PubMed

Related Articles Disposition and metabolic profiling of [(14)C]cerlapirdine using accelerator mass spectrometry. Drug Metab Dispos. 2014 Dec;42(12):2023-32 Authors: Tse S, Leung L, Raje S, Seymour M, Shishikura Y, Obach RS Abstract Cerlapirdine (SAM-531, PF-05212365) is a selective, potent, full antagonist of the 5-hydroxytryptamine 6 (5-HT6) receptor. Cerlapirdine and other 5-HT6 receptor antagonists have been in clinical development for the symptomatic treatment of Alzheimer's disease. A human absorption, distribution, metabolism, and excretion study was conducted to gain further understanding of the metabolism and disposition of cerlapirdine. Because of the low amount of radioactivity administered, total (14)C content and metabolic profiles in plasma, urine, and feces were determined using accelerator mass spectrometry (AMS). After a single, oral 5-mg dose of [(14)C]cerlapirdine (177 nCi), recovery of total (14)C was almost complete, with feces being the major route of elimination of the administered dose, whereas urinary excretion played a lesser role. The extent of absorption was estimated to be at least 70%. Metabolite profiling in pooled plasma samples showed that unchanged cerlapirdine was the major drug-related component in circulation, representing 51% of total (14)C exposure in plasma. One metabolite (M1, desmethylcerlapirdine) was detected in plasma, and represented 9% of the total (14)C exposure. In vitro cytochrome P450 reaction phenotyping studies showed that M1 was formed primarily by CYP2C8 and CYP3A4. In pooled urine samples, three major drug-related peaks were detected, corresponding to cerlapirdine-N-oxide (M3), cerlapirdine, and desmethylcerlapirdine. In feces, cerlapirdine was the major (14)C component excreted, followed by desmethylcerlapirdine. The results of this study demonstrate that the use of the AMS technique enables comprehensive quantitative elucidation of the disposition and metabolic profiles of compounds administered at a low radioactive dose. PMID: 25217486 [PubMed - indexed for MEDLINE]

Related Articles MetabNet: An R Package for Metabolic Association Analysis of High-Resolution Metabolomics Data. Front Bioeng Biotechnol. 2015;3:87 Authors: Uppal K, Soltow QA, Promislow DE, Wachtman LM, Quyyumi AA, Jones DP Abstract Liquid-chromatography high-resolution mass spectrometry provides capability to measure >40,000 ions derived from metabolites in biologic samples. This presents challenges to confirm identities of known chemicals and delineate potential metabolic pathway associations of unidentified chemicals. We provide an R package for metabolic network analysis, MetabNet, to perform targeted metabolome-wide association study of specific metabolites to facilitate detection of their related metabolic pathways and network structures. PMID: 26125020 [PubMed]

Related Articles Chronic inflammation: is it the driver or is it paving the road for malignant transformation? Genes Cancer. 2015 May;6(5-6):214-9 Authors: Afrasiabi K, Zhou YH, Fleischman A Abstract Chronic inflammation in well-defined mouse models such as Giα2 knock out mouse has been shown to trigger formation and expansion of hypoxic niches and also leads to up regulation of NFĸB, offering cells which have adapted their genetic machinery to hypoxia a unique survival advantage. These adapted cells have been shown to acquire stem cell-like capabilities as shown by up regulation of stem cell markers. Such long lived cells become permanent residents in sub mucosa and acquire a malignant phenotype from long-term exposure to noxious environmental agents due to a barrier defect secondary to down regulation of barrier proteins such as Zo1 and Occludin. Indeed mitotic spindle disorientation in such mice has been proposed as another contributory factor to malignant transformation. Sterilization of bowel lumen of these mice through different techniques has prevented malignant transformation in the presence of chronic inflammation. These facts stand strongly against chronic inflammation as a true driver of carcinogenesis but clearly support its role in facilitating the emergence of the neoplastic clone. PMID: 26124920 [PubMed]

Related Articles The therapy of gefitinib towards breast cancer partially through reversing breast cancer biomarker arginine. Afr Health Sci. 2015 Jun;15(2):594-7 Authors: Geng D, Sun D, Zhang L, Zhang W Abstract BACKGROUND: Breast cancer remains the leading reason of cancer death among women worldwide, and gefitinib is the efficient drug for breast cancer. AIMS: To use targeted metabolomics method to elucidate the therapeutic mechanism of gefitinib through profiling the amino acids. METHODS: Healthy women (n=56) and women with breast cancer (n=60) were enrolled in Affiliated Yuhuangding hospital, medical college of Qingdao University from 2012-2014. API 3200 triple quadrupole mass spectrometer was used to analyze the serum samples. RESULTS: The concentration of amino acids was compared between healthy women and women with breast cancers. Compared with the healthy women, the concentration of arginine in breast cancer women significantly decreased (p<0.0001). To show the representative capability of arginine towards the pathogenesis of breast cancers, the receiver operating characteristic (ROC) curve was drawn, and the area under the curve (AUC) was calculated to be 0.96 ± 0.02, indicating the high predictive capability of arginine for breast cancer . The reversing ability of gefitinib towards the level of arginine was further determined, and 1 month treatment of gefitinib (500 mg/day) significantly reversed the arginine level of breast cancer patients (p<0.0001). CONCLUSION: The therapy of gefitinib towards breast cancer through reversing breast cancer biomarker arginine was demonstrated. PMID: 26124808 [PubMed - in process]

Related Articles Educating future nursing scientists: Recommendations for integrating omics content in PhD programs. Nurs Outlook. 2015 Jun 12; Authors: Conley YP, Heitkemper M, McCarthy D, Anderson CM, Corwin EJ, Daack-Hirsch S, Dorsey SG, Gregory KE, Groer MW, Henly SJ, Landers T, Lyon DE, Taylor JY, Voss J Abstract Preparing the next generation of nursing scientists to conduct high-impact, competitive, sustainable, innovative, and interdisciplinary programs of research requires that the curricula for PhD programs keep pace with emerging areas of knowledge and health care/biomedical science. A field of inquiry that holds great potential to influence our understanding of the underlying biology and mechanisms of health and disease is omics. For the purpose of this article, omics refers to genomics, transcriptomics, proteomics, epigenomics, exposomics, microbiomics, and metabolomics. Traditionally, most PhD programs in schools of nursing do not incorporate this content into their core curricula. As part of the Council for the Advancement of Nursing Science's Idea Festival for Nursing Science Education, a work group charged with addressing omics preparation for the next generation of nursing scientists was convened. The purpose of this article is to describe key findings and recommendations from the work group that unanimously and enthusiastically support the incorporation of omics content into the curricula of PhD programs in nursing. The work group also calls to action faculty in schools of nursing to develop strategies to enable students needing immersion in omics science and methods to execute their research goals. PMID: 26123776 [PubMed - as supplied by publisher]

Related Articles Computational analysis and ratiometric comparison approaches aimed to assist column selection in hydrophilic interaction liquid chromatography-tandem mass spectrometry targeted metabolomics. J Chromatogr A. 2015 Jun 14; Authors: Sampsonidis I, Witting M, Koch W, Virgiliou C, Gika HG, Schmitt-Kopplin P, Theodoridis GA Abstract In the present work two different approaches, a semi-quantitative and a Derringer function approach, were developed to assist column selection for method development in targeted metabolomics. These approaches were applied in the performance assessment of three HILIC columns with different chemistries (an amide, a diol and a zwitterionic phase). This was the first step for the development of a HILIC UPLC-MS/MS method that should be capable to analyze a large number of polar metabolites. Two gradient elution profiles and two mobile phase pH values were tested for the analysis of multi-analyte mixtures. Acquired chromatographic data were firstly treated by a ratiometric, "semi-quantitative" approach which quantifies various overall analysis parameters (e.g. the percent of detected compounds, retentivity and resolved critical pairs). These parameters were used to assess chromatographic performance in a rather conventional/traditional and cumbersome/labor-intensive way. Secondly, a comprehensive and automated comparison of the three columns was performed by monitoring several well-known chromatographic parameters (peak width, resolution, tailing factor, etc.) using a lab-built programming script which calculates overall desirability utilizing Derringer functions. Derringer functions exhibit the advantage that column performance is ultimately expressed in an objective single and quantitative value which can be easily interpreted. In summary, results show that each column exhibits unique strengths in metabolic profiling of polar compounds. The applied methodology proved useful for the selection of the most effective chromatographic system during method development for LC-MS/MS targeted metabolomics, while it could further assist in the selection of chromatographic conditions for the development of multi-analyte methods. PMID: 26122858 [PubMed - as supplied by publisher]

Related Articles Isoprene emission by poplar is not important for the feeding behaviour of poplar leaf beetles. BMC Plant Biol. 2015;15:165 Authors: Müller A, Kaling M, Faubert P, Gort G, Smid HM, Van Loon JJ, Dicke M, Kanawati B, Schmitt-Kopplin P, Polle A, Schnitzler JP, Rosenkranz M Abstract BACKGROUND: Chrysomela populi (poplar leaf beetle) is a common herbivore in poplar plantations whose infestation causes major economic losses. Because plant volatiles act as infochemicals, we tested whether isoprene, the main volatile organic compound (VOC) produced by poplars (Populus x canescens), affects the performance of C. populi employing isoprene emitting (IE) and transgenic isoprene non-emitting (NE) plants. Our hypothesis was that isoprene is sensed and affects beetle orientation or that the lack of isoprene affects plant VOC profiles and metabolome with consequences for C. populi feeding. RESULTS: Electroantennographic analysis revealed that C. populi can detect higher terpenes, but not isoprene. In accordance to the inability to detect isoprene, C. populi showed no clear preference for IE or NE poplar genotypes in the choice experiments, however, the beetles consumed a little bit less leaf mass and laid fewer eggs on NE poplar trees in field experiments. Slight differences in the profiles of volatile terpenoids between IE and NE genotypes were detected by gas chromatography - mass spectrometry. Non-targeted metabolomics analysis by Fourier Transform Ion Cyclotron Resonance Mass Spectrometer revealed genotype-, time- and herbivore feeding-dependent metabolic changes both in the infested and adjacent undamaged leaves under field conditions. CONCLUSIONS: We show for the first time that C. populi is unable to sense isoprene. The detected minor differences in insect feeding in choice experiments and field bioassays may be related to the revealed changes in leaf volatile emission and metabolite composition between the IE and NE poplars. Overall our results indicate that lacking isoprene emission is of minor importance for C. populi herbivory under natural conditions, and that the lack of isoprene is not expected to change the economic losses in poplar plantations caused by C. populi infestation. PMID: 26122266 [PubMed - in process]

Related Articles The current epidemiology and clinical decisions surrounding acute respiratory infections. Trends Mol Med. 2014 Oct;20(10):579-88 Authors: Zaas AK, Garner BH, Tsalik EL, Burke T, Woods CW, Ginsburg GS Abstract Acute respiratory infection (ARI) is a common diagnosis in outpatient and emergent care settings. Currently available diagnostics are limited, creating uncertainty in the use of antibacterial, antiviral, or supportive care. Up to 72% of ambulatory care patients with ARI are treated with an antibacterial, despite only a small fraction actually needing one. Antibiotic overuse is not restricted to ambulatory care: ARI accounts for approximately 5 million emergency department (ED) visits annually in the USA, where 52-61% of such patients receive antibiotics. Thus, an accurate test for the presence or absence of viral or bacterial infection is needed. In this review, we focus on recent research showing that the host-response (genomic, proteomic, or miRNA) can accomplish this task. PMID: 25201713 [PubMed - indexed for MEDLINE]

Related Articles Evaluation of volatile metabolites as markers in Lycopersicon esculentum L. cultivars discrimination by multivariate analysis of headspace solid phase microextraction and mass spectrometry data. Food Chem. 2014 Feb 15;145:653-63 Authors: Figueira J, Câmara H, Pereira J, Câmara JS Abstract To gain insights on the effects of cultivar on the volatile metabolomic expression of different tomato (Lycopersicon esculentum L.) cultivars--Plum, Campari, Grape, Cherry and Regional, cultivated under similar edafoclimatic conditions, and to identify the most discriminate volatile marker metabolites related to the cultivar, the chromatographic profiles resulting from headspace solid phase microextraction (HS-SPME) and gas chromatography-mass spectrometry (GC-qMS) analysis, combined with multivariate analysis were investigated. The data set composed by the 77 volatile metabolites identified in the target tomato cultivars, 5 of which (2,2,6-trimethylcyclohexanone, 2-methyl-6-methyleneoctan-2-ol, 4-octadecyl-morpholine, (Z)-methyl-3-hexenoate and 3-octanone) are reported for the first time in tomato volatile metabolomic composition, was evaluated by chemometrics. Firstly, principal component analysis was carried out in order to visualise data trends and clusters, and then, linear discriminant analysis in order to detect the set of volatile metabolites able to differentiate groups according to tomato cultivars. The results obtained revealed a perfect discrimination between the different Lycopersicon esculentum L. cultivars considered. The assignment success rate was 100% in classification and 80% in prediction ability by using "leave-one-out" cross-validation procedure. The volatile profile was able to differentiate all five cultivars and revealed complex interactions between them including the participation in the same biosynthetic pathway. The volatile metabolomic platform for tomato samples obtained by HS-SPME/GC-qMS here described, and the interrelationship detected among the volatile metabolites can be used as a roadmap for biotechnological applications, namely to improve tomato aroma and their acceptance in the final consumer, and for traceability studies. PMID: 24128528 [PubMed - indexed for MEDLINE]

Looking into living cell systems: Planar waveguide microfluidic NMR detector for in vitro metabolomics of tumor spheroids. Anal Chem. 2015 Jun 29; Authors: Kalfe A, Telfah A, Lambert J, Hergenroeder R Abstract The complex cell metabolism and its link to oncogenic signaling pathways have received huge interest within the last years. But the lack of advanced analytical tools for the investigation of living cell metabolism is still a challenge to be faced. Therefore, we designed and fabricated a novel miniaturized microslot NMR detector with on-board heater integrated with a microfluidic device as NMR sample holder. For the first time, a tumor spheroid of 500 µm diameter and consisting of 9000 cells has been studied non-invasively and online for 24 hours. The dynamic process of production and degradation of 23 intra- and extracellular metabolites were monitored. Remarkably high concentrations of lactate and alanine were observed being an indicator for a shift from oxidative to glycolytic metabolism. In summary, this methodical development has proven to be a successful analytical tool for the elucidation of cellular functions and their corresponding biochemical pathways. Additionally, the planar geometry of the microslot NMR detector allows the hyphenation with versatile lab-on-a chip (LOC) technology. This opens a new window for metabolomics studies on living cells and can be implemented into new application fields in biotechnology and life sciences. PMID: 26121119 [PubMed - as supplied by publisher]

Related Articles New insights and biomarkers for Type 1 Diabetes: Review for Scandinavian Journal of Immunology. Scand J Immunol. 2015 Jun 28; Authors: Heinonen MT, Moulder R, Lahesmaa R Abstract The increasing incidence of type 1 diabetes observed in the past 60 years has spawned massive efforts in multiple research fields to elucidate the etiology of this disease. While GWAS studies provide a good genetic basis for the current knowledge, it is clear that environmental triggers and their influence in disease prevalence and origin are is highly important. The realization of disease heterogeneity has created a requirement for better biomarkers to complement the known autoantibody markers and to more successfully predict the severity and onset time of the disease. Such biomarkers would be needed both for prevention as well as for monitoring disease activity and response to preventive and therapeutic measures. Systematic holistic approaches concentrating on the triggering molecular mechanisms, pancreatic beta cells, immune response as well as the influence of diet and environment are necessary to understand the disease pathogenesis and find a cure. The current genomic knowledge is being broadened with accompanying studies in epigenetics and transcriptomic regulation, metabolomics, proteomics and lipidomics, covering the whole system from beta cells, the profile and cellular balance of the infiltrating lymphocytes to gut microbiota and viral infections. Here we highlight interesting recent findings in type 1 diabetes research. This article is protected by copyright. All rights reserved. PMID: 26119046 [PubMed - as supplied by publisher]

Related Articles Metabolome progression during early gut microbial colonization of gnotobiotic mice. Sci Rep. 2015;5:11589 Authors: Marcobal A, Yusufaly T, Higginbottom S, Snyder M, Sonnenburg JL, Mias GI Abstract The microbiome has been implicated directly in host health, especially host metabolic processes and development of immune responses. These are particularly important in infants where the gut first begins being colonized, and such processes may be modeled in mice. In this investigation we follow longitudinally the urine metabolome of ex-germ-free mice, which are colonized with two bacterial species, Bacteroides thetaiotaomicron and Bifidobacterium longum. High-throughput mass spectrometry profiling of urine samples revealed dynamic changes in the metabolome makeup, associated with the gut bacterial colonization, enabled by our adaptation of non-linear time-series analysis to urine metabolomics data. Results demonstrate both gradual and punctuated changes in metabolite production and that early colonization events profoundly impact the nature of small molecules circulating in the host. The identified small molecules are implicated in amino acid and carbohydrate metabolic processes, and offer insights into the dynamic changes occurring during the colonization process, using high-throughput longitudinal methodology. PMID: 26118551 [PubMed - in process]

Related Articles [UPLC/Q-TOF MS and NMR plant metabolomics approach in studying the effect of growth year on the quality of Polygala tenuifolia]. Yao Xue Xue Bao. 2015 Mar;50(3):340-7 Authors: Xue Y, Li XW, Li ZY, Zeng ZP, Zhang FS, Li AP, Qin XM, Peng B Abstract Growth year is one of the important factors for the quality of Polygala tenufolia. In this study, primary metabolites and secondary metabolites were compared in 1, 2 and 3 years old P. tenufolia cultivated in Shaanxi Heyang. The samples were subjected to ultra-high performance liquid chromatography (UPLC)-quadrupole time-of-flight mass spectrometry (Q-TOF MS) and nuclear magnetic resonance (NMR) analysis, and the obtained data were analyzed using principal component analysis (PCA) and other statistical analysis methods. In addition, content and correlation of different metabolites were also calculated. The results showed no significance between main component contents in 2 year-old and 3 year-old P. Tenufolia, but 1 year-old was statistically different. The contents of primary metabolites, such as fructose, sucrose, and choline increased as time goes on, while glycine and raffinose decreased. The contents of secondary metabolites, such as onjisaponin Fg, polygalasaponin XXVIII, polygalasaponin XXXII increased, while polygalaxanthone III and parts of oligosaccharide multi-ester including tenuifoliose A, tenuifoliose C, tenuifoliose C2 and tenuifoliose H decreased with the extension of the growth years. Growth years has important impact on the quality of P. tenuifolia and the existing growing years of commodity P. tenuifolia have its scientific evidence. This study supplied a new method for the quality evaluation of Chinese medicinal materials. PMID: 26118115 [PubMed - in process]

Related Articles Evaluation of comprehensive two-dimensional gas chromatography with accurate mass time-of-flight mass spectrometry for the metabolic profiling of plant-fungus interaction in Aquilaria malaccensis. J Chromatogr A. 2015 Mar 27;1387:104-15 Authors: Wong YF, Chin ST, Perlmutter P, Marriott PJ Abstract To explore the possible obligate interactions between the phytopathogenic fungus and Aquilaria malaccensis which result in generation of a complex array of secondary metabolites, we describe a comprehensive two-dimensional gas chromatography (GC × GC) method, coupled to accurate mass time-of-flight mass spectrometry (TOFMS) for the untargeted and comprehensive metabolic profiling of essential oils from naturally infected A. malaccensis trees. A polar/non-polar column configuration was employed, offering an improved separation pattern of components when compared to other column sets. Four different grades of the oils displayed quite different metabolic patterns, suggesting the evolution of a signalling relationship between the host tree (emergence of various phytoalexins) and fungi (activation of biotransformation). In total, ca. 550 peaks/metabolites were detected, of which tentative identification of 155 of these compounds was reported, representing between 20.1% and 53.0% of the total ion count. These are distributed over the chemical families of monoterpenic and sesquiterpenic hydrocarbons, oxygenated monoterpenes and sesquiterpenes (comprised of ketone, aldehyde, oxide, alcohol, lactone, keto-alcohol and diol), norterpenoids, diterpenoids, short chain glycols, carboxylic acids and others. The large number of metabolites detected, combined with the ease with which they are located in the 2D separation space, emphasises the importance of a comprehensive analytical approach for the phytochemical analysis of plant metabolomes. Furthermore, the potential of this methodology in grading agarwood oils by comparing the obtained metabolic profiles (pattern recognition for unique metabolite chemical families) is discussed. The phytocomplexity of the agarwood oils signified the production of a multitude of plant-fungus mediated secondary metabolites as chemical signals for natural ecological communication. To the best of our knowledge, this is the most complete information available so far about essential oils of A. malaccensis, which represents a valuable extension to available data for advanced studies on microbial-mediated biotransformation of terpenes, and offers promise for potential discovery of unanticipated phytochemicals, and biotechnological exploitation. PMID: 25704770 [PubMed - indexed for MEDLINE]

Related Articles Enhancement of antibiotic activity against multidrug-resistant bacteria by the efflux pump inhibitor 3,4-dibromopyrrole-2,5-dione isolated from a Pseudoalteromonas sp. J Nat Prod. 2015 Mar 27;78(3):402-12 Authors: Whalen KE, Poulson-Ellestad KL, Deering RW, Rowley DC, Mincer TJ Abstract Members of the resistance nodulation cell division (RND) of efflux pumps play essential roles in multidrug resistance (MDR) in Gram-negative bacteria. Here, we describe the search for new small molecules from marine microbial extracts to block efflux and thus restore antibiotic susceptibility in MDR bacterial strains. We report the isolation of 3,4-dibromopyrrole-2,5-dione (1), an inhibitor of RND transporters, from Enterobacteriaceae and Pseudomonas aeruginosa, from the marine bacterium Pseudoalteromonas piscicida. 3,4-Dibromopyrrole-2,5-dione decreased the minimum inhibitory concentrations (MICs) of two fluoroquinolones, an aminoglycoside, a macrolide, a beta-lactam, tetracycline, and chloramphenicol between 2- and 16-fold in strains overexpressing three archetype RND transporters (AcrAB-TolC, MexAB-OprM, and MexXY-OprM). 3,4-Dibromopyrrole-2,5-dione also increased the intracellular accumulation of Hoechst 33342 in wild-type but not in transporter-deficient strains and prevented H33342 efflux (IC50 = 0.79 μg/mL or 3 μM), a hallmark of efflux pump inhibitor (EPI) functionality. A metabolomic survey of 36 Pseudoalteromonas isolates mapped the presence of primarily brominated metabolites only within the P. piscicida phylogenetic clade, where a majority of antibiotic activity was also observed, suggesting a link between halogenation and enhanced secondary metabolite biosynthetic potential. In sum, 3,4-dibromopyrrole-2,5-dione is a potent EPI and deserves further attention as an adjuvant to enhance the effectiveness of existing antibiotics. PMID: 25646964 [PubMed - indexed for MEDLINE]

Related Articles Genetic variation in the nuclear and organellar genomes modulates stochastic variation in the metabolome, growth, and defense. PLoS Genet. 2015 Jan;11(1):e1004779 Authors: Joseph B, Corwin JA, Kliebenstein DJ Abstract Recent studies are starting to show that genetic control over stochastic variation is a key evolutionary solution of single celled organisms in the face of unpredictable environments. This has been expanded to show that genetic variation can alter stochastic variation in transcriptional processes within multi-cellular eukaryotes. However, little is known about how genetic diversity can control stochastic variation within more non-cell autonomous phenotypes. Using an Arabidopsis reciprocal RIL population, we showed that there is significant genetic diversity influencing stochastic variation in the plant metabolome, defense chemistry, and growth. This genetic diversity included loci specific for the stochastic variation of each phenotypic class that did not affect the other phenotypic classes or the average phenotype. This suggests that the organism's networks are established so that noise can exist in one phenotypic level like metabolism and not permeate up or down to different phenotypic levels. Further, the genomic variation within the plastid and mitochondria also had significant effects on the stochastic variation of all phenotypic classes. The genetic influence over stochastic variation within the metabolome was highly metabolite specific, with neighboring metabolites in the same metabolic pathway frequently showing different levels of noise. As expected from bet-hedging theory, there was more genetic diversity and a wider range of stochastic variation for defense chemistry than found for primary metabolism. Thus, it is possible to begin dissecting the stochastic variation of whole organismal phenotypes in multi-cellular organisms. Further, there are loci that modulate stochastic variation at different phenotypic levels. Finding the identity of these genes will be key to developing complete models linking genotype to phenotype. PMID: 25569687 [PubMed - indexed for MEDLINE]

Related Articles Insight in genome-wide association of metabolite quantitative traits by exome sequence analyses. PLoS Genet. 2015 Jan;11(1):e1004835 Authors: Demirkan A, Henneman P, Verhoeven A, Dharuri H, Amin N, van Klinken JB, Karssen LC, de Vries B, Meissner A, Göraler S, van den Maagdenberg AM, Deelder AM, C 't Hoen PA, van Duijn CM, van Dijk KW Abstract Metabolite quantitative traits carry great promise for epidemiological studies, and their genetic background has been addressed using Genome-Wide Association Studies (GWAS). Thus far, the role of less common variants has not been exhaustively studied. Here, we set out a GWAS for metabolite quantitative traits in serum, followed by exome sequence analysis to zoom in on putative causal variants in the associated genes. 1H Nuclear Magnetic Resonance (1H-NMR) spectroscopy experiments yielded successful quantification of 42 unique metabolites in 2,482 individuals from The Erasmus Rucphen Family (ERF) study. Heritability of metabolites were estimated by SOLAR. GWAS was performed by linear mixed models, using HapMap imputations. Based on physical vicinity and pathway analyses, candidate genes were screened for coding region variation using exome sequence data. Heritability estimates for metabolites ranged between 10% and 52%. GWAS replicated three known loci in the metabolome wide significance: CPS1 with glycine (P-value  = 1.27×10-32), PRODH with proline (P-value  = 1.11×10-19), SLC16A9 with carnitine level (P-value  = 4.81×10-14) and uncovered a novel association between DMGDH and dimethyl-glycine (P-value  = 1.65×10-19) level. In addition, we found three novel, suggestively significant loci: TNP1 with pyruvate (P-value  = 1.26×10-8), KCNJ16 with 3-hydroxybutyrate (P-value  = 1.65×10-8) and 2p12 locus with valine (P-value  = 3.49×10-8). Exome sequence analysis identified potentially causal coding and regulatory variants located in the genes CPS1, KCNJ2 and PRODH, and revealed allelic heterogeneity for CPS1 and PRODH. Combined GWAS and exome analyses of metabolites detected by high-resolution 1H-NMR is a robust approach to uncover metabolite quantitative trait loci (mQTL), and the likely causative variants in these loci. It is anticipated that insight in the genetics of intermediate phenotypes will provide additional insight into the genetics of complex traits. PMID: 25569235 [PubMed - indexed for MEDLINE]

Related Articles Liver safety assessment: required data elements and best practices for data collection and standardization in clinical trials. Drug Saf. 2014 Nov;37 Suppl 1:S19-31 Authors: Avigan MI, Bjornsson ES, Pasanen M, Cooper C, Andrade RJ, Watkins PB, Lewis JH, Merz M Abstract A workshop was convened to discuss best practices for the assessment of drug-induced liver injury (DILI) in clinical trials. In a breakout session, workshop attendees discussed necessary data elements and standards for the accurate measurement of DILI risk associated with new therapeutic agents in clinical trials. There was agreement that in order to achieve this goal the systematic acquisition of protocol-specified clinical measures and lab specimens from all study subjects is crucial. In addition, standard DILI terms that address the diverse clinical and pathologic signatures of DILI were considered essential. There was a strong consensus that clinical and lab analyses necessary for the evaluation of cases of acute liver injury should be consistent with the US Food and Drug Administration (FDA) guidance on pre-marketing risk assessment of DILI in clinical trials issued in 2009. A recommendation that liver injury case review and management be guided by clinicians with hepatologic expertise was made. Of note, there was agreement that emerging DILI signals should prompt the systematic collection of candidate pharmacogenomic, proteomic and/or metabonomic biomarkers from all study subjects. The use of emerging standardized clinical terminology, CRFs and graphic tools for data review to enable harmonization across clinical trials was strongly encouraged. Many of the recommendations made in the breakout session are in alignment with those made in the other parallel sessions on methodology to assess clinical liver safety data, causality assessment for suspected DILI, and liver safety assessment in special populations (hepatitis B, C, and oncology trials). Nonetheless, a few outstanding issues remain for future consideration. PMID: 25352325 [PubMed - indexed for MEDLINE]

Metabolomics Applied to the Pancreatic Islet. Arch Biochem Biophys. 2015 Jun 24; Authors: Gooding JR, Jensen MV, Newgard CB Abstract Metabolomics, the characterization of the set of small molecules in a biological system, is advancing research in multiple areas of islet biology. Measuring a breadth of metabolites simultaneously provides a broad perspective on metabolic changes as the islets respond dynamically to glucose or environmental stressors. As a result, metabolomics has the potential to provide new mechanistic insights into islet physiology and pathophysiology. Here we summarize advances in our understanding of islet physiology and the etiologies of type-1 and type-2 diabetes derived from metabolomics studies. PMID: 26116790 [PubMed - as supplied by publisher]

Related Articles Metabolomic and transcriptomic insights into how cotton fiber transitions to secondary wall synthesis, represses lignification, and prolongs elongation. BMC Genomics. 2015;16(1):477 Authors: Tuttle JR, Nah G, Duke MV, Alexander DC, Guan X, Song Q, Chen ZJ, Scheffler BE, Haigler CH Abstract BACKGROUND: The morphogenesis of single-celled cotton fiber includes extreme elongation and staged cell wall differentiation. Designing strategies for improving cotton fiber for textiles and other uses relies on uncovering the related regulatory mechanisms. In this research we compared the transcriptomes and metabolomes of two Gossypium genotypes, Gossypium barbadense cv Phytogen 800 and G. hirsutum cv Deltapine 90. When grown in parallel, the two types of fiber developed similarly except for prolonged fiber elongation in the G. barbadense cultivar. The data were collected from isolated fibers between 10 to 28 days post anthesis (DPA) representing: primary wall synthesis to support elongation; transitional cell wall remodeling; and secondary wall cellulose synthesis, which was accompanied by continuing elongation only in G. barbadense fiber. RESULTS: Of 206 identified fiber metabolites, 205 were held in common between the two genotypes. Approximately 38,000 transcripts were expressed in the fiber of each genotype, and these were mapped to the reference set and interpreted by homology to known genes. The developmental changes in the transcriptomes and the metabolomes were compared within and across genotypes with several novel implications. Transitional cell wall remodeling is a distinct stable developmental stage lasting at least four days (18 to 21 DPA). Expression of selected cell wall related transcripts was similar between genotypes, but cellulose synthase gene expression patterns were more complex than expected. Lignification was transcriptionally repressed in both genotypes. Oxidative stress was lower in the fiber of G. barbadense cv Phytogen 800 as compared to G. hirsutum cv Deltapine 90. Correspondingly, the G. barbadense cultivar had enhanced capacity for management of reactive oxygen species during its prolonged elongation period, as indicated by a 138-fold increase in ascorbate concentration at 28 DPA. CONCLUSIONS: The parallel data on deep-sequencing transcriptomics and non-targeted metabolomics for two genotypes of single-celled cotton fiber showed that a discrete developmental stage of transitional cell wall remodeling occurs before secondary wall cellulose synthesis begins. The data showed how lignification can be transcriptionally repressed during secondary cell wall synthesis, and they implicated enhanced capacity to manage reactive oxygen species through the ascorbate-glutathione cycle as a positive contributor to fiber length. PMID: 26116072 [PubMed - as supplied by publisher]