PubMed

Related Articles Elevated O-GlcNAcylation enhances pro-inflammatory Th17 function by altering the intracellular lipid microenvironment. J Biol Chem. 2019 05 31;294(22):8973-8990 Authors: Machacek M, Saunders H, Zhang Z, Tan EP, Li J, Li T, Villar MT, Artigues A, Lydic T, Cork G, Slawson C, Fields PE Abstract Chronic, low-grade inflammation increases the risk for atherosclerosis, cancer, and autoimmunity in diseases such as obesity and diabetes. Levels of CD4+ T helper 17 (Th17) cells, which secrete interleukin 17A (IL-17A), are increased in obesity and contribute to the inflammatory milieu; however, the relationship between signaling events triggered by excess nutrient levels and IL-17A-mediated inflammation is unclear. Here, using cytokine, quantitative real-time PCR, immunoprecipitation, and ChIP assays, along with lipidomics and MS-based approaches, we show that increased levels of the nutrient-responsive, post-translational protein modification, O-GlcNAc, are present in naive CD4+ T cells from a diet-induced obesity murine model and that elevated O-GlcNAc levels increase IL-17A production. We also found that increased binding of the Th17 master transcription factor RAR-related orphan receptor γ t variant (RORγt) at the IL-17 gene promoter and enhancer, as well as significant alterations in the intracellular lipid microenvironment, elevates the production of ligands capable of increasing RORγt transcriptional activity. Importantly, the rate-limiting enzyme of fatty acid biosynthesis, acetyl-CoA carboxylase 1 (ACC1), is O-GlcNAcylated and necessary for production of these RORγt-activating ligands. Our results suggest that increased O-GlcNAcylation of cellular proteins may be a potential link between excess nutrient levels and pathological inflammation. PMID: 31010828 [PubMed - indexed for MEDLINE]

27 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2020/02/18PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Metabolism and Effects on Endogenous Metabolism of Paracetamol (Acetaminophen) in a Porcine Model of Liver Failure. Toxicol Sci. 2020 Feb 15;: Authors: Dargue R, Zia R, Lau C, Nicholls AW, Dare TO, Lee K, Jalan R, Coen M, Wilson ID Abstract The metabolic fate, toxicity and effects on endogenous metabolism of paracetamol (acetaminophen, APAP) in 22 female Landrace cross large white pigs were evaluated in a model of acute liver failure (ALF). Anaesthetized pigs were initially dosed at 250 mg/kg via an oroduodenal tube with APAP serum concentrations maintained above 300 mg/L using maintenance doses of 0.5-4g/h until ALF. Studies were undertaken to determine both the metabolic fate of APAP and its effects on the endogenous metabolic phenotype of ALF in using 1H NMR spectroscopy. Increased concentrations of citrate combined with pre-ALF increases in circulating lactate, pyruvate and alanine in plasma suggest mitochondrial dysfunction and a switch in hepatic energy metabolism to glycolysis in response to APAP treatment. A specific liquid chromatography-tandem mass spectrometry assay was used to quantify APAP and metabolites. The major circulating and urinary metabolite of APAP was the phenolic glucuronide (APAP-G), followed by p-aminophenol glucuronide (PAP-G) formed from N-deacetylated APAP. The PAP produced by N-deacetylation was the likely cause of the methaemoglobinemia and kidney toxicity observed in this, and previous, studies in the pig. The phenolic sulfate of APAP, and the glutathione-derived metabolites of the drug were only found as minor components (with the cysteinyl conjugate detected but not the mercapturate). Given its low sulfation, combined with significant capacity for N-deacetylation the pig may represent a poor translational model for toxicology studies for compounds undergoing significant metabolism by sulfation, or which contain amide bonds which when hydrolysed to unmask an aniline lead to toxicity. However, the pig may provide a useful model where extensive amide hydrolysis is seen for drugs or environmental chemicals in humans, but not in e.g., the rat and dog which are the pre-clinical species normally employed for safety assessment. PMID: 32061126 [PubMed - as supplied by publisher]

Related Articles Inhibition of human CYP1 enzymes by a classical inhibitor α-naphthoflavone and a novel inhibitor N-(3, 5- dichlorophenyl)cyclopropanecarboxamide - an in vitro and in silico study. Chem Biol Drug Des. 2020 Feb 14;: Authors: Juvonen RO, Jokinen EM, Javaid A, Lehtonen M, Raunio H, Pentikäinen OT Abstract Enzymes in the cytochrome P450 family 1 (CYP1) catalyze metabolic activation of procarcinogens and deactivation of certain anticancer drugs. Inhibition of these enzymes is a potential approach for cancer chemoprevention and treatment of CYP1-mediated drug resistance. We characterized inhibition of human CYP1A1, CYP1A2 and CYP1B1 enzymes by the novel inhibitor N-(3,5-dichlorophenyl) cyclopropanecarboxamide (DCPCC) and α-naphthoflavone (ANF). Depending on substrate, IC50 values of DCPCC for CYP1A1 or CYP1B1 were 10-95 times higher than for CYP1A2. IC50 of DCPCC for CYP1A2 was 100-fold lower than for enzymes in CYP2 and CYP3 families. DCPCC IC50 values were 10-680 times higher than the ones of ANF. DCPCC was a mixed type inhibitor of CYP1A2. ANF was a competitive tight-binding inhibitor of CYP1A1, CYP1A2 and CYP1B1. CYP1A1 oxidized DCPCC more rapidly than CYP1A2 or CYP1B1 to the same metabolite. Molecular dynamics simulations and binding free energy calculations explained the differences of binding of DCPCC and ANF to the active sites of all three CYP1 enzymes. We conclude that DCPCC is a more selective inhibitor for CYP1A2 than ANF. DCPCC is a candidate structure to modulate CYP1A2 mediated metabolism of procarcinogens and anticancer drugs. PMID: 32060993 [PubMed - as supplied by publisher]

Related Articles Targeted Metabolomics Analysis Reveals that Dietary Supranutritional Selenium Regulates Sugar and Acylcarnitine Metabolism Homeostasis in Pig Liver. J Nutr. 2020 Feb 14;: Authors: Zhang K, Han Y, Zhao Q, Zhan T, Li Y, Sun W, Li S, Sun D, Si X, Yu X, Qin Y, Tang C, Zhang J Abstract BACKGROUND: The association between high selenium (Se) intake and metabolic disorders such as type 2 diabetes has raised great concern, but the underlying mechanism remains unclear. OBJECTIVE: Through targeted metabolomics analysis, we examined the liver sugar and acylcarnitine metabolism responses to supranutritional selenomethionine (SeMet) supplementation in pigs. METHODS: Thirty-six castrated male pigs (Duroc-Landrace-Yorkshire, 62.0 ± 3.3 kg) were fed SeMet adequate (Se-A, 0.25 mg Se/kg) or SeMet supranutritional (Se-S, 2.5 mg Se/kg) diets for 60 d. The Se concentration, biochemical, gene expression, enzyme activity, and energy-targeted metabolite profiles were analyzed. RESULTS: The Se-S group had greater fasting serum concentrations of glucose (1.9-fold), insulin (1.4-fold), and free fatty acids (FFAs,1.3-fold) relative to the Se-A group (P < 0.05). The liver total Se concentration was 4.2-fold that of the Se-A group in the Se-S group (P < 0.05), but expression of most selenoprotein genes and selenoenzyme activity did not differ between the 2 groups. Seven of 27 targeted sugar metabolites and 4 of 21 acylcarnitine metabolites significantly changed in response to high SeMet (P < 0.05). High SeMet supplementation significantly upregulated phosphoenolpyruvate carboxy kinase (PEPCK) activity by 64.4% and decreased hexokinase and succinate dehydrogenase (SDH) activity by 46.5-56.7% (P < 0.05). The relative contents of glucose, dihydroxyacetone phosphate, α-ketoglutarate, fumarate, malate, erythrose-4-phosphate, and sedoheptulose-7-phosphate in the Se-S group were 21.1-360% greater than those in the Se-A group (P < 0.05). The expression of fatty acid synthase (FASN) and the relative contents of carnitine, hexanoyl-carnitine, decanoyl-carnitine, and tetradecanoyl-carnitine in the Se-S group were 35-97% higher than those in the Se-A group (P < 0.05). CONCLUSIONS: Dietary high SeMet-induced hyperglycemia and hyperinsulinemia were associated with suppression of sugar metabolism and elevation of lipid synthesis in pig livers. Our research provides novel insights into high SeMet intake-induced type 2 diabetes. PMID: 32060554 [PubMed - as supplied by publisher]

Related Articles Glycolysis/gluconeogenesis- and tricarboxylic acid cycle-related metabolites, Mediterranean diet, and type 2 diabetes. Am J Clin Nutr. 2020 Feb 14;: Authors: Guasch-Ferré M, Santos JL, Martínez-González MA, Clish CB, Razquin C, Wang D, Liang L, Li J, Dennis C, Corella D, Muñoz-Bravo C, Romaguera D, Estruch R, Santos-Lozano JM, Castañer O, Alonso-Gómez A, Serra-Majem L, Ros E, Canudas S, Asensio EM, Fitó M, Pierce K, Martínez JA, Salas-Salvadó J, Toledo E, Hu FB, Ruiz-Canela M Abstract BACKGROUND: Glycolysis/gluconeogenesis and tricarboxylic acid (TCA) cycle metabolites have been associated with type 2 diabetes (T2D). However, the associations of these metabolites with T2D incidence and the potential effect of dietary interventions remain unclear. OBJECTIVES: We aimed to evaluate the association of baseline and 1-y changes in glycolysis/gluconeogenesis and TCA cycle metabolites with insulin resistance and T2D incidence, and the potential modifying effect of Mediterranean diet (MedDiet) interventions. METHODS: We included 251 incident T2D cases and 638 noncases in a nested case-cohort study within the PREDIMED Study during median follow-up of 3.8 y. Participants were allocated to MedDiet + extra-virgin olive oil, MedDiet + nuts, or control diet. Plasma metabolites were measured using a targeted approach by LC-tandem MS. We tested the associations of baseline and 1-y changes in glycolysis/gluconeogenesis and TCA cycle metabolites with subsequent T2D risk using weighted Cox regression models and adjusting for potential confounders. We designed a weighted score combining all these metabolites and applying the leave-one-out cross-validation approach. RESULTS: Baseline circulating concentrations of hexose monophosphate, pyruvate, lactate, alanine, glycerol-3 phosphate, and isocitrate were significantly associated with higher T2D risk (17-44% higher risk for each 1-SD increment). The weighted score including all metabolites was associated with a 30% (95% CI: 1.12, 1.51) higher relative risk of T2D for each 1-SD increment. Baseline lactate and alanine were associated with baseline and 1-y changes of homeostasis model assessment of insulin resistance. One-year increases in most metabolites and in the weighted score were associated with higher relative risk of T2D after 1 y of follow-up. Lower risks were observed in the MedDiet groups than in the control group although no significant interactions were found after adjusting for multiple comparisons. CONCLUSIONS: We identified a panel of glycolysis/gluconeogenesis-related metabolites that was significantly associated with T2D risk in a Mediterranean population at high cardiovascular disease risk. A MedDiet could counteract the detrimental effects of these metabolites.This trial was registered at controlled-trials.com as ISRCTN35739639. PMID: 32060497 [PubMed - as supplied by publisher]

Related Articles Genomic determinants of hypertension with a focus on metabolomics and the gut microbiome. Am J Hypertens. 2020 Feb 15;: Authors: Louca P, Menni C, Padmanabhan S Abstract Epidemiologic and genomic studies have progressively improved our understanding of the causation of hypertension and the complex relationship with diet and environment. The majority of mendelian forms of syndromic hypotension and HTN have all been linked to mutations in genes whose encoded proteins regulate salt-water balance in the kidney, supporting the primacy of the kidneys in BP regulation. There are over 1,477 single nucleotide polymorphisms associated with blood pressure and hypertension and the challenge is establishing a causal role for these variants. Hypertension is a complex multifactorial phenotype and it is likely to be influenced by multiple factors including interactions between diet and lifestyle factors, microbiome and epigenetics. Given the finite genetic variability that is possible in humans, it is likely that incremental gains from single marker analyses have now plateaued and a greater leap in our understanding of the genetic basis of disease will come from integration of other omics and the interacting environmental factors. In this review, we focus on emerging results from the microbiome and metabolomics and discuss how leveraging these findings may facilitate a deeper understanding of the interrelationships between genomics, diet and microbial ecology in humans in the causation of essential hypertension. PMID: 32060494 [PubMed - as supplied by publisher]

Related Articles Investigation of α-Glucosidase Inhibitory Metabolites from Tetracera scandens Leaves by GC-MS Metabolite Profiling and Docking Studies. Biomolecules. 2020 Feb 12;10(2): Authors: Nokhala A, Siddiqui MJ, Ahmed QU, Ahamad Bustamam MS, Zakaria AZA Abstract Stone leaf (Tetracera scandens) is a Southeast Asian medicinal plant that has been traditionally used for the management of diabetes mellitus. The underlying mechanisms of the antidiabetic activity have not been fully explored yet. Hence, this study aimed to evaluate the α-glucosidase inhibitory potential of the hydromethanolic extracts of T. scandens leaves and to characterize the metabolites responsible for such activity through gas chromatography-mass spectrometry (GC-MS) metabolomics. Crude hydromethanolic extracts of different strengths were prepared and in vitro assayed for α-glucosidase inhibition. GC-MS analysis was further carried out and the mass spectral data were correlated to the corresponding α-glucosidase inhibitory IC50 values via an orthogonal partial least squares (OPLS) model. The 100%, 80%, 60% and 40% methanol extracts displayed potent α-glucosidase inhibitory potentials. Moreover, the established model identified 16 metabolites to be responsible for the α-glucosidase inhibitory activity of T. scandens. The putative α-glucosidase inhibitory metabolites showed moderate to high affinities (binding energies of -5.9 to -9.8 kcal/mol) upon docking into the active site of Saccharomyces cerevisiae isomaltase. To sum up, an OPLS model was developed as a rapid method to characterize the α-glucosidase inhibitory metabolites existing in the hydromethanolic extracts of T. scandens leaves based on GC-MS metabolite profiling. PMID: 32059529 [PubMed - in process]

42 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2020/02/15PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

42 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2020/02/15PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Related Articles Urinary chemical fingerprint left behind by repeated NSAID administration: Discovery of putative biomarkers using artificial intelligence. PLoS One. 2020;15(2):e0228989 Authors: Broughton-Neiswanger LE, Rivera-Velez SM, Suarez MA, Slovak JE, Piñeyro PE, Hwang JK, Villarino NF Abstract Prediction and early detection of kidney damage induced by nonsteroidal anti-inflammatories (NSAIDs) would provide the best chances of maximizing the anti-inflammatory effects while minimizing the risk of kidney damage. Unfortunately, biomarkers for detecting NSAID-induced kidney damage in cats remain to be discovered. To identify potential urinary biomarkers for monitoring NSAID-based treatments, we applied an untargeted metabolomics approach to urine collected from cats treated repeatedly with meloxicam or saline for up to 17 days. Applying multivariate analysis, this study identified a panel of seven metabolites that discriminate meloxicam treated from saline treated cats. Combining artificial intelligence machine learning algorithms and an independent testing urinary metabolome data set from cats with meloxicam-induced kidney damage, a panel of metabolites was identified and validated. The panel of metabolites including tryptophan, tyrosine, taurine, threonic acid, pseudouridine, xylitol and lyxitol, successfully distinguish meloxicam-treated and saline-treated cats with up to 75-100% sensitivity and specificity. This panel of urinary metabolites may prove a useful and non-invasive diagnostic tool for monitoring potential NSAID induced kidney injury in feline patients and may act as the framework for identifying urine biomarkers of NSAID induced injury in other species. PMID: 32053695 [PubMed - in process]

Related Articles 2'-O-ribose methylation of transfer RNA promotes recovery from oxidative stress in Saccharomyces cerevisiae. PLoS One. 2020;15(2):e0229103 Authors: Endres L, Rose RE, Doyle F, Rahn T, Lee B, Seaman J, McIntyre WD, Fabris D Abstract Chemical modifications that regulate protein expression at the translational level are emerging as vital components of the cellular stress response. Transfer RNAs (tRNAs) are significant targets for methyl-based modifications, which are catalyzed by tRNA methyltransferases (Trms). Here, Saccharomyces cerevisiae served as a model eukaryote system to investigate the role of 2'-O-ribose tRNA methylation in the cell's response to oxidative stress. Using 2'-O-ribose deletion mutants for trms 3, 7, 13, and 44, in acute and chronic exposure settings, we demonstrate a broad cell sensitivity to oxidative stress-inducing toxicants (i.e., hydrogen peroxide, rotenone, and acetic acid). A global analysis of hydrogen peroxide-induced tRNA modifications shows a complex profile of decreased, or undetectable, 2'-O-ribose modification events in 2'-O-ribose trm mutant strains, providing a critical link between this type of modification event and Trm status post-exposure. Based on the pronounced oxidative stress sensitivity observed for trm7 mutants, we used a bioinformatic tool to identify transcripts as candidates for regulation by Trm7-catalyzed modifications (i.e., enriched in UUC codons decoded by tRNAPheGmAA). This screen identified transcripts linked to diverse biological processes that promote cellular recovery after oxidative stress exposure, including DNA repair, chromatin remodeling, and nutrient acquisition (i.e., CRT10, HIR3, HXT2, and GNP1); moreover, these mutants were also oxidative stress-sensitive. Together, these results solidify a role for TRM3, 7, 13, and 44, in the cellular response to oxidative stress, and implicate 2'-O-ribose tRNA modification as an epitranscriptomic strategy for oxidative stress recovery. PMID: 32053677 [PubMed - in process]

Related Articles Effects of scion/rootstock combination on flavor quality of orange juice from Huanglongbing (HLB) -affected trees: a two-year study of the targeted metabolomics. J Agric Food Chem. 2020 Feb 13;: Authors: Huang L, Grosser JW, Gmitter FG, Sims CA, Wang Y Abstract The bacterial disease Huanglongbing (HLB) has been causing large economic losses in the citrus industry worldwide. Aimed at unravelling the mechanisms of scion/rootstock combination on improving HLB-affected orange juice quality, a specific scion/rootstock combination field trial was designed using three sibling rootstocks and two late maturing sweet orange scion cultivars. Scion/rootstock combination significantly improved the overall consumer liking of orange juice from the trees, all of which were affected by HLB. Using a three-way ANOVA assay, rootstocks showed significant effects on the consumer liking and overall flavor, while scions had significant effects on the freshness and overall orange flavor intensity of the juice. A PLS-DA model combined with KEGG pathway enrichment analysis and some biomarker metabolites further indicated that scions mainly affected metabolism of alanine, aspartate and glutamate in orange fruit. Meanwhile, rootstocks had an impact on the biosynthetic pathways of secondary metabolites, especially the flavonoids biosynthesis with diosmin, narirutin and rutin involved. Sugars and organic acids were not closely correlated with the overall liking and sensory perception of orange juice. Rather, flavonoids such as diosmin and hesperidin, terpenoids such as limonin and nomilin, and volatile aromas played important roles in improving consumer overall liking. These results indicated that an optimum tolerant scion/rootstock combination can make a positive contribution towards improved fruit or juice quality from HLB-affected citrus trees and enabled a better understanding of fruit quality improvement based on scion and rootstock combinations. PMID: 32052973 [PubMed - as supplied by publisher]

Related Articles Comparative lipidomic analysis of inflammatory mediators in the aqueous humor and tear fluid of humans and rabbits. Metabolomics. 2020 Feb 12;16(2):27 Authors: Chistyakov DV, Azbukina NV, Astakhova AA, Goriainov SV, Chistyakov VV, Tiulina VV, Baksheeva VE, Kotelin VI, Fedoseeva EV, Zamyatnin AA, Philippov PP, Kiseleva OA, Bessmertny AM, Senin II, Iomdina EN, Sergeeva MG, Zernii EY Abstract INTRODUCTION: Ocular inflammation is a key pathogenic factor in most blindness-causing visual disorders. It can manifest in the aqueous humor (AH) and tear fluid (TF) as alterations in polyunsaturated fatty acids (PUFAs) and their metabolites, oxylipins, lipid mediators, which are biosynthesized via enzymatic pathways involving lipoxygenase, cyclooxygenase or cytochrome P450 monooxygenase and specifically regulate inflammation and resolution pathways. OBJECTIVES: This study aimed to establish the baseline patterns of PUFAs and oxylipins in AH and TF by their comprehensive lipidomic identification and profiling in humans in the absence of ocular inflammation and comparatively analyze these compounds in the eye liquids of rabbits, the species often employed in investigative ophthalmology. METHODS: Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used for qualitative and quantitative characterization of lipid compounds in the analyzed samples. RESULTS: A total of 28 lipid compounds were identified, including phospholipid derivatives and PUFAs, as well as 22 oxylipins. Whereas the PUFAs included arachidonic, docosahexaenoic and eicosapentaenoic acids, the oxylipins were derived mainly from arachidonic, linoleic and α-linolenic acids. Remarkably, although the concentration of oxylipins in AH was lower compared to TF, these liquids showed pronounced similarity in their lipid profiles, which additionally exhibited noticeable interspecies concordance. CONCLUSION: The revealed correlations confirm the feasibility of rabbit models for investigating pathogenesis and trialing therapies of human eye disorders. The identified metabolite patterns suggest enzymatic mechanisms of oxylipin generation in AH and TF and might be used as a reference in ocular inflammation studies. PMID: 32052201 [PubMed - in process]

Related Articles Targeted metabolomics of CSF in healthy individuals and patients with secondary progressive multiple sclerosis using high-resolution mass spectrometry. Metabolomics. 2020 Feb 12;16(2):26 Authors: Carlsson H, Abujrais S, Herman S, Khoonsari PE, Åkerfeldt T, Svenningsson A, Burman J, Kultima K Abstract INTRODUCTION: Standardized commercial kits enable targeted metabolomics analysis and may thus provide an attractive complement to the more explorative approaches. The kits are typically developed for triple quadrupole mass spectrometers using serum and plasma. OBJECTIVES: Here we measure the concentrations of preselected metabolites in cerebrospinal fluid (CSF) using a kit developed for high-resolution mass spectrometry (HRMS). Secondarily, the study aimed to investigate metabolite alterations in patients with secondary progressive multiple sclerosis (SPMS) compared to controls. METHODS: We performed targeted metabolomics in human CSF on twelve SPMS patients and twelve age and sex-matched healthy controls using the Absolute IDQ-p400 kit (Biocrates Life Sciences AG) developed for HRMS. The extracts were analysed using two methods; liquid chromatography-mass spectrometry (LC-HRMS) and flow injection analysis-MS (FIA-HRMS). RESULTS: Out of 408 targeted metabolites, 196 (48%) were detected above limit of detection and 35 were absolutely quantified. Metabolites analyzed using LC-HRMS had a median coefficient of variation (CV) of 3% and 2.5% between reinjections the same day and after prolonged storage, respectively. The corresponding results for the FIA-HRMS were a median CV of 27% and 21%, respectively. We found significantly (p < 0.05) elevated levels of glycine, asymmetric dimethylarginine (ADMA), glycerophospholipid PC-O (34:0) and sum of hexoses in SPMS patients compared to controls. CONCLUSION: The Absolute IDQ-p400 kit could successfully be used for quantifying targeted metabolites in the CSF. Metabolites quantified using LC-HRMS showed superior reproducibility compared to FIA-HRMS. PMID: 32052189 [PubMed - in process]

Related Articles Author Correction: Metabolomics reveals perturbations in endometrium and serum of minimal and mild endometriosis. Sci Rep. 2020 Feb 12;10(1):2790 Authors: Dutta M, Singh B, Joshi M, Das D, Subramani E, Maan M, Jana SK, Sharma U, Das S, Dasgupta S, Ray CD, Chakravarty B, Chaudhury K Abstract An amendment to this paper has been published and can be accessed via a link at the top of the paper. PMID: 32051518 [PubMed - in process]

Related Articles Toxic tall fescue grazing increases susceptibility of the Angus steer fecal microbiota and plasma/urine metabolome to environmental effects. Sci Rep. 2020 Feb 12;10(1):2497 Authors: Mote RS, Hill NS, Skarlupka JH, Tran VT, Walker DI, Turner ZB, Sanders ZP, Jones DP, Suen G, Filipov NM Abstract Impaired thermoregulation and lowered average daily gains (ADG) result when livestock graze toxic endophyte (Epichloë coenophialum)-infected tall fescue (E+) and are hallmark signs of fescue toxicosis (FT), a disease exacerbated by increased temperature and humidity (+temperature-humidity index; +THI). We previously reported FT is associated with metabolic and microbiota perturbations under thermoneutral conditions; here, we assessed the influence of E+ grazing and +THI on the microbiota:metabolome interactions. Using high-resolution metabolomics and 16S rRNA gene sequencing, plasma/urine metabolomes and the fecal microbiota of Angus steers grazing non-toxic or E+ tall fescue were evaluated in the context of +THI. E+ grazing affected the fecal microbiota profile; +THI conditions modulated the microbiota only in E+ steers. E+ also perturbed many metabolic pathways, namely amino acid and inflammation-related metabolism; +THI affected these pathways only in E+ steers. Integrative analyses revealed the E+ microbiota correlated and co-varied with the metabolomes in a THI-dependent manner. Operational taxonomic units in the families Peptococcaceae, Clostridiaceae, and Ruminococcaceae correlated with production parameters (e.g., ADG) and with multiple plasma/urine metabolic features, providing putative FT biomarkers and/or targets for the development of FT therapeutics. Overall, this study suggests that E+ grazing increases Angus steer susceptibility to +THI, and offers possible targets for FT interventions. PMID: 32051515 [PubMed - in process]

Related Articles Dysregulated metabolic pathways in age-related macular degeneration. Sci Rep. 2020 Feb 12;10(1):2464 Authors: Zhang M, Jiang N, Chu Y, Postnikova O, Varghese R, Horvath A, Cheema AK, Golestaneh N Abstract Age-related macular degeneration is a major cause of vision impairment in the Western world among people of 55 years and older. Recently we have shown that autophagy is dysfunctional in the retinal pigment epithelium (RPE) of the AMD donor eyes (AMD RPE). We also showed increased reactive oxygen (ROS) production, increased cytoplasmic glycogen accumulation, mitochondrial dysfunction and disintegration, and enlarged and annular LAMP-1-positive organelles in AMD RPE. However, the underlying mechanisms inducing these abnormalities remain to be elucidated. Here, by performing a comprehensive study, we show increased PAPR2 expression, deceased NAD+, and SIRT1, increased PGC-1α acetylation (inactive form), lower AMPK activity, and overactive mTOR pathway in AMD RPE as compared to normal RPE. Metabolomics and lipidomics revealed dysregulated metabolites in AMD RPE as compared to normal RPE, including glycerophospholipid metabolism, involved in autophagy, lipid, and protein metabolisms, glutathione, guanosine, and L-glutamic acid, which are implicated in protection against oxidative stress and neurotoxicity, further supporting our observations. Our data show dysregulated metabolic pathways as important contributors to AMD pathophysiology, and facilitate the development of new treatment strategies for this debilitating disease of the visual system. PMID: 32051464 [PubMed - in process]

Related Articles Elevated plasma β-hydroxybutyrate predicts adverse outcomes and disease progression in patients with arrhythmogenic cardiomyopathy. Sci Transl Med. 2020 Feb 12;12(530): Authors: Song JP, Chen L, Chen X, Ren J, Zhang NN, Tirasawasdichai T, Hu ZL, Hua W, Hu YR, Tang HR, Chen HV, Hu SS Abstract Sudden death could be the first symptom of patients with arrhythmogenic cardiomyopathy (AC), a disease for which clinical indicators predicting adverse progression remain lacking. Recent findings suggest that metabolic dysregulation is present in AC. We performed this study to identify metabolic indicators that predicted major adverse cardiac events (MACEs) in patients with AC and their relatives. Comparing explanted hearts from patients with AC and healthy donors, we identified deregulated metabolic pathways using quantitative proteomics. Right ventricles (RVs) from patients with AC displayed elevated ketone metabolic enzymes, OXCT1 and HMGCS2, suggesting higher ketone metabolism in AC RVs. Analysis of matched coronary artery and sinus plasma suggested potential ketone body synthesis at early-stage AC, which was validated using patient-derived induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) in vitro. Targeted metabolomics analysis in RVs from end-stage AC revealed a "burned-out" state, with predominant medium-chain fatty acid rather than ketone body utilization. In an independent validation cohort, 65 probands with mostly non-heart failure manifestations of AC had higher plasma β-hydroxybutyrate (β-OHB) than 62 healthy volunteers (P < 0.001). Probands with AC with MACE had higher β-OHB than those without MACE (P < 0.001). Among 94 relatives of probands, higher plasma β-OHB distinguished 25 relatives having suspected AC from nonaffected relatives. This study demonstrates that elevated plasma β-OHB predicts MACE in probands and disease progression in patients with AC and their clinically asymptomatic relatives. PMID: 32051229 [PubMed - in process]

Related Articles A century-old mystery unveiled: Sekizaisou is a natural lignin mutant. Plant Physiol. 2020 Feb 12;: Authors: Yamamoto M, Tomiyama H, Koyama A, Okuizumi H, Liu S, Vanholme R, Goeminne G, Hirai Y, Shi H, Nuoendagula N, Takata N, Ikeda T, Uesugi M, Kim H, Sakamoto S, Mitsuda N, Boerjan WA, Ralph J, Kajita S PMID: 32051179 [PubMed - as supplied by publisher]