ATF4 Deficiency Promotes Intestinal Inflammation in Mice by Reducing Uptake of Glutamine and Expression of Antimicrobial Peptides. Hu Xiaoming,Deng Jiali,Yu Tianming,Chen Shanghai,Ge Yadong,Zhou Ziheng,Guo Yajie,Ying Hao,Zhai Qiwei,Chen Yan,Yuan Feixiang,Niu Yuguo,Shu Weigang,Chen Huimin,Ma Caiyun,Liu Zhanju,Guo Feifan Gastroenterology BACKGROUND & AIMS:Activating transcription factor 4 (ATF4) regulates genes involved in the inflammatory response, amino acid metabolism, autophagy, and endoplasmic reticulum stress. We investigated whether its activity is altered in patients with inflammatory bowel diseases (IBDs) and mice with enterocolitis. METHODS:We obtained biopsy samples during endoscopy from inflamed and/or uninflamed regions of the colon from 21 patients with active Crohn's disease (CD), 22 patients with active ulcerative colitis (UC), and 38 control individuals without IBD and of the ileum from 19 patients with active CD and 8 individuals without IBD in China. Mice with disruption of Atf4 specifically in intestinal epithelial cells (Atf4ΔIEC mice) and Atf4-floxed mice (controls) were given dextran sodium sulfate (DSS) to induce colitis. Some mice were given injections of recombinant defensin α1 (DEFA1) and supplementation of l-alanyl-glutamine or glutamine in drinking water. Human and mouse ileal and colon tissues were analyzed by quantitative real-time polymerase chain reaction, immunoblots, and immunohistochemistry. Serum and intestinal epithelial cell (IEC) amino acids were measured by high-performance liquid chromatography-tandem mass spectrometry. Levels of ATF4 were knocked down in IEC-18 cells with small interfering RNAs. Microbiomes were analyzed in ileal feces from mice by using 16S ribosomal DNA sequencing. RESULTS:Levels of ATF4 were significantly decreased in inflamed intestinal mucosa from patients with active CD or active UC compared with those from uninflamed regions or intestinal mucosa from control individuals. ATF4 was also decreased in colonic epithelia from mice with colitis vs mice without colitis. Atf4ΔIEC mice developed spontaneous enterocolitis and colitis of greater severity than control mice after administration of DSS. Atf4ΔIEC mice had decreased serum levels of glutamine and reduced levels of antimicrobial peptides, such as Defa1, Defa4, Defa5, Camp, and Lyz1, in ileal Paneth cells. Atf4ΔIEC mice had alterations in ileal microbiomes compared with control mice; these changes were reversed by administration of glutamine. Injections of DEFA1 reduced the severity of spontaneous enteritis and DSS-induced colitis in Atf4ΔIEC mice. We found that expression of solute carrier family 1 member 5 (SLC1A5), a glutamine transporter, was directly regulated by ATF4 in cell lines. Overexpression of SLC1A5 in IEC-18 or primary IEC cells increased glutamine uptake and expression of antimicrobial peptides. Knockdown of ATF4 in IEC-18 cells increased expression of inflammatory cytokines, whereas overexpression of SLC1A5 in the knockdown cells reduced cytokine expression. Levels of SLC1A5 were decreased in inflamed intestinal mucosa of patients with CD and UC and correlated with levels of ATF4. CONCLUSIONS:Levels of ATF4 are decreased in inflamed intestinal mucosa from patients with active CD or UC. In mice, ATF4 deficiency reduces glutamine uptake by intestinal epithelial cells and expression of antimicrobial peptides by decreasing transcription of Slc1a5. ATF4 might therefore be a target for the treatment of IBD. 10.1053/j.gastro.2018.11.033
    An Updated Overview of Metabolomic Profile Changes in Chronic Obstructive Pulmonary Disease. Ran Nan,Pang Zhiqiang,Gu Yinuo,Pan He,Zuo Xu,Guan Xuewa,Yuan Yuze,Wang Ziyan,Guo Yingqiao,Cui Zixu,Wang Fang Metabolites Chronic obstructive pulmonary disease (COPD), a common and heterogeneous respiratory disease, is characterized by persistent and incompletely reversible airflow limitation. Metabolomics is applied to analyze the difference of metabolic profile based on the low-molecular-weight metabolites (<1 kDa). Emerging metabolomic analysis may provide insights into the pathogenesis and diagnosis of COPD. This review aims to summarize the alteration of metabolites in blood/serum/plasma, urine, exhaled breath condensate, lung tissue samples, etc. from COPD individuals, thereby uncovering the potential pathogenesis of COPD according to the perturbed metabolic pathways. Metabolomic researches have indicated that the dysfunctions of amino acid metabolism, lipid metabolism, energy production pathways, and the imbalance of oxidations and antioxidations might lead to local and systematic inflammation by activating the Nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway and releasing inflammatory cytokines, like interleutin-6 (IL-6), tumor necrosis factor-α, and IL-8. In addition, they might cause protein malnutrition and oxidative stress and contribute to the development and exacerbation of COPD. 10.3390/metabo9060111
    Stable Redox-Cycling Nitroxide Tempol Has Antifungal and Immune-Modulatory Properties. Hosseinzadeh Ava,Stylianou Marios,Lopes José Pedro,Müller Daniel C,Häggman André,Holmberg Sandra,Grumaz Christian,Johansson Anders,Sohn Kai,Dieterich Christoph,Urban Constantin F Frontiers in microbiology Invasive mycoses remain underdiagnosed and difficult to treat. Hospitalized individuals with compromised immunity increase in number and constitute the main risk group for severe fungal infections. Current antifungal therapy is hampered by slow and insensitive diagnostics and frequent toxic side effects of standard antifungal drugs. Identification of new antifungal compounds with high efficacy and low toxicity is therefore urgently required. We investigated the antifungal activity of tempol, a cell-permeable nitroxide. To narrow down possible mode of action we used RNA-seq technology and metabolomics to probe for pathways specifically disrupted in the human fungal pathogen due to tempol administration. We found genes upregulated which are involved in iron homeostasis, mitochondrial stress, steroid synthesis, and amino acid metabolism. In an whole blood infection, tempol treatment reduced colony forming units and at the same time increased the release of pro-inflammatory cytokines, such as interleukin 8 (IL-8, monocyte chemoattractant protein-1, and macrophage migration inhibitory factor). In a systemic mouse model, tempol was partially protective with a significant reduction of fungal burden in the kidneys of infected animals during infection onset. The results obtained propose tempol as a promising new antifungal compound and open new opportunities for the future development of novel therapies. 10.3389/fmicb.2019.01843
    Proteomic profiling of splenic interstitial fluid of malnourished mice infected with Leishmania infantum reveals defects on cell proliferation and pro-inflammatory response. Losada-Barragán Monica,Umaña-Pérez Adriana,Rodriguez-Vega Andrés,Cuervo-Escobar Sergio,Azevedo Renata,Morgado Fernanda N,de Frias Carvalho Vinicius,Aquino Priscila,Carvalho Paulo C,Porrozzi Renato,Sánchez-Gómez Myriam,Padron Gabriel,Cuervo Patricia Journal of proteomics Protein malnutrition is a risk factor for developing visceral leishmaniasis. Because we previously demonstrated that protein malnutrition and infection with Leishmania infantum disrupts the splenic microarchitecture in BALB/c mice, alters T cell-subsets and increases splenic parasite load, we hypothesize that splenic microenvironment is precociously compromised in infected animals that suffered a preceding malnutrition. To evaluate this, we characterized the abundance of proteins secreted in the splenic interstitial fluid (IF) using an iTRAQ-based quantitative proteomics approach. In addition, local levels of pro-inflammatory and proliferation molecules were analyzed. Whereas well-nourished infected animals showed increased IL-1β and IL-2 levels, malnourished-infected mice displayed significant reduction of these cytokines. Remarkably, a two-weeks infection with L. infantum already modified protein abundance in the splenic IF of well-nourished mice, but malnourished animals failed to respond to infection in the same fashion. Malnutrition induced significant reduction of chemotactic and pro-inflammatory molecules as well as of proteins involved in nucleic acid and amino acid metabolism, indicating an impaired proliferative microenvironment. Accordingly, a significant decrease in Ki67 expression was observed, suggesting that splenocyte proliferation is compromised in malnourished animals. Together, our results show that malnutrition compromises the splenic microenvironment and alters the immune response to the parasite in malnourished individuals. SIGNIFICANCE: Protein malnutrition is recognized as an important epidemiological risk factor for developing visceral leishmaniasis (VL). Locally secreted factors present in the interstitial fluid have important roles in initiating immune responses and in regulating fluid volume during inflammation. However, the regulation of secreted factors under pathological conditions such as malnutrition and infection are widely unknown. To analyze how protein malnutrition alters secreted proteins involved in the immune response to L. infantum infection we evaluated the proteomic profile of the interstitial fluid of the spleen in malnourished BALB/c mice infected with L. infantum. Our work revealed new elements that contribute to the understanding of the immunopathological events in the spleen of malnourished animals infected with L. infantum and opens new pathways for consideration of other aspects that could improve VL treatment in malnourished individuals. 10.1016/j.jprot.2019.103492
    Gas chromatography-mass spectrometric method-based urine metabolomic profile of rats with pelvic inflammatory disease. Zou Wei,Wen Xiaoke,Sheng Xiaoqi,Zheng Y I,Xiao Zuoqi,Luo Jieying,Chen Shuqiong,Wang Yichao,Cheng Zeneng,Xiang Daxiong,Nie Yichu Experimental and therapeutic medicine Pelvic inflammatory disease (PID) can lead to a poor outcome of severe sequelae, and the current methods of clinical diagnosis are not satisfactory. Metabolomics is an effective method for the identification of disease-related metabolite biomarkers to facilitate disease diagnosis. However, to the best of our knowledge, no PID-associated metabolomic study has yet been carried out. The metabolomic changes of rats with PID were investigated in the present study. A PID model was constructed by the multi-pathogenic infection of the upper genital tract in rats. Infiltration of inflammatory cells and elevated expression levels of the cytokines interleukin (IL)-1β and IL-6 in the uterus and fallopian tubes validated the disease model. Gas chromatography-mass spectrometry coupled with derivatization was used to determine the urine metabolomic profile. Principal component analysis and partial least squares-discriminant analysis of the data sets showed a clear separation of metabolic profiles between rats with PID and control rats. Eighteen differentiating metabolites were found, including four amino acids, three fatty acids, nine organic acids, and two sugars, which indicated alterations in sugar metabolism, the citric acid cycle, amino acid metabolism and fatty acid metabolism. These metabolites could be potential biomarkers of PID, and this research may offer a new approach to evaluate the effect of anti-PID drugs in pre-clinical or clinical trials. 10.3892/etm.2016.3142
    Downregulation of SLC7A7 Triggers an Inflammatory Phenotype in Human Macrophages and Airway Epithelial Cells. Rotoli Bianca Maria,Barilli Amelia,Visigalli Rossana,Ingoglia Filippo,Milioli Marco,Di Lascia Maria,Riccardi Benedetta,Puccini Paola,Dall'Asta Valeria Frontiers in immunology Lysinuric protein intolerance (LPI) is a recessively inherited aminoaciduria caused by mutations of SLC7A7, the gene encoding y+LAT1 light chain of system yL for cationic amino acid transport. The pathogenesis of LPI is still unknown. In this study, we have utilized a gene silencing approach in macrophages and airway epithelial cells to investigate whether complications affecting lung and immune system are directly ascribable to the lack of SLC7A7 or, rather, mediated by an abnormal accumulation of arginine in mutated cells. When SLC7A7/y+LAT1 was silenced in human THP-1 macrophages and A549 airway epithelial cells by means of short interference RNA (siRNA), a significant induction of the expression and release of the inflammatory mediators IL1β and TNFα was observed, no matter the intracellular arginine availability. This effect was mainly regulated at transcriptional level through the activation of NFκB signaling pathway. Moreover, since respiratory epithelial cells are the important sources of chemokines in response to pro-inflammatory stimuli, the effect of IL1β has been addressed on SLC7A7 silenced A549 cells. Results obtained indicated that the downregulation of SLC7A7/y+LAT1 markedly strengthened the stimulatory effect of the cytokine on CCL5/RANTES expression and release without affecting the levels of CXCL8/IL8. Consistently, also the conditioned medium of silenced THP-1 macrophages activated airway epithelial cells in terms of CCL5/RANTES expression due to the presence of elevated amount of proinflammatory cytokines. In conclusion, our results point to a novel thus far unknown function of SLC7A7/y+LAT1, that, under physiological conditions, besides transporting arginine, may act as a brake to restrain inflammation. 10.3389/fimmu.2018.00508
    Pathophysiological mechanisms in acute pancreatitis: Current understanding. Singh Pankaj,Garg Pramod Kumar Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology The precise mechanisms involved in the pathophysiology of acute pancreatitis (AP) are still far from clear. Several earlier studies have focused mainly on pancreatic enzyme activation as the key intracellular perturbation in the pancreatic acinar cells. For decades, the trypsin-centered hypothesis has remained the focus of the intra-acinar events in acute pancreatitis. Recent advances in basic science research have lead to the better understanding of various other mechanisms such as oxidative and endoplasmic stress, impaired autophagy, mitochondrial dysfunction, etc. in causing acinar cell injury. Despite all efforts, the clinical outcome of patients with AP has not changed significantly over the years. This suggests that the knowledge of the critical molecular pathways in the pathophysiology of AP is still limited. The mechanisms through which the acinar cell injury leads to local and systemic inflammation are not well understood. The role of inflammatory markers and immune system activation is an area of much relevance from the point of view of finding a target for therapeutic intervention. Some data are available from experimental animal models but not much is known in human pancreatitis. This review intends to highlight the current understanding in this area. 10.1007/s12664-016-0647-y
    The pretransplant systemic metabolic profile reflects a risk of acute graft versus host disease after allogeneic stem cell transplantation. Reikvam Håkon,Hatfield Kimberley,Bruserud Øystein Metabolomics : Official journal of the Metabolomic Society Allogeneic stem cell transplantation is used in the treatment of younger patients with severe hematological diseases, especially hematological malignancies, and acute graft versus host disease (GVHD) is then an important immune-mediated posttransplant complication. Several risk factors for acute GVHD have been identified, including pretransplant factors that possibly influence the posttranspant course through their effects on host immunocompetent cells. Metabolic regulation is important for immunoregulation, and we therefore investigated whether the pretransplant metabolic status of allotransplant recipients was associated with later acute GVHD. In our population-based study we investigated the systemic (serum) metabolic profile for 86 consecutive allotransplant recipients. The samples were collected before start of the pretransplant conditioning therapy. Patients who developed later acute GVHD especially showed altered pretransplant amino acid metabolism, including (1) altered metabolism of immunoregulatory branched chain amino acids (leucine, isoleucine and valine); and (2) altered levels of potentially proinflammatory tyrosine metabolites (p-cresol sulphate, 3-phenylpropionate) formed by the gastrointestinal microbial flora. However, isobutyrylcarnitine and propyonylcarnitine levels were also altered; the carnitines are important for the transport of fatty acids and may also be important for the release of immunoregulatory cytokines in allotransplant recipients. These metabolic alterations were associated with an ongoing pretransplant acute phase reaction or early hematopoietic/immune reconstitution. Thus, allotransplant recipients developing acute GVHD showed altered preconditioning/pretransplant levels of several immunoregulatory metabolites. Our hypothesis is that these metabolites alter or activate recipient immunocompetent cells and thereby enhance or initiate anti-recipient immune reactivity. 10.1007/s11306-015-0880-x
    Reactive Oxygen Species Regulate T Cell Immune Response in the Tumor Microenvironment. Chen Xinfeng,Song Mengjia,Zhang Bin,Zhang Yi Oxidative medicine and cellular longevity Reactive oxygen species (ROS) produced by cellular metabolism play an important role as signaling messengers in immune system. ROS elevated in the tumor microenvironment are associated with tumor-induced immunosuppression. T cell-based therapy has been recently approved to be effective for cancer treatment. However, T cells often become dysfunctional after reaching the tumor site. It has been reported that ROS participate extensively in T cells activation, apoptosis, and hyporesponsiveness. The sensitivity of T cells to ROS varies among different subsets. ROS can be regulated by cytokines, amino acid metabolism, and enzymatic activity. Immunosuppressive cells accumulate in the tumor microenvironment and induce apoptosis and functional suppression of T cells by producing ROS. Thus, modulating the level of ROS may be important to prolong survival of T cells and enhance their antitumor function. Combining T cell-based therapy with antioxidant treatment such as administration of ROS scavenger should be considered as a promising strategy in cancer treatment, aiming to improve antitumor T cells immunity. 10.1155/2016/1580967
    Increased plasma levels of competing amino acids, rather than lowered plasma tryptophan levels, are associated with a non-response to treatment in major depression. Ormstad Heidi,Dahl Johan,Verkerk Robert,Andreassen Ole A,Maes Michael European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology Lowered plasma tryptophan (TRP) and TRP/competing amino acid (CAA) ratio may be involved in the pathophysiology of major depression (MDD). Increased cortisol and immune-inflammatory mediators in MDD may affect the availability of TRP to the brain. We investigated whether baseline or post-treatment TRP, CAAs and TRP/CAA ratio are associated with a treatment response in MDD and whether these effects may be mediated by cortisol or immune biomarkers. We included 50 medication-free MDD patients with a depressive episode (DSM diagnosis) and assessed symptom severity with the Inventory of Depressive Symptomatology (IDS) before and after treatment as usual for 12 weeks (endpoint). Plasma levels of TRP, CAAs, the ratio, cortisol, CRP and 6 selected cytokines were assayed. The primary outcome was a 50% reduction in the IDS, while the secondary was a remission of the depressive episode. In IDS non-responders, CAAs increased and the TRP/CAA ratio decreased, while in IDS responders CAAs decreased and the TRP/CAA ratio increased from baseline to endpoint. In patients who were still depressed at endpoint TRP and CAAs levels had increased from baseline, while in remitted patients no such effects were found. Increases in CAAs were inversely correlated with changes in interleukin-1 receptor antagonist levels. The results show that increased CAA levels from baseline to endpoint are associated with a non-response to treatment in MDD patients. This suggests that the mechanism underpinning the CAA-related treatment resistance may be related to changes in immune pathways. CAA levels and amino acid metabolism may be new drug targets in depression. 10.1016/j.euroneuro.2016.05.005
    Dose-Dependent Metabolic Reprogramming and Differential Gene Expression in TCDD-Elicited Hepatic Fibrosis. Nault Rance,Fader Kelly A,Ammendolia Dustin A,Dornbos Peter,Potter Dave,Sharratt Bonnie,Kumagai Kazuyoshi,Harkema Jack R,Lunt Sophia Y,Matthews Jason,Zacharewski Tim Toxicological sciences : an official journal of the Society of Toxicology We have previously shown that in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-elicited NAFLD progression, central carbon, glutaminolysis, and serine/folate metabolism are reprogrammed to support NADPH production and ROS defenses. To further investigate underlying dose-dependent responses associated with TCDD-induced fibrosis, female C57BL/6 mice were gavaged with TCDD every 4 days (d) for 28 d or 92 d. RNA-Seq, ChIP-Seq (2 h), and 28 d metabolomic (urine, serum, and hepatic extract) analyses were conducted with complementary serum marker assessments at 92 d. Additional vehicle and 30 µg/kg treatment groups were allowed to recover for 36 d following the 92-d treatment regimen to examine recovery from TCDD-elicited fibrosis. Histopathology revealed dose-dependent increases in hepatic fat accumulation, inflammation, and periportal collagen deposition at 92 days, with increased fibrotic severity in the recovery group. Serum proinflammatory and profibrotic interleukins-1β, -2, -4, -6, and -10, as well as TNF-α and IFN-γ, exhibited dose-dependent induction. An increase in glucose tolerance was observed with a concomitant 3.0-fold decrease in hepatic glycogen linked to increased ascorbic acid biosynthesis and proline metabolism, consistent with increased fibrosis. RNA-Seq identified differential expression of numerous matrisome genes including an 8.8-fold increase in Tgfb2 indicating myofibroblast activation. Further analysis suggests reprogramming of glycogen, ascorbic acid, and amino acid metabolism in support of collagen deposition and the use of proline as a substrate for ATP production via the proline cycle. In summary, we demonstrate that glycogen, ascorbic acid, and amino acid metabolism are also reorganized to support remodeling of the extracellular matrix, progressing to hepatic fibrosis in response to chronic injury from TCDD. 10.1093/toxsci/kfw163
    [Peculiar features of immunological and metabolic status associated with polypous rhinosinusitis]. Kolenchukova O A,Smirnova S V,Lapteva A M Vestnik otorinolaringologii The objective of the present work was to study peculiar features of immunological and metabolic status associated with polypous rhinosinusitis (PRS). We determined the population and subpopulation composition of blood lymphocytes, concentration of cytokines in blood sera and nasal secretion as well as the level of intracellular enzymes in blood lymphocytes of the patients presenting with polypous rhinosinusitis and of the control subjects. It was shown that PRS was associated with activation of Th1-lymphocytes and determined the character of the immune response largely of the cell-mediated type. The study has demonstrated the differently directed changes in the activation of the intracellular processes in blood lymphocytes. Specifically, the intensity of the aerobic processes and lipid anabolism was increased while that of the anaerobic processes and amino acid metabolism (NAD-GDG and NADH-GDG) was suppressed. 10.17116/otorino201580622-27
    Deficiency of immunoregulatory indoleamine 2,3-dioxygenase 1in juvenile diabetes. Orabona Ciriana,Mondanelli Giada,Pallotta Maria T,Carvalho Agostinho,Albini Elisa,Fallarino Francesca,Vacca Carmine,Volpi Claudia,Belladonna Maria L,Berioli Maria G,Ceccarini Giulia,Esposito Susanna Mr,Scattoni Raffaella,Verrotti Alberto,Ferretti Alessandra,De Giorgi Giovanni,Toni Sonia,Cappa Marco,Matteoli Maria C,Bianchi Roberta,Matino Davide,Iacono Alberta,Puccetti Matteo,Cunha Cristina,Bicciato Silvio,Antognelli Cinzia,Talesa Vincenzo N,Chatenoud Lucienne,Fuchs Dietmar,Pilotte Luc,Van den Eynde Benoît,Lemos Manuel C,Romani Luigina,Puccetti Paolo,Grohmann Ursula JCI insight A defect in indoleamine 2,3-dioxygenase 1 (IDO1), which is responsible for immunoregulatory tryptophan catabolism, impairs development of immune tolerance to autoantigens in NOD mice, a model for human autoimmune type 1 diabetes (T1D). Whether IDO1 function is also defective in T1D is still unknown. We investigated IDO1 function in sera and peripheral blood mononuclear cells (PBMCs) from children with T1D and matched controls. These children were further included in a discovery study to identify SNPs in IDO1 that might modify the risk of T1D. T1D in children was characterized by a remarkable defect in IDO1 function. A common haplotype, associated with dysfunctional IDO1, increased the risk of developing T1D in the discovery and also confirmation studies. In T1D patients sharing such a common IDO1 haplotype, incubation of PBMCs in vitro with tocilizumab (TCZ) - an IL-6 receptor blocker - would, however, rescue IDO1 activity. In an experimental setting with diabetic NOD mice, TCZ was found to restore normoglycemia via IDO1-dependent mechanisms. Thus, functional SNPs of IDO1 are associated with defective tryptophan catabolism in human T1D, and maneuvers aimed at restoring IDO1 function would be therapeutically effective in at least a subgroup of T1D pediatric patients. 10.1172/jci.insight.96244
    Induction of a Proinflammatory Response in Cortical Astrocytes by the Major Metabolites Accumulating in HMG-CoA Lyase Deficiency: the Role of ERK Signaling Pathway in Cytokine Release. Fernandes Carolina Gonçalves,Rodrigues Marília Danyelle Nunes,Seminotti Bianca,Colín-González Ana Laura,Santamaria Abel,Quincozes-Santos André,Wajner Moacir Molecular neurobiology 3-Hydroxy-3-methylglutaric aciduria (HMGA) is an inherited metabolic disorder caused by 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. It is biochemically characterized by predominant tissue accumulation and high urinary excretion of 3-hydroxy-3-methylglutarate (HMG) and 3-methylglutarate (MGA). Affected patients commonly present acute symptoms during metabolic decompensation, including vomiting, seizures, and lethargy/coma accompanied by metabolic acidosis and hypoketotic hypoglycemia. Although neurological manifestations are common, the pathogenesis of brain injury in this disease is poorly known. Astrocytes are important for neuronal protection and are susceptible to damage by neurotoxins. In the present study, we investigated the effects of HMG and MGA on important parameters of redox homeostasis and cytokine production in cortical cultured astrocytes. The role of the metabolites on astrocyte mitochondrial function (thiazolyl blue tetrazolium bromide (MTT) reduction) and viability (propidium iodide incorporation) was also studied. Both organic acids decreased astrocytic mitochondrial function and the concentrations of reduced glutathione without altering cell viability. In contrast, they increased reactive species formation (2'-7'-dichlorofluorescein diacetate (DCFHDA) oxidation), as well as IL-1β, IL-6, and TNF α release through the ERK signaling pathway. Taken together, the data indicate that the principal compounds accumulating in HMGA induce a proinflammatory response in cultured astrocytes that may possibly be involved in the neuropathology of this disease. 10.1007/s12035-015-9289-9
    A multi-method evaluation of the effects of Inflammatory cytokines (IL-1β, IFN-γ, TNF-α) on pancreatic β-cells. Xie Kaipeng,Xu Bo,Zhang Yuqing,Chen Minjian,Ji Yinwen,Wang Jie,Huang Zhenyao,Zhou Kun,Xia Yankai,Tang Wei Journal of cellular physiology We aimed to explore the effects of Inflammatory cytokines (IL-1β, IFN-γ, TNF-α) on pancreatic β-cells. CCK-8 assay showed that the cell viability decreased after 24 hr treatment of TNF-α, 48 hr of IFN-γ, and 84 hr of IL-1β. EdU assay illustrated that after 24 hr treatment, there were significantly reduced EdU-labeled red fluorescence cells in TNF-α group while not in IFN-γ and IL-1β groups. Flow Cytometry results displayed that TNF-α and IFN-γ groups increased apoptosis while IL-1β group did not. Cell apoptosis results found that there was an increase in the S-phase population of IL-1β and TNF-α groups, however, there was no significant difference in cell cycle between IFN-γ group and the control. TEM images showed that there were reduction in the number of granules and mitochondria in IL-1β and IFN-γ groups, in particular paucity of insulin granules and mitochondria in TNF-α group. Radioimmunoassay results presented that TNF-α inhibited glucose-induced insulin secretion, while there were no significant changes in IL-1β and IFN-γ groups when compared with the control. Metabolomic analysis found amino acid metabolism and Krebs cycle were the most robust altered metabolism pathways after inflammatory cytokines treatments. Overall, the altered amino acid metabolism and Krebs cycle metabolism might be important mechanisms of TNF-α induced mouse pancreatic β-cells dysfuction. 10.1002/jcp.26518
    Melatonin alters amino acid metabolism and inflammatory responses in colitis mice. Liu Gang,Jiang Qian,Chen Shuai,Fang Jun,Ren Wenkai,Yin Jie,Yao Kang,Yin Yulong Amino acids Inflammatory bowel disease is a chronic inflammatory dysfunction of the gastrointestinal tract. This study explored the hypothesis that melatonin has beneficial functions in the mouse model of colitis induced by dextran sodium sulfate (DSS), with a specific focus on the expression of intestinal inflammatory cytokines and the serum levels of amino acids. The results revealed that mice with melatonin supplementation had a reduction in weight loss and disease index induced by DSS treatment. Melatonin stifled the expression of colonic IL-17 in mice with DSS-induced colitis. Melatonin also lowered the serum levels of Asp, Ser, Met, and Leu (p < 0.05), but increased those of Glu and Cys (p < 0.05). Thus, melatonin treatment is promising and may function as a potential adjuvant therapy to alleviate the clinical symptoms of patients with inflammatory bowel disease. 10.1007/s00726-017-2489-z
    Amino acid metabolism inhibits antibody-driven kidney injury by inducing autophagy. Chaudhary Kapil,Shinde Rahul,Liu Haiyun,Gnana-Prakasam Jaya P,Veeranan-Karmegam Rajalakshmi,Huang Lei,Ravishankar Buvana,Bradley Jillian,Kvirkvelia Nino,McMenamin Malgorzata,Xiao Wei,Kleven Daniel,Mellor Andrew L,Madaio Michael P,McGaha Tracy L Journal of immunology (Baltimore, Md. : 1950) Inflammatory kidney disease is a major clinical problem that can result in end-stage renal failure. In this article, we show that Ab-mediated inflammatory kidney injury and renal disease in a mouse nephrotoxic serum nephritis model was inhibited by amino acid metabolism and a protective autophagic response. The metabolic signal was driven by IFN-γ-mediated induction of indoleamine 2,3-dioxygenase 1 (IDO1) enzyme activity with subsequent activation of a stress response dependent on the eIF2α kinase general control nonderepressible 2 (GCN2). Activation of GCN2 suppressed proinflammatory cytokine production in glomeruli and reduced macrophage recruitment to the kidney during the incipient stage of Ab-induced glomerular inflammation. Further, inhibition of autophagy or genetic ablation of Ido1 or Gcn2 converted Ab-induced, self-limiting nephritis to fatal end-stage renal disease. Conversely, increasing kidney IDO1 activity or treating mice with a GCN2 agonist induced autophagy and protected mice from nephritic kidney damage. Finally, kidney tissue from patients with Ab-driven nephropathy showed increased IDO1 abundance and stress gene expression. Thus, these findings support the hypothesis that the IDO-GCN2 pathway in glomerular stromal cells is a critical negative feedback mechanism that limits inflammatory renal pathologic changes by inducing autophagy. 10.4049/jimmunol.1500277
    Excessive Methionine Supplementation Exacerbates the Development of Abdominal Aortic Aneurysm in Rats. Fan Yichuan,Li Nan,Liu Chengwei,Dong Haipeng,Hu Xinhua Journal of vascular research OBJECTIVE:The relationship between methionine (Met) and abdominal aortic aneurysm (AAA) has been previously demonstrated, but the mechanisms controlling this association remain unclear. This study investigated the potential contribution of hypermethioninemia (HMet) to the development of AAA. METHODS:A model of AAA was induced by intraluminal porcine pancreatic elastase (PPE) infusion in 60 male Sprague-Dawley rats divided into 4 groups (n = 15 per group). Met was supplied by intragastric administration (1 g/kg body weight/day) from 1 week before surgery until 4 weeks after surgery. The aortic diameter was measured by ultrasound. Aortas were collected 4 weeks after surgery and subjected to biochemical analysis, histological assays, and transmission electron microscopy. RESULTS:After 5 weeks of Met supplementation, HMet increased the dilation ratio of the HMet + PPE group, and hyperhomocysteinemia was also induced in HMet and HMet + PPE rats. Increased matrix metalloproteinase-2 (MMP-2), osteopontin, and interleukin-6 expression was detected in HMet + PPE rats. Furthermore, increased autophagy was detected in the HMet + PPE group. CONCLUSION:This study demonstrates that HMet may exacerbate the formation of AAA due to the increased dilation ratio partially via enhancing MMP-2 and inflammatory responses. 10.1159/000501313
    Serum metabolic signatures of coronary and carotid atherosclerosis and subsequent cardiovascular disease. Tzoulaki Ioanna,Castagné Raphaële,Boulangé Claire L,Karaman Ibrahim,Chekmeneva Elena,Evangelou Evangelos,Ebbels Timothy M D,Kaluarachchi Manuja R,Chadeau-Hyam Marc,Mosen David,Dehghan Abbas,Moayyeri Alireza,Ferreira Diana L Santos,Guo Xiuqing,Rotter Jerome I,Taylor Kent D,Kavousi Maryam,de Vries Paul S,Lehne Benjamin,Loh Marie,Hofman Albert,Nicholson Jeremy K,Chambers John,Gieger Christian,Holmes Elaine,Tracy Russell,Kooner Jaspal,Greenland Philip,Franco Oscar H,Herrington David,Lindon John C,Elliott Paul European heart journal AIMS:To characterize serum metabolic signatures associated with atherosclerosis in the coronary or carotid arteries and subsequently their association with incident cardiovascular disease (CVD). METHODS AND RESULTS:We used untargeted one-dimensional (1D) serum metabolic profiling by proton nuclear magnetic resonance spectroscopy (1H NMR) among 3867 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), with replication among 3569 participants from the Rotterdam and LOLIPOP studies. Atherosclerosis was assessed by coronary artery calcium (CAC) and carotid intima-media thickness (IMT). We used multivariable linear regression to evaluate associations between NMR features and atherosclerosis accounting for multiplicity of comparisons. We then examined associations between metabolites associated with atherosclerosis and incident CVD available in MESA and Rotterdam and explored molecular networks through bioinformatics analyses. Overall, 30 1H NMR measured metabolites were associated with CAC and/or IMT, P = 1.3 × 10-14 to 1.0 × 10-6 (discovery) and P = 5.6 × 10-10 to 1.1 × 10-2 (replication). These associations were substantially attenuated after adjustment for conventional cardiovascular risk factors. Metabolites associated with atherosclerosis revealed disturbances in lipid and carbohydrate metabolism, branched chain, and aromatic amino acid metabolism, as well as oxidative stress and inflammatory pathways. Analyses of incident CVD events showed inverse associations with creatine, creatinine, and phenylalanine, and direct associations with mannose, acetaminophen-glucuronide, and lactate as well as apolipoprotein B (P < 0.05). CONCLUSION:Metabolites associated with atherosclerosis were largely consistent between the two vascular beds (coronary and carotid arteries) and predominantly tag pathways that overlap with the known cardiovascular risk factors. We present an integrated systems network that highlights a series of inter-connected pathways underlying atherosclerosis. 10.1093/eurheartj/ehz235
    Mucosal Metabolomic Profiling and Pathway Analysis Reveal the Metabolic Signature of Ulcerative Colitis. Diab Joseph,Hansen Terkel,Goll Rasmus,Stenlund Hans,Jensen Einar,Moritz Thomas,Florholmen Jon,Forsdahl Guro Metabolites The onset of ulcerative colitis (UC) is characterized by a dysregulated mucosal immune response triggered by several genetic and environmental factors in the context of host-microbe interaction. This complexity makes UC ideal for metabolomic studies to unravel the disease pathobiology and to improve the patient stratification strategies. This study aims to explore the mucosal metabolomic profile in UC patients, and to define the UC metabolic signature. Treatment- naïve UC patients ( = 18), UC patients in deep remission ( = 10), and healthy volunteers ( = 14) were recruited. Mucosa biopsies were collected during colonoscopies. Metabolomic analysis was performed by combined gas chromatography coupled to time-of-flight mass spectrometry (GC-TOF-MS) and ultra-high performance liquid chromatography coupled with mass spectrometry (UHPLC-MS). In total, 177 metabolites from 50 metabolic pathways were identified. The most prominent metabolome changes among the study groups were in lysophosphatidylcholine, acyl carnitine, and amino acid profiles. Several pathways were found perturbed according to the integrated pathway analysis. These pathways ranged from amino acid metabolism (such as tryptophan metabolism) to fatty acid metabolism, namely linoleic and butyrate. These metabolic changes during UC reflect the homeostatic disturbance in the gut, and highlight the importance of system biology approaches to identify key drivers of pathogenesis which prerequisite personalized medicine. 10.3390/metabo9120291
    Metabolic Fingerprints of Circulating IGF-1 and the IGF-1/IGFBP-3 Ratio: A Multifluid Metabolomics Study. Knacke Henrike,Pietzner Maik,Do Kieu Trinh,Römisch-Margl Werner,Kastenmüller Gabi,Völker Uwe,Völzke Henry,Krumsiek Jan,Artati Anna,Wallaschofski Henri,Nauck Matthias,Suhre Karsten,Adamski Jerzy,Friedrich Nele The Journal of clinical endocrinology and metabolism OBJECTIVE:IGF-1 is known for its various physiological and severe pathophysiological effects on human metabolism; however, underlying molecular mechanisms still remain unsolved. To reveal possible molecular mechanisms mediating these effects, for the first time, we associated serum IGF-1 levels with multifluid untargeted metabolomics data. METHODS:Plasma/urine samples of 995 nondiabetic participants of the Study of Health in Pomerania were characterized by mass spectrometry. Sex-specific linear regression analyses were performed to assess the association of IGF-1 and IGF-1/IGF binding protein 3 ratio with metabolites. Additionally, the predictive ability of the plasma and urine metabolome for IGF-1 was assessed by orthogonal partial least squares analyses. RESULTS AND CONCLUSIONS:We revealed a multifaceted image of associated metabolites with large sex differences. Confirming previous reports, we detected relations between IGF-1 and steroid hormones or related intermediates. Furthermore, various associated metabolites were previously mentioned regarding IGF-1-associated diseases, eg, betaine and cortisol in cardiovascular disease and metabolic syndrome, lipid disorders, and diabetes, or have previously been found to associate with differentiation and proliferation or mitochondrial functionality, eg, phospholipids. bradykinin, fatty acid derivatives, and cortisol, which were inversely associated with IGF-1, might establish a link of IGF-1 with inflammation. For the first time, we showed an association between IGF-1 and pipecolate, a metabolite linked to amino acid metabolism. Our study demonstrates that IGF-1 action on metabolism is tractable, even in healthy subjects, and that the findings provide a solid basis for further experimental/clinical investigation, eg, searching for inflammatory or cardiovascular disease- or metabolic syndrome-associated biomarkers and therapeutic targets. 10.1210/jc.2016-2588
    Ammonia role in glial dysfunction in methylmalonic acidemia. Gabbi Patricia,Nogueira Viviane,Haupental Fernanda,Rodrigues Fernanda Silva,do Nascimento Patricia Severo,Barbosa Sílvia,Arend Josi,Furian Ana Flávia,Oliveira Mauro Schneider,Dos Santos Adair Roberto Soares,Royes Luiz Fernando Freire,Fighera Michele Rechia Toxicology letters Hyperammonemia is a common finding in patients with methylmalonic acidemia. However, its contribution to methylmalonate (MMA)-induced neurotoxicity is poorly understood. The aim of this study was evaluate whether an acute metabolic damage to brain during the neonatal period may disrupt cerebral development, leading to neurodevelopmental disorders, as memory deficit. Mice received a single intracerebroventricular dose of MMA and/or NHCl, administered 12 hs after birth. The maze tests showed that MMA and NHCl injected animals (21 and 40 days old) exhibited deficit in the working memory test, but not in the reference memory test. Furthermore, MMA and NHCl increased the levels of 2',7'-dichlorofluorescein-diacetate (DCF), TNF-α, IL-1β in the cortex, hippocampus and striatum of mice. MMA and NHCl also increased glial proliferation in all structures. Since the treatment of MMA and ammonia increased cytokines levels, we suggested that it might be a consequence of the glial activation induced by the acid and ammonia, leading to delay in the developing brain and contributing to behavioral alterations. However, this hypothesis is speculative in nature and more studies are needed to clarify this possibility. 10.1016/j.toxlet.2018.06.1070
    Maternal Hypermethioninemia Affects Neurons Number, Neurotrophins Levels, Energy Metabolism, and Na,K-ATPase Expression/Content in Brain of Rat Offspring. Schweinberger Bruna M,Rodrigues André F,Turcatel Elias,Pierozan Paula,Pettenuzzo Leticia F,Grings Mateus,Scaini Giselli,Parisi Mariana M,Leipnitz Guilhian,Streck Emilio L,Barbé-Tuana Florencia M,Wyse Angela T S Molecular neurobiology In the current study, we verified the effects of maternal hypermethioninemia on the number of neurons, apoptosis, nerve growth factor, and brain-derived neurotrophic factor levels, energy metabolism parameters (succinate dehydrogenase, complex II, and cytochrome c oxidase), expression and immunocontent of Na,K-ATPase, edema formation, inflammatory markers (tumor necrosis factor-alpha and interleukin-6), and mitochondrial hydrogen peroxide levels in the encephalon from the offspring. Pregnant Wistar rats were divided into two groups: the first one received saline (control) and the second group received 2.68 μmol methionine/g body weight by subcutaneous injections twice a day during gestation (approximately 21 days). After parturition, pups were killed at the 21st day of life for removal of encephalon. Neuronal staining (anti-NeuN) revealed a reduction in number of neurons, which was associated to decreased nerve growth factor and brain-derived neurotrophic factor levels. Maternal hypermethioninemia also reduced succinate dehydrogenase and complex II activities and increased expression and immunocontent of Na,K-ATPase alpha subunits. These results indicate that maternal hypermethioninemia may be a predisposing factor for damage to the brain during the intrauterine life. 10.1007/s12035-017-0383-z
    Effects of vitamin B6 on growth, diarrhea rate, intestinal morphology, function, and inflammatory factors expression in a high-protein diet fed to weaned piglets1. Li Jun,Yin Lanmei,Wang Lei,Li Jianzhong,Huang Pengfei,Yang Huansheng,Yin Yulong Journal of animal science Vitamin B6 (VB6) is an important coenzyme factor which participates in many metabolic reactions, especially amino acid metabolism. There are few reports on how VB6 mediates weaned piglet intestinal health. This study purposed to investigate dietary VB6 effects on growth, diarrhea rates, and intestinal morphology and function in weaned piglets fed a high-crude protein (22% CP) diet. Eighteen 21-d-old weaned [(Yorkshire × Landrace) × Duroc] piglets with body weights of 7.03 ± 0.15 (means ± SEM) kg were randomly assigned into 3 VB6-containing dietary treatments. Vitamin B6 content was: 0, 4, and 7 mg/kg, respectively. The feeding period lasted 14 d. The results showed that no significant difference existed for the growth performance. The 7 mg/kg VB6 group had a tendency to decrease diarrhea rate (P = 0.065). Blood biochemical parameters analysis demonstrated that total protein, cholesterol, and high-density lipoprotein significantly increased in the 7 mg/kg VB6 group (P < 0.05). In the jejunum, no significant differences were detected for villus height, villus width, crypt depth, villus height and crypt depth ratios, and positive Ki67 counts and the mRNA expression of inflammatory cytokines. Vitamin B6 significantly increased the mRNA expression of SLC6A19 and SLC6A20 (P < 0.05) and decreased the mRNA expression of SLC36A1 (P < 0.05). In the ileum, VB6 significantly increased villus height and villus width (P < 0.05) while decreased positive Ki67 cell counts for 7 mg/kg VB6 group (P < 0.05). Vitamin B6 had significantly increased the mRNA expression of interleukin-1β, tumor necrosis factor-α,cyclo-oxygen-ase-2, and transforming growth factor-β (P < 0.05). Vitamin B6 also had significantly increased mRNA expression of SLC6A19, SLC7A6, SLC7A7, and SLC36A1 (P < 0.05). These findings suggest that dietary supplementation with VB6 may affect the intestinal morphology and absorption and metabolism of protein in weaned piglets fed a high-protein diet by altering the expression of intestinal inflammatory cytokines and amino acid transporters. 10.1093/jas/skz338
    Alterations of amino acid metabolism in osteoarthritis: its implications for nutrition and health. Li Yusheng,Xiao Wenfeng,Luo Wei,Zeng Chao,Deng Zhenhan,Ren Wenkai,Wu Guoyao,Lei Guanghua Amino acids Osteoarthritis (OA) is a common form of arthritis in humans. It has long been regarded as a non-inflammatory disease, but a degree of inflammation is now recognized as being a vital inducer of subpopulation of OA. Besides inflammation, the establishment and development of OA are associated with alterations in metabolism and profiles of amino acids (AA), including glutamate- and arginine-family AA as well as their related metabolites (e.g., creatinine, hydroxyproline, γ-aminobutyrate, dimethylarginines and homoarginine). Functional AA (e.g., glutamine, arginine, glutamate, glycine, proline, and tryptophan) have various benefits (i.e., anti-inflammation and anti-oxidation) in treatment of inflammation-associated diseases, including OA. Thus, these AA have potential as immunomodulatory nutrients for patients with inflammation-induced OA. 10.1007/s00726-015-2168-x
    Immune control by amino acid catabolism during tumorigenesis and therapy. Lemos Henrique,Huang Lei,Prendergast George C,Mellor Andrew L Nature reviews. Cancer Immune checkpoints arise from physiological changes during tumorigenesis that reprogramme inflammatory, immunological and metabolic processes in malignant lesions and local lymphoid tissues, which constitute the immunological tumour microenvironment (TME). Improving clinical responses to immune checkpoint blockade will require deeper understanding of factors that impact local immune balance in the TME. Elevated catabolism of the amino acids tryptophan (Trp) and arginine (Arg) is a common TME hallmark at clinical presentation of cancer. Cells catabolizing Trp and Arg suppress effector T cells and stabilize regulatory T cells to suppress immunity in chronic inflammatory diseases of clinical importance, including cancers. Processes that induce Trp and Arg catabolism in the TME remain incompletely defined. Indoleamine 2,3 dioxygenase (IDO) and arginase 1 (ARG1), which catabolize Trp and Arg, respectively, respond to inflammatory cues including interferons and transforming growth factor-β (TGFβ) cytokines. Dying cells generate inflammatory signals including DNA, which is sensed to stimulate the production of type I interferons via the stimulator of interferon genes (STING) adaptor. Thus, dying cells help establish local conditions that suppress antitumour immunity to promote tumorigenesis. Here, we review evidence that Trp and Arg catabolism contributes to inflammatory processes that promote tumorigenesis, impede immune responses to therapy and might promote neurological comorbidities associated with cancer. 10.1038/s41568-019-0106-z
    Activation of the Amino Acid Response Pathway Blunts the Effects of Cardiac Stress. Qin Pu,Arabacilar Pelin,Bernard Roberta E,Bao Weike,Olzinski Alan R,Guo Yuanjun,Lal Hind,Eisennagel Stephen H,Platchek Michael C,Xie Wensheng,Del Rosario Julius,Nayal Mohamad,Lu Quinn,Roethke Theresa,Schnackenberg Christine G,Wright Fe,Quaile Michael P,Halsey Wendy S,Hughes Ashley M,Sathe Ganesh M,Livi George P,Kirkpatrick Robert B,Qu Xiaoyan A,Rajpal Deepak K,Faelth Savitski Maria,Bantscheff Marcus,Joberty Gerard,Bergamini Giovanna,Force Thomas L,Gatto Gregory J,Hu Erding,Willette Robert N Journal of the American Heart Association BACKGROUND:The amino acid response (AAR) is an evolutionarily conserved protective mechanism activated by amino acid deficiency through a key kinase, general control nonderepressible 2. In addition to mobilizing amino acids, the AAR broadly affects gene and protein expression in a variety of pathways and elicits antifibrotic, autophagic, and anti-inflammatory activities. However, little is known regarding its role in cardiac stress. Our aim was to investigate the effects of halofuginone, a prolyl-tRNA synthetase inhibitor, on the AAR pathway in cardiac fibroblasts, cardiomyocytes, and in mouse models of cardiac stress and failure. METHODS AND RESULTS:Consistent with its ability to inhibit prolyl-tRNA synthetase, halofuginone elicited a general control nonderepressible 2-dependent activation of the AAR pathway in cardiac fibroblasts as evidenced by activation of known AAR target genes, broad regulation of the transcriptome and proteome, and reversal by l-proline supplementation. Halofuginone was examined in 3 mouse models of cardiac stress: angiotensin II/phenylephrine, transverse aortic constriction, and acute ischemia reperfusion injury. It activated the AAR pathway in the heart, improved survival, pulmonary congestion, left ventricle remodeling/fibrosis, and left ventricular function, and rescued ischemic myocardium. In human cardiac fibroblasts, halofuginone profoundly reduced collagen deposition in a general control nonderepressible 2-dependent manner and suppressed the extracellular matrix proteome. In human induced pluripotent stem cell-derived cardiomyocytes, halofuginone blocked gene expression associated with endothelin-1-mediated activation of pathologic hypertrophy and restored autophagy in a general control nonderepressible 2/eIF2α-dependent manner. CONCLUSIONS:Halofuginone activated the AAR pathway in the heart and attenuated the structural and functional effects of cardiac stress. 10.1161/JAHA.116.004453
    HLA-DRB1 Amino Acid Positions 11/13, 71, and 74 Are Associated With Inflammation Level, Disease Activity, and the Health Assessment Questionnaire Score in Patients With Inflammatory Polyarthritis. Ling Stephanie F,Viatte Sebastien,Lunt Mark,Van Sijl Alper M,Silva-Fernandez Lucia,Symmons Deborah P M,Young Adam,Macgregor Alexander J,Barton Anne Arthritis & rheumatology (Hoboken, N.J.) OBJECTIVE:Rheumatoid arthritis (RA) susceptibility HLA-DRB1 haplotypes based on amino acid positions 11/13, 71, and 74 predict radiographic damage. The mechanism of action is unknown, but it may be mediated by inflammation. We undertook this study to systematically investigate the effect of these amino acids on nonradiographic measures of disease activity/outcomes. METHODS:We tested the association of RA susceptibility HLA-DRB1 amino acids with the C-reactive protein (CRP) level, the tender joint count (TJC), the swollen joint count (SJC), the Disease Activity Score in 28 joints (DAS28), and the Health Assessment Questionnaire (HAQ) score in the Norfolk Arthritis Register (NOAR) and Early Rheumatoid Arthritis Study (ERAS) cohorts. Longitudinal modeling of disease activity/outcomes was performed using generalized linear latent and mixed models. Mediation analysis was performed using directed acyclic graphs to investigate the paths from genetic factors to outcome. RESULTS:A total of 2,158 patients were available for analysis in the NOAR cohort. Valine at position 11 showed the strongest association with the CRP level (P = 2.21 × 10 ), the SJC (P = 7.51 × 10 ), and the DAS28 (P = 0.002); it was marginally associated with the HAQ score (P = 0.044) but not with the TJC. The same amino acid and haplotype risk hierarchy observed for susceptibility and radiographic severity was observed for the CRP level and nonradiographic measures of disease activity/outcome, apart from the TJC. The results were replicated in the ERAS cohort. The effect of valine at position 11 on the SJC was mainly mediated by anti-citrullinated protein antibody status, the effect of which was mainly mediated by inflammation; however, the effect of valine at position 11 was also independent of the CRP level (P = 1.6 × 10 ). CONCLUSION:Genetic markers of RA susceptibility located within HLA-DRB1 determine the levels of clinical and systemic inflammation independently, and also determine all objective measures of disease activity and outcome. 10.1002/art.39780
    Differences in plasma amino acid levels in patients with and without bacterial infection during the early stage of acute exacerbation of COPD. Inoue Saki,Ikeda Hideki International journal of chronic obstructive pulmonary disease Purpose:No consensus has been reached regarding appropriate nutritional intervention and rehabilitation during early acute exacerbation of COPD (AECOPD). Given the individual differences in symptoms of AECOPD, patients should be classified by their pathology. For example, it is known that there are differences in the inflammatory response between AECOPD with and without bacterial infection. However, there have been few reports on AECOPD from a nutritional perspective. The aim of this study was to investigate amino acid levels in patients with AECOPD. Patients and methods:Blood was collected from patients who were hospitalized with AECOPD and from patients with COPD that was in a stable state. We divided the patients with AECOPD into those without bacterial infection (group A) and those with bacterial infection (group B). The patients with COPD that was stable served as controls (group C). The plasma levels of 9 essential amino acids, 13 nonessential amino acids, and total amino acids were compared between the three groups. Results:In the early stages of AECOPD, differences in plasma levels of only three amino acids (glycine, phenylalanine, and arginine) were observed between groups C and A. Differences in total amino acids and 13 amino acids were observed between groups C and B. Group B had lower levels of total amino acids and of seven amino acids (asparagine, citrulline, glutamine, histidine, methionine, serine, and threonine) compared with the other study groups. Conclusion:The findings of this study show that amino acid levels in plasma differ in patients with AECOPD depending on whether or not bacterial infection is present. Our results suggest that specific amino acids (ie, asparagine, citrulline, glutamine, histidine, serine, and threonine) have potential utility as diagnostic markers to distinguish between bacterial and nonbacterial AECOPD. 10.2147/COPD.S188422
    A review on fish immuno-nutritional response to indispensable amino acids in relation to TOR, NF-κB and Nrf2 signaling pathways: Trends and prospects. Habte-Tsion Habte-Michael Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology Indispensable amino acids (IAAs) are important regulators of key metabolic pathways associated with protein synthesis, tight junction proteins, inflammatory cytokines and immune-antioxidant related signaling molecules. However, the information pertaining to the immune functions of IAAs in relation to molecular approaches for commercially important fish species are scarce and discordant. This review summarizes the dietary requirements for IAAs necessary for improved growth and immune response in variety of fish species, using molecular approaches (nutrigenomics), particularly the interrelationships between IAAs and genes. Briefly, antioxidant status of fish as well as gene transcriptions regulating antioxidant enzymes are profoundly governed by the nutritional factors including a set of IAAs, and these genes expression are often regulated by the nuclear factor erythoid 2-related factor 2 signaling pathway (Nrf2). IAAs level could also attenuate the inflammatory response in fish partly by down-regulating the expression levels of pro-inflammatory cytokines and up-regulating the anti-inflammatory cytokines. The regulation of these cytokines by IAAs could be mediated by the signaling molecules nuclear transcription factor-κB (NF-κB) and target of rapamycin (TOR). Overall, this review provides clear and recent molecular mechanisms of fish immuno-nutritional interrelation and highlights regulatory pathways underlying dietary IAAs mediated enhancement in the antioxidant, anti-inflammatory, and immune defense capacities, presenting trends and future perspectives. 10.1016/j.cbpb.2019.110389
    Amino acid levels in nascent metabolic syndrome: A contributor to the pro-inflammatory burden. Reddy Priya,Leong Joseph,Jialal Ishwarlal Journal of diabetes and its complications AIMS:Metabolic Syndrome (MetS) is a cluster of cardio-metabolic risk factors characterized by low-grade inflammation which confers an increased risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Prior studies have linked elevated branched chain amino acids (BCAA) and aromatic amino acids (AAA) with T2DM and CVD. Due to the paucity of data in MetS, the aim of this study was to investigate the status of amino acids as early biomarkers of nascent MetS patients without T2DM and CVD or smoking. RESEARCH DESIGN AND METHODS:Healthy controls (n = 20) and MetS (n = 29) patients were recruited for the study. MetS was defined by criteria of National Cholesterol Education Program Adult Treatment Panel III of having at least 3 risk factors. Urinary amino acids were quantified by gas chromatography time-of-flight mass spectrometry at the Western NIH Metabolomics Center as expressed to urinary creatinine. RESULTS:Tyrosine and Isoleucine levels were significantly elevated in MetS patients. Isoleucine positively correlated with salient cardio-metabolic features and inflammatory biomarkers. Lysine and Methionine levels were decreased in MetS patients. Lysine correlated negatively with cardio-metabolic features and inflammatory bimarkers. Methionine also correlated negatively with blood pressure and certain inflammatory biomarkers. CONCLUSION:Our novel results suggest that with regards to the cardio-metabolic risk factors and pro-inflammatory features of MetS, isoleucine (BCAA) demonstrated a positive correlation while lysine demonstrated a negative correlation. Thus, increased levels of isoleucine and decreased levels of lysine could be potential early biomarkers of MetS. 10.1016/j.jdiacomp.2018.02.005
    Administration of branched-chain amino acids alters the balance between pro-inflammatory and anti-inflammatory cytokines. Rosa Luciana,Scaini Giselli,Furlanetto Camila B,Galant Leticia S,Vuolo Francieli,Dall'Igna Dhébora M,Schuck Patrícia F,Ferreira Gustavo C,Dal-Pizzol Felipe,Streck Emilio L International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience Acute leucine intoxication and neurologic deterioration can develop rapidly at any age as a result of net protein degradation precipitated by infection or psychological stress in patients with maple syrup urine disease (MSUD). Here, we investigated the effects of acute and chronic Hyper-BCAA (H-BCAA) administration on pro- and anti-inflammatory cytokines in the brains of rats. For acute administration, Wistar rats (10 and 30 days) received three injections of BCAA pool (15.8 μL/g at 1-h intervals) or saline, subcutaneously. For chronic administration, Wistar rats (7 days) received of BCAA pool or saline twice a day for 21 days, subcutaneously. Our results showed that acute administration of H-BCAA increased IL-1β (∼ 78%; p ≤ 0.009) and TNF-α (∼ 155%; p ≤ 0.026) levels in the cerebral cortex but not in the hippocampus of infant rats. Moreover, IL-6 levels were increased in the hippocampus (∼ 135%; p ≤ 0.009) and cerebral cortex (∼ 417%; p ≤ 0.008), whereas IL-10 levels were decreased only in the hippocampus (∼ 42%; p ≤ 0.009). However, repeated administration of H-BCAA decreased IL-1β (∼ 59%; p ≤ 0.047), IL-6 (∼ 70%; p ≤ 0.009) and IFN-γ (∼ 70%; p ≤ 0.008) levels in the cerebral cortex, whereas the IL-6 (∼ 67%; p ≤ 0.009), IL-10 (∼ 58%; p ≤ 0.01) and IFN-γ (∼ 67%; p ≤ 0.009) levels were decreased in the hippocampus. These findings suggest that a better understanding of the inflammatory response in MSUD patients may be useful to develop therapeutic strategies to modulate the hyperinflammatory/hypoinflammatory axis. 10.1016/j.ijdevneu.2015.11.002
    Tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase 1 make separate, tissue-specific contributions to basal and inflammation-induced kynurenine pathway metabolism in mice. Larkin Paul B,Sathyasaikumar Korrapati V,Notarangelo Francesca M,Funakoshi Hiroshi,Nakamura Toshikazu,Schwarcz Robert,Muchowski Paul J Biochimica et biophysica acta BACKGROUND:In mammals, the majority of the essential amino acid tryptophan is degraded via the kynurenine pathway (KP). Several KP metabolites play distinct physiological roles, often linked to immune system functions, and may also be causally involved in human diseases including neurodegenerative disorders, schizophrenia and cancer. Pharmacological manipulation of the KP has therefore become an active area of drug development. To target the pathway effectively, it is important to understand how specific KP enzymes control levels of the bioactive metabolites in vivo. METHODS:Here, we conducted a comprehensive biochemical characterization of mice with a targeted deletion of either tryptophan 2,3-dioxygenase (TDO) or indoleamine 2,3-dioxygenase (IDO), the two initial rate-limiting enzymes of the KP. These enzymes catalyze the same reaction, but differ in biochemical characteristics and expression patterns. We measured KP metabolite levels and enzyme activities and expression in several tissues in basal and immune-stimulated conditions. RESULTS AND CONCLUSIONS:Although our study revealed several unexpected downstream effects on KP metabolism in both knockout mice, the results were essentially consistent with TDO-mediated control of basal KP metabolism and a role of IDO in phenomena involving stimulation of the immune system. 10.1016/j.bbagen.2016.07.002
    Metabolic pathways of lung inflammation revealed by high-resolution metabolomics (HRM) of H1N1 influenza virus infection in mice. Chandler Joshua D,Hu Xin,Ko Eun-Ju,Park Soojin,Lee Young-Tae,Orr Michael,Fernandes Jolyn,Uppal Karan,Kang Sang-Moo,Jones Dean P,Go Young-Mi American journal of physiology. Regulatory, integrative and comparative physiology Influenza is a significant health concern worldwide. Viral infection induces local and systemic activation of the immune system causing attendant changes in metabolism. High-resolution metabolomics (HRM) uses advanced mass spectrometry and computational methods to measure thousands of metabolites inclusive of most metabolic pathways. We used HRM to identify metabolic pathways and clusters of association related to inflammatory cytokines in lungs of mice with H1N1 influenza virus infection. Infected mice showed progressive weight loss, decreased lung function, and severe lung inflammation with elevated cytokines [interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ] and increased oxidative stress via cysteine oxidation. HRM showed prominent effects of influenza virus infection on tryptophan and other amino acids, and widespread effects on pathways including purines, pyrimidines, fatty acids, and glycerophospholipids. A metabolome-wide association study (MWAS) of the aforementioned inflammatory cytokines was used to determine the relationship of metabolic responses to inflammation during infection. This cytokine-MWAS (cMWAS) showed that metabolic associations consisted of distinct and shared clusters of 396 metabolites highly correlated with inflammatory cytokines. Strong negative associations of selected glycosphingolipid, linoleate, and tryptophan metabolites with IFN-γ contrasted strong positive associations of glycosphingolipid and bile acid metabolites with IL-1β, TNF-α, and IL-10. Anti-inflammatory cytokine IL-10 had strong positive associations with vitamin D, purine, and vitamin E metabolism. The detailed metabolic interactions with cytokines indicate that targeted metabolic interventions may be useful during life-threatening crises related to severe acute infection and inflammation. 10.1152/ajpregu.00298.2016
    Different tissue phagocytes sample apoptotic cells to direct distinct homeostasis programs. Cummings Ryan J,Barbet Gaetan,Bongers Gerold,Hartmann Boris M,Gettler Kyle,Muniz Luciana,Furtado Glaucia C,Cho Judy,Lira Sergio A,Blander J Magarian Nature Recognition and removal of apoptotic cells by professional phagocytes, including dendritic cells and macrophages, preserves immune self-tolerance and prevents chronic inflammation and autoimmune pathologies. The diverse array of phagocytes that reside within different tissues, combined with the necessarily prompt nature of apoptotic cell clearance, makes it difficult to study this process in situ. The full spectrum of functions executed by tissue-resident phagocytes in response to homeostatic apoptosis, therefore, remains unclear. Here we show that mouse apoptotic intestinal epithelial cells (IECs), which undergo continuous renewal to maintain optimal barrier and absorptive functions, are not merely extruded to maintain homeostatic cell numbers, but are also sampled by a single subset of dendritic cells and two macrophage subsets within a well-characterized network of phagocytes in the small intestinal lamina propria. Characterization of the transcriptome within each subset before and after in situ sampling of apoptotic IECs revealed gene expression signatures unique to each phagocyte, including macrophage-specific lipid metabolism and amino acid catabolism, and a dendritic-cell-specific program of regulatory CD4 T-cell activation. A common 'suppression of inflammation' signature was noted, although the specific genes and pathways involved varied amongst dendritic cells and macrophages, reflecting specialized functions. Apoptotic IECs were trafficked to mesenteric lymph nodes exclusively by the dendritic cell subset and served as critical determinants for the induction of tolerogenic regulatory CD4 T-cell differentiation. Several of the genes that were differentially expressed by phagocytes bearing apoptotic IECs overlapped with susceptibility genes for inflammatory bowel disease. Collectively, these findings provide new insights into the consequences of apoptotic cell sampling, advance our understanding of how homeostasis is maintained within the mucosa and set the stage for development of novel therapeutics to alleviate chronic inflammatory diseases such as inflammatory bowel disease. 10.1038/nature20138
    Homocysteine and hydrogen sulfide in epigenetic, metabolic and microbiota related renovascular hypertension. Weber Gregory J,Pushpakumar Sathnur,Tyagi Suresh C,Sen Utpal Pharmacological research Over the past several years, hydrogen sulfide (HS) has been shown to be an important player in a variety of physiological functions, including neuromodulation, vasodilation, oxidant regulation, inflammation, and angiogenesis. HS is synthesized primarily through metabolic processes from the amino acid cysteine and homocysteine in various organ systems including neuronal, cardiovascular, gastrointestinal, and kidney. Derangement of cysteine and homocysteine metabolism and clearance, particularly in the renal vasculature, leads to HS biosynthesis deregulation causing or contributing to existing high blood pressure. While a variety of environmental influences, such as diet can have an effect on HS regulation and function, genetic factors, and more recently epigenetics, also have a vital role in HS regulation and function, and therefore disease initiation and progression. In addition, new research into the role of gut microbiota in the development of hypertension has highlighted the need to further explore these microorganisms and how they influence the levels of HS throughout the body and possibly exploiting microbiota for use of hypertension treatment. In this review, we summarize recent advances in the field of hypertension research emphasizing renal contribution and how HS physiology can be exploited as a possible therapeutic strategy to ameliorate kidney dysfunction as well as to control blood pressure. 10.1016/j.phrs.2016.09.002
    Mechanisms of Inflammation-Associated Depression: Immune Influences on Tryptophan and Phenylalanine Metabolisms. Strasser Barbara,Sperner-Unterweger Barbara,Fuchs Dietmar,Gostner Johanna M Current topics in behavioral neurosciences Metabolic parameters have a direct role in the regulation of immune cell function. Thereby the inflammation-induced metabolism of aromatic amino acids, most importantly of tryptophan and phenylalanine, plays a central role. In addition, neuropsychiatric conditions that go along with disorders that are characterized by acute or chronic inflammation, such as the development of depression, decreased quality of life or cognitive impairments, are connected to disturbed amino acid and subsequent neurotransmitter metabolism.The bioanalytical procedures for the determination of concentrations of tryptophan and phenylalanine and their respective first stable intermediates kynurenine and tyrosine as well as some analytical finesses and potential sources of errors are discussed in this chapter. Monitoring of these immunometabolic parameters throughout therapies in addition to biomarkers of immune response and inflammation such as neopterin can be useful to determine disease progression but also to plan psychiatric interventions timely, thus to establish personalized treatments. 10.1007/7854_2016_23
    Interleukin 37 reverses the metabolic cost of inflammation, increases oxidative respiration, and improves exercise tolerance. Cavalli Giulio,Justice Jamie N,Boyle Kristen E,D'Alessandro Angelo,Eisenmesser Elan Z,Herrera Jonathan J,Hansen Kirk C,Nemkov Travis,Stienstra Rinke,Garlanda Cecilia,Mantovani Alberto,Seals Douglas R,Dagna Lorenzo,Joosten Leo A B,Ballak Dov B,Dinarello Charles A Proceedings of the National Academy of Sciences of the United States of America IL-1 family member interleukin 37 (IL-37) has broad antiinflammatory properties and functions as a natural suppressor of innate inflammation. In this study, we demonstrate that treatment with recombinant human IL-37 reverses the decrease in exercise performance observed during systemic inflammation. This effect was associated with a decrease in the levels of plasma and muscle cytokines, comparable in extent to that obtained upon IL-1 receptor blockade. Exogenous administration of IL-37 to healthy mice, not subjected to an inflammatory challenge, also improved exercise performance by 82% compared with vehicle-treated mice ( = 0.01). Treatment with eight daily doses of IL-37 resulted in a further 326% increase in endurance running time compared with the performance level of mice receiving vehicle ( 0.001). These properties required the engagement of the IL-1 decoy receptor 8 (IL-1R8) and the activation of AMP-activated protein kinase (AMPK), because both inhibition of AMPK and IL-1R8 deficiency abrogated the positive effects of IL-37 on exercise performance. Mechanistically, treatment with IL-37 induced marked metabolic changes with higher levels of muscle AMPK, greater rates of oxygen consumption, and increased oxidative phosphorylation. Metabolomic analyses of plasma and muscles of mice treated with IL-37 revealed an increase in AMP/ATP ratio, reduced levels of proinflammatory mediator succinate and oxidative stress-related metabolites, as well as changes in amino acid and purine metabolism. These effects of IL-37 to limit the metabolic costs of chronic inflammation and to foster exercise tolerance provide a rationale for therapeutic use of IL-37 in the treatment of inflammation-mediated fatigue. 10.1073/pnas.1619011114
    L-arginine attenuates Interleukin-1β (IL-1β) induced Nuclear Factor Kappa-Beta (NF-κB) activation in Caco-2 cells. Meng Qinghe,Cooney Mitchell,Yepuri Natesh,Cooney Robert N PloS one BACKGROUND:Specific nutrients like L-arginine (L-Arg) ameliorate intestinal inflammation, however the exact mechanisms of this effect are unclear. We hypothesized the anti-inflammatory effects of L-Arg require active transport and metabolism by inducible nitric oxide synthase (iNOS) to generate nitric oxide (NO). To test this hypothesis we examined the effects of L-Arg, L-Arg transport activity, NO production and iNOS inhibitor on IL-1β-mediated NF-κB-activation in Caco-2 cells. METHODS:Caco-2 cells were cultured, transfected with a NF-κB promoter luciferase vector, incubated ± L-Arg, ± IL-1β and luciferase activity was measured. Using siRNA we inhibited the L-Arg cationic amino acid transporter system y+ (CAT1) expression and examined its effects on L-Arg transport activity and IL-1β-mediated NF-κB-activation. Finally, the effects of sodium nitroprusside (SNP, a NO donor) and Nω-nitro-L-arginine (NNA, an iNOS inhibitor) on IL-1β-mediated NF-κB-activation were examined. RESULTS:IL-1β increased NF-κB luciferase activity (8-fold) and NF-κB expression (mRNA and protein), both of these were significantly decreased by L-Arg. System y+ CAT1 siRNA decreased CAT1 expression, L-Arg transport activity and attenuated the inhibitory effects of L-Arg on NF- κB activity. SNP attenuated the IL-1β-induced increase in NF-κB luciferase activity and expression, whereas NNA diminished the inhibitory effects of L-Arg on IL-1β-inducible NF- κB luciferase activity. CONCLUSION:The inhibitory effects of L-Arg on IL-1β-mediated NF-κB-activation in Caco-2 cells involve L-Arg transport activity by CAT1, regulation of IL-1β-mediated increases in NF-κB expression, changes in iNOS expression and NO production. Our data suggest the inhibitory effects of L-Arg on NF-κB activation are mediated in part by iNOS since SNP preserves and NNA attenuates the effects of L-Arg on IL-1β-mediated NF-κB-activation and expression. 10.1371/journal.pone.0174441
    Role of activating transcription factor 4 in the hepatic response to amino acid depletion by asparaginase. Al-Baghdadi Rana J T,Nikonorova Inna A,Mirek Emily T,Wang Yongping,Park Jinhee,Belden William J,Wek Ronald C,Anthony Tracy G Scientific reports The anti-leukemic agent asparaginase activates the integrated stress response (ISR) kinase GCN2 and inhibits signaling via mechanistic target of rapamycin complex 1 (mTORC1). The study objective was to investigate the protective role of activating transcription factor 4 (ATF4) in controlling the hepatic transcriptome and mediating GCN2-mTORC1 signaling during asparaginase. We compared global gene expression patterns in livers from wildtype, Gcn2 , and Atf4 mice treated with asparaginase or excipient and further explored selected responses in livers from Atf4 mice. Here, we show that ATF4 controls a hepatic gene expression profile that overlaps with GCN2 but is not required for downregulation of mTORC1 during asparaginase. Ingenuity pathway analysis indicates GCN2 independently influences inflammation-mediated hepatic processes whereas ATF4 uniquely associates with cholesterol metabolism and endoplasmic reticulum (ER) stress. Livers from Atf4 or Atf4 mice displayed an amplification of the amino acid response and ER stress response transcriptional signatures. In contrast, reduction in hepatic mTORC1 signaling was retained in Atf4 mice treated with asparaginase. CONCLUSIONS:GCN2 and ATF4 serve complementary roles in the hepatic response to asparaginase. GCN2 functions to limit inflammation and mTORC1 signaling whereas ATF4 serves to limit the amino acid response and prevent ER stress during amino acid depletion by asparaginase. 10.1038/s41598-017-01041-7
    Targeting Inflammation and Downstream Protein Metabolism in Sarcopenia: A Brief Up-Dated Description of Concurrent Exercise and Leucine-Based Multimodal Intervention. Xia Zhi,Cholewa Jason,Zhao Yan,Shang Hua-Yu,Yang Yue-Qin,Araújo Pessôa Kassiana,Su Quan-Sheng,Lima-Soares Fernanda,Zanchi Nelo Eidy Frontiers in physiology Sarcopenia is defined as the progressive loss of muscle mass with age, and poses a serious threat to the physiological and psychological health of the elderly population with consequential economic and social burdens. Chronic low-grade inflammation plays a central role in the development of sarcopenia such that it alters cellular protein metabolism to favor proteolysis over synthesis, and thereby accelerates muscular atrophy. The purpose of this review is to highlight how exercise and nutrition intervention strategies can attenuate or treat sarcopenia. Resistance exercise increases not only muscle mass but also muscle strength, while aerobic exercise is able to ameliorate the age-related metabolic disorders. Concurrent exercise training integrates the advantages of both aerobic and resistance exercise, and may exert a significant synergistic effect in the aging organism. Higher protein intakes rich in the amino acid leucine appear to restore skeletal muscle protein metabolism balance by rescuing protein synthesis in older adults. There is good reason to believe that a multimodal treatment, a combination of exercise and increased leucine consumption in the diet, can combat some of the muscle loss associated with aging. Future research is needed to consolidate these findings to humans, and to further clarify to what extent and by which mechanisms protein metabolism might be directly involved in sarcopenia pathogenesis and the multimodal treatment responses. 10.3389/fphys.2017.00434
    Insight on the impacts of free amino acids and their metabolites on the immune system from a perspective of inborn errors of amino acid metabolism. Pakula Malgorzata M,Maier Thorsten J,Vorup-Jensen Thomas Expert opinion on therapeutic targets INTRODUCTION:Amino acids (AAs) support a broad range of functions in living organisms, including several that affect the immune system. The functions of the immune system are affected when free AAs are depleted or in excess because of external factors, such as starvation, or because of genetic factors, such as inborn errors of metabolism. Areas covered: In this review, we discuss the current insights into how free AAs affect immune responses. When possible, we make comparisons to known disease states resulting from inborn errors of metabolism, in which changed levels of AAs or AA metabolites provide insight into the impact of AAs on the human immune system in vivo. We also explore the literature describing how changes in AA levels might provide pharmaceutical targets for safe immunomodulatory treatment. Expert opinion: The impact of free AAs on the immune system is a neglected topic in most immunology textbooks. That neglect is undeserved, because free AAs have both direct and indirect effects on the immune system. Consistent choices of pre-clinical models and better strategies for creating formulations are required to gain clinical impact. 10.1080/14728222.2017.1323879
    Citrulline decreases hepatic endotoxin-induced injury in fructose-induced non-alcoholic liver disease: an ex vivo study in the isolated perfused rat liver. Ouelaa Wassila,Jegatheesan Prasanthi,M'bouyou-Boungou Japhète,Vicente Christelle,Nakib Samir,Nubret Esther,De Bandt Jean-Pascal The British journal of nutrition Steatosis can sensitise the liver to various challenges and favour the development of non-alcoholic fatty liver disease (NAFLD). In this context, fructose feeding promotes endotoxin translocation from the gut, contributing to disease progression via an inflammatory process. Citrulline is protective against fructose-induced NAFLD; we hypothesised that this property might be related to its anti-inflammatory and antioxidative action against endotoxin-induced hepatic injuries. This hypothesis was evaluated in a model of perfused liver isolated from NAFLD rats. Male Sprague-Dawley rats (n 30) were fed either a standard rodent chow or a 60 % fructose diet alone, or supplemented with citrulline (1 g/kg per d) for 4 weeks. After an evaluation of their metabolic status, fasted rats received an intraperitoneal injection of lipopolysaccharide (LPS) (2·5 mg/kg). After 1 h, the livers were isolated and perfused for 1 h to study liver function and metabolism, inflammation and oxidative status. In vivo, citrulline significantly decreased dyslipidaemia induced by a high-fructose diet and insulin resistance. In the isolated perfused rat livers, endotoxaemia resulted in higher cytolysis (alanine aminotransferase release) and higher inflammation (Toll-like receptor 4) in livers of fructose-fed rats, and it was prevented by citrulline supplementation. Oxidative stress and antioxidative defences were similar in all three groups. Amino acid exchanges and metabolism (ammonia and urea release) were only slightly different between the three groups. In this context of mild steatosis, our results suggest that fructose-induced NAFLD leads to an increased hepatic sensitivity to LPS-induced inflammation. Citrulline-induced restriction of the inflammatory process may thus contribute to the prevention of NAFLD. 10.1017/S0007114517001453
    Amino Acid Concentrations in HIV-Infected Youth Compared to Healthy Controls and Associations with CD4 Counts and Inflammation. Ziegler Thomas R,Judd Suzanne E,Ruff Joshua H,McComsey Grace A,Eckard Allison Ross AIDS research and human retroviruses Amino acids play critical roles in metabolism, cell function, body composition and immunity, but little data on plasma amino acid concentrations in HIV are available. We evaluated plasma amino acid concentrations and associations with CD4 counts and inflammatory biomarkers in HIV-infected youth. HIV-infected subjects with a high (≥500 cells/mm) and low (<500 cells/mm) current CD4 T cell counts were compared to one another and to a matched healthy control group. Plasma concentrations of 19 amino acids were determined with an amino acid analyzer. Plasma levels of interleukin-6, tumor necrosis factor receptor-I, and soluble vascular cellular adhesion molecule-I were also measured. Seventy-nine HIV-infected subjects (40 and 39 with high and low CD4 T cell counts, respectively) and 40 controls were included. There were no differences in amino acid concentrations between HIV-infected subjects with high or low CD4 T cell counts. When combined, the HIV-infected group exhibited significantly lower median plasma concentrations compared to controls for total, essential, branched-chain and sulfur amino acids, as well as for 12 individual amino acids. Glutamate was the only amino acid that was higher in the HIV-infected group. There were no significant correlations between amino acid endpoints and inflammatory biomarkers for either HIV-infected group or controls. Plasma amino acid concentrations were lower in HIV-infected youth compared to healthy controls, regardless of immune status, while glutamate concentrations were elevated. These findings can inform future interventional studies designed to improve metabolic and clinical parameters influenced by amino acid nutriture. 10.1089/AID.2015.0369
    PPARδ promotes tumor progression via activation of Glut1 and SLC1-A5 transcription. Zhang Wenbo,Xu Ying,Xu Qinggang,Shi Haifeng,Shi Juanjuan,Hou Yongzhong Carcinogenesis Malignant cancer cell uncontrolled growth depends on the persistent nutrient availability such as glucose and amino acids, which is required for cancer cell energetic and biosynthetic pathways. As a nuclear hormone receptor, peroxisome-proliferator-activated receptor δ (PPARδ) plays a critical role in inflammation and cancer, however, it is still unclear the regulatory mechanism of PPARδ on cancer cell metabolism. Here, we found that PPARδ directly regulated neutral amino acid transporter SLC1-A5 (solute carrier family 1 member 5) and glucose transporter-1 (Glut1) gene transcription, leading to uptake of glucose and amino acid, activation of mTOR signaling, and tumor progression. In contrast, silence of PPARδ or its antagonist inhibited this event. More importantly, PPARδ promoted cancer cell metabolic reprogramming resulting in chemoresistance, which was alleviated by PPARδ antagonist. These findings revealed a novel mechanism of PPARδ-mediated tumor progression, which provided a potential strategy for cancer treatment. 10.1093/carcin/bgx035
    Metabolomics Analysis To Evaluate the Anti-Inflammatory Effects of Polyphenols: Glabridin Reversed Metabolism Change Caused by LPS in RAW 264.7 Cells. Liu Kaiqin,Pi Fuwei,Zhang Hongxia,Ji Jian,Xia Shuang,Cui Fangchao,Sun Jiadi,Sun Xiulan Journal of agricultural and food chemistry Inflammation has been shown to play a critical role in the development of many diseases. In this study, we used metabolomics to evaluate the inflammatory effect of lipopolysaccharide (LPS) and the anti-inflammatory effect of glabridin (GB, a polyphenol from Glycurrhiza glabra L. roots) in RAW 264.7 cells. Multivariate statistical analysis showed that in comparison with the LPS group, the metabolic profile of the GB group was more similar to that of the control group. LPS impacted the amino acid, energy, and lipid metabolisms in RAW 264.7 cells, and metabolic pathway analysis showed that GB reversed some of those LPS impacts. Metabolomics analysis provided us with a new perspective to better understand the inflammatory response and the anti-inflammatory effects of GB. Metabolic pathway analysis can be an effective tool to elucidate the mechanism of inflammation and to potentially find new anti-inflammatory agents. 10.1021/acs.jafc.7b01692
    Endogenous glutamine decrease is associated with pancreatic cancer progression. Roux Cecilia,Riganti Chiara,Borgogno Sammy Ferri,Curto Roberta,Curcio Claudia,Catanzaro Valeria,Digilio Giuseppe,Padovan Sergio,Puccinelli Maria Paola,Isabello Monica,Aime Silvio,Cappello Paola,Novelli Francesco Oncotarget Pancreatic ductal adenocarcinoma (PDAC) is becoming the second leading cause of cancer-related death in the Western world. The mortality is very high, which emphasizes the need to identify biomarkers for early detection. As glutamine metabolism alteration is a feature of PDAC, its evaluation may provide a useful tool for biomarker identification. Our aim was to identify a handy method to evaluate blood glutamine consumption in mouse models of PDAC. We quantified the glutamine uptake by Mass Spectrometry (MS) in tumor cell supernatants and showed that it was higher in PDAC compared to non-PDAC tumor and pancreatic control human cells. The increased glutamine uptake was paralleled by higher activity of most glutamine pathway-related enzymes supporting nucleotide and ATP production. Free glutamine blood levels were evaluated in orthotopic and spontaneous mouse models of PDAC and other pancreatic-related disorders by High-Performance Liquid Chromatography (HPLC) and/or MS. Notably we observed a reduction of blood glutamine as much as the tumor progressed from pancreatic intraepithelial lesions to invasive PDAC, but was not related to chronic pancreatitis-associated inflammation or diabetes. In parallel the increased levels of branched-chain amino acids (BCAA) were observed. By contrast blood glutamine levels were stable in non-tumor bearing mice. These findings demonstrated that glutamine uptake is measurable both and . The higher avidity of PDAC cells corresponded to a lower blood glutamine level as soon as the tumor mass grew. The reduction in circulating glutamine represents a novel tool exploitable to implement other diagnostic or prognostic PDAC biomarkers. 10.18632/oncotarget.20545
    Cell Origin Dictates Programming of Resident versus Recruited Macrophages during Acute Lung Injury. Mould Kara J,Barthel Lea,Mohning Michael P,Thomas Stacey M,McCubbrey Alexandra L,Danhorn Thomas,Leach Sonia M,Fingerlin Tasha E,O'Connor Brian P,Reisz Julie A,D'Alessandro Angelo,Bratton Donna L,Jakubzick Claudia V,Janssen William J American journal of respiratory cell and molecular biology Two populations of alveolar macrophages (AMs) coexist in the inflamed lung: resident AMs that arise during embryogenesis, and recruited AMs that originate postnatally from circulating monocytes. The objective of this study was to determine whether origin or environment dictates the transcriptional, metabolic, and functional programming of these two ontologically distinct populations over the time course of acute inflammation. RNA sequencing demonstrated marked transcriptional differences between resident and recruited AMs affecting three main areas: proliferation, inflammatory signaling, and metabolism. Functional assays and metabolomic studies confirmed these differences and demonstrated that resident AMs proliferate locally and are governed by increased tricarboxylic acid cycle and amino acid metabolism. Conversely, recruited AMs produce inflammatory cytokines in association with increased glycolytic and arginine metabolism. Collectively, the data show that even though they coexist in the same environment, inflammatory macrophage subsets have distinct immunometabolic programs and perform specialized functions during inflammation that are associated with their cellular origin. 10.1165/rcmb.2017-0061OC
    Perspective on the dynamics of cancer. Derbal Youcef Theoretical biology & medical modelling BACKGROUND:The genetic diversity of cancer and the dynamic interactions between heterogeneous tumor cells, the stroma and immune cells present daunting challenges to the development of effective cancer therapies. Although cancer biology is more understood than ever, this has not translated into therapies that overcome drug resistance, cancer recurrence and metastasis. The future development of effective therapies will require more understanding of the dynamics of homeostatic dysregulation that drives cancer growth and progression. RESULTS:Cancer dynamics are explored using a model involving genes mediating the regulatory interactions between the signaling and metabolic pathways. The exploration is informed by a proposed genetic dysregulation measure of cellular processes. The analysis of the interaction dynamics between cancer cells, cancer associated fibroblasts, and tumor associate macrophages suggests that the mutual dependence of these cells promotes cancer growth and proliferation. In particular, MTOR and AMPK are hypothesized to be concurrently activated in cancer cells by amino acids recycled from the stroma. This leads to a proliferative growth supported by an upregulated glycolysis and a tricarboxylic acid cycle driven by glutamine sourced from the stroma. In other words, while genetic aberrations ignite carcinogenesis and lead to the dysregulation of key cellular processes, it is postulated that the dysregulation of metabolism locks cancer cells in a state of mutual dependence with the tumor microenvironment and deepens the tumor's inflammation and immunosuppressive state which perpetuates as a result the growth and proliferation dynamics of cancer. CONCLUSIONS:Cancer therapies should aim for a progressive disruption of the dynamics of interactions between cancer cells and the tumor microenvironment by targeting metabolic dysregulation and inflammation to partially restore tissue homeostasis and turn on the immune cancer kill switch. One potentially effective cancer therapeutic strategy is to induce the reduction of lactate and steer the tumor microenvironment to a state of reduced inflammation so as to enable an effective intervention of the immune system. The translation of this therapeutic approach into treatment regimens would however require more understanding of the adaptive complexity of cancer resulting from the interactions of cancer cells with the tumor microenvironment and the immune system. 10.1186/s12976-017-0066-5
    Effect of Arginase-1 Inhibition on the Incidence of Autoimmune Diabetes in NOD Mice. Hernandez Luis F,Buchwald Peter,Abdulreda Midhat H Current research in diabetes & obesity journal Metabolism of the amino acid L-arginine is implicated in many physiological and pathophysiological processes including autoimmune conditions such as type 1 diabetes (T1D). Alternate arginine metabolism through the citrulline-nitric oxide (NO) or the ornithine pathways can lead to proinflammatory or immune regulatory effects, respectively. In this report, we blocked the arginine-ornithine metabolic pathway by inhibiting the enzyme arginase-1 with Nω-hydroxy-nor-arginine (nor-NOHA) to make arginine more available to the alternate citrulline pathway for augmented NO production and increased incidence of autoimmune T1D in female non-obese diabetic (NOD) mice. Unexpectedly, mice receiving nor-NOHA did not develop diabetes although increased NO production is proinflammatory and expected to increase diabetes incidence. These results warrant further studies of the mechanism of action of nor-NOHA, and highlight its potential as a therapeutic agent for the treatment or prevention of T1D.
    Metabolic Imbalance of Homocysteine and Hydrogen Sulfide in Kidney Disease. Karmin O,Siow Yaw L Current medicinal chemistry Homocysteine (Hcy) and hydrogen sulfide (H2S) are important molecules produced during the metabolism of sulfur-containing amino acids. Hcy metabolism is central to the supply of methyl groups that are essential for biological function. Hcy can be either regenerated to methionine or metabolized to cysteine, a precursor for glutathione synthesis. Cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) play a crucial role in metabolizing Hcy to cysteine through the transsulfuration pathway. These two enzymes are also responsible for H2S generation through desulfuration reactions. H2S, at physiological levels serves as a gaseous mediator and has multifaceted effects. Metabolic imbalance of Hcy and H2S has been implicated in pathological conditions including oxidative stress, inflammation, cardiovascular and cerebral dysfunction, fatty liver disease and ischemiareperfusion injury. Organs such as liver, kidney, gut and pancreas contain all the enzymes that are required for Hcy metabolism. The kidney plays an important role in removing Hcy from the circulation. Hyperhomocysteinemia, a condition of elevated blood Hcy level, is a common clinical finding in patients with chronic kidney disease (CKD) or acute kidney injury (AKI), the latter is often caused by ischemia-reperfusion. This paper reviews exiting literatures regarding (1) the role of kidney in regulating Hcy and H2S metabolism; (2) disruption of sulfur-containing amino acid metabolism during ischemiareperfusion; (3) impact of metabolic imbalance of Hcy and H2S on kidney function. Better understanding of molecular mechanisms that regulate Hcy and H2S metabolism under physiological and pathophysiological conditions will help improve therapeutic strategies for patients with kidney disease or other organ injuries. 10.2174/0929867324666170509145240
    Coronary Microvascular and Cardiac Dysfunction Due to Homocysteine Pathometabolism; A Complex Therapeutic Design. Koller Akos,Szenasi Annamaria,Dornyei Gabriella,Kovacs Nora,Lelbach Adam,Kovacs Imre Current pharmaceutical design In various metabolic diseases, both the coronary circulation and cardiac metabolism are altered. Here we summarize the effects of a condition called hyperhomocysteinemia (HHcy) - which can develop due to genetic and/or environmental causes - on the function of coronary microvessels and heart. This metabolic disease is underappreciated, yet even mild or moderate elevation of plasma concentrations of homocystein (Hcy, plasma Hcy >16 µM), a sulfur-containing amino acid produced via methionine metabolism) leads to coronary and peripheral artery and even venous vessel diseases, eliciting vasomotor dysfunction and increased thrombosis, consequently increased morbidity and mortality. Yet the underlying mechanisms have not yet been revealed. Recent studies indicated that there are common pathomechanisms, which may affect several cellular functions. With methionin diet-induced HHcy two main pathomechanisms were revealed: the dysfunction of nitric oxide (NO) pathway resulting in reduced dilator responses of arteries and arterioles, and the simultaneously increased thromboxane A2 (TXA2) activity both in vessels and platelets. These changes are likely due to an increased production of reactive oxidative species (oxidative stress) due to increased NADPH oxidase assembly, which eventually lead to inflammatory processes (indicated by increases in TNFα, NFκbeta, p22phox, p67phox, and rac-1, levels) and changes in various gene expressions and morphological remodeling of vessels. Increased superoxide production and reduced availability of NO alter the regulation of mitochondrial function in the myocardium. The interactions of these pathomechanisms may explain why HHcy increases the uptake of glucose and lactate and decreases the uptake of free fatty acid by the heart. The pathological consequences of HHcy could be worsening by the simultaneous presence of other risk factors, such as hyperlipidemia, diabetes mellitus and metabolic syndrome. All in all, HHcy and associated pathometabolism lead to severe changes and dysfunctions of coronary arterial vessels and cardiac function, which may not always be apparent in clinical settings but most likely contribute to the increased prevalence of cardiovascular diseases and mortality, which however can be reduced by appropriate prevention and treatments. We believe that HHcy is an underestimated - likely due to inappropriate clinical trials - but serious disease condition because it promotes the development of atherosclerosis in large arterial vessels, vasomotor dysfunction in microvessels, hypertension and thrombosis. In this review, we will summarize previous functional findings focusing on coronary vessels and cardiac function and the underlying cellular and molecular mechanisms enabling the development of novel treatments. 10.2174/1381612824666180625125450
    Role of cellular metabolism in regulating type I interferon responses: Implications for tumour immunology and treatment. Ahmed Duale,Cassol Edana Cancer letters Type I interferons (IFN) are increasingly recognized for their role in regulating anti-tumour immune responses. However, chronic activation of these pathways can result in immunosuppression and has been linked to poor responses to genotoxic and radiotoxic therapies. Emerging evidence suggests energy, lipid and amino acid metabolism play an important role in regulating and fine tuning type I IFN responses. Further, dysregulation of these processes has been implicated in the pathogenesis of chronic viral infections and autoimmune disorders. Systematic evaluation of these interrelationships in cancer models and patients may have important implications for the development of targeted IFN based anti-cancer therapeutics with minimal toxicity and limited off target effects. 10.1016/j.canlet.2017.08.037
    Antioxidant effects of selenocysteine on replicative senescence in human adipose-derived mesenchymal stem cells. Suh Nayoung,Lee Eun-Bi BMB reports In most clinical applications, human mesenchymal stem cells (hMSCs) are expanded in large scale before their administration. Prolonged culture in vitro results in cellular senescenceassociated phenotypes, including accumulation of reactive oxygen species (ROS) and decreased cell viabilities. Profiling of stem cell-related genes during in vitro expansion revealed that numerous canonical pathways were significantly changed. To determine the effect of selenocysteine (Sec), a rare amino acid found in several antioxidant enzymes, on the replicative senescence in hMSCs, we treated senescent hMSCs with Sec. Supplementation of Sec in the culture medium in late-passage hMSCs reduced ROS levels and improved the survival of hMSCs. In addition, a subset of key antioxidant genes and Sec-containing selenoproteins showed increased mRNA levels after Sec treatment. Furthermore, ROS metabolism and inflammation pathways were predicted to be downregulated. Taken together, our results suggest that Sec has antioxidant effects on the replicative senescence of hMSCs. [BMB Reports 2017; 50(11): 572-577]. 10.5483/bmbrep.2017.50.11.174
    Beneficial effects of high dose taurine treatment in juvenile dystrophic mdx mice are offset by growth restriction. Terrill Jessica R,Pinniger Gavin J,Nair Keshav V,Grounds Miranda D,Arthur Peter G PloS one Duchenne Muscular Dystrophy (DMD) is a fatal muscle wasting disease manifested in young boys, for which there is no current cure. We have shown that the amino acid taurine is safe and effective at preventing dystropathology in the mdx mouse model for DMD. This study aimed to establish if treating growing mdx mice with a higher dose of taurine was more effective at improving strength and reducing inflammation and oxidative stress. Mice were treated with a dose of taurine estimated to be 16 g/kg/day, in drinking water from 1-6 weeks of age, after which in vivo and ex vivo muscle strength was assessed, as were measures of inflammation, oxidative stress and taurine metabolism. While the dose did decrease inflammation and protein oxidation in dystrophic muscles, there was no improvement in muscle strength (in contrast with benefits observed with the lower dose) and growth of the young mice was significantly restricted. We present novel data that a high taurine dose increases the cysteine content of both mdx liver and plasma, a possible result of down regulation of the taurine synthesis pathway in the liver (which functions to dispose of excess cysteine, which is toxic). These data caution that a high dose of taurine can have adverse effects and may be less efficacious than lower taurine doses. Therefore, monitoring of taurine dosage needs to be considered in future pre-clinical trials, in anticipation of using taurine as a clinical therapy for growing DMD boys (and other conditions). 10.1371/journal.pone.0187317
    Structural basis for amino acid transport by the CAT family of SLC7 transporters. Jungnickel Katharina E J,Parker Joanne L,Newstead Simon Nature communications Amino acids play essential roles in cell biology as regulators of metabolic pathways. Arginine in particular is a major signalling molecule inside the cell, being a precursor for both l-ornithine and nitric oxide (NO) synthesis and a key regulator of the mTORC1 pathway. In mammals, cellular arginine availability is determined by members of the solute carrier (SLC) 7 family of cationic amino acid transporters. Whereas CAT-1 functions to supply cationic amino acids for cellular metabolism, CAT-2A and -2B are required for macrophage activation and play important roles in regulating inflammation. Here, we present the crystal structure of a close homologue of the mammalian CAT transporters that reveals how these proteins specifically recognise arginine. Our structural and functional data provide a model for cationic amino acid transport in mammalian cells and reveals mechanistic insights into proton-coupled, sodium-independent amino acid transport in the wider APC superfamily. 10.1038/s41467-018-03066-6
    The metabolism and significance of homocysteine in nutrition and health. Kumar Avinash,Palfrey Henry A,Pathak Rashmi,Kadowitz Philip J,Gettys Thomas W,Murthy Subramanyam N Nutrition & metabolism An association between arteriosclerosis and homocysteine (Hcy) was first demonstrated in 1969. Hcy is a sulfur containing amino acid derived from the essential amino acid methionine (Met). Hyperhomocysteinemia (HHcy) was subsequently shown in several age-related pathologies such as osteoporosis, Alzheimer's disease, Parkinson's disease, stroke, and cardiovascular disease (CVD). Also, Hcy is associated with (but not limited to) cancer, aortic aneurysm, hypothyroidism and end renal stage disease to mention some. The circulating levels of Hcy can be increased by defects in enzymes of the metabolism of Met, deficiencies of vitamins B, B and folate or by feeding Met enriched diets. Additionally, some of the pharmaceuticals currently in clinical practice such as lipid lowering, and anti-Parkinsonian drugs are known to elevate Hcy levels. Studies on supplementation with folate, vitamins B and B have shown reduction in Hcy levels but concomitant reduction in certain associated pathologies have not been definitive. The enormous importance of Hcy in health and disease is illustrated by its prevalence in the medical literature (e.g. > 22,000 publications). Although there are compelling data in favor of Hcy as a modifiable risk factor, the debate regarding the significance of Hcy mediated health effects is still ongoing. Despite associations between increased levels of Hcy with several pathologies being well documented, whether it is a causative factor, or an effect remains inconclusive. The present review though not exhaustive, is focused on several important aspects of Hcy metabolism and their relevance to health. 10.1186/s12986-017-0233-z
    Amino Acid Sensing General Control Nonderepressible-2 Kinase and Immunological Programming. Battu Srikanth,Minhas Gillipsie,Mishra Aman,Khan Nooruddin Frontiers in immunology Metabolic adaptation to the changing nutrient levels in the cellular microenvironment plays a decisive role in the maintenance of homeostasis. Eukaryotic cells are equipped with nutrient sensors, which sense the fluctuating nutrients levels and accordingly program the cellular machinery to mount an appropriate response. Nutrients including amino acids play a vital role in maintaining cellular homeostasis. Therefore, over the evolution, different species have developed diverse mechanisms to detect amino acids abundance or scarcity. Immune responses have been known to be closely associated with the cellular metabolism especially amino acid sensing pathway, which influences innate as well as adaptive immune-effector functions. Thus, exploring the cross-talk between amino acid sensing mechanisms and immune responses in disease as well as in normal physiological conditions might open up avenues to explore how this association can be exploited to tailor immunological functions toward the design of better therapeutics for controlling metabolic diseases. In this review, we discuss the advances in the knowledge of various amino acid sensing pathways including general control nonderepressible-2 kinase in the control of inflammation and metabolic diseases. 10.3389/fimmu.2017.01719
    Multiplatform plasma fingerprinting in cancer cachexia: a pilot observational and translational study. Cala Mónica Patricia,Agulló-Ortuño María Teresa,Prieto-García Elena,González-Riano Carolina,Parrilla-Rubio Lucía,Barbas Coral,Díaz-García Carmen Vanesa,García Antonia,Pernaut Cristina,Adeva Jorge,Riesco María Carmen,Rupérez Francisco Javier,Lopez-Martin Jose Antonio Journal of cachexia, sarcopenia and muscle BACKGROUND:Cachexia is a metabolic syndrome that affects up to 50-80% of cancer patients. The pathophysiology is characterized by a variable combination of reduced food intake and abnormal metabolism, including systemic inflammation and negative protein and energy balance. Despite its high clinical significance, defined diagnostic criteria and established therapeutic strategies are lacking. The 'omics' technologies provide a global view of biological systems. We hypothesize that blood-based metabolomics might identify findings in cachectic patients that could provide clues to gain knowledge on its pathophysiology, and eventually postulate new therapeutic strategies. METHODS:This is a cross-sectional observational study in two cohorts of cancer patients, with and without cachexia. Patients were consecutively recruited from routine clinical practice of a General Oncology Department at '12 de Octubre' University Hospital. Selected clinical and biochemical features were collected. Blood metabolite fingerprinting was performed using three analytical platforms, gas chromatography coupled to mass spectrometry (GC-MS), capillary electrophoresis coupled to mass spectrometry (CE-MS), and liquid chromatography coupled to mass spectrometry (LC-MS). Besides, we performed pathway-based metabolite analyses to obtain more information on biological functions. RESULTS:A total of 15 subjects were included in this study, 8 cachectic and 7 non-cachectic patients. Metabolomic analyses were able to correctly classify their samples in 80% (GC-MS), 97% (CE-MS), 96% [LC-MS (positive mode)], and 89% [LC-MS (negative mode)] of the cases. The most prominent metabolic alteration in plasma of cachectic patients was the decrease of amino acids and derivatives [especially arginine, tryptophan, indolelactic acid, and threonine, with 0.4-fold change (FC) compared with non-cachectic patients], along with the reduction of glycerophospholipids [mainly lysophosphatidylcholines(O-16:0) and lysophosphatidylcholines(20:3) sn-1, FC = 0.1] and sphingolipids [SM(d30:0), FC = 0.5]. The metabolite with the highest increase was cortisol (FC = 1.6). Such alterations suggest a role of the following metabolic pathways in the pathophysiology of cancer cachexia: arginine and proline metabolism; alanine, aspartate, and glutamate metabolism; phenylalanine metabolism; lysine degradation; aminoacyl-tRNA biosynthesis; fatty acid elongation in mitochondria; tricarboxylic acids cycle; among others. CONCLUSIONS:These findings suggest that plasma amino acids and lipids profiling has great potential to find the mechanisms involved in the pathogenesis of cachexia. Metabolic profiling of plasma from cancer patients show differences between cachexia and non-cachexia in amino acids and lipids that might be related to mechanisms involved in its pathophysiology. A better understanding of these mechanisms might identify novel therapeutic approaches to palliate this unmet medical condition. 10.1002/jcsm.12270
    Increased Tryptophan Metabolism Is Associated With Activity of Inflammatory Bowel Diseases. Nikolaus Susanna,Schulte Berenice,Al-Massad Natalie,Thieme Florian,Schulte Dominik M,Bethge Johannes,Rehman Ateequr,Tran Florian,Aden Konrad,Häsler Robert,Moll Natalie,Schütze Gregor,Schwarz Markus J,Waetzig Georg H,Rosenstiel Philip,Krawczak Michael,Szymczak Silke,Schreiber Stefan Gastroenterology BACKGROUND & AIMS:Administration of tryptophan and some of its metabolites reduces the severity of colitis in mice, whereas removing tryptophan from the diet increases susceptibility to colitis. Transfer of the intestinal microbiome transfers the colitogenic phenotype from tryptophan starved animals to normally nourished mice. We aimed to systematically evaluate serum levels of tryptophan and its metabolites in patients with inflammatory bowel diseases (IBD), and study their association with clinical and serologic features. METHODS:We studied 535 consecutive patients with IBD (211 with ulcerative colitis [UC], 234 with Crohn's disease [CD]; 236 male), enrolled in Germany from August 2013 through April 2014 and followed until July 2016. Serum samples were collected from patients and 291 matched individuals without IBD (controls); levels of tryptophan were measured using high-performance liquid chromatography. Metabolites of tryptophan were measured in serum from 148 patients and 100 controls by mass spectrometry. We measured levels of interleukin 22 in serum from 28 patients by enzyme-linked immunosorbent assay. Paired stool and serum samples were collected from a subset of patients with active UC (n = 10) or CD (n = 8) to investigate associations between serum levels of tryptophan and composition of the fecal microbiota, analyzed by 16S ribosomal DNA amplicon sequencing. We used real-time polymerase chain reaction to measure levels of messenger RNAs in colonic biopsies from 60 patients with UC, 50 with CD, and 30 controls. We collected information on patients' disease activity scores, medications, laboratory assessments, and clinical examinations during recruitment and follow-up visits. RESULTS:Serum levels of tryptophan were significantly lower in patients with IBD than in controls (P = 5.3 × 10) with a stronger reduction in patients with CD (vs control; P = 1.1 × 10) than UC (vs control; P = 2.8 × 10). We found a negative correlation between serum levels of tryptophan and disease activity or levels of C-reactive protein. Levels of messenger RNAs encoding tryptophan 2,3-dioxygenase-2 and solute carrier family 6 member 19 (also called B0AT1) were significantly decreased in colonic biopsies from patients with IBD compared with controls, whereas level of messenger RNA encoding indoleamine 2,3-dioxygenase-1 was significantly increased. The composition of the fecal microbiota associated with serum levels of tryptophan. Analysis of tryptophan metabolites revealed activation of the kynurenine pathway, based on high levels of quinolinic acid, in patients with IBD compared with controls. Serum concentration of interleukin 22 associated with disease activity in patients with IBD; there was an inverse association between levels of interleukin 22 and serum levels of tryptophan. CONCLUSIONS:In an analysis of serum samples from more than 500 patients with IBD, we observed a negative correlation between serum levels of tryptophan and disease activity. Increased levels of tryptophan metabolites-especially of quinolinic acid-indicated a high activity of tryptophan degradation in patients with active IBD. Tryptophan deficiency could contribute to development of IBD or aggravate disease activity. Interventional clinical studies are needed to determine whether modification of intestinal tryptophan pathways affects the severity of IBD. 10.1053/j.gastro.2017.08.028
    Altered peripheral amino acid profile indicate a systemic impact of active celiac disease and a possible role of amino acids in disease pathogenesis. Torinsson Naluai Åsa,Saadat Vafa Ladan,Gudjonsdottir Audur H,Arnell Henrik,Browaldh Lars,Nilsson Staffan,Agardh Daniel PloS one BACKGROUND:We have previously performed a Genome Wide Association and linkage study that indicated a new disease triggering mechanism involving amino acid metabolism and nutrient sensing signaling pathways. OBJECTIVE:The aim of this study was to investigate if plasma amino acid levels differed among children with celiac disease compared with disease controls. MATERIALS AND METHODS:Fasting plasma samples from 141 children with celiac disease and 129 non-celiac disease controls, were analyzed for amino acid levels by liquid chromatography-tandem mass spectrometry (LC/MS). A general linear model using age and experimental effects as covariates was used to compare amino acid levels between children with a diagnosis of celiac disease and controls. RESULTS:Seven out of twenty-three analyzed amino acids were elevated in children with celiac disease compared with controls (tryptophan, taurine, glutamic acid, proline, ornithine, alanine and methionine). The significance of the individual amino acids do not survive multiple correction, however, multivariate analyses of the amino acid profile showed significantly altered amino acid levels in children with celiac disease overall and after correction for age, sex and experimental effects (p = 8.4 × 10-8). CONCLUSION:These findings support the idea that amino acids could influence systemic inflammation and play a possible role in disease pathogenesis. 10.1371/journal.pone.0193764
    Protein-Amino Acid Metabolism Disarrangements: The Hidden Enemy of Chronic Age-Related Conditions. Pasini Evasio,Corsetti Giovanni,Aquilani Roberto,Romano Claudia,Picca Anna,Calvani Riccardo,Dioguardi Francesco Saverio Nutrients Proteins are macro-molecules crucial for cell life, which are made up of amino acids (AAs). In healthy people, protein synthesis and degradation are well balanced. However, in the presence of hypercatabolic stimulation (i.e., inflammation), protein breakdown increases as the resulting AAs are consumed for metabolic proposes. Indeed, AAs are biochemical totipotent molecules which, when deaminated, can be transformed into energy, lipids, carbohydrates, and/or biochemical intermediates of fundamental cycles, such as the Krebs' cycle. The biochemical consequence of hyper-catabolism is protein disarrangement, clinically evident with signs such as sarcopenia, hypalbuminemia, anaemia, infection, and altered fluid compartmentation, etc. Hypercatabolic protein disarrangement (HPD) is often underestimated by clinicians, despite correlating with increased mortality, hospitalization, and morbidity quite independent of the primary disease. Simple, cheap, repeatable measurements can be used to identify HPD. Therefore, identification and treatment of proteins' metabolic impairment with appropriate measurements and therapy is a clinical strategy that could improve the prognosis of patients with acute/chronic hypercatabolic inflammatory disease. Here, we describe the metabolism of protein and AAs in hypercatabolic syndrome, illustrating the clinical impact of protein disarrangement. We also illustrate simple, cheap, repeatable, and worldwide available measurements to identify these conditions. Finally, we provide scientific evidence for HPD nutritional treatment. 10.3390/nu10040391
    Altered metabolism distinguishes high-risk from stable carotid atherosclerotic plaques. Tomas Lukas,Edsfeldt Andreas,Mollet Inês G,Perisic Matic Ljubica,Prehn Cornelia,Adamski Jerzy,Paulsson-Berne Gabrielle,Hedin Ulf,Nilsson Jan,Bengtsson Eva,Gonçalves Isabel,Björkbacka Harry European heart journal Aims:Identification and treatment of the rupture prone atherosclerotic plaque remains a challenge for reducing the burden of cardiovascular disease. The interconnection of metabolic and inflammatory processes in rupture prone plaques is poorly understood. Herein, we investigate associations between metabolite profiles, inflammatory mediators and vulnerability in carotid atherosclerotic plaques. Methods and results:We collected 159 carotid plaques from patients undergoing endarterectomy and measured 165 different metabolites in a targeted metabolomics approach. We identified a metabolite profile in carotid plaques that associated with histologically evaluated vulnerability and inflammatory mediators, as well as presence of symptoms in patients. The distinct metabolite profiles identified in high-risk and stable plaques were in line with different transcription levels of metabolic enzymes in the two groups, suggesting an altered metabolism in high-risk plaques. The altered metabolic signature in high-risk plaques was consistent with a change to increased glycolysis, elevated amino acid utilization and decreased fatty acid oxidation, similar to what is found in activated leucocytes and cancer cells. Conclusion:These results highlight a possible key role of cellular metabolism to support inflammation and a high-risk phenotype of atherosclerotic plaques. Targeting the metabolism of atherosclerotic plaques with novel metabolic radiotracers or inhibitors might therefore be valid future approaches to identify and treat the high-risk atherosclerotic plaque. 10.1093/eurheartj/ehy124
    LC-MS-based serum metabolomics reveals a distinctive signature in patients with rheumatoid arthritis. Li Ju,Che Nan,Xu Lingxiao,Zhang Qian,Wang Qi,Tan Wenfeng,Zhang Miaojia Clinical rheumatology Metabolomics has been applied to explore altered metabolite profiles in disease and identify unique metabolic signatures in recent years. We aim to characterize the metabolic profile of rheumatoid arthritis patients and explore its underlying pathological processes using metabolomics approach. Serum samples from 30 rheumatoid arthritis (RA) patients, 30 primary Sjogren's syndrome (pSS) patients, and 32 healthy controls (HC) were collected. The sample was analyzed by ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry (UPLC-HRMS). Potential biomarkers were screened from orthogonal projection to latent structure discriminate analysis (OPLS-DA) and further evaluated by receiver operating characteristic analysis (ROC). Compared with HC and pSS patients, the RA patients had increased serum levels of 4-methoxyphenylacetic acid, glutamic acid, L-leucine, L-phenylalanine, L-tryptophan, L-proline, glyceraldehyde, fumaric acid, and cholesterol as well as decreased capric acid, argininosuccinic acid, and billirubin. A total of eight potential biomarkers were screened and tentatively identified for RA. A panel of three metabolites (4-methoxyphenylacetic acid, L-phenylalanine, and L-leucine) was identified as specific biomarkers of RA. ROC analysis showed that the panel had a sensitivity of 93.30% with a specificity of 95.20% in discrimination RA from other groups. UPLC-HRMS-based quantification of circulating metabolites was a useful tool for identifying RA patients from pSS patients and healthy controls. The potential biomarkers indicated that the RA metabolic disturbance might be associated with inflammation injury, amino acid metabolism, oxidative stress, and phospholipid metabolism. 10.1007/s10067-018-4021-6
    Effects of dietary tryptophan supplementation in the acetic acid-induced colitis mouse model. Chen Shuai,Wang Meiwei,Yin Lanmei,Ren Wenkai,Bin Peng,Xia Yaoyao,Liu Gang,Yang Huansheng,Tan Bie,Yin Yulong Food & function Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract and is strongly associated with intestinal immunity and the microbiome. Tryptophan (Trp) is an inflammatory inhibitor and modulator of the intestinal microflora. We explored the serum profile of amino acids and the effects of diet supplementation with Trp (1.0 g kg-1) on intestinal immunity and microbiota in the acetic acid-induced colitis mouse model. We analyzed the survival rate, colonic morphological parameters, profiles of serum amino acids, microbiota in colonic contents and the relative gene abundance of intestinal proinflammatory cytokines. Although the dietary Trp supplementation failed to improve the survival rate and ameliorate the morphological parameters of colon in mice with colitis, Trp modulated the general serum amino acid profile by reducing the amino acid profiles of threonine, methionine and proline, affected intestinal immunity by inhibiting the colonic expression of interleukin-22 and changed the microbiota by reducing the abundance of Candidatus, Clostridium and Coprococcus at the genus level. In conclusion, dietary Trp supplementation in a mouse model of colitis did not ameliorate the survival rate and morphological parameters of colon but did modulate the serum amino acid profiles, intestinal immunity and microbiota. These findings enhance our understanding of the roles of Trp in the metabolism of serum amino acids, intestinal immunity and microbiota. 10.1039/c8fo01025k
    Particulate metal exposures induce plasma metabolome changes in a commuter panel study. Ladva Chandresh Nanji,Golan Rachel,Liang Donghai,Greenwald Roby,Walker Douglas I,Uppal Karan,Raysoni Amit U,Tran ViLinh,Yu Tianwei,Flanders W Dana,Miller Gary W,Jones Dean P,Sarnat Jeremy A PloS one INTRODUCTION:Advances in liquid chromatography-mass spectrometry (LC-MS) have enabled high-resolution metabolomics (HRM) to emerge as a sensitive tool for measuring environmental exposures and corresponding biological response. Using measurements collected as part of a large, panel-based study of car commuters, the current analysis examines in-vehicle air pollution concentrations, targeted inflammatory biomarker levels, and metabolomic profiles to trace potential metabolic perturbations associated with on-road traffic exposures. METHODS:A 60-person panel of adults participated in a crossover study, where each participant conducted a highway commute and randomized to either a side-street commute or clinic exposure session. In addition to in-vehicle exposure characterizations, participants contributed pre- and post-exposure dried blood spots for 2-hr changes in targeted proinflammatory and vascular injury biomarkers and 10-hr changes in the plasma metabolome. Samples were analyzed on a Thermo QExactive MS system in positive and negative electrospray ionization (ESI) mode. Data were processed and analyzed in R using apLCMS, xMSanalyzer, and limma. Features associated with environmental exposures or biological endpoints were identified with a linear mixed effects model and annotated through human metabolic pathway analysis in mummichog. RESULTS:HRM detected 10-hr perturbations in 110 features associated with in-vehicle, particulate metal exposures (Al, Pb, and Fe) which reflect changes in arachidonic acid, leukotriene, and tryptophan metabolism. Two-hour changes in proinflammatory biomarkers hs-CRP, IL-6, IL-8, and IL-1β were also associated with 10-hr changes in the plasma metabolome, suggesting diverse amino acid, leukotriene, and antioxidant metabolism effects. A putatively identified metabolite, 20-OH-LTB4, decreased after in-vehicle exposure to particulate metals, suggesting a subclinical immune response. CONCLUSIONS:Acute exposures to traffic-related air pollutants are associated with broad inflammatory response, including several traditional markers of inflammation. 10.1371/journal.pone.0203468
    Krüppel-Like Factors in Metabolic Homeostasis and Cardiometabolic Disease. Oishi Yumiko,Manabe Ichiro Frontiers in cardiovascular medicine Members of the Krüppel-like factor (KLF) family of transcription factors, which are characterized by the presence of three conserved Cys/His zinc-fingers in their C-terminal domains, control a wide variety of biological processes. In particular, recent studies have revealed that KLFs play diverse and essential roles in the control of metabolism at the cellular, tissue and systemic levels. In both liver and skeletal muscle, KLFs control glucose, lipid and amino acid metabolism so as to coordinate systemic metabolism in the steady state and in the face of metabolic stresses, such as fasting. The functions of KLFs within metabolic tissues are also important contributors to the responses to injury and inflammation within those tissues. KLFs also control the function of immune cells, such as macrophages, which are involved in the inflammatory processes underlying both cardiovascular and metabolic diseases. This review focuses mainly on the physiological and pathological functions of KLFs in the liver and skeletal muscle. The involvement of KLFs in inflammation in these tissues is also summarized. We then discuss the implications of KLFs' control of metabolism and inflammation in cardiometabolic diseases. 10.3389/fcvm.2018.00069
    Combined Inflammation and Metabolism Biomarker Indices of Robust and Impaired Physical Function in Older Adults. Zuo Xintong,Luciano Alison,Pieper Carl F,Bain James R,Kraus Virginia B,Kraus William E,Morey Miriam C,Cohen Harvey J Journal of the American Geriatrics Society OBJECTIVES:To determine whether combinations of inflammatory markers are related to physical function. DESIGN AND SUBJECTS:secondary analysis of baseline of three observational studies of community-dwelling older adults MEASUREMENTS: The baseline data from 3 cohorts of older adults with different health and disease status were employed. Twenty markers of inflammation and metabolism were individually assessed for correlation with usual gait speed and were separated into robust and impairment quartiles. For the robustness and impairment indices, individual markers were selected using step-wise regression over bootstrapping iterations, and regression coefficients were estimated for the markers individually and collectively as an additive score. RESULTS:We developed a robustness index involving 6 markers and an impairment index involving 8 markers corresponding positively and negatively with gait speed. Two markers, glycine and tumor necrosis factor receptor 1 (TNFR1), appeared only in the robustness index, and TNFR2; regulated on activation, normal T-cell expressed and secreted; the amino acid factor; and matrix metallopeptidase 3; appeared only in the impairment index. CONCLUSION:Indices of biomarkers were associated with robust and impaired physical performance but differ, in composition suggesting potential biological differences that may contribute to robustness and impairment. 10.1111/jgs.15393
    Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women. Hoyles Lesley,Fernández-Real José-Manuel,Federici Massimo,Serino Matteo,Abbott James,Charpentier Julie,Heymes Christophe,Luque Jèssica Latorre,Anthony Elodie,Barton Richard H,Chilloux Julien,Myridakis Antonis,Martinez-Gili Laura,Moreno-Navarrete José Maria,Benhamed Fadila,Azalbert Vincent,Blasco-Baque Vincent,Puig Josep,Xifra Gemma,Ricart Wifredo,Tomlinson Christopher,Woodbridge Mark,Cardellini Marina,Davato Francesca,Cardolini Iris,Porzio Ottavia,Gentileschi Paolo,Lopez Frédéric,Foufelle Fabienne,Butcher Sarah A,Holmes Elaine,Nicholson Jeremy K,Postic Catherine,Burcelin Rémy,Dumas Marc-Emmanuel Nature medicine Hepatic steatosis is a multifactorial condition that is often observed in obese patients and is a prelude to non-alcoholic fatty liver disease. Here, we combine shotgun sequencing of fecal metagenomes with molecular phenomics (hepatic transcriptome and plasma and urine metabolomes) in two well-characterized cohorts of morbidly obese women recruited to the FLORINASH study. We reveal molecular networks linking the gut microbiome and the host phenome to hepatic steatosis. Patients with steatosis have low microbial gene richness and increased genetic potential for the processing of dietary lipids and endotoxin biosynthesis (notably from Proteobacteria), hepatic inflammation and dysregulation of aromatic and branched-chain amino acid metabolism. We demonstrated that fecal microbiota transplants and chronic treatment with phenylacetic acid, a microbial product of aromatic amino acid metabolism, successfully trigger steatosis and branched-chain amino acid metabolism. Molecular phenomic signatures were predictive (area under the curve = 87%) and consistent with the gut microbiome having an effect on the steatosis phenome (>75% shared variation) and, therefore, actionable via microbiome-based therapies. 10.1038/s41591-018-0061-3
    Endothelial Cell Metabolism in Atherosclerosis. Theodorou Kosta,Boon Reinier A Frontiers in cell and developmental biology Atherosclerosis and its sequelae, such as myocardial infarction and stroke, are the leading cause of death worldwide. Vascular endothelial cells (EC) play a critical role in vascular homeostasis and disease. Atherosclerosis as well as its independent risk factors including diabetes, obesity, and aging, are hallmarked by endothelial activation and dysfunction. Metabolic pathways have emerged as key regulators of many EC functions, including angiogenesis, inflammation, and barrier function, processes which are deregulated during atherogenesis. In this review, we highlight the role of glucose, fatty acid, and amino acid metabolism in EC functions during physiological and pathological states, specifically atherosclerosis, diabetes, obesity and aging. 10.3389/fcell.2018.00082
    Upregulation of tryptophanyl-tRNA synthethase adapts human cancer cells to nutritional stress caused by tryptophan degradation. Adam Isabell,Dewi Dyah L,Mooiweer Joram,Sadik Ahmed,Mohapatra Soumya R,Berdel Bianca,Keil Melanie,Sonner Jana K,Thedieck Kathrin,Rose Adam J,Platten Michael,Heiland Ines,Trump Saskia,Opitz Christiane A Oncoimmunology Tryptophan (Trp) metabolism is an important target in immuno-oncology as it represents a powerful immunosuppressive mechanism hijacked by tumors for protection against immune destruction. However, it remains unclear how tumor cells can proliferate while degrading the essential amino acid Trp. Trp is incorporated into proteins after it is attached to its tRNA by tryptophanyl-tRNA synthestases. As the tryptophanyl-tRNA synthestases compete for Trp with the Trp-catabolizing enzymes, the balance between these enzymes will determine whether Trp is used for protein synthesis or is degraded. In human cancers expression of the Trp-degrading enzymes indoleamine-2,3-dioxygenase-1 (IDO1) and tryptophan-2,3-dioxygenase (TDO2) was positively associated with the expression of the tryptophanyl-tRNA synthestase WARS. One mechanism underlying the association between IDO1 and WARS identified in this study is their joint induction by IFNγ released from tumor-infiltrating T cells. Moreover, we show here that IDO1- and TDO2-mediated Trp deprivation upregulates WARS expression by activating the general control non-derepressible-2 (GCN2) kinase, leading to phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α) and induction of activating transcription factor 4 (ATF4). Trp deprivation induced cytoplasmic WARS expression but did not increase nuclear or extracellular WARS levels. GCN2 protected the cells against the effects of Trp starvation and enabled them to quickly make use of Trp for proliferation once it was replenished. Computational modeling of Trp metabolism revealed that Trp deficiency shifted Trp flux towards WARS and protein synthesis. Our data therefore suggest that the upregulation of WARS via IFNγ and/or GCN2-peIF2α-ATF4 signaling protects Trp-degrading cancer cells from excessive intracellular Trp depletion. 10.1080/2162402X.2018.1486353
    Hepatic Steatosis Is Associated With Adverse Molecular Signatures in Subjects Without Diabetes. Pietzner Maik,Budde Kathrin,Homuth Georg,Kastenmüller Gabi,Henning Ann-Kristin,Artati Anna,Krumsiek Jan,Völzke Henry,Adamski Jerzy,Lerch Markus M,Kühn Jens P,Nauck Matthias,Friedrich Nele The Journal of clinical endocrinology and metabolism Background and Aims:Exaggerated hepatic triglyceride accumulation (i.e., hepatic steatosis) represents a strong risk factor for type 2 diabetes mellitus and cardiovascular disease. Despite the clear association of hepatic steatosis with impaired insulin signaling, the precise molecular mechanisms involved are still under debate. We combined data from several metabolomics techniques to gain a comprehensive picture of molecular alterations related to the presence of hepatic steatosis in a diabetes-free sample (N = 769) of the population-based Study of Health in Pomerania. Methods:Liver fat content (LFC) was assessed using MRI. Metabolome measurements of plasma and urine samples were done by mass spectrometry and nuclear magnetic resonance spectroscopy. Linear regression analyses were used to detect significant associations with either LFC or markers of hepatic damage. Possible mediations through insulin resistance, hypertriglyceridemia, and inflammation were tested. A predictive molecular signature of hepatic steatosis was established using regularized logistic regression. Results:The LFC-associated atherogenic lipid profile, tightly connected to shifts in the phospholipid content, and a prediabetic amino acid cluster were mediated by insulin resistance. Molecular surrogates of oxidative stress and multiple associations with urine metabolites (e.g., indicating altered cortisol metabolism or phase II detoxification products) were unaffected in mediation analyses. Incorporation of urine metabolites slightly improved classification of hepatic steatosis. Conclusions:Comprehensive metabolic profiling allowed us to reveal molecular patterns accompanying hepatic steatosis independent of the known hallmarks. Novel biomarkers from urine (e.g., cortisol glucuronide) are worthwhile for follow-up in patients suffering from more severe liver impairment compared with our merely healthy population-based sample. 10.1210/jc.2018-00999
    Amino Acid Profile of Synovial Fluid Following Intra-articular Ankle Fracture. Leimer Elizabeth M,Tanenbaum Laura M,Nettles Dana L,Bell Richard D,Easley Mark E,Setton Lori A,Adams Samuel B Foot & ankle international BACKGROUND:Post-traumatic osteoarthritis (PTOA) is a frequent complication in patients with a previous traumatic joint injury, and the pathophysiology is not well understood. The goal of this study was to characterize the biochemical signature of amino acids, peptides, and amino acid metabolites in ankle synovial fluid following intra-articular fracture. METHODS:Synovial fluid from both the injured and contralateral ankles of 19 patients with an intra-articular ankle fracture was obtained and analyzed via metabolic profiling. Follow-up analysis was performed after 6 months in 7 of these patients. RESULTS:Statistical comparisons between injured and contralateral ankles revealed that 19 of the 66 measured amino acids, peptides, and amino acid metabolites were significantly elevated at time of fracture. Metabolites associated with glutathione metabolism exhibited the most elevated mean-fold changes, indicating a possible role for oxidative stress in fractured ankles. None of the metabolites elevated at baseline were significantly elevated after 6 months, but 6 metabolites had mean-fold changes greater than 2.1 at this time point. Multiple metabolites also exhibited significant correlations ( r > 0.575) with matrix metalloproteinase-1 and -9. CONCLUSION:These results indicate the presence of amino acid metabolic products in the setting of ankle fracture and suggest that these changes in amino acid metabolism may be chronic and indicate a role for inflammation and collagen degradation in disease progression. CLINICAL RELEVANCE:Changes in amino acid metabolism following intra-articular fracture may contribute to the progression to PTOA. This knowledge may allow for the identification and early treatment of patients at risk of developing PTOA. LEVEL OF EVIDENCE:Level III, comparative series. 10.1177/1071100718786163
    Possible Clues for Brain Energy Translation via Endolysosomal Trafficking of APP-CTFs in Alzheimer's Disease. Sivanesan Senthilkumar,Mundugaru Ravi,Rajadas Jayakumar Oxidative medicine and cellular longevity Vascular dysfunctions, hypometabolism, and insulin resistance are high and early risk factors for Alzheimer's disease (AD), a leading neurological disease associated with memory decline and cognitive dysfunctions. Early defects in glucose transporters and glycolysis occur during the course of AD progression. Hypometabolism begins well before the onset of early AD symptoms; this timing implicates the vulnerability of hypometabolic brain regions to beta-secretase 1 (BACE-1) upregulation, oxidative stress, inflammation, synaptic failure, and cell death. Despite the fact that ketone bodies, astrocyte-neuron lactate shuttle, pentose phosphate pathway (PPP), and glycogenolysis compensate to provide energy to the starving AD brain, a considerable energy crisis still persists and increases during disease progression. Studies that track brain energy metabolism in humans, animal models of AD, and studies reveal striking upregulation of beta-amyloid precursor protein (-APP) and carboxy-terminal fragments (CTFs). Currently, the precise role of CTFs is unclear, but evidence supports increased endosomal-lysosomal trafficking of -APP and CTFs through autophagy through a vague mechanism. While intracellular accumulation of A is attributed as both the cause and consequence of a defective endolysosomal-autophagic system, much remains to be explored about the other -APP cleavage products. Many recent works report altered amino acid catabolism and expression of several urea cycle enzymes in AD brains, but the precise cause for this dysregulation is not fully explained. In this paper, we try to connect the role of CTFs in the energy translation process in AD brain based on recent findings. 10.1155/2018/2764831
    Myeloid-derived suppressor cells (MDSC): an important partner in cellular/tissue senescence. Salminen Antero,Kauppinen Anu,Kaarniranta Kai Biogerontology The aging process is associated with a low-grade chronic inflammation and the accumulation of senescent cells into tissues. Diverse stresses can trigger cellular senescence, a cell fate characterized by cell-cycle arrest and flat morphology. Oncogenic signaling can also induce cellular senescence which has been termed oncogene-induced senescence (OIS). Senescent cells display a pro-inflammatory phenotype which has been called the senescence-associated secretory phenotype (SASP). The secretomes associated with SASP contain colony-stimulating factors and chemokines which stimulate the generation of myeloid-derived suppressor cells (MDSC) by enhancing myelopoiesis in bone marrow and spleen. Enhanced myelopoiesis and increased level of MDSCs have been observed in bone marrow, spleen, and blood in both tumor-bearing and aged mice. Immunosuppressive MDSCs are recruited via chemotaxis into inflamed tissues where they proliferate and consequently suppress acute inflammatory reactions by inhibiting the functions of distinct components of innate and adaptive immunity. For instance, MDSCs stimulate the activity of immunosuppressive regulatory T-cells (Tregs). They also increase the expression of amino acid catabolizing enzymes and the secretion of anti-inflammatory cytokines, e.g. IL-10 and TGF-β, and reactive oxygen species (ROS). On the other hand, the accumulation of MDSCs into tissues exerts harmful effects in chronic pathological disorders, e.g. tumors and many age-related diseases, since the immunosuppression induced by MDSCs impairs the clearance of senescent and cancer cells and also disturbs the maintenance of energy metabolism and tissue proteostasis. The co-operation between senescent cells and immunosuppressive MDSCs regulates not only tumorigenesis and chronic inflammatory disorders but it also might promote inflammaging during the aging process. 10.1007/s10522-018-9762-8
    Synthesis and evaluation of an N-[F]fluorodeoxyglycosyl amino acid for PET imaging of tumor metabolism. Wu Zhifang,Ma Jingxin,Brownell Anna-Liisa,Wang Hongliang,Li Chaomin,Meng Xiaxia,Yuan Ling,Liu Haiyan,Li Sijin,Xie Jun Nuclear medicine and biology INTRODUCTION:The limitations of [F]fluorodeoxyglucose ([F]FDG), including producing false-positive or -negative results, low image contrast in brain tumor diagnosis and poor differentiation of tumor and inflammatory, necessitate the development of new radiopharmaceuticals. In the present study, a novel [F]fluoroglycoconjugate tracer, [F]FDGly-NH-Phe, for tumor metabolism imaging was prepared and evaluated. METHODS:[F]FDGly-NH-Phe was prepared by condensing [F]FDG with L-4-aminophenylalanine in an acidic condition, and purified with semi-preparative-high performance liquid chromatography (HPLC). The in vitro stability study was conducted in phosphate-buffered saline (PBS, pH 4.0-9.18) at room temperature (RT) and in fetal bovine serum (FBS) at 37 °C. The preliminary cellular uptake studies were performed using Hep-2 cell. The bio-distribution studies, PET/CT imaging and metabolism studies were performed and compared with [F]FDG on ICR or BALB/c nude model mice. RESULTS:[F]FDGly-NH-Phe was derived from a direct condensation of [F]FDG with L-4-aminophenylalanine with high stability in FBS and PBS (pH of 6.5-9.18). In vitro cell experiments showed that [F]FDGly-NH-Phe uptake in Hep-2 cells was primarily transported through amino acid transporters including Na-dependent A system, ASC system, and system B system. The bio-distribution of [F]FDGly-NH-Phe in normal ICR mice showed faster blood radioactivity clearance, and lower uptake in brain and heart than [F]FDG. The performance of PET/CT imaging for [F]FDGly-NH-Phe in the mice model manifested excellent tumor visualization, high tumor-to-background ratios, and low accumulation in inflammatory lesions. Metabolism studies for [F]FDGly-NH-Phe indicated high in vivo stability in plasma and urine and decomposition into [F]FDG in the tumor microenvironment. CONCLUSION:The results demonstrated that [F]FDGly-NH-Phe as a novel amino acid PET tracer showed the capability to differentiate tumor from inflammation, and the potentials for future clinical applications. 10.1016/j.nucmedbio.2018.08.002
    Conjugation of urate-derived electrophiles to proteins during normal metabolism and inflammation. Turner Rufus,Brennan Stephen O,Ashby Louisa V,Dickerhof Nina,Hamzah Melanie R,Pearson John F,Stamp Lisa K,Kettle Anthony J The Journal of biological chemistry Urate is often viewed as an antioxidant. Here, we present an alternative perspective by showing that, when oxidized, urate propagates oxidative stress. Oxidation converts urate to the urate radical and the electrophilic products dehydrourate, 5-hydroxyisourate, and urate hydroperoxide, which eventually break down to allantoin. We investigated whether urate-derived electrophiles are intercepted by nucleophilic amino acid residues to form stable adducts on proteins. When urate was oxidized in the presence of various peptides and proteins, two adducts derived from urate ( 167 Da) were detected and had mass additions of 140 and 166 Da, occurring mainly on lysine residues and N-terminal amines. The adduct with a 140-Da mass addition was detected more frequently and was stable. Dehydrourate ( 166 Da) also formed transient adducts with cysteine residues. Urate-derived adducts were detected on human serum albumin in plasma of healthy donors. Basal adduct levels increased when neutrophils were added to plasma and stimulated, and relied on the NADPH oxidase, myeloperoxidase, hydrogen peroxide, and superoxide. Adducts of oxidized urate on serum albumin were elevated in plasma and synovial fluid from individuals with gout and rheumatoid arthritis. We propose that rather than acting as an antioxidant, urate's conversion to electrophiles contributes to oxidative stress. The addition of urate-derived electrophiles to nucleophilic amino acid residues, a process we call oxidative uratylation, will leave a footprint on proteins that could alter their function when critical sites are modified. 10.1074/jbc.RA118.005237
    Metabolism Plays a Key Role during Macrophage Activation. Stunault Marion I,Bories Gaël,Guinamard Rodolphe R,Ivanov Stoyan Mediators of inflammation Monocyte and macrophage diversity is evidenced by the modulation of cell surface markers and differential production of soluble mediators. These immune cells play key roles in controlling tissue homeostasis, infections, and excessive inflammation. Macrophages remove dead cells in a process named efferocytosis, contributing to the healthy tissue maintenance. Recently, it became clear that the main macrophage functions are under metabolic control. Modulation of glucose, fatty acid, and amino acid metabolism is associated with various macrophage activations in response to external stimuli. Deciphering these metabolic pathways provided critical information about macrophage functions. 10.1155/2018/2426138
    Metabolomic analyses reveal lipid abnormalities and hepatic dysfunction in non-human primate model for Yersinia pestis. Gautam Aarti,Muhie Seid,Chakraborty Nabarun,Hoke Allison,Donohue Duncan,Miller Stacy Ann,Hammamieh Rasha,Jett Marti Metabolomics : Official journal of the Metabolomic Society INTRODUCTION:Pneumonic plague is caused by the aerosolized form of Yersinia pestis and is a highly virulent infection with complex clinical consequences, and without treatment, the fatality rate approaches 100%. The exact mechanisms of disease progression are unclear, with limited work done using metabolite profiling to study disease progression. OBJECTIVE:The aim of this pilot study was to profile the plasma metabolomics in an animal model of Y. pestis infection. METHODS:In this study, African Green monkeys were challenged with the highly virulent, aerosolized Y. pestis strain CO92, and untargeted metabolomics profiling of plasma was performed using liquid and gas chromatography with mass spectrometry. RESULTS:At early time points post-exposure, we found significant increases in polyunsaturated, long chain fatty acid metabolites with p values ranging from as low as 0.000001 (ratio = 1.94) for the metabolite eicosapentaenoate to 0.04 (ratio = 1.36) for the metabolite adrenate when compared to time-matched controls. Multiple acyl carnitines metabolites were increased at earlier time points and could be a result of fatty acid oxidation defects with p values ranging from as low as 0.00001 (ratio = 2.95) for the metabolite octanoylcarnitine to 0.04 (ratio = 1.33) for metabolite deoxycarnitine when compared to time-matched controls. Dicarboxylic acids are important metabolic products of fatty acids oxidation, and when compared to time matched controls, were higher at earlier time points where metabolite tetradecanedioate has a ratio of 4.09 with significant p value of 0.000002 and adipate with a ratio of 1.12 and p value of 0.004. The metabolites from lysolipids (with significant p values ranging from 0.00006 for 1-oleoylglycerophosphoethanolamine to 0.04 for 1-stearoylglycerophosphoethanolamine and a ratio of 0.47 and 0.78, respectively) and bile acid metabolism (with significant p values ranging from 0.02 for cholate to 0.04 for deoxycholate and a ratio of 0.39 and 0.66, respectively) pathways were significantly lower compared to their time-matched controls during the entire course of infection. Metabolite levels from amino acid pathways were disrupted, and a few from the leucine, isoleucine and valine pathway were significantly higher (p values ranging from 0.002 to 0.04 and ratios ranging from 1.3 to 1.5, respectively), whereas metabolites from the urea cycle, arginine and proline pathways were significantly lower (p values ranging from 0.00008 to 0.02 and ratios ranging from 0.5 to 0.7, respectively) during the course of infection. CONCLUSIONS:The involvement of several lipid pathways post-infection suggested activation of pathways linked to inflammation and oxidative stress. Metabolite data further showed increased energy demand, and multiple metabolites indicated potential hepatic dysfunction. Integration of blood metabolomics and transcriptomics data identified linoleate as a core metabolite with cross-talk with multiple genes from various time points. Collectively, the data from this study provided new insights into the mechanisms of Y. pestis pathogenesis that may aid in development of therapeutics. 10.1007/s11306-018-1457-2
    Protein-leucine ingestion activates a regenerative inflammo-myogenic transcriptome in skeletal muscle following intense endurance exercise. Rowlands David S,Nelson Andre R,Raymond Frederic,Metairon Sylviane,Mansourian Robert,Clarke Jim,Stellingwerff Trent,Phillips Stuart M Physiological genomics Protein-leucine supplement ingestion following strenuous endurance exercise accentuates skeletal-muscle protein synthesis and adaptive molecular responses, but the underlying transcriptome is uncharacterized. In a randomized single-blind triple-crossover design, 12 trained men completed 100 min of high-intensity cycling then ingested 70/15/180/30 g protein-leucine-carbohydrate-fat (15LEU), 23/5/180/30 g (5LEU), or 0/0/274/30 g (CON) beverages during the first 90 min of a 240 min recovery period. Vastus lateralis muscle samples (30 and 240 min postexercise) underwent transcriptome analysis by microarray followed by bioinformatic analysis. Gene expression was regulated by protein-leucine in a dose-dependent manner affecting the inflammatory response and muscle growth and development. At 30 min, 15LEU and 5LEU vs. CON activated transcriptome networks with gene-set functions involving cell-cycle arrest (Z-score 2.0-2.7, P < 0.01), leukocyte maturation (1.7, P = 0.007), cell viability (2.4, P = 0.005), promyogenic networks encompassing myocyte differentiation and myogenin (MYOD1, MYOG), and a proteinaceous extracellular matrix, adhesion, and development program correlated with plasma lysine, arginine, tyrosine, taurine, glutamic acid, and asparagine concentrations. High protein-leucine dose (15LEU-5LEU) activated an IL-1I-centered proinflammatory network and leukocyte migration, differentiation, and survival functions (2.0-2.6, <0.001). By 240 min, the protein-leucine transcriptome was anti-inflammatory and promyogenic (IL-6, NF- β, SMAD, STAT3 network inhibition), with overrepresented functions including decreased leukocyte migration and connective tissue development (-1.8-2.4, P < 0.01), increased apoptosis of myeloid and muscle cells (2.2-3.0, P < 0.002), and cell metabolism (2.0-2.4, P < 0.01). The analysis suggests protein-leucine ingestion modulates inflammatory-myogenic regenerative processes during skeletal muscle recovery from endurance exercise. Further cellular and translational research is warranted to validate amino acid-mediated myeloid and myocellular mechanisms within skeletal-muscle functional plasticity. 10.1152/physiolgenomics.00068.2015
    Leucine supplementation via drinking water reduces atherosclerotic lesions in apoE null mice. Zhao Yang,Dai Xiao-yan,Zhou Zhou,Zhao Ge-xin,Wang Xian,Xu Ming-jiang Acta pharmacologica Sinica AIM:Recent evidence suggests that the essential amino acid leucine may be involved in systemic cholesterol metabolism. In this study, we investigated the effects of leucine supplementation on the development of atherosclerosis in apoE null mice. METHODS:ApoE null mice were fed with chow supplemented with leucine (1.5% w/v) in drinking water for 8 week. Aortic atherosclerotic lesions were examined using Oil Red O staining. Plasma lipoprotein-cholesterol levels were measured with fast protein liquid chromatography. Hepatic gene expression was detected using real-time PCR and Western blot analyses. RESULTS:Leucine supplementation resulted in 57.6% reduction of aortic atherosclerotic lesion area in apoE null mice, accompanied by 41.2% decrease of serum LDL-C levels and 40.2% increase of serum HDL-C levels. The body weight, food intake and blood glucose level were not affected by leucine supplementation. Furthermore, leucine supplementation increased the expression of Abcg5 and Abcg8 (that were involved in hepatic cholesterol efflux) by 1.28- and 0.86-fold, respectively, and significantly increased their protein levels. Leucine supplementation also increased the expression of Srebf1, Scd1 and Pgc1b (that were involved in hepatic triglyceride metabolism) by 3.73-, 1.35- and 1.71-fold, respectively. Consequently, leucine supplementation resulted in 51.77% reduction of liver cholesterol content and 2.2-fold increase of liver triglyceride content. Additionally, leucine supplementation did not affect the serum levels of IL-6, IFN-γ, TNF-α, IL-10 and IL-12, but markedly decreased the serum level of MCP-1. CONCLUSION:Leucine supplementation effectively attenuates atherosclerosis in apoE null mice by improving the plasma lipid profile and reducing systemic inflammation. 10.1038/aps.2015.88
    5-Aminolevulinic acid regulates the inflammatory response and alloimmune reaction. Fujino Masayuki,Nishio Yoshiaki,Ito Hidenori,Tanaka Tohru,Li Xiao-Kang International immunopharmacology 5-Aminolevulinic acid (5-ALA) is a naturally occurring amino acid and precursor of heme and protoporphyrin IX (PpIX). Exogenously administrated 5-ALA increases the accumulation of PpIX in tumor cells specifically due to the compromised metabolism of 5-ALA to heme in mitochondria. PpIX emits red fluorescence by the irradiation of blue light and the formation of reactive oxygen species and singlet oxygen. Thus, performing a photodynamic diagnosis (PDD) and photodynamic therapy (PDT) using 5-ALA have given rise to a new strategy for tumor diagnosis and therapy. In addition to the field of tumor therapy, 5-ALA has been implicated in the treatment of inflammatory disease, autoimmune disease and transplantation due to the anti-inflammation and immunoregulation properties that are elicited with the expression of heme oxygenase (HO)-1, an inducible enzyme that catalyzes the rate-limiting step in the oxidative degradation of heme to free iron, biliverdin and carbon monoxide (CO), in combination with sodium ferrous citrate (SFC), because an inhibitor of HO-1 abolishes the effects of 5-ALA. Furthermore, NF-E2-related factor 2 (Nrf2), mitogen-activated protein kinase (MAPK), and heme are involved in the HO-1 expression. Biliverdin and CO are also known to have anti-apoptotic, anti-inflammatory and immunoregulatory functions. We herein review the current use of 5-ALA in inflammatory diseases, transplantation medicine, and tumor therapy. 10.1016/j.intimp.2015.11.034
    Methionine and methionine sulfoxide treatment induces M1/classical macrophage polarization and modulates oxidative stress and purinergic signaling parameters. Dos Santos Lien M,da Silva Tatiane M,Azambuja Juliana H,Ramos Priscila T,Oliveira Pathise S,da Silveira Elita F,Pedra Nathalia S,Galdino Kennia,do Couto Carlus A T,Soares Mayara S P,Tavares Rejane G,Spanevello Roselia M,Stefanello Francieli M,Braganhol Elizandra Molecular and cellular biochemistry Methionine is an essential amino acid involved in critical metabolic process, and regulation of methionine flux through metabolism is important to supply this amino acid for cell needs. Elevation in plasma methionine commonly occurs due to mutations in methionine-metabolizing enzymes, such as methionine adenosyltransferase. Hypermethioninemic patients exhibit clinical manifestations, including neuronal and liver disorders involving inflammation and tissue injury, which pathophysiology is not completely established. Here, we hypothesize that alterations in macrophage inflammatory response may contribute to deleterious effects of hypermethioninemia. To this end, macrophage primary cultures were exposed to methionine (1 mM) and/or its metabolite methionine sulfoxide (0.5 mM), and M1/proinflammatory or M2/anti-inflammatory macrophage polarization was evaluated. In addition, inflammation-related pathways including oxidative stress parameters, as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities; reactive oxygen species (ROS) production, and purinergic signaling, as ATP/ADP/AMPase activities, were investigated. Methionine and/or methionine sulfoxide induced M1/classical macrophage activation, which is related to proinflammatory responses characterized by increased iNOS activity and TNF-α release. Further experiments showed that treatments promoted alterations on redox state of macrophages by differentially modulated SOD and CAT activities and ROS levels. Finally, methionine and/or methionine sulfoxide treatment also altered the extracellular nucleotide metabolism, promoting an increase of ATPase/ADPase activities in macrophages. In conclusion, these findings contribute to better understand the participation of proinflammatory responses in cell injury observed in hypermethioninemic patients. 10.1007/s11010-016-2843-6
    T-cell metabolism governing activation, proliferation and differentiation; a modular view. Dimeloe Sarah,Burgener Anne-Valérie,Grählert Jasmin,Hess Christoph Immunology T lymphocytes are a critical component of the adaptive immune system mediating protection against infection and malignancy, but also implicated in many immune pathologies. Upon recognition of specific antigens T cells clonally expand, traffic to inflamed sites and acquire effector functions, such as the capacity to kill infected and malignantly transformed cells and secrete cytokines to coordinate the immune response. These processes have significant bioenergetic and biosynthetic demands, which are met by dynamic changes in T-cell metabolism, specifically increases in glucose uptake and metabolism; mitochondrial function; amino acid uptake, and cholesterol and lipid synthesis. These metabolic changes are coordinate by key cellular kinases and transcription factors. Dysregulated T-cell metabolism is associated with impaired immunity in chronic infection and cancer and conversely with excessive T-cell activity in autoimmune and inflammatory pathologies. Here we review the key aspects of T-cell metabolism relevant to their immune function, and discuss evidence for the potential to therapeutically modulate T-cell metabolism in disease. 10.1111/imm.12655
    Taurine supplementation regulates Iκ-Bα protein expression in adipose tissue and serum IL-4 and TNF-α concentrations in MSG obesity. Caetano Luiz Carlos,Bonfleur Maria Lúcia,Ribeiro Rosane Aparecida,Nardelli Tarlliza Romanna,Lubaczeuski Camila,do Nascimento da Silva Juliana,Carneiro Everardo Magalhães,Balbo Sandra Lucinei European journal of nutrition PURPOSE:Obesity is usually associated with low-grade inflammation, which impairs insulin action. The amino acid, taurine (TAU), regulates glucose homeostasis and lipid metabolism and presents anti-inflammatory actions. Here, we evaluated whether inflammatory markers are altered in the serum and retroperitoneal adipose tissue of monosodium glutamate (MSG) obese rats, supplemented or not with TAU. METHODS:Male Wistar rats received subcutaneous injections of MSG (4 mg/kg body weight/day, MSG group) or hypertonic saline (CTL) during the first 5 days of life. From 21 to 120 days of age, half of each of the MSG and CTL groups received 2.5 % TAU in their drinking water (CTAU and MTAU). RESULTS:At 120 days of age, MSG rats were obese and hyperinsulinemic. TAU supplementation reduced fat deposition without affecting insulinemia in MTAU rats. MSG rats presented increased pIκ-Bα/Iκ-Bα protein expression in the retroperitoneal adipose tissue. TAU supplementation decreased the ratio of pIκ-Bα/Iκ-Bα protein, possibly contributing to the increased Iκ-Bα content in MTAU adipose tissue. Furthermore, MSG obesity or supplementation did not alter TNF-α, IL-1β or IL-6 content in adipose tissue. In contrast, MSG rats presented lower serum TNF-α, IL-4 and IL-10 concentrations, and these alterations were prevented by TAU treatment. CONCLUSION:MSG obesity in rats was not associated with alterations in pro-inflammatory markers in retroperitoneal fat stores; however, reductions in the serum concentrations of anti-inflammatory cytokines and of TNF-α were observed. TAU treatment decreased adiposity, and this effect was associated with the normalization of circulating TNF-α and IL-4 concentrations in MTAU rats. 10.1007/s00394-015-1114-8
    The 2015 ESPEN Sir David Cuthbertson lecture: Inflammation as the driving force of muscle wasting in cancer. Argilés Josep M Clinical nutrition (Edinburgh, Scotland) Alterations in amino acid protein metabolism are a key feature of the cancer cachexia syndrome. These changes -induced by both hormonal changes (that affect insulin sensitivity) and inflammatory mediators- are present in skeletal muscle influencing both, amino acid uptake and protein synthesis. In addition, skeletal muscle protein turnover is characterized by an exacerbated rate of protein degradation, promoted by an activation of different proteolytic systems that include the ubiquitin-proteasome and the autophagic-lysosomal pathways. Changes in the rate of myogenesis/apoptosis also determine skeletal muscle mass during cancer cachexia. Indeed, a decreased skeletal muscle regeneration capacity is observed together with an increased rate of cell death, resulting in muscle wasting. Mitochondrial dysfunction also results in changes in skeletal muscle metabolism and further contributes to the exacerbation of the cancer-wasting syndrome. Different inflammatory mediators -either released by the tumor or by healthy cells of the cancer patient- are responsible for the activation of these catabolic processes that take place in skeletal muscle. 10.1016/j.clnu.2016.05.010
    Features of the bronchial bacterial microbiome associated with atopy, asthma, and responsiveness to inhaled corticosteroid treatment. Durack Juliana,Lynch Susan V,Nariya Snehal,Bhakta Nirav R,Beigelman Avraham,Castro Mario,Dyer Anne-Marie,Israel Elliot,Kraft Monica,Martin Richard J,Mauger David T,Rosenberg Sharon R,Sharp-King Tonya,White Steven R,Woodruff Prescott G,Avila Pedro C,Denlinger Loren C,Holguin Fernando,Lazarus Stephen C,Lugogo Njira,Moore Wendy C,Peters Stephen P,Que Loretta,Smith Lewis J,Sorkness Christine A,Wechsler Michael E,Wenzel Sally E,Boushey Homer A,Huang Yvonne J, The Journal of allergy and clinical immunology BACKGROUND:Compositional differences in the bronchial bacterial microbiota have been associated with asthma, but it remains unclear whether the findings are attributable to asthma, to aeroallergen sensitization, or to inhaled corticosteroid treatment. OBJECTIVES:We sought to compare the bronchial bacterial microbiota in adults with steroid-naive atopic asthma, subjects with atopy but no asthma, and nonatopic healthy control subjects and to determine relationships of the bronchial microbiota to phenotypic features of asthma. METHODS:Bacterial communities in protected bronchial brushings from 42 atopic asthmatic subjects, 21 subjects with atopy but no asthma, and 21 healthy control subjects were profiled by using 16S rRNA gene sequencing. Bacterial composition and community-level functions inferred from sequence profiles were analyzed for between-group differences. Associations with clinical and inflammatory variables were examined, including markers of type 2-related inflammation and change in airway hyperresponsiveness after 6 weeks of fluticasone treatment. RESULTS:The bronchial microbiome differed significantly among the 3 groups. Asthmatic subjects were uniquely enriched in members of the Haemophilus, Neisseria, Fusobacterium, and Porphyromonas species and the Sphingomonodaceae family and depleted in members of the Mogibacteriaceae family and Lactobacillales order. Asthma-associated differences in predicted bacterial functions included involvement of amino acid and short-chain fatty acid metabolism pathways. Subjects with type 2-high asthma harbored significantly lower bronchial bacterial burden. Distinct changes in specific microbiota members were seen after fluticasone treatment. Steroid responsiveness was linked to differences in baseline compositional and functional features of the bacterial microbiome. CONCLUSION:Even in subjects with mild steroid-naive asthma, differences in the bronchial microbiome are associated with immunologic and clinical features of the disease. The specific differences identified suggest possible microbiome targets for future approaches to asthma treatment or prevention. 10.1016/j.jaci.2016.08.055
    Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance. Gaggini Melania,Carli Fabrizia,Rosso Chiara,Buzzigoli Emma,Marietti Milena,Della Latta Veronica,Ciociaro Demetrio,Abate Maria Lorena,Gambino Roberto,Cassader Maurizio,Bugianesi Elisabetta,Gastaldelli Amalia Hepatology (Baltimore, Md.) Plasma concentrations of amino acids (AAs), in particular, branched chain AAs (BCAAs), are often found increased in nonalcoholic fatty liver disease (NAFLD); however, if this is due to increased muscular protein catabolism, obesity, and/or increased insulin resistance (IR) or impaired tissue metabolism is unknown. Thus, we evaluated a) if subjects with NAFLD without obesity (NAFLD-NO) compared to those with obesity (NAFLD-Ob) display altered plasma AAs compared to controls (CTs); and b) if AA concentrations are associated with IR and liver histology. Glutamic acid, serine, and glycine concentrations are known to be altered in NAFLD. Because these AAs are involved in glutathione synthesis, we hypothesized they might be related to the severity of NAFLD. We therefore measured the AA profile of 44 subjects with NAFLD without diabetes and who had a liver biopsy (29 NAFLD-NO and 15 NAFLD-Ob) and 20 CTs without obesity, by gas chromatography-mass spectrometry, homeostasis model assessment of insulin resistance, hepatic IR (Hep-IR; Hep-IR = endogenous glucose production × insulin), and the new glutamate-serine-glycine (GSG) index (glutamate/[serine + glycine]) and tested for an association with liver histology. Most AAs were increased only in NAFLD-Ob subjects. Only alanine, glutamate, isoleucine, and valine, but not leucine, were increased in NAFLD-NO subjects compared to CTs. Glutamate, tyrosine, and the GSG-index were correlated with Hep-IR. The GSG-index correlated with liver enzymes, in particular, gamma-glutamyltransferase (R = 0.70), independent of body mass index. Ballooning and/or inflammation at liver biopsy were associated with increased plasma BCAAs and aromatic AAs and were mildly associated with the GSG-index, while only the new GSG-index was able to discriminate fibrosis F3-4 from F0-2 in this cohort. CONCLUSION:Increased plasma AA concentrations were observed mainly in subjects with obesity and NAFLD, likely as a consequence of increased IR and protein catabolism. The GSG-index is a possible marker of severity of liver disease independent of body mass index. (Hepatology 2018;67:145-158). 10.1002/hep.29465
    Metabolic pathways at the crossroads of diabetes and inborn errors. Goetzman Eric S,Gong Zhenwei,Schiff Manuel,Wang Yan,Muzumdar Radhika H Journal of inherited metabolic disease Research over the past two decades has led to advances in our understanding of the genetic and metabolic factors that underlie the pathogenesis of type 2 diabetes mellitus (T2DM). While T2DM is defined by its hallmark metabolic symptoms, the genetic risk factors for T2DM are more immune-related than metabolism-related, and the observed metabolic disease may be secondary to chronic inflammation. Regardless, these metabolic changes are not benign, as the accumulation of some metabolic intermediates serves to further drive the inflammation and cell stress, eventually leading to insulin resistance and ultimately to T2DM. Because many of the biochemical changes observed in the pre-diabetic state (i.e., ectopic lipid storage, increased acylcarnitines, increased branched-chain amino acids) are also observed in patients with rare inborn errors of fatty acid and amino acid metabolism, an interesting question is raised regarding whether isolated metabolic gene defects can confer an increased risk for T2DM. In this review, we attempt to address this question by summarizing the literature regarding the metabolic pathways at the crossroads of diabetes and inborn errors of metabolism. Studies using cell culture and animal models have revealed that, within a given pathway, disrupting some genes can lead to insulin resistance while for others there may be no effect or even improved insulin sensitivity. This differential response to ablating a single metabolic gene appears to be dependent upon the specific metabolic intermediates that accumulate and whether these intermediates subsequently activate inflammatory pathways. This highlights the need for future studies to determine whether certain inborn errors may confer increased risk for diabetes as the patients age. 10.1007/s10545-017-0091-x
    Monocyte and macrophage immunometabolism in atherosclerosis. Groh Laszlo,Keating Samuel T,Joosten Leo A B,Netea Mihai G,Riksen Niels P Seminars in immunopathology Atherosclerosis is characterized by chronic low grade inflammation of arteries that results in the development of lipid dense plaques. Chronic inflammation induced by Western-type diet is associated with the risk of developing atherosclerosis, and new insights shed light on the importance of metabolic and functional reprogramming in monocytes and macrophages for progression of atherosclerosis. This review aims to provide an overview of our current understanding into how the metabolic reprogramming of glucose, cholesterol, fatty acid, and amino acid metabolism in macrophages contributes to inflammation during atherosclerosis. Recent insights suggest that transcriptional and epigenetic adaptation within innate immune cells (termed trained immunity) play an important role in the pathogenesis of atherosclerosis. We propose that metabolic changes induced by pro-atherogenic lipoproteins partly mediate these changes in trained macrophages. Finally, we discuss the possibility of manipulating cellular metabolism of immune cells for targeted therapeutic intervention against atherosclerosis. 10.1007/s00281-017-0656-7
    Angiotensin receptor blocker irbesartan reduces stress-induced intestinal inflammation via AT1a signaling and ACE2-dependent mechanism in mice. Yisireyili Maimaiti,Uchida Yasuhiro,Yamamoto Koji,Nakayama Takayuki,Cheng Xian Wu,Matsushita Tadashi,Nakamura Shigeo,Murohara Toyoaki,Takeshita Kyosuke Brain, behavior, and immunity Stress is associated with pathophysiology of both irritable bowel syndrome (IBS) and hypertension. Angiotensin receptor blockers (ARB) have anti-inflammatory properties via inhibition of angiotensin II (Ang II)/Ang II type I receptor axis (AT1). Inhibition of the classical RAS pathway is also involved in upregulation of angiotensin converting enzyme-2 (ACE2), which activates the Ang-(1-7)/Mas pathway to counteract inflammatory signaling and acts as a partner of the amino acid transporter, BAT-1, to absorb tryptophan for regulation of microbiota-gut-brain axis. In this study, we determined the effects of ARB irbesartan on stress-induced intestinal inflammation. C57BL/6J mice were subjected to 2-week intermittent restraint stress. They were orally treated during the stress with either vehicle, 3 or 10 mg/kg/day irbesartan. Restraint stress resulted in colon inflammation with higher histological damage scores, increased expression of Nox4, TLR-4 and IL1-β, accumulation of reactive oxygen species (ROS), and activation of the ACE-angiotensin II-AT1 receptor axis. Stress also downregulated intestinal amino acid transporter, ACE2/BAT-1, and activity of intestinal mammalian target of rapamycin (mTOR) and p70 S6 kinase (p70S6K), resulting in decrease in α-defensins, changes in intestinal microbial contents, and perturbation of tryptophan metabolism with activation of the kynurenine pathway. Administration of irbesartan inhibited activation of stress-induced AT1 pathway to reduce intestinal ROS accumulation and inflammation, restored expression of ACE2/BAT-1, activity of mTOR and p70S6K, dysbiosis and tryptophan metabolism. Our results suggest that AT1 is a potentially suitable therapeutic target in stress-induced intestinal inflammation, and that irbesartan could be beneficially suitable for the treatment of stressed patients with IBS. 10.1016/j.bbi.2017.11.010
    Hyperhomocysteinaemia and vascular injury: advances in mechanisms and drug targets. Fu Yi,Wang Xian,Kong Wei British journal of pharmacology Homocysteine is a sulphur-containing non-proteinogenic amino acid. Hyperhomocysteinaemia (HHcy), the pathogenic elevation of plasma homocysteine as a result of an imbalance of its metabolism, is an independent risk factor for various vascular diseases, such as atherosclerosis, hypertension, vascular calcification and aneurysm. Treatments aimed at lowering plasma homocysteine via dietary supplementation with folic acids and vitamin B are more effective in preventing vascular disease where the population has a normally low folate consumption than in areas with higher dietary folate. To date, the mechanisms of HHcy-induced vascular injury are not fully understood. HHcy increases oxidative stress and its downstream signalling pathways, resulting in vascular inflammation. HHcy also causes vascular injury via endoplasmic reticulum stress. Moreover, HHcy up-regulates pathogenic genes and down-regulates protective genes via DNA demethylation and methylation respectively. Homocysteinylation of proteins induced by homocysteine also contributes to vascular injury by modulating intracellular redox state and altering protein function. Furthermore, HHcy-induced vascular injury leads to neuronal damage and disease. Also, an HHcy-activated sympathetic system and HHcy-injured adipose tissue also cause vascular injury, thus demonstrating the interactions between the organs injured by HHcy. Here, we have summarized the recent developments in the mechanisms of HHcy-induced vascular injury, which are further considered as potential therapeutic targets in this condition. LINKED ARTICLES:This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc. 10.1111/bph.13988
    Chronic Mild Hyperhomocysteinemia Alters Inflammatory and Oxidative/Nitrative Status and Causes Protein/DNA Damage, as well as Ultrastructural Changes in Cerebral Cortex: Is Acetylsalicylic Acid Neuroprotective? de S Moreira Daniella,Figueiró Paula W,Siebert Cassiana,Prezzi Caroline A,Rohden Francieli,Guma Fatima C R,Manfredini Vanusa,Wyse Angela T S Neurotoxicity research Homocysteine is a sulfur-containing amino acid derived from methionine metabolism. When plasma homocysteine levels exceed 10-15 μM, there is a condition known as hyperhomocysteinemia, which occur as a result of an inborn error of methionine metabolism or by non-genetic causes. Mild hyperhomocysteinemia is considered a risk factor for development of neurodegenerative diseases. The objective of the present study was to evaluate whether acetylsalicylic acid has neuroprotective role on the effect of homocysteine on inflammatory, oxidative/nitrative stress, and morphological parameters in cerebral cortex of rats subjected to chronic mild hyperhomocysteinemia. Wistar male rats received homocysteine (0.03 μmol/g of body weight) by subcutaneous injections twice a day and acetylsalicylic acid (25 mg/Kg of body weight) by intraperitoneal injections once a day from the 30th to the 60th postpartum day. Control rats received vehicle solution in the same volume. Results showed that rats subjected to chronic mild hyperhomocysteinemia significantly increased IL-1β, IL-6, and acetylcholinesterase activity and reduced nitrite levels. Homocysteine decreased catalase activity and immunocontent and superoxide dismutase activity, caused protein and DNA damage, and altered neurons ultrastructure. Acetylsalicylic acid totally prevented the effect of homocysteine on acetylcholinesterase activity and catalase activity and immunocontent, as well as the ultrastructural changes, and partially prevented alterations on IL-1β levels, superoxide dismutase activity, sulfhydryl content, and comet assay. Acetylsalicylic acid per se increased DNA damage index. In summary, our findings showed that chronic chemically induced model of mild hyperhomocysteinemia altered some parameters and acetylsalicylic acid administration seemed to be neuroprotective, at least in part, on neurotoxicity of homocysteine. 10.1007/s12640-017-9847-1
    NADPH metabolism: a survey of its theoretical characteristics and manipulation strategies in amino acid biosynthesis. Xu Jian-Zhong,Yang Han-Kun,Zhang Wei-Guo Critical reviews in biotechnology Reduced nicotinamide adenine nucleotide phosphate (NADPH), which is one of the key cofactors in the metabolic network, plays an important role in the biochemical reactions, and physiological function of amino acid-producing strains. The manipulation of NADPH availability and form is an efficient and easy method of redirecting the carbon flux to the amino acid biosynthesis in industrial strains. In this review, we survey the metabolic mode of NADPH. Furthermore, we summarize the research developments in the understanding of the relationship between NADPH metabolism and amino acid biosynthesis. Detailed strategies to manipulate NADPH availability are addressed based on this knowledge. Finally, the uses of NADPH manipulation strategies to enhance the metabolic function of amino acid-producing strains are discussed. 10.1080/07388551.2018.1437387
    Perturbations in amino acids and metabolic pathways in osteoarthritis patients determined by targeted metabolomics analysis. Chen Rui,Han Su,Liu Xuefeng,Wang Kunpeng,Zhou Yong,Yang Chundong,Zhang Xi Journal of chromatography. B, Analytical technologies in the biomedical and life sciences Osteoarthritis (OA) is a degenerative synovial joint disease affecting people worldwide. However, the exact pathogenesis of OA remains unclear. Metabolomics analysis was performed to obtain insight into possible pathogenic mechanisms and diagnostic biomarkers of OA. Ultra-high performance liquid chromatography-triple quadrupole mass spectrometry (UPLC-TQ-MS), followed by multivariate statistical analysis, was used to determine the serum amino acid profiles of 32 OA patients and 35 healthy controls. Variable importance for project values and Student's t-test were used to determine the metabolic abnormalities in OA. Another 30 OA patients were used as independent samples to validate the alterations in amino acids. MetaboAnalyst was used to identify the key amino acid pathways and construct metabolic networks describing their relationships. A total of 25 amino acids and four biogenic amines were detected by UPLC-TQ-MS. Differences in amino acid profiles were found between the healthy controls and OA patients. Alanine, γ-aminobutyric acid and 4-hydroxy-l-proline were important biomarkers distinguishing OA patients from healthy controls. The metabolic pathways with the most significant effects were involved in metabolism of alanine, aspartate, glutamate, arginine and proline. The results of this study improve understanding of the amino acid metabolic abnormalities and pathogenic mechanisms of OA at the molecular level. The metabolic perturbations may be important for the diagnosis and prevention of OA. 10.1016/j.jchromb.2018.03.047
    Amino acid metabolism in hematologic malignancies and the era of targeted therapy. Tabe Yoko,Lorenzi Philip L,Konopleva Marina Blood Tumor cells rewire metabolic pathways to adapt to their increased nutritional demands for energy, reducing equivalents, and cellular biosynthesis. Alternations in amino acid metabolism are 1 modality for satisfying those demands. Amino acids are not only components of proteins but also intermediate metabolites fueling multiple biosynthetic pathways. Amino acid-depletion therapies target amino acid uptake and catabolism using heterologous enzymes or recombinant or engineered human enzymes. Notably, such therapies have minimal effect on normal cells due to their lower demand for amino acids compared with tumor cells and their ability to synthesize the targeted amino acids under conditions of nutrient stress. Here, we review novel aspects of amino acid metabolism in hematologic malignancies and deprivation strategies, focusing on 4 key amino acids: arginine, asparagine, glutamine, and cysteine. We also present the roles of amino acid metabolism in the immunosuppressive tumor microenvironment and in drug resistance. This summary also offers an argument for the reclassification of amino acid-depleting enzymes as targeted therapeutic agents. 10.1182/blood.2019001034