PubMed

Comparative metabolomic profiling reveals that dysregulated glycolysis stemming from lack of salvage NAD+ biosynthesis impairs reproductive development in C. elegans. J Biol Chem. 2015 Sep 8; Authors: Wang W, McReynolds MR, Goncalves JF, Shu M, Dhondt I, Braeckman BP, Lange SE, Kho K, Detwiler AC, Pacella MJ, Hanna-Rose W Abstract Temporal developmental progression is highly coordinated in Caenorhabditis elegans. However, loss of nicotinamidase PNC-1 activity slows reproductive development, uncoupling it from its typical progression relative to the soma. Using LC/MS we demonstrate that pnc-1 mutants do not salvage the nicotinamide released by NAD+ consumers to resynthesize NAD+, resulting in a reduction in global NAD+ bioavailability. We manipulate NAD+ levels to demonstrate that a minor deficit in NAD+ availability is incompatible with a normal pace of gonad development. The NAD+ deficit compromises NAD+ consumer activity, but we surprisingly found no functional link between consumer activity and reproductive development. As a result, we turned to a comparative metabolomics approach to identify the cause of the developmental phenotype. We reveal wide-spread metabolic perturbations, and using complementary pharmacological and genetic approaches, we demonstrate that a glycolytic block accounts for the slow pace of reproductive development. Interestingly, mitochondria are protected from both the deficiency in NAD+ biosynthesis and the effects of reduced glycolytic output. We suggest that compensatory metabolic processes that maintain mitochondrial activity in the absence of efficient glycolysis are incompatible with the requirements for reproductive development, which requires high levels of cell division. In addition to demonstrating metabolic requirements for reproductive development, this work also has implications for understanding the mechanisms behind therapeutic interventions that target NAD+ salvage biosynthesis for the purposes of inhibiting tumor growth. PMID: 26350462 [PubMed - as supplied by publisher]

Related Articles A comprehensive high-resolution mass spectrometry approach for characterization of metabolites by combination of ambient ionization, chromatography and imaging methods. Rapid Commun Mass Spectrom. 2014 Aug 30;28(16):1779-91 Authors: Berisha A, Dold S, Guenther S, Desbenoit N, Takats Z, Spengler B, Römpp A Abstract RATIONALE: An ideal method for bioanalytical applications would deliver spatially resolved quantitative information in real time and without sample preparation. In reality these requirements can typically not be met by a single analytical technique. Therefore, we combine different mass spectrometry approaches: chromatographic separation, ambient ionization and imaging techniques, in order to obtain comprehensive information about metabolites in complex biological samples. METHODS: Samples were analyzed by laser desorption followed by electrospray ionization (LD-ESI) as an ambient ionization technique, by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging for spatial distribution analysis and by high-performance liquid chromatography/electrospray ionization mass spectrometry (HPLC/ESI-MS) for quantitation and validation of compound identification. All MS data were acquired with high mass resolution and accurate mass (using orbital trapping and ion cyclotron resonance mass spectrometers). Grape berries were analyzed and evaluated in detail, whereas wheat seeds and mouse brain tissue were analyzed in proof-of-concept experiments. RESULTS: In situ measurements by LD-ESI without any sample preparation allowed for fast screening of plant metabolites on the grape surface. MALDI imaging of grape cross sections at 20 µm pixel size revealed the detailed distribution of metabolites which were in accordance with their biological function. HPLC/ESI-MS was used to quantify 13 anthocyanin species as well as to separate and identify isomeric compounds. A total of 41 metabolites (amino acids, carbohydrates, anthocyanins) were identified with all three approaches. Mass accuracy for all MS measurements was better than 2 ppm (root mean square error). CONCLUSIONS: The combined approach provides fast screening capabilities, spatial distribution information and the possibility to quantify metabolites. Accurate mass measurements proved to be critical in order to reliably combine data from different MS techniques. Initial results on the mycotoxin deoxynivalenol (DON) in wheat seed and phospholipids in mouse brain as a model for mammalian tissue indicate a broad applicability of the presented workflow. PMID: 25559448 [PubMed - indexed for MEDLINE]

Related Articles Fruit of Ziziphus jujuba (Jujube) at two stages of maturity: distinction by metabolic profiling and biological assessment. J Agric Food Chem. 2015 Jan 21;63(2):739-44 Authors: Chen J, Chan PH, Lam CT, Li Z, Lam KY, Yao P, Dong TT, Lin H, Lam H, Tsim KW Abstract The fruit of Ziziphus jujuba, named as jujube or Chinese date, is used as a health supplement worldwide. Two kinds of jujubes are commonly found in the market: immature jujubes eaten as fruits, and mature jujubes employed as medicinal herbs. To study the variation of jujubes at two developmental stages, we investigated their chemical and biological properties by metabolic profiling and cellular assays. In NMR profiling, the levels of 11 metabolites were measured. Statistically differences in the levels of threonine, alanine, acetate, creatine, glucose, sucrose, and formate were found between mature and immature jujubes. In parallel, their neuro-protecting and erythropoietic activities were compared. The water extract of mature jujube possessed better effect in inducing neurofilament expression than that of the immature one, while immature jujube extract performed better in activating HRE-mediated transcriptional activity. These findings suggest the maturity of jujube has to be considered when it is being used for health food products. PMID: 25544316 [PubMed - indexed for MEDLINE]

Related Articles Comprehensive analysis of the mouse brain proteome sampled in mass spectrometry imaging. Anal Chem. 2015 Feb 3;87(3):1867-75 Authors: Heijs B, Carreira RJ, Tolner EA, de Ru AH, van den Maagdenberg AM, van Veelen PA, McDonnell LA Abstract On-tissue enzymatic digestion is performed in mass spectrometry imaging (MSI) experiments to access larger proteins and to assign protein identities. Most on-tissue digestion MSI studies have focused on method development rather than identifying the molecular features observed. Herein, we report a comprehensive study of the mouse brain proteome sampled by MSI. Using complementary proteases, we were able to identify 5337 peptides in the matrix-assisted laser desorption/ionization (MALDI) matrix, corresponding to 1198 proteins. 630 of these peptides, corresponding to 280 proteins, could be assigned to peaks in MSI data sets. Gene ontology and pathway analyses revealed that many of the proteins are involved in neurodegenerative disorders, such as Alzheimer's, Parkinson's, and Huntington's disease. PMID: 25535922 [PubMed - indexed for MEDLINE]

Related Articles Non-invasive biomarkers in non-alcoholic steatohepatitis-induced hepatocellular carcinoma. J Gastrointestin Liver Dis. 2014 Dec;23(4):425-9 Authors: Voiculescu M, Nanau RM, Neuman MG Abstract Non-alcoholic fatty liver disease (NAFLD) is by far the most common form of chronic liver disease worldwide, affecting adults as well as children. Under the term of NAFLD there is a wide spectrum of diseases ranging from simple steatosis to the non-alcoholic steatohepatitis (NASH), which can progress to cirrhosis and hepatocellular carcinoma (HCC). Several mechanisms have been described to influence the progression of the disease from the benign NAFL to the aggressive NASH. The imbalance between pro- and anti-oxidant mechanisms and between pro- and anti-inflammatory cytokines is thought to play a pivotal role in the pathogenesis of NAFLD and disease progression toward NASH and fibrosis. The present review intends to look at some of the mechanistic biomarkers to be employed in establishing an early diagnosis in HCC derived from NASH. PMID: 25532002 [PubMed - indexed for MEDLINE]

Related Articles Multifaceted investigation of metabolites during nitrogen fixation in Medicago via high resolution MALDI-MS imaging and ESI-MS. J Am Soc Mass Spectrom. 2015 Jan;26(1):149-58 Authors: Gemperline E, Jayaraman D, Maeda J, Ané JM, Li L Abstract Legumes have developed the unique ability to establish a symbiotic relationship with soil bacteria known as rhizobia. This interaction results in the formation of root nodules in which rhizobia thrive and reduce atmospheric dinitrogen into plant-usable ammonium through biological nitrogen fixation (BNF). Owing to the availability of genetic information for both of the symbiotic partners, the Medicago truncatula-Sinorhizobium meliloti association is an excellent model for examining the BNF process. Although metabolites are important in this symbiotic association, few studies have investigated the array of metabolites that influence this process. Of these studies, most target only a few specific metabolites, the roles of which are either well known or are part of a well-characterized metabolic pathway. Here, we used a multifaceted mass spectrometric (MS) approach to detect and identify the key metabolites that are present during BNF using the Medicago truncatula-Sinorhizobium meliloti association as the model system. High mass accuracy and high resolution matrix-assisted laser desorption/ionization (MALDI) and electrospray ionization (ESI) Orbitrap instruments were used in this study and provide complementary results for more in-depth characterization of the nitrogen-fixation process. We used well-characterized plant and bacterial mutants to highlight differences between the metabolites that are present in functional versus nonfunctional nodules. Our study highlights the benefits of using a combination of mass spectrometric techniques to detect differences in metabolite composition and the distributions of these metabolites in plant biology. PMID: 25323862 [PubMed - indexed for MEDLINE]

Related Articles Metabonomics study on the hot syndrome of traditional Chinese medicine by rapid resolution liquid chromatography combined with quadrupole time-of-flight tandem mass spectrometry. Arch Pharm Res. 2014 Jul;37(7):899-906 Authors: Wang Y, Ma L, Sun Y, Yang L, Yue H, Liu S Abstract The hot syndrome refers to any feverish conditions during a pathological development, a sub-health phenomenon, and is a potential risk for human health. The metabonomics study on the hot syndrome may provide insight into understanding of its pathology and play a role in the prevention and treatment of its related diseases. In this paper, the rats were dosed with the hot syndrome prescription, ginseng and water. The corresponding urine samples were identified by rapid resolution liquid chromatography combined with quadrupole time-of-flight tandem mass spectrometry. More than 1,000 metabolic compounds from different urine samples could be further differentiated by principal component analysis. As a result, the rat body temperature and weight were recognized as the hot syndrome related factors. Some specific metabolites have been discovered as a pattern of the potential biomarkers for the hot syndrome. The results showed that ginseng cannot cause the hot syndrome in a reasonable dose, but the hot syndrome prescription can. It is suggested that ginseng cannot be used only as a tradition Chinese medicine but also as a nutrient. The work showed metabonomics method is a valuable tool in studying mechanism of the hot syndrome. PMID: 24085628 [PubMed - indexed for MEDLINE]

An Optimized Method of Metabolite Extraction from Formalin-Fixed Paraffin-Embedded Tissue for GC/MS Analysis. PLoS One. 2015;10(9):e0136902 Authors: Wojakowska A, Marczak Ł, Jelonek K, Polanski K, Widlak P, Pietrowska M Abstract Formalin-fixed paraffin-embedded (FFPE) tissue specimens constitute a highly valuable source of clinical material for retrospective molecular studies. However, metabolomic assessment of such archival material remains still in its infancy. Hence, there is an urgent need for efficient methods enabling extraction and profiling of metabolites present in FFPE tissue specimens. Here we demonstrate the methodology for isolation of primary metabolites from archival tissues; either fresh-frozen, formalin-fixed or formalin-fixed and paraffin-embedded specimens of mouse kidney were analysed and compared in this work. We used gas chromatography followed by mass spectrometry (GC/MS approach) to identify about 80 metabolites (including amino acids, saccharides, carboxylic acids, fatty acids) present in such archive material. Importantly, about 75% of identified compounds were detected in all three types of specimens. Moreover, we observed that fixation with formalin itself (and their duration) did not affect markedly the presence of particular metabolites in tissue-extracted material, yet fixation for 24h could be recommended as a practical standard. Paraffin embedding influenced efficiency of extraction, which resulted in reduced quantities of several compounds. Nevertheless, we proved applicability of FFPE specimens for non-targeted GS/MS-based profiling of tissue metabolome, which is of great importance for feasibility of metabolomics studies using retrospective clinical material. PMID: 26348873 [PubMed - as supplied by publisher]

Related Articles Metabolomics reveals differences of metal toxicity in cultures of Pseudomonas pseudoalcaligenes KF707 grown on different carbon sources. Front Microbiol. 2015;6:827 Authors: Booth SC, Weljie AM, Turner RJ Abstract Co-contamination of metals and organic pollutants is a global problem as metals interfere with the metabolism of complex organics by bacteria. Based on a prior observation that metal tolerance was altered by the sole carbon source being used for growth, we sought to understand how metal toxicity specifically affects bacteria using an organic pollutant as their sole carbon source. To this end metabolomics was used to compare cultures of Pseudomonas pseudoalcaligenes KF707 grown on either biphenyl (Bp) or succinate (Sc) as the sole carbon source in the presence of either aluminum (Al) or copper (Cu). Using multivariate statistical analysis it was found that the metals caused perturbations to more cellular processes in the cultures grown on Bp than those grown on Sc. Al induced many changes that were indicative of increased oxidative stress as metabolites involved in DNA damage and protection, the Krebs cycle and anti-oxidant production were altered. Cu also caused metabolic changes that were indicative of similar stress, as well as appearing to disrupt other key enzymes such as fumarase. Additionally, both metals caused the accumulation of Bp degradation intermediates indicating that they interfered with Bp metabolism. Together these results provide a basic understanding of how metal toxicity specifically affects bacteria at a biochemical level during the degradation of an organic pollutant and implicate the catabolism of this carbon source as a major factor that exacerbates metal toxicity. PMID: 26347721 [PubMed]

Related Articles Energetics of endurance exercise in young horses determined by nuclear magnetic resonance metabolomics. Front Physiol. 2015;6:198 Authors: Luck MM, Le Moyec L, Barrey E, Triba MN, Bouchemal N, Savarin P, Robert C Abstract Long-term endurance exercise severely affects metabolism in both human and animal athletes resulting in serious risk of metabolic disorders during or after competition. Young horses (up to 6 years old) can compete in races up to 90 km despite limited scientific knowledge of energetic metabolism responses to long distance exercise in these animals. The hypothesis of this study was that there would be a strong effect of endurance exercise on the metabolomic profiles of young horses and that the energetic metabolism response in young horses would be different from that of more experienced horses. Metabolomic profiling is a powerful method that combines Nuclear Magnetic Resonance (NMR) spectrometry with supervised Orthogonal Projection on Latent Structure (OPLS) statistical analysis. (1)H-NMR spectra were obtained from plasma samples drawn from young horses (before and after competition). The spectra obtained before and after the race from the same horse (92 samples) were compared using OPLS. The statistical parameters showed the robustness of the model (R2Y = 0.947, Q2Y = 0.856 and cros-validated ANOVA p < 0.001). For confirmation of the predictive value of the model, a test set of 104 sample spectra were projected by the model, which provided perfect predictions as the area under the receiving-operator curve was 1. The metabolomic profile determined with the OPLS model showed that glycemia after the race was lower than glycemia before the race, despite the involvement of lipid and protein catabolism. An OPLS model was calculated to compare spectra obtained on plasma taken after the race from 6-year-old horses and from experienced horses (cross-validated ANOVA p < 0.001). The comparison of metabolomic profiles in young horses to those from experienced horses showed that experienced horses maintained their glycemia with higher levels of lactate and a decrease of plasma lipids after the race. PMID: 26347654 [PubMed]

Related Articles Seasonal Variations of Metabolome and Tyrosinase Inhibitory Activity of Lespedeza maximowiczii During the Growth Periods. J Agric Food Chem. 2015 Sep 8; Authors: Kim NK, Park HM, Lee J, Ku KM, Lee CH Abstract Lespedeza species are useful for pasture and energy crops and medical plant. We determined the metabolites discriminated from the each growth period (3, 4, 6, 8, 15, and 18 months) after germination in leaves and stems of Lespedeza maximowizii by metabolomics technique. Specifically, levels of sugars and luteolin-dominated derivatives were significantly elevated in samples harvested in November. This maybe related with cold tolerance mechanism against the low temperatures of the winter season. The concentrations of secondary metabolites, isoflavones and flavanones, as well as tyrosinase inhibitory activity were the highest in 6 months samples, which were harvested in September, fall season. The tyrosinase inhibitory activity in leaves was higher than stems irrespective of the growth period. This study suggests that MS-based metabolite profiling could be used as a tool to examine quantitative or qualitative metabolite changes related to seasonal variations, and to understand the correlation between activity and metabolites. PMID: 26345477 [PubMed - as supplied by publisher]

Related Articles [Effect of Psoraleae Fructus and Myristicae Semen in "Ershen pill" on serum metabonomics in spleen-kidney Yang deficiency diarrhea rats before and after processing]. Zhongguo Zhong Yao Za Zhi. 2015 Apr;40(7):1400-3 Authors: Chen ZM, Hu CJ, Xiong R, Cui YY, Zhang M, Pan X, Zhao L Abstract The metabonomics method was used to study the intervention effect of Psoraleae Fructus and Myristicae Semen in "Ershen pill" on the changes in serum endogenous metabolites in spleen-kidney Yang deficiency diarrhea rats before and after processing, screen out differentiated metabolites related to spleen-kidney Yang deficiency diarrhea and explore the metabolic patterns related to spleen-kidney Yang deficiency diarrhea and the processing synergy mechanism of Psoraleae Fructus and Myristicae Semen in "Ershen pill". Efforts were made to detect SOD and MDA of each group, test rat serum metabolic fingerprints in different stages by using GC-MS, analyze by PCA and PLS-DA methods and screen out potential biomarks through VIP and t test. The results revealed that "Ershen pill" could enhance the level of SOD and decrease the level of MDA and identified 10 differentiated metabolites related to spleen-kidney Yang deficiency diarrhea. Compared with the model group, all of metabolites recovered to varying levels after being intervened with "Ershen pill", with the best effect shown in the "Ershen pill" IV group (salt-processed Psoraleae Fructus + bran-roasted Myristicae Semen). It is speculated that that Psoraleae Fructus and Semen Myristicae in "Ershen pill" show a synergistic effect by inhibiting peroxide, improving aglucolipid, amino acids and energy metabolism, with multiple target sites. PMID: 26281569 [PubMed - indexed for MEDLINE]

Related Articles A New View of Vitiligo: Looking at Normal-Appearing Skin. J Invest Dermatol. 2015 Jul;135(7):1713-4 Authors: Picardo M, Bastonini E Abstract Debate over the pathogenesis of vitiligo is still ongoing among scientists, with several hypotheses currently under consideration. The study by Wagner et al. in this issue focuses on the role of E-cadherin-mediated cell adhesion in vitiliginous epidermis under oxidative and mechanical stress. Their work highlights how alterations in cell-cell adhesion across nonlesional melanocyte membranes in patients with vitiligo argue for primary intrinsic defects in the melanocytes. PMID: 26066890 [PubMed - indexed for MEDLINE]

Related Articles Normalization to specific gravity prior to analysis improves information recovery from high resolution mass spectrometry metabolomic profiles of human urine. Anal Chem. 2014 Nov 4;86(21):10925-31 Authors: Edmands WM, Ferrari P, Scalbert A Abstract Extraction of meaningful biological information from urinary metabolomic profiles obtained by liquid-chromatography coupled to mass spectrometry (MS) necessitates the control of unwanted sources of variability associated with large differences in urine sample concentrations. Different methods of normalization either before analysis (preacquisition normalization) through dilution of urine samples to the lowest specific gravity measured by refractometry, or after analysis (postacquisition normalization) to urine volume, specific gravity and median fold change are compared for their capacity to recover lead metabolites for a potential future use as dietary biomarkers. Twenty-four urine samples of 19 subjects from the European Prospective Investigation into Cancer and nutrition (EPIC) cohort were selected based on their high and low/nonconsumption of six polyphenol-rich foods as assessed with a 24 h dietary recall. MS features selected on the basis of minimum discriminant selection criteria were related to each dietary item by means of orthogonal partial least-squares discriminant analysis models. Normalization methods ranked in the following decreasing order when comparing the number of total discriminant MS features recovered to that obtained in the absence of normalization: preacquisition normalization to specific gravity (4.2-fold), postacquisition normalization to specific gravity (2.3-fold), postacquisition median fold change normalization (1.8-fold increase), postacquisition normalization to urinary volume (0.79-fold). A preventative preacquisition normalization based on urine specific gravity was found to be superior to all curative postacquisition normalization methods tested for discovery of MS features discriminant of dietary intake in these urinary metabolomic datasets. PMID: 25285402 [PubMed - indexed for MEDLINE]

Insights into the impact of silver nanoparticles on human keratinocytes metabolism through NMR metabolomics. Arch Biochem Biophys. 2015 Sep 3; Authors: Carrola J, Bastos V, Ferreira de Oliveira JM, Oliveira H, Santos C, Gil AM, Duarte IF Abstract Due to their antimicrobial properties, silver nanoparticles (AgNPs) are increasingly incorporated into consumer goods and medical products. Their potential toxicity to human cells is however a major concern, and there is a need for improved understanding of their effects on cell metabolism and function. Here, Nuclear Magnetic Resonance (NMR) metabolomics was used to investigate the metabolic profile of human epidermis keratinocytes (HaCaT cell line) exposed for 48h to 30 nm citrate-stabilized spherical AgNPs (10 and 40 μg/mL). Intracellular aqueous extracts, organic extracts and extracellular culture medium were analysed to provide an integrated view of the cellular metabolic response. The specific metabolite variations, highlighted through multivariate analysis and confirmed by spectral integration, suggested that HaCaT cells exposed to AgNPs displayed upregulated glutathione-based antioxidant protection, increased glutaminolysis, downregulated tricarboxylic acid (TCA) cycle activity, energy depletion and cell membrane modification. Importantly, most metabolic changes were apparent in cells exposed to a concentration of AgNPs which did not affect cell viability at significant levels, thus underlying the sensitivity of NMR metabolomics to detect early biochemical events, even in the absence of a clear cytotoxic response. It can be concluded that NMR metabolomics is an important new tool in the field of in vitro nanotoxicology. PMID: 26344855 [PubMed - as supplied by publisher]

Metabolomic approach for improving ethanol stress tolerance in Saccharomyces cerevisiae. J Biosci Bioeng. 2015 Sep 3; Authors: Ohta E, Nakayama Y, Mukai Y, Bamba T, Fukusaki E Abstract The budding yeast Saccharomyces cerevisiae is widely used for brewing and ethanol production. The ethanol sensitivity of yeast cells is still a serious problem during ethanol fermentation, and a variety of genetic approaches (e.g., random mutant screening under selective pressure of ethanol) have been developed to improve ethanol tolerance. In this study, we developed a strategy for improving ethanol tolerance of yeast cells based on metabolomics as a high-resolution quantitative phenotypic analysis. We performed gas chromatography-mass spectrometry analysis to identify and quantify 36 compounds on 14 mutant strains including knockout strains for transcription factor and metabolic enzyme genes. A strong relation between metabolome of these mutants and their ethanol tolerance was observed. Data mining of the metabolomic analysis showed that several compounds (such as trehalose, valine, inositol and proline) contributed highly to ethanol tolerance. Our approach successfully detected well-known ethanol stress related metabolites such as trehalose and proline thus, to further prove our strategy, we focused on valine and inositol as the most promising target metabolites in our study. Our results show that simultaneous deletion of LEU4 and LEU9 (leading to accumulation of valine) or INM1 and INM2 (leading to reduction of inositol) significantly enhanced ethanol tolerance. This study shows the potential of the metabolomic approach to identify target genes for strain improvement of S. cerevisiae with higher ethanol tolerance. PMID: 26344121 [PubMed - as supplied by publisher]

Hepatic Mitochondrial Pyruvate Carrier 1 Is Required for Efficient Regulation of Gluconeogenesis and Whole-Body Glucose Homeostasis. Cell Metab. 2015 Sep 2; Authors: Gray LR, Sultana MR, Rauckhorst AJ, Oonthonpan L, Tompkins SC, Sharma A, Fu X, Miao R, Pewa AD, Brown KS, Lane EE, Dohlman A, Zepeda-Orozco D, Xie J, Rutter J, Norris AW, Cox JE, Burgess SC, Potthoff MJ, Taylor EB Abstract Gluconeogenesis is critical for maintenance of euglycemia during fasting. Elevated gluconeogenesis during type 2 diabetes (T2D) contributes to chronic hyperglycemia. Pyruvate is a major gluconeogenic substrate and requires import into the mitochondrial matrix for channeling into gluconeogenesis. Here, we demonstrate that the mitochondrial pyruvate carrier (MPC) comprising the Mpc1 and Mpc2 proteins is required for efficient regulation of hepatic gluconeogenesis. Liver-specific deletion of Mpc1 abolished hepatic MPC activity and markedly decreased pyruvate-driven gluconeogenesis and TCA cycle flux. Loss of MPC activity induced adaptive utilization of glutamine and increased urea cycle activity. Diet-induced obesity increased hepatic MPC expression and activity. Constitutive Mpc1 deletion attenuated the development of hyperglycemia induced by a high-fat diet. Acute, virally mediated Mpc1 deletion after diet-induced obesity decreased hyperglycemia and improved glucose tolerance. We conclude that the MPC is required for efficient regulation of gluconeogenesis and that the MPC contributes to the elevated gluconeogenesis and hyperglycemia in T2D. PMID: 26344103 [PubMed - as supplied by publisher]

Metabolomic profiling in inner ear fluid by gas chromatography/mass spectrometry in guinea pig cochlea. Neurosci Lett. 2015 Sep 3; Authors: Fujita T, Yamashita D, Irino Y, Kitamoto J, Fukuda Y, Inokuchi G, Hasegawa S, Otsuki N, Yoshida M, Nibu KI Abstract The composition and homeostasis of inner ear fluids are important in hearing function. The purpose of this study was to perform metabolomic analysis of the inner ear fluid in guinea pig cochlea, which has not been previously reported in literature, using gas chromatography/mass spectrometry (GC/MS). Seventy-seven kinds of metabolites were detected in the inner ear fluid. Six metabolites, ascorbic acid, fructose, galactosamine, inositol, pyruvate + oxaloacetic acid, and meso-erythritol, were significantly more abundant, and nine metabolites, phosphate, valine, glycine, glycerol, ornithine, glucose, citric acid + isocitric acid, mannose, and trans-4-hydroxy-L-proline, were less abundant in the inner ear fluid than in plasma. The levels of ten metabolites, 3-hydroxy-butyrate, glycerol, fumaric acid, galactosamine, pyruvate + oxaloacetic acid, phosphate, meso-erythritol, citric acid + isocitric acid, mannose, and inositol, in the inner ear fluid significantly changed after loud noise exposure. These observations may help to elucidate various clinical conditions of sensorineural hearing loss, including noise-induced hearing loss. PMID: 26343935 [PubMed - as supplied by publisher]

Subversion of anticancer immunosurveillance by radiotherapy. Nat Immunol. 2015 Sep 7; Authors: Zitvogel L, Kroemer G PMID: 26343538 [PubMed - as supplied by publisher]

A metabolomic perspective of griseofulvin-inducedliver injury in mice. Biochem Pharmacol. 2015 Sep 4; Authors: Liu K, Yan J, Sachar M, Zhang X, Guan M, Xie W, Ma X Abstract Griseofulvin (GSF) causes hepatic porphyria in mice, which mimics the liver injury associated with erythropoietic protoporphyria (EPP) in humans. The current study investigated the biochemical basis of GSF-induced liver injury in mice using a metabolimic approach. GSF treatment in mice resulted in significant accumulations of protoporphyrin IX (PPIX), N-methyl PPIX, bile acids, and glutathione (GSH) in the liver. Metabolomic analysis also revealed bioactivation pathways of GSF that contributed to the formation of GSF-PPIX, GSF-GSH and GSF-proline adducts. GSF-PPIX is the precursor of N-methyl PPIX. A six-fold increase of N-methyl PPIX was observed in the liver of mice after GSF treatment. N-methyl PPIX strongly inhibits ferrochelatase, the enzyme that converts PPIX to heme, and leads to PPIX accumulation. Excessive PPIX in the liver results in bile duct blockage and disturbs bile acid homeostasis. The accumulation of GSH in the liver was likely due to Nrf2-mediated upregulation of GSH synthesis. In summary, this study provides the biochemical basis of GSF-induced liver injury that can be used to understand the pathophysiology of EPP-associated liver injury in humans. PMID: 26343413 [PubMed - as supplied by publisher]