PubMed

Novel biomarker identification using metabolomic profiling to differentiate radiation necrosis and recurrent tumor following Gamma Knife radiosurgery. J Neurosurg. 2016 Nov 25;:1-9 Authors: Lu AY, Turban JL, Damisah EC, Li J, Alomari AK, Eid T, Vortmeyer AO, Chiang VL Abstract OBJECTIVE Following an initial response of brain metastases to Gamma Knife radiosurgery, regrowth of the enhancing lesion as detected on MRI may represent either radiation necrosis (a treatment-related inflammatory change) or recurrent tumor. Differentiation of radiation necrosis from tumor is vital for management decision making but remains difficult by imaging alone. In this study, gas chromatography with time-of-flight mass spectrometry (GC-TOF) was used to identify differential metabolite profiles of the 2 tissue types obtained by surgical biopsy to find potential targets for noninvasive imaging. METHODS Specimens of pure radiation necrosis and pure tumor obtained from patient brain biopsies were flash-frozen and validated histologically. These formalin-free tissue samples were then analyzed using GC-TOF. The metabolite profiles of radiation necrosis and tumor samples were compared using multivariate and univariate statistical analysis. Statistical significance was defined as p ≤ 0.05. RESULTS For the metabolic profiling, GC-TOF was performed on 7 samples of radiation necrosis and 7 samples of tumor. Of the 141 metabolites identified, 17 (12.1%) were found to be statistically significantly different between comparison groups. Of these metabolites, 6 were increased in tumor, and 11 were increased in radiation necrosis. An unsupervised hierarchical clustering analysis found that tumor had elevated levels of metabolites associated with energy metabolism, whereas radiation necrosis had elevated levels of metabolites that were fatty acids and antioxidants/cofactors. CONCLUSIONS To the authors' knowledge, this is the first tissue-based metabolomics study of radiation necrosis and tumor. Radiation necrosis and recurrent tumor following Gamma Knife radiosurgery for brain metastases have unique metabolite profiles that may be targeted in the future to develop noninvasive metabolic imaging techniques. PMID: 27885954 [PubMed - as supplied by publisher]

Urinary signature of pig carcasses with boar taint by liquid chromatography-high resolution mass spectrometry. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2016 Nov 25; Authors: Jacob CC, Dervilly-Pinel G, Deceuninck Y, Gicquiau A, Chevillon P, Bonneau M, Le Bizec B Abstract Boar taint is an offensive odor that can occur while cooking pork or pork products and is identified in some uncastrated male pigs that have reached puberty. It is widely held that boar taint is the result of the accumulation in back-fat of two malodorous compounds: androstenone and skatole. The purpose of the present study was to assess a mass spectrometry-based metabolomics strategy to investigate the metabolic profile of urine samples from pig carcasses presenting low (untainted) and high (tainted) levels of androstenone and skatole in back fat. Urine samples were analyzed by LC-ESI(+)-HRMS. Discrimination between tainted and untainted animals was observed by application of multivariate statistical analysis, which allowed to highlight candidate urinary biomarkers. These urinary metabolites were positively correlated to androstenone and skatole levels in back fat. Therefore, the present study suggested that the measurement of these urinary metabolites might provide information with regard to androstenone and skatole levels in live pigs. PMID: 27885948 [PubMed - as supplied by publisher]

Metabolomic Analysis of Campylobacter jejuni by Direct-Injection Electrospray Ionization Mass Spectrometry. Methods Mol Biol. 2017;1512:189-197 Authors: Howlett RM, Davey MP, Kelly DJ Abstract Direct-injection mass spectrometry (DIMS) is a means of rapidly obtaining metabolomic phenotype data in both prokaryotes and eukaryotes. Given our generally poor understanding of Campylobacter metabolism, the high-throughput and relatively simple sample preparation of DIMS has made this an attractive technique for metabolism-related studies and hypothesis generation, especially when attempting to analyze metabolic mutants with no clear phenotype. Here we describe a metabolomic fingerprinting approach with sampling and extraction methodologies optimized for direct-injection electrospray ionization mass spectrometry (ESI-MS), which we have used as a means of comparing wild-type and isogenic mutant strains of C. jejuni with various metabolic blocks. PMID: 27885608 [PubMed - in process]

Whole genome sequence analysis of serum amino acid levels. Genome Biol. 2016 Nov 24;17(1):237 Authors: Yu B, de Vries PS, Metcalf GA, Wang Z, Feofanova EV, Liu X, Muzny DM, Wagenknecht LE, Gibbs RA, Morrison AC, Boerwinkle E Abstract BACKGROUND: Blood levels of amino acids are important biomarkers of disease and are influenced by synthesis, protein degradation, and gene-environment interactions. Whole genome sequence analysis of amino acid levels may establish a paradigm for analyzing quantitative risk factors. RESULTS: In a discovery cohort of 1872 African Americans and a replication cohort of 1552 European Americans we sequenced exons and whole genomes and measured serum levels of 70 amino acids. Rare and low-frequency variants (minor allele frequency ≤5%) were analyzed by three types of aggregating motifs defined by gene exons, regulatory regions, or genome-wide sliding windows. Common variants (minor allele frequency >5%) were analyzed individually. Over all four analysis strategies, 14 gene-amino acid associations were identified and replicated. The 14 loci accounted for an average of 1.8% of the variance in amino acid levels, which ranged from 0.4 to 9.7%. Among the identified locus-amino acid pairs, four are novel and six have been reported to underlie known Mendelian conditions. These results suggest that there may be substantial genetic effects on amino acid levels in the general population that may underlie inborn errors of metabolism. We also identify a predicted promoter variant in AGA (the gene that encodes aspartylglucosaminidase) that is significantly associated with asparagine levels, with an effect that is independent of any observed coding variants. CONCLUSIONS: These data provide insights into genetic influences on circulating amino acid levels by integrating -omic technologies in a multi-ethnic population. The results also help establish a paradigm for whole genome sequence analysis of quantitative traits. PMID: 27884205 [PubMed - in process]

Recent applications of metabolomics to advance microbial biofuel production. Curr Opin Biotechnol. 2016 Nov 21;43:118-126 Authors: Martien JI, Amador-Noguez D Abstract Biofuel production from plant biomass is a promising source of renewable energy [1]. However, efficient biofuel production involves the complex task of engineering high-performance microorganisms, which requires detailed knowledge of metabolic function and regulation. This review highlights the potential of mass-spectrometry-based metabolomic analysis to guide rational engineering of biofuel-producing microbes. We discuss recent studies that apply knowledge gained from metabolomic analyses to increase the productivity of engineered pathways, characterize the metabolism of emerging biofuel producers, generate novel bioproducts, enable utilization of lignocellulosic feedstock, and improve the stress tolerance of biofuel producers. PMID: 27883952 [PubMed - as supplied by publisher]

Circulating adipocyte-derived exosomal MicroRNAs associated with decreased insulin resistance after gastric bypass. Obesity (Silver Spring). 2016 Nov 24;: Authors: Hubal MJ, Nadler EP, Ferrante SC, Barberio MD, Suh JH, Wang J, Dohm GL, Pories WJ, Mietus-Snyder M, Freishtat RJ Abstract OBJECTIVE: Exosomes from obese adipose contain dysregulated microRNAs linked to insulin signaling, as compared with lean controls, providing a direct connection between adiposity and insulin resistance. This study tested the hypotheses that gastric bypass surgery and its subsequent weight loss would normalize adipocyte-derived exosomal microRNAs associated with insulin signaling and the associated metabolome related to glucose homeostasis. METHODS: African American female subjects with obesity (N = 6; age: 38.5 ± 6.8 years; BMI: 51.2 ± 8.8 kg/m(2) ) were tested before and 1 year after surgery. Insulin resistance (HOMA), serum metabolomics, and global microRNA profiles of circulating adipocyte-derived exosomes were evaluated via ANCOVA and correlational analyses. RESULTS: One year postsurgery, patients showed decreased BMI (-18.6 ± 5.1 kg/m(2) ; P < 0.001), ameliorated insulin resistance (HOMA: 1.94 ± 0.6 presurgery, 0.49 ± 0.1 postsurgery; P < 0.001), and altered metabolites including branched chain amino acids (BCAA). Biological pathway analysis of predicted mRNA targets of 168 surgery-responsive microRNAs (P < 0.05) identified the insulin signaling pathway (P = 1.27E-10; 52/138 elements), among others, in the data set. The insulin signaling pathway was also a target of 10 microRNAs correlated to changes in HOMA (P < 0.05; r > 0.4), and 48 microRNAs correlated to changes in BCAA levels. CONCLUSIONS: These data indicate that circulating adipocyte-derived exosomes are modified following gastric bypass surgery and correlate to improved postsurgery insulin resistance. PMID: 27883272 [PubMed - as supplied by publisher]

Effects of MeJA on Arabidopsis metabolome under endogenous JA deficiency. Sci Rep. 2016 Nov 24;6:37674 Authors: Cao J, Li M, Chen J, Liu P, Li Z Abstract Jasmonates (JAs) play important roles in plant growth, development and defense. Comprehensive metabolomics profiling of plants under JA treatment provides insights into the interaction and regulation network of plant hormones. Here we applied high resolution mass spectrometry based metabolomics approach on Arabidopsis wild type and JA synthesis deficiency mutant opr3. The effects of exogenous MeJA treatment on the metabolites of opr3 were investigated. More than 10000 ion signals were detected and more than 2000 signals showed significant variation in different genotypes and treatment groups. Multivariate statistic analyses (PCA and PLS-DA) were performed and a differential compound library containing 174 metabolites with high resolution precursor ion-product ions pairs was obtained. Classification and pathway analysis of 109 identified compounds in this library showed that glucosinolates and tryptophan metabolism, amino acids and small peptides metabolism, lipid metabolism, especially fatty acyls metabolism, were impacted by endogenous JA deficiency and exogenous MeJA treatment. These results were further verified by quantitative reverse transcription PCR (RT-qPCR) analysis of 21 related genes involved in the metabolism of glucosinolates, tryptophan and α-linolenic acid pathways. The results would greatly enhance our understanding of the biological functions of JA. PMID: 27883040 [PubMed - in process]

The mevalonate pathway regulates primitive streak formation via protein farnesylation. Sci Rep. 2016 Nov 24;6:37697 Authors: Okamoto-Uchida Y, Yu R, Miyamura N, Arima N, Ishigami-Yuasa M, Kagechika H, Yoshida S, Hosoya T, Nawa M, Kasama T, Asaoka Y, Alois RW, Elling U, Penninger JM, Nishina S, Azuma N, Nishina H Abstract The primitive streak in peri-implantation embryos forms the mesoderm and endoderm and controls cell differentiation. The metabolic cues regulating primitive streak formation remain largely unknown. Here we utilised a mouse embryonic stem (ES) cell differentiation system and a library of well-characterised drugs to identify these metabolic factors. We found that statins, which inhibit the mevalonate metabolic pathway, suppressed primitive streak formation in vitro and in vivo. Using metabolomics and pharmacologic approaches we identified the downstream signalling pathway of mevalonate and revealed that primitive streak formation requires protein farnesylation but not cholesterol synthesis. A tagging-via-substrate approach revealed that nuclear lamin B1 and small G proteins were farnesylated in embryoid bodies and important for primitive streak gene expression. In conclusion, protein farnesylation driven by the mevalonate pathway is a metabolic cue essential for primitive streak formation. PMID: 27883036 [PubMed - in process]

Plasma Metabolomics Implicate Modified Transfer RNAs and Altered Bioenergetics in the Outcome of Pulmonary Arterial Hypertension. Circulation. 2016 Nov 21;: Authors: Rhodes CJ, Ghataorhe P, Wharton J, Rue-Albrecht KC, Hadinnapola C, Watson G, Bleda M, Haimel M, Coghlan G, Corris PA, Howard LS, Kiely DG, Peacock AJ, Pepke-Zaba J, Toshner M, Wort SJ, Gibbs JS, Lawrie A, Gräf S, Morrell NW, Wilkins MR Abstract BACKGROUND: -Pulmonary arterial hypertension (PAH) is a heterogeneous disorder with high mortality. METHODS: -We conducted a comprehensive study of plasma metabolites using ultra-performance liquid chromatography mass-spectrometry to (1) identify patients at high risk of early death, (2) identify patients who respond well to treatment and (3) provide novel molecular insights into disease pathogenesis. RESULTS: -53 circulating metabolites distinguished well-phenotyped patients with idiopathic or heritable PAH (n=365) from healthy controls (n=121) following correction for multiple testing (p<7.3e-5) and confounding factors, including drug therapy, renal and hepatic impairment. A subset of 20/53 metabolites also discriminated PAH patients from disease controls (symptomatic patients without pulmonary hypertension, n=139). 62 metabolites were prognostic in PAH, with 36/62 independent of established prognostic markers. Increased levels of tRNA-specific modified nucleosides (N2,N2-dimethylguanosine, N1-methylinosine), TCA cycle intermediates (malate, fumarate), glutamate, fatty acid acylcarnitines, tryptophan and polyamine metabolites and decreased levels of steroids, sphingomyelins and phosphatidylcholines distinguished patients from controls. The largest differences correlated with increased risk of death and correction of several metabolites over time was associated with a better outcome. Patients who responded to calcium channel blocker therapy had metabolic profiles similar to healthy controls. CONCLUSIONS: -Metabolic profiles in PAH are strongly related to survival and should be considered part of the deep phenotypic characterisation of this disease. Our results support the investigation of targeted therapeutic strategies that seek to address the alterations in translational regulation and energy metabolism that characterize these patients. PMID: 27881557 [PubMed - as supplied by publisher]

Genome, transcriptome and proteome: the rise of omics data and their integration in biomedical sciences. Brief Bioinform. 2016 Nov 22;: Authors: Manzoni C, Kia DA, Vandrovcova J, Hardy J, Wood NW, Lewis PA, Ferrari R Abstract Advances in the technologies and informatics used to generate and process large biological data sets (omics data) are promoting a critical shift in the study of biomedical sciences. While genomics, transcriptomics and proteinomics, coupled with bioinformatics and biostatistics, are gaining momentum, they are still, for the most part, assessed individually with distinct approaches generating monothematic rather than integrated knowledge. As other areas of biomedical sciences, including metabolomics, epigenomics and pharmacogenomics, are moving towards the omics scale, we are witnessing the rise of inter-disciplinary data integration strategies to support a better understanding of biological systems and eventually the development of successful precision medicine. This review cuts across the boundaries between genomics, transcriptomics and proteomics, summarizing how omics data are generated, analysed and shared, and provides an overview of the current strengths and weaknesses of this global approach. This work intends to target students and researchers seeking knowledge outside of their field of expertise and fosters a leap from the reductionist to the global-integrative analytical approach in research. PMID: 27881428 [PubMed - as supplied by publisher]

A novel glucagon-like peptide 1/glucagon receptor dual agonist improves steatohepatitis and liver regeneration in mice. Hepatology. 2016 Nov 23;: Authors: Valdecantos MP, Pardo V, Ruiz L, Castro-Sánchez L, Lanzón B, Fernández-Millán E, García-Monzón C, Arroba AI, González-Rodríguez Á, Escrivá F, Carmen Á, Rupérez FJ, Barbas C, Konkar A, Naylor J, Hornigold D, Dos Santos A, Bednarek M, Grimsby J, Rondinone CM, Valverde ÁM Abstract BACKGROUND AND AIMS: Since non-alcoholic steatohepatitis (NASH) is associated with impaired liver regeneration, we investigated the effects of G49, a dual glucagon-like peptide-1(GLP-1)/glucagon (GCG) receptor agonist, on NASH and hepatic regeneration. METHODS: C57Bl/6 mice fed chow or methionine and choline-deficient (MCD) diet for one week were divided into 4 groups: C (chow diet), MCD (MCD diet), C+G49 (chow diet plus G49) and M+G49 (MCD diet plus G49). Mice fed high fat diet (HFD) for 10 weeks were divided in groups: HFD and H+G49 (HFD plus G49). Following 2 (MCD groups) or 3 (HFD groups) weeks of treatment with G49, partial hepatectomy (PH) was performed and all mice were maintained on the same treatment schedule for 2 additional weeks. Analysis of liver function, hepatic regeneration and comprehensive genomic and metabolic profiling was conducted. RESULTS: NASH was ameliorated in M+G49 group manifested by reduced inflammation, steatosis, oxidative stress, apoptosis and increased mitochondrial biogenesis. G49 treatment was also associated with replenishment of intrahepatic glucose due to enhanced gluconeogenesis and reduced glucose utilization via pentose phosphate cycle (PPC) and oxidative metabolism. Following PH, G49 treatment increased survival, restored cytokine-mediated priming phase and enhanced proliferative capacity and hepatic regeneration ratio in mice on MCD diet. NASH markers remained decreased in M+G49 mice after PH and glucose utilization was shifted to PPC and oxidative metabolism. G49 administered immediately after PH was also effective in alleviating the pathological changes induced by the MCD diet. Benefits on liver regeneration were also found in mice fed HFD and treated with G49. CONCLUSION: Dual acting GLP-1R/GCGR agonists such as G49 represent a novel therapeutic approach for patients with NASH and particularly in those requiring PH. This article is protected by copyright. All rights reserved. PMID: 27880981 [PubMed - as supplied by publisher]

Potential Antidepressant and Resilience Mechanism Revealed by Metabolomic Study on Peripheral Blood Mononuclear Cells of Stress Resilient Rats. Behav Brain Res. 2016 Nov 20;: Authors: Li J, Zhang SX, Wang W, Cheng K, Guo H, Rao CL, Yang DY, He Y, Zou DZ, Han Y, Zhao LB, Li PF, Xie P Abstract Resilience is an active coping response to stress, which plays a very important role in major depressive disorder study. The molecular mechanisms underlying such resilience are poorly understood. Peripheral blood mononuclear cells (PBMCs) were promising objects in unveiling the underlying pathogenesis of resilience. Hereby we carried out successive study on PBMCs metabolomics in resilient rats of chronic unpredictable mild stress (CUMS) model. A gas chromatography-mass spectrometry (GC-MS) metabolomic approach coupled with principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis (OPLS-DA) was used to detect differential metabolites in PBMCs of resilient rats. Ingenuity Pathways Analysis (IPA) was applied for pathway analysis. A set of differential metabolites including Malic acid, Ornithine, L-Lysine, Stigmasterol, Oleic acid, γ-Tocopherol, Adenosine and N-Acetyl-D-glucosamine were significantly altered in resilient rats, meanwhile promoting antidepressant research. As revealed by IPA that aberrant energy metabolism, HIFα signaling, neurotransmitter, O-GlcNAcylation and cAMP signaling cascade in peripheral might be evolved in the pathogenesis of coping mechanism. The GC-MS based metabolomics may contribute to better understanding of resilience, as well as shedding light on antidepressant discovery. PMID: 27880890 [PubMed - as supplied by publisher]

Multi-omics analysis of serum samples demonstrates reprogramming of organ functions via systemic calcium mobilization and platelet activation in metastatic melanoma. Mol Cell Proteomics. 2016 Nov 22;: Authors: Muqaku B, Eisninger M, Meier SM, Tahir A, Prokop T, Haferkamp S, Slany A, Reichle A, Gerner C Abstract Pathophysiologies of cancer-associated syndroms such as cachexia are poorly understood and no routine biomarkers have been established, yet. Using shotgun proteomics, known marker molecules including PMEL, CRP, SAA and CSPG4 were found deregulated in patients with metastatic melanoma. Targeted analysis of 58 selected proteins with multiple reaction monitoring was applied for independent data verification. In three patients, two of which suffered from cachexia, a tissue damage signature was determined, consisting of nine proteins, PLTP, CD14, TIMP1, S10A8, S10A9, GP1BA, PTPRJ, CD44 and C4A, as well as increased levels of glycine and asparagine, and decreased levels of polyunsaturated phosphatidylcholine concentrations, as determined by targeted metabolomics. Remarkably, these molecules are known to be involved in key processes of cancer cachexia. Based on these results, we propose a model how metastatic melanoma may lead to reprogramming of organ functions via formation of platelet activating factors from long-chain polyunsaturated phosphatidylcholines under oxidative conditions and via systemic induction of intracellular calcium mobilization. Calcium mobilization in platelets was demonstrated to alterate levels of several of these marker molecules. Additionally, platelets from melanoma patients proved to be in a rather exhausted state, and platelet-derived eicosanoids implicated in tumor growth were found massively increased in blood from three melanoma patients. Platelets were thus identified as important source of serum protein and lipid alterations in late stage melanoma patients. As a result, the proposed model describes the crosstalk between lipolysis of fat tissue and muscle wasting mediated by oxidative stress, resulting in the metabolic deregulations characteristic for cachexia. PMID: 27879288 [PubMed - as supplied by publisher]

Metabolomics Reveals that Momordica charantia Attenuates Metabolic Changes in Experimental Obesity. Phytother Res. 2016 Nov 23;: Authors: Gong ZG, Zhang J, Xu YJ Abstract Momordica charantia L., also known as bitter melon, has been shown to ameliorate obesity and insulin resistance. However, metabolic changes regulated by M. charantia in obesity are not clearly understood. In this study, serums obtained from obese and M. charantia-treated mice were analyzed by using gas and liquid chromatography-mass spectrometry, and multivariate statistical analysis was performed by Orthogonal partial least squares discriminant analysis. The results from this study indicated that body weight fat and insulin levels of obese mice are dramatically suppressed by 8 weeks of dietary supplementation of M. charantia. Metabolomic data revealed that overproductions of energy and nutrient metabolism in obese mice were restored by M. charantia treatment. The antiinflammatory and inhibition of insulin resistance effect of M. charantia in obesity was illustrated with the restoration of free fatty acids and eicosanoids. The findings achieved in this study further strengthen the therapeutic value of using M. charantia to treat obesity. Copyright © 2016 John Wiley & Sons, Ltd. PMID: 27878888 [PubMed - as supplied by publisher]

Metabolomics of Head and Neck Cancer: A Mini-Review. Front Physiol. 2016;7:526 Authors: Shin JM, Kamarajan P, Fenno JC, Rickard AH, Kapila YL Abstract Metabolomics is used in systems biology to enhance the understanding of complex disease processes, such as cancer. Head and neck cancer (HNC) is an epithelial malignancy that arises in the upper aerodigestive tract and affects more than half a million people worldwide each year. Recently, significant effort has focused on integrating multiple "omics" technologies for oncological research. In particular, research has been focused on identifying tumor-specific metabolite profiles using different sample types (biological fluids, cells and tissues) and a variety of metabolomic platforms and technologies. With our current understanding of molecular abnormalities of HNC, the addition of metabolomic studies will enhance our knowledge of the pathogenesis of this disease and potentially aid in the development of novel strategies to prevent and treat HNC. In this review, we summarize the proposed hypotheses and conclusions from publications that reported findings on the metabolomics of HNC. In addition, we address the potential influence of host-microbe metabolomics in cancer. From a systems biology perspective, the integrative use of genomics, transcriptomics and proteomics will be extremely important for future translational metabolomic-based research discoveries. PMID: 27877135 [PubMed - in process]

mTORC1 is Required for Brown Adipose Tissue Recruitment and Metabolic Adaptation to Cold. Sci Rep. 2016 Nov 23;6:37223 Authors: Labbé SM, Mouchiroud M, Caron A, Secco B, Freinkman E, Lamoureux G, Gélinas Y, Lecomte R, Bossé Y, Chimin P, Festuccia WT, Richard D, Laplante M Abstract In response to cold, brown adipose tissue (BAT) increases its metabolic rate and expands its mass to produce heat required for survival, a process known as BAT recruitment. The mechanistic target of rapamycin complex 1 (mTORC1) controls metabolism, cell growth and proliferation, but its role in regulating BAT recruitment in response to chronic cold stimulation is unknown. Here, we show that cold activates mTORC1 in BAT, an effect that depends on the sympathetic nervous system. Adipocyte-specific mTORC1 loss in mice completely blocks cold-induced BAT expansion and severely impairs mitochondrial biogenesis. Accordingly, mTORC1 loss reduces oxygen consumption and causes a severe defect in BAT oxidative metabolism upon cold exposure. Using in vivo metabolic imaging, metabolomics and transcriptomics, we show that mTORC1 deletion impairs glucose and lipid oxidation, an effect linked to a defect in tricarboxylic acid (TCA) cycle activity. These analyses also reveal a severe defect in nucleotide synthesis in the absence of mTORC1. Overall, these findings demonstrate an essential role for mTORC1 in the regulation of BAT recruitment and metabolism in response to cold. PMID: 27876792 [PubMed - in process]

Microbial, metabolomic, and immunologic dynamics in a relapsing genetic mouse model of colitis induced by T-synthase deficiency. Gut Microbes. 2016 Nov 22;:0 Authors: Jacobs JP, Lin L, Goudarzi M, Ruegger P, McGovern DP, Fornace AJ, Borneman J, Xia L, Braun J Abstract Intestinal dysbiosis is thought to confer susceptibility to inflammatory bowel disease (IBD), but it is unknown whether dynamic changes in the microbiome contribute to fluctuations in disease activity. We explored this question using mice with intestine-specific deletion of C1galt1 (also known as T-synthase) (Tsyn mice). These mice develop spontaneous microbiota-dependent colitis with a remitting/relapsing course due to loss of mucin core-1 derived O-glycans. 16S rRNA sequencing and untargeted metabolomics demonstrated age-specific perturbations in the intestinal microbiome and metabolome of Tsyn mice compared to littermate controls at weeks 3 (disease onset), 5 (during remission), and 9 (after relapse). Colitis remission corresponded to increased levels of FoxP3+RORγt+CD4+ T cells in the colonic lamina propria that were positively correlated with operational taxonomic units (OTUs) in the S24-7 family and negatively correlated with OTUs in the Clostridiales order. Relapse was characterized by marked expansion of FoxP3-RORγt+CD4+ T cells expressing IFNγ and IL17A, which were associated with Clostridiales OTUs distinct from those negatively correlated with FoxP3+RORγt+CD4+ T cells. Our findings suggest that colitis remission and relapse in the Tsyn model may reflect alterations in the microbiome due to reduced core-1 O-glycosylation that shift the balance of regulatory and pro-inflammatory T cell subsets. We investigated whether genetic variation in C1galt1 correlated with the microbiome in a cohort of 78 Crohn's disease patients and 101 healthy controls. Polymorphisms near C1galt1 (rs10486157) and its molecular chaperone, Cosmc (rs4825729), were associated with altered composition of the colonic mucosal microbiota, supporting the relevance of core-1 O-glycosylation to host regulation of the microbiome. PMID: 27874308 [PubMed - as supplied by publisher]

High-throughput ultra high performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry method for the rapid analysis and characterization of multiple constituents of radix polygalae. J Sep Sci. 2016 Nov 22;: Authors: Liu C, Zhang A, Yan GL, Shi H, Sun H, Han Y, Zhou Y, Wang X Abstract Radix polygalae, the dried roots of Polygala tenuifolia and P. sibirica, is one of the most well-known traditional Chinese medicinal plants. It is an important medicinal plant that has been used as a sedative and to improve memory for a number of years in most of Asia. However, the in vivo constituents of the multiple constituents from Radix Polygalae remain unknown. In the current study, ultra high performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry and the MarkerLynx(TM) software combined with multiple data processing approach were used to study the constituents in vitro and in vivo. A rapid and efficient method for the characterization of multiple constituents in the herb medicine Radix Polygalae by ultra high performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry is described. In total, 35 compounds in the Radix Polygalae and 13 compounds absorbed into blood were characterized. Of the 35 compounds in vitro, ten were reported for first time. In the 13 compounds in vivo, six were prototype components and seven were metabolites were also elucidated for first time. This work narrowed the range of screening the potentially bioactive components and provided a basis for the quality control and mechanism of action. This article is protected by copyright. All rights reserved. PMID: 27874254 [PubMed - as supplied by publisher]

Related Articles Prognostic Metabolite Biomarkers for Soft Tissue Sarcomas Discovered by Mass Spectrometry Imaging. J Am Soc Mass Spectrom. 2016 Nov 21; Authors: Lou S, Balluff B, Cleven AH, Bovée JV, McDonnell LA Abstract Metabolites can be an important read-out of disease. The identification and validation of biomarkers in the cancer metabolome that can stratify high-risk patients is one of the main current research aspects. Mass spectrometry has become the technique of choice for metabolomics studies, and mass spectrometry imaging (MSI) enables their visualization in patient tissues. In this study, we used MSI to identify prognostic metabolite biomarkers in high grade sarcomas; 33 high grade sarcoma patients, comprising osteosarcoma, leiomyosarcoma, myxofibrosarcoma, and undifferentiated pleomorphic sarcoma were analyzed. Metabolite MSI data were obtained from sections of fresh frozen tissue specimens with matrix-assisted laser/desorption ionization (MALDI) MSI in negative polarity using 9-aminoarcridine as matrix. Subsequent annotation of tumor regions by expert pathologists resulted in tumor-specific metabolite signatures, which were then tested for association with patient survival. Metabolite signals with significant clinical value were further validated and identified by high mass resolution Fourier transform ion cyclotron resonance (FTICR) MSI. Three metabolite signals were found to correlate with overall survival (m/z 180.9436 and 241.0118) and metastasis-free survival (m/z 160.8417). FTICR-MSI identified m/z 241.0118 as inositol cyclic phosphate and m/z 160.8417 as carnitine. Graphical Abstract ᅟ. PMID: 27873216 [PubMed - as supplied by publisher]

Related Articles Untargeted polar metabolomics of transformed MDA-MB-231 breast cancer cells expressing varying levels of human arylamine N-acetyltransferase 1. Metabolomics. 2016 Jul;12(7): Authors: Carlisle SM, Trainor PJ, Yin X, Doll MA, Stepp MW, States JC, Zhang X, Hein DW Abstract INTRODUCTION: Human arylamine N-acetyltransferase 1 (NAT1) is a phase II xenobiotic metabolizing enzyme found in almost all tissues. Expression of NAT1 is elevated in several cancers including breast cancer. However, the exact mechanism by which NAT1 expression affects cancer risk and progression remains unclear. OBJECTIVE: This study explored polar metabolome differences between MDA-MB-231 breast cancer cells expressing varying levels of NAT1 activity using an untargeted approach. METHODS: Three MDA-MB-231 breast adenocarcinoma cell lines that stably express wild-type, increased, and decreased levels of human NAT1 were investigated for differences in polar metabolic profile using a comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry (GC×GC-TOF MS) system. RESULTS: Increased levels of human NAT1 in the transformed cell lines resulted in a statistically significant decreased abundance of the metabolite palmitoleic acid (q = 0.0006), when compared to normal and decreased levels of human NAT1. The fatty acid synthesis pathway utilizes acetyl coenzyme A (acetyl-CoA) in the first two reactions of the pathway and eventually leads to the synthesis of palmitoleic acid. CONCLUSION: These data suggest a link between increased levels of NAT1 activity and decreased flux of acetyl-CoA through this portion of the fatty acid synthesis pathway. PMID: 27872580 [PubMed - in process]