PubMed

Biomarker Discovery in Human Prostate Cancer: an Update in Metabolomics Studies. Transl Oncol. 2016 Aug;9(4):357-370 Authors: Lima AR, Bastos ML, Carvalho M, Guedes de Pinho P Abstract Prostate cancer (PCa) is the most frequently diagnosed cancer and the second leading cause of cancer death among men in Western countries. Current screening techniques are based on the measurement of serum prostate specific antigen (PSA) levels and digital rectal examination. A decisive diagnosis of PCa is based on prostate biopsies; however, this approach can lead to false-positive and false-negative results. Therefore, it is important to discover new biomarkers for the diagnosis of PCa, preferably noninvasive ones. Metabolomics is an approach that allows the analysis of the entire metabolic profile of a biological system. As neoplastic cells have a unique metabolic phenotype related to cancer development and progression, the identification of dysfunctional metabolic pathways using metabolomics can be used to discover cancer biomarkers and therapeutic targets. In this study, we review several metabolomics studies performed in prostatic fluid, blood plasma/serum, urine, tissues and immortalized cultured cell lines with the objective of discovering alterations in the metabolic phenotype of PCa and thus discovering new biomarkers for the diagnosis of PCa. Encouraging results using metabolomics have been reported for PCa, with sarcosine being one of the most promising biomarkers identified to date. However, the use of sarcosine as a PCa biomarker in the clinic remains a controversial issue within the scientific community. Beyond sarcosine, other metabolites are considered to be biomarkers for PCa, but they still need clinical validation. Despite the lack of metabolomics biomarkers reaching clinical practice, metabolomics proved to be a powerful tool in the discovery of new biomarkers for PCa detection. PMID: 27567960 [PubMed - as supplied by publisher]

Discrimination of wild types and hybrids of Duboisia myoporoides and Duboisia leichhardtii at different growth stages using (1)H NMR-based metabolite profiling and tropane alkaloids-targeted HPLC-MS analysis. Phytochemistry. 2016 Aug 23; Authors: Ullrich SF, Averesch NJ, Castellanos L, Choi YH, Rothauer A, Kayser O Abstract Duboisia species, which belong to the family of Solanaceae, are commercially cultivated in large scale, as they are main source of the pharmaceutically-used active compound scopolamine. In this study, (1)H NMR-based metabolite profiling linking primary with secondary metabolism and additional quantification via HPCL-MS with special focus on the tropane alkaloids were applied to compare leaf and root extracts of three wild types and two hybrids of Duboisia myoporoides and D. leichhardtii at different developmental stages grown under controlled conditions in climate chambers and under agricultural field plantation. Based on the leaf extracts, a clear distinction between the Duboisia hybrids and the wild types Duboisia myoporoides and D. leichhardtii using principal component analysis of (1)H NMR data was observed. The average content in scopolamine in the hybrids of Duboisia cultivated in climate chambers increased significantly from month 3-6 after potting of the rooted cuttings, however not so for the examined wild types. The Duboisia hybrids grown in climate chambers showed higher growth and contained more sugars and amino acids than Duboisia hybrids grown in the field, which in contrast showed an enhanced flux towards tropane alkaloids as well as flavonoids. For a more detailed analysis of tropane alkaloids, an appropriate HPLC-MS method was developed and validated. The measurements revealed large differences in the alkaloid pattern within the different genotypes under investigation, especially regarding the last enzymatic step, the conversion from hyoscamine to scopolamine by the hyoscyamine 6β-hydroxylase. Scopolamine was found in highest concentrations in Duboisia hybrids (20.04 ± 4.05 and 17.82 ± 3.52 mg/g dry wt) followed by Duboisia myoporoides (12.71 ± 2.55 mg/g dry wt), both showing a high selectivity for scopolamine in contrast to Duboisia leichhardtii (3.38 ± 0.59 and 5.09 ± 1.24 mg/g dry wt) with hyoscyamine being the predominant alkaloid. PMID: 27567452 [PubMed - as supplied by publisher]

Non-targeted and targeted metabolomics approaches to diagnosing lung cancer and predicting patient prognosis. Oncotarget. 2016 Aug 23; Authors: Zhang X, Zhu X, Wang C, Zhang H, Cai Z Abstract Lung cancer is the most common cause of cancer death in China. We characterized metabolic alterations in lung cancer using two analytical platforms: a non-targeted metabolic profiling strategy based on proton nuclear magnetic resonance (1H-NMR) spectroscopy and a targeted metabolic profiling strategy based on rapid resolution liquid chromatography (RRLC). Changes in serum metabolite levels during oncogenesis were evaluated in 25 stage I lung cancer patients and matched healthy controls. We identified 25 metabolites that were differentially regulated between the lung cancer patients and matched controls. Of those, 16 were detected using the non-targeted approach and 9 were identified using the targeted approach. Both groups of metabolites could differentiate between lung cancer patients and healthy controls with 100% sensitivity and specificity. The principal metabolic alternations in lung cancer included changes in glycolysis, lipid metabolism, choline phospholipid metabolism, one-carbon metabolism, and amino acid metabolism. The targeted metabolomics approach was more sensitive, accurate, and specific than the non-targeted metabolomics approach. However, our data suggest that both metabolomics strategies could be used to detect early-stage lung cancer and predict patient prognosis. PMID: 27566571 [PubMed - as supplied by publisher]

Exploration of Candidate Biomarkers for Human Psoriasis Based on GC-MS Serum Metabolomics. Br J Dermatol. 2016 Aug 26; Authors: Kang H, Li X, Zhou Q, Quan S, Xue F, Zheng J, Yu Y Abstract BACKGROUND: Recent studies have shown that dysregulated metabolic pathways are linked to psoriasis pathogenesis. However, an extensive, unbiased metabolic analysis in psoriatic patients has not been completely explored. The metabolome represents the end products of proteomics or cellular processes which may be closely associated with the pathogenesis of psoriasis. OBJECTIVES: To determine the differences in serum metabolomic profiles among psoriasis patients and healthy controls with the goal of identifying potential biomarkers in patients with psoriasis. METHODS: Serum metabolomic profiles from 29 subjects (14 psoriasis patients and 15 age and gender matched healthy controls). The serum metabolites were analyzed by gas chromatography mass spectrometry based on a combined full scan and selected-ion monitoring mode. RESULTS: Multivariate statistical analysis of metabolomics data revealed altered serum metabolites between the patients with psoriasis and healthy individuals. Compared to healthy individuals, psoriasis patients had higher levels of amino acids including asparagine, aspartic acid, isoleucine, phenylalanine, ornithine and proline, and higher levels of lactic acid and urea; while a lower level of crotonic acid, azelaic acid, ethanolamine and cholesterol. CONCLUSIONS: It appears that glycolysis pathway and amino acid metabolic activity are increased in psoriasis patients. These metabolic perturbations may stem from increased demand for protein biosynthesis and keratinocyte hyperproliferation. Our findings may help elucidate the pathogenesis of psoriasis and provide insights into early diagnosis and therapeutic intervention. This article is protected by copyright. All rights reserved. PMID: 27564527 [PubMed - as supplied by publisher]

Comparative metabolic and lipidomic profiling of human breast cancer cells with different metastatic potentials. Oncotarget. 2016 Aug 24; Authors: Kim HY, Lee KM, Kim SH, Kwon YJ, Chun YJ, Choi HK Abstract This study conducted comprehensive and comparative metabolic and lipidomic profiling of a human epithelial breast cell line (MCF-10A), a slightly metastatic (MCF-7), and a highly metastatic (MDA-MB-231) breast cancer cell line using gas chromatography mass spectrometry (GC-MS) and direct infusion mass spectrometry (DI-MS). Among 39 metabolites identified by GC-MS analysis, xanthine, glucose-6-phosphate, mannose-6-phosphate, guanine, and adenine were selected as prognostic markers of breast cancer metastasis. Major metabolic pathways involved in differentiation of the cell lines were alanine, aspartate, and glutamate metabolism, purine metabolism and glycine, serine, and threonine metabolism. Among 44 intact lipid species identified by DI-MS analysis, the levels of most phospholipids were higher in both metastatic groups than in normal cells. Specifically, the levels of phosphatidylserine (PS) 18:0/20:4, phosphatidylinositol (PI) 18:0/20:4, and phosphatidylcholine (PC) 18:0/20:4 were markedly higher while those of phosphatidylethanolamine (PE) 18:1/18:1 and PI 18:0/18:1 were lower in MDA-MB-231 cells than in MCF-7 cells. A partial-least-squares regression model was developed and validated for predicting the metastatic potential of breast cancer cells. The information obtained in this study will be useful when developing diagnostic tools and for identifying potential therapeutic targets for metastatic breast cancer. PMID: 27564096 [PubMed - as supplied by publisher]

Breathomics for Gastric Cancer Classification Using Back-propagation Neural Network. J Med Signals Sens. 2016 Jul-Sep;6(3):172-82 Authors: Daniel DA, Thangavel K Abstract Breathomics is the metabolomics study of exhaled air. It is a powerful emerging metabolomics research field that mainly focuses on health-related volatile organic compounds (VOCs). Since the quantity of these compounds varies with health status, breathomics assures to deliver noninvasive diagnostic tools. Thus, the main aim of breathomics is to discover patterns of VOCs related to abnormal metabolic processes occurring in the human body. Classification systems, however, are not designed for cost-sensitive classification domains. Therefore, they do not work on the gastric carcinoma (GC) domain where the benefit of correct classification of early stages is more than that of later stages, and also the cost of wrong classification is different for all pairs of predicted and actual classes. The aim of this work is to demonstrate the basic principles for the breathomics to classify the GC, for that the determination of VOCs such as acetone, carbon disulfide, 2-propanol, ethyl alcohol, and ethyl acetate in exhaled air and stomach tissue emission for the detection of GC has been analyzed. The breath of 49 GC and 30 gastric ulcer patients were collected for the study to distinguish the normal, suspected, and positive cases using back-propagation neural network (BPN) and produced the accuracy of 93%, sensitivity of 94.38%, and specificity of 89.93%. This study carries out the comparative study of the result obtained by the single- and multi-layer cascade-forward and feed-forward BPN with different activation functions. From this study, the multilayer cascade-forward outperforms the classification of GC from normal and benign cases. PMID: 27563574 [PubMed]

Metabolic Reprogramming Regulates the Proliferative and Inflammatory Phenotype of Adventitial Fibroblasts in Pulmonary Hypertension Through the Transcriptional Co-Repressor C-terminal Binding Protein-1. Circulation. 2016 Aug 25; Authors: Li M, Riddle S, Zhang H, D'Alessandro A, Flockton A, Serkova NJ, Hansen KC, Moldvan R, McKeon BA, Frid M, Kumar S, Li H, Liu H, Cánovas A, Medrano JF, Thomas MG, Iloska D, Plecita-Hlavata L, Jezek P, Pullamsetti S, Fini MA, El Kasmi KC, Zhang Q, Stenmark KR Abstract BACKGROUND: --Changes in metabolism have been suggested to contribute to the aberrant phenotype of vascular wall cells including fibroblasts in pulmonary hypertension (PH). Herein, we test the hypothesis that metabolic reprogramming to aerobic glycolysis is a critical adaptation of fibroblasts in the hypertensive vessel wall that drives proliferative and pro-inflammatory activation through a mechanism involving increased activity of the NADH-sensitive transcriptional co-repressor C-terminal binding protein 1 (CtBP1). METHODS: -RNA-Sequencing, qPCR, (13)C-NMR, fluorescence-lifetime imaging, mass spectrometry-based metabolomics and tracing experiments with U-(13)C-glucose were used to assess glycolytic reprogramming and to measure NADH/NAD(+) ratio in bovine and human adventitial fibroblasts, and mouse lung tissues. Immunohistochemistry was utilized to assess CtBP1 expression in the whole lung tissues. CtBP1 siRNA and the pharmacologic inhibitor 4-methylthio-2-oxobutyric acid (MTOB) were utilized to abrogate CtBP1 activity in cells and hypoxic mice. RESULTS: -We found adventitial fibroblasts from calves with severe hypoxia-induced PH and humans with IPAH (PH-Fibs) displayed aerobic glycolysis when cultured under normoxia, accompanied by increased free NADH and NADH/NAD(+) ratios. Expression of the NADH sensor CtBP1 was increased in vivo and in vitro in fibroblasts within the pulmonary adventitia of humans with IPAH and animals with PH and cultured PH-Fibs, respectively. Decreasing NADH pharmacologically with MTOB, or genetically blocking CtBP1 using siRNA, upregulated the cyclin-dependent genes (p15 and p21) and pro-apoptotic regulators (NOXA and PERP), attenuated proliferation, corrected the glycolytic reprogramming phenotype of PH-Fibs, and augmented transcription of the anti-inflammatory gene HMOX1 ChIP analysis demonstrated that CtBP1 directly binds the HMOX1 promoter. Treatment of hypoxic mice with MTOB decreased glycolysis and expression of inflammatory genes, attenuated proliferation, and suppressed macrophage numbers and remodeling in the distal pulmonary vasculature. CONCLUSIONS: -CtBP1 is a critical factor linking changes in cell metabolism to cell phenotype in hypoxic and other forms of PH and a therapeutic target. PMID: 27562971 [PubMed - as supplied by publisher]

Colonic transit time is related to bacterial metabolism and mucosal turnover in the gut. Nat Microbiol. 2016;1(9):16093 Authors: Roager HM, Hansen LB, Bahl MI, Frandsen HL, Carvalho V, Gøbel RJ, Dalgaard MD, Plichta DR, Sparholt MH, Vestergaard H, Hansen T, Sicheritz-Pontén T, Nielsen HB, Pedersen O, Lauritzen L, Kristensen M, Gupta R, Licht TR Abstract Little is known about how colonic transit time relates to human colonic metabolism and its importance for host health, although a firm stool consistency, a proxy for a long colonic transit time, has recently been positively associated with gut microbial richness. Here, we show that colonic transit time in humans, assessed using radio-opaque markers, is associated with overall gut microbial composition, diversity and metabolism. We find that a long colonic transit time associates with high microbial richness and is accompanied by a shift in colonic metabolism from carbohydrate fermentation to protein catabolism as reflected by higher urinary levels of potentially deleterious protein-derived metabolites. Additionally, shorter colonic transit time correlates with metabolites possibly reflecting increased renewal of the colonic mucosa. Together, this suggests that a high gut microbial richness does not per se imply a healthy gut microbial ecosystem and points at colonic transit time as a highly important factor to consider in microbiome and metabolomics studies. PMID: 27562254 [PubMed - in process]

Deep sexual dimorphism in adult medaka fish liver highlighted by multi-omic approach. Sci Rep. 2016;6:32459 Authors: Qiao Q, Le Manach S, Sotton B, Huet H, Duvernois-Berthet E, Paris A, Duval C, Ponger L, Marie A, Blond A, Mathéron L, Vinh J, Bolbach G, Djediat C, Bernard C, Edery M, Marie B Abstract Sexual dimorphism describes the features that discriminate between the two sexes at various biological levels. Especially, during the reproductive phase, the liver is one of the most sexually dimorphic organs, because of different metabolic demands between the two sexes. The liver is a key organ that plays fundamental roles in various physiological processes, including digestion, energetic metabolism, xenobiotic detoxification, biosynthesis of serum proteins, and also in endocrine or immune response. The sex-dimorphism of the liver is particularly obvious in oviparous animals, as the female liver is the main organ for the synthesis of oocyte constituents. In this work, we are interested in identifying molecular sexual dimorphism in the liver of adult medaka fish and their sex-variation in response to hepatotoxic exposures. By developing an integrative approach combining histology and different high-throughput omic investigations (metabolomics, proteomics and transcriptomics), we were able to globally depict the strong sexual dimorphism that concerns various cellular and molecular processes of hepatocytes comprising protein synthesis, amino acid, lipid and polysaccharide metabolism, along with steroidogenesis and detoxification. The results of this work imply noticeable repercussions on the biology of oviparous organisms environmentally exposed to chemical or toxin issues. PMID: 27561897 [PubMed - in process]

Related Articles Systemic Metabolic Responses of Broiler Chickens and Piglets to Acute T-2 Toxin Intravenous Exposure. J Agric Food Chem. 2016 Jan 27;64(3):714-23 Authors: Wan Q, He Q, Deng X, Hao F, Tang H, Wang Y Abstract The aim of this study is to thoroughly investigate the toxicity mechanism of mycotoxin T-2 toxin and to further understand the endogenous metabolic alterations induced by T-2 toxin. To achieve this, a nuclear magnetic resonance (NMR)-based metabonomics approach was used to analyze the metabolic alterations induced by a single intravenous injection of T-2 toxin (0.5 mg/kg of body weight) in piglets and broiler chickens. A range of metabolites in the plasma, liver, kidney, and spleen of broiler chickens and plasma of piglets was changed following T-2 toxin injection. For example, a rapid increase of amino acids together with a significant reduction of glucose and lipid occurred in the plasma of broiler chickens and piglets following T-2 toxin treatment. A significant accumulation of amino acids and modulated nucleotides were detected in the liver, kidney, and spleen of T-2 toxin-treated broiler chickens. These data indicated that T-2 toxin caused endogenous metabolic changes in multiple organs and perturbed various metabolic pathways, including energy, amino acid, and nucleotide metabolism, as well as oxidative stress. We also observed elevated levels of tryptophan in the T-2 toxin-treated broiler chickens, which may explain the reported neurotoxic effects of T-2 toxin. These findings provide important information on the toxicity of T-2 toxin and demonstrate the power of the NMR-based metabonomics approach in exploring the toxicity mechanism of xenobiotics. PMID: 26714875 [PubMed - indexed for MEDLINE]

Related Articles Variable alterations of the microbiota, without metabolic or immunological change, following faecal microbiota transplantation in patients with chronic pouchitis. Sci Rep. 2015;5:12955 Authors: Landy J, Walker AW, Li JV, Al-Hassi HO, Ronde E, English NR, Mann ER, Bernardo D, McLaughlin SD, Parkhill J, Ciclitira PJ, Clark SK, Knight SC, Hart AL Abstract Faecal microbiota transplantation (FMT) is effective in the treatment of Clostridium difficile infection, where efficacy correlates with changes in microbiota diversity and composition. The effects of FMT on recipient microbiota in inflammatory bowel diseases (IBD) remain unclear. We assessed the effects of FMT on microbiota composition and function, mucosal immune response, and clinical outcome in patients with chronic pouchitis. Eight patients with chronic pouchitis (current PDAI ≥7) were treated with FMT via nasogastric administration. Clinical activity was assessed before and four weeks following FMT. Faecal coliform antibiotic sensitivities were analysed, and changes in pouch faecal and mucosal microbiota assessed by 16S rRNA gene pyrosequencing and (1)H NMR spectroscopy. Lamina propria dendritic cell phenotype and cytokine profiles were assessed by flow cytometric analysis and multiplex assay. Following FMT, there were variable shifts in faecal and mucosal microbiota composition and, in some patients, changes in proportional abundance of species suggestive of a "healthier" pouch microbiota. However, there were no significant FMT-induced metabolic or immunological changes, or beneficial clinical response. Given the lack of clinical response following FMT via a single nasogastric administration our results suggest that FMT/bacteriotherapy for pouchitis patients requires further optimisation. PMID: 26264409 [PubMed - indexed for MEDLINE]

An analytical strategy to investigate Semen Strychni nephrotoxicity based on simultaneous HILIC-ESI-MS/MS detection of Semen Strychni alkaloids, tyrosine and tyramine in HEK 293t cell lysates. J Chromatogr B Analyt Technol Biomed Life Sci. 2016 Aug 16;1033-1034:157-165 Authors: Gu L, Hou P, Zhang R, Liu Z, Bi K, Chen X Abstract A Previous metabolomics study has demonstrated that tyrosine metabolism might be disrupted by treating with Semen Strychni on the cell nephrotoxicity model. To investigate the relationship between Semen Strychni alkaloids (SAs) and endogenous tyrosine, tyramine under the nephrotoxicity condition, an HILIC-ESI-MS/MS based analytical strategy was applied in this study. Based on the established Semen Strychni nephrotoxicity cell model, strychnine and brucine were identified and screened as the main SAs by an HPLC-Q Exactive hybrid quadrupole Orbitrap mass system. Then, a sensitive HILIC-ESI-MS/MS method was developed to simultaneously monitor strychnine, brucine, tyrosine and tyramine in cell lysate. The analytes were separated by a Shiseido CAPCELL CORE PC (150mm×2.1mm, 2.7μm) HILIC column in an acetonitrile/0.1% formic acid gradient system. All the calibration curves were linear with regression coefficients above 0.9924. The absolute recoveries were more than 80.5% and the matrix effects were between 91.6%-107.0%. With the developed method, analytes were successfully determined in cell lysates. Decreased levels of tyrosine and tyramine were observed only in combination with increased levels of SAs, indicating that the disturbance of tyrosine metabolism might be induced by the accumulation of SAs in kidney cell after exposure of Semen Strychni. The HILIC-ESI-MS/MS based analytical strategy is a useful tool to reveal the relationships between the toxic herb components and the endogenous metabolite profiling in the toxicity investigation of herb medicines. PMID: 27561182 [PubMed - as supplied by publisher]

The Role of High-Resolution Magic Angle Spinning 1H Nuclear Magnetic Resonance Spectroscopy for Predicting the Invasive Component in Patients with Ductal Carcinoma In Situ Diagnosed on Preoperative Biopsy. PLoS One. 2016;11(8):e0161038 Authors: Chae EY, Shin HJ, Kim S, Baek HM, Yoon D, Kim S, Shim YE, Kim HH, Cha JH, Choi WJ, Lee JH, Shin JH, Lee HJ, Gong G Abstract The purpose of this study was to evaluate the role of high-resolution magic angle spinning (HR-MAS) 1H nuclear magnetic resonance (NMR) spectroscopy in patients with ductal carcinoma in situ (DCIS) diagnosed on preoperative biopsy. We investigated whether the metabolic profiling of tissue samples using HR-MAS 1H NMR spectroscopy could be used to distinguish between DCIS lesions with or without an invasive component. Our institutional review board approved this combined retrospective and prospective study. Tissue samples were collected from 30 patients with pure DCIS and from 30 with DCIS accompanying invasive carcinoma. All patients were diagnosed with DCIS by preoperative core-needle biopsy and underwent surgical resection. The metabolic profiling of tissue samples was performed by HR-MAS 1H NMR spectroscopy. All observable metabolite signals were identified and quantified in all tissue samples. Metabolite intensity normalized by total spectral intensities was compared according to the tumor type using the Mann-Whitney test. Multivariate analysis was performed with orthogonal projections to latent structure-discriminant analysis (OPLS-DA). By univariate analysis, the metabolite concentrations of choline-containing compounds obtained with HR-MAS 1H NMR spectroscopy did not differ significantly between the pure DCIS and DCIS accompanying invasive carcinoma groups. However, the GPC/PC ratio was higher in the pure DCIS group than in the DCIS accompanying invasive carcinoma group (p = 0.004, Bonferroni-corrected p = 0.064), as well as the concentration of myo-inositol and succinate. By multivariate analysis, the OPLS-DA models built with HR-MAS MR metabolic profiles could clearly discriminate between pure DCIS and DCIS accompanying invasive carcinoma. Our preliminary results suggest that HR-MAS MR metabolomics on breast tissue may be able to distinguish between DCIS lesions with or without an invasive component. PMID: 27560937 [PubMed - as supplied by publisher]

Rifaximin Exerts Beneficial Effects Independent of its Ability to Alter Microbiota Composition. Clin Transl Gastroenterol. 2016;7(8):e187 Authors: Kang DJ, Kakiyama G, Betrapally NS, Herzog J, Nittono H, Hylemon PB, Zhou H, Carroll I, Yang J, Gillevet PM, Jiao C, Takei H, Pandak WM, Iida T, Heuman DM, Fan S, Fiehn O, Kurosawa T, Sikaroodi M, Sartor RB, Bajaj JS Abstract OBJECTIVES: Rifaximin has clinical benefits in minimal hepatic encephalopathy (MHE) but the mechanism of action is unclear. The antibiotic-dependent and -independent effects of rifaximin need to be elucidated in the setting of MHE-associated microbiota. To assess the action of rifaximin on intestinal barrier, inflammatory milieu and ammonia generation independent of microbiota using rifaximin. METHODS: Four germ-free (GF) mice groups were used (1) GF, (2) GF+rifaximin, (3) Humanized with stools from an MHE patient, and (4) Humanized+rifaximin. Mice were followed for 30 days while rifaximin was administered in chow at 100 mg/kg from days 16-30. We tested for ammonia generation (small-intestinal glutaminase, serum ammonia, and cecal glutamine/amino-acid moieties), systemic inflammation (serum IL-1β, IL-6), intestinal barrier (FITC-dextran, large-/small-intestinal expression of IL-1β, IL-6, MCP-1, e-cadherin and zonulin) along with microbiota composition (colonic and fecal multi-tagged sequencing) and function (endotoxemia, fecal bile acid deconjugation and de-hydroxylation). RESULTS: All mice survived until day 30. In the GF setting, rifaximin decreased intestinal ammonia generation (lower serum ammonia, increased small-intestinal glutaminase, and cecal glutamine content) without changing inflammation or intestinal barrier function. Humanized microbiota increased systemic/intestinal inflammation and endotoxemia without hyperammonemia. Rifaximin therapy significantly ameliorated these inflammatory cytokines. Rifaximin also favorably impacted microbiota function (reduced endotoxin and decreased deconjugation and formation of potentially toxic secondary bile acids), but not microbial composition in humanized mice. CONCLUSIONS: Rifaximin beneficially alters intestinal ammonia generation by regulating intestinal glutaminase expression independent of gut microbiota. MHE-associated fecal colonization results in intestinal and systemic inflammation in GF mice, which is also ameliorated with rifaximin. PMID: 27560928 [PubMed - as supplied by publisher]

Smartphone Analytics: Expanding the Lab into the Cloud. Anal Chem. 2016 Aug 25; Authors: Montenegro Burke JR, Phommavongsay T, Aisporna AE, Huan T, Rinehart D, Forsberg EM, Poole FL, Thorgersen MP, Adams MW, Krantz G, Fields MW, Robbins PD, Niedernhofer LJ, Lairson LL, Benton HP, Siuzdak G Abstract Active data screening is an integral part of many scientific activities and mobile technologies have greatly facilitated this process by minimizing the reliance on large hardware instrumentation. In order to meet with the increasingly growing field of metabolomics and heavy workload of data processing, we designed the first remote metabolomic data screening platform for mobile devices. Two mobile applications (apps), XCMS Mobile and METLIN Mobile, facilitate access to XCMS and METLIN, which are the most important components in the computer-based XCMS Online platforms. These mobile apps allow for the visualization and analysis of metabolic data throughout the entire analytical process. Specifically, XCMS Mobile and METLIN Mobile provide the capabilities for remote monitoring of data processing, real time notifications for the data processing, visualization and interactive analysis of processed data (e.g. cloud plots, principle component analysis, box-plots, extracted ion chromatograms and hierarchical cluster analysis) and database searching for metabolite identification. These apps, available on Apple iOS and Google Android operating systems, allow for the migration of metabolomic research onto mobile devices for better accessibility beyond direct instrument operation. The utility of XCMS Mobile and METLIN Mobile functionalities was developed and is demonstrated here through the metabolomic LC-MS analyses of stem cells, colon cancer, aging and bacterial metabolism. PMID: 27560777 [PubMed - as supplied by publisher]

A validated metabolomic signature for colorectal cancer: exploration of the clinical value of metabolomics. Br J Cancer. 2016 Aug 25; Authors: Farshidfar F, Weljie AM, Kopciuk KA, Hilsden R, McGregor SE, Buie WD, MacLean A, Vogel HJ, Bathe OF Abstract BACKGROUND: Timely diagnosis and classification of colorectal cancer (CRC) are hindered by unsatisfactory clinical assays. Our aim was to construct a blood-based biomarker series using a single assay, suitable for CRC detection, prognostication and staging. METHODS: Serum metabolomic profiles of adenoma (N=31), various stages of CRC (N=320) and healthy matched controls (N=254) were analysed by gas chromatography-mass spectrometry (GC-MS). A diagnostic model for CRC was derived by orthogonal partial least squares-discriminant analysis (OPLS-DA) on a training set, and then validated on an independent data set. Metabolomic models suitable for identifying adenoma, poor prognosis stage II CRC and discriminating various stages were generated. RESULTS: A diagnostic signature for CRC with remarkable multivariate performance (R(2)Y=0.46, Q(2)Y=0.39) was constructed, and then validated (sensitivity 85%; specificity 86%). Area under the receiver-operating characteristic curve was 0.91 (95% CI, 0.87-0.96). Adenomas were also detectable (R(2)Y=0.35, Q(2)Y=0.26, internal AUROC=0.81, 95% CI, 0.70-0.92). Also of particular interest, we identified models that stratified stage II by prognosis, and classified cases by stage. CONCLUSIONS: Using a single assay system, a suite of CRC biomarkers based on circulating metabolites enables early detection, prognostication and preliminary staging information. External population-based studies are required to evaluate the repeatability of our findings and to assess the clinical benefits of these biomarkers.British Journal of Cancer advance online publication, 25 August 2016; doi:10.1038/bjc.2016.243 www.bjcancer.com. PMID: 27560555 [PubMed - as supplied by publisher]

The 1-SToP Approach to Annotation of LC-MS Metabolomics Data. Anal Chem. 2016 Aug 25; Authors: Broeckling CD, Ganna A, Layer MC, Brown K, Sutton B, Ingelsson E, Peers G, Prenni JE Abstract Liquid chromatography coupled to electrospray ionization mass spectrometry (LC-ESI-MS) is a versatile and robust platform for metabolomic analysis. However, while ESI is a soft ionization technique, in-source phenomena including multimerization, non-proton cation adduction, and in-source fragmentation complicate interpretation of MS data. Here, we report chromatographic and mass spectrometric behavior of 904 authentic standards collected under conditions identical to a typical non-targeted profiling experiment. The data illustrate that the often high level of complexity in MS spectra is likely to result in misinterpretation during the annotation phase of the experiment and a large overestimation of the number of compounds detected. However, our analysis of this MS spectral library data indicates that in-source phenomena are not random, but depend at least in part on chemical structure. These non-random patterns enabled predictions to be made as to which in-source signals are likely to be observed for a given compound. Using the authentic standard spectra as a training set, we modeled the in-source phenomena for all compounds in the Human Metabolome Database to generate a theoretical in-source spectrum and retention time library. A novel spectral similarity matching platform was developed to facilitate efficient spectral searching for non-targeted profiling applications. Taken together, this collection of experimental spectral data, predictive modeling, and informatic tools enables more efficient, reliable, and transparent metabolite annotation. PMID: 27560453 [PubMed - as supplied by publisher]

Metabolic Reconstruction of Setaria italica: A Systems Biology Approach for Integrating Tissue-Specific Omics and Pathway Analysis of Bioenergy Grasses. Front Plant Sci. 2016;7:1138 Authors: de Oliveira Dal'Molin CG, Orellana C, Gebbie L, Steen J, Hodson MP, Chrysanthopoulos P, Plan MR, McQualter R, Palfreyman RW, Nielsen LK Abstract The urgent need for major gains in industrial crops productivity and in biofuel production from bioenergy grasses have reinforced attention on understanding C4 photosynthesis. Systems biology studies of C4 model plants may reveal important features of C4 metabolism. Here we chose foxtail millet (Setaria italica), as a C4 model plant and developed protocols to perform systems biology studies. As part of the systems approach, we have developed and used a genome-scale metabolic reconstruction in combination with the use of multi-omics technologies to gain more insights into the metabolism of S. italica. mRNA, protein, and metabolite abundances, were measured in mature and immature stem/leaf phytomers, and the multi-omics data were integrated into the metabolic reconstruction framework to capture key metabolic features in different developmental stages of the plant. RNA-Seq reads were mapped to the S. italica resulting for 83% coverage of the protein coding genes of S. italica. Besides revealing similarities and differences in central metabolism of mature and immature tissues, transcriptome analysis indicates significant gene expression of two malic enzyme isoforms (NADP- ME and NAD-ME). Although much greater expression levels of NADP-ME genes are observed and confirmed by the correspondent protein abundances in the samples, the expression of multiple genes combined to the significant abundance of metabolites that participates in C4 metabolism of NAD-ME and NADP-ME subtypes suggest that S. italica may use mixed decarboxylation modes of C4 photosynthetic pathways under different plant developmental stages. The overall analysis also indicates different levels of regulation in mature and immature tissues in carbon fixation, glycolysis, TCA cycle, amino acids, fatty acids, lignin, and cellulose syntheses. Altogether, the multi-omics analysis reveals different biological entities and their interrelation and regulation over plant development. With this study, we demonstrated that this systems approach is powerful enough to complement the functional metabolic annotation of bioenergy grasses. PMID: 27559337 [PubMed]

Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer. Proc Natl Acad Sci U S A. 2016 Aug 24; Authors: Elgogary A, Xu Q, Poore B, Alt J, Zimmermann SC, Zhao L, Fu J, Chen B, Xia S, Liu Y, Neisser M, Nguyen C, Lee R, Park JK, Reyes J, Hartung T, Rojas C, Rais R, Tsukamoto T, Semenza GL, Hanes J, Slusher BS, Le A Abstract Targeting glutamine metabolism via pharmacological inhibition of glutaminase has been translated into clinical trials as a novel cancer therapy, but available drugs lack optimal safety and efficacy. In this study, we used a proprietary emulsification process to encapsulate bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), a selective but relatively insoluble glutaminase inhibitor, in nanoparticles. BPTES nanoparticles demonstrated improved pharmacokinetics and efficacy compared with unencapsulated BPTES. In addition, BPTES nanoparticles had no effect on the plasma levels of liver enzymes in contrast to CB-839, a glutaminase inhibitor that is currently in clinical trials. In a mouse model using orthotopic transplantation of patient-derived pancreatic tumor tissue, BPTES nanoparticle monotherapy led to modest antitumor effects. Using the HypoxCR reporter in vivo, we found that glutaminase inhibition reduced tumor growth by specifically targeting proliferating cancer cells but did not affect hypoxic, noncycling cells. Metabolomics analyses revealed that surviving tumor cells following glutaminase inhibition were reliant on glycolysis and glycogen synthesis. Based on these findings, metformin was selected for combination therapy with BPTES nanoparticles, which resulted in significantly greater pancreatic tumor reduction than either treatment alone. Thus, targeting of multiple metabolic pathways, including effective inhibition of glutaminase by nanoparticle drug delivery, holds promise as a novel therapy for pancreatic cancer. PMID: 27559084 [PubMed - as supplied by publisher]

Correction to 'Metabolomics of reef benthic interactions reveals a bioactive lipid involved in coral defence'. Proc Biol Sci. 2016 Aug 31;283(1837) Authors: Quinn RA, Vermeij MJ, Hartmann AC, d'Auriac IG, Benler S, Haas A, Quistad SD, Lim YW, Little M, Sandin S, Smith JE, Dorrestein PC, Rohwer F PMID: 27559065 [PubMed - in process]