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

PubMed
NCBI: db=pubmed; Term=metabolomics
Updated: 7 min 12 sec ago

Tackling the Complexity of the Exposome: Considerations from the Gunma University Initiative for Advanced Research (GIAR) Exposome Symposium.

Sun, 09/06/2019 - 15:23
Related Articles Tackling the Complexity of the Exposome: Considerations from the Gunma University Initiative for Advanced Research (GIAR) Exposome Symposium. Metabolites. 2019 Jun 06;9(6): Authors: Zhang P, Arora M, Chaleckis R, Isobe T, Jain M, Meister I, Melén E, Perzanowski M, Torta F, Wenk MR, Wheelock CE Abstract The attempt to describe complex diseases by solely genetic determination has not been successful. There is increasing recognition that the development of disease is often a consequence of interactions between multiple genetic and environmental factors. To date, much of the research on environmental determinants of disease has focused on single exposures generally measured at a single time point. In order to address this limitation, the concept of the exposome has been introduced as a comprehensive approach, studying the full complement of environmental exposures from conception onwards. However, exposures are vast, dynamic, and diverse, and only a small proportion can be reasonably measured due to limitations in technology and feasibility. In addition, the interplay between genes and exposure as well as between different exposures is complicated and multifaceted, which leads to difficulties in linking disease or health outcomes with exposures. The large numbers of collected samples require well-designed logistics. Furthermore, the immense data sets generated from exposome studies require a significant computational investment for both data analysis and data storage. This report summarizes discussions during an international exposome symposium held at Gunma University in Japan regarding the concept of the exposome, challenges in exposome research, and future perspectives in the field. PMID: 31174297 [PubMed]

Perigestational low-dose BDE-47 exposure alters maternal serum metabolome and results in sex-specific weight gain in adult offspring.

Sat, 08/06/2019 - 12:07
Perigestational low-dose BDE-47 exposure alters maternal serum metabolome and results in sex-specific weight gain in adult offspring. Chemosphere. 2019 May 30;233:174-182 Authors: Gao H, Li P, Liu L, Yang K, Xiao B, Zhou G, Tian Z, Luo C, Xia T, Dong L, Zhao Q, Wang A, Zhang S Abstract Emerging evidence suggests environmental contaminant exposures during critical windows of development may contribute to the increasing prevalence of obesity. It has been shown that early life polybrominated diphenyl ethers exposures have critical impacts on child weight trajectories, however, little is known about their maternal mechanisms responsible for offspring obesity development. In this study, we investigated the effects of perigestational low-dose 2, 2', 4, 4'-tetrabromodiphenyl ether (BDE-47) exposure on maternal metabolome, and its possible link to adult offspring bodyweight changes. Female Sprague-Dawley rats were exposed to daily doses of 0.1, or 1 mg/kg BDE-47 from 10 days prior to conception until offspring were weaned on postnatal day 21, and then a gas chromatography-mass spectrometry based metabolomics analysis was used to uncover the global metabolic response in dams. The pups continued to grow into adulthood for measurements of bodyweight. Perigestational BDE-47 exposure caused increased adult bodyweight in male but not in female offspring and dams. Metabolomics revealed significant changes in maternal serum metabolites that clearly distinguish BDE-47 from control rats. These differentially expressed metabolites were primarily implicated in amino acid, lipid, carbohydrate, and energy metabolisms, which was confirmed by pathway analysis. Importantly, most of these identified metabolites were decreased, a state similar to maternal malnutrition that can predispose adult male offspring to weight increase and adiposity in a postnatal environment with abundant calories. Collectively, our data suggest that perigestational exposure to low-dose BDE-47 produces altered maternal serum metabolome, which may be an additional contributing factor to weight gain in adult male offspring. PMID: 31173955 [PubMed - as supplied by publisher]

α-Ketoglutarate inhibits autophagy.

Sat, 08/06/2019 - 12:07
α-Ketoglutarate inhibits autophagy. Aging (Albany NY). 2019 Jun 07;: Authors: Baracco EE, Castoldi F, Durand S, Enot DP, Tadic J, Kainz K, Madeo F, Chery A, Izzo V, Maiuri MC, Pietrocola F, Kroemer G Abstract The metabolite α-ketoglutarate is membrane-impermeable, meaning that it is usually added to cells in the form of esters such as dimethyl -ketoglutarate (DMKG), trifluoromethylbenzyl α-ketoglutarate (TFMKG) and octyl α-ketoglutarate (O-KG). Once these compounds cross the plasma membrane, they are hydrolyzed by esterases to generate α-ketoglutarate, which remains trapped within cells. Here, we systematically compared DMKG, TFMKG and O-KG for their metabolic and functional effects. All three compounds similarly increased the intracellular levels of α-ketoglutarate, yet each of them had multiple effects on other metabolites that were not shared among the three agents, as determined by mass spectrometric metabolomics. While all three compounds reduced autophagy induced by culture in nutrient-free conditions, TFMKG and O-KG (but not DMKG) caused an increase in baseline autophagy in cells cultured in complete medium. O-KG (but neither DMKG nor TFMK) inhibited oxidative phosphorylation and exhibited cellular toxicity. Altogether, these results support the idea that intracellular α-ketoglutarate inhibits starvation-induced autophagy and that it has no direct respiration-inhibitory effect. PMID: 31173576 [PubMed - as supplied by publisher]

Serum metabolites as predictive molecular markers of ovarian response to controlled stimulation: a pilot study.

Sat, 08/06/2019 - 12:07
Serum metabolites as predictive molecular markers of ovarian response to controlled stimulation: a pilot study. JBRA Assist Reprod. 2019 Jun 07;: Authors: Borges E, Montani DA, Setti AS, Zanetti BF, Figueira RCS, Iaconelli A, Oliveira-Silva D, Braga DPAF Abstract OBJECTIVE: This study aimed to look into the use of serum metabolites as potential biomarkers of response to controlled ovarian stimulation (COS) in patients undergoing intracytoplasmic sperm injection (ICSI) cycles. METHODS: This case-control study analyzed serum samples from 30 patients aged <36 years undergoing COS for ICSI in a university-affiliated assisted reproduction center from January 2017 to August 2017. The samples were split into three groups based on response to COS as follows: poor responders: <4 retrieved oocytes (PR group, n=10); normal responders: ≥ 8 and ≤ 12 retrieved oocytes (NR group, n=10); and hyper-responders: >25 retrieved oocytes (HR, n=10). The metabolic profiles of the serum samples were compared between the groups through Principal Component Analysis (PCA). Receiver Operating Characteristic (ROC) curves were built to assess the power of the model at predicting response to COS. RESULTS: PCA clearly distinguished between PR, NR and HR, and 10 ions were chosen as potential biomarkers of response to COS. These ions were more specific for PR than for NR. The ROC curve considering PR and NR had an area under the curve of 99.6% (95% CI: 88.9 - 100%). CONCLUSION: The preliminary evidence discussed in this study suggests that serum metabolites may be used as predictive molecular markers of ovarian response to controlled stimulation. The integration of clinical and "omics" findings may allow the migration toward an era of personalized treatment in reproductive medicine. PMID: 31173494 [PubMed - as supplied by publisher]

Emerging applications of metabolomics in clinical pharmacology.

Sat, 08/06/2019 - 12:07
Emerging applications of metabolomics in clinical pharmacology. Clin Pharmacol Ther. 2019 Jun 07;: Authors: Pang H, Jia W, Hu Z Abstract Metabolic disturbances have been associated with many human diseases, including cancer, diabetes, and cardiovascular disease. Metabolomics, a rapidly growing member of the 'omics family, investigates cellular metabolism by quantifying metabolites on a large-scale and provides a link between metabolic pathways and the upstream genome that governs them. With the advances in analytical technologies, metabolomics is becoming a powerful tool for identifying diagnostic biomarkers of diseases, elucidating the pathological mechanisms, discovering novel drug targets, predicting drug responses, interpreting the mechanisms of drug action, as well as enabling precision treatment of patients. In this review, we highlight the recent advances of technologies and methodologies in metabolomics and their applications to the field of clinical pharmacology. Recent publications from 2013 to 2018 are covered in the review, and current challenges and potential future directions in the field are also discussed. This article is protected by copyright. All rights reserved. PMID: 31173340 [PubMed - as supplied by publisher]

[Metabonomics studies of urine from APP/PS1 mice with early-stage Alzheimer's disease].

Sat, 08/06/2019 - 12:07
Related Articles [Metabonomics studies of urine from APP/PS1 mice with early-stage Alzheimer's disease]. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2018 Dec 25;47(6):636-642 Authors: Zheng Y, Zhang X, Chen J, Zhou Q, Gao H Abstract OBJECTIVE: To investigate the metabolic profiles of urine from APP/PS1 mice with early-stage Alzheimer's disease (AD). METHODS: Urine samples were collected from 13 APP/PS1 mice of 16 weeks and 15 wild-type mice. 1H-NMR spectroscopy was acquired with a one-dimensional NOESY pulse sequence, and the integral values were imported to SIMCA-P+12.0 software for analysis. RESULTS: The metabonomic analysis showed that the metabolic profiles of the APP/PS1 mice were significantly different from that of age-matched wild-type mice. The levels of 3-hydroxybutyrate, 2-hydroxybutyrate, succinic acid, 2-ketoglutaric acid, citric acid, cis-aconitic acid, fumaric acid decreased, and those of acetic acid, trimethylamine, taurine, creatinine, hippuric acid, formic acid, trigonelline, urea increased (all P<0.05). CONCLUSIONS: Metabolic pathways including glucose metabolism and methylamine metabolism may be involved in the pathogenesis of early AD. PMID: 30900843 [PubMed - indexed for MEDLINE]

[Effects of Niaoduqing granule on urine metabolic profile in chronic renal failure rats].

Sat, 08/06/2019 - 12:07
Related Articles [Effects of Niaoduqing granule on urine metabolic profile in chronic renal failure rats]. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2018 Dec 25;47(6):628-635 Authors: Zhu M, Wu Y, Shou Z Abstract OBJECTIVE: To investigate the effects of Niaoduqing granule on the urine metabolic profile in chronic renal failure (CRF) rats. METHODS: Thirty six male SD rats were divided into the normal control group, the model group, and the Niaoduqing group with 12 rats in each group. The CRF was induced by gavage of 250 mg·kg-1·d-1 adenine for 21 d. UPLC-Q-TOF-MS/MS technique was used in combination with principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) to analyze the urine metabolic profiles in three groups. The endogenous substances with the variable importance projection (VIP)>1 and P<0.05 were screened as the potential biomarkers for CRF, and enrichment analysis of metabolic pathways was carried out. RESULTS: Compared with the normal control group, the model group had lower body weight, higher kidney coefficient, higher serum creatinine and urea nitrogen levels (all P<0.01), while the above indexes in the Niaoduqing group were ameliorated compared with the model group (all P<0.01). Fifteen potential biomarkers were found in the urine of the model group, which were involved in 9 metabolic pathways including phenylalanine, tyrosine and tryptophan biosynthesis, glyoxylate and dicarboxylate metabolism, valine, leucine and isoleucine biosynthesis, arachidonic acid metabolism, cysteine and methionine metabolism, tricarboxylic acid cycle, glycerophosphatide metabolism, tryptophan metabolism and tyrosine metabolism. CONCLUSIONS: Niaoduqing granules has therapeutic effect on rats with CRF, which may be related to the regulation of amino acid metabolism, lipid metabolism and energy metabolism. PMID: 30900842 [PubMed - indexed for MEDLINE]

NMR and MS urinary metabolic phenotyping in kidney diseases is fit-for-purpose in the presence of a protease inhibitor.

Sat, 08/06/2019 - 12:07
Related Articles NMR and MS urinary metabolic phenotyping in kidney diseases is fit-for-purpose in the presence of a protease inhibitor. Mol Omics. 2019 02 11;15(1):39-49 Authors: Boulangé CL, Rood IM, Posma JM, Lindon JC, Holmes E, Wetzels JFM, Deegens JKJ, Kaluarachchi MR Abstract Nephrotic syndrome with idiopathic membranous nephropathy as a major contributor, is characterized by proteinuria, hypoalbuminemia and oedema. Diagnosis is based on renal biopsy and the condition is treated using immunosuppressive drugs; however nephrotic syndrome treatment efficacy varies among patients. Multi-omic urine analyses can discover new markers of nephrotic syndrome that can be used to develop personalized treatments. For proteomics, a protease inhibitor (PI) is sometimes added at sample collection to conserve proteins but its impact on urine metabolic phenotyping needs to be evaluated. Urine from controls (n = 4) and idiopathic membranous nephropathy (iMN) patients (n = 6) were collected with and without PI addition and analysed using 1H NMR spectroscopy and UPLC-MS. PI-related data features were observed in the 1H NMR spectra but their removal followed by a median fold change normalisation, eliminated the PI contribution. PI-related metabolites in UPLC-MS data had limited effect on metabolic patterns specific to iMN. When using an appropriate data processing pipeline, PI-containing urine samples are appropriate for 1H NMR and MS metabolic profiling of patients with nephrotic syndrome. PMID: 30672550 [PubMed - indexed for MEDLINE]

Exploratory metabolomic study to identify blood-based biomarkers as a potential screen for colorectal cancer.

Sat, 08/06/2019 - 12:07
Related Articles Exploratory metabolomic study to identify blood-based biomarkers as a potential screen for colorectal cancer. Mol Omics. 2019 02 11;15(1):21-29 Authors: Asante I, Pei H, Zhou E, Liu S, Chui D, Yoo E, Conti DV, Louie SG Abstract INTRODUCTION: colorectal cancer (CRC) continues to be difficult to diagnose due to the lack of reliable and predictive biomarkers. OBJECTIVE: to identify blood-based biomarkers that can be used to distinguish CRC cases from controls. METHODS: a workflow for untargeted followed by targeted metabolic profiling was conducted on the plasma samples of 26 CRC cases and ten healthy volunteers (controls) using liquid chromatography-mass spectrometry (LCMS). The data acquired in the untargeted scan was processed and analyzed using MarkerView™ software. The significantly different ions that distinguish CRC cases from the controls were identified using a mass-based human metabolome search. The result was further used to inform the targeted scan workflow. RESULTS: the untargeted scan yielded putative biomarkers some of which were related to the folate-dependent one-carbon metabolism (FOCM). Analysis of the targeted scan found the plasma levels of nine FOCM metabolites to be significantly different between cases and controls. The classification models of the cases and controls, in both the targeted and untargeted approaches, each yielded a 97.2% success rate after cross-validation. CONCLUSION: we have identified plasma metabolites with screening potential to discriminate between CRC cases and controls. PMID: 30515501 [PubMed - indexed for MEDLINE]

Vacuolar sucrose cleavage prevents limitation of cytosolic carbohydrate metabolism and stabilizes photosynthesis under abiotic stress.

Sat, 08/06/2019 - 12:07
Related Articles Vacuolar sucrose cleavage prevents limitation of cytosolic carbohydrate metabolism and stabilizes photosynthesis under abiotic stress. FEBS J. 2018 11;285(21):4082-4098 Authors: Weiszmann J, Fürtauer L, Weckwerth W, Nägele T Abstract Stabilization of central carbohydrate metabolism plays a key role in plant stress response. Carbohydrates are substrate for numerous metabolic and stress-responsive reactions and have been shown to be involved in diverse signalling processes on a whole-plant level. Regulation of enzymatic sucrose synthesis and degradation is well-known to be central to many stress-related processes as it significantly impacts stress tolerance. Leaf sucrose metabolism involves sucrose cleavage by invertases and ATP-consuming resynthesis catalysed by hexokinase and sucrose phosphate synthase. These reactions establish a metabolic cycle. To study the physiological role of sucrose cycling, a kinetic model was developed to simulate dynamics of subcellular sugar concentrations in Arabidopsis thaliana under combined cold and high-light stress. Model simulation revealed that subcellular reprogramming of invertase-driven sucrose cleavage varies substantially between natural accessions of Arabidopsis which differ in their cold tolerance levels. A stress-induced shift of sucrose cleavage from the cytosol into the vacuole could only be observed for the tolerant accession while the susceptible accession increased the cytosolic proportion of sucrose cleavage. Under stress, reduction in vacuolar invertase activity significantly affected maximum quantum yield of photosystem II and CO2 assimilation rates. While wild-type plants circumvented a limitation of sucrose cleavage by increasing vacuolar invertase activity, mutant plants were not able to compensate their deficiency of vacuolar by cytosolic activity. Consequently, the capacity for cytosolic hexose generation was lower than for enzymatic hexose phosphorylation suggesting a role of vacuolar invertase activity in preventing a limitation in cytosolic hexose metabolism under stress. ENZYMES: Invertase, EC 3.2.1.26; Hexokinase, EC 2.7.1.1. PMID: 30216682 [PubMed - indexed for MEDLINE]

Beta-hydroxybutyrate infusion identifies acutely differentially expressed genes related to metabolism and reproduction in the hypothalamus and pituitary of castrated male sheep.

Sat, 08/06/2019 - 12:07
Related Articles Beta-hydroxybutyrate infusion identifies acutely differentially expressed genes related to metabolism and reproduction in the hypothalamus and pituitary of castrated male sheep. Physiol Genomics. 2018 06 01;50(6):468-477 Authors: Cope ER, Voy BH, Whitlock BK, Staton M, Lane T, Davitt J, Mulliniks JT Abstract To identify molecular pathways that couple metabolic imbalances and reproduction, we randomly assigned 10 castrated male sheep to be centrally injected into the lateral ventricle through intracerebroventricular cannulas with 1 ml of β-hydroxybutyric acid sodium salt solution (BHB; 12,800 µmol/l) or saline solution (CON; 0.9% NaCl). Approximately 2 h postinjection, sheep were humanely euthanized, and hypothalamus and pituitary tissues were harvested for transcriptome characterization by RNA sequencing. RNA was extracted from the hypothalamus and pituitary and sequenced at a high depth (hypothalamus: 468,912,732 reads; pituitary: 515,106,092 reads) with the Illumina Hi-Seq 2500 platform and aligned to Bos taurus and Ovis aries genomes. Of the total raw reads, 87% (hypothalamus) and 90.5% (pituitary) mapped to the reference O. aries genome. Within these read sets, ~56% in hypothalamus and 69% in pituitary mapped to either known or putative protein coding genes. Fragments per kilobase of transcripts per million normalized counts were averaged and ranked to identify the transcript expression level. Gene Ontology analysis (DAVID Bioinformatics Resources) was utilized to identify biological process functions related to genes shared between tissues, as well as functional categories with tissue-specific enrichment. Between CON- and BHB-treated sheep, 11 and 44 genes were differentially expressed (adj. P < 0.05) within the pituitary and hypothalamus, respectively. Functional enrichment analyses revealed BHB altered expression of genes in pathways related to stimulus perception, inflammation, and cell cycle control. The set of genes altered by BHB creates a foundation from which to identify the signaling pathways that impact reproduction during metabolic imbalances. PMID: 29625019 [PubMed - indexed for MEDLINE]

Transcriptomic analysis reveals inflammatory and metabolic pathways that are regulated by renal perfusion pressure in the outer medulla of Dahl-S rats.

Sat, 08/06/2019 - 12:07
Related Articles Transcriptomic analysis reveals inflammatory and metabolic pathways that are regulated by renal perfusion pressure in the outer medulla of Dahl-S rats. Physiol Genomics. 2018 06 01;50(6):440-447 Authors: Evans LC, Dayton A, Yang C, Liu P, Kurth T, Ahn KW, Komas S, Stingo FC, Laud PW, Vannucci M, Liang M, Cowley AW Abstract Studies exploring the development of hypertension have traditionally been unable to distinguish which of the observed changes are underlying causes from those that are a consequence of elevated blood pressure. In this study, a custom-designed servo-control system was utilized to precisely control renal perfusion pressure to the left kidney continuously during the development of hypertension in Dahl salt-sensitive rats. In this way, we maintained the left kidney at control blood pressure while the right kidney was exposed to hypertensive pressures. As each kidney was exposed to the same circulating factors, differences between them represent changes induced by pressure alone. RNA sequencing analysis identified 1,613 differently expressed genes affected by renal perfusion pressure. Three pathway analysis methods were applied, one a novel approach incorporating arterial pressure as an input variable allowing a more direct connection between the expression of genes and pressure. The statistical analysis proposed several novel pathways by which pressure affects renal physiology. We confirmed the effects of pressure on p-Jnk regulation, in which the hypertensive medullas show increased p-Jnk/Jnk ratios relative to the left (0.79 ± 0.11 vs. 0.53 ± 0.10, P < 0.01, n = 8). We also confirmed pathway predictions of mitochondrial function, in which the respiratory control ratio of hypertensive vs. control mitochondria are significantly reduced (7.9 ± 1.2 vs. 10.4 ± 1.8, P < 0.01, n = 6) and metabolomic profile, in which 14 metabolites differed significantly between hypertensive and control medullas ( P < 0.05, n = 5). These findings demonstrate that subtle differences in the transcriptome can be used to predict functional changes of the kidney as a consequence of pressure elevation. PMID: 29602296 [PubMed - indexed for MEDLINE]

metabolomics; +33 new citations

Fri, 07/06/2019 - 18:02
33 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 2019/06/07PubMed 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.

Molecular Profiling and Functional Analysis of Macrophage-Derived Tumor Extracellular Vesicles.

Thu, 06/06/2019 - 14:52
Related Articles Molecular Profiling and Functional Analysis of Macrophage-Derived Tumor Extracellular Vesicles. Cell Rep. 2019 Jun 04;27(10):3062-3080.e11 Authors: Cianciaruso C, Beltraminelli T, Duval F, Nassiri S, Hamelin R, Mozes A, Gallart-Ayala H, Ceada Torres G, Torchia B, Ries CH, Ivanisevic J, De Palma M Abstract Extracellular vesicles (EVs), including exosomes, modulate multiple aspects of cancer biology. Tumor-associated macrophages (TAMs) secrete EVs, but their molecular features and functions are poorly characterized. Here, we report methodology for the enrichment, quantification, and proteomic and lipidomic analysis of EVs released from mouse TAMs (TAM-EVs). Compared to source TAMs, TAM-EVs present molecular profiles associated with a Th1/M1 polarization signature, enhanced inflammation and immune response, and a more favorable patient prognosis. Accordingly, enriched TAM-EV preparations promote T cell proliferation and activation ex vivo. TAM-EVs also contain bioactive lipids and biosynthetic enzymes, which may alter pro-inflammatory signaling in the cancer cells. Thus, whereas TAMs are largely immunosuppressive, their EVs may have the potential to stimulate, rather than limit, anti-tumor immunity. PMID: 31167148 [PubMed - in process]

Application of Ion Chromatography Coupled with Mass Spectrometry for Human Serum and Urine Metabolomics.

Thu, 06/06/2019 - 14:52
Related Articles Application of Ion Chromatography Coupled with Mass Spectrometry for Human Serum and Urine Metabolomics. SLAS Discov. 2019 Jun 05;:2472555219850082 Authors: Sun Y, Saito K, Iiji R, Saito Y Abstract Biomarkers that indicate the presence or severity of organ damage caused by diseases and toxicities are useful diagnostic tools. Metabolomics platforms using chromatography coupled with mass spectrometry (MS) have been widely used for biomarker screening. In this study, we aimed to establish a novel metabolomics platform using ion chromatography coupled with MS (IC-MS) for human biofluids. We found that ethylenediaminetetraacetic acid (EDTA) plasma is not suitable for IC-MS metabolomics platforms because of the desensitization of MS. IC-MS enabled detection of 131 polar metabolites in human serum and urine from healthy volunteers. Pathway analysis demonstrated that the metabolites detectable using our platform were composed of a broad spectrum of organic acids with carboxylic moieties. These metabolites were significantly associated with pathways such as the tricarboxylic acid (TCA) cycle; glyoxylate and dicarboxylate metabolism; alanine, aspartate, and glutamate metabolism; butanoate metabolism; and the pentose phosphate pathway. Moreover, comparison of serum and urine samples showed that four metabolites (4-hydroxybutyric acid, aspartic acid, lactic acid, and γ-glutamyl glutamine) were abundant in serum, whereas 62 metabolites, including phosphoric acid, vanillylmandelic acid, and N-tiglylglycine, were abundant in urine. In addition, allantoin and uric acid were abundant in male serum, whereas no gender-associated differences were found for polar metabolites in urine. Our results demonstrate that the present established IC-MS metabolomics platform can be applied for analysis of human serum and urine as well as detection of a broad spectrum of polar metabolites in human biofluids. PMID: 31166806 [PubMed - as supplied by publisher]

CREB mediates glucagon action to upregulate hepatic MPC1: inhibitory effect of ginsenoside Rb1 on hepatic gluconeogenesis.

Thu, 06/06/2019 - 14:52
Related Articles CREB mediates glucagon action to upregulate hepatic MPC1: inhibitory effect of ginsenoside Rb1 on hepatic gluconeogenesis. Br J Pharmacol. 2019 Jun 05;: Authors: Lou MD, Li J, Cheng Y, Xiao N, Ma G, Li P, Liu B, Liu Q, Qi LW Abstract BACKGROUND AND PURPOSE: Hepatic mitochondrial pyruvate carrier (MPC) transports pyruvate into mitochondria. This study investigated the involvement of MPC1 in hepatic glucagon response, with the aim of finding a potential for pharmacological intervention. EXPERIMENTAL APPROACH: The correlation between hepatic glucagon response and MPC1 induction was investigated in fasted mice and primary hepatocytes. The effects of ginsenoside Rb1 on MPC1 function were observed. KEY RESULTS: Glucagon challenge raised blood glucose with hepatic MPC1 induction and inhibition of MPC induction coincided with a reduced rise in blood glucose. Cyclic AMP-responsive element-binding protein (CREB) knockdown abrogated glucagon-induced MPC1 expression, while CREB overexpression increased MPC1 expression. Luciferase reporter, ChIP assay and promoter mutation confirmed that CREB increased MPC1 transcription through gene promoter induction. CRTC2 nuclear translocation was also required for CREB to promote MPC1 induction. Glucagon shifted mitochondrial pyruvate towards carboxylation for gluconeogenesis via the opposite regulation of pyruvate dehydrogenase and carboxylase with respect to MPC1 induction. MPC1 induction was necessary for glucagon to promote pyruvate-driven HGP, while glucagon failed to influence HGP from other gluconeogenic substrates that are routed into the TCA cycle independent of MPC. Rb1 blocked cAMP signaling by inhibition of adenyl cyclase activity and deactivated CREB by dephosphorylation, likely contributing to inhibiting MPC1 induction to reduce HGP. CONCLUSIONS AND IMPLICATIONS: CREB transcriptionally upregulates MPC1 to ensure pyruvate availability for gluconeogenesis. Rb1 reduced cAMP formation which consequently reduced CREB-mediated MPC1 induction, and thereby might contribute to limiting pyruvate-dependent HGP. These results suggest a therapeutic strategy to reduce hyperglycemia in diabetes. PMID: 31166615 [PubMed - as supplied by publisher]

Association of Dimethylguanidino Valeric Acid With Partial Resistance to Metabolic Health Benefits of Regular Exercise.

Thu, 06/06/2019 - 14:52
Related Articles Association of Dimethylguanidino Valeric Acid With Partial Resistance to Metabolic Health Benefits of Regular Exercise. JAMA Cardiol. 2019 Jun 05;: Authors: Robbins JM, Herzig M, Morningstar J, Sarzynski MA, Cruz DE, Wang TJ, Gao Y, Wilson JG, Bouchard C, Rankinen T, Gerszten RE Abstract Importance: Metabolic responses to exercise training are variable. Metabolite profiling may aid in the clinical assessment of an individual's responsiveness to exercise interventions. Objective: To investigate the association between a novel circulating biomarker of hepatic fat, dimethylguanidino valeric acid (DMGV), and metabolic health traits before and after 20 weeks of endurance exercise training. Design, Setting, and Participants: This study involved cross-sectional and longitudinal analyses of the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study, a 20-week, single-arm endurance exercise clinical trial performed in multiple centers between 1993 and 1997. White participants with sedentary lifestyles who were free of cardiometabolic disease were included. Metabolomic tests were performed using a liquid chromatography, tandem mass spectrometry method on plasma samples collected before and after exercise training in the HERITAGE study. Metabolomics and data analysis were performed from August 2017 to May 2018. Exposures: Plasma DMGV levels. Main Outcome and Measures: The association between DMGV levels and measures of body composition, plasma lipids, insulin, and glucose homeostasis before and after exercise training. Results: Among the 439 participants included in analyses from HERITAGE, the mean (SD) age was 36 (15) years, 228 (51.9%) were female, and the median (interquartile range) body mass index was 25 (22-28). Baseline levels of DMGV were positively associated with body fat percentage, abdominal visceral fat, very low-density lipoprotein cholesterol, and triglycerides, and inversely associated with insulin sensitivity, low-density lipoprotein cholesterol, high-density lipoprotein size, and high-density lipoprotein cholesterol (range of β coefficients, 0.17-0.46 [SEs, 0.026-0.050]; all P < .001, after adjusting for age and sex). After adjusting for age, sex, and baseline traits, baseline DMGV levels were positively associated with changes in small high-density lipoprotein particles (β, 0.14 [95% CI, 0.05-0.23]) and inversely associated with changes in medium and total high-density lipoprotein particles (β, -0.15 [95% CI, -0.24 to -0.05] and -0.19 [95% CI, -0.28 to -0.10], respectively), apolipoprotein A1 (β, -0.14 [95% CI, -0.23 to -0.05]), and insulin sensitivity (β, -0.13; P = 3.0 × 10-3) after exercise training. Conclusions and Relevance: Dimethylguanidino valeric acid is an early marker of cardiometabolic dysfunction that is associated with attenuated improvements in lipid traits and insulin sensitivity after exercise training. Levels of DMGV may identify individuals who require additional therapies beyond guideline-directed exercise to improve their metabolic health. PMID: 31166569 [PubMed - as supplied by publisher]

Application of Omics and Bioinformatics Tools in Streptococcus Research.

Thu, 06/06/2019 - 14:52
Related Articles Application of Omics and Bioinformatics Tools in Streptococcus Research. Curr Issues Mol Biol. 2019 Jun 05;32:327-376 Authors: Liao M, Tong T, Zong Y, Zhou X, Cheng L, Huang R, Ren B, Alterovitz G Abstract Researchers used to focus on analyzing single gene or protein expression of the microbes. But recently, genome, transcriptome, proteome and metabolome have gained more and more attention. Based on technologies of omics, including genomics, transcriptomics and metabolomics, a large quantity of information about cells, microbes and human, such as the information about phylogeny, virulence, antibiotic resistance and other aspects, has been revealed. Genus Streptococcus is one of the most invasive groups of bacteria that cause both human and animal diseases, threatening public health. In this review, we summarize the application of omics to analyze this genus-Streptococcus. PMID: 31166175 [PubMed - as supplied by publisher]

Parahydrogen induced hyperpolarization provides a tool for NMR metabolomics at nanomolar concentrations.

Thu, 06/06/2019 - 14:52
Related Articles Parahydrogen induced hyperpolarization provides a tool for NMR metabolomics at nanomolar concentrations. Chem Commun (Camb). 2019 Jun 05;: Authors: Sellies L, Reile I, Aspers RLEG, Feiters MC, Rutjes FPJT, Tessari M Abstract An NMR approach based on parahydrogen hyperpolarization is presented to detect and resolve specific classes of metabolites in complex biomixtures at down to nanomolar concentrations. We demonstrate our method on solid phase extracts of urine, by simultaneously observing hundreds of metabolites well below the limits of detection of thermal NMR. PMID: 31165813 [PubMed - as supplied by publisher]

Metabolomic signatures of asthma-COPD overlap (ACO) are different from asthma and COPD.

Thu, 06/06/2019 - 14:52
Related Articles Metabolomic signatures of asthma-COPD overlap (ACO) are different from asthma and COPD. Metabolomics. 2019 Jun 04;15(6):87 Authors: Ghosh N, Choudhury P, Subramani E, Saha D, Sengupta S, Joshi M, Banerjee R, Roychowdhury S, Bhattacharyya P, Chaudhury K Abstract INTRODUCTION: Asthma-chronic obstructive pulmonary disease (COPD) overlap, termed as ACO, is a complex heterogeneous disease without any clear diagnostic or therapeutic guidelines. The pathophysiology of the disease, its characteristic features, and existence as a unique disease entity remains unclear. Individuals with ACO have a faster lung function decline, more frequent exacerbations, and worse quality of life than those with COPD or asthma alone. OBJECTIVES: The present study aims to determine whether ACO has a distinct metabolic profile in comparison to asthma and COPD. METHODS: Two different groups of patients were recruited as discovery (D) and validation (V) cohorts. Serum samples obtained from moderate and severe asthma patients diagnosed as per GINA guidelines [n = 34(D); n = 32(V)], moderate and severe COPD cases identified by GOLD guidelines [n = 30(D); 32(V)], ACO patients diagnosed by joint GOLD and GINA guidelines [n = 35(D); 40(V)] and healthy controls [n = 33(D)] were characterized using nuclear magnetic resonance (NMR) spectrometry. RESULTS: Multivariate and univariate analysis indicated that 12 metabolites [lipid, isoleucine, N-acetylglycoproteins (NAG), valine, glutamate, citric acid, glucose, L-leucine, lysine, asparagine, phenylalanine and histidine] were dysregulated in ACO patients when compared with both asthma and COPD. These metabolites were further validated in a fresh cohort of patients, which again exhibited a similar expression pattern. CONCLUSIONS: Our findings suggest that ACO has an enhanced energy and metabolic burden associated with it as compared to asthma and COPD. It is anticipated that our results will stimulate researchers to further explore ACO and unravel the pathophysiological complexities associated with the disease. PMID: 31165288 [PubMed - in process]

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