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

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PubMed
NCBI: db=pubmed; Term=metabolomics
Updated: 2 hours 21 min ago

Headspace versus direct immersion solid phase microextraction in complex matrices: investigation of analyte behavior in multicomponent mixtures.

Wed, 22/07/2015 - 13:23
Headspace versus direct immersion solid phase microextraction in complex matrices: investigation of analyte behavior in multicomponent mixtures. Anal Chem. 2015 Jul 21; Authors: Gionfriddo E, Souza-Silva EA, Pawliszyn J Abstract This work aims to investigate the behavior of analytes in complex mixtures and matrices with the use of solid-phase microextraction (SPME). Various factors that influence analyte uptake such as coating chemistry, extraction mode, the physicochemical properties of analytes, and matrix complexity were considered. At first, an aqueous system containing analytes bearing different hydrophobicities, molecular weights and chemical functionalities was investigated by using commercially available liquid and solid porous coatings. The differences in the mass transfer mechanisms resulted in a more pronounced occurrence of coating saturation in headspace mode. Contrariwise direct immersion extraction minimizes the occurrence of artefacts related to coating saturation and provides enhanced extraction of polar compounds. In addition, matrix-compatible PDMS-modified solid coatings, characterized by a new morphology that avoids coating fouling, were compared to their non-modified analogous. The obtained results indicate that PDMS-modified coatings reduce artefacts associated with coating saturation, even in headspace mode. This factor, coupled to their matrix compatibility, make the use of direct SPME very practical as a quantification approach and the best choice for metabolomics studies where wide coverage is intended. To further understand the influence on analyte uptake on a system where additional interactions occur due to matrix components, ex vivo and in vivo sampling conditions were simulated using a starch matrix model, with the aim of mimicking plant-derived materials. Our results corroborate the fact that matrix handling can affect analyte/matrix equilibria, with consequent release of high concentrations of previously bound hydrophobic compounds, potentially leading to coating saturation. Direct immersion SPME limited the occurrence of the artefacts, which confirms the suitability of SPME for in vivo applications. These findings shed light into the implementation of in vivo SPME strategies in quantitative metabolomics studies of complex plant-based systems. PMID: 26196654 [PubMed - as supplied by publisher]

Metabolomics: Applications and Promise in Mycobacterial Disease.

Wed, 22/07/2015 - 13:23
Metabolomics: Applications and Promise in Mycobacterial Disease. Ann Am Thorac Soc. 2015 Jul 21; Authors: Mirsaeidi M, Banoei MM, Winston BW, Schraufnagel DE Abstract Until recently, the study of mycobacterial diseases was trapped in culture-based technology that is more than a century old. The use of nucleic acid amplification is changing this, and powerful new technologies are on the horizon. Metabolomics, which is the study of sets of metabolites of both the bacteria and host, is being used to clarifying mechanisms of disease, and can identify changes leading to better diagnosis, treatment, and prognostication of mycobacterial diseases. Metabolomic profiles are arrays of biochemical products of genes in their environment. These complex patterns are biomarkers that can allow a more complete understanding of cell function, dysfunction, and perturbation than genomics or proteomics. Metabolomics could herald sweeping advances in personalized medicine and clinical trial design, but the challenges in metabolomics are also great. Measured metabolite concentrations vary with the timing within a condition, the intrinsic biology, the instruments, and the sample preparation. Metabolism profoundly changes with age, gender, variations in gut microbial flora, and lifestyle. Validation of biomarkers is complicated by measurement accuracy, selectivity, linearity, reproducibility, robustness, and limits of detection. The statistical challenges include analysis, interpretation, and description of the vast amount data generated. Despite these drawbacks, metabolomics provides a great opportunity and potential for understanding and managing mycobacterial diseases.  . PMID: 26196272 [PubMed - as supplied by publisher]

An Interactive Cluster Heat Map to Visualize and Explore Multidimensional Metabolomic Data.

Wed, 22/07/2015 - 13:23
Related Articles An Interactive Cluster Heat Map to Visualize and Explore Multidimensional Metabolomic Data. Metabolomics. 2015 Aug 1;11(4):1029-1034 Authors: Benton PH, Ivanisevic J, Rinehart D, Epstein A, Kurczy ME, Boska MD, Gendelman HE, Siuzdak G Abstract Heat maps are a commonly used visualization tool for metabolomic data where the relative abundance of ions detected in each sample is represented with color intensity. A limitation of applying heat maps to global metabolomic data, however, is the large number of ions that have to be displayed and the lack of information provided about important metabolomic parameters such as m/z and retention time. Here we address these challenges by introducing the interactive cluster heat map in the data-processing software XCMS Online. XCMS Online (xcmsonline.scripps.edu) is a cloud-based informatic platform designed to process, statistically evaluate, and visualize mass-spectrometry based metabolomic data. An interactive heat map is provided for all data processed by XCMS Online. The heat map is clickable, allowing users to zoom and explore specific metabolite metadata (EICs, Box-and-whisker plots, mass spectra) that are linked to the METLIN metabolite database. The utility of the XCMS interactive heat map is demonstrated on metabolomic data set generated from different anatomical regions of the mouse brain. PMID: 26195918 [PubMed - as supplied by publisher]

Evaluation of steroidomics by liquid chromatography hyphenated to mass spectrometry as a powerful analytical strategy for measuring human steroid perturbations.

Wed, 22/07/2015 - 13:23
Related Articles Evaluation of steroidomics by liquid chromatography hyphenated to mass spectrometry as a powerful analytical strategy for measuring human steroid perturbations. J Chromatogr A. 2015 Jul 7; Authors: Jeanneret F, Tonoli D, Rossier MF, Saugy M, Boccard J, Rudaz S Abstract This review presents the evolution of steroid analytical techniques, including gas chromatography coupled to mass spectrometry (GC-MS), immunoassay (IA) and targeted liquid chromatography coupled to mass spectrometry (LC-MS), and it evaluates the potential of extended steroid profiles by a metabolomics-based approach, namely steroidomics. Steroids regulate essential biological functions including growth and reproduction, and perturbations of the steroid homeostasis can generate serious physiological issues; therefore, specific and sensitive methods have been developed to measure steroid concentrations. GC-MS measuring several steroids simultaneously was considered the first historical standard method for analysis. Steroids were then quantified by immunoassay, allowing a higher throughput; however, major drawbacks included the measurement of a single compound instead of a panel and cross-reactivity reactions. Targeted LC-MS methods with selected reaction monitoring (SRM) were then introduced for quantifying a small steroid subset without the problems of cross-reactivity. The next step was the integration of metabolomic approaches in the context of steroid analyses. As metabolomics tends to identify and quantify all the metabolites (i.e., the metabolome) in a specific system, appropriate strategies were proposed for discovering new biomarkers. Steroidomics, defined as the untargeted analysis of the steroid content in a sample, was implemented in several fields, including doping analysis, clinical studies, in vivo or in vitro toxicology assays, and more. This review discusses the current analytical methods for assessing steroid changes and compares them to steroidomics. Steroids, their pathways, their implications in diseases and the biological matrices in which they are analysed will first be described. Then, the different analytical strategies will be presented with a focus on their ability to obtain relevant information on the steroid pattern. The future technical requirements for improving steroid analysis will also be presented. PMID: 26195035 [PubMed - as supplied by publisher]

Metabolomics for characterization of gender differences in patients infected with dengue virus.

Wed, 22/07/2015 - 13:23
Related Articles Metabolomics for characterization of gender differences in patients infected with dengue virus. Asian Pac J Trop Med. 2015 Jun;8(6):451-6 Authors: Shahfiza N, Osman H, Hock TT, Shaari K, Abdel-Hamid AH Abstract OBJECTIVE: To determine the metabolic response associate with dengue infection based on human gender metabolic differences by means of (1)H NMR-spectrometry. METHODS: The mid-stream urine collected from both male and female patients diagnosed with dengue fever at Penang General Hospital and fourty-three healthy individuals were analyzed with (1)H NMR spectroscopy, followed by chemometric multivariate analysis. NMR signals which highlighted in the OPLS-DA S-plot were further selected and identified using Human Metabolome Database, Chenomx Profiler. RESULTS: The results pointed out that NMR urine profiling was able to capture human gender metabolic differences that are important for the distinction of classes of individuals of similar physiological conditions; infected with dengue. Distinct differences between dengue infected patients versus healthy individuals and subtle differences in male versus female infected with dengue were found to be related to the metabolism of amino acid and tricarboxylic acid intermediates cycle. CONCLUSIONS: The (1)H NMR metabolomic investigation combined with appropriate algorithms and pattern recognition procedures, gave an evidence for the existence of distinct metabolic differentiation of individuals, according to their gender, modulates with the infection risk. PMID: 26194829 [PubMed]

Metabolic Impacts of Using Nitrogen and Copper-Regulated Promoters to Regulate Gene Expression in Neurospora crassa.

Wed, 22/07/2015 - 13:23
Related Articles Metabolic Impacts of Using Nitrogen and Copper-Regulated Promoters to Regulate Gene Expression in Neurospora crassa. G3 (Bethesda). 2015 Jul 20; Authors: Ouyang S, Beecher CN, Wang K, Larive CK, Borkovich KA Abstract The filamentous fungus Neurospora crassa is a long-studied eukaryotic microbial system amenable to heterologous expression of native and foreign proteins. However, relatively few highly tunable promoters have been developed for this species. In this study, we compare the tcu-1 and nit-6 promoters for controlled expression of a GFP reporter gene in N. crassa. Though the copper-regulated tcu-1 has been previously characterized, this is the first investigation exploring nitrogen-controlled nit-6 for expression of heterologous genes in N. crassa. We determined that fragments corresponding to 1.5 kb fragments upstream of the tcu-1 and nit-6 open reading frames are needed for optimal repression and expression of GFP mRNA and protein. nit-6 was repressed using concentrations of glutamine from 2-20 mM and induced in medium containing 0.5-20 mM nitrate as the nitrogen source. Highest levels of expression were achieved within 3 hours of induction for each promoter and GFP mRNA could not be detected within an hour after transfer to repressing conditions using the nit-6 promoter. We also performed metabolic profiling experiments using proton NMR to identify changes in metabolite levels under inducing and repressing conditions for each promoter. The results demonstrate that conditions used to regulate tcu-1 do not significantly change the primary metabolome and that the differences between inducing and repressing conditions for nit-6 can be accounted for by growth under nitrate or glutamine as a nitrogen source. Our findings demonstrate that nit-6 is a tunable promoter that joins tcu-1 as a choice for regulation of gene expression in N. crassa. PMID: 26194204 [PubMed - as supplied by publisher]

Efficient searching and annotation of metabolic networks using chemical similarity.

Wed, 22/07/2015 - 13:23
Related Articles Efficient searching and annotation of metabolic networks using chemical similarity. Bioinformatics. 2015 Apr 1;31(7):1016-24 Authors: Pertusi DA, Stine AE, Broadbelt LJ, Tyo KE Abstract MOTIVATION: The urgent need for efficient and sustainable biological production of fuels and high-value chemicals has elicited a wave of in silico techniques for identifying promising novel pathways to these compounds in large putative metabolic networks. To date, these approaches have primarily used general graph search algorithms, which are prohibitively slow as putative metabolic networks may exceed 1 million compounds. To alleviate this limitation, we report two methods--SimIndex (SI) and SimZyme--which use chemical similarity of 2D chemical fingerprints to efficiently navigate large metabolic networks and propose enzymatic connections between the constituent nodes. We also report a Byers-Waterman type pathway search algorithm for further paring down pertinent networks. RESULTS: Benchmarking tests run with SI show it can reduce the number of nodes visited in searching a putative network by 100-fold with a computational time improvement of up to 10(5)-fold. Subsequent Byers-Waterman search application further reduces the number of nodes searched by up to 100-fold, while SimZyme demonstrates ∼ 90% accuracy in matching query substrates with enzymes. Using these modules, we have designed and annotated an alternative to the methylerythritol phosphate pathway to produce isopentenyl pyrophosphate with more favorable thermodynamics than the native pathway. These algorithms will have a significant impact on our ability to use large metabolic networks that lack annotation of promiscuous reactions. AVAILABILITY AND IMPLEMENTATION: Python files will be available for download at http://tyolab.northwestern.edu/tools/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID: 25417203 [PubMed - indexed for MEDLINE]

Comparison of metabolomic profiles of microbial communities between stable and deteriorated methanogenic processes.

Wed, 22/07/2015 - 13:23
Related Articles Comparison of metabolomic profiles of microbial communities between stable and deteriorated methanogenic processes. Bioresour Technol. 2014 Nov;172:83-90 Authors: Sasaki D, Sasaki K, Tsuge Y, Morita M, Kondo A Abstract Central metabolite profiles from glucose in microbial communities during methanogenic process were compared between a stable methanogenic reactor (MR) and a deteriorated reactor (DR). The concentrations of intracellular metabolites related to the Embden-Meyerhof and pentose phosphate pathways, with the exception of pyruvate, remained high in the MR, showing increased carbon flux in the glycolysis pathway during stable methanogenesis. Extracellular acetate temporarily accumulated in the MR, consistent with higher ATP level in the MR. Intracellular concentrations of the intermediates in the reductive branch of tricarboxylic acid cycle, malate, fumarate, and succinate were higher in the DR. Low NADH/NAD(+) ratio both in the MR and DR would suggest NADH consumption during acetate and lactate/succinate production in the MR and DR, respectively. Intracellular glutamate levels were higher in the MR, correlating with lower NADPH/NADP(+) ratio concentrations in the MR. These findings contribute to a better understanding of the metabolic state during stable methanogenesis. PMID: 25237777 [PubMed - indexed for MEDLINE]

Comparative evaluation of extraction methods for simultaneous mass-spectrometric analysis of complex lipids and primary metabolites from human blood plasma.

Wed, 22/07/2015 - 13:23
Related Articles Comparative evaluation of extraction methods for simultaneous mass-spectrometric analysis of complex lipids and primary metabolites from human blood plasma. Anal Bioanal Chem. 2014 Nov;406(28):7275-86 Authors: Lee do Y, Kind T, Yoon YR, Fiehn O, Liu KH Abstract Metabolomic results on human blood plasma largely depend on the sample preparation protocols employed for protein precipitation and metabolite extraction. Five different extraction methods were examined, which can be grouped into two categories, liquid-liquid extraction and protein precipitation methods, including long-standing protocols such as the Folch extraction and Bligh-Dyer extraction in comparison to modern methods such as the Matyash protocol and two global metabolite extraction methods. Extracts were subjected to analysis of blood plasma lipids and primary metabolites by using chip-based direct infusion nanoelectrospray tandem mass spectrometry and gas chromatography coupled to time-of-flight mass spectrometry, respectively. Optimal extraction schemes were evaluated based on the number of identified metabolites, extraction efficiency, compound diversity, reproducibility, and convenience for high-throughput sample preparations. Results showed that Folch and Matyash methods were equally valid and robust for lipidomic assessments while primary metabolites were better assessed by the protein precipitation methods with organic solvent mixtures. PMID: 25171832 [PubMed - indexed for MEDLINE]

Metabolomic analysis of amino acid and fat metabolism in rats with L-tryptophan supplementation.

Wed, 22/07/2015 - 13:23
Related Articles Metabolomic analysis of amino acid and fat metabolism in rats with L-tryptophan supplementation. Amino Acids. 2014 Dec;46(12):2681-91 Authors: Ruan Z, Yang Y, Wen Y, Zhou Y, Fu X, Ding S, Liu G, Yao K, Wu X, Deng Z, Wu G, Yin Y Abstract Tryptophan (TRP) is an important precursor for several neurotransmitters and metabolic regulators, which play a vital role in regulating nutrient metabolism. The purpose of this study was to investigate the effects of tryptophan supplementation on the biochemical profiles, intestinal structure, liver structure and serum metabolome in rats. Rats received daily intragastric administration of either tryptophan at doses of 200 mg/kg body weight per day or saline (control group) for 7 days. TRP supplementation had a tendency to decrease the body weight of rats (P > 0.05). The levels of urea and CHO in serum were decreased in the TRP-supplemented group rats compared with control group rats (P < 0.05). TRP supplementation increased the villus height and the ratio of villus height to crypt depth in the jejunum compared to control group rats (P < 0.05). Metabolic effects of tryptophan supplementation include: (1) increases in the serum concentrations of lysine, glycine, alanine, glutamate, glutamine, citrulline, methionine, tyrosine, 1-methylhistidine, and albumin, and decreases in the concentrations of serum branched-chain amino acid (isoleucine, valine and leucine); (2) decreases in the serum concentrations of formate and nitrogenous products (trimethylamine, TMAO, methylamine and dimethylamine), and in the contraction of trimethylamine in feces; (3) decreases in serum levels of lipids, low density lipoprotein, very low density lipoprotein, together with the elevated ratio of acetoacetate to β-hydroxybutyrate. The results indicate that tryptophan supplementation reduced the catabolism of dietary amino acids and promoted protein synthesis in rats, promoted the oxidation of fatty acid and reduced fat deposition in the body of rats. PMID: 25139634 [PubMed - indexed for MEDLINE]

A Genome-wide Scenario of Terpene Pathways in Self-pollinated Artemisia annua L.

Tue, 21/07/2015 - 12:29
A Genome-wide Scenario of Terpene Pathways in Self-pollinated Artemisia annua L. Mol Plant. 2015 Jul 17; Authors: Ma DM, Wang Z, Wang L, Alejos-Gonzales F, Sun MA, Xie DY Abstract Scenarios of genes to metabolites in Artemisia annua remain uninvestigated. Here, we report the use of an integrated approach combining metabolomics, transcriptomics and gene function analyses to characterize gene-to-terpene and terpene pathway scenarios in a self-pollinating variety of this species. Eighty-eight metabolites including twenty-two sesquiterpenes (e.g., artemisinin), twenty-six monoterpenes, three triterpenes and thirty-eight other non-polar metabolites were identified from fourteen tissues. These metabolites were differentially produced by leaves and flowers at lower to higher positions. Sequences from cDNA libraries of six tissues were assembled into 18,871 contigs, and genome-wide gene expression profiles in tissues were strongly associated with developmental stages and spatial specificities. Sequence mining identified forty-seven genes that mapped to the artemisinin, non-amorphadiene sesquiterpene, monoterpene, triterpene, 2-C-methyl-D-erythritol 4-phosphate (MEP) and mevalonate pathways. Pearson correlation analysis resulted in network integration that characterized significant correlations of gene-to-gene expression patterns and gene expression-to-metabolite levels in six tissues simultaneously. More importantly, manipulations of amorpha-4,11-diene synthase (ADS) gene expression not only controlled the activity of this pathway toward artemisinin, artemisinic acid and arteannuin b but also altered non-amorphadiene sesquiterpene and genome-wide volatile profiles. Such gene-to-terpene landscapes associated with different tissues are fundamental to the metabolic engineering of artemisinin. PMID: 26192869 [PubMed - as supplied by publisher]

Temporal metabolomic responses of cultured HepG2 liver cells to high fructose and high glucose exposures.

Tue, 21/07/2015 - 12:29
Related Articles Temporal metabolomic responses of cultured HepG2 liver cells to high fructose and high glucose exposures. Metabolomics. 2015 Jun 1;11(3):707-721 Authors: Meissen JK, Hirahatake KM, Adams SH, Fiehn O Abstract High fructose consumption has been implicated with deleterious effects on human health, including hyperlipidemia elicited through de novo lipogenesis. However, more global effects of fructose on cellular metabolism have not been elucidated. In order to explore the metabolic impact of fructose-containing nutrients, we applied both GC-TOF and HILIC-QTOF mass spectrometry metabolomic strategies using extracts from cultured HepG2 cells exposed to fructose, glucose, or fructose + glucose. Cellular responses were analyzed in a time-dependent manner, incubated in media containing 5.5 mM glucose + 5.0 mM fructose in comparison to controls incubated in media containing either 5.5 mM glucose or 10.5 mM glucose. Mass spectrometry identified 156 unique known metabolites and a large number of unknown compounds, which revealed metabolite changes due to both utilization of fructose and high-carbohydrate loads independent of hexose structure. Fructose was shown to be partially converted to sorbitol, and generated higher levels of fructose-1-phosphate as a precursor for glycolytic intermediates. Differentially regulated ratios of 3-phosphoglycerate to serine pathway intermediates in high fructose media indicated a diversion of carbon backbones away from energy metabolism. Additionally, high fructose conditions changed levels of complex lipids toward phosphatidylethanolamines. Patterns of acylcarnitines in response to high hexose exposure (10.5 mM glucose or glucose/fructose combination) suggested a reduction in mitochondrial beta-oxidation. PMID: 26190955 [PubMed - as supplied by publisher]

Nuclear magnetic resonance: a key metabolomics platform in the drug discovery process.

Tue, 21/07/2015 - 12:29
Related Articles Nuclear magnetic resonance: a key metabolomics platform in the drug discovery process. Drug Discov Today Technol. 2015 Jun;13:39-46 Authors: Leenders J, Frédérich M, de Tullio P Abstract Metabolomics is an innovative tool that is now emerging in the drug discovery process. Indeed, its ability to follow the dynamic perturbations in the metabolome resulting from pathologies but also from drug treatment and or/toxicity is of value for the development of new therapeutic approaches. Nuclear magnetic resonance (NMR) spectroscopy, which is an important analytical technique for several steps of the lead discovery, validation and optimization processes, has been described, together with mass spectrometry (MS) as one of the major platform that could be used for metabolomics studies. This review highlights why NMR could be considered a key tool for the application of metabolomics in drug discovery. PMID: 26190682 [PubMed - in process]

Metabolomics in the pharmaceutical industry.

Tue, 21/07/2015 - 12:29
Related Articles Metabolomics in the pharmaceutical industry. Drug Discov Today Technol. 2015 Jun;13:25-31 Authors: Reily MD, Tymiak AA Abstract Metabolomics has roots in the pharmaceutical industry that go back nearly three decades. Initially focused on applications in toxicology and disease pathology, more recent academic and commercial efforts have helped advance metabolomics as a tool to reveal the molecular basis of biological processes and pharmacological responses to drugs. This article will discuss areas where metabolomic technologies and applications are poised to have the greatest impact in the discovery and development of pharmaceuticals. PMID: 26190680 [PubMed - in process]

The emergence of metabolomics as a key discipline in the drug discovery process.

Tue, 21/07/2015 - 12:29
Related Articles The emergence of metabolomics as a key discipline in the drug discovery process. Drug Discov Today Technol. 2015 Jun;13:19-24 Authors: Fillet M, Frédérich M Abstract Metabolomics is a recent science that could be defined as the comprehensive qualitative and quantitative analysis of all small molecular weight compounds present in a cell, organ (including biofluids) or organism at a specific time point. More and more applications have been found these past years to metabolomics in the pharmaceutical field. Specifically in the drug discovery process, metabolomics open new perspectives, in new targets identification, in toxicological studies and in bioactive natural products discovery. The challenge in metabolomics is to find a technological approach allowing the reproducible identification and quantitation of as much metabolites as possible. In this context, mass spectrometry and NMR are emerging as key and complementary technologies. PMID: 26190679 [PubMed - in process]

Metabolomics in the natural products field - a gateway to novel antibiotics.

Tue, 21/07/2015 - 12:29
Related Articles Metabolomics in the natural products field - a gateway to novel antibiotics. Drug Discov Today Technol. 2015 Jun;13:11-7 Authors: Wu C, Kim HK, van Wezel GP, Choi YH Abstract Metabolomics is a high throughput analytical technique used to globally measure low molecular weight metabolites, allowing simultaneous metabolic comparison of different biological samples and thus highlighting differentially produced compounds as potential biomarkers. Although microbes are renowned as prolific sources of antibiotics, the traditional approach for new anti-infectives discovery is time-consuming and labor-intensive. In this review, the use of NMR- or MS-based metabolomics is proposed as an efficient approach to find antimicrobials in microbial single- or co-cultures. PMID: 26190678 [PubMed - in process]

2-Hydroxyglutarate Inhibits ATP Synthase and mTOR Signaling.

Tue, 21/07/2015 - 12:29
Related Articles 2-Hydroxyglutarate Inhibits ATP Synthase and mTOR Signaling. Cell Metab. 2015 Jul 14; Authors: Fu X, Chin RM, Vergnes L, Hwang H, Deng G, Xing Y, Pai MY, Li S, Ta L, Fazlollahi F, Chen C, Prins RM, Teitell MA, Nathanson DA, Lai A, Faull KF, Jiang M, Clarke SG, Cloughesy TF, Graeber TG, Braas D, Christofk HR, Jung ME, Reue K, Huang J Abstract We discovered recently that the central metabolite α-ketoglutarate (α-KG) extends the lifespan of C. elegans through inhibition of ATP synthase and TOR signaling. Here we find, unexpectedly, that (R)-2-hydroxyglutarate ((R)-2HG), an oncometabolite that interferes with various α-KG-mediated processes, similarly extends worm lifespan. (R)-2HG accumulates in human cancers carrying neomorphic mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes. We show that, like α-KG, both (R)-2HG and (S)-2HG bind and inhibit ATP synthase and inhibit mTOR signaling. These effects are mirrored in IDH1 mutant cells, suggesting a growth-suppressive function of (R)-2HG. Consistently, inhibition of ATP synthase by 2-HG or α-KG in glioblastoma cells is sufficient for growth arrest and tumor cell killing under conditions of glucose limitation, e.g., when ketone bodies (instead of glucose) are supplied for energy. These findings inform therapeutic strategies and open avenues for investigating the roles of 2-HG and metabolites in biology and disease. PMID: 26190651 [PubMed - as supplied by publisher]

Discrimination of honey of different floral origins by a combination of various chemical parameters.

Tue, 21/07/2015 - 12:29
Related Articles Discrimination of honey of different floral origins by a combination of various chemical parameters. Food Chem. 2015 Dec 15;189:52-9 Authors: Jandrić Z, Haughey SA, Frew RD, McComb K, Galvin-King P, Elliott CT, Cannavan A Abstract Honey is a high value food commodity with recognized nutraceutical properties. A primary driver of the value of honey is its floral origin. The feasibility of applying multivariate data analysis to various chemical parameters for the discrimination of honeys was explored. This approach was applied to four authentic honeys with different floral origins (rata, kamahi, clover and manuka) obtained from producers in New Zealand. Results from elemental profiling, stable isotope analysis, metabolomics (UPLC-QToF MS), and NIR, FT-IR, and Raman spectroscopic fingerprinting were analyzed. Orthogonal partial least square discriminant analysis (OPLS-DA) was used to determine which technique or combination of techniques provided the best classification and prediction abilities. Good prediction values were achieved using metabolite data (for all four honeys, Q(2)=0.52; for manuka and clover, Q(2)=0.76) and the trace element/isotopic data (for manuka and clover, Q(2)=0.65), while the other chemical parameters showed promise when combined (for manuka and clover, Q(2)=0.43). PMID: 26190600 [PubMed - in process]

Acute Activation of Oxidative Pentose Phosphate Pathway as First-Line Response to Oxidative Stress in Human Skin Cells.

Tue, 21/07/2015 - 12:29
Related Articles Acute Activation of Oxidative Pentose Phosphate Pathway as First-Line Response to Oxidative Stress in Human Skin Cells. Mol Cell. 2015 Jul 14; Authors: Kuehne A, Emmert H, Soehle J, Winnefeld M, Fischer F, Wenck H, Gallinat S, Terstegen L, Lucius R, Hildebrand J, Zamboni N Abstract Integrity of human skin is endangered by exposure to UV irradiation and chemical stressors, which can provoke a toxic production of reactive oxygen species (ROS) and oxidative damage. Since oxidation of proteins and metabolites occurs virtually instantaneously, immediate cellular countermeasures are pivotal to mitigate the negative implications of acute oxidative stress. We investigated the short-term metabolic response in human skin fibroblasts and keratinocytes to H2O2 and UV exposure. In time-resolved metabolomics experiments, we observed that within seconds after stress induction, glucose catabolism is routed to the oxidative pentose phosphate pathway (PPP) and nucleotide synthesis independent of previously postulated blocks in glycolysis (i.e., of GAPDH or PKM2). Through ultra-short (13)C labeling experiments, we provide evidence for multiple cycling of carbon backbones in the oxidative PPP, potentially maximizing NADPH reduction. The identified metabolic rerouting in oxidative and non-oxidative PPP has important physiological roles in stabilization of the redox balance and ROS clearance. PMID: 26190262 [PubMed - as supplied by publisher]

Metabolic changes in Citrus leaf volatiles in response to environmental stress.

Tue, 21/07/2015 - 12:29
Related Articles Metabolic changes in Citrus leaf volatiles in response to environmental stress. J Biosci Bioeng. 2015 Jul 15; Authors: Asai T, Matsukawa T, Kajiyama S Abstract Citrus plants are well known as a rich source of VOCs, and several have important roles in defense responses. However, how VOCs are regulated in response to environmental stress is not yet well understood. In this study, we investigated dynamic changes of VOCs present in leaves of seven Citrus species (Citrus sinensis, C. limon, C. paradisi, C. unshiu, C. kinokuni, C. grandis, and C. hassaku) in response to mechanical wounding, jasmonic acid (JA), and salicylic acid (SA) as determined by gas chromatography/mass spectrometric analysis followed by multivariate analysis (principal component analysis, PCA, and orthogonal partial least squares-discriminant analysis, OPLS-DA). PCA and OPLS-DA suggested that changes in VOC profiles against stress stimuli were much diverse among Citrus species. OPLS-DA showed that C6 volatiles, such as hexanal and trans-2-hexenal, were induced in response to JA and SA stimuli in C. sinensis and C. grandis, while the other VOCs were decreased under all tested stress conditions. α-Farnesene was induced in all species except C. hassaku after wounding or JA treatment. In addition, α-farnesene was also induced in response to SA stimuli in C. unshiu and C. kinokuni. Therefore these volatiles can be candidates of the common stress biomarkers in Citrus. Our results will give a new insight into defense mechanisms in Citrus species. PMID: 26188419 [PubMed - as supplied by publisher]

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