PubMed

A guide to the identification of metabolites in NMR-based metabonomics/metabolomics experiments. Comput Struct Biotechnol J. 2016;14:135-53 Authors: Dona AC, Kyriakides M, Scott F, Shephard EA, Varshavi D, Veselkov K, Everett JR Abstract Metabonomics/metabolomics is an important science for the understanding of biological systems and the prediction of their behaviour, through the profiling of metabolites. Two technologies are routinely used in order to analyse metabolite profiles in biological fluids: nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS), the latter typically with hyphenation to a chromatography system such as liquid chromatography (LC), in a configuration known as LC-MS. With both NMR and MS-based detection technologies, the identification of the metabolites in the biological sample remains a significant obstacle and bottleneck. This article provides guidance on methods for metabolite identification in biological fluids using NMR spectroscopy, and is illustrated with examples from recent studies on mice. PMID: 27087910 [PubMed]

The individual human metabolic phenotype analyzed by (1)H-NMR of saliva samples. J Proteome Res. 2016 Apr 18; Authors: Wallner-Liebmann S, Tenori L, Mazzoleni A, Dieber-Rotheneder M, Konrad M, Hofmann P, Luchinat C, Turano P, Zatloukal K Abstract Saliva is an important physiological fluid, which contains a complex mixture of analytes that may produce a character-is-tic individual signature. In recent years, it has been demonstrated that urine possesses a clear signature of the indi-vidual metabolic phenotype. Here, NMR based metabolomics was employed to analyze saliva from 23 healthy volun-teers. About six saliva samples were collected daily from each individual, for 10 consecutive days: 7 days in a real life situ-ation (days 1-7, Phase I) and 3 days (days 8-10, Phase II) under a standardized diet plus a physical exercise program at day 10. The result is the first demonstration of the existence of an individual metabolic phenotype in saliva. A systematic comparative analysis with urine samples from the same collection scheme demonstrates that the individual phenotype in saliva is slightly weaker than in urine, but less influenced by diet. PMID: 27087681 [PubMed - as supplied by publisher]

Halogenated hydrocarbon solvent-related cholangiocarcinoma risk: biliary excretion of glutathione conjugates of 1,2-dichloropropane evidenced by untargeted metabolomics analysis. Sci Rep. 2016;6:24586 Authors: Toyoda Y, Takada T, Suzuki H Abstract Recently, the International Agency for Research on Cancer issued a warning about the carcinogenicity of 1,2-dichloropropane (1,2-DCP) to humans based on an epidemiological study suggesting a relationship between the incidence of cholangiocarcinoma and occupational exposure to halogenated hydrocarbon solvent comprised mostly of 1,2-DCP. Although this dihaloalkane has been used in various industrial fields, there has been no biological evidence explaining the cholangiocarcinoma latency, as well as little understanding of general cholangiocarcinoma risk. In the present study, we explored the biliary excretion of 1,2-DCP metabolites by an untargeted metabolomics approach and the related molecular mechanism with in vitro and in vivo experiments. We hypothesized that the biliary excretion of carcinogens derived from 1,2-DCP contribute to the increased cholangiocarcinoma risk. We found that 1,2-DCP was conjugated with glutathione in the liver, and that the glutathione-conjugated forms of 1,2-DCP, including a potential carcinogen that contains a chloride atom, were excreted into bile by the bile canalicular membrane transporter, ABCC2. These results may reflect a risk in the backfiring of biliary excretion as a connatural detoxification systems for xenobiotics. Our findings would contribute to uncover the latent mechanism by which the chronic exposure to 1,2-DCP increases cholangiocarcinoma risk and future understanding of cholangiocarcinoma biology. PMID: 27087417 [PubMed - in process]

Objective Definition of Monofloral and Polyfloral Honeys Based on NMR Metabolomic Profiling. J Agric Food Chem. 2016 Apr 17; Authors: Schievano E, Finotello C, Uddin J, Mammi S, Piana L Abstract This paper describes a remarkably precise, simple and objective definition of monofloral and polyfloral honey based on NMR metabolomics. The spectra of organic extracts of 983 samples of 16 botanical origins were used to derive one-vs-all OPLS-DA classification models. The predictive components of the statistical models reveal not only the principal but also the secondary floral origins present in a sample of honey, a novel feature with respect to the methods present in the literature that are able to confirm the authenticity of monofloral honeys but not to characterize a mixture of honey types. This result descends from the peculiar features of the chloroform spectra that show diagnostic resonances for almost each botanical origin, making these NMR spectra suitable fingerprints. The reliability of the method was tested with additional 120 samples and the class assignments were compared with those obtained by traditional analysis. The two approaches are in excellent agreement in identifying the floral species present in honeys and in the botanical classification. Therefore, the NMR method may prove to be a valid solution to the huge limitations of the traditional classification that is very demanding and complex. PMID: 27086991 [PubMed - as supplied by publisher]

Recurrent Clostridium difficile infection associates with distinct bile acid and microbiome profiles. Aliment Pharmacol Ther. 2016 Apr 18; Authors: Allegretti JR, Kearney S, Li N, Bogart E, Bullock K, Gerber GK, Bry L, Clish CB, Alm E, Korzenik JR Abstract BACKGROUND: The healthy microbiome protects against the development of Clostridium difficile infection (CDI), which typically develops following antibiotics. The microbiome metabolises primary to secondary bile acids, a process if disrupted by antibiotics, may be critical for the initiation of CDI. AIM: To assess the levels of primary and secondary bile acids associated with CDI and associated microbial changes. METHODS: Stool and serum were collected from patients with (i) first CDI (fCDI), (ii) recurrent CDI (rCDI) and (iii) healthy controls. 16S rRNA sequencing and bile salt metabolomics were performed. Random forest regression models were constructed to predict disease status. PICRUSt analyses were used to test for associations between predicted bacterial bile salt hydrolase (BSH) gene abundances and bile acid levels. RESULTS: Sixty patients (20 fCDI, 19 rCDI and 21 controls) were enrolled. Secondary bile acids in stool were significantly elevated in controls compared to rCDI and fCDI (P < 0.0001 and P = 0.0007 respectively). Primary bile acids in stool were significantly elevated in rCDI compared to controls (P < 0.0001) and in rCDI compared to fCDI (P = 0.02). Using random forest regression, we distinguished rCDI and fCDI patients 84.2% of the time using bile acid ratios. Stool deoxycholate to glycoursodeoxycholate ratio was the single best predictor. PICRUSt analyses found significant differences in predicted abundances of bacterial BSH genes in stool samples across the groups. CONCLUSION: Primary and secondary bile acid composition in stool was different in those with rCDI, fCDI and controls. The ratio of stool deoxycholate to glycoursodeoxycholate was the single best predictor of disease state and may be a potential biomarker for recurrence. PMID: 27086647 [PubMed - as supplied by publisher]

Related Articles Extreme Vulnerability of IDH1 Mutant Cancers to NAD+ Depletion. Cancer Cell. 2015 Dec 14;28(6):773-84 Authors: Tateishi K, Wakimoto H, Iafrate AJ, Tanaka S, Loebel F, Lelic N, Wiederschain D, Bedel O, Deng G, Zhang B, He T, Shi X, Gerszten RE, Zhang Y, Yeh JR, Curry WT, Zhao D, Sundaram S, Nigim F, Koerner MV, Ho Q, Fisher DE, Roider EM, Kemeny LV, Samuels Y, Flaherty KT, Batchelor TT, Chi AS, Cahill DP Abstract Heterozygous mutation of IDH1 in cancers modifies IDH1 enzymatic activity, reprogramming metabolite flux and markedly elevating 2-hydroxyglutarate (2-HG). Here, we found that 2-HG depletion did not inhibit growth of several IDH1 mutant solid cancer types. To identify other metabolic therapeutic targets, we systematically profiled metabolites in endogenous IDH1 mutant cancer cells after mutant IDH1 inhibition and discovered a profound vulnerability to depletion of the coenzyme NAD+. Mutant IDH1 lowered NAD+ levels by downregulating the NAD+ salvage pathway enzyme nicotinate phosphoribosyltransferase (Naprt1), sensitizing to NAD+ depletion via concomitant nicotinamide phosphoribosyltransferase (NAMPT) inhibition. NAD+ depletion activated the intracellular energy sensor AMPK, triggered autophagy, and resulted in cytotoxicity. Thus, we identify NAD+ depletion as a metabolic susceptibility of IDH1 mutant cancers. PMID: 26678339 [PubMed - indexed for MEDLINE]

Related Articles Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents. Cancer Cell. 2015 Dec 14;28(6):690-714 Authors: Galluzzi L, Buqué A, Kepp O, Zitvogel L, Kroemer G Abstract The tremendous clinical success of checkpoint blockers illustrates the potential of reestablishing latent immunosurveillance for cancer therapy. Although largely neglected in the clinical practice, accumulating evidence indicates that the efficacy of conventional and targeted anticancer agents does not only involve direct cytostatic/cytotoxic effects, but also relies on the (re)activation of tumor-targeting immune responses. Chemotherapy can promote such responses by increasing the immunogenicity of malignant cells, or by inhibiting immunosuppressive circuitries that are established by developing neoplasms. These immunological "side" effects of chemotherapy are desirable, and their in-depth comprehension will facilitate the design of novel combinatorial regimens with improved clinical efficacy. PMID: 26678337 [PubMed - indexed for MEDLINE]

Related Articles Development of metabolic and inflammatory mediator biomarker phenotyping for early diagnosis and triage of pediatric sepsis. Crit Care. 2015;19:320 Authors: Mickiewicz B, Thompson GC, Blackwood J, Jenne CN, Winston BW, Vogel HJ, Joffe AR, Alberta Sepsis Network Abstract INTRODUCTION: The first steps in goal-directed therapy for sepsis are early diagnosis followed by appropriate triage. These steps are usually left to the physician's judgment, as there is no accepted biomarker available. We aimed to determine biomarker phenotypes that differentiate children with sepsis who require intensive care from those who do not. METHODS: We conducted a prospective, observational nested cohort study at two pediatric intensive care units (PICUs) and one pediatric emergency department (ED). Children ages 2-17 years presenting to the PICU or ED with sepsis or presenting for procedural sedation to the ED were enrolled. We used the judgment of regional pediatric ED and PICU attending physicians as the standard to determine triage location (PICU or ED). We performed metabolic and inflammatory protein mediator profiling with serum and plasma samples, respectively, collected upon presentation, followed by multivariate statistical analysis. RESULTS: Ninety-four PICU sepsis, 81 ED sepsis, and 63 ED control patients were included. Metabolomic profiling revealed clear separation of groups, differentiating PICU sepsis from ED sepsis with accuracy of 0.89, area under the receiver operating characteristic curve (AUROC) of 0.96 (standard deviation [SD] 0.01), and predictive ability (Q(2)) of 0.60. Protein mediator profiling also showed clear separation of the groups, differentiating PICU sepsis from ED sepsis with accuracy of 0.78 and AUROC of 0.88 (SD 0.03). Combining metabolomic and protein mediator profiling improved the model (Q(2) =0.62), differentiating PICU sepsis from ED sepsis with accuracy of 0.87 and AUROC of 0.95 (SD 0.01). Separation of PICU sepsis or ED sepsis from ED controls was even more accurate. Prespecified age subgroups (2-5 years old and 6-17 years old) improved model accuracy minimally. Seventeen metabolites or protein mediators accounted for separation of PICU sepsis and ED sepsis with 95% confidence. CONCLUSIONS: In children ages 2-17 years, combining metabolomic and inflammatory protein mediator profiling early after presentation may differentiate children with sepsis requiring care in a PICU from children with or without sepsis safely cared for outside a PICU. This may aid in making triage decisions, particularly in an ED without pediatric expertise. This finding requires validation in an independent cohort. PMID: 26349677 [PubMed - indexed for MEDLINE]

Related Articles Lipid and Metabolic Changes in Rheumatoid Arthritis. Curr Rheumatol Rep. 2015 Sep;17(9):57 Authors: McGrath CM, Young SP Abstract While the most obvious manifestations of rheumatoid arthritis (RA) involve inflammation and damage in the synovial joints, the systemic effects of the condition are widespread and life-threatening. Of particular interest is the 'lipid paradox' of RA, where patients with a numerically equivocal starting lipid profile have a significantly raised risk of cardiovascular (CV) events and response to therapy results in a 'normalization' of lipid levels and reduction in events. Changes in lipids can be seen before overt disease manifestations which suggest that they are closely linked to the more widespread inflammation-driven metabolic changes associated with tumour necrosis factor (TNF). Cachexia involves a shift in body mass from muscle to fat, which may or may not directly increase the cardiovascular risk. However, since TNF inhibition is associated with reduction in cardiovascular events, it does suggest that these widespread metabolic changes involving lipids are of importance. Analysis of single lipids or metabolites have been used to identify some of the key changes, but more recently, metabolomic and lipidomic approaches have been applied to identify a broad spectrum of small molecule changes and identify potentially altered metabolic pathways. Further work is needed to understand fully the metabolic changes in lipid profiles and identify novel ways of targeting desired profile changes, but work so far does suggest that a better understanding may allow management of patients to downregulate the systemic effects of their disease that puts them at risk of cardiovascular complications. PMID: 26210510 [PubMed - indexed for MEDLINE]

Related Articles Macroscopic optical physiological parameters correlate with microscopic proliferation and vessel area breast cancer signatures. Breast Cancer Res. 2015;17:72 Authors: Chung SH, Feldman MD, Martinez D, Kim H, Putt ME, Busch DR, Tchou J, Czerniecki BJ, Schnall MD, Rosen MA, DeMichele A, Yodh AG, Choe R Abstract INTRODUCTION: Non-invasive diffuse optical tomography (DOT) and diffuse correlation spectroscopy (DCS) can detect and characterize breast cancer and predict tumor responses to neoadjuvant chemotherapy, even in patients with radiographically dense breasts. However, the relationship between measured optical parameters and pathological biomarker information needs to be further studied to connect information from optics to traditional clinical cancer biology. Thus we investigate how optically measured physiological parameters in malignant tumors such as oxy-, deoxy-hemoglobin concentration, tissue blood oxygenation, and metabolic rate of oxygen correlate with microscopic histopathological biomarkers from the same malignant tumors, e.g., Ki67 proliferation markers, CD34 stained vasculature markers and nuclear morphology. METHODS: In this pilot study, we investigate correlations of macroscopic physiological parameters of malignant tumors measured by diffuse optical technologies with microscopic histopathological biomarkers of the same tumors, i.e., the Ki67 proliferation marker, the CD34 stained vascular properties marker, and nuclear morphology. RESULTS: The tumor-to-normal relative ratio of Ki67-positive nuclei is positively correlated with DOT-measured relative tissue blood oxygen saturation (R = 0.89, p-value: 0.001), and lower tumor-to-normal deoxy-hemoglobin concentration is associated with higher expression level of Ki67 nuclei (p-value: 0.01). In a subset of the Ki67-negative group (defined by the 15 % threshold), an inverse correlation between Ki67 expression level and mammary metabolic rate of oxygen was observed (R = -0.95, p-value: 0.014). Further, CD34 stained mean-vessel-area in tumor is positively correlated with tumor-to-normal total-hemoglobin and oxy-hemoglobin concentration. Finally, we find that cell nuclei tend to have more elongated shapes in less oxygenated DOT-measured environments. CONCLUSIONS: Collectively, the pilot data are consistent with the notion that increased blood is supplied to breast cancers, and it also suggests that less conversion of oxy- to deoxy-hemoglobin occurs in more proliferative cancers. Overall, the observations corroborate expectations that macroscopic measurements of breast cancer physiology using DOT and DCS can reveal microscopic pathological properties of breast cancer and hold potential to complement pathological biomarker information. PMID: 26013572 [PubMed - indexed for MEDLINE]

Related Articles Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25. Cell Res. 2015 Feb;25(2):208-24 Authors: Hannani D, Vétizou M, Enot D, Rusakiewicz S, Chaput N, Klatzmann D, Desbois M, Jacquelot N, Vimond N, Chouaib S, Mateus C, Allison JP, Ribas A, Wolchok JD, Yuan J, Wong P, Postow M, Mackiewicz A, Mackiewicz J, Schadendorff D, Jaeger D, Zörnig I, Hassel J, Korman AJ, Bahjat K, Maio M, Calabro L, Teng MW, Smyth MJ, Eggermont A, Robert C, Kroemer G, Zitvogel L Abstract The cytotoxic T lymphocyte antigen-4 (CTLA-4)-blocking antibody ipilimumab induces immune-mediated long-term control of metastatic melanoma in a fraction of patients. Although ipilimumab undoubtedly exerts its therapeutic effects via immunostimulation, thus far clinically useful, immunologically relevant biomarkers that predict treatment efficiency have been elusive. Here, we show that neutralization of IL-2 or blocking the α and β subunits of the IL-2 receptor (CD25 and CD122, respectively) abolished the antitumor effects and the accompanying improvement of the ratio of intratumoral T effector versus regulatory cells (Tregs), which were otherwise induced by CTLA-4 blockade in preclinical mouse models. CTLA-4 blockade led to the reduction of a suppressive CD4(+) T cell subset expressing Lag3, ICOS, IL-10 and Egr2 with a concomitant rise in IL-2-producing effector cells that lost FoxP3 expression and accumulated in regressing tumors. While recombinant IL-2 improved the therapeutic efficacy of CTLA-4 blockade, the decoy IL-2 receptor α (IL-2Rα, sCD25) inhibited the anticancer effects of CTLA-4 blockade. In 262 metastatic melanoma patients receiving ipilimumab, baseline serum concentrations of sCD25 represented an independent indicator of overall survival, with high levels predicting resistance to therapy. Altogether, these results unravel a role for IL-2 and IL-2 receptors in the anticancer activity of CTLA-4 blockade. Importantly, our study provides the first immunologically relevant biomarker, namely elevated serum sCD25, that predicts resistance to CTLA-4 blockade in patients with melanoma. PMID: 25582080 [PubMed - indexed for MEDLINE]

Related Articles Ultra-trace graphene oxide in a water environment triggers Parkinson's disease-like symptoms and metabolic disturbance in zebrafish larvae. Biomaterials. 2016 Mar 31;93:83-94 Authors: Ren C, Hu X, Li X, Zhou Q Abstract Over the past decade, the safety of nanomaterials has attracted attention due to their rapid development. The relevant health threat of these materials remains largely unknown, particularly at environmentally or biologically relevant ultra-trace concentrations. To address this, we first found that graphene oxide (GO, a carbon nanomaterial that receives extensive attention across various disciplines) at concentrations of 0.01 μg/L-1 μg/L induced Parkinson's disease-like symptoms in zebrafish larvae. In this model, zebrafish showed a loss of more than 90% of dopamine neurons, a 69-522% increase in Lewy bodies (α-synuclein and ubiquitin) and significantly disturbed locomotive activity. Moreover, it was also shown that GO was able to translocate from the water environment to the brain and localize to the nucleus of the diencephalon, thereby inducing structural and morphological damage in the mitochondria. Cell apoptosis and senescence were triggered via oxidative stress, as shown by the upregulation of caspase 8 and β-galactosidase. Using metabolomics, we found that the upregulation of amino acid and some fatty acids (e.g. dodecanoic acid, hexadecanoic acid, octadecenoic acid, nonanoic acid, arachidonic acid, eicosanoic acid, propanoic acid and benzenedicarboxylic acid) metabolism and the downregulation of some other fatty acids (e.g. butanoic acid, phthalic acid and docosenoic acid) are linked to these Parkinson's disease-like symptoms. These findings broaden our understanding of nanomaterial safety at ultra-trace concentrations. PMID: 27085073 [PubMed - as supplied by publisher]

Related Articles Unique microbial-derived volatile organic compounds in portal venous circulation in murine non-alcoholic fatty liver disease. Biochim Biophys Acta. 2016 Apr 13; Authors: Reid DT, McDonald B, Khalid T, Vo T, Schenck LP, Surette MG, Beck PL, Reimer RA, Probert CS, Rioux KP, Eksteen B Abstract BACKGROUND AND AIMS: Non-alcoholic fatty liver disease is now the leading liver disease in North America. The progression of non-alcoholic fatty liver disease to the inflammatory condition, non-alcoholic steatohepatitis is complex and currently not well understood. Intestinal microbial dysbiosis has been implicated in the development of non-alcoholic fatty liver disease and progression of non-alcoholic steatohepatitis. Volatile organic compounds are byproducts of microbial metabolism in the gut that may enter portal circulation and have hepatotoxic effects contributing to the pathogenesis of non-alcoholic steatohepatitis. To test this hypothesis, we measured volatile organic compounds in cecal luminal contents and portal venous blood in a mouse model of non-alcoholic steatohepatitis. METHODS: Gas chromatography-mass spectrometry analysis was conducted on cecal content and portal vein blood for volatile organic compound detection from mice fed a methionine and choline deficient diet, which induces non-alcoholic steatohepatitis. The colonic microbiome was studied by 16S rRNA gene amplification using the Illumina MiSeq platform. RESULTS: Sixty-eight volatile organic compounds were detected in cecal luminal content, a subset of which was also present in portal venous blood. Importantly, differences in portal venous volatile organic compounds were associated with diet-induced steatohepatitis establishing a biochemical link between gut microbiota-derived volatile organic compounds and increased susceptibility to non-alcoholic steatohepatitis. CONCLUSION: Our model creates a novel tool to further study the role of gut-derived volatile organic compounds in the pathogenesis of non-alcoholic steatohepatitis. PMID: 27085070 [PubMed - as supplied by publisher]

Related Articles MBROLE 2.0-functional enrichment of chemical compounds. Nucleic Acids Res. 2016 Apr 15; Authors: López-Ibáñez J, Pazos F, Chagoyen M Abstract Metabolites Biological Role (MBROLE) is a server that performs functional enrichment analysis of a list of chemical compounds derived from a metabolomics experiment, which allows this list to be interpreted in biological terms. Since its release in 2011, MBROLE has been used by different groups worldwide to analyse metabolomics experiments from a variety of organisms. Here we present the latest version of the system, MBROLE2, accessible athttp://csbg.cnb.csic.es/mbrole2 MBROLE2 has been supplemented with 10 databases not available in the previous version, which allow analysis over a larger, richer set of vocabularies including metabolite-protein and drug-protein interactions. This new version performs automatic conversion of compound identifiers from different databases, thus simplifying usage. In addition, the user interface has been redesigned to generate an interactive, more intuitive representation of the results. PMID: 27084944 [PubMed - as supplied by publisher]

Related Articles Longitudinal Metabolite Profiling of Cerebrospinal Fluid in Normal Pressure Hydrocephalus Links Brain Metabolism with Exercise-Induced VEGF Production and Clinical Outcome. Neurochem Res. 2016 Apr 15; Authors: Huang H, Yang J, Luciano M, Shriver LP Abstract Idiopathic normal pressure hydrocephalus is a neurological disease caused by abnormal cerebrospinal fluid flow and presents with symptoms such as dementia. Current therapy involves the removal of excess cerebrospinal fluid by shunting. Not all patients respond to this therapy and biomarkers are needed that could facilitate the characterization of patients likely to benefit from this treatment. Here, we measure brain metabolism in normal pressure hydrocephalus patients by performing a novel longitudinal metabolomic profiling study of cerebrospinal fluid. We find that the levels of brain metabolites correlate with clinical parameters, the amount of vascular endothelial growth factor in the cerebrospinal fluid, and environmental stimuli such as exercise. Metabolomic analysis of normal pressure hydrocephalus patients provides insight into changes in brain metabolism that accompany cerebrospinal fluid disorders and may facilitate the development of new biomarkers for this condition. PMID: 27084769 [PubMed - as supplied by publisher]

Related Articles Metabolomics processing made easier. Comput Methods Programs Biomed. 2016 Jun;129:A1-2 Authors: Lu R, Wu CC, Yang HC, Jack Li YC PMID: 27084327 [PubMed - in process]

Related Articles Peripheral fibroblast metabolic pathway alterations in juvenile rhesus monkeys undergoing long-term fluoxetine administration. Eur Neuropsychopharmacol. 2016 Apr 12; Authors: Su SY, Hogrefe-Phi CE, Asara JM, Turck CW, Golub MS Abstract We report on biochemical pathways perturbed upon chronic fluoxetine administration to juvenile macaques using global metabolomics analyses of fibroblasts derived from skin biopsies. After exposure to tissue culture conditions confounding environmental factors are eliminated and identification of metabolites whose levels are affected by the drug become apparent with a better signal-to-noise ratio compared to data obtained from plasma and cerebrospinal fluid (CSF). Levels of more than 200 metabolites were analyzed to interrogate affected molecular pathways and identify biomarkers of drug response. In addition, we have correlated the metabolomics results with monoamine oxidase (MAOA) genotype and impulsivity behavioral data. Affected pathways include Purine and Pyrimidine metabolisms that have been previously implicated to contribute to neuropsychiatric disorders. PMID: 27084303 [PubMed - as supplied by publisher]

Related Articles Sepsis results in an altered renal metabolic and osmolyte profile. J Surg Res. 2016 May 1;202(1):8-12 Authors: Waltz P, Carchman E, Gomez H, Zuckerbraun B Abstract BACKGROUND: Sepsis remains a major health-care burden and source of morbidity and mortality. Acute kidney injury and failure frequently accompanies severe sepsis and contributes to this burden. Despite a great deal of research, the exact mechanisms underlying renal failure in sepsis are poorly understood. This study aims to further understand metabolic changes in renal tissue during sepsis. MATERIALS AND METHODS: Experimental sepsis was induced by cecal ligation and puncture (CLP) in C57BL/6 mice. Serum and organs were harvested 8 h after CLP. Markers of renal function including serum creatinine, blood urea nitrogen, and cystatin C were measured. Whole kidneys were analyzed for a global biochemical profile via liquid chromatography/tandem mass spectrometry by Metabolon. RESULTS: CLP induced renal injury as evidenced by elevated serum creatinine, blood urea nitrogen, and cystatin C. Global energetic profile in sepsis showed an increase in glycolytic intermediates with decreased flux through the tricarboxylic acid (TCA) cycle. Multiple inflammatory markers were elevated in response to CLP. Levels of osmotic regulators varied, with an overall increase in pinitol, urea, and taurine in response to CLP. CONCLUSIONS: CLP resulted in dramatic changes in the renal macromolecular milieu. There appears to be an increased dependence on glycolysis and diminished flush through the TCA cycle. In addition, changes in renal osmolytes including pinitol, urea, and taurine were observed, perhaps uncovering an additional change with implications on renal function during sepsis. PMID: 27083942 [PubMed - in process]

Related Articles Benzoyl chloride derivatization with liquid chromatography-mass spectrometry for targeted metabolomics of neurochemicals in biological samples. J Chromatogr A. 2016 Apr 4; Authors: Wong JT, Malec PA, Mabrouk OS, Ro J, Dus M, Kennedy RT Abstract Widely targeted metabolomic assays are useful because they provide quantitative data on large groups of related compounds. We report a high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method that utilizes benzoyl chloride labeling for 70 neurologically relevant compounds, including catecholamines, indoleamines, amino acids, polyamines, trace amines, antioxidants, energy compounds, and their metabolites. The method includes neurotransmitters and metabolites found in both vertebrates and insects. This method was applied to analyze microdialysate from rats, human cerebrospinal fluid, human serum, fly tissue homogenate, and fly hemolymph, demonstrating its broad versatility for multiple physiological contexts and model systems. Limits of detection for most assayed compounds were below 10nM, relative standard deviations were below 10%, and carryover was less than 5% for 70 compounds separated in 20min, with a total analysis time of 33min. This broadly applicable method provides robust monitoring of multiple analytes, utilizes small sample sizes, and can be applied to diverse matrices. The assay will be of value for evaluating normal physiological changes in metabolism in neurochemical systems. The results demonstrate the utility of benzoyl chloride labeling with HPLC-MS/MS for widely targeted metabolomics assays. PMID: 27083258 [PubMed - as supplied by publisher]

The oncolytic peptide LTX-315 overcomes resistance of cancers to immunotherapy with CTLA4 checkpoint blockade. Cell Death Differ. 2016 Apr 15; Authors: Yamazaki T, Pitt JM, Vétizou M, Marabelle A, Flores C, Rekdal Ø, Kroemer G, Zitvogel L Abstract Intratumoral immunotherapies aim at reducing local immunosuppression, as well as reinstating and enhancing systemic anticancer T-cell functions, without inducing side effects. LTX-315 is a first-in-class oncolytic peptide-based local immunotherapy that meets these criteria by inducing a type of malignant cell death that elicits anticancer immune responses. Here, we show that LTX-315 rapidly reprograms the tumor microenvironment by decreasing the local abundance of immunosuppressive Tregs and myeloid-derived suppressor cells and by increasing the frequency of polyfunctional T helper type 1/type 1 cytotoxic T cells with a concomitant increase in cytotoxic T-lymphocyte antigen-4 (CTLA4) and drop in PD-1 expression levels. Logically, in tumors that were resistant to intratumoral or systemic CTLA4 blockade, subsequent local inoculation of LTX-315 cured the animals or caused tumor regressions with abscopal effects. This synergistic interaction between CTLA4 blockade and LTX-315 was reduced upon blockade of the β-chain of the interleukin-2 receptor (CD122). This preclinical study provides a strong rationale for administering the oncolytic peptide LTX-315 to patients who are receiving treatment with the CTLA4 blocking antibody ipilimumab.Cell Death and Differentiation advance online publication, 15 April 2016; doi:10.1038/cdd.2016.35. PMID: 27082453 [PubMed - as supplied by publisher]