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This article discusses a study that used nontargeted metabolomics and machine learning to identify potential biomarkers for cardiovascular diseases (CVD), specifically coronary heart disease (CHD) and myocardial infarction (MI). The study analyzed serum samples from a Chinese cohort of patients with CHD, MI, and controls, and identified differential metabolites that could distinguish between the groups. The researchers also conducted pathway enrichment analysis to explore the metabolic pathways involved in CHD and MI progression. They developed a model based on three metabolites (arginine, hypoxanthine, and acetylcarnitine) that could discriminate between CHD and MI with high accuracy. The study suggests that metabolomics and machine learning have the potential to improve the diagnosis of CHD and MI. [Extracted from the article]

Objective: The objective of this study was to discover differential metabolites and pathways underlying infrequent gout flares (InGF) and frequent gout flares (FrGF) using metabolomics and to establish a predictive model by machine learning (ML) algorithms. Methods: Serum samples from a discovery cohort of 163 patients with InGF and 239 patients with FrGF were analyzed by mass spectrometry–based untargeted metabolomics to profile differential metabolites and explore dysregulated metabolic pathways using pathway enrichment analysis and network propagation–based algorithms. ML algorithms were performed to establish a predictive model based on selected metabolites, which was further optimized by a quantitative targeted metabolomics method and validated in an independent validation cohort with 97 participants with InGF and 139 participants with FrGF. Results: A total of 439 differential metabolites between InGF and FrGF groups were identified. Top dysregulated pathways included carbohydrates, amino acids, bile acids, and nucleotide metabolism. Subnetworks with maximum disturbances in the global metabolic networks featured cross‐talk between purine metabolism and caffeine metabolism, as well as interactions among pathways involving primary bile acid biosynthesis, taurine and hypotaurine metabolism, alanine, aspartate, and glutamate metabolism, suggesting epigenetic modifications and gut microbiome in metabolic alterations underlying InGF and FrGF. Potential metabolite biomarkers were identified using ML‐based multivariable selection and further validated by targeted metabolomics. Area under receiver operating characteristics curve for differentiating InGF and FrGF achieved 0.88 and 0.67 for the discovery and validation cohorts, respectively. Conclusion: Systematic metabolic alterations underlie InGF and FrGF, and distinct profiles are associated with differences in gout flare frequencies. Predictive modeling based on selected metabolites from metabolomics can differentiate InGF and FrGF. [ABSTRACT FROM AUTHOR]

Obesity is associated with metabolic disorders and chronic inflammation. However, the obesity‐associated metabolic contribution to inflammatory induction remains elusive. Here, we show that, compared with lean mice, CD4+ T cells from obese mice exhibit elevated basal levels of fatty acid β‐oxidation (FAO), which promote T cell glycolysis and thus hyperactivation, leading to enhanced induction of inflammation. Mechanistically, the FAO rate‐limiting enzyme carnitine palmitoyltransferase 1a (Cpt1a) stabilizes the mitochondrial E3 ubiquitin ligase Goliath, which mediates deubiquitination of calcineurin and thus enhances activation of NF‐AT signaling, thereby promoting glycolysis and hyperactivation of CD4+ T cells in obesity. We also report the specific GOLIATH inhibitor DC‐Gonib32, which blocks this FAO‐glycolysis metabolic axis in CD4+ T cells of obese mice and reduces the induction of inflammation. Overall, these findings establish a role of a Goliath‐bridged FAO‐glycolysis axis in mediating CD4+ T cell hyperactivation and thus inflammation in obese mice. Synopsis: The mitochondrial E3 ubiquitin ligase Goliath links fatty acid β‐oxidation (FAO) to glycolysis and mediates CD4+ T cell hyperactivation and inflammation in obese mice. A FAO‐glycolysis metabolic axis in CD4+ T cells promotes inflammation in obese mice.The FAO rate‐limiting enzyme Cpt1a stabilizes Goliath in mitochondria.Obesity‐upregulated Goliath links levels of FAO to the glycolytic rate in CD4+ T cells.A GOLIATH inhibitor curtails obesity‐related inflammation by blocking the FAO‐glycolysis axis. [ABSTRACT FROM AUTHOR]

Objective: To systematically profile metabolic alterations and dysregulated metabolic pathways in hyperuricemia and gout, and to identify potential metabolite biomarkers to discriminate gout from asymptomatic hyperuricemia. Methods: Serum samples from 330 participants, including 109 with gout, 102 with asymptomatic hyperuricemia, and 119 normouricemic controls, were analyzed by high‐resolution mass spectrometry–based metabolomics. Multivariate principal components analysis and orthogonal partial least squares discriminant analysis were performed to explore differential metabolites and pathways. A multivariate methods with Unbiased Variable selection in R (MUVR) algorithm was performed to identify potential biomarkers and build multivariate diagnostic models using 3 machine learning algorithms: random forest, support vector machine, and logistic regression. Results: Univariate analysis demonstrated that there was a greater difference between the metabolic profiles of patients with gout and normouricemic controls than between the metabolic profiles of individuals with hyperuricemia and normouricemic controls, while gout and hyperuricemia showed clear metabolomic differences. Pathway enrichment analysis found diverse significantly dysregulated pathways in individuals with hyperuricemia and patients with gout compared to normouricemic controls, among which arginine metabolism appeared to play a critical role. The multivariate diagnostic model using MUVR found 13 metabolites as potential biomarkers to differentiate hyperuricemia and gout from normouricemia. Two‐thirds of the samples were randomly selected as a training set, and the remainder were used as a validation set. Receiver operating characteristic analysis of 7 metabolites yielded an area under the curve of 0.83–0.87 in the training set and 0.78–0.84 in the validation set for distinguishing gout from asymptomatic hyperuricemia by 3 machine learning algorithms. Conclusion: Gout and hyperuricemia have distinct serum metabolomic signatures. This diagnostic model has the potential to improve current gout care through early detection or prediction of progression to gout from hyperuricemia. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Here, we identified that increased miR‐23a expression in HCC tissues was associated with worse survival. More importantly, we found that STAT5A was a target of miR‐23a, whose levels significantly decreased in tumor tissues. Stable expression of STAT5A in Huh7 cells suppressed glucose metabolism and tumor growth. Finally, this study showed that increased miR‐23a negatively regulated STAT5A, which further activated AKT signaling to enable rapid metabolism for accelerated tumor growth in HCC. Taken together, our results demonstrated that the miR‐23a‐STAT5A‐AKT signaling pathway is critical to alter glucose metabolism in HCC and may offer new opportunities for effective therapy. [ABSTRACT FROM AUTHOR]

A series of benzotriazole (BTA) derivatives were synthesized as tyrosine protein kinase inhibitors using fragment‐based design strategy. All desired compounds were synthesized with the reaction of benzotriazole, chloroacetonitrile and aromatic aldehyde using Ultrasonic‐Microwave method and characterized by IR, 1H and 13C‐NMR, mass spectrometry (MS) and elemental analysis. The anticancer activity of these compounds was evaluated by CCK‐8 method against carcinoma VX2, lung cancer A549, stomach cancer cell lines MKN45 and MGC in vitro. The results showed that all compounds showed good antiproliferative activity. In particular, compound 2.1 showed the most prominent inhibition of VX2 cell lines with IC50 of 3.80 ± 0.75 μM. Compound 2.2 exhibited highly potent anticancer activity of stomach MGC cell lines with IC50 of 3.72 ± 0.11 μM. A549 and MKN45 cell lines were sensitive to compound 2.5 with IC50 of 5.47 ± 1.11 and 3.04 ± 0.02 μM, respectively. [ABSTRACT FROM AUTHOR]

Abstract: The metabolism of polyunsaturated fatty acids (PUFAs) remains poorly characterized in ovarian tissues of patients with polycystic ovary syndrome (PCOS). This study aimed to explore alterations in the levels of PUFAs and their metabolites in serum and ovarian tissues in a PCOS rat model treated with a high‐fat diet and andronate. Levels of PUFAs and their metabolites were measured using gas/liquid chromatography‐mass spectrometry after the establishment of a PCOS rat model. Only 3 kinds of PUFAs [linoleic acid, arachidonic acid (AA) and docosahexaenoic acid] were detected in both the circulation and ovarian tissues of the rats, and their concentrations were lower in ovarian tissues than in serum. Moreover, significant differences in the ovarian levels of AA were observed between control, high‐fat diet‐fed and PCOS rats. The levels of prostaglandins, AA metabolites via the cyclooxygenase (COX) pathway, in ovarian tissues of the PCOS group were significantly increased compared to those in the controls. Further studies on the mechanism underlying this phenomenon showed a correlation between decreased expression of phosphorylated cytosolic phospholipase A2 (p‐cPLA2) and increased mRNA and protein expression of COX2, potentially leading to a deeper understanding of altered AA and prostaglandin levels in ovarian tissues of PCOS rats. [ABSTRACT FROM AUTHOR]

Background and Purpose: An appropriate inflammatory response is necessary for cardiac healing after acute myocardial infarction (MI). Resolvin E1 (RvE1) is an anti-inflammatory and pro-resolution lipid mediator derived from eicosapentaenoic acid. Here we have investigated the effects of RvE1 on the recovery of cardiac function after MI in mice.Experimental Approach: Acute MI was induced by surgical ligation of the left anterior descending artery in male C57BL/6 mice. RvE1 (5 ng·g-1 ·day-1 ; i.p.) was given to mice at different times following MI. Cardiac function was monitored by transthoracic echocardiography at days 3, 7 and 14 after MI. Effects of RvE1 on the migration of subpopulations of monocytes/macrophages (Mos/Mps, Ly6Chi and Ly6Clow ) were examined by flow cytometry and transwell assay.Key Results: RvE1 administration from days 1 to 7 post-MI improved cardiac function, whereas treatment from days 7 to 14 markedly inhibited recovery of cardiac function. Early treatment with RvE1 post-MI suppressed the infiltration of dominant Ly6Chi Mos/Mps and secretion of pro-inflammatory cytokines in injured hearts, which protected cardiomyocytes against apoptosis in the peri-infarct zones. Contrastingly, treatment with RvE1 1 week after MI decreased infiltration of Ly6Clow Mos/Mps and expression of pro-angiogenic factors in cardiac tissue, consequently reducing neovascularization in the peri-infarct zones. Additionally, RvE1 inhibited Mp migration by activating ChemR23 receptors.Conclusion and Implications: Treatment with RvE1 during the initial 7 days after MI facilitated cardiac healing by suppressing pro-inflammatory cytokine secretion, indicating that RvE1 may serve as an early therapeutic agent for acute MI.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. [ABSTRACT FROM AUTHOR]

Background and Purpose: Although aspirin (acetylsalicylic acid) is commonly used to prevent ischaemic events in patients with coronary artery disease, many patients fail to respond to aspirin treatment. Dietary fish oil (FO), containing ω3 polyunsaturated fatty acids (PUFAs), has anti-inflammatory and cardio-protective properties, such as lowering cholesterol and modulating platelet activity. The objective of the present study was to investigate the potential additional effects of aspirin and FO on platelet activity and vascular response to injury.Experimental Approach: Femoral arterial remodelling was induced by wire injury in mice. Platelet aggregation, and photochemical- and ferric chloride-induced carotid artery thrombosis were employed to evaluate platelet function.Key Results: FO treatment increased membrane ω3 PUFA incorporation, lowered plasma triglyceride and cholesterol levels, and reduced systolic BP in mice. FO or aspirin alone inhibited platelet aggregation; however, when combined, they exhibited synergistic suppression of platelet activity in mice, independent of COX-1 inhibition. FO alone, but not aspirin, attenuated arterial neointimal growth in response to injury. Strikingly, a combination of FO and aspirin synergistically inhibited injury-induced neointimal hyperplasia and reduced perivascular inflammatory reactions. Moreover, co-administration of FO and aspirin decreased the expression of pro-inflammatory cytokines and adhesion molecules in inflammatory cells. Consistently, a pro-resolution lipid mediator-Resolvin E1, was significantly elevated in plasma in FO/aspirin-treated mice.Conclusions and Implications: Co-administration of FO and low-dose aspirin may act synergistically to protect against thrombosis and injury-induced vascular remodelling in mice. Our results support further investigation of adjuvant FO supplementation for patients with stable coronary artery disease. [ABSTRACT FROM AUTHOR]

Polyunsaturated fatty acids ( PUFAs) exert immunosuppressive effects that could prove beneficial in clinical therapies for certain autoimmune and inflammatory disorders. However, the mechanism of PUFA-mediated immunosuppression is far from understood. Here, we provide evidence that PUFAs enhance the accumulation of myeloid-derived suppressor cells ( MDSCs), a negative immune regulator. PUFA-induced MDSCs have a more potent suppressive effect on T-cell responses than do control MDSCs. These observations were found both in cultured mouse bone marrow cells in vitro and in vivo in mice fed diets enriched in PUFAs. The enhanced suppressive activity of MDSCs by PUFAs administration was coupled with a dramatic induction of nicotinamide adenine dinucleo- tide phosphate oxidase subunit p47phox and was dependent on reactive oxygen species ( ROS) production. Mechanistic studies revealed that PUFAs mediate its effects through JAK- STAT3 signaling. Inhibition of STAT3 phosphorylation by JAK inhibitor JSI-124 almost completely abrogated the effects of PUFAs on MDSCs. Moreover, the effects of PUFAs on MDSCs and the underlying mechanisms were confirmed in tumor-bearing mice. In summary, this study sheds new light on the immune modulatory role of PUFAs, and demonstrates that MDSCs expansion may mediate the effects of PUFAs on the immune system. [ABSTRACT FROM AUTHOR]

The cytotoxic aldehydes 4-hydroxynonenal, 4-hydroperoxynonenal (4-HPNE), and 4-oxononenal are formed during lipid peroxidation via oxidative transformation of the hydroxy or hydroperoxy precursor fatty acids, respectively. The mechanism of the carbon chain cleavage reaction leading to the aldehyde fragments is not known, but Hock-cleavage of a suitable dihydroperoxide derivative was implicated to account for the fragmentation [Schneider, C., Tallman, K.A., Porter, N.A., and Brash, A.R. (2001) Two Distinct Pathways of Formation of 4-Hydroxynonenal. Mechanisms of Nonenzymatic Transformation of the 9- and 13-Hydroperoxides of Linoleic Acid to 4-Hydroxyalkenals, J. Biol. Chem. 275, 20831–20838]. Both 8,13- and 10,13-dihydroperoxyoctadecadienoic acids (diHPODE) could serve as precursors in a Hock-cleavage leading to 4-HPNE via two different pathways. Here, we synthesized diastereomeric 9,12-, 10,12-, and 10,13-diHPODE using singlet oxidation of linoleic acid. 8,13-Dihydroperoxyoctadecatrienoic acid was synthesized by vitamin E-controlled autoxidation of γ-linolenic acid followed by reaction with soybean lipoxygenase. The transformation of these potential precursors to 4-HPNE was studied under conditions of autoxidation, hematin-, and acid-catalysis. In contrast to 9- or 13-HPODE, neither of the dihydroperoxides formed 4-HPNE on autoxidation (lipid film, 37°C), regardless of whether the free acid or the methyl ester derivative was used. Acid treatment of 10,13-diHPODE led to the expected formation of 4-HPNE as a significant product, in accord with a Hock-type cleavage reaction. We conclude that, although the suppression of 4-H(P)NE formation from monohydroperoxides by α-tocopherol indicates peroxyl radical reactions in the major route of carbon chain cleavage, the dihydroperoxides previously implicated are not intermediates in the autoxidative transformation of monohydroperoxy fatty acids to 4-HPNE and related aldehydes. [ABSTRACT FROM AUTHOR]

Isoprostanes (IsoPs), lipid peroxidation products formed via the free radical-mediated oxidation of arachidonic acid, have become the “gold standard” biomarker of oxidative stress in vivo over the past 15 yr. Significant advances have been made in understanding this important pathway of lipid peroxidation. Recent studies from our laboratory are discussed that have provided insights into the mechanism of formation and regioisomeric distribution of these compounds and that have identified novel products of the IsoP pathway such as cyclized dioxolane IsoPs, IsoP-derived racemic prostaglandins, and reactive cyclopentenone IsoP, the latter of which possess potent biological actions. Furthermore, new independent studies have demonstrated that IsoPs are the most reliable available marker of lipid peroxidation in vivo, and recent work examining IsoP formation has provided valuable infromation about the pathogenesis of numerous human diseases. Thus, the complexity of the IsoP pathway has expanded, providing novel insights into mechanisms of lipid peroxidation in vivo and allowing investigators to explore the role of oxidative stress in human disease. [ABSTRACT FROM AUTHOR]

Niacin, as an antidyslipidemic drug, elicits a strong flushing response by release of prostaglandin (PG) D 2 However, whether niacin is beneficial for inflammatory bowel disease (IBD) remains unclear. Here, we observed niacin administration-enhanced PGD 2 production in colon tissues in dextran sulfate sodium (DSS)-challenged mice, and protected mice against DSS or 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in D prostanoid receptor 1 (DP1)-dependent manner. Specific ablation of DP1 receptor in vascular endothelial cells, colonic epithelium, and myeloid cells augmented DSS/TNBS-induced colitis in mice through increasing vascular permeability, promoting apoptosis of epithelial cells, and stimulating pro-inflammatory cytokine secretion of macrophages, respectively. Niacin treatment improved vascular permeability, reduced apoptotic epithelial cells, promoted epithelial cell update, and suppressed pro-inflammatory gene expression of macrophages. Moreover, treatment with niacin-containing retention enema effectively promoted UC clinical remission and mucosal healing in patients with moderately active disease. Therefore, niacin displayed multiple beneficial effects on DSS/TNBS-induced colitis in mice by activation of PGD 2 /DP1 axis. The potential efficacy of niacin in management of IBD warrants further investigation., (© 2017 The Authors. Published under the terms of the CC BY 4.0 license.)