PubMed

Related Articles Cytoplasmic Peptidoglycan Intermediate Levels in Staphylococcus aureus. Biochimie. 2015 Nov 20; Authors: Vemula H, Ayon NJ, Gutheil WG Abstract Intracellular cytoplasmic peptidoglycan (PG) intermediate levels were determined in S. aureus during log-phase growth in enriched media. Levels of UDP-linked intermediates were quantitatively determined using ion pairing LC-MS/MS in negative mode, and amine intermediates were quantitatively determined stereospecifically as their Marfey's reagent derivatives in positive mode. Levels of UDP-linked intermediates in S. aureus varied from 1.4 μM for UDP-GlcNAc-Enolpyruvyate to 1200 μM for UDP-MurNAc. Levels of amine intermediates (L-Ala, D-Ala, D-Ala-D-Ala, L-Glu, D-Glu, and L-Lys) varied over a range of from 860 μM for D-Ala-D-Ala to 30-260 mM for the others. Total PG was determined from the D-Glu content of isolated PG, and used to estimate the rate of PG synthesis (in terms of cytoplasmic metabolite flux) as 690 μM/min. The total UDP-linked intermediates pool (2490 μM) is therefore sufficient to sustain growth for 3.6 min. Comparison of UDP-linked metabolite levels with published pathway enzyme characteristics demonstrates that enzymes on the UDP-branch range from >80% saturation for MurA, Z, and C, to <5% saturation for MurB. Metabolite levels were compared with literature values for E. coli, with the major difference in UDP-intermediates being the level of UDP-MurNAc, which was high in S. aureus (1200 μM) and low in E. coli (45 μM). PMID: 26612730 [PubMed - as supplied by publisher]

Related Articles Autophagy Mediates Tumor Suppression via Cellular Senescence. Trends Cell Biol. 2015 Nov 20; Authors: Galluzzi L, Bravo-San Pedro JM, Kroemer G Abstract Autophagy not only constitutes a robust barrier against malignant transformation at the cell-intrinsic level, but also contributes to the organismal control of potentially oncogenic cells. Recent data provide molecular insights into the mechanisms whereby oncogene hyperactivation induces autophagy to establish a permanent proliferative arrest commonly known as cellular senescence. PMID: 26612212 [PubMed - as supplied by publisher]

Related Articles Systems analysis of methylerythritol-phosphate pathway flux in E. coli: insights into the role of oxidative stress and the validity of lycopene as an isoprenoid reporter metabolite. Microb Cell Fact. 2015;14(1):193 Authors: Bongers M, Chrysanthopoulos PK, Behrendorff JB, Hodson MP, Vickers CE, Nielsen LK Abstract BACKGROUND: High-throughput screening methods assume that the output measured is representative of changes in metabolic flux toward the desired product and is not affected by secondary phenotypes. However, metabolic engineering can result in unintended phenotypes that may go unnoticed in initial screening. The red pigment lycopene, a carotenoid with antioxidant properties, has been used as a reporter of isoprenoid pathway flux in metabolic engineering for over a decade. Lycopene production is known to vary between wild-type Escherichia coli hosts, but the reasons behind this variation have never been fully elucidated. RESULTS: In an examination of six E. coli strains we observed that strains also differ in their capacity for increased lycopene production in response to metabolic engineering. A combination of genetic complementation, quantitative SWATH proteomics, and biochemical analysis in closely-related strains was used to examine the mechanistic reasons for variation in lycopene accumulation. This study revealed that rpoS, a gene previously identified in lycopene production association studies, exerts its effect on lycopene accumulation not through modulation of pathway flux, but through alteration of cellular oxidative status. Specifically, absence of rpoS results in increased accumulation of reactive oxygen species during late log and stationary phases. This change in cellular redox has no effect on isoprenoid pathway flux, despite the presence of oxygen-sensitive iron-sulphur cluster enzymes and the heavy redox requirements of the methylerythritol phosphate pathway. Instead, decreased cellular lycopene in the ΔrpoS strain is caused by degradation of lycopene in the presence of excess reactive oxygen species. CONCLUSIONS: Our results demonstrate that lycopene is not a reliable indicator of isoprenoid pathway flux in the presence of oxidative stress, and suggest that caution should be exercised when using lycopene as a screening tool in genome-wide metabolic engineering studies. More extensive use of systems biology for strain analysis will help elucidate such unpredictable side-effects in metabolic engineering projects. PMID: 26610700 [PubMed - as supplied by publisher]

Related Articles Structural characterization and discrimination of Chinese medicinal materials with multiple botanical origins based on metabolite profiling and chemometrics analysis: Clematidis Radix et Rhizoma as a case study. J Chromatogr A. 2015 Nov 10; Authors: Guo LX, Li R, Liu K, Yang J, Li HJ, Li SL, Liu JQ, Liu LF, Xin GZ Abstract Traditional Chinese medicines (TCMs)-based products are becoming more and more popular over the world. To ensure the safety and efficacy, authentication of Chinese medicinal materials has been an important issue, especially for that with multiple botanical origins (one-to-multiple). Taking Clematidis Radix et Rhizoma (CRR) as a case study, we herein developed an integrated platform based on metabolite profiling and chemometrics analysis to characterize, classify, and predict the "one-to-multiple" herbs. Firstly, the predominant constituents, triterpenoid saponins, in three Clematis CRR were rapid characterized by a novel UPLC-QTOF/MS-based strategy, and a total of 49 triterpenoid saponins were identified. Secondly, metabolite profiling was performed by UPLC-QTOF/MS, and 4623 variables were extracted and aligned as dataset. Thirdly, by using pattern recognition analysis, a clear separation of the three Clematis CRR was achieved as well as a total number of 28 variables were screened as the valuable variables for discrimination. By matching with identified saponins, these 28 variables were corresponding to 10 saponins which were identified as marker compounds. Fourthly, based on the relative intensity of the marker compounds-related variables, genetic algorithm optimized support vector machines (GA-SVM) was employed to predict the species of CRR samples. The obtained model showed excellent prediction performance with a prediction accuracy of 100%. Finally, a heatmap visualization was employed for clarifying the distribution of identified saponins, which could be useful for phytochemotaxonomy study of Clematis herbs. These results indicated that our proposed platform was a powerful tool for chemical profiling and discrimination of herbs with multiple botanical origins, providing promising perspectives in tracking the formulation processes of TCMs products. PMID: 26610614 [PubMed - as supplied by publisher]

Related Articles Metabolite Profile of Cervicovaginal Fluids from Early Pregnancy Is Not Predictive of Spontaneous Preterm Birth. Int J Mol Sci. 2015;16(11):27741-27748 Authors: Thomas MM, Sulek K, McKenzie EJ, Jones B, Han TL, Villas-Boas SG, Kenny LC, McCowan LM, Baker PN Abstract In our study, we used a mass spectrometry-based metabolomic approach to search for biomarkers that may act as early indicators of spontaneous preterm birth (sPTB). Samples were selected as a nested case-control study from the Screening for Pregnancy Endpoints (SCOPE) biobank in Auckland, New Zealand. Cervicovaginal swabs were collected at 20 weeks from women who were originally assessed as being at low risk of sPTB. Samples were analysed using gas chromatography-mass spectrometry (GC-MS). Despite the low amount of biomass (16-23 mg), 112 compounds were detected. Statistical analysis showed no significant correlations with sPTB. Comparison of reported infection and plasma inflammatory markers from early pregnancy showed two inflammatory markers were correlated with reported infection, but no correlation with any compounds in the metabolite profile was observed. We hypothesise that the lack of biomarkers of sPTB in the cervicovaginal fluid metabolome is simply because it lacks such markers in early pregnancy. We propose alternative biofluids be investigated for markers of sPTB. Our results lead us to call for greater scrutiny of previously published metabolomic data relating to biomarkers of sPTB in cervicovaginal fluids, as the use of small, high risk, or late pregnancy cohorts may identify metabolite biomarkers that are irrelevant for predicting risk in normal populations. PMID: 26610472 [PubMed - as supplied by publisher]

Protocol for quality control in metabolic profiling of biological fluids by U(H)PLC-MS. J Chromatogr B Analyt Technol Biomed Life Sci. 2015 Nov 10;1008:15-25 Authors: Gika HG, Zisi C, Theodoridis G, Wilson ID Abstract The process of untargeted metabolic profiling/phenotyping of complex biological matrices, i.e., biological fluids such as blood plasma/serum, saliva, bile, and tissue extracts, provides the analyst with a wide range of challenges. Not the least of these challenges is demonstrating that the acquired data are of "good" quality and provide the basis for more detailed multivariate, and other, statistical analysis necessary to detect, and identify, potential biomarkers that might provide insight into the process under study. Here straightforward and pragmatic "quality control (QC)" procedures are described that allow investigators to monitor the analytical processes employed for global, untargeted, metabolic profiling. The use of this methodology is illustrated with an example from the analysis of human urine where an excel spreadsheet of the preprocessed LC-MS output is provided with embedded macros, calculations and visualization plots that can be used to explore the data. Whilst the use of these procedures is exemplified on human urine samples, this protocol is generally applicable to metabonomic/metabolomic profiling of biofluids, tissue and cell extracts from many sources. PMID: 26610079 [PubMed - as supplied by publisher]

Complete nitrification by Nitrospira bacteria. Nature. 2015 Nov 26; Authors: Daims H, Lebedeva EV, Pjevac P, Han P, Herbold C, Albertsen M, Jehmlich N, Palatinszky M, Vierheilig J, Bulaev A, Kirkegaard RH, Bergen MV, Rattei T, Bendinger B, Nielsen PH, Wagner M Abstract Nitrification, the oxidation of ammonia via nitrite to nitrate, has always been considered to be a two-step process catalysed by chemolithoautotrophic microorganisms oxidizing either ammonia or nitrite. No known nitrifier carries out both steps, although complete nitrification should be energetically advantageous. This functional separation has puzzled microbiologists for a century. Here we report on the discovery and cultivation of a completely nitrifying bacterium from the genus Nitrospira, a globally distributed group of nitrite oxidizers. The genome of this chemolithoautotrophic organism encodes the pathways both for ammonia and nitrite oxidation, which are concomitantly activated during growth by ammonia oxidation to nitrate. Genes affiliated with the phylogenetically distinct ammonia monooxygenase and hydroxylamine dehydrogenase genes of Nitrospira are present in many environments and were retrieved on Nitrospira-contigs in new metagenomes from engineered systems. These findings fundamentally change our picture of nitrification and point to completely nitrifying Nitrospira as key components of nitrogen-cycling microbial communities. PMID: 26610024 [PubMed - as supplied by publisher]

Metabolite Signatures in Hydrophilic Extracts of Mouse Lungs Exposed to Cigarette Smoke Revealed by (1)H NMR Metabolomics Investigation. Metabolomics (Los Angel). 2015 Jun;5(2) Authors: Jz H, X W, J F, Bj R, Km W, Sc T, Jg P, Ra C, M L, M H Abstract (1)H-NMR metabolomics was used to investigate the changes of metabolites in the lungs of mice with and without being exposed to a controlled amount of cigarette smoke. It was found that the concentrations of adenosine derivatives (i.e. ATP, ADP and AMP), inosine and uridine were significantly changed in the lungs of mice exposed to cigarette smoke when compared with controls regardless the mice were obese or of regular weight. The decreased ATP, ADP, AMP and elevated inosine suggested that the deaminases in charge of adenosine derivatives to inosine derivatives conversion would be significantly changed in the lungs of mice exposed to cigarette smoke. Indeed, transcriptional study confirmed that the concentrations of adenosine monophosphate deaminase 2 and adenosine deaminase 2 were significantly changed in the lungs of mice exposed to cigarette smoke. We also found that the ratio of glycerophosphocholine (GPC) to phosphocholine (PC) was significantly increased in the lungs of obese mice compared with those of the regular weight mice. The GPC/PC ratio was further elevated in the lungs of obese group exposed to cigarette smoke. PMID: 26609465 [PubMed - as supplied by publisher]

Metabolomics: a state-of-the-art technology for better understanding of male infertility. Andrologia. 2015 Nov 26; Authors: Minai-Tehrani A, Jafarzadeh N, Gilany K Abstract Male factor infertility affects approximately half of the infertile couples, in spite of many years of research on male infertility treatment and diagnosis; several outstanding questions remain to be addressed. In this regard, metabolomics as a novel field of omics has been suggested to be applied for male infertility problems. A variety of terms associated with metabolite quantity and quality have been established to demonstrate mixtures of metabolites. Despite metabolomics and metabolite analyses have been around more than decades, a limited number of studies concerning male infertility have been carried out. In this review, we summarised the latest finding in metabolomics techniques and metabolomics biomarkers correlated with male infertility. The rapid progress of a variety of metabolomics platforms, such as nonoptical and optical spectroscopy, could ease separation, recognition, classification and quantification of several metabolites and their metabolic pathways. Here, we recommend that the novel biomarkers determined in the course of metabolomics analysis may stand for potential application of treatment and future clinical practice. PMID: 26608970 [PubMed - as supplied by publisher]

(1)H NMR Metabolomic Footprinting Analysis for the In Vitro Screening of Potential Chemopreventive Agents. Methods Mol Biol. 2016;1379:89-97 Authors: Casadei L, Valerio M Abstract Metabolomics is the quantification and analysis of the concentration profiles of low-molecular-weight compounds present in biological samples. In particular metabolic footprinting analysis, based on the monitoring of metabolites consumed from and secreted into the growth medium, is a valuable tool for the study of pharmacological and toxicological effects of drugs. Mass spectrometry and nuclear magnetic resonance (NMR) are the two main complementary techniques used in this field. Although less sensitive, NMR gives a direct fingerprint of the system, and the spectra obtained contain metabolic information that can be distilled by chemometric techniques.In this chapter, we present how metabolomic footprinting can be used to assess in vitro a potential chemopreventive molecule as metformin. PMID: 26608292 [PubMed - in process]

LC-MS-Based Metabolomic Investigation of Chemopreventive Phytochemical-Elicited Metabolic Events. Methods Mol Biol. 2016;1379:77-88 Authors: Wang L, Yao D, Chen C Abstract Phytochemicals are under intensive investigation for their potential use as chemopreventive agents in blocking or suppressing carcinogenesis. Metabolic interactions between phytochemical and biological system play an important role in determining the efficacy and toxicity of chemopreventive phytochemicals. However, complexities of phytochemical biotransformation and intermediary metabolism pose challenges for studying phytochemical-elicited metabolic events. Metabolomics has become a highly effective technical platform to detect subtle changes in a complex metabolic system. Here, using green tea polyphenols as an example, we describe a workflow of LC-MS-based metabolomics study, covering the procedures and techniques in sample collection, preparation, LC-MS analysis, data analysis, and interpretation. PMID: 26608291 [PubMed - in process]

Effects of sodium nitrite supplementation on vascular function and related small metabolite signatures in middle-aged and older adults. J Appl Physiol (1985). 2015 Nov 25;:jap.00879.2015 Authors: DeVan AE, Johnson LC, Brooks FA, Evans TD, Justice JN, Cruickshank-Quinn C, Reisdorph N, Bryan NS, McQueen MB, Santos-Parker JR, Chonchol MB, Bassett CJ, Sindler AL, Giordano T, Seals DR Abstract Insufficient nitric oxide (NO) bioavailability plays an important role in endothelial dysfunction and arterial stiffening with aging. Supplementation with sodium nitrite, a precursor of NO, ameliorates age-related vascular endothelial dysfunction and arterial stiffness in mice, but effects on humans, including the metabolic pathways altered, are unknown. The purpose of this study was to determine the safety, feasibility and efficacy of oral sodium nitrite supplementation for improving vascular function in middle-aged and older adults, and to identify related circulating metabolites. Ten weeks of sodium nitrite (80 or 160 mg/day, capsules, TheraVasc, Inc., randomized, placebo-control, double-blind) increased plasma nitrite acutely (5- to 15-fold, p<0.001 vs. placebo) and chronically (p<0.10), and was well-tolerated without symptomatic hypotension or clinically-relevant elevations in blood methemoglobin. Endothelial function, measured by brachial artery flow-mediated dilation, increased 45-60% vs. baseline (p<0.10) without changes in body mass or blood lipids. Measures of carotid artery elasticity (ultrasound and applanation tonometry) improved (decreased β-stiffness index, increased cross-sectional compliance, p<0.05) without changes in brachial or carotid artery blood pressure. Aortic pulse wave velocity was unchanged. Nitrite-induced changes in vascular measures were significantly related to 11 plasma metabolites identified by untargeted analysis. Baseline abundance of multiple metabolites, including glycerophospholids and fatty acyls, predicted vascular changes with nitrite. This study provides evidence that sodium nitrite supplementation is well-tolerated, increases plasma nitrite concentrations, improves endothelial function and lessens carotid artery stiffening in middle-aged and older adults, perhaps by altering multiple metabolic pathways, thereby warranting a larger clinical trial. PMID: 26607249 [PubMed - as supplied by publisher]

29 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 2015/11/26PubMed 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.

22 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 2015/11/25PubMed 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.

Related Articles NMR based metabolic snapshot from Minibronchoalveolar lavage fluid: an approach to unfold human respiratory metabolomics. J Proteome Res. 2015 Nov 20; Authors: Viswan A, Sharma RK, Azim A, Sinha N Abstract Utility of Mini Bronchoalveolar lavage (mBAL) and its applicability in metabolomics has not been explored in the field of human respiratory disease. mBAL "an archetype" of the local lung environment ensures a potent technique to get the snapshot of the epithelial lining fluid afflicted to human lung disorders. Characterization of the mBAL fluid has potential to help in elucidating the composition of the alveoli and airways in the diseased state, yielding diagnostic information of clinical applicability. In this study one of the first attempts has been made to comprehensively assign and detect metabolites in mBAL fluid, extracted from human lungs, by the composite use of 800 MHz one dimensional (1D) and two dimensional (2D) NMR, homonuclear J-resolved, COSY, TOCSY and heteronuclear HSQC correlation methods. A foremost all-inclusive sketch of the 50 metabolites have been corroborated and assigned, which can be a resourceful archive to further lung directed metabolomics, prognosis and diagnosis. Thus NMR based mBALF studies, as proposed in this article, will leverage many more prospective respiratory researches for routine clinical application and proves to be a viable approach to mirror the key predisposing factors contributing to the onset of lung disease. PMID: 26587756 [PubMed - as supplied by publisher]

Related Articles Ion Mobility in Clinical Analysis: Current Progress and Future Perspectives. Clin Chem. 2015 Nov 19; Authors: Chouinard CD, Wei MS, Beekman CR, Kemperman RH, Yost RA Abstract BACKGROUND: Ion mobility spectrometry (IMS) is a rapid separation tool that can be coupled with several sampling/ionization methods, other separation techniques (e.g., chromatography), and various detectors (e.g., mass spectrometry). This technique has become increasingly used in the last 2 decades for applications ranging from illicit drug and chemical warfare agent detection to structural characterization of biological macromolecules such as proteins. Because of its rapid speed of analysis, IMS has recently been investigated for its potential use in clinical laboratories. CONTENT: This review article first provides a brief introduction to ion mobility operating principles and instrumentation. Several current applications will then be detailed, including investigation of rapid ambient sampling from exhaled breath and other volatile compounds and mass spectrometric imaging for localization of target compounds. Additionally, current ion mobility research in relevant fields (i.e., metabolomics) will be discussed as it pertains to potential future application in clinical settings. SUMMARY: This review article provides the authors' perspective on the future of ion mobility implementation in the clinical setting, with a focus on ambient sampling methods that allow IMS to be used as a "bedside" standalone technique for rapid disease screening and methods for improving the analysis of complex biological samples such as blood plasma and urine. PMID: 26585928 [PubMed - as supplied by publisher]

Related Articles Automated Multiplex LC-MS/MS Assay for Quantifying Serum Apolipoproteins A-I, B, C-I, C-II, C-III, and E with Qualitative Apolipoprotein E Phenotyping. Clin Chem. 2015 Nov 19; Authors: van den Broek I, Romijn FP, Nouta J, van der Laarse A, Drijfhout JW, Smit NP, van der Burgt YE, Cobbaert CM Abstract BACKGROUND: Direct and calculated measures of lipoprotein fractions for cardiovascular risk assessment suffer from analytical inaccuracy in certain dyslipidemic and pathological states, most commonly hypertriglyceridemia. LC-MS/MS has proven suitable for multiplexed quantification and phenotyping of apolipoproteins. We developed and provisionally validated an automated assay for quantification of apolipoprotein (apo) A-I, B, C-I, C-II, C-III, and E and simultaneous qualitative assessment of apoE phenotypes. METHODS: We used 5 value-assigned human serum pools for external calibration. Serum proteins were denatured, reduced, and alkylated according to standard mass spectrometry-based proteomics procedures. After trypsin digestion, peptides were analyzed by LC-MS/MS. For each peptide, we measured 2 transitions. We compared LC-MS/MS results to those obtained by an immunoturbidimetric assay or ELISA. RESULTS: Intraassay CVs were 2.3%-5.5%, and total CVs were 2.5%-5.9%. The LC-MS/MS assay correlated (R = 0.975-0.995) with immunoturbidimetric assays with Conformité Européenne marking for apoA-I, apoB, apoC-II, apoC-III, and apoE in normotriglyceridemic (n = 54) and hypertriglyceridemic (n = 46) sera. Results were interchangeable for apoA-I ≤3.0 g/L (Deming slope 1.014) and for apoB-100 ≤1.8 g/L (Deming slope 1.016) and were traceable to higher-order standards. CONCLUSIONS: The multiplex format provides an opportunity for new diagnostic and pathophysiologic insights into types of dyslipidemia and allows a more personalized approach for diagnosis and treatment of lipid abnormalities. PMID: 26585923 [PubMed - as supplied by publisher]

Related Articles AMPK, a metabolic sensor, is involved in isoeugenol-induced glucose uptake in muscle cells. J Endocrinol. 2015 Nov 19; Authors: Kim N, Lee JO, Lee HJ, Lee YW, Kim HI, Kim SJ, Park SH, Lee CS, Ryoo SW, Hwang GS, Kim HS Abstract Isoeugenol exerts various beneficial effects on human health. However, mechanisms underlying these effects are poorly understood. In this study, we observed that isoeugenol activated AMP-activated protein kinase (AMPK) and increased glucose uptake in rat L6 myotubes. Isoeugenol-induced increase in intracellular calcium concentration and glucose uptake was inhibited by STO-609, an inhibitor of calcium/calmodulin-dependent protein kinase kinase (CaMKK). Isoeugenol also increased the phosphorylation of protein kinase C-α (PKCα). Chelation of calcium with BAPTA-AM blocked isoeugenol-induced AMPK phosphorylation and glucose uptake. Isoeugenol stimulated p38MAPK phosphorylation that was inhibited after pretreatment with compound C, an AMPK inhibitor. Isoeugenol also increased Glucose transporter type 4 (GLUT4) expression and its translocation to the plasma membrane. GLUT4 translocation was not observed after the inhibition of AMPK and CaMKK. In addition, isoeugenol activated the Akt substrate 160 (AS160) pathway, which is downstream of the p38MAPK pathway. Knockdown of the gene encoding AS160 inhibited isoeugenol-induced glucose uptake. Together, these results indicated that isoeugenol exerted beneficial health effects by activating the AMPK/p38MAPK/AS160 pathways in the skeletal muscles. PMID: 26585419 [PubMed - as supplied by publisher]

Related Articles Aspirin Reduces Plasma Concentrations of the Oncometabolite 2-Hydroxyglutarate: Results of a Randomized, Double-Blind, Crossover Trial. Cancer Epidemiol Biomarkers Prev. 2015 Nov 19; Authors: Liesenfeld DB, Botma A, Habermann N, Toth R, Weigel C, Popanda O, Klika KD, Potter JD, Lampe JW, Ulrich CM Abstract BACKGROUND: Aspirin use is an effective strategy for the chemoprevention of colorectal cancer, even at low doses. However, in order to implement aspirin interventions, risk-benefit balances and biologic mechanisms need to be better defined; to further this aim, we used a metabolomics approach. METHODS: We metabolically profiled 40 healthy, nonsmoking men and women ages 20 to 45 years enrolled in a randomized, double-blind, crossover trial of 325 mg aspirin/day over a period of 60 days. Gas and liquid chromatography-mass spectrometry were used to comprehensively profile participants' plasma samples after aspirin and placebo interventions. RESULTS: A total of 363 metabolites, covering most human biochemical pathways, were measured. Compared with placebo-treated participants, plasma concentrations of the oncometabolite 2-hydroxyglutarate (R+S) decreased after aspirin treatment in both men and women (P = 0.005). This signal proved robust during 20-fold random splitting of the data using 80% of the samples in each split. We subsequently performed functional follow-up studies using targeted, enantiospecific detection in human colorectal cancer cell lines and observed an aspirin-induced reduction of (R)-2-hydroxyglutarate. We further showed that salicylate, the primary aspirin metabolite, inhibits the hydroxyacid-oxoacid transhydrogenase mediated production of (R)-2-hydroxyglutarate, thereby providing mechanistic evidence for the clinically observed effects of aspirin on total-2-hydroxyglutarate. CONCLUSIONS: Using a metabolomics approach with functional follow-up, we propose that a decrease in the oncometabolite (R)-2-hydroxyglutarate may identify an additional mechanism for aspirin or its metabolites in cancer prevention. IMPACT: Reduction of the oncometabolite (R)-2-hydroxyglutarate identifies a novel, non-COX-inhibition-mediated mechanism of aspirin. Cancer Epidemiol Biomarkers Prev; 1-8. ©2015 AACR. PMID: 26585118 [PubMed - as supplied by publisher]

Related Articles Cold adaptation mechanisms in the ghost moth Hepialus xiaojinensis: metabolic regulation and thermal compensation. J Insect Physiol. 2015 Nov 13; Authors: Zhu W, Zhang H, Li X, Meng Q, Shu R, Wang M, Zhou G, Wang H, Miao L, Zhang J, Qin Q Abstract Ghost moths (Lepidoptera: Hepialidae) are cold-adapted stenothermal species inhabiting alpine meadows on the Tibetan Plateau. They have an optimal developmental temperature of 12-16 °C but can maintain feeding and growth at 0 °C. Their survival strategies have received little attention, but these insects are a promising model for environmental adaptation. Here, biochemical adaptations and energy metabolism in response to cold were investigated in larvae of the ghost moth Hepialus xiaojinensis. Metabolic rate and respiratory quotient decreased dramatically with decreasing temperature (15 to 4 °C), suggesting that the energy metabolism of ghost moths, especially glycometabolism, was sensitive to cold. However, the metabolic rate at 4 °C increased with the duration of cold exposure, indicating thermal compensation to sustain energy budgets under cold conditions. Underlying regulation strategies were studied by analyzing metabolic differences between cold-acclimated (4 °C for 48 h) and control larvae (15 °C). In cold-acclimated larvae, the energy generating pathways of carbohydrates, instead of the overall consumption of carbohydrates, was compensated in the fat body by improving the transcription of related enzymes. The mobilization of lipids was also promoted, with higher diacylglycerol, monoacylglycerol and free fatty acid content in hemolymph. These results indicated that cold acclimation induced a reorganisation on metabolic structure to prioritise energy metabolism. Within the aerobic process, flux throughout the tricarboxylic acid (TCA) cycle was encouraged in the fat body, and the activity of α-ketoglutarate dehydrogenase was the likely compensation target. Increased mitochondrial cristae density was observed in the midgut of cold-acclimated larvae. The thermal compensation strategies in this ghost moth span the entire process of energy metabolism, including degration of metabolic substrate, TCA cycle and oxidative phosphorylation, and from an energy budget perspective explains how ghost moths sustain physiological activity in cold environments. PMID: 26585102 [PubMed - as supplied by publisher]