PubMed

Related Articles Metabolomics and cytokine analysis for identification of severe drug-induced liver injury. J Proteome Res. 2019 Apr 19;: Authors: Xie Z, Chen E, Ouyang X, Xu X, Ma S, Ji F, Wu D, Zhang S, Zhao Y, Li L Abstract AIM: To evaluate the levels of metabolites and cytokines in the serum of patients with severe and non-severe idiosyncratic drug-induced liver injury (DILI), and to identify biomarkers of DILI severity. METHODS: Gas chromatography-mass spectrometry (GC-MS) and ultra-performance liquid chromatography-mass spectrometry (UPLC-MS)-based metabolomic approaches were used to evaluate the metabolome of serum samples from 29 DILI patients of severity grade 3 (non-severe), 27 of severity grade 4 (severe), and 36 healthy controls (HCs). The levels of total Keratin-18 (K18), fragment K18 and 27 cytokines were determined by enzyme-linked immunosorbent assay. RESULTS: The alkaline phosphatase activity (p = 0.021) and international normalized ratio (INR) (p < 0.001) differed significantly between the severe and non-severe groups. The severe group had a higher serum fragment K18 level than the non-severe group. A multivariate analysis showed good separation between all pairs of the HC, non-severe, and severe groups. According to the orthogonal partial least squares-discriminant analysis (OPLS-DA) model, 14 metabolites were selected by GC-MS and 17 by UPLC-MS. Among these metabolites, the levels of 16 were increased and of 15 were decreased in the severe group. A pathway analysis revealed major changes in the primary bile acid biosynthesis and alpha-linolenic acid metabolic pathways. The levels of PDGF-bb, IP-10, IL-1Rα, MIP-1β, and TNF-α differed significantly between the severe and non-severe groups, and the levels of most of the metabolites were negatively correlated with those of these cytokines. An OPLS model that included the detected metabolites and cytokines revealed clear separation of the severe and non-severe groups. CONCLUSION: We identified 31 metabolites and 5 cytokines related to the severity of idiosyncratic DILI. The primary bile-acid biosynthesis and alpha-linolenic acid metabolism pathways were also related to the severity of DILI. A model that incorporated the metabolites and cytokines showed clear separation between patients with severe and non-severe DILI, suggesting that these biomarkers have potential as indicators of DILI severity. PMID: 31002254 [PubMed - as supplied by publisher]

Related Articles Comparative global metabolite profiling of xylose-fermenting Saccharomyces cerevisiae SR8 and Scheffersomyces stipitis. Appl Microbiol Biotechnol. 2019 Apr 19;: Authors: Shin M, Kim JW, Ye S, Kim S, Jeong D, Lee DY, Kim JN, Jin YS, Kim KH, Kim SR Abstract Bioconversion of lignocellulosic biomass into ethanol requires efficient xylose fermentation. Previously, we developed an engineered Saccharomyces cerevisiae strain, named SR8, through rational and inverse metabolic engineering strategies, thereby improving its xylose fermentation and ethanol production. However, its fermentation characteristics have not yet been fully evaluated. In this study, we investigated the xylose fermentation and metabolic profiles for ethanol production in the SR8 strain compared with native Scheffersomyces stipitis. The SR8 strain showed a higher maximum ethanol titer and xylose consumption rate when cultured with a high concentration of xylose, mixed sugars, and under anaerobic conditions than Sch. stipitis. However, its ethanol productivity was less on 40 g/L xylose as the sole carbon source, mainly due to the formation of xylitol and glycerol. Global metabolite profiling indicated different intracellular production rates of xylulose and glycerol-3-phosphate in the two strains. In addition, compared with Sch. stipitis, SR8 had increased abundances of metabolites from sugar metabolism and decreased abundances of metabolites from energy metabolism and free fatty acids. These results provide insights into how to control and balance redox cofactors for the production of fuels and chemicals from xylose by the engineered S. cerevisiae. PMID: 31001747 [PubMed - as supplied by publisher]

Related Articles Egg Protein Transferrin-Derived Peptides IRW and IQW Regulate Citrobacter rodentium-Induced, Inflammation-Related Microbial and Metabolomic Profiles. Front Microbiol. 2019;10:643 Authors: Ma Y, Ding S, Liu G, Fang J, Yan W, Duraipandiyan V, Al-Dhabi NA, Esmail GA, Jiang H Abstract Bioactive peptides that target the gastrointestinal tract can strongly affect the health of animals and humans. This study aimed to evaluate the abilities of two peptides derived from egg albumin transferrin, IRW and IQW, to treat enteritis in a mouse model of Citrobacter rodentium-induced colitis by evaluating serum metabolomics and gut microbes. Forty-eight mice were randomly assigned to six groups: basal diet (CTRL), intragastric administration Citrobacter rodentium (CR), basal diet with 0.03%IRW (IRW), CR with 0.03% IRW (IRW+CR), basal diet with 0.03%IQW (IQW) and CR with 0.03% IQW (IQW+CR). CR administration began on day 10 and continued for 7 days. After 14 days of IRW and IQW treatment, serum was collected and subjected to a metabolomics analysis. The length and weight of each colon were measured, and the colon contents were collected for 16srRNA sequencing. The colons were significantly longer in the CR group, compared to the CTRL group. A serum metabolomics analysis revealed no significant difference in microbial diversity between the six groups. Compared with the CTRL group, the proportions of Firmicutes and Actinobacteria species decreased significantly and the proportions of Bacteroidetes and Proteobacteria species increased in the CR group. There were no significant differences between the CTRL and other groups. The serum metabolomics analysis revealed that Infected by CR increased the levels of oxalic acid, homogentisic acid and prostaglandin but decreased the levels of L-glutamine, L-acetyl carnitine, 1-methylhistidine and gentisic acid. Therefore, treatment with IRW and IQW was shown to regulate the intestinal microorganisms associated with colonic inflammation and serum metabolite levels, thus improving intestinal health. PMID: 31001226 [PubMed]

Related Articles Metabolic potential of uncultured bacteria and archaea associated with petroleum seepage in deep-sea sediments. Nat Commun. 2019 Apr 18;10(1):1816 Authors: Dong X, Greening C, Rattray JE, Chakraborty A, Chuvochina M, Mayumi D, Dolfing J, Li C, Brooks JM, Bernard BB, Groves RA, Lewis IA, Hubert CRJ Abstract The lack of microbial genomes and isolates from the deep seabed means that very little is known about the ecology of this vast habitat. Here, we investigate energy and carbon acquisition strategies of microbial communities from three deep seabed petroleum seeps (3 km water depth) in the Eastern Gulf of Mexico. Shotgun metagenomic analysis reveals that each sediment harbors diverse communities of chemoheterotrophs and chemolithotrophs. We recovered 82 metagenome-assembled genomes affiliated with 21 different archaeal and bacterial phyla. Multiple genomes encode enzymes for anaerobic oxidation of aliphatic and aromatic compounds, including those of candidate phyla Aerophobetes, Aminicenantes, TA06 and Bathyarchaeota. Microbial interactions are predicted to be driven by acetate and molecular hydrogen. These findings are supported by sediment geochemistry, metabolomics, and thermodynamic modelling. Overall, we infer that deep-sea sediments experiencing thermogenic hydrocarbon inputs harbor phylogenetically and functionally diverse communities potentially sustained through anaerobic hydrocarbon, acetate and hydrogen metabolism. PMID: 31000700 [PubMed - in process]

Related Articles Evaluation of E-beam irradiation and storage time in pork exudates using NMR metabolomics. Food Res Int. 2019 Jun;120:553-559 Authors: García-García AB, Herrera A, Fernández-Valle ME, Cambero MI, Castejón D Abstract Seventy-two exudates from pork tenderloin samples, subjected to E-beam irradiation treatments, have been employed to monitor, through 1H NMR analysis, the effects of irradiation dose (0, 1, 2 and 6 kGy) and storage time (1, 6 and 12 days). As far as we know, this is the first study where meat exudate is employed to monitor the effects of irradiation dose and storage time. The 1H NMR spectra, obtained after ~ 2 min, allowed to determine the main components of the pork exudate. Results show that 1H NMR-based metabolomics provides valuable information about the metabolic changes suffered during storage and how these transformations could be affected by E-beam irradiation treatment. The ease to obtain exudates, the simple NMR sample preparation, the good correlation between the selected metabolites, the irradiation treatment and the storage times point to that this study could be the first step to develop a new method for analysis and control of meat conservation and to evaluate its irradiation treatment. PMID: 31000271 [PubMed - in process]

Related Articles Changes in pericarp metabolite profiling of four litchi cultivars during browning. Food Res Int. 2019 Jun;120:339-351 Authors: Chen X, Wu Q, Chen Z, Li T, Zhang Z, Gao H, Yun Z, Jiang Y Abstract The pericarp browning is an important physiological index during the postharvest storage, which seriously shortens the shelf-life of litchi fruit. In this study, the browning index of four litchi cultivars were compared, and the shelf-life, from longer to shorter, was 'Feizixiao (FXZ)', 'Jingganghongnuo (JGHN)', 'Huaizhi (HZ)' and 'Nuomici (NMC)', respectively. Then, comparative metabolomics were performed in the pericarp of four litchi cultivars during browning. Finding results showed that a total of 119 kinds of metabolites were detected in litchi pericarp, including 30 kinds of primary metabolites, 44 kinds of volatile compounds, 29 kinds of free amino acids and 16 kinds of hydrolytic amino acids. After ANOVA and OPLS-DA, 52 kinds of metabolites were important with predictive VIP > 1 and p < 0.05. In FZX pericarp, the contents of many amino acids increased significantly, which might be related to the yellow-green pericarp and play an important role in delaying browning. In the pericarp of JGHN, NMC and HZ, a great number of soluble sugars and some free amino acids were induced during browning, which was negatively correlated with the browning speed of three red pericarp cultivars. The browning induced a large number of sesquiterpenes in the pericarp of FZX, NMC and HZ, which was positively correlated with the browning index. In addition, the correlation analysis showed that the amino acids were negatively correlated with the volatile compounds, suggesting that pericarp browning could induce the conversion of metabolic products from amino acids to terpenes. PMID: 31000248 [PubMed - in process]

Related Articles In vitro large intestine fermentation of gluten-free rice cookies containing alfalfa seed (Medicago sativa L.) flour: A combined metagenomic/metabolomic approach. Food Res Int. 2019 Jun;120:312-321 Authors: Rocchetti G, Senizza A, Gallo A, Lucini L, Giuberti G, Patrone V Abstract Alfalfa seed flour (ASF) at different inclusion levels (0% as control, 30% and 45% w/w) was used to prepare rice flour-based gluten-free (GF) cookies (CK). Samples underwent a simulated in vitro digestion and fermentation process. The comprehensive changes in the phenolic profiles were evaluated during 48 h of fermentation by means of untargeted UHPLC-QTOF mass spectrometry followed by multivariate statistics. Furthermore, the modifications in microbial profile and the production of short chain fatty acids (SCFA) were investigated. Cookies presenting 30% (30-CK) and 45% (45-CK) ASF possessed the greater total phenolic content when compared to the control, being 0.42 and 0.56 mg/g versus 0.15 mg/g, respectively. The orthogonal projection to latent structure discriminant analysis, applied to untargeted metabolomics-based data, showed a clear modulation of the profile in phenolic metabolites over time (from 8 up to 48 h of in vitro fermentation). In this regard, the in vitro fermentation of 30-CK and 45-CK resulted in the maximum increase in lignans and phenolic acids, whose bioaccessibility at 24 h of in vitro fermentation was 16.2% and 12.2%, respectively. In addition, the metagenomic sequencing approach allowed to identify in Clostridiaceae, Ruminococcaceae, Lachnospiraceae and Streptococcaceae the most represented bacterial populations during the in vitro fermentation. A greater total SCFA production (p < .05) was recorded overtime for all ASF-enriched cookies when compared to the control. Therefore, ASF proved to be an excellent alternative to common non-wheat cereal flours (such as pseudocereals or legumes) for improving possible health-promoting properties in GF cookie formulation. PMID: 31000244 [PubMed - in process]

Related Articles Physiological and Metabolomic Analysis of Cold Plasma Treated Fresh-Cut Strawberries. J Agric Food Chem. 2019 Apr 10;67(14):4043-4053 Authors: Li M, Li X, Han C, Ji N, Jin P, Zheng Y Abstract Cold plasma technology offers new opportunities to the decontamination and preservation of fruits and vegetables. In the present research, strawberries were cut into four wedges and then treated with dielectric barrier discharge plasma at 45 kV for 1 min and stored for 1 week (4 °C). Metabolomic analysis suggested that plasma treatment improved the biosynthesis of the metabolites in the "flavones and flavonol biosynthesis" pathway and "biosynthesis of phenylpropanoids" pathway in fresh-cut strawberries. Physiological assay demonstrated that plasma treatment maintained the texture properties and inhibited microbial growth of fresh-cut strawberries. In addition, plasma treatment also promoted the accumulation of total phenolics, total flavonoid, and anthocyanin by enhancing the critical enzyme activities and activating related gene expression in phenylpropanoid as well as reactive oxygen species metabolism, which contributed greatly to the enhancement of antioxidant capacity of strawberry wedges. Our investigation provided a new perspective of the effect of plasma treatment on the safety and quality of strawberry wedges and suggested that cold plasma treatment holds promise as an emerging processing technology for improving the quality and antioxidant activity of postharvest fruits and vegetables. PMID: 30883111 [PubMed - indexed for MEDLINE]

Related Articles Comparative investigation on metabolite changes in 'wu mi' production by Vaccinium bracteatum Thunb. leaves based on multivariate data analysis using UPLC-QToF-MS. Food Chem. 2019 Jul 15;286:146-153 Authors: Fan M, Fan Y, Rao Z, Li Y, Qian H, Zhang H, Wu G, Qi X, Wang L Abstract Vaccinium bracteatum Thunb. leaves (VBTL) are used to juicing and dye rice to produce 'Wu mi', which displays a deep blue color. However, little information is known about the formation mechanism of the pigments. In this research, non-targeted metabolic profiling of VBTL and VBTL juice samples at different growth stages was studied for searching the pigment precursors through UPLC-QToF-MS and multivariate data analysis. The results showed the L* and b* values of 'Wu mi' produced by spring leaves (stages of 2WAB, 4WAB and 6WAB) were significantly lower than other growth stages. Principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) of the VBTL and VBTL juice samples showed distinct classifications. Further variable importance in projection (VIP) plot in PLS-DA model demonstrated the discriminatory potential biomarkers between VBTL and VBTL juice samples. Some of the identified biomarkers were tentatively identified as the precursor compounds of the iridoid-derived pigments. PMID: 30827588 [PubMed - indexed for MEDLINE]

Related Articles Integration of multi-omics data and deep phenotyping enables prediction of cytokine responses. Nat Immunol. 2018 07;19(7):776-786 Authors: Bakker OB, Aguirre-Gamboa R, Sanna S, Oosting M, Smeekens SP, Jaeger M, Zorro M, Võsa U, Withoff S, Netea-Maier RT, Koenen HJPM, Joosten I, Xavier RJ, Franke L, Joosten LAB, Kumar V, Wijmenga C, Netea MG, Li Y Abstract The immune response to pathogens varies substantially among people. Whereas both genetic and nongenetic factors contribute to interperson variation, their relative contributions and potential predictive power have remained largely unknown. By systematically correlating host factors in 534 healthy volunteers, including baseline immunological parameters and molecular profiles (genome, metabolome and gut microbiome), with cytokine production after stimulation with 20 pathogens, we identified distinct patterns of co-regulation. Among the 91 different cytokine-stimulus pairs, 11 categories of host factors together explained up to 67% of interindividual variation in cytokine production induced by stimulation. A computational model based on genetic data predicted the genetic component of stimulus-induced cytokine production (correlation 0.28-0.89), and nongenetic factors influenced cytokine production as well. PMID: 29784908 [PubMed - indexed for MEDLINE]

16 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 2019/04/19PubMed 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.

Related Articles Lethal Poisoning of Cancer Cells by Respiratory Chain Inhibition plus Dimethyl α-Ketoglutarate. Cell Rep. 2019 Apr 16;27(3):820-834.e9 Authors: Sica V, Bravo-San Pedro JM, Izzo V, Pol J, Pierredon S, Enot D, Durand S, Bossut N, Chery A, Souquere S, Pierron G, Vartholomaiou E, Zamzami N, Soussi T, Sauvat A, Mondragón L, Kepp O, Galluzzi L, Martinou JC, Hess-Stumpp H, Ziegelbauer K, Kroemer G, Maiuri MC Abstract Inhibition of oxidative phosphorylation (OXPHOS) by 1-cyclopropyl-4-(4-[(5-methyl-3-(3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)methyl]pyridin-2-yl)piperazine (BAY87-2243, abbreviated as B87), a complex I inhibitor, fails to kill human cancer cells in vitro. Driven by this consideration, we attempted to identify agents that engage in synthetically lethal interactions with B87. Here, we report that dimethyl α-ketoglutarate (DMKG), a cell-permeable precursor of α-ketoglutarate that lacks toxicity on its own, kills cancer cells when combined with B87 or other inhibitors of OXPHOS. DMKG improved the antineoplastic effect of B87, both in vitro and in vivo. This combination caused MDM2-dependent, tumor suppressor protein p53 (TP53)-independent transcriptional reprogramming and alternative exon usage affecting multiple glycolytic enzymes, completely blocking glycolysis. Simultaneous inhibition of OXPHOS and glycolysis provoked a bioenergetic catastrophe culminating in the activation of a cell death program that involved disruption of the mitochondrial network and activation of PARP1, AIFM1, and APEX1. These results unveil a metabolic liability of human cancer cells that may be harnessed for the development of therapeutic regimens. PMID: 30995479 [PubMed - in process]

Related Articles Metabolic Fingerprinting of Chorionic Villous Samples in Normal Pregnancy and Chromosomal Disorders. Prenat Diagn. 2019 Apr 17;: Authors: Murgia F, Iuculano A, Peddes C, Santoru ML, Tronci L, Deiana M, Atzori L, Monni G Abstract OBJECTIVE: Placenta-related biological samples are used in biomedical research to investigate placental development. Metabolomics represents a promising approach for studying placental metabolism in an effort to explain physiological and pathological mechanisms. The aim of this study was to investigate metabolic changes in chorionic villi during the first trimester of pregnancy in euploid and aneuploid cases. METHODS: Samples from 21 women (13 euploid, 8 aneuploid) were analyzed with 1 H-Nuclear Magnetic Resonance (NMR), Gas Chromatography-Mass Spectrometry (GC-MS) and High-Performance Liquid chromatography (HPLC). Multivariate statistical analysis was performed and differences in metabolites were used to identify the altered metabolic pathways. RESULTS: A regression model to test the correlation between fetal crown-rump length (CRL) and metabolic profile of chorionic villous was performed in euploid pregnancies (R2 was 0.69 for the NMR analysis and 0.94 for the GC-MS analysis). Supervised Analysis was used to compare chorionic villi of euploid and aneuploid fetuses (NMR: R2 X=0.70, R2 Y=0.65, Q2=0.30 R2 X=0.62; GC-MS: R2 Y=0.704, Q2 =0.444). Polyol pathways, myo-inositol and oxidative stress seem to have a fundamental role in euploid and aneuploid pregnancies. CONCLUSION: Polyol pathways may have a crucial role in energy production in early pregnancy. Excessive activation in aneuploid pregnancies may lead to increased oxidative stress. Metabolomics represents a promising approach to investigate placental metabolic changes. PMID: 30995342 [PubMed - as supplied by publisher]

Related Articles The Unique Protein Composition of Honey Revealed by Comprehensive Proteomic Analysis: Allergens, Venom-like Proteins, Antibacterial Properties, Royal Jelly Proteins, Serine Proteases, and Their Inhibitors. J Nat Prod. 2019 Apr 17;: Authors: Erban T, Shcherbachenko E, Talacko P, Harant K Abstract Honey is a unique natural product produced by European honeybees. Due to its high economic value, honey is considered to be well characterized chemically, and it is often discovered to be an adulterated commodity. However, this study shows that our knowledge of honey protein composition, which is of high medical and pharmaceutical importance, is incomplete. In this in-depth proteomic study of 13 honeys, we identified a number of proteins that are important for an understanding of honey properties and merit additional pharmaceutical research. Our major result is an expanded understanding of the proteins underlying honey's antimicrobial properties, such as hymenoptaecin and defensin-1, glucose dehydrogenase isoforms, venom allergens and other venom-like proteins, serine proteases and serine protease inhibitors, and a series of royal jelly proteins. In addition, we performed quantitative comparisons of all of the proteins previously known or newly identified. The honey proteins, determined using label-free nLC-MS/MS in which the same protein quantity was analyzed in one series, were found in relatively similar proportions, although eucalyptus honey differed most widely from the remaining honeys. Overall, the proteome analysis indicated that honeybees supply proteins to honey in a relatively stable ratio within each proteome, but total protein quantity can differ by approximately an order of magnitude in different honeys. PMID: 30995037 [PubMed - as supplied by publisher]

Related Articles Metabolomics Assay identified a novel virulence-associated siderophore encoded by the High-Pathogenicity Island in uropathogenic Escherichia coli. J Proteome Res. 2019 Apr 17;: Authors: Xu G, Guo H, Lv H Abstract To date, yersiniabactin remains the only identified siderophore encoded by the high pathogenicity island (HPI) in uropathogenic Escherichia coli (UPEC). In the present study, we aim to discover and identify new siderophores in the HPI-dependent biosynthetic pathway using a combinational strategy of metabolomics and genetics. A global metabolome assay of wild-type UTI89, UTI89ΔybtS and UTI89ΔybtS with the substrate addition of salicylic acid found numerous unknown metabolite features that were encoded by the HPI with an obvious substrate dependency on salicylic acid. One metabolite feature with m/z 307.0206 was shown to have a similar phenotype as yersiniabactin. Furthermore, isotope mass spectrum calculations and MS/MS annotations were combined to identify this metabolite as HPTzTn-COOH. HPTzTn-COOH was verified as a new siderophore in this study, and it was observed to have a robust capacity to chelate different metals, including Al3+, Ni2+ and Ca2+, in addition to binding Fe3+. Our data revealed that HPTzTn-COOH has a stronger diagnostic ability over the more conventionally used yersiniabactin, as characterized by its high production throughout UPEC strains harboring HPI. Altogether, our discoveries revise the siderophore family, and HPTzTn-COOH can be classified as an additional key siderophore along with yersiniabactin. PMID: 30994357 [PubMed - as supplied by publisher]

Related Articles Chemical Composition of Commercial Cow's Milk. J Agric Food Chem. 2019 Apr 17;: Authors: Foroutan A, Guo AC, Vazquez-Fresno R, Lipfert M, Zhang L, Zheng J, Badran H, Budinski Z, Mandal R, Ametaj BN, Wishart DS Abstract Bovine milk is a nutritionally rich, chemically complex biofluid consisting of hundreds of different components. While the chemical composition of cow's milk has been studied for decades, much of this information is fragmentary and very dated. In an effort to consolidate and update this information, we have applied modern, quantitative metabolomics techniques along with computer-aided literature mining to obtain the most comprehensive and up-to-date characterization of the chemical constituents in commercial cow's milk. Using nuclear magnetic resonance (NMR) spectroscopy, liquid chromatography-mass spectrometry (LC-MS), and inductively coupled plasma-mass spectrometry (ICP-MS), we were able to identify and quantify 296 bovine milk metabolites or metabolite species (corresponding to 1447 unique structures) from a variety of commercial milk samples. Through our literature analysis, we also found another 676 metabolites or metabolite species (corresponding to 908 unique structures). Detailed information regarding all 2355 of the identified chemicals in bovine milk have been made freely available through a Web-accessible database called the Milk Composition Database or MCDB ( http://www.mcdb.ca/ ). PMID: 30994344 [PubMed - as supplied by publisher]

Related Articles Metabolomics reveals tepotinib-related mitochondrial dysfunction in MET activating mutations-driven models. FEBS J. 2019 Apr 16;: Authors: Poliaková M, Felser A, Pierzchala K, Nuoffer JM, Aebersold DM, Zimmer Y, Zamboni N, Medová M Abstract Genetic aberrations in the hepatocyte growth factor receptor tyrosine kinase MET induce oncogenic addiction in various types of human cancers, advocating MET as a viable anticancer target. Here, we report that MET signaling plays an important role in conferring a unique metabolic phenotype to cellular models expressing MET-activating mutated variants that are either sensitive or resistant towards MET small molecule inhibitors. MET phosphorylation downregulated by the specific MET inhibitor tepotinib resulted in markedly decreased viability and increased apoptosis in tepotinib-sensitive cells. Moreover, prior to the induction of MET inhibition-dependent cell death, tepotinib also led to an altered metabolic signature, characterized by a prominent reduction of metabolite ions related to amino sugar metabolism, gluconeogenesis, glycine and serine metabolism and of numerous TCA cycle-related metabolites such as succinate, malate and citrate. Functionally, a decrease in oxygen consumption rate, a reduced citrate synthase activity, a drop in membrane potential and an associated misbalanced mitochondrial function were observed exclusively in MET inhibitor-sensitive cells. These data imply that interference with metabolic state can be considered an early indicator of efficient MET inhibition and particular changes reported here could be explored in the future as markers of efficacy of anti-MET therapies. This article is protected by copyright. All rights reserved. PMID: 30993872 [PubMed - as supplied by publisher]

Related Articles Improvement of Bioactive Metabolite Production in Microbial Cultures - A systems approach by OSMAC and deconvolution-based 1 HNMR quantification. Magn Reson Chem. 2019 Apr 16;: Authors: Selegato DM, Freire RT, Pilon AC, Biasetto CR, de Oliveira HC, de Abreu LM, Araujo AR, Bolzani VDS, Castro-Gamboa I Abstract Traditionally, the screening of metabolites in microbial matrices is performed by monocultures. Nonetheless, the absence of biotic and abiotic interactions generally observed in nature still limit the chemical diversity and leads to "poorer" chemical profiles. Nowadays, several methods have been developed to determine the conditions under which cryptic genes are activated, in an attempt to induce these silenced biosynthetic pathways. Among those, the One Strain Many Compounds (OSMAC) strategy has been applied to enhance metabolic production by a systematic variation of growth parameters. The complexity of the chemical profiles from OSMAC experiments has required increasingly robust and accurate techniques. In this sense, deconvolution-based 1 HNMR quantification have emerged as a promising methodology to decrease complexity and provide a comprehensive perspective for metabolomics studies. Our present work shows an integrated strategy for the increased production and rapid quantification of compounds from microbial sources. Specifically, an OSMAC-Design of Experiments (DoE) was used to optimize the microbial production of bioactive fusaric acid, cytochalasin D and 3-nitropropionic acid, and Global Spectral Deconvolution (GSD)-based 1 HNMR quantification was carried out for their measurement. The results showed that OSMAC increased the production of the metabolites by up to 33% and that GSD was able to extract accurate NMR integrals even in heavily coalescence spectral regions. Moreover, GSD-1 HNMR quantification was reproducible for all species and exhibited validated results that were more selective and accurate than comparative methods. Overall, this strategy up-regulated important metabolites using a reduced number of experiments and provided fast analyte monitor directly in raw extracts. PMID: 30993742 [PubMed - as supplied by publisher]

Related Articles BLANKA: an Algorithm for Blank Subtraction in Mass Spectrometry of Complex Biological Samples. J Am Soc Mass Spectrom. 2019 Apr 16;: Authors: Cleary JL, Luu GT, Pierce EC, Dutton RJ, Sanchez LM Abstract Multispecies microbiome systems are known to be closely linked to human, animal, and plant life processes. The growing field of metabolomics presents the opportunity to detect changes in overall metabolomic profiles of microbial species interactions. These metabolomic changes provide insight into function of metabolites as they correlate to different species presence and the observed phenotypic changes, but detection of subtle changes is often difficult in samples with complex backgrounds. Natural environments such as soil and food contain many molecules that convolute mass spectrometry-based analyses, and identification of microbial metabolites amongst environmental metabolites is an informatics problem we begin to address here. Our microbes are grown on solid or liquid cheese curd media. This medium, which is necessary for microbial growth, contains high amounts of salts, lipids, and casein breakdown products which make statistical analyses using LC-MS/MS data difficult due to the high background from the media. We have developed a simple algorithm to carry out background subtraction from microbes grown on solid or liquid cheese curd media to aid in our ability to conduct statistical analyses so that we may prioritize metabolites for further structure elucidation. Graphical Abstract . PMID: 30993641 [PubMed - as supplied by publisher]

Related Articles Two data pre-processing workflows to facilitate the discovery of biomarkers by 2D NMR metabolomics. Metabolomics. 2019 Apr 16;15(4):63 Authors: Féraud B, Leenders J, Martineau E, Giraudeau P, Govaerts B, de Tullio P Abstract INTRODUCTION: The pre-processing of analytical data in metabolomics must be considered as a whole to allow the construction of a global and unique object for any further simultaneous data analysis or multivariate statistical modelling. For 1D 1H-NMR metabolomics experiments, best practices for data pre-processing are well defined, but not yet for 2D experiments (for instance COSY in this paper). OBJECTIVE: By considering the added value of a second dimension, the objective is to propose two workflows dedicated to 2D NMR data handling and preparation (the Global Peak List and Vectorization approaches) and to compare them (with respect to each other and with 1D standards). This will allow to detect which methodology is the best in terms of amount of metabolomic content and to explore the advantages of the selected workflow in distinguishing among treatment groups and identifying relevant biomarkers. Therefore, this paper explores both the necessity of novel 2D pre-processing workflows, the evaluation of their quality and the evaluation of their performance in the subsequent determination of accurate (2D) biomarkers. METHODS: To select the more informative data source, MIC (Metabolomic Informative Content) indexes are used, based on clustering and inertia measures of quality. Then, to highlight biomarkers or critical spectral zones, the PLS-DA model is used, along with more advanced sparse algorithms (sPLS and L-sOPLS). RESULTS: Results are discussed according to two different experimental designs (one which is unsupervised and based on human urine samples, and the other which is controlled and based on spiked serum media). MIC indexes are shown, leading to the choice of the more relevant workflow to use thereafter. Finally, biomarkers are provided for each case and the predictive power of each candidate model is assessed with cross-validated measures of RMSEP. CONCLUSION: In conclusion, it is shown that no solution can be universally the best in every case, but that 2D experiments allow to clearly find relevant cross peak biomarkers even with a poor initial separability between groups. The MIC measures linked with the candidate workflows (2D GPL, 2D vectorization, 1D, and with specific parameters) lead to visualize which data set must be used as a priority to more easily find biomarkers. The diversity of data sources, mainly 1D versus 2D, may often lead to complementary or confirmatory results. PMID: 30993405 [PubMed - in process]