Integrative Molecular Phenotyping
INTEGRATIVE MOLECULAR
PHENOTYPING
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

PubMed

PubMed
NCBI: db=pubmed; Term=metabolomics
Updated: 57 min 32 sec ago

Bile acid metabolites in early pregnancy and risk of gestational diabetes in Chinese women: A nested case-control study.

Sun, 19/08/2018 - 14:00
Related Articles Bile acid metabolites in early pregnancy and risk of gestational diabetes in Chinese women: A nested case-control study. EBioMedicine. 2018 Aug 14;: Authors: Li J, Huo X, Cao YF, Li SN, Du Z, Shao P, Leng J, Zhang C, Sun XY, Ma RCW, Fang ZZ, XilinYang Abstract BACKGROUND: Bile acid metabolism plays an important role in metabolism but it is uncertain whether bile acid metabolites in early pregnancy are associated with risk of gestational diabetes mellitus (GDM). METHODS: We organized a 1:1 case-control study nested in a prospective cohort of 22,302 pregnant women recruited from 2010 to 2012 in China: 243 women with GDM were matched with 243 non-GDM controls on age (±1 year). Conditional logistic regression and restricted cubic spline were used to examine full-range associations of bile acid metabolites with GDM. FINDINGS: All the 9 detectable bile acids were inversely associated with the risk of GDM, among them, 8 in nonlinear and one in largely linear manners in multivariable analysis. Glycoursodeoxycholic acid (GUDCA) at ≤0.07 nmol/mL and deoxycholic acid (DCA) at ≤0.28 nmol/mL had threshold effects and their decreasing levels below the cutoff points were associated with rapid rises in the risk of GDM. In traditional risk factor model, the stepwise procedure identified that GUDCA ≤ 0.07 nmol/mL and DCA ≤ 0.280 nmol/mL were still significant (OR: 6.84, 95%CI: 1.10-42.48 & 2.06, 1.26-3.37), while other bile acids were not. Inclusion of the two bile acids in the model increased the area under operating characteristic's curve from 0.69 to 0.76 (95% CI: 0.71-0.80) (P < .05). INTERPRETATION: Serum GUDCA ≤ 0.07 nmol/mL and DCA ≤ 0.28 nmol/mL in early pregnancy were independently associated with increased risk of GDM in Chinese pregnant women. FUNDING: Talent Recruitment Scheme grant of Tianjin Medical University and National Key Research and Development Program, etc. PMID: 30120081 [PubMed - as supplied by publisher]

Intestinal bitter taste receptor activation alters hormone secretion and imparts metabolic benefits.

Sun, 19/08/2018 - 14:00
Related Articles Intestinal bitter taste receptor activation alters hormone secretion and imparts metabolic benefits. Mol Metab. 2018 Aug 04;: Authors: Kok BP, Galmozzi A, Littlejohn NK, Albert V, Godio C, Kim W, Kim SM, Bland JS, Grayson N, Fang M, Meyerhof W, Siuzdak G, Srinivasan S, Behrens M, Saez E Abstract OBJECTIVES: Extracts of the hops plant have been shown to reduce weight and insulin resistance in rodents and humans, but elucidation of the mechanisms responsible for these benefits has been hindered by the use of heterogeneous hops-derived mixtures. Because hop extracts are used as flavoring agents for their bitter properties, we hypothesized that bitter taste receptors (Tas2rs) could be mediating their beneficial effects in metabolic disease. Studies have shown that exposure of cultured enteroendocrine cells to bitter tastants can stimulate release of hormones, including glucagon-like peptide 1 (GLP-1). These findings have led to the suggestion that activation of Tas2rs may be of benefit in diabetes, but this tenet has not been tested. Here, we have assessed the ability of a pure derivative of a hops isohumulone with anti-diabetic properties, KDT501, to signal through Tas2rs. We have further used this compound as a tool to systematically assess the impact of bitter taste receptor activation in obesity-diabetes. METHODS: KDT501 was tested in a panel of bitter taste receptor signaling assays. Diet-induced obese mice (DIO) were dosed orally with KDT501 and acute effects on glucose homeostasis determined. A wide range of metabolic parameters were evaluated in DIO mice chronically treated with KDT501 to establish the full impact of activating gut bitter taste signaling. RESULTS: We show that KDT501 signals through Tas2r108, one of 35 mouse Tas2rs. In DIO mice, acute treatment stimulated GLP-1 secretion and enhanced glucose tolerance. Chronic treatment caused weight and fat mass loss, increased energy expenditure, enhanced glucose tolerance and insulin sensitivity, normalized plasma lipids, and induced broad suppression of inflammatory markers. Chronic KDT501 treatment altered enteroendocrine hormone levels and bile acid homeostasis and stimulated sustained GLP-1 release. Combined treatment with a dipeptidyl peptidase IV inhibitor amplified the incretin-based benefits of this pure isohumulone. CONCLUSIONS: Activation of Tas2r108 in the gut results in a remodeling of enteroendocrine hormone release and bile acid metabolism that ameliorates multiple features of metabolic syndrome. Targeting extraoral bitter taste receptors may be useful in metabolic disease. PMID: 30120064 [PubMed - as supplied by publisher]

Transketolase like 1 (TKTL1) expression alterations in prostate cancer tumorigenesis.

Sun, 19/08/2018 - 14:00
Related Articles Transketolase like 1 (TKTL1) expression alterations in prostate cancer tumorigenesis. Urol Oncol. 2018 Aug 14;: Authors: da Costa IA, Hennenlotter J, Stühler V, Kühs U, Scharpf M, Todenhöfer T, Stenzl A, Bedke J Abstract BACKGROUND: Prostate cancer (CaP) is the most common nonepidermal cancer in elderly males. Due to its heterogeneity and high variability in regards to clinical outcome and therapeutic response, urologists' handling of this disease remains a challenge. The objective of this study was to assess Transketolase like 1 (TKTL1) expression in benign prostatic tissue, peritumoral tissue and in CaP (in different stages of disease), and its correlation with clinicopathological findings, in order to detect if TKTL1 expression is associated with CaP tumorigenesis. METHODS: In total, 100 tissue samples were included: (i) 22 benign specimens, (ii) 46 specimens with nonmetastatic CaP, and (iii) 32 specimens from patients with metastatic CaP. From the tissue microarray slides, we evaluated immunohistochemically the expression of the TKTL1 protein, using the H-score. RESULTS: The TKTL1 protein expression pattern ranges from a low level in benign prostatic tissue (100 [57.5-105]), moderately low in peritumoral tissue (135.42 [100-195.16]), moderate expression in nonmetastatic CaP (200 [172.19-254.38]) to high in metastatic CaP (300 [222.50-300]). A significant rise of TKTL1 mean expression was seen throughout disease progression. A significant difference was also found in TKTL1 expression between peritumoral tissue and benign tissue. CONCLUSION: The results obtained in this study suggest that pentose phosphate pathway and its key enzyme TKTL1 is altered throughout the CaP tumorigenesis, and this pathway merits further investigation. PMID: 30119993 [PubMed - as supplied by publisher]

A strategy for the metabolomics-based screening of active constituents and quality consistency control for natural medicinal substance toad venom.

Sun, 19/08/2018 - 14:00
Related Articles A strategy for the metabolomics-based screening of active constituents and quality consistency control for natural medicinal substance toad venom. Anal Chim Acta. 2018 Nov 15;1031:108-118 Authors: Ma H, Zhou J, Guo H, Shang E, Zhu Z, Kuzmanov U, Lv X, Di L, Yu B, Wu Q, Duan J Abstract Natural medicinal substances (NMS) have great inconsistency due to chemical variability, seriously limiting their development as therapeutics. Here, we chose toad venom with anti-tumor activities as a model and developed a pipeline of metabolomics-based screening and quality consistency control (MSQCC) as one potential solution to this long-standing problem. Our study firstly exemplified the power of the co-correlation screen of metabolomic and biological profiles of 180 fractions prepared from natural heterogeneous venom samples, to identify a series of bufadinolides as quality control markers for cancer cell inhibition. The next quantitative monitoring of these markers revealed great batch-to-batch variation of toad venoms. Finally, we developed a marker-based blending program (Markers-NMBT) to normalize heterogeneity of NMS. It created the blends for the conversion of the unqualified venoms with high variation in the contents of bufadienolides, into qualified products consistent with the reference. Thus, this work provides a strategy for rapid, large-scale discovery, quantification and application of quality control markers to ensure batch-to-batch consistency, and can be a crucial technology in the development of modern NMS preparations. PMID: 30119728 [PubMed - in process]

Online Liquid Chromatography - Sheath-Flow Surface Enhanced Raman Detection of Phosphorylated Carbohydrates.

Sun, 19/08/2018 - 14:00
Related Articles Online Liquid Chromatography - Sheath-Flow Surface Enhanced Raman Detection of Phosphorylated Carbohydrates. Anal Chem. 2018 Aug 17;: Authors: Nguyen AH, Deutsch JM, Xiao L, Schultz ZD Abstract Online detection and quantification of three phosphorylated carbohydrate molecules: glucose 1-phosphate, glucose 6-phosphate and fructose 6-phosphate, was achieved by coupling sheath-flow surface enhanced Raman spectroscopy (SERS) to liquid chromatography. The presence of an alkanethiol (hexanethiol) self-assembled monolayer adsorbed to a silver SERS-active substrate helps retain and concentrate the analytes of interest at the SERS substrate to improve the detection sensitivity significantly. Mixtures of 2 µM of phosphorylated carbohydrates in pure water as well as in cell culture media were successfully separated by HPLC, with identification using the sheath-flow SERS detector. The quantification of each analyte was achieved using partial least squares (PLS) regression analysis and acetonitrile in the mobile phases as an internal standard. These results illustrate the utility of sheath-flow SERS for molecular specific detection in complex biological samples appropriate for metabolomics and other applications. PMID: 30119606 [PubMed - as supplied by publisher]

metabolomics; +19 new citations

Sat, 18/08/2018 - 13:31
19 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2018/08/18PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

metabolomics; +17 new citations

Fri, 17/08/2018 - 16:14
17 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2018/08/17PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

metabolomics; +17 new citations

Fri, 17/08/2018 - 13:11
17 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2018/08/17PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Metabolic and immunological responses of male and female New Zealand Greenshell™ mussels (Perna canaliculus) infected with Vibrio sp.

Thu, 16/08/2018 - 12:42
Metabolic and immunological responses of male and female New Zealand Greenshell™ mussels (Perna canaliculus) infected with Vibrio sp. J Invertebr Pathol. 2018 Aug 12;: Authors: Nguyen TV, Alfaro AC, Merien F, Young T, Grandiosa R Abstract Massive mortalities due to pathogens are routinely reported in bivalve cultivation that have significant economic consequences for the global aquaculture industry. However, host-pathogen interactions and infection mechanisms that mediate these interactions are poorly understood. In addition, gender-specific immunological responses have been reported for some species, but the reasons for such differences have not been elucidated. In this study, we used a GC/MS-based metabolomics platform and flow cytometry approach to characterize metabolic and immunological responses in haemolymph of male and female mussels (Perna canaliculus) experimentally infected with Vibrio sp. Sex-based differences in immunological responses were identified, with male mussels displaying higher mortality, oxidative stress and apoptosis after pathogen exposure. However, central metabolic processes appeared to be similar between sexes at 24 h post injection with Vibrio sp. DO1. Significant alterations in relative levels of 37 metabolites were detected between infected and uninfected mussels. These metabolites are involved in major perturbations on the host's innate immune system. In addition, there were alterations of seven metabolites in profiles of mussels sampled on the second day and mussels that survived six days after exposure. These metabolites include itaconic acid, isoleucine, phenylalanine, creatinine, malonic acid, glutaric acid and hydroxyproline. Among these, itaconic acid has the potential to be an important biomarker for Vibrio sp. DO1 infection. These findings provide new insights on the mechanistic relationship between a bivalve host and a pathogenic bacterium and highlight the need to consider host sex as a biological variable in future immunological studies. PMID: 30110610 [PubMed - as supplied by publisher]

The fecal microbiome and metabolome differs between dogs fed Bones and Raw Food (BARF) diets and dogs fed commercial diets.

Thu, 16/08/2018 - 12:42
The fecal microbiome and metabolome differs between dogs fed Bones and Raw Food (BARF) diets and dogs fed commercial diets. PLoS One. 2018;13(8):e0201279 Authors: Schmidt M, Unterer S, Suchodolski JS, Honneffer JB, Guard BC, Lidbury JA, Steiner JM, Fritz J, Kölle P Abstract INTRODUCTION: Feeding a Bones and Raw Food (BARF) diet has become an increasing trend in canine nutrition. Bones and Raw Food diets contain a high amount of animal components like meat, offal, and raw meaty bones, combined with comparatively small amounts of plant ingredients like vegetables and fruits as well as different sorts of oil and supplements. While many studies have focused on transmission of pathogens via contaminated meat and on nutritional imbalances, only few studies have evaluated the effect of BARF diets on the fecal microbiome and metabolome. The aim of the study was to investigate differences in the fecal microbiome and the metabolome between dogs on a BARF diet and dogs on a commercial diet (canned and dry dog food). METHODS: Naturally passed fecal samples were obtained from 27 BARF and 19 commercially fed dogs. Differences in crude protein, fat, fiber, and NFE (Nitrogen-Free Extract) between diets were calculated with a scientific nutrient database. The fecal microbiota was analyzed by 16S rRNA gene sequencing and quantitative PCR assays. The fecal metabolome was analyzed in 10 BARF and 9 commercially fed dogs via untargeted metabolomics approach. RESULTS: Dogs in the BARF group were fed a significantly higher amount of protein and fat and significantly lower amount of NFE and fiber. There was no significant difference in alpha-diversity measures between diet groups. Analysis of similarity (ANOSIM) revealed a significant difference in beta-diversity (p < 0.01) between both groups. Linear discriminant analysis effect size (LefSe) showed a higher abundance of Lactobacillales, Enterobacteriaceae, Fusobacterium and, Clostridium in the BARF group while conventionally fed dogs had a higher abundance of Clostridiaceae, Erysipelotrichaceae, Ruminococcaceae, and Lachnospiraceae. The qPCR assays revealed significantly higher abundance of Escherichia coli (E. coli) and Clostridium (C.). perfringens and an increased Dysbiosis Index in the BARF group. Principal component analysis (PCA) plots of metabolomics data showed clustering between diet groups. Random forest analysis showed differences in the abundance of various components, including increased 4-hydroxybutryric acid (GBH) and 4-aminobutyric acid (GABA) in the BARF group. Based on univariate statistics, several metabolites were significantly different between diet groups, but lost significance after adjusting for multiple comparison. No differences were found in fecal bile acid concentrations, but the BARF group had a higher fecal concentration of cholesterol in their feces compared to conventionally fed dogs. CONCLUSION: Microbial communities and metabolome vary significantly between BARF and commercially fed dogs. PMID: 30110340 [PubMed - in process]

PHAB toxins: a unique family of predatory sea anemone toxins evolving via intra-gene concerted evolution defines a new peptide fold.

Thu, 16/08/2018 - 12:42
Related Articles PHAB toxins: a unique family of predatory sea anemone toxins evolving via intra-gene concerted evolution defines a new peptide fold. Cell Mol Life Sci. 2018 Aug 14;: Authors: Madio B, Peigneur S, Chin YKY, Hamilton BR, Henriques ST, Smith JJ, Cristofori-Armstrong B, Dekan Z, Boughton BA, Alewood PF, Tytgat J, King GF, Undheim EAB Abstract Sea anemone venoms have long been recognized as a rich source of peptides with interesting pharmacological and structural properties, but they still contain many uncharacterized bioactive compounds. Here we report the discovery, three-dimensional structure, activity, tissue localization, and putative function of a novel sea anemone peptide toxin that constitutes a new, sixth type of voltage-gated potassium channel (KV) toxin from sea anemones. Comprised of just 17 residues, κ-actitoxin-Ate1a (Ate1a) is the shortest sea anemone toxin reported to date, and it adopts a novel three-dimensional structure that we have named the Proline-Hinged Asymmetric β-hairpin (PHAB) fold. Mass spectrometry imaging and bioassays suggest that Ate1a serves a primarily predatory function by immobilising prey, and we show this is achieved through inhibition of Shaker-type KV channels. Ate1a is encoded as a multi-domain precursor protein that yields multiple identical mature peptides, which likely evolved by multiple domain duplication events in an actinioidean ancestor. Despite this ancient evolutionary history, the PHAB-encoding gene family exhibits remarkable sequence conservation in the mature peptide domains. We demonstrate that this conservation is likely due to intra-gene concerted evolution, which has to our knowledge not previously been reported for toxin genes. We propose that the concerted evolution of toxin domains provides a hitherto unrecognised way to circumvent the effects of the costly evolutionary arms race considered to drive toxin gene evolution by ensuring efficient secretion of ecologically important predatory toxins. PMID: 30109357 [PubMed - as supplied by publisher]

Increased glutamine anabolism sensitizes non-small cell lung cancer to gefitinib treatment.

Thu, 16/08/2018 - 12:42
Related Articles Increased glutamine anabolism sensitizes non-small cell lung cancer to gefitinib treatment. Cell Death Discov. 2018;5:24 Authors: Wang L, Peng W, Wu T, Deng P, Zhao YL Abstract To better understand the resistance mechanism of non-small cell lung cancers (NSCLCs) to gefitinib, the metabolic profiles of gefitinib-resistant A549 cells and gefitinib-sensitive PC-9 cells were analyzed with a metabolomics analytical platform. A549 and PC-9 cells exhibited significant differences in the levels of glutamine-related metabolites. After gefitinib treatment, the glutamine level decreased in A549 cells but showed no change in PC-9 cells. The glutamine consumed by A549 cells was used to generate ATP and glutathione (GSH). As glutamine utilization was suppressed in gefitinib-treated PC-9 cells, the resulting ATP shortage and ROS accumulation led to cell death. The difference in glutamine metabolism was caused by differential changes in the levels of glutamine synthetase (GS, encoded by glutamate-ammonia ligase (GLUL)). GLUL expression was upregulated in gefitinib-sensitive cells, but it was either absent from gefitinib-resistant cells or no significant change was observed in the gefitinib-treated cells. GLUL overexpression in A549 cells significant sensitized them to gefitinib and decreased their invasive capacity. Conversely, knockout GS in PC-9 cells reduced gefitinib sensitivity and enhanced metastasis. Furthermore, the continuous exposure of gefitinib-sensitive HCC827 cells to gefitinib created gefitinib-resistant (GR) HCC827 cells, which exhibited a GLUL deletion and resistance to gefitinib. Thus, GLUL plays a vital role in determining the sensitivity of NSCLCs to gefitinib. Elevated GS levels mediate increased glutamine anabolism, and this novel mechanism sensitizes NSCLCs to gefitinib. The inhibition of glutamine utilization may serve as a potential therapeutic strategy to overcome gefitinib resistance in the clinic. PMID: 30109143 [PubMed]

Best practice data life cycle approaches for the life sciences.

Thu, 16/08/2018 - 12:42
Related Articles Best practice data life cycle approaches for the life sciences. F1000Res. 2017;6:1618 Authors: Griffin PC, Khadake J, LeMay KS, Lewis SE, Orchard S, Pask A, Pope B, Roessner U, Russell K, Seemann T, Treloar A, Tyagi S, Christiansen JH, Dayalan S, Gladman S, Hangartner SB, Hayden HL, Ho WWH, Keeble-Gagnère G, Korhonen PK, Neish P, Prestes PR, Richardson MF, Watson-Haigh NS, Wyres KL, Young ND, Schneider MV Abstract Throughout history, the life sciences have been revolutionised by technological advances; in our era this is manifested by advances in instrumentation for data generation, and consequently researchers now routinely handle large amounts of heterogeneous data in digital formats. The simultaneous transitions towards biology as a data science and towards a 'life cycle' view of research data pose new challenges. Researchers face a bewildering landscape of data management requirements, recommendations and regulations, without necessarily being able to access data management training or possessing a clear understanding of practical approaches that can assist in data management in their particular research domain. Here we provide an overview of best practice data life cycle approaches for researchers in the life sciences/bioinformatics space with a particular focus on 'omics' datasets and computer-based data processing and analysis. We discuss the different stages of the data life cycle and provide practical suggestions for useful tools and resources to improve data management practices. PMID: 30109017 [PubMed - in process]

Gingerol suppresses sepsis-induced acute kidney injury by modulating methylsulfonylmethane and dimethylamine production.

Thu, 16/08/2018 - 12:42
Related Articles Gingerol suppresses sepsis-induced acute kidney injury by modulating methylsulfonylmethane and dimethylamine production. Sci Rep. 2018 Aug 14;8(1):12154 Authors: Rodrigues FAP, Santos ADDC, de Medeiros PHQS, Prata MMG, Santos TCS, da Silva JA, Brito GAC, Dos Santos AA, Silveira ER, Lima AÂM, Havt A Abstract Acute kidney injury (AKI) and metabolic dysfunction are critical complications in sepsis syndrome; however, their pathophysiological mechanisms remain poorly understood. Therefore, we evaluated whether the pharmacological properties of 6-gingerol (6G) and 10-gingerol (10G) could modulate AKI and metabolic disruption in a rat model of sepsis (faecal peritonitis). Animals from the sham and AKI groups were intraperitoneally injected with 6G or 10G (25 mg/kg). Septic AKI decreased creatinine clearance and renal antioxidant activity, but enhanced oxidative stress and the renal mRNA levels of tumour necrosis factor-α, interleukin-1β, and transforming growth factor-β. Both phenol compounds repaired kidney function through antioxidant activity related to decreased oxidative/nitrosative stress and proinflammatory cytokines. Metabolomics analysis indicated different metabolic profiles for the sham surgery group, caecal ligation and puncture model alone group, and sepsis groups treated with gingerols. 1H nuclear magnetic resonance analysis detected important increases in urinary creatine, allantoin, and dimethylglycine levels in septic rats. However, dimethylamine and methylsulfonylmethane metabolites were more frequently detected in septic animals treated with 6G or 10G, and were associated with increased survival of septic animals. Gingerols attenuated septic AKI by decreasing renal disturbances, oxidative stress, and inflammatory response through a mechanism possibly correlated with increased production of dimethylamine and methylsulfonylmethane. PMID: 30108263 [PubMed - in process]

Natural genetic variation in C. elegans identified genomic loci controlling metabolite levels.

Thu, 16/08/2018 - 12:42
Related Articles Natural genetic variation in C. elegans identified genomic loci controlling metabolite levels. Genome Res. 2018 Aug 14;: Authors: Gao AW, Sterken MG, Uit de Bos J, van Creij J, Kamble R, Snoek BL, Kammenga JE, Houtkooper RH Abstract Metabolic homeostasis is sustained by complex biological networks that respond to nutrient availability. Genetic and environmental factors may disrupt this equilibrium, leading to metabolic disorders, including obesity and type 2 diabetes. To identify the genetic factors controlling metabolism, we performed quantitative genetic analysis using a population of 199 recombinant inbred lines (RILs) in the nematode Caenorhabditis elegans We focused on the genomic regions that control metabolite levels by measuring fatty acid (FA) and amino acid (AA) composition in the RILs using targeted metabolomics. The genetically diverse RILs showed a large variation in their FA and AA levels with a heritability ranging from 32% to 82%. We detected strongly co-correlated metabolite clusters and 36 significant metabolite QTL (mQTL). We focused on mQTL displaying highly significant linkage and heritability, including an mQTL for the FA C14:1 on Chromosome I, and another mQTL for the FA C18:2 on Chromosome IV. Using introgression lines (ILs), we were able to narrow down both mQTL to a 1.4-Mbp and a 3.6-Mbp region, respectively. RNAi-based screening focusing on the Chromosome I mQTL identified several candidate genes for the C14:1 mQTL, including lagr-1, Y87G2A.2, nhr-265, nhr-276, and nhr-81 Overall, this systems approach provides us with a powerful platform to study the genetic basis of C. elegans metabolism. Furthermore, it allows us to investigate interventions such as nutrients and stresses that maintain or disturb the regulatory network controlling metabolic homeostasis, and identify gene-by-environment interactions. PMID: 30108180 [PubMed - as supplied by publisher]

Biochemical and Epigenetic Insights into L-2-Hydroxyglutarate, a Potential Therapeutic Target in Renal Cancer.

Thu, 16/08/2018 - 12:42
Related Articles Biochemical and Epigenetic Insights into L-2-Hydroxyglutarate, a Potential Therapeutic Target in Renal Cancer. Clin Cancer Res. 2018 Aug 14;: Authors: Shelar S, Shim EH, Brinkley G, Kundu A, Carobbio F, Poston T, Tan J, Parekh V, Benson D, Crossman DK, Buckhaults PJ, Rakheja D, Kirkman R, Sato Y, Ogawa S, Dutta S, Velu SE, Emberley E, Pan A, Chen J, Huang T, Absher D, Becker A, Kunick C, Sudarshan S Abstract PURPOSE: Elevation of L-2-hydroxylgutarate (L-2-HG) in renal cell carcinoma (RCC) is due in part to reduced expression of L-2-HG dehydrogenase (L2HGDH). However, the contribution of L-2-HG to renal carcinogenesis and insight into the biochemistry and targets of this small molecule remains to be elucidated. EXPERIMENTAL DESIGN: Genetic and pharmacologic approaches to modulate L-2-HG levels were assessed for effects onin vitro and in vivophenotypes. Metabolomics was used to dissect the biochemical mechanisms that promote L-2-HG accumulation in RCC cells. Transcriptomic analysis was utilized to identify relevant targets of L-2-HG. Finally, bioinformatic and metabolomic analyses were used to assess the L-2-HG/L2HGDH axis as a function of patient outcome and cancer progression. RESULTS: L2HGDH suppresses both in vitrocell migration and in vivotumor growth and these effects are mediated by L2HGDH's catalytic activity. Biochemical studies indicate that glutamine is the predominant carbon source for L-2-HG via the activity of malate dehydrogenase 2 (MDH2). Inhibition of the glutamine-MDH2 axis suppresses in vitrophenotypes in a L-2-HG dependent manner. Moreover, in vivogrowth of RCC cells with basal elevation of L-2-HG is suppressed by glutaminase inhibition. Transcriptomic and functional analyses demonstrate that the histone demethylase KDM6A is a target of L-2-HG in RCC. Finally, increased L-2-HG levels, L2HGDHcopy loss, and lower L2HGDH expression are associated with tumor progression and/or worsened prognosis in RCC patients. CONCLUSIONS: Collectively, our studies provide biochemical and mechanistic insight into the biology of this small molecule and provide new opportunities for treating L-2-HG driven kidney cancers. PMID: 30108105 [PubMed - as supplied by publisher]

Characterizing the lipid and metabolite changes associated with placental function and pregnancy complications using ion mobility spectrometry-mass spectrometry and mass spectrometry imaging.

Thu, 16/08/2018 - 12:42
Related Articles Characterizing the lipid and metabolite changes associated with placental function and pregnancy complications using ion mobility spectrometry-mass spectrometry and mass spectrometry imaging. Placenta. 2017 12;60 Suppl 1:S67-S72 Authors: Burnum-Johnson KE, Baker ES, Metz TO Abstract Successful pregnancy is dependent upon discrete biological events, which include embryo implantation, decidualization, and placentation. Problems associated with each of these events can cause infertility or conditions such as preeclampsia. A greater understanding of the molecular changes associated with these complex processes is necessary to aid in identifying treatments for each condition. Previous nuclear magnetic resonance spectroscopy and mass spectrometry studies have been used to identify metabolites and lipids associated with pregnancy-related complications. However, due to limitations associated with conventional implementations of both techniques, novel technology developments are needed to more fully understand the initiation and development of pregnancy related problems at the molecular level. In this perspective, we describe current analytical techniques for metabolomic and lipidomic characterization of pregnancy complications and discuss the potential for new technologies such as ion mobility spectrometry-mass spectrometry and mass spectrometry imaging to contribute to a better understanding of the molecular changes that affect the placenta and pregnancy outcomes. PMID: 28392013 [PubMed - indexed for MEDLINE]

Automated Detection of Natural Halogenated Compounds from LC-MS Profiles-Application to the Isolation of Bioactive Chlorinated Compounds from Marine-Derived Fungi.

Thu, 16/08/2018 - 12:42
Related Articles Automated Detection of Natural Halogenated Compounds from LC-MS Profiles-Application to the Isolation of Bioactive Chlorinated Compounds from Marine-Derived Fungi. Anal Chem. 2016 09 20;88(18):9143-50 Authors: Roullier C, Guitton Y, Valery M, Amand S, Prado S, Robiou du Pont T, Grovel O, Pouchus YF Abstract A collection of culture extracts obtained from several marine-derived fungal strains collected on the French Atlantic coast was investigated by high performance liquid chromatography-high resolution mass spectrometry (HPLC-HRMS) in order to prospect for halogenated compounds and to identify potentially new ones. To achieve a fast, automated, and efficient data analysis, a bioinformatics tool named MeHaloCoA (Marine Halogenated Compound Analysis) was developed and included into R. After extraction of all the peaks from the metabolic fingerprints and their associated mass spectra, a mathematical filter based on mass isotopic profiles allowed the selective detection of halogenated (Cl and Br) molecules. Integrating MeHaloCoA into a dereplication approach allowed the identification of known and new halogenated compounds in a competitive amount of time. Subsequent targeted purification led to the isolation of several chlorinated metabolites, including two new natural products with bioactive potential, griseophenone I and chlorogriseofulvin, from a marine-derived Penicillium canescens strain. PMID: 27537349 [PubMed - indexed for MEDLINE]

Development and Application of Ultra-Performance Liquid Chromatography-TOF MS for Precision Large Scale Urinary Metabolic Phenotyping.

Thu, 16/08/2018 - 12:42
Related Articles Development and Application of Ultra-Performance Liquid Chromatography-TOF MS for Precision Large Scale Urinary Metabolic Phenotyping. Anal Chem. 2016 09 20;88(18):9004-13 Authors: Lewis MR, Pearce JT, Spagou K, Green M, Dona AC, Yuen AH, David M, Berry DJ, Chappell K, Horneffer-van der Sluis V, Shaw R, Lovestone S, Elliott P, Shockcor J, Lindon JC, Cloarec O, Takats Z, Holmes E, Nicholson JK Abstract To better understand the molecular mechanisms underpinning physiological variation in human populations, metabolic phenotyping approaches are increasingly being applied to studies involving hundreds and thousands of biofluid samples. Hyphenated ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) has become a fundamental tool for this purpose. However, the seemingly inevitable need to analyze large studies in multiple analytical batches for UPLC-MS analysis poses a challenge to data quality which has been recognized in the field. Herein, we describe in detail a fit-for-purpose UPLC-MS platform, method set, and sample analysis workflow, capable of sustained analysis on an industrial scale and allowing batch-free operation for large studies. Using complementary reversed-phase chromatography (RPC) and hydrophilic interaction liquid chromatography (HILIC) together with high resolution orthogonal acceleration time-of-flight mass spectrometry (oaTOF-MS), exceptional measurement precision is exemplified with independent epidemiological sample sets of approximately 650 and 1000 participant samples. Evaluation of molecular reference targets in repeated injections of pooled quality control (QC) samples distributed throughout each experiment demonstrates a mean retention time relative standard deviation (RSD) of <0.3% across all assays in both studies and a mean peak area RSD of <15% in the raw data. To more globally assess the quality of the profiling data, untargeted feature extraction was performed followed by data filtration according to feature intensity response to QC sample dilution. Analysis of the remaining features within the repeated QC sample measurements demonstrated median peak area RSD values of <20% for the RPC assays and <25% for the HILIC assays. These values represent the quality of the raw data, as no normalization or feature-specific intensity correction was applied. While the data in each experiment was acquired in a single continuous batch, instances of minor time-dependent intensity drift were observed, highlighting the utility of data correction techniques despite reducing the dependency on them for generating high quality data. These results demonstrate that the platform and methodology presented herein is fit-for-use in large scale metabolic phenotyping studies, challenging the assertion that such screening is inherently limited by batch effects. Details of the pipeline used to generate high quality raw data and mitigate the need for batch correction are provided. PMID: 27479709 [PubMed - indexed for MEDLINE]

metabolomics; +21 new citations

Wed, 15/08/2018 - 15:13
21 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2018/08/15PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

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