1,729 research outputs found

    Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation.

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    PI3K plays a key role in cellular metabolism and cancer. Using a mass spectrometry-based metabolomics platform, we discovered that plasma concentrations of 26 metabolites, including amino acids, acylcarnitines, and phosphatidylcholines, were decreased in mice bearing PTEN-deficient tumors compared with non-tumor-bearing controls and in addition were increased following dosing with class I PI3K inhibitor pictilisib (GDC-0941). These candidate metabolomics biomarkers were evaluated in a phase I dose-escalation clinical trial of pictilisib. Time- and dose-dependent effects were observed in patients for 22 plasma metabolites. The changes exceeded baseline variability, resolved after drug washout, and were recapitulated on continuous dosing. Our study provides a link between modulation of the PI3K pathway and changes in the plasma metabolome and demonstrates that plasma metabolomics is a feasible and promising strategy for biomarker evaluation. Also, our findings provide additional support for an association between insulin resistance, branched-chain amino acids, and related metabolites following PI3K inhibition. Mol Cancer Ther; 15(6); 1412-24. ©2016 AACR.The Institute of Cancer ResearchThis is the author accepted manuscript. The final version is available from the American Association for Cancer Research via http://dx.doi.org/10.1158/1535-7163.MCT-15-081

    Arteriovenous Blood Metabolomics: A Readout of Intra-Tissue Metabostasis.

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    The human circulatory system consists of arterial blood that delivers nutrients to tissues, and venous blood that removes the metabolic by-products. Although it is well established that arterial blood generally has higher concentrations of glucose and oxygen relative to venous blood, a comprehensive biochemical characterization of arteriovenous differences has not yet been reported. Here we apply cutting-edge, mass spectrometry-based metabolomic technologies to provide a global characterization of metabolites that vary in concentration between the arterial and venous blood of human patients. Global profiling of paired arterial and venous plasma from 20 healthy individuals, followed up by targeted analysis made it possible to measure subtle (<2 fold), yet highly statistically significant and physiologically important differences in water soluble human plasma metabolome. While we detected changes in lactic acid, alanine, glutamine, and glutamate as expected from skeletal muscle activity, a number of unanticipated metabolites were also determined to be significantly altered including Krebs cycle intermediates, amino acids that have not been previously implicated in transport, and a few oxidized fatty acids. This study provides the most comprehensive assessment of metabolic changes in the blood during circulation to date and suggests that such profiling approach may offer new insights into organ homeostasis and organ specific pathology

    Plasma metabolome of children with aberrant cholesterol and modulation by navy bean and rice bran consumption

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    2018 Spring.Includes bibliographical references.Abnormal cholesterol in childhood predicts cardiovascular disease (CVD) risk in adulthood. Navy beans and rice bran have demonstrated efficacy in regulating blood lipids in adults and children; however, their effects on modulating the child plasma metabolome has not been investigated and warrants investigation. A pilot, randomized-controlled, clinical trial was conducted in 38 children (10 ± 0.8 years old) with abnormal cholesterol. Participants consumed a snack for 4 weeks containing either: no navy bean or rice bran (control); 17.5 g/day cooked navy bean powder; 15 g/day heat-stabilized rice bran, or; 9 g/day navy beans and 8 g/day rice bran. Plasma metabolites were extracted using 80% methanol for global, non-targeted metabolic profiling via ultra-high performance liquid-chromatography tandem mass spectrometry. To examine correlations between baseline serum lipid levels and plasma metabolites, non-parametric Spearman's correlation coefficients (rs) were computed between serum total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides (TG) with 805 plasma metabolites. Differences in plasma metabolite levels after 4 weeks of dietary intervention compared to control and baseline were analyzed using analysis of variance and Welch's t-tests (p≤0.05). Approximately 29% of the plasma metabolome (235 metabolites) were significantly correlated with serum lipids. Plasma cholesterol was positively correlated with serum total cholesterol, and 27 plasma metabolites were found to be strongly correlated with serum TG (rs ≥0.60; p≤0.0001). Navy bean and/or rice bran consumption influenced 71 plasma compounds compared to control (p≤0.05), with lipids representing 46% of the total plasma metabolome. Significant changes were determined for 18 plasma lipids in the navy bean group and 10 plasma lipids for the rice bran group compared to control, and 48 lipids in the navy bean group and 40 in the rice bran group compared to baseline. This supports the hypothesis that consumption of these foods impact blood lipid metabolism with implications for reducing CVD risk in children. Complementary and distinct lipid pathways were affected by the diet groups, including acylcarnitines and lysolipids (navy bean), sphingolipids (rice bran), and phospholipids (navy bean + rice bran). Navy bean consumption decreased free fatty acids associated with metabolic diseases (palmitate and arachidonate) and increased the relative abundance of endogenous anti-inflammatory lipids (endocannabinoids, N-linoleoylglycine, 12,13-diHOME). Several diet-derived amino acids, phytochemicals, and cofactors/vitamins with cardioprotective properties were increased compared to control and/or baseline, including 6-oxopiperidine-2-carboxylate (1.87-fold), N-methylpipecolate (1.89-fold), trigonelline (4.44- to 7.75-fold), S-methylcysteine (2.12-fold) (navy bean), salicylate (2.74-fold), and pyridoxal (3.35- to 3.96-fold) (rice bran). Findings from this pilot study support the need for investigating the effects of these foods for longer durations to reduce CVD risk

    Short-term oral atrazine exposure alters the plasma metabolome of male C57BL/6 mice and disrupts α -linolenate, tryptophan, tyrosine and other major metabolic pathways

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    Overexposure to the commonly used herbicide atrazine (ATR) affects several organ systems, including the brain. Previously, we demonstrated that short-term oral ATR exposure causes behavioral deficits and dopaminergic and serotonergic dysfunction in the brains of mice. Using adult male C57BL/6 mice, the present study aimed to investigate effects of a 10-day oral ATR exposure (0, 5, 25, 125, or 250 mg/kg) on the mouse plasma metabolome and to determine metabolic pathways affected by ATR that may be reflective of ATR’s effects on the brain and useful to identify peripheral biomarkers of neurotoxicity. Four h after the last dosing on day 10, plasma was collected and analyzed with high-performance, dual chromatography-Fourier-transform mass spectrometry that was followed by biostatistical and bioinformatic analyses. ATR exposure (≥5 mg/kg) significantly altered plasma metabolite profile and resulted in a dose-dependent increase in the number of metabolites with ion intensities significantly different from the control group. Pathway analyses revealed that ATR exposure strongly correlated with and disrupted multiple metabolic pathways. Tyrosine, tryptophan, linoleic acid and α-linolenic acid metabolic pathways were among the affected pathways, with α-linolenic acid metabolism being affected to the greatest extent. Observed effects of ATR on plasma tyrosine and tryptophan metabolism may be reflective of the previously reported perturbations of brain dopamine and serotonin homeostasis, respectively. ATR-caused alterations in the plasma profile of α-linolenic acid metabolism are a potential novel and sensitive plasma biomarker of ATR effect and plasma metabolomics could be used to better assess the risks, including to the brain, associated with ATR overexposure

    Effects of Repeated Sublethal External Exposure to Deep Water Horizon Oil on the Avian Metabolome

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    We assessed adverse effects of external sublethal exposure of Deepwater Horizon, Mississippi Canyon 252 oil on plasma and liver metabolome profiles of the double-crested cormorant (Phalacrocorax auritus), a large (1.5 to 3.0 kg) diving waterbird common in the Gulf of Mexico. Metabolomics analysis of avian plasma showed significant negative effects on avian metabolic profiles, in some cases after only two external exposures (26 g cumulative) to oil. We observed significant (p \u3c 0.05) changes in intermediate metabolites of energy metabolism and fatty acid and amino acid metabolic pathways in cormorants after repeated exposure to oil. Exposure to oil increased several metabolites (glycine, betaine, serine and methionine) that are essential to the one-carbon metabolism pathway. Lipid metabolism was affected, causing an increase in production of ketone bodies, suggesting lipids were used as an alternative energy source for energy production in oil exposed birds. In addition, metabolites associated with hepatic bile acid metabolism were affected by oil exposure which was correlated with changes observed in bile acids in exposed birds. These changes at the most basic level of phenotypic expression caused by sublethal exposure to oil can have effects that would be detrimental to reproduction, migration, and survival in avian species

    Insights into the mode of action of tannin-based feed additives in broiler chickens: looking for connections with the plasma metabolome and caecal microbiota

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    This study assessed the effects of three tannin-based feed additives on the productive performance, foot-pad conditions, plasma metabolome, and caecal microbiota of meat-type chickens. A total of 2,340 male broilers were divided into 4 treatments (9 replicates each) fed either a commercial basal diet (CON) or the basal diet supplemented with one of the three tested products (A, B, or C) up to 49 days. According to manufacturers\u2019 instructions, product A was added to the basal diet at 0.3% from 0 to 49 d, while B and C at 0.13% from 0 to 21 d and 0.12% from 22 to 49 d. Compared to CON, tannin-supplemented birds consumed less feed (6.59 vs. 6.37, 6.49, and 6.35 kg, for CON vs. A, B, and C, respectively; p <.001) and reached a lower slaughter weight (3,599 vs. 3,494, 3,546, and 3,472 g, for CON vs. A, B, and C, respectively; p <.05). Feed conversion ratio (FCR) was not affected by the tannin supplementations, except for the starter phase when CON exhibited lower FCR than the other groups (p <.01). The observed differences in the plasma metabolome between CON and treated groups might indicate an impaired energy metabolism of tannin-supplemented chickens. The significant reduction in the caecal microbial diversity and short-chain fatty acid producer bacteria can also be related to the depressed performance of tannin-fed chickens. In contrast to earlier findings, pododermatitis was unaffected by our treatments. Further dose-response studies can help better exploit tannin-based additives in broiler diets