PubMed

Strategies for large-scale targeted metabolomics quantification by liquid chromatography-mass spectrometry. Analyst. 2016 Oct 10;: Authors: Zhou J, Yin Y Abstract Advances in liquid chromatography-mass spectrometry (LC-MS) instruments and analytical strategies have brought about great progress in targeted metabolomics analysis. This methodology is now capable of performing precise targeted measurement of dozens or hundreds of metabolites in complex biological samples. Classic targeted quantification assay using the multiple reaction monitoring (MRM) mode has been the foundation of high-quality metabolite quantitation. However, utilization of this strategy in biological studies has been limited by its relatively low metabolite coverage and throughput capacity. A number of methods for large-scale targeted metabolomics assay which have been developed overcome these limitations. These strategies have enabled extended metabolite coverage which is defined as targeting of large numbers of metabolites, while maintaining reliable quantification performance. These recently developed techniques thus bridge the gap between traditional targeted metabolite quantification and untargeted metabolomics profiling, and have proven to be powerful tools for metabolomics study. Although the LC-MRM-MS strategy has been used widely in large-scale metabolomics quantification analysis due to its fast scan speed and ideal analytic stability, there are still drawbacks which are due to the low resolution of the triple quadrupole instruments used for MRM assays. New approaches have been developed to expand the options for large-scale targeted metabolomics study, using high-resolution instruments such as parallel reaction monitoring (PRM). MRM and PRM-based techniques are now attractive strategies for quantitative metabolomics analysis and high-throughput biomarker discovery. Here we provide an overview of the major developments in LC-MS-based strategies for large-scale targeted metabolomics quantification in biological samples. The advantages of LC-MRM/PRM-MS based analytical strategies which may be used in multiplexed and high throughput quantitation for a wide range of metabolites are highlighted. In particular, PRM and MRM strategies are compared, and we summarize the work flow commonly used for large-scale targeted metabolomics analysis including sample preparation, LC separation and data analysis, as well as recent applications in biological studies. PMID: 27722450 [PubMed - as supplied by publisher]

Metabolization and degradation kinetics of the urban-use pesticide fipronil by white rot fungus Trametes versicolor. Environ Sci Process Impacts. 2016 Sep 9;: Authors: Wolfand JM, LeFevre GH, Luthy RG Abstract Fipronil is a recalcitrant phenylpyrazole-based pesticide used for flea/tick treatment and termite control that is distributed in urban aquatic environments via stormwater and contributes to stream toxicity. We discovered that fipronil is rapidly metabolized (t1/2 = 4.2 d) by the white rot fungus Trametes versicolor to fipronil sulfone and multiple previously unknown fipronil transformation products, lowering fipronil concentration by 96.5%. Using an LC-QTOF-MS untargeted metabolomics approach, we identified four novel fipronil fungal transformation products: hydroxylated fipronil sulfone, glycosylated fipronil sulfone, and two compounds with unresolved structures. These results are consistent with identified enzymatic detoxification pathways wherein conjugation with sugar moieties follows initial ring functionalization (hydroxylation). The proposed pathway is supported by kinetic evidence of transformation product formation. Fipronil loss by sorption, hydrolysis, and photolysis was negligible. When T. versicolor was exposed to the cytochrome P450 enzyme inhibitor 1-aminobenzotriazole, oxidation of fipronil and production of hydroxylated and glycosylated transformation products significantly decreased (p = 0.038, 0.0037, 0.0023, respectively), indicating that fipronil is metabolized intracellularly by cytochrome P450 enzymes. Elucidating fipronil transformation products is critical because pesticide target specificity can be lost via structural alteration, broadening classes of impacted organisms. Integration of fungi in engineered natural treatment systems could be a viable strategy for pesticide removal from stormwater runoff. PMID: 27722395 [PubMed - as supplied by publisher]

Uncertainty budgeting in fold change determination and implications for non-targeted metabolomics studies in model systems. Analyst. 2016 Oct 6;: Authors: Ortmayr K, Charwat V, Kasper C, Hann S, Koellensperger G Abstract The p-value is the most prominent established metric for statistical significance in non-targeted metabolomics. However, its adequacy has repeatedly been the subject of discussion criticizing its uncertainty and its dependence on sample size and statistical power. These issues compromise non-targeted metabolomics in model systems, where studies typically investigate 5-10 samples per group. In this paper we propose a different approach for assessing the relevance of fold change (FC) data, where the FC is treated as a quantitative value and is validated by uncertainty budgeting. For the purpose of large-scale application in non-targeted metabolomics, we present a simplified approach for uncertainty propagation using experimental standard deviations of metabolite intensities as type A-summarized standard uncertainties. The resulting expanded FC uncertainty can be used to derive a minimum relevant FC as a complementary criterion in metabolomics data evaluation. This concept overcomes the need for a uniform p-value cut-off for all metabolites by considering the experimental uncertainty for each metabolite individually. The proposed procedure is part of analytical method validation, however the concept has not previously been applied to non-targeted metabolomics. A case study on mesenchymal stem cells cultured in normoxia and hypoxia demonstrates the practical value of this approach, in particular for studies with a small sample size. An online two-dimensional LC method coupled to mass spectrometry was crucial in providing both broad metabolome coverage and excellent experimental precision (<8% CV for peak areas, on average 0.5% CV for retention times) that was required for sensitive differential analysis as low as FC 1.1. PMID: 27722392 [PubMed - as supplied by publisher]

Decreased glutathione biosynthesis contributes to EGFR T790M-driven erlotinib resistance in non-small cell lung cancer. Cell Discov. 2016;2:16031 Authors: Li H, Stokes W, Chater E, Roy R, de Bruin E, Hu Y, Liu Z, Smit EF, Heynen GJ, Downward J, Seckl MJ, Wang Y, Tang H, Pardo OE Abstract Epidermal growth factor receptor (EGFR) inhibitors such as erlotinib are novel effective agents in the treatment of EGFR-driven lung cancer, but their clinical impact is often impaired by acquired drug resistance through the secondary T790M EGFR mutation. To overcome this problem, we analysed the metabonomic differences between two independent pairs of erlotinib-sensitive/resistant cells and discovered that glutathione (GSH) levels were significantly reduced in T790M EGFR cells. We also found that increasing GSH levels in erlotinib-resistant cells re-sensitised them, whereas reducing GSH levels in erlotinib-sensitive cells made them resistant. Decreased transcription of the GSH-synthesising enzymes (GCLC and GSS) due to the inhibition of NRF2 was responsible for low GSH levels in resistant cells that was directly linked to the T790M mutation. T790M EGFR clinical samples also showed decreased expression of these key enzymes; increasing intra-tumoural GSH levels with a small-molecule GST inhibitor re-sensitised resistant tumours to erlotinib in mice. Thus, we identified a new resistance pathway controlled by EGFR T790M and a therapeutic strategy to tackle this problem in the clinic. PMID: 27721983 [PubMed - in process]

Inaccurate quantitation of palmitate in metabolomics and isotope tracer studies due to plastics. Metabolomics. 2016 Sep;12: Authors: Yao CH, Liu GY, Yang K, Gross RW, Patti GJ Abstract INTRODUCTION: Palmitate, the typical end product released from fatty acid synthase, is of interest to many researchers performing metabolomics. Although palmitate can be readily detected by using mass spectrometry, many metabolomic platforms involve the use of plastic consumables that introduce a competing background signal of palmitate. OBJECTIVES: The goal of this study was to quantify palmitate contamination in metabolomics and isotope tracer studies and to examine the reliability of approaches for reducing error. METHODS: We measured the quantitative error introduced by palmitate contamination from 4 vendors of plastic consumables used in combination with several different extraction solvents. RESULTS: The background palmitate signal was as much as sixfold higher than the biological palmitate signal from 4 million 3T3-L1 cells. Importantly, the palmitate contamination signal was highly variable between plastic consumables (even within the same lot) and therefore could not be accurately removed by subtracting the background as measured from a blank. In addition to affecting relative and absolute quantitation, the palmitate background signal from disposable plastics also led to the underestimation of labeled palmitate in isotope tracer experiments. CONCLUSION: When measuring palmitate standard solutions, the best results were obtained when glass vials and glass pipettes were used. However, much of the palmitate background signal could be eliminated by pre-rinsing plastic vials and plastic pipette tips with methanol prior to sample introduction. For isotope tracer studies, error could also be minimized by estimating palmitate enrichment from palmitoylcarnitine, which does not have a competing contamination signal from plastic consumables. PMID: 27721678 [PubMed - in process]

Comprehensive Plasma Metabolomic Analyses of Atherosclerotic Progression Reveal Alterations in Glycerophospholipid and Sphingolipid Metabolism in Apolipoprotein E-deficient Mice. Sci Rep. 2016 Oct 10;6:35037 Authors: Dang VT, Huang A, Zhong LH, Shi Y, Werstuck GH Abstract Atherosclerosis is the major underlying cause of most cardiovascular diseases. Despite recent advances, the molecular mechanisms underlying the pathophysiology of atherogenesis are not clear. In this study, comprehensive plasma metabolomics were used to investigate early-stage atherosclerotic development and progression in chow-fed apolipoprotein E-deficient mice at 5, 10 and 15 weeks of age. Comprehensive plasma metabolomic profiles, based on 4365 detected metabolite features, differentiate atherosclerosis-prone from atherosclerosis-resistant models. Metabolites in the sphingomyelin pathway were significantly altered prior to detectable lesion formation and at all subsequent time-points. The cytidine diphosphate-diacylglycerol pathway was up-regulated during stage I of atherosclerosis, while metabolites in the phosphatidylethanolamine and glycosphingolipid pathways were augmented in mice with stage II lesions. These pathways, involving glycerophospholipid and sphingolipid metabolism, were also significantly affected during the course of atherosclerotic progression. Our findings suggest that distinct plasma metabolomic profiles can differentiate the different stages of atherosclerotic progression. This study reveals that alteration of specific, previously unreported pathways of glycerophospholipid and sphingolipid metabolism are associated with atherosclerosis. The clear difference in the level of several metabolites supports the use of plasma lipid profiling as a diagnostic tool of atherogenesis. PMID: 27721472 [PubMed - in process]

Development of chemical isotope labeling liquid chromatography mass spectrometry for silkworm hemolymph metabolomics. Anal Chim Acta. 2016 Oct 26;942:1-11 Authors: Shen W, Han W, Li Y, Meng Z, Cai L, Li L Abstract Silkworm (Bombyx mori) is a very useful target insect for evaluation of endocrine disruptor chemicals (EDCs) due to mature breeding techniques, complete endocrine system and broad basic knowledge on developmental biology. Comparative metabolomics of silkworms with and without EDC exposure offers another dimension of studying EDCs. In this work, we report a workflow on metabolomic profiling of silkworm hemolymph based on high-performance chemical isotope labeling (CIL) liquid chromatography mass spectrometry (LC-MS) and demonstrate its application in studying the metabolic changes associated with the pesticide dichlorodiphenyltrichloroethane (DDT) exposure in silkworm. Hemolymph samples were taken from mature silkworms after growing on diet that contained DDT at four different concentrations (1, 0.1, 0.01, 0.001 ppm) as well as on diet without DDT as controls. They were subjected to differential (12)C-/(13)C-dansyl labeling of the amine/phenol submetabolome, LC-UV quantification of the total amount of labeled metabolites for sample normalization, and LC-MS detection and relative quantification of individual metabolites in comparative samples. The total concentration of labeled metabolites did not show any significant change between four DDT-treatment groups and one control group. Multivariate statistical analysis of the metabolome data set showed that there was a distinct metabolomic separation between the five groups. Out of the 2044 detected peak pairs, 338 and 1471 metabolites have been putatively identified against the HMDB database and the EML library, respectively. 65 metabolites were identified by the dansyl library searching based on the accurate mass and retention time. Among the 65 identified metabolites, 33 positive metabolites had changes of greater than 1.20-fold or less than 0.83-fold in one or more groups with p-value of smaller than 0.05. Several useful biomarkers including serine, methionine, tryptophan, asymmetric dimethylarginine, N-Methyl-D-aspartic and tyrosine were identified. The changes of these biomarkers were likely due to the disruption of the endocrine system of silkworm by DDT. This work illustrates that the method of CIL LC-MS is useful to generate quantitative submetabolome profiles from a small volume of silkworm hemolymph with much higher coverage than conventional LC-MS methods, thereby facilitating the discovery of potential metabolite biomarkers related to EDC or other chemical exposure. PMID: 27720112 [PubMed - in process]

A Novel Methodology for Bioenergetic Analysis of Plasmodium falciparum Reveals a Glucose-regulated Metabolic Shift and Enables Mode of Action Analyses of Mitochondrial Inhibitors. ACS Infect Dis. 2016 Oct 9;: Authors: Sakata-Kato T, Wirth DF Abstract Given that resistance to all drugs in clinical use has arisen, discovery of new anti-malarial drug targets is eagerly anticipated. The Plasmodium mitochondrion has been considered a promising drug target largely based on its significant divergence from the host organelle as well as its involvement in ATP production and pyrimidine biosynthesis. However, the functions of Plasmodium mitochondrial protein complexes and associated metabolic pathways are not fully characterized. Here, we report the development of novel and robust bioenergetic assay protocols for Plasmodium falciparum asexual parasites utilizing a Seahorse Bioscience XFe24 Extracellular Flux Analyzer. These protocols allowed us to simultaneously assess the direct effects of metabolites and inhibitors on mitochondrial respiration and glycolytic activity in real-time with the readout of oxygen consumption rate and extracellular acidification rate. Using saponin-freed parasites at the schizont stage, we found that succinate, malate, glycerol-3-phosphate and glutamate, but not pyruvate, were able to increase the oxygen consumption rate, and that glycerol-3-phosphate dehydrogenase had the largest potential as an electron donor among tested mitochondrial dehydrogenases. Furthermore, we revealed the presence of a glucose-regulated metabolic shift between oxidative phosphorylation and glycolysis. We measured proton leak and reserve capacity and found bioenergetic evidence for oxidative phosphorylation in erythrocytic stage parasites, but at a level much lower than that observed in mammalian cells. Lastly we developed an assay platform for target identification and mode of action studies of mitochondria-targeting antimalarials. This study provides new insights into the bioenergetics and metabolomics of the Plasmodium mitochondria. PMID: 27718558 [PubMed - as supplied by publisher]

Related Articles Systems-Level Nutrition Approaches to Define Phenotypes Resulting from Complex Gene-Environment Interactions. Nestle Nutr Inst Workshop Ser. 2016;84:1-13 Authors: Kaput J Abstract High-throughput metabolomic, proteomic, and genomic technologies have delivered 21st-century data showing that humans cannot be randomized into groups: individuals are genetically and biochemically distinct. Gene-environment interactions caused by unique dietary and lifestyle factors contribute to the heterogeneity in physiologies observed in human studies. The risk factors determined for populations (i.e. the population-attributable risk) cannot be applied to the individual. Developing individual risk/benefit factors in light of the genetic diversity of human populations, the complexity of foods, culture and lifestyle, and the variety in metabolic processes that lead to health or disease are significant challenges for personalizing dietary advice for healthy or diseased individuals. PMID: 26764468 [PubMed - indexed for MEDLINE]

Comparative metabolomics analysis of Callosobruchus chinensis larvae under hypoxia, hypoxia/hypercapnia and normoxia. Pest Manag Sci. 2016 Oct 8;: Authors: Cui S, Wang L, Qiu J, Liu Z, Geng X Abstract BACKGOUND: The tolerance to low oxygen (hypoxia) and high carbon dioxide (hypercapnia) is criticalfor insect control. On the basis of bioassay, metabolism profiles were built to dissect adaptive mechanism in bean weevil under hypoxia, hypoxia/hypercapnia, and normoxia usinggas chromatography-time-of-flight mass spectrometry (GC-TOF-MS). RESULT: The growth and development of bean weevils were suppressed significantly by two hypoxia situations, and hypercapnia enhanced the mortality, but after 24-d exposure, the surviving insects emerged adults earlier than those under hypoxia only. Metabolism profiles also showed striking difference in metabolites among three groups, both quantitatively and qualitatively. A total of 61 metabolites changed significantly in three pairs of comparison, among them, 40 were in hypoxia and 37 in hypoxia/hypercapnia relative to control groups, 16 metabolites were found between two treatments. Increased metabolites were mainly carbohydrates, amino acids and organic acids, while free fatty acids were decreased. Furthermore, the changes were further strengthened by the addition of hypercapnia, but excluding free fatty acids. CONCLUTION: Our findings showed bean weevil has high tolerance to hypoxia, even hypoxia/hypercapnia at biologically achievable levels and provides more direct evidence for stored-product insect mechanism regulation under hypoxia stress, especially free fatty acid regulation by hypercapnia, but not hypoxia. PMID: 27718517 [PubMed - as supplied by publisher]

The great importance of normalization of LC-MS data for highly-accurate non-targeted metabolomics. Biomed Chromatogr. 2016 Oct 7;: Authors: Mizuno H, Ueda K, Kobayashi Y, Tsuyama N, Todoroki K, Min JZ, Toyo'oka T Abstract The non-targeted metabolomics analysis of biological samples is very important in order to understand biological functions and diseases. Liquid chromatography combined with electrospray ionization-based mass spectrometry (LC-ESI-MS) has been a powerful tool and widely used for metabolomic analyses. However, the ionization efficiency of ESI fluctuates for various unexpected reasons such as matrix effects and intra-day variations of the instrument performances. In order to remove these fluctuations, normalization methods have been developed. Such techniques include increasing the sensitivity, separating co-eluting components and normalizing the ionization efficiencies. Normalization techniques allow simultaneously correcting of the ionization efficiencies of the detected metabolite peaks and achieving quantitative non-targeted metabolomics. In this review paper, we focused on these normalization methods for non-targeted metabolomics by LC-MS. PMID: 27718276 [PubMed - as supplied by publisher]

CE-MS for metabolomics: developments and applications in the period 2014-2016. Electrophoresis. 2016 Oct 8;: Authors: Ramautar R, Somsen GW, de Jong GJ Abstract Capillary electrophoresis-mass spectrometry (CE-MS) can be considered a useful analytical technique for the global profiling of (highly) polar and charged metabolites in various samples. Over the past few years, significant advancements have been made in CE-MS approaches for metabolomics studies. In this paper, which is a follow-up of a previous review paper covering the years 2012-2014 (Electrophoresis 2015, 36, 212-224), recent CE-MS strategies developed for metabolomics covering the literature from July 2014 to June 2016 are outlined. Attention will be paid to new CE-MS approaches for the profiling of anionic metabolites and the potential of solid-phase extraction (SPE) coupled to CE-MS is also demonstrated. Representative examples illustrate the applicability of CE-MS in the fields of biomedical, clinical, microbial, plant and food metabolomics. A complete overview of recent CE-MS-based metabolomics studies is given in a table, which provides information on sample type and pretreatment, capillary coatings and MS detection mode. Finally, general conclusions and perspectives are given. This article is protected by copyright. All rights reserved. PMID: 27718257 [PubMed - as supplied by publisher]

Enterococcus hirae and Barnesiella intestinihominis Facilitate Cyclophosphamide-Induced Therapeutic Immunomodulatory Effects. Immunity. 2016 Sep 28;: Authors: Daillère R, Vétizou M, Waldschmitt N, Yamazaki T, Isnard C, Poirier-Colame V, Duong CP, Flament C, Lepage P, Roberti MP, Routy B, Jacquelot N, Apetoh L, Becharef S, Rusakiewicz S, Langella P, Sokol H, Kroemer G, Enot D, Roux A, Eggermont A, Tartour E, Johannes L, Woerther PL, Chachaty E, Soria JC, Golden E, Formenti S, Plebanski M, Madondo M, Rosenstiel P, Raoult D, Cattoir V, Boneca IG, Chamaillard M, Zitvogel L Abstract The efficacy of the anti-cancer immunomodulatory agent cyclophosphamide (CTX) relies on intestinal bacteria. How and which relevant bacterial species are involved in tumor immunosurveillance, and their mechanism of action are unclear. Here, we identified two bacterial species, Enterococcus hirae and Barnesiella intestinihominis that are involved during CTX therapy. Whereas E. hirae translocated from the small intestine to secondary lymphoid organs and increased the intratumoral CD8/Treg ratio, B. intestinihominis accumulated in the colon and promoted the infiltration of IFN-γ-producing γδT cells in cancer lesions. The immune sensor, NOD2, limited CTX-induced cancer immunosurveillance and the bioactivity of these microbes. Finally, E. hirae and B. intestinihominis specific-memory Th1 cell immune responses selectively predicted longer progression-free survival in advanced lung and ovarian cancer patients treated with chemo-immunotherapy. Altogether, E. hirae and B. intestinihominis represent valuable "oncomicrobiotics" ameliorating the efficacy of the most common alkylating immunomodulatory compound. PMID: 27717798 [PubMed - as supplied by publisher]

17 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 2016/10/08PubMed comprises more than 24 million 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.

State-of-the-Art Advances in Radiation Biodosimetry for Mass Casualty Events Involving Radiation Exposure. Radiat Res. 2016 Oct 6;: Authors: Sproull M, Camphausen K Abstract With the possibility of large-scale terrorist attacks around the world, the need for modeling and development of new medical countermeasures for potential future chemical, biological, radiological and nuclear (CBRN) has been well established. Project Bioshield, initiated in 2004, provided a framework to develop and expedite research in the field of CBRN exposures. To respond to large-scale population exposures from a nuclear event or radiation dispersal device (RDD), new methods for determining received dose using biological modeling became necessary. The field of biodosimetry has advanced significantly beyond this original initiative, with expansion into the fields of genomics, proteomics, metabolomics and transcriptomics. Studies are ongoing to evaluate the use of lymphocyte kinetics for dose assessment, as well as the development of field-deployable EPR technology. In addition, expansion of traditional cytogenetic assessment methods through the use of automated platforms and the development of laboratory surge capacity networks have helped to advance our biodefense preparedness. In this review of the latest advances in the field of biodosimetry we evaluate our progress and identify areas that still need to be addressed to achieve true field-deployment readiness. PMID: 27710702 [PubMed - as supplied by publisher]

Metabolic fingerprints of circulating IGF-I and the IGF-I/IGFBP-3 ratio: a multi-fluid metabolomics study. J Clin Endocrinol Metab. 2016 Oct 6;:jc20162588 Authors: Knacke H, Pietzner M, Do KT, Römisch-Margl W, Kastenmüller G, Völker U, Völzke H, Krumsiek J, Artati A, Wallaschofski H, Nauck M, Suhre K, Adamski J, Friedrich N Abstract OBJECTIVE: Insulin-like Growth Factor (IGF-I) 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-I levels with multi-fluid untargeted metabolomics data. METHODS: Plasma/urine samples of 995 non-diabetic participants of the Study of Health in Pomerania (SHIP-TREND) were characterized by mass spectrometry. Sex-specific linear regression analyses were performed to assess the association of IGF-I and IGF-I/IGFBP3 ratio with metabolites. Additionally, the predictive ability of the plasma and urine metabolome for IGF-I was assessed by OPLS analyses. RESULTS: and discussion: We revealed a multi-faceted image of associated metabolites with large sex differences. Confirming previous reports, we detected relations between IGF-I and steroid hormones or related intermediates. Furthermore, various associated metabolites were previously mentioned regarding IGF-I associated diseases, e.g. 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, e.g. phospholipids. Bradykinin, fatty acid derivatives and cortisol, which were inversely associated with IGF-I, might establish a link of IGF-I with inflammation. For the first time we showed an association between IGF-I and pipecolate, a metabolite linked to amino acid metabolism. Our study demonstrates that IGF-I action on metabolism is tractable even in healthy subjects and that the findings provide a solid basis for further experimental/clinical investigation, e.g. searching for inflammatory, cardiovascular disease or metabolic syndrome associated biomarkers and therapeutic targets. PMID: 27710242 [PubMed - as supplied by publisher]

Related Articles Metabolomics-identified metabolites associated with body mass index and prospective weight gain among Mexican American women. Obes Sci Pract. 2016 Sep;2(3):309-317 Authors: Zhao H, Shen J, Djukovic D, Daniel-MacDougall C, Gu H, Wu X, Chow WH Abstract OBJECTIVE: Obesity is a metabolic disease. However, the underlying molecular mechanisms linking metabolic profiles and weight gain are largely unknown. METHODS: Here, we used semi-targeted metabolomics to assay 156 metabolites selected from 25 key metabolic pathways in plasma samples from 300 non-smoking healthy women identified from Mano-A-Mano, the Mexican American Cohort study. The study subjects were randomly divided into two cohorts: training (N = 200) and testing (N = 100) cohorts. Linear regression and Cox proportional hazard regression were used to assess the effect of body mass index (BMI) at baseline on metabolite levels and the effects of metabolites on significant weight gain during a 5-year follow-up. RESULTS: At baseline, we observed 7 metabolites significantly associated with BMI in both training and testing cohorts. They were Methyl succinate, Asparagine, Urate, Kynurenic acid, Glycine, Glutamic acid, and Serine. In further analysis, we identified 6 metabolites whose levels at baseline predicted significant weight gain during 5-year follow-up in both cohorts. They were Acetylcholine, Leucine, Hippuric acid, Acetylglycine, Urate, and Xanthine. CONCLUSIONS: The findings establish the baseline metabolic profiles for BMI, and suggest new metabolic targets for researchers attempting to understand the molecular mechanisms of weight gain and obesity. PMID: 27708848 [PubMed - in process]

Related Articles Connective tissue diseases: Promises and challenges of metabolomics in SLE. Nat Rev Rheumatol. 2016 Oct 06;: Authors: Ding H, Mohan C PMID: 27708401 [PubMed - as supplied by publisher]

Related Articles Fragment-based de novo design of a cystathionine γ-lyase selective inhibitor blocking hydrogen sulfide production. Sci Rep. 2016 Oct 06;6:34398 Authors: Corvino A, Severino B, Fiorino F, Frecentese F, Magli E, Perissutti E, Santagada V, Bucci M, Cirino G, Kelly G, Servillo L, Popowicz G, Pastore A, Caliendo G Abstract Hydrogen sulfide is an essential catabolite that intervenes in the pathophysiology of several diseases from hypertension to stroke, diabetes and pancreatitis. It is endogenously synthesized mainly by two pyridoxal-5'-phosphate-dependent enzymes involved in L-cysteine metabolism: cystathionine-ß-synthase (CBS) and cystathionine-γ-lyase (CSE). Research in this field is currently impaired by the lack of pharmacological tools such as selective enzymatic inhibitors that could target specifically only one of these pathways. We used a novel approach based on a hybrid method that includes drug design, synthetic biology, metabolomics and pharmacological assays to rationally design a new inhibitor selective for the CSE enzyme. The identification of this compound opens new frontiers towards a better understanding of the role of CSE over CBS in the pathophysiology of diseases where a role for the H2S pathway has been proposed and the development of new lead compounds that could target the CSE enzyme. PMID: 27708394 [PubMed - in process]

Related Articles High-resolution metabolomics of occupational exposure to trichloroethylene. Int J Epidemiol. 2016 Oct 5;: Authors: Walker DI, Uppal K, Zhang L, Vermeulen R, Smith M, Hu W, Purdue MP, Tang X, Reiss B, Kim S, Li L, Huang H, Pennell KD, Jones DP, Rothman N, Lan Q Abstract BACKGROUND: Occupational exposure to trichloroethylene (TCE) has been linked to adverse health outcomes including non-Hodgkin's lymphoma and kidney and liver cancer; however, TCE's mode of action for development of these diseases in humans is not well understood. METHODS: Non-targeted metabolomics analysis of plasma obtained from 80 TCE-exposed workers [full shift exposure range of 0.4 to 230 parts-per-million of air (ppma)] and 95 matched controls were completed by ultra-high resolution mass spectrometry. Biological response to TCE exposure was determined using a metabolome-wide association study (MWAS) framework, with metabolic changes and plasma TCE metabolites evaluated by dose-response and pathway enrichment. Biological perturbations were then linked to immunological, renal and exposure molecular markers measured in the same population. RESULTS: Metabolic features associated with TCE exposure included known TCE metabolites, unidentifiable chlorinated compounds and endogenous metabolites. Exposure resulted in a systemic response in endogenous metabolism, including disruption in purine catabolism and decreases in sulphur amino acid and bile acid biosynthesis pathways. Metabolite associations with TCE exposure included uric acid (β = 0.13, P-value = 3.6 × 10(-5)), glutamine (β = 0.08, P-value = 0.0013), cystine (β = 0.75, P-value = 0.0022), methylthioadenosine (β = -1.6, P-value = 0.0043), taurine (β = -2.4, P-value = 0.0011) and chenodeoxycholic acid (β = -1.3, P-value = 0.0039), which are consistent with known toxic effects of TCE, including immunosuppression, hepatotoxicity and nephrotoxicity. Correlation with additional exposure markers and physiological endpoints supported known disease associations. CONCLUSIONS: High-resolution metabolomics correlates measured occupational exposure to internal dose and metabolic response, providing insight into molecular mechanisms of exposure-related disease aetiology. PMID: 27707868 [PubMed - as supplied by publisher]