlikely to be carcinogenic in humans. 10.1016/j.fct.2021.112045
Structural dependence of antidiabetic effect of steviol glycosides and their metabolites on streptozotocin-induced diabetic mice. Myint Khaing Zar,Chen Jun-Ming,Zhou Zhuo-Yu,Xia Yong-Mei,Lin Jianguo,Zhang Jue Journal of the science of food and agriculture BACKGROUND:Stevia has been proposed as a potential antidiabetic sweetener, mainly based on inconsistent results from stevioside or the plant extract, yet lacking relative experimental evidence from individual steviol glycosides (SGs) and their metabolites. RESULTS:The results systematically revealed that the typical SGs and their final metabolite (steviol) presented an antidiabetic effect on streptozotocin (STZ) diabetic mice in all assayed antidiabetic aspects. In general, the performance strength of the samples followed the sequence steviol > steviol glucosyl ester > steviolbioside > rubusoside > stevioside > rebaudioside A, which is opposite to their sweetness strength order, and generally in accordance with the glucosyl group numbers in their molecules. This may imply that the antidiabetic effect of the SGs might be achieved through steviol, which presented antidiabetic performance similar to that of metformin with a dose of 1/20 that of metformin. Moreover, the F-fluorodeoxyglucose traced micro-PET experiment revealed that stevioside and steviol could increase the uptake of glucose in the myocardium and brain of the diabetic mice within 60 min, and decrease the accumulation of glucose in the liver and kidney. CONCLUSIONS:The SGs and steviol presented an antidiabetic effect on STZ diabetic mice in all assayed aspects, with an induction time to start the effect of the SGs. Stevioside and steviol could increase uptake of glucose in the myocardium and brain of the diabetic mice, and decrease accumulation of glucose in the liver and kidney. The performance strength of the SGs is generally in accordance with glucosyl group numbers in their molecules. 10.1002/jsfa.10421
Erythritol modulates the polarization of macrophages: Potential role of tumor necrosis factor-α and Akt pathway. Alamri Hassan S,Akiel Maaged A,Alghassab Talal S,Alfhili Mohammad A,Alrfaei Bahauddeen M,Aljumaa Maha,Barhoumi Tlili Journal of food biochemistry Low-calorie sweeteners are substitutes for sugar and frequently used by patients with cardiometabolic diseases. Erythritol, a natural low-calorie sugar alcohol, was linked to cardiometabolic diseases in several recent metabolomics studies. However, the characterization of its role in disease development is lacking. Macrophage polarization orchestrates the immune response in various inflammatory conditions, most notably cardiometabolic disease. Therefore, the physiological effects of Erythritol on THP-1 macrophages were investigated. We observed an increased cellular abundance of proinflammatory M1 macrophages, characterized by CD11c, TNF-α, CD64, CD38, and HLA-DR markers and decreased anti-inflammatory M2 macrophages, characterized by mannose receptor CD206. The, Erythritol increased ROS generation, and the activation of the AKT pathway, cytosolic calcium overload, and cell cycle arrest at the G1 phase. Concomitantly, an increased population of necroptotic macrophages was observed. In conclusion, we provide evidence that Erythritol induced the proinflammatory phenotype in THP-1 macrophages and this was associated with an increased population of necroptotic macrophages. PRACTICAL APPLICATIONS: This assessment provides evidence of the effects of Erythritol on macrophages, particularly THP-1-derived macrophages. Our results support the role of Erythritol in driving the inflammation that is associated with cardiometabolic diseases and provide insights in the role of Erythritol as an inducer of necroptosis in THP-1 derived macrophages that could be associated the disease. 10.1111/jfbc.13960
The Role of D-allulose and Erythritol on the Activity of the Gut Sweet Taste Receptor and Gastrointestinal Satiation Hormone Release in Humans: A Randomized, Controlled Trial. The Journal of nutrition BACKGROUND:Glucose induces the release of gastrointestinal (GI) satiation hormones, such as glucagon-like peptide 1 (GLP-1) and peptide tyrosine tyrosine (PYY), in part via the activation of the gut sweet taste receptor (T1R2/T1R3). OBJECTIVES:The primary objective was to investigate the importance of T1R2/T1R3 for the release of cholecystokinin (CCK), GLP-1, and PYY in response to D-allulose and erythritol by assessing the effect of the T1R2/T1R3 antagonist lactisole on these responses and as secondary objectives to study the effect of the T1R2/T1R3 blockade on gastric emptying, appetite-related sensations, and GI symptoms. METHODS:In this randomized, controlled, double-blind, crossover study, 18 participants (5 men) with a mean ± SD BMI (in kg/m2) of 21.9 ± 1.7 and aged 24 ± 4 y received an intragastric administration of 25 g D-allulose, 50 g erythritol, or tap water, with or without 450 parts per million (ppm) lactisole, respectively, in 6 different sessions. 13C-sodium acetate was added to all solutions to determine gastric emptying. At fixed time intervals, blood and breath samples were collected, and appetite-related sensations and GI symptoms were assessed. Data were analyzed with linear mixed-model analysis. RESULTS:D-allulose and erythritol induced a significant release of CCK, GLP-1, and PYY compared with tap water (all PHolm < 0.0001, dz >1). Lactisole did not affect the D-allulose- and erythritol-induced release of CCK, GLP-1, and PYY (all PHolm > 0.1). Erythritol significantly delayed gastric emptying, increased fullness, and decreased prospective food consumption compared with tap water (PHolm = 0.0002, dz = -1.05; PHolm = 0.0190, dz = 0.69; and PHolm = 0.0442, dz = -0.62, respectively). CONCLUSIONS:D-allulose and erythritol stimulate the secretion of GI satiation hormones in humans. Lactisole had no effect on CCK, GLP-1, and PYY release, indicating that D-allulose- and erythritol-induced GI satiation hormone release is not mediated via T1R2/T1R3 in the gut. 10.1093/jn/nxac026
Erythritol and xylitol differentially impact brain networks involved in appetite regulation in healthy volunteers. Nutritional neuroscience BACKGROUND:There is a growing consensus that sugar consumption should be reduced and the naturally occurring, low-calorie sweeteners xylitol and erythritol are gaining popularity as substitutes, but their effect on brain circuitry regulating appetite is unknown. AIM:The study's objective was to examine the effects of the two sweeteners on cerebral blood flow (rCBF) and resting functional connectivity in brain networks involved in appetite regulation, and test whether these effects are related to gut hormone release. METHODS:The study was performed as a randomized, double-blind, placebo-controlled, cross-over trial. Twenty volunteers received intragastric (ig) loads of 50g xylitol, 75g erythritol, 75g glucose dissolved in 300mL tap water or 300mL tap water. Resting perfusion and blood oxygenation level-dependent data were acquired to assess rCBF and functional connectivity. Blood samples were collected for determination of CCK, PYY, insulin and glucose. RESULTS:We found: (i) xylitol, but not erythritol, increased rCBF in the hypothalamus, whereas glucose had the opposite effect; (ii) graph analysis of resting functional connectivity revealed a complex pattern of similarities and differences in brain network properties following xylitol, erythritol, and glucose; (iii) erythritol and xylitol induced a rise in CCK and PYY, (iv) erythritol had no and xylitol only minimal effects on glucose and insulin. CONCLUSION:Xylitol and erythritol have a unique combination of properties: no calories, virtually no effect on glucose and insulin while promoting the release of gut hormones, and impacting appetite-regulating neurocircuitry consisting of both similarities and differences with glucose. 10.1080/1028415X.2021.1965787
Ribotype-dependent growth inhibition and promotion by erythritol in Cutibacterium acnes. Journal of cosmetic dermatology BACKGROUND:The close balance between Cutibacterium acnes and the skin flora, particularly between C. acnes phylotypes, has been suggested to play an important role in the onset of acne. C. acnes has been classified into ribotypes (RTs) based on polymorphisms in its 16S rRNA sequence, with RT4 and RT5 being associated with the onset of acne and RT6 with healthy skin. AIMS:The present study investigated the impact of erythritol on the growth of C. acnes strains classified into different RTs and attempted to elucidate the molecular mechanisms underlying its effects. METHODS:Culturing tests were performed on several RTs of C. acnes with or without erythritol. A transcriptional analysis of HM554 (RT6) and HM514 (RT5) was also conducted. RESULTS:The growth of RT2 and RT6, RTs associated with healthy skin, was significantly promoted in a medium containing 10% (W/W) erythritol, whereas that of RT1, RT3, RT4, RT5, and RT8, RTs associated with the development of acne, was inhibited. A RNA-seq analysis of HM554 showed that the expression of six genes (EIGs) potentially involved in carbohydrate metabolism was strongly induced by the presence of 10% erythritol (Log fold change >2.0 and p-value <0.05). A comparative expression analysis by qPCR revealed that EIGs other than g3pD were strongly induced by erythritol in HM514, similar to HM554, whereas g3pD was only slightly induced. CONCLUSION:Erythritol inhibited the growth of RTs associated with acne and promoted that of RTs associated with healthy skin. The enzyme encoded by g3pD may play an important role in the metabolism of erythritol and the dissolution of its growth inhibitory effects on C. acnes. 10.1111/jocd.14958
Oral Erythritol Reduces Energy Intake during a Subsequent Test Meal: A Randomized, Controlled, Crossover Trial in Healthy Humans. Nutrients The impact of oral erythritol on subsequent energy intake is unknown. The aim was to assess the effect of oral erythritol compared to sucrose, sucralose, or tap water on energy intake during a subsequent ad libitum test meal and to examine the release of cholecystokinin (CCK) in response to these substances. In this randomized, crossover trial, 20 healthy volunteers received 50 g erythritol, 33.5 g sucrose, or 0.0558 g sucralose dissolved in tap water, or tap water as an oral preload in four different sessions. Fifteen minutes later, a test meal was served and energy intake was assessed. At set time points, blood samples were collected to quantify CCK concentrations. The energy intake (ad libitum test meal) was significantly lower after erythritol compared to sucrose, sucralose, or tap water (p < 0.05). Before the start of the ad libitum test meal, erythritol led to a significant increase in CCK compared to sucrose, sucralose, or tap water (p < 0.001). Oral erythritol given alone induced the release of CCK before the start of the ad libitum test meal and reduced subsequent energy intake compared to sucrose, sucralose, or tap water. These properties make erythritol a useful sugar alternative. 10.3390/nu14193918
Xylitol acts as an anticancer monosaccharide to induce selective cancer death via regulation of the glutathione level. Tomonobu Nahoko,Komalasari Ni Luh Gede Yoni,Sumardika I Wayan,Jiang Fan,Chen Youyi,Yamamoto Ken-Ichi,Kinoshita Rie,Murata Hitoshi,Inoue Yusuke,Sakaguchi Masakiyo Chemico-biological interactions Herbal medicines and their bioactive compounds are increasingly being recognized as useful drugs for cancer treatments. The parasitic fungus Cordyceps militaris is an attractive anticancer herbal since it shows very powerful anticancer activity due to its phytocompound cordycepin. We previously discovered and reported that a high amount of xylitol is present in Cordyceps militaris extract, and that xylitol unexpectedly showed anticancer activity in a cancer-selective manner. We thus hypothesized that xylitol could become a useful supplement to help prevent various cancers, if we can clarify the specific machinery by which xylitol induces cancer cell death. It is also unclear whether xylitol acts on cancer suppression in vivo as well as in vitro. Here we show for the first time that induction of the glutathione-degrading enzyme CHAC1 is the main cause of xylitol-induced apoptotic cell death in cancer cells. The induction of CHAC1 is required for the endoplasmic reticulum (ER) stress that is triggered by xylitol in cancer cells, and is linked to a second induction of oxidative stress in the treated cells, and eventually leads to apoptotic cell death. Our in vivo approach also demonstrated that an intravenous injection of xylitol had a tumor-suppressing effect in mice, to which the xylitol-triggered ER stress also greatly contributed. We also observed that xylitol efficiently sensitized cancer cells to chemotherapeutic drugs. Based on our findings, a chemotherapeutic strategy combined with xylitol might improve the outcomes of patients facing cancer. 10.1016/j.cbi.2020.109085
Inhibitory effects of xylitol and sorbitol on Streptococcus mutans and Candida albicans biofilms are repressed by the presence of sucrose. Chan Ally,Ellepola Kassapa,Truong Thuyen,Balan Preethi,Koo Hyun,Seneviratne Chaminda Jayampath Archives of oral biology OBJECTIVE:Among the preventive and therapeutic options available for dental caries, sugar alcohols (xylitol and sorbitol) have been widely promoted as oral healthcare products due to its perceived anticariogenic effect. However, the therapeutic efficacy of these sugar alcohols against Streptococcus mutans and Candida albicans in a sucrose supplemented environment, as found in disease-prone conditions in the oral cavity, has not been adequately investigated. METHODS:Single and mixed-species biofilm formation was evaluated in medium with different concentrations of xylitol, sorbitol with or without sucrose supplementation. Biofilm quantification methods such as crystal violet assay, XTT assay, CFU counting complemented with confocal and electron microscopic techniques were used. RESULTS:Under sucrose-free conditions, xylitol and sorbitol demonstrated a significant dose-dependent inhibitory effect on S. mutans biofilms, whereas inhibitory effect on C. albicans biofilm was weak. The presence of 1 % sucrose in the environment diminished the inhibitory effect of both xylitol and sorbitol on S. mutans and C. albicans mono-species biofilms. Sucrose supplementation on pre-formed S. mutans biofilms also reduced the inhibitory effect of xylitol. Xylitol and sorbitol presence reduced mixed-species biofilm formation and altered the biofilm architecture and glucan production. However, sucrose supplementation reduced the inhibitory effect of sugar alcohols and enhanced the mixed-species biofilm formation. CONCLUSIONS:Xylitol and sorbitol exerts an inhibitory effect on S. mutans and C. albicans biofilm formation and this inhibitory effect is repressed by the presence of sucrose. 10.1016/j.archoralbio.2020.104886
Partial Substitution of Glucose with Xylitol Prolongs Survival and Suppresses Cell Proliferation and Glycolysis of Mice Bearing Orthotopic Xenograft of Oral Cancer. Nutrients Many types of cancer have metabolic alterations with increased glycolysis. Identification of alternative sweeteners that do not fuel cancer is a novel approach to cancer control. The present study aimed to investigate the effects of xylitol on tumor growth and survival of mice bearing orthotopic xenograft of tongue cancers. The results showed that partial substitution of glucose with xylitol (glucose 0.35 g plus xylitol 2.06 g/kg body weight) non-significantly reduced tumor volume, and significantly prolonged the median survival time from 19 days in the control to 30.5 days in the xylitol group. Immunohistochemical data of the tongue tissue shows significantly lower intense-to-mild staining ratios of the proliferation marker Ki-67 in the xylitol than those of the control group ( = 0.04). Furthermore, the xylitol substitution significantly reduced the expression of the rate-limiting glycolytic enzyme, phosphofructokinase-1 (PFK-1) ( = 0.03), and showed a non-significant inhibition of PFK activity. In summary, partial substitution of glucose with xylitol at the equivalent dose to human household use of 10 g/day slows down tumor proliferation and prolongs survival of mice bearing an orthotopic oral cancer xenograft, possibly through glycolytic inhibition, with minimal adverse events. The insight warrants clinical studies to confirm xylitol as a candidate sweetener in food products for cancer survivors. 10.3390/nu14102023
High Concentrations of Aspartame Induce Pro-Angiogenic Effects in Ovo and Cytotoxic Effects in HT-29 Human Colorectal Carcinoma Cells. Maghiari Anca Laura,Coricovac Dorina,Pinzaru Iulia Andreea,Macașoi Ioana Gabriela,Marcovici Iasmina,Simu Sebastian,Navolan Dan,Dehelean Cristina Nutrients Aspartame (ASP), an artificial sweetener abundantly consumed in recent years in an array of dietary products, has raised some concerns in terms of toxicity, and it was even suggested a link with the risk of carcinogenesis (colorectal cancer), though the present scientific data are rather inconclusive. This study aims at investigating the potential role of aspartame in colorectal cancer by suggesting two experimental approaches: (i) an in vitro cytotoxicity screening in HT-29 human colorectal carcinoma cells based on cell viability (Alamar blue assay), cell morphology and cell migration (scratch assay) assessment and (ii) an in ovo evaluation in terms of angiogenic and irritant potential by means of the chorioallantoic membrane method (CAM). The in vitro results showed a dose-dependent cytotoxic effect, with a significant decrease of viable cells at the highest concentrations tested (15, 30 and 50 mM) and morphological cellular changes. In ovo, aspartame (15 and 30 mM) proved to have a pro-angiogenic effect and a weak irritant potential at the vascular level. These data suggest new directions of research regarding aspartame's role in colorectal cancer. 10.3390/nu12123600
Novel cannabidiol aspartame combination treatment (JW-100) significantly reduces ISGA score in atopic dermatitis: Results from a randomized double-blinded placebo-controlled interventional study. Gao Yanrui,Li Yingfang,Tan Yimei,Liu Wei,Ouaddi Sara,McCoy John,Kovacevic Maja,Situm Mirna,Stanimirovic Andrija,Li Marissa,Wambier Carlos,Goren Andy,Zou Ying Journal of cosmetic dermatology BACKGROUND:Atopic dermatitis (AD) is a common and chronic inflammatory skin disease that erupts periodically. Although the negative impact of the disorder on overall quality of life has been well established, new treatments for AD are still needed. Various studies have reported on cannabidiol's effectiveness in relieving pain and easing inflammation while not presenting major health risks. AIMS:In this communication, we aim to demonstrate the effectiveness of a novel cannabidiol (CBD) and aspartame formulation, JW-100, in relieving signs and symptoms of AD. PATIENTS/METHODS:We conducted a double-blinded placebo-controlled interventional study randomizing patients to one of three treatment groups: JW-100 (CBD plus aspartame), CBD only, or placebo topical formulations. The Investigator's Static Global Assessment (ISGA) score was used to document any changes in AD resulting from the applied interventions at 14 days. RESULTS:Fifty-seven patients completed the trial and were included in the final analysis. The ISGA score of the patients at baseline was 2.56, 2.24, and 2.24, for the JW-100, CBD, and placebo groups, respectively. After two weeks of treatment, the ISGA score reduced by 1.28, 0.81, and 0.71, for the JW-100, CBD, and placebo groups, respectively. The JW-100 cohorts demonstrated statistically significant ISGA score reduction (p = 0.042). 50% of patients in the JW-100 group achieved ISGA score of clear or almost clear (0 or 1) with at least a 2-grade improvement from baseline after treatment (p = 0.028). Only 20% and 15% of patients in the CBD only and placebo groups reported ISGA score of clear or almost clear (0 or 1). CONCLUSIONS:JW-100, a novel topical formulation containing CBD and aspartame, was demonstrated to produce statistically significant improvements in AD following 14 days of topical application. 10.1111/jocd.14263
Insight into the mechanism of aspartame-induced toxicity in male reproductive system following long-term consumption in mice model. Anbara Hojat,Sheibani Mohammad Taghi,Razi Mazdak,Kian Mehdi Environmental toxicology Aspartame is one of the most common consumed artificial sweeteners utilized in many food products and beverages. It has been indicated that long-term consumption of aspartame leads to reproductive toxicity but its mechanism is not well-clear. In this study we investigated mechanism of aspartame-induced reproductive toxicity in male mice. For this purpose, 36 NMRI mature male mice received three doses of 40, 80, and 160 mg/kg body weight of aspartame, respectively per day by gavage for 90 days and also a control group was considered which received 0.5 mL of normal saline as the same route. The results revealed that long-term administration of aspartame at high doses significantly (P < .05) reduced gonadosomatic index, serum concentration of pituitary-testicular axis hormones (FSH, LH, and testosterone). It also decreased sperm parameters and total antioxidant capacity, antioxidant enzyme activities (superoxide dismutase, catalase, and glutathione peroxidase), while it caused increase in nitric oxide and malondialdehyde levels in testis tissue and sperm samples. Also, it decreased attenuated testicular histomorphometric indices (tubular differentiation index, spermiogenesis index, and repopulation index), and steroidogenic foci, while increased mRNA damages and apoptosis rate, downregulated antiapoptotic (Bcl-2) and upregulated proapoptotic (P53, BAX, and caspase-3) mediators respectively in testis. These findings indicated that consumption of aspartame for a long period results in male reproductive toxicity by decrease in serum concentration of pituitary-testis axis hormones and induction of oxidative stress and apoptosis in testis. 10.1002/tox.23028
Accidental Consumption of Aspartame in Phenylketonuria: Patient Experiences. Newbould Ella,Pinto Alex,Evans Sharon,Ford Suzanne,O'Driscoll Mike,Ashmore Catherine,Daly Anne,MacDonald Anita Nutrients Aspartame is a phenylalanine containing sweetener, added to foods and drinks, which is avoided in phenylketonuria (PKU). However, the amount of phenylalanine provided by aspartame is unidentifiable from food and drinks labels. We performed a cross-sectional online survey aiming to examine the accidental aspartame consumption in PKU. 206 questionnaires (58% female) were completed. 55% of respondents ( = 114) were adults with PKU or their parent/carers and 45% ( = 92) were parents/carers of children with PKU. 74% ( = 152/206) had consumed food/drinks containing aspartame. Repeated accidental aspartame consumption was common and more frequent in children ( < 0.0001). The aspartame containing food/drinks accidentally consumed were fizzy drinks (68%, = 103/152), fruit squash (40%, = 61/152), chewing gum (30%, = 46/152), flavoured water (25%, = 38/152), ready to drink fruit squash cartons (23%, = 35/152) and sports drinks (21%, = 32/152). The main reasons described for accidental consumption, were manufacturers' changing recipes (81%, = 123/152), inability to check the ingredients in pubs/restaurants/vending machines (59%, = 89/152) or forgetting to check the label (32%, = 49/152). 23% (= 48/206) had been prescribed medicines containing aspartame and 75% ( = 36/48) said that medicines were not checked by medics when prescribed. 85% ( = 164/192) considered the sugar tax made accidental aspartame consumption more likely. Some of the difficulties for patients were aspartame identification in drinks consumed in restaurants, pubs, vending machines (77%, = 158/206); similarities in appearance of aspartame and non-aspartame products (62%, = 127/206); time consuming shopping/checking labels (56%, = 115/206); and unclear labelling (55%, = 114/206). These issues caused anxiety for the person with PKU (52%, = 106/206), anxiety for parent/caregivers (46%, = 95/206), guilt for parent/carers (42%, = 87/206) and social isolation (42%, = 87/206). It is important to understand the impact of aspartame and legislation such as the sugar tax on people with PKU. Policy makers and industry should ensure that the quality of life of people with rare conditions such as PKU is not compromised through their action. 10.3390/nu13020707
Aspartame and cancer - new evidence for causation. Environmental health : a global access science source BACKGROUND:Aspartame is one of the world's most widely used artificial sweeteners and is an ingredient in more than 5000 food products globally. A particularly important use is in low-calorie beverages consumed by children and pregnant women. The Ramazzini Institute (RI) reported in 2006 and 2007 that aspartame causes dose-related increases in malignant tumors in multiple organs in rats and mice. Increased cancer risk was seen even at low exposure levels approaching the Acceptable Daily Intake (ADI). Prenatal exposures caused increased malignancies in rodent offspring at lower doses than in adults. These findings generated intense controversy focused on the accuracy of RI's diagnoses of hematopoietic and lymphoid tissue tumors (HLTs). Critics made the claim that pulmonary lesions observed in aspartame-exposed animals were inflammatory lesions caused by Mycoplasma infection rather than malignant neoplasms. METHODS:To address this question, RI subjected all HLTs from aspartame-exposed animals to immunohistochemical analysis using a battery of markers and to morphological reassessment using the most recent Internationally Harmonized Nomenclature and Diagnostic (INHAND) criteria. FINDINGS:This immunohistochemical and morphological re-evaluation confirmed the original diagnoses of malignancy in 92.3% of cases. Six lesions originally diagnosed as lymphoma (8% of all HLTs) were reclassified: 3 to lymphoid hyperplasia, and 3 to chronic inflammation with fibrosis. There was no evidence of Mycoplasma infection. INTERPRETATION:These new findings confirm that aspartame is a chemical carcinogen in rodents. They confirm the very worrisome finding that prenatal exposure to aspartame increases cancer risk in rodent offspring. They validate the conclusions of the original RI studies. These findings are of great importance for public health. In light of them, we encourage all national and international public health agencies to urgently reexamine their assessments of aspartame's health risks - especially the risks of prenatal and early postnatal exposures. We call upon food agencies to reassess Acceptable Daily Intake (ADI) levels for aspartame. We note that an Advisory Group to the International Agency for Research on Cancer has recommended high-priority reevaluation of aspartame's carcinogenicity to humans. 10.1186/s12940-021-00725-y
Aspartame induces cancer stem cell enrichment through p21, NICD and GLI1 in human PANC-1 pancreas adenocarcinoma cells. Gezginci-Oktayoglu Selda,Ercin Merve,Sancar Serap,Celik Ertan,Koyuturk Meral,Bolkent Sema,Bolkent Sehnaz Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association This study aimed to investigate the molecular effects of the common natural sugar glucose and artificial sweetener aspartame on cancer stem cell (CSC) population and cancer aggressiveness of PANC-1 human pancreas adenocarcinoma cells. According to our findings while aspartame exposure significantly increased the CSC population, high glucose had no effect on it. The epithelial-mesenchymal transition marker N-cadherin increased only in the aspartame group. The findings indicate that a high level of glucose exposure does not effect the invasion and migration of PANC-1 cells, while aspartame increases both of these aggressiveness criteria. The findings also suggest that a high concentration of glucose maintains CSC population through induction of nuclear Oct3/4 and differentiation to parental cells via increasing cytoplasmic c-myc. Aspartame exposure to PANC-1 cells activated AKT and deactivated GSK3β by increasing levels of ROS and cytoplasmic Ca, respectively, through T1R2/T1R3 stimulation. Then p-GSK3β(Ser9) boosted the CSC population by increasing pluripotency factors Oct3/4 and c-myc via NICD, GLI1 and p21. In the aspartame group, T1R1 silencing further increased the CSC population but decreased cell viability and suppressed the p21, NICD and GLI activation. The presence and amount of T1R subunits in the membrane fraction of PANC-1 cells are demonstrated for the first time in this study, as is the regulatory effect of T1R1's on CSC population. In conclusion, the present study demonstrated that long-term aspartame exposure increases CSC population and tumor cell aggressiveness through p21, NICD, GLI1. Moreover, while aspartame had no tumorigenic effect, it could potentially advance an existing tumor. 10.1016/j.fct.2021.112264
Effectiveness of the use of xylitol chewing gum in prevention of dental caries: A systematic review. Mota Kelly Rodrigues,da Silva João Vitor Farias,Borges Cristine D'Almeida,Leite de Marcelos Priscylla Goncalves Correia,Alvares Pamella Recco,Santos Júnior Valdeci Elias Dos Journal of the Indian Society of Pedodontics and Preventive Dentistry This systematic review of the literature assessed the effectiveness of using chewing gum containing only xylitol compared to prevention strategies or placebo in reducing the incidence of carious lesions in children using data obtained from randomized controlled trials. Electronic search was carried out in PubMed MEDLINE, Latin American and Caribbean Literature on the Health Science, Web of Science, Scopus, Science Direct, and Scientific Electronic Library Online through the period between 2000 and 2020. Included clinical studies were done in children when the xylitol was dispensed in gum and the preventive effect of xylitol on tooth decay was compared to other preventive strategies or control groups. The studies were evaluated for their quality to obtain the level of evidence. The preventive fraction of each study was extracted. Two hundred studies were found. After analyzing the inclusion and removal of duplicates, only five studies were analyzed for the quality of evidence. With the analysis through the Grading of Recommendations Assessment, Development, and Evaluation system, it was possible to verify the very low level of scientific evidence on the effectiveness of gums containing only xylitol for the prevention of caries in children. The preventive fraction obtained varied between - 0.31 and 0.57 depending on the compared prevention strategy. The conflicting results, limitations, and inconsistencies of the studies allow us to establish that there is insufficient evidence to support the use of gums containing only xylitol for the prevention of caries in children. Other properly designed clinical trials need to be carried out. 10.4103/JISPPD.JISPPD_330_20
Saccharin and other sweeteners: mutagenic properties. Batzinger R P,Ou S Y,Bueding E Science (New York, N.Y.) Saccharin preparations commonly distributed as artificial sweeteners exhibited mutagenic activity in bacterial tests. When administered orally to mice, mutagenic activity was demonstrable in the urines of these animals as well as in a host-mediated assay. Highly purified saccharin was not mutagenic in the direct assay, but the urines of mice to which this material had been administered exhibited mutagenic effects on one tester strain (Salmonella typhimurium TA100). Two other sweeteners, neohesperidin dihydrochalcone and xylitol, had no detectable mutagenic activity in any of these assays using his- Salmonella typhimurium strains TA100 or TA98. 10.1126/science.337489
Erythritol is a pentose-phosphate pathway metabolite and associated with adiposity gain in young adults. Hootman Katie C,Trezzi Jean-Pierre,Kraemer Lisa,Burwell Lindsay S,Dong Xiangyi,Guertin Kristin A,Jaeger Christian,Stover Patrick J,Hiller Karsten,Cassano Patricia A Proceedings of the National Academy of Sciences of the United States of America Metabolomic markers associated with incident central adiposity gain were investigated in young adults. In a 9-mo prospective study of university freshmen ( = 264). Blood samples and anthropometry measurements were collected in the first 3 d on campus and at the end of the year. Plasma from individuals was pooled by phenotype [incident central adiposity, stable adiposity, baseline hemoglobin A1c (HbA1c) > 5.05%, HbA1c < 4.92%] and assayed using GC-MS, chromatograms were analyzed using MetaboliteDetector software, and normalized metabolite levels were compared using Welch's test. Assays were repeated using freshly prepared pools, and statistically significant metabolites were quantified in a targeted GC-MS approach. Isotope tracer studies were performed to determine if the potential marker was an endogenous human metabolite in men and in whole blood. Participants with incident central adiposity gain had statistically significantly higher blood erythritol [ < 0.001, false discovery rate (FDR) = 0.0435], and the targeted assay revealed 15-fold [95% confidence interval (CI): 13.27, 16.25] higher blood erythritol compared with participants with stable adiposity. Participants with baseline HbA1c > 5.05% had 21-fold (95% CI: 19.84, 21.41) higher blood erythritol compared with participants with lower HbA1c ( < 0.001, FDR = 0.00016). Erythritol was shown to be synthesized endogenously from glucose via the pentose-phosphate pathway (PPP) in stable isotope-assisted ex vivo blood incubation experiments and through in vivo conversion of erythritol to erythronate in stable isotope-assisted dried blood spot experiments. Therefore, endogenous production of erythritol from glucose may contribute to the association between erythritol and obesity observed in young adults. 10.1073/pnas.1620079114
Erythritol Ameliorates Small Intestinal Inflammation Induced by High-Fat Diets and Improves Glucose Tolerance. International journal of molecular sciences BACKGROUND:Erythritol, a sugar alcohol, is widely used as a substitute for sugar in diets for patients with diabetes or obesity. METHODS:In this study, we aimed to investigate the effects of erythritol on metabolic disorders induced by a high-fat diet in C57BL/6J mice, while focusing on changes in innate immunity. RESULTS:Mice that were fed a high-fat diet and administered water containing 5% erythritol (Ery group) had markedly lower body weight, improved glucose tolerance, and markedly higher energy expenditure than the control mice (Ctrl group) ( = 6). Furthermore, compared with the Ctrl group, the Ery group had lesser fat deposition in the liver, smaller adipocytes, and significantly better inflammatory findings in the small intestine. The concentrations of short-chain fatty acids (SCFAs), such as acetic acid, propanoic acid, and butanoic acid, in the serum, feces, and white adipose tissue of the Ery group were markedly higher than those in the Ctrl group. In flow cytometry experiments, group 3 innate lymphoid cell (ILC3) counts in the lamina propria of the small intestine and ILC2 counts in the white adipose tissue of the Ery group were markedly higher than those in the Ctrl group. Quantitative real-time reverse transcription polymerase chain reaction analyses showed that the Il-22 expression in the small intestine of the Ery group was markedly higher than that in the Ctrl group. CONCLUSIONS:Erythritol markedly decreased metabolic disorders such as diet-induced obesity, glucose intolerance, dyslipidemia, and fat accumulation in the mouse liver by increasing SCFAs and modulating innate immunity. 10.3390/ijms22115558
Chronic Dietary Erythritol Exposure Elevates Plasma Erythritol Concentration in Mice but Does Not Cause Weight Gain or Modify Glucose Homeostasis. The Journal of nutrition BACKGROUND:Erythritol is both a common nonnutritive sweetener and an endogenous product of glucose metabolism. Recent reports suggest that elevated plasma erythritol is a predictive biomarker of cardiometabolic disease onset and complications. OBJECTIVES:Although short-term erythritol consumption has been evaluated, the effect of chronically elevated circulating erythritol on adiposity and glucose metabolism has not. This study investigated the effect of longer-term erythritol consumption on weight gain and glucose tolerance in young/adolescent mice. METHODS:Four erythritol supplementation experiments were completed and analyzed separately in male C57BL/6J mice. In experiments 1 and 2, mice aged 8 wk or 20 wk, respectively, were randomly allocated to consume 16% fat diet (LFD) or LFD with 40 g/kg erythritol. In experiments 3 and 4, mice aged 8 wk or 20 wk were fed 45% fat diet (HFD) or HFD with 40 g/kg erythritol (HFD + ERY). In each experiment, we compared the effect of erythritol consumption on plasma erythritol, body weight and composition, glucose tolerance, and brown adipose tissue (BAT) uncoupling protein 1 (UCP1) expression. We also investigated relative endogenous tissue erythritol concentrations in a subset of control (LFD or HFD) mice in experiments 1 and 3. RESULTS:There was no effect of erythritol supplementation on body weight or glucose tolerance in experiments 1-3. In experiment 4, in the 20-wk-old mice fed HFD or HFD + ERY, there was a significant interaction of time and erythritol on body weight (P < 0.0001), but the main effect of diet was not significant. Plasma erythritol was elevated 40-fold in mice consuming erythritol-supplemented diets relative to mice consuming LFD or HFD controls. We found no effect of chronic erythritol consumption on BAT UCP1 protein concentrations. Liver and kidney tissue contained significantly higher endogenous erythritol than quadriceps and visceral adipose (P < 0.001) in young mice fed LFD and HFD. CONCLUSIONS:In young/adolescent mice, prolonged erythritol consumption did not significantly affect body weight, composition, or glucose tolerance. 10.1093/jn/nxab130
Effect of a Chronic Intake of the Natural Sweeteners Xylitol and Erythritol on Glucose Absorption in Humans with Obesity. Bordier Valentine,Teysseire Fabienne,Schlotterbeck Götz,Senner Frank,Beglinger Christoph,Meyer-Gerspach Anne Christin,Wölnerhanssen Bettina K Nutrients In patients with obesity, accelerated nutrients absorption is observed. Xylitol and erythritol are of interest as alternative sweeteners, and it has been shown in rodent models that their acute ingestion reduces intestinal glucose absorption. This study aims to investigate whether a chronic intake of xylitol and erythritol impacts glucose absorption in humans with obesity. Forty-six participants were randomized to take either 8 g of xylitol or 12 g of erythritol three times a day for five to seven weeks, or to be part of the control group (no substance). Before and after the intervention, intestinal glucose absorption was assessed during an oral glucose tolerance test with 3--methyl-glucose (3-OMG). The effect of xylitol or erythritol intake on the area under the curve for 3-OMG concentration was not significant. Neither the time (pre or post intervention), nor the group (control, xylitol, or erythritol), nor the time-by-group interaction effects were significant ( 0.829, 0.821, and 0.572, respectively). Therefore, our results show that a chronic intake of the natural sweeteners xylitol and erythritol does not affect intestinal glucose absorption in humans with obesity. 10.3390/nu13113950
The use of fructose as a sweetener. Is it a safe alternative for our immune system? Pasqualli Thaís,Chaves Pamella Eduardha Espindola,da Veiga Pereira Lavínia,Serpa Élvio Adílio,Flávio Souza de Oliveira Luís,Mansur Machado Michel Journal of food biochemistry Fructose is a constituent of sucrose and other polymers referred to as inulin or fructans. We can find in cereals, vegetables, and honey. It has the property of being 1.5 times sweeter than sucrose. Our objective was to test this sweetener under and at average concentrations of consumption, evaluating parameters of cytotoxicity, genotoxicity, and immunotoxicity. For this purpose, we made use of lymphocyte cultures and the analysis of their CD4 and CD8 subpopulations. Computational methods propose the mechanism of action. Our data showed a reduction in all lymphocyte subfractions evaluated, resulting in a reduction in total lymphocytes, as well as an increase in the DNA damage of cells exposed to fructose. It was possible to propose that fructose modulates gene expression, mainly interfering with the MAPK8, APTX, TUBGCP3, and LST1 genes. Although fructose is used globally as a sweetener, its use should be cautious, as our study points out that it has cytotoxic and genotoxic effects. PRACTICAL APPLICATIONS: Fructose is one of the most sold and used sweeteners in the world. We show here that its use must be restricted and used carefully because it can alter the gene expression and also interfere with cellular and genetic metabolism and may even interfere with the immune response. 10.1111/jfbc.13496
Chronic Low-Calorie Sweetener Use and Risk of Abdominal Obesity among Older Adults: A Cohort Study. Chia Chee W,Shardell Michelle,Tanaka Toshiko,Liu David D,Gravenstein Kristofer S,Simonsick Eleanor M,Egan Josephine M,Ferrucci Luigi PloS one INTRODUCTION:Low-calorie sweetener use for weight control has come under increasing scrutiny as obesity, especially abdominal obesity, remain entrenched despite substantial low-calorie sweetener use. We evaluated whether chronic low-calorie sweetener use is a risk factor for abdominal obesity. PARTICIPANTS AND METHODS:We used 8268 anthropometric measurements and 3096 food diary records with detailed information on low-calorie sweetener consumption in all food products, from 1454 participants (741 men, 713 women) in the Baltimore Longitudinal Study of Aging collected from 1984 to 2012 with median follow-up of 10 years (range: 0-28 years). At baseline, 785 were low-calorie sweetener non-users (51.7% men) and 669 participants were low-calorie sweetener users (50.1% men). Time-varying low-calorie sweetener use was operationalized as the proportion of visits since baseline at which low-calorie sweetener use was reported. We used marginal structural models to determine the association between baseline and time-varying low-calorie sweetener use with longitudinal outcomes-body mass index, waist circumference, obesity and abdominal obesity-with outcome status assessed at the visit following low-calorie sweetener ascertainment to minimize the potential for reverse causality. All models were adjusted for year of visit, age, sex, age by sex interaction, race, current smoking status, dietary intake (caffeine, fructose, protein, carbohydrate, and fat), physical activity, diabetes status, and Dietary Approaches to Stop Hypertension score as confounders. RESULTS:With median follow-up of 10 years, low-calorie sweetener users had 0.80 kg/m2 higher body mass index (95% confidence interval [CI], 0.17-1.44), 2.6 cm larger waist circumference (95% CI, 0.71-4.39), 36.7% higher prevalence (prevalence ratio = 1.37; 95% CI, 1.10-1.69) and 53% higher incidence (hazard ratio = 1.53; 95% CI 1.10-2.12) of abdominal obesity than low-calorie sweetener non-users. CONCLUSIONS:Low-calorie sweetener use is independently associated with heavier relative weight, a larger waist, and a higher prevalence and incidence of abdominal obesity suggesting that low-calorie sweetener use may not be an effective means of weight control. 10.1371/journal.pone.0167241
Steviol, the active principle of the stevia sweetener, causes a reduction of the cells of the immunological system even consumed in low concentrations. Pasqualli Thaís,Chaves Pamella Eduardha Espindola,Pereira C Lavínia da Veiga,Serpa Élvio Adílio,Oliveira Luís Flávio Souza de,Machado Michel Mansur Immunopharmacology and immunotoxicology AIM:Steviol is a natural diterpenoid glycoside isolated from Bertoni leaves and widely used as a non-caloric sweetener. In addition to their sweet taste, Steviol glycosides may also have some therapeutic benefits. There are few reports on the cytotoxicity of Steviol in human cells. Our objective was to test this sweetener under and at average concentrations of consumption, evaluating parameters of cytotoxicity, genotoxicity, and immunotoxicity. METHODS:For this purpose, we made use of lymphocyte cultures and the analysis of their CD3, CD4, and CD8 subpopulations. In a complementary way, the mechanism of action is proposed here by computational methods. RESULTS AND CONCLUSION:Our results showed that Steviol reduces the number of lymphocytes due to falls of CD4, CD8, and CD4CD8 subpopulations. Besides, we observed an increase in the level of DNA damage and a gradual incidence of structural changes in the lymphocyte chromosomal sets. It was possible to propose that Steviol modulates gene expression, mainly interfering with the SESN1, NAP1L1, SOX4, and TREX1 genes. Although Steviol is used globally as a sweetener, its use should be cautious, as our study points out that Steviol has cytotoxic, genotoxic and mutagenic effects in the concentrations and conditions tested in the culture of human lymphocyte cells. 10.1080/08923973.2020.1811309
Sweeteners Maintain Epithelial Barrier Function Through the miR-15b/RECK/MMP-9 Axis, Remodel Microbial Homeostasis, and Attenuate Dextran Sodium Sulfate-Induced Colitis in Mice. Zhang Xuejiao,Gu Jiaxin,Zhao Congying,Hu Yaozhong,Zhang Bowei,Wang Jin,Lv Huan,Ji Xuemeng,Wang Shuo Journal of agricultural and food chemistry Non-nutritive sweeteners are the most widely used food additives designed to provide sweetness and reduce caloric intake. Studies have confirmed a link between sweeteners and colitis, yet supporting scientific data remain exiguous and controversial. In this study, three common sweeteners (Saccharin sodium, Stevioside, and Sucralose) in acceptable daily intake dosage were added to water in order to determine their effects on dextran sodium sulfate-induced colitis in mice. Our results show that the three sweeteners meliorate colitis to varying degrees─Saccharin exerts the most pronounced effect, followed by Stevioside and Sucralose. Intake of sweeteners alleviates colitis symptoms, alters gut microbiota, reshapes the TH17/Treg balance, protects the intestinal barrier, and reduces inflammation. Most significantly, sweeteners can enhance the abundance of and which are conducive to colitis recovery, and upregulate the expression of E-cadherin through the miR-15b/RECK/MMP-9 axis to improve intestinal barrier integrity. Moreover, by inhibiting the MMP-9/AKT/NF-κB pathway, inflammation is relieved, as reflected in the restoration of the Th17/Treg balance. Our results link the consumption of sweeteners to the remission of colitis, which provides new scientific evidence for the safe use of sweeteners. 10.1021/acs.jafc.1c06788
Brain activity and connectivity changes in response to nutritive natural sugars, non-nutritive natural sugar replacements and artificial sweeteners. Van Opstal Anna M,Hafkemeijer Anne,van den Berg-Huysmans Annette A,Hoeksma Marco,Mulder Theo P J,Pijl Hanno,Rombouts Serge A R B,van der Grond Jeroen Nutritional neuroscience INTRODUCTION:The brain plays an important regulatory role in directing energy homeostasis and eating behavior. The increased ingestion of sugars and sweeteners over the last decades makes investigating the effects of these substances on the regulatory function of the brain of particular interest. We investigated whole brain functional response to the ingestion of nutrient shakes sweetened with either the nutritive natural sugars glucose and fructose, the low- nutritive natural sugar replacement allulose or the non-nutritive artificial sweetener sucralose. METHODS:Twenty healthy, normal weight, adult males underwent functional MRI on four separate visits. In a double-blind randomized study setup, participants received shakes sweetened with glucose, fructose, allulose or sucralose. Resting state functional MRI was performed before and after ingestion. Changes in Blood Oxygen Level Dependent (BOLD) signal, functional network connectivity and voxel based connectivity by Eigenvector Centrality Mapping (ECM) were measured. RESULTS:Glucose and fructose led to significant decreased BOLD signal in the cingulate cortex, insula and the basal ganglia. Glucose led to a significant increase in eigen vector centrality throughout the brain and a significant decrease in eigen vector centrality in the midbrain. Sucralose and allulose had no effect on BOLD signal or network connectivity but sucralose did lead to a significant increase in eigen vector centrality values in the cingulate cortex, central gyri and temporal lobe. DISCUSSION:Taken together our findings show that even in a shake containing fat and protein, the type of sweetener can affect brain responses and might thus affect reward and satiety responses and feeding behavior. The sweet taste without the corresponding energy content of the non-nutritive sweeteners appeared to have only small effects on the brain. Indicating that the while ingestion of nutritive sugars could have a strong effect on feeding behavior, both in a satiety aspect as well as rewarding aspects, non-nutritive sweeteners appear to not have these effects. TRIAL REGISTRATION:This study is registered at clinicaltrials.gov under number NCT02745730. 10.1080/1028415X.2019.1639306
Nonnutritive sweeteners and cardiometabolic health: a systematic review and meta-analysis of randomized controlled trials and prospective cohort studies. Azad Meghan B,Abou-Setta Ahmed M,Chauhan Bhupendrasinh F,Rabbani Rasheda,Lys Justin,Copstein Leslie,Mann Amrinder,Jeyaraman Maya M,Reid Ashleigh E,Fiander Michelle,MacKay Dylan S,McGavock Jon,Wicklow Brandy,Zarychanski Ryan CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne BACKGROUND:Nonnutritive sweeteners, such as aspartame, sucralose and stevioside, are widely consumed, yet their long-term health impact is uncertain. We synthesized evidence from prospective studies to determine whether routine consumption of non-nutritive sweeteners was associated with long-term adverse cardiometabolic effects. METHODS:We searched MEDLINE, Embase and Cochrane Library (inception to January 2016) for randomized controlled trials (RCTs) that evaluated interventions for nonnutritive sweeteners and prospective cohort studies that reported on consumption of non-nutritive sweeteners among adults and adolescents. The primary outcome was body mass index (BMI). Secondary outcomes included weight, obesity and other cardiometabolic end points. RESULTS:From 11 774 citations, we included 7 trials (1003 participants; median follow-up 6 mo) and 30 cohort studies (405 907 participants; median follow-up 10 yr). In the included RCTs, nonnutritive sweeteners had no significant effect on BMI (mean difference -0.37 kg/m; 95% confidence interval [CI] -1.10 to 0.36; 9%; 242 participants). In the included cohort studies, consumption of nonnutritive sweeteners was associated with a modest increase in BMI (mean correlation 0.05, 95% CI 0.03 to 0.06; 0%; 21 256 participants). Data from RCTs showed no consistent effects of nonnutritive sweeteners on other measures of body composition and reported no further secondary outcomes. In the cohort studies, consumption of nonnutritive sweeteners was associated with increases in weight and waist circumference, and higher incidence of obesity, hypertension, metabolic syndrome, type 2 diabetes and cardiovascular events. Publication bias was indicated for studies with diabetes as an outcome. INTERPRETATION:Evidence from RCTs does not clearly support the intended benefits of nonnutritive sweeteners for weight management, and observational data suggest that routine intake of nonnutritive sweeteners may be associated with increased BMI and cardiometabolic risk. Further research is needed to fully characterize the long-term risks and benefits of nonnutritive sweeteners. PROSPERO-CRD42015019749. 10.1503/cmaj.161390
Low-calorie sweetener use and energy balance: Results from experimental studies in animals, and large-scale prospective studies in humans. Fowler Sharon P G Physiology & behavior For more than a decade, pioneering animal studies conducted by investigators at Purdue University have provided evidence to support a central thesis: that the uncoupling of sweet taste and caloric intake by low-calorie sweeteners (LCS) can disrupt an animal's ability to predict the metabolic consequences of sweet taste, and thereby impair the animal's ability to respond appropriately to sweet-tasting foods. These investigators' work has been replicated and extended internationally. There now exists a body of evidence, from a number of investigators, that animals chronically exposed to any of a range of LCSs - including saccharin, sucralose, acesulfame potassium, aspartame, or the combination of erythritol+aspartame - have exhibited one or more of the following conditions: increased food consumption, lower post-prandial thermogenesis, increased weight gain, greater percent body fat, decreased GLP-1 release during glucose tolerance testing, and significantly greater fasting glucose, glucose area under the curve during glucose tolerance testing, and hyperinsulinemia, compared with animals exposed to plain water or - in many cases - even to calorically-sweetened foods or liquids. Adverse impacts of LCS have appeared diminished in animals on dietary restriction, but were pronounced among males, animals genetically predisposed to obesity, and animals with diet-induced obesity. Impacts have been especially striking in animals on high-energy diets: diets high in fats and sugars, and diets which resemble a highly-processed 'Western' diet, including trans-fatty acids and monosodium glutamate. These studies have offered both support for, and biologically plausible mechanisms to explain, the results from a series of large-scale, long-term prospective observational studies conducted in humans, in which longitudinal increases in weight, abdominal adiposity, and incidence of overweight and obesity have been observed among study participants who reported using diet sodas and other LCS-sweetened beverages daily or more often at baseline. Furthermore, frequent use of diet beverages has been associated prospectively with increased long-term risk and/or hazard of a number of cardiometabolic conditions usually considered to be among the sequelae of obesity: hypertension, metabolic syndrome, diabetes, depression, kidney dysfunction, heart attack, stroke, and even cardiovascular and total mortality. Reverse causality does not appear to explain fully the increased risk observed across all of these studies, the majority of which have included key potential confounders as covariates. These have included body mass index or waist circumference at baseline; total caloric intake and specific macronutrient intake; physical activity; smoking; demographic and other relevant risk factors; and/or family history of disease. Whether non-LCS ingredients in diet beverages might have independently increased the weight gain and/or cardiometabolic risk observed among frequent consumers of LCS-sweetened beverages deserves further exploration. In the meantime, however, there is a striking congruence between results from animal research and a number of large-scale, long-term observational studies in humans, in finding significantly increased weight gain, adiposity, incidence of obesity, cardiometabolic risk, and even total mortality among individuals with chronic, daily exposure to low-calorie sweeteners - and these results are troubling. 10.1016/j.physbeh.2016.04.047
Effects of intraduodenal administration of the artificial sweetener sucralose on blood pressure and superior mesenteric artery blood flow in healthy older subjects. The American journal of clinical nutrition Background:Postprandial hypotension (PPH) occurs frequently, particularly in older people and those with type 2 diabetes, and is associated with increased morbidity and mortality. The magnitude of the decrease in blood pressure (BP) induced by carbohydrate, fat, and protein appears to be comparable and results from the interaction of macronutrients with the small intestine, including an observed stimulation of mesenteric blood flow. It is not known whether artificial sweeteners, such as sucralose, which are widely used, affect BP. Objective:The aim of this study was to evaluate the effects of intraduodenal sucralose on BP and superior mesenteric artery (SMA) blood flow, compared with intraduodenal glucose and saline (control), in healthy older subjects. Design:Twelve healthy subjects (6 men, 6 women; aged 66-79 y) were studied on 3 separate occasions in a randomized, double-blind, crossover design. After an overnight fast, subjects had concurrent measurements of BP and heart rate (HR; automated device), SMA blood flow (Doppler ultrasound), and blood glucose (glucometer) during intraduodenal infusion of 1) glucose (25% wt:vol, ∼1400 mOsmol/L), 2) sucralose (4 mmol/L, ∼300 mOsmol/L), or 3) saline (0.9% wt:vol, ∼300 mOsmol/L) at a rate of 3 mL/min for 60 min followed by intraduodenal saline for a further 60 min. Results:There was a decrease in mean arterial BP (P < 0.001) during intraduodenal glucose [baseline (mean ± SEM): 91.7 ± 2.6 mm Hg compared with t = 60 min: 85.9 ± 2.8 mm Hg] but not during intraduodenal saline or intraduodenal sucralose. The HR (P < 0.0001) and SMA blood flow (P < 0.0001) also increased during intraduodenal glucose but not during intraduodenal saline or intraduodenal sucralose. As expected, blood glucose concentrations increased in response to glucose (P < 0.0001) but not saline or sucralose. Conclusions:In healthy older subjects, intraduodenal administration of the artificial sweetener sucralose was not associated with changes in BP or SMA blood flow. Further studies are therefore warranted to determine the potential role for artificial sweeteners as a therapy for PPH. This trial was registered at http://www.ANZCTR.org.au as ACTRN12617001249347. 10.1093/ajcn/nqy060
Recent evidence for the effects of nonnutritive sweeteners on glycaemic control. Ahmad Samar Y,Azad Meghan B,Friel James,MacKay Dylan Current opinion in clinical nutrition and metabolic care PURPOSE OF REVIEW:By replacing sugar, nonnutritive sweeteners (NNSs) are thought to aid in weight management and decrease insulin resistance. We reviewed the latest randomized clinical trials (RCTs) investigating the effects NNSs on glycaemic control. RECENT FINDINGS:Six RCTs addressed this topic between 2017 and 2018; the majority tested artificial NNS (sucralose or aspartame), with only one testing natural NNS (stevia and monk fruit extract). Most found no effect of NNS on blood glucose, insulin, gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) levels; however, two trials showed an effect of sucralose on the acute insulin response. SUMMARY:We are still incapable of reaching a definite judgement on which types of NNS, if any, impact glycaemic control. There is a need for more research to overcome the limitations of recent RCTs, related to sample size, intervention duration, dose, form of NNSs used, and inclusion of males or female participants only. Future studies should also compare different NNS types with each other, and include the increasingly popular 'natural' NNS. 10.1097/MCO.0000000000000566
Stevia Beverage Consumption prior to Lunch Reduces Appetite and Total Energy Intake without Affecting Glycemia or Attentional Bias to Food Cues: A Double-Blind Randomized Controlled Trial in Healthy Adults. The Journal of nutrition BACKGROUND:Stevia is a zero-calorie alternative to caloric sugars. Substituting caloric sweeteners with noncaloric sweeteners reduces available energy, but their effects on appetite, subsequent food intake, and neurocognitive responses are still unclear. OBJECTIVE:The aim was to examine whether sweetness with or without calories influences food intake, appetite, blood glucose concentrations, and attentional bias (AB) to food cues. METHODS:This was a randomized, controlled, double-blind crossover study. Healthy participants [n = 20; aged 27 ± 5 y,  55% female; BMI (kg/m2): 21.8 ± 1.5] completed 5 visits, consuming 5 study beverages: 330 mL water (control, no sweet taste, no calories) and either 330 mL water containing 40 g glucose or sucrose (sweet taste; calories, both 160 kcal), maltodextrin (no sweet taste; calories, 160 kcal), or 240 ppm stevia (sweet taste, no calories). Glucose and stevia beverages were matched for sweetness. Subjective appetite ratings and blood glucose were measured at baseline and at 15, 30, and 60 min postprandially. At 15 min participants performed a visual-dot probe task to assess AB to food cues; at 30 min, participants were offered an ad libitum lunch; food intake was measured. RESULTS:Subjective appetite ratings showed that preload sweetness and calorie content both affected appetite. The total AUC for glycemia was significantly higher after the caloric beverages (mean ± SD: maltodextrin, 441 ± 57.6;  glucose, 462 ± 68.1;  sucrose, 425 ± 53.6 mmol × min × L-1 ) compared with both stevia (320 ± 34.2 mmol × min × L-1) and water (304 ± 32.0 mmol × min × L-1) (all P < 0.001). Total energy intake (beverage and meal) was significantly lower after the stevia beverage (727 ± 239 kcal) compared with water (832 ± 198 kcal,  P = 0.013), with no significant difference between the water and caloric beverages (P = 1.00 for water vs. maltodextrin, glucose, and sucrose). However, food-related AB did not differ across conditions (P = 0.140). CONCLUSIONS:This study found a beneficial and specific effect of a stevia beverage consumed prior to a meal on appetite and energy intake in healthy adults. This trial is registered at clinicaltrials.gov as NCT03711084. 10.1093/jn/nxaa038
Sugar-sweetened beverage and diet soda consumption and the 7-year risk for type 2 diabetes mellitus in middle-aged Japanese men. Sakurai M,Nakamura K,Miura K,Takamura T,Yoshita K,Nagasawa S Y,Morikawa Y,Ishizaki M,Kido T,Naruse Y,Suwazono Y,Sasaki S,Nakagawa H European journal of nutrition PURPOSE:This cohort study investigated the association between sugar-sweetened beverage (SSB) and diet soda consumption and the incidence of type 2 diabetes in Japanese men. METHODS:The participants were 2,037 employees of a factory in Japan. We measured consumption of SSB and diet soda using a self-administered diet history questionnaire. The incidence of diabetes was determined in annual medical examinations over a 7-year period. Hazard ratios (HRs) with 95 % confidence intervals (CIs) for diabetes were estimated after adjusting for age, body mass index, family history, and dietary and other lifestyle factors. RESULTS:During the study, 170 participants developed diabetes. The crude incidence rates (/1,000 person-years) across participants who were rare/never SSB consumers, <1 serving/week, ≥ 1 serving/week and <1 serving/day, and ≥ 1 serving/day were 15.5, 12.7, 14.9, and 17.4, respectively. The multivariate-adjusted HR compared to rare/never SSB consumers was 1.35 (95 % CI 0.80-2.27) for participants who consumed ≥ 1 serving/day SSB. Diet soda consumption was significantly associated with the incident risk of diabetes (P for trend = 0.013), and multivariate-adjusted HRs compared to rare/never diet soda consumers were 1.05 (0.62-1.78) and 1.70 (1.13-2.55), respectively, for participants who consumed <1 serving/week and ≥ 1 serving/week. CONCLUSIONS:Consumption of diet soda was significantly associated with an increased risk for diabetes in Japanese men. Diet soda is not always effective at preventing type 2 diabetes even though it is a zero-calorie drink. 10.1007/s00394-013-0523-9
Low- and No-Calorie Sweetener (LNCS) Consumption Patterns Amongst the Spanish Adult Population. Redruello-Requejo Marina,González-Rodríguez María,Samaniego-Vaesken Mª de Lourdes,Montero-Bravo Ana,Partearroyo Teresa,Varela-Moreiras Gregorio Nutrients Low- and no-calorie sweeteners (LNCS) are a group of food additives characterized by their high sweetness intensity and virtually zero caloric content, attributes that make them potential substitutes for added sugars in processed foods and beverages. However, there is currently scarce information available about both the different LNCS used in food products available in Spain and their consumption patterns. Prompted by these reasons, the aim of this research work was to identify the presence and consumption of LNCS in food and beverages consumed by a representative sample of the Spanish adult population ( = 507). For this purpose, a Food Frequency Questionnaire was carried out. Overall, it was found that 4.5% of the foods and 22.3% of the beverages consumed by the surveyed population contained LNCS. The food groups that presented the highest percentage of daily servings containing LNCS were non-alcoholic beverages such as soft drinks and juices (36.1%); sugars and sweets such as chocolates, candies, or chewing gum (14.2%); milk and dairy products (7.0%); meat and derivative products (5.1%); cereals and derivatives (4.3%); appetizers (1.7%); and, finally, sauces and condiments such as ketchup or mustard (1.0%). The main LNCS consumed were acesulfame-K, sucralose, sorbitol, aspartame, and cyclamate, although their prevalence of use differs greatly among foods, beverages, or tabletop sweeteners. Our results show the great diversity of food groups that are currently including these compounds as ingredients. Consequently, there is a need for these food additives to be included in food composition databases, which should be regularly updated to include LNCS in order to facilitate their assessment and monitoring in dietary nutritional surveys. 10.3390/nu13061845