Integrative Molecular Phenotyping
INTEGRATIVE MOLECULAR
PHENOTYPING
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

PubMed

Inaccurate quantitation of palmitate in metabolomics and isotope tracer studies due to plastics.

Tue, 11/10/2016 - 13:10
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.

Tue, 11/10/2016 - 13:10
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.

Tue, 11/10/2016 - 13:10
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.

Tue, 11/10/2016 - 13:10
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]

Systems-Level Nutrition Approaches to Define Phenotypes Resulting from Complex Gene-Environment Interactions.

Tue, 11/10/2016 - 13:10
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.

Sun, 09/10/2016 - 12:12
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.

Sun, 09/10/2016 - 12:12
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.

Sun, 09/10/2016 - 12:12
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.

Sun, 09/10/2016 - 12:12
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]

metabolomics; +17 new citations

Sat, 08/10/2016 - 14:27
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.

Fri, 07/10/2016 - 13:54
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.

Fri, 07/10/2016 - 13:54
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]

Metabolomics-identified metabolites associated with body mass index and prospective weight gain among Mexican American women.

Fri, 07/10/2016 - 13:54
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]

Connective tissue diseases: Promises and challenges of metabolomics in SLE.

Fri, 07/10/2016 - 13:54
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]

Fragment-based de novo design of a cystathionine γ-lyase selective inhibitor blocking hydrogen sulfide production.

Fri, 07/10/2016 - 13:54
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]

High-resolution metabolomics of occupational exposure to trichloroethylene.

Fri, 07/10/2016 - 13:54
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]

Chiba study of Mother and Children's Health (C-MACH): cohort study with omics analyses.

Fri, 07/10/2016 - 13:54
Related Articles Chiba study of Mother and Children's Health (C-MACH): cohort study with omics analyses. BMJ Open. 2016 Jan 29;6(1):e010531 Authors: Sakurai K, Miyaso H, Eguchi A, Matsuno Y, Yamamoto M, Todaka E, Fukuoka H, Hata A, Mori C, Chiba study of Mother and Children's Health Group Abstract PURPOSE: Recent epidemiological studies have shown that environmental factors during the fetal period to early childhood might affect the risk of non-communicable diseases in adulthood. This is referred to as the developmental origins of health and disease (DOHaD) concept. The Chiba study of Mother and Children's Health (C-MACH) is a birth cohort study based on the DOHaD hypothesis and involves multiomics analysis. This study aims to explore the effects of genetic and environmental factors--particularly the fetal environment and postbirth living environment--on children's health, and to identify potential biomarkers for these effects. PARTICIPANTS: The C-MACH consists of three hospital-based cohorts. The study participants are pregnant women at <13 weeks gestation. Women who underwent an examination in one of the three hospitals received an explanation of the study. The participants consented to completing questionnaire surveys and the collection and storage of biological and house/environmental samples. Participants were provided unique study numbers. All of the data and biological specimens will be stored in the Chiba University Center for Preventive Medical Sciences and Chiba University Center for Preventive Medical Sciences BioBank, respectively. FINDINGS TO DATE: Consent to participate was obtained from 433 women. Of these women, 376 women completed questionnaires in the early gestational period. The mean age was 32.5 (4.4) years. The mean body mass index (BMI) was 21.1 (3.0) kg/m(2). Before pregnancy, 72.3% of the women had a BMI of 18.5-24.9 kg/m(2). During early pregnancy, 5.0% of the participants smoked. FUTURE PLANS: Primary outcomes are allergy, obesity, endocrine and metabolic disorders, and developmental disorders. Genome-level, metabolome-level, umbilical cord DNA methylation (epigenome), gut microbiota and environmental chemical exposure variables will be evaluated. We will analyse the relationships between the outcomes and analytical variables. PMID: 26826157 [PubMed - indexed for MEDLINE]

Metabolomic analysis of serum from obese adults with hyperlipemia by UHPLC-Q-TOF MS/MS.

Fri, 07/10/2016 - 13:54
Related Articles Metabolomic analysis of serum from obese adults with hyperlipemia by UHPLC-Q-TOF MS/MS. Biomed Chromatogr. 2016 Jan;30(1):48-54 Authors: Wang Y, Liu D, Li Y, Guo L, Cui Y, Zhang X, Li E Abstract The prevalence of obesity has dramatically increased and poses a major threat to human health. Obesity often accompanies hyperlipemia, which is strongly related to the occurrence and development of obesity-related chronic diseases. Differences in metabolomic profiling of serum between obese (with hyperlipemia) and normal-weight men (n = 30 in each group) were investigated using ultrahigh-pressure liquid chromatography-quadrupole-time of flight mass spectrometry (UHPLC-Q-TOF MS/MS) and partial least-squares-discriminant analysis (PLS-DA). Obese men showed higher levels of weight, body mass index, fat mass, systolic blood pressure, fasting plasma glucose, triglyeride, total cholesterol, insulin, HOMA-IR and high-sensitivity CRP. Obese and normal-weight groups were clearly discriminated from each other on a PLS-DA score plot and nine major metabolites contributing to the discrimination were assigned, including increased 2-octenoylcarnitine, eicosadienoic acid, 12-hydroperoxyeicosatetraenoic acid, 4-hydroxyestrone sulfate, lysoPE[18:1(11Z)/0:0], thromboxane B2 and pyridinoline and decreased vitamin D3 glucosiduronate and 9,10-DHOME. These metabolites were associated with lipid metabolism and obesity-related diseases, and reflected the metabolic differences between normal and obese men, which may be important for future clinical diagnosis, treatment and assessment of the therapeutic effect on obesity-related chronic disease. PMID: 26043712 [PubMed - indexed for MEDLINE]

Strategies for Extending Metabolomics Studies with Stable Isotope Labelling and Fluxomics.

Thu, 06/10/2016 - 13:11
Strategies for Extending Metabolomics Studies with Stable Isotope Labelling and Fluxomics. Metabolites. 2016 Oct 01;6(4): Authors: Srivastava A, Kowalski GM, Callahan DL, Meikle PJ, Creek DJ Abstract This is a perspective from the peer session on stable isotope labelling and fluxomics at the Australian &amp; New Zealand Metabolomics Conference (ANZMET) held from 30 March to 1 April 2016 at La Trobe University, Melbourne, Australia. This report summarizes the key points raised in the peer session which focused on the advantages of using stable isotopes in modern metabolomics and the challenges in conducting flux analyses. The session highlighted the utility of stable isotope labelling in generating reference standards for metabolite identification, absolute quantification, and in the measurement of the dynamic activity of metabolic pathways. The advantages and disadvantages of different approaches of fluxomics analyses including flux balance analysis, metabolic flux analysis and kinetic flux profiling were also discussed along with the use of stable isotope labelling in in vivo dynamic metabolomics. A number of crucial technical considerations for designing experiments and analyzing data with stable isotope labelling were discussed which included replication, instrumentation, methods of labelling, tracer dilution and data analysis. This report reflects the current viewpoint on the use of stable isotope labelling in metabolomics experiments, identifying it as a great tool with the potential to improve biological interpretation of metabolomics data in a number of ways. PMID: 27706078 [PubMed - in process]

Metabolomics and Cheminformatics Analysis of Antifungal Function of Plant Metabolites.

Thu, 06/10/2016 - 13:11
Metabolomics and Cheminformatics Analysis of Antifungal Function of Plant Metabolites. Metabolites. 2016 Sep 30;6(4): Authors: Cuperlovic-Culf M, Rajagopalan N, Tulpan D, Loewen MC Abstract Fusarium head blight (FHB), primarily caused by Fusarium graminearum, is a devastating disease of wheat. Partial resistance to FHB of several wheat cultivars includes specific metabolic responses to inoculation. Previously published studies have determined major metabolic changes induced by pathogens in resistant and susceptible plants. Functionality of the majority of these metabolites in resistance remains unknown. In this work we have made a compilation of all metabolites determined as selectively accumulated following FHB inoculation in resistant plants. Characteristics, as well as possible functions and targets of these metabolites, are investigated using cheminformatics approaches with focus on the likelihood of these metabolites acting as drug-like molecules against fungal pathogens. Results of computational analyses of binding properties of several representative metabolites to homology models of fungal proteins are presented. Theoretical analysis highlights the possibility for strong inhibitory activity of several metabolites against some major proteins in Fusarium graminearum, such as carbonic anhydrases and cytochrome P450s. Activity of several of these compounds has been experimentally confirmed in fungal growth inhibition assays. Analysis of anti-fungal properties of plant metabolites can lead to the development of more resistant wheat varieties while showing novel application of cheminformatics approaches in the analysis of plant/pathogen interactions. PMID: 27706030 [PubMed - in process]

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