PubMed

Related Articles Bax Inhibitor-1 protects from Non-Alcoholic Steatohepatitis by limiting IRE1α signaling. Hepatology. 2018 Feb 19;: Authors: Lebeaupin C, Vallée D, Rousseau D, Patouraux S, Bonnafous S, Adam G, Luciano F, Luci C, Anty R, Iannelli A, Marchetti S, Kroemer G, Lacas-Gervais S, Tran A, Gual P, Bailly-Maitre B Abstract Endoplasmic reticulum (ER) stress is activated in non-alcoholic fatty liver disease (NAFLD), raising the possibility that ER stress-dependent metabolic dysfunction, inflammation and cell death underlie the transition from steatosis to steatohepatitis (NASH). Bax inhibitor-1 (BI-1), a negative regulator of the ER stress sensor IRE1α, has yet to be explored in NAFLD as a hepatoprotective agent. We hypothesized that the genetic ablation of BI-1 would render the liver vulnerable to NASH due to unrestrained IRE1α signaling. ER stress was induced in wild-type and BI-1-/- mice acutely by tunicamycin injection (1 mg/kg) or chronically by high-fat diet (HFD) feeding to determine the NAFLD phenotype. Livers of tunicamycin-treated BI-1-/- mice showed IRE1α-dependent NLRP3 inflammasome activation, hepatocyte death, fibrosis and dysregulated lipid homeostasis that led to liver failure within a week. The analysis of human NAFLD liver biopsies revealed BI-1 downregulation parallel to the upregulation of IRE1α endoribonuclease (RNase) signaling. In HFD-fed BI-1-/- mice that presented NASH and type-2 diabetes, exaggerated hepatic IRE1α, XBP1 and CHOP expression was linked to activated NLRP3 inflammasome and caspase-1/-11. Rises in IL-1β, IL-6, MCP1, CXCL1 and ALT/AST levels revealed significant inflammation and injury, respectively. The pharmacological inhibition of IRE1α RNase activity with the small molecules STF-083010 or 4µ8c was evaluated in HFD-induced NAFLD. In BI-1-/- mice, either treatment effectively counteracted IRE1α RNase activity, improving glucose tolerance and rescuing from NASH. The hepatocyte-specific role of IRE1α RNase activity in mediating NLRP3 inflammasome activation and cell death was confirmed in primary mouse hepatocytes by IRE1α axis knockdown or its inhibition with STF-083010 or 4µ8c. CONCLUSION: Targeting IRE1α-dependent NLRP3 inflammasome signaling with pharmacological agents or via BI-1 may represent a tangible therapeutic strategy for NASH. This article is protected by copyright. All rights reserved. PMID: 29457838 [PubMed - as supplied by publisher]

Related Articles Urinary metabolomic study of the antagonistic effect of P. ginseng in rats with estrogen decline using ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Food Funct. 2018 Feb 19;: Authors: Lin H, Liu Z, Pi Z, Men L, Chen W, Liu Z Abstract Estrogens are biologically active steroid hormones mainly released from the ovary by ovarian secretion of estrogen into the circulating blood to regulate or function at the distal target. Estrogens play an important role in the central nervous system, cardiovascular system and immune system, especially for post-menopausal women. Panax ginseng Mayer has been reported to relieve women's menopausal symptoms and affect estrogen activities. However, the mechanism of its estrogen regulation has not yet been clearly investigated. In this work, ovariectomized rats were administered a P. ginseng decoction intragastrically for 8 weeks. Urine samples were analyzed by ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) to identify metabolites. The estrous cycle, body weight, uterine weight index and serum hormone levels were measured. The results showed that P. ginseng significantly prolonged the estrus stage, decreased the body weight and serum luteinizing hormone (LH) levels and increased the uterine weight index and serum estradiol (E2) levels of ovariectomized rats. A total of twelve potential biomarkers for which levels changed markedly upon treatment have been identified based on metabolomics. A systematic network analysis of their corresponding pathways indicates that the antagonistic effect of P. ginseng on ovariectomized rats occurs mainly through regulating steroid hormone metabolism, fatty acid biosynthesis, the citric acid cycle and tryptophan metabolism. In conclusion, this study validated the antagonistic effect of P. ginseng in rats with estrogen decline and explored the metabolic and biochemical mechanisms involved. PMID: 29457805 [PubMed - as supplied by publisher]

Related Articles Metabolic Profile of Oral Squamous Carcinoma Cell Lines Relies on a Higher Demand of Lipid Metabolism in Metastatic Cells. Front Oncol. 2018;8:13 Authors: Sant'Anna-Silva ACB, Santos GC, Campos SPC, Oliveira Gomes AM, Pérez-Valencia JA, Rumjanek FD Abstract Tumor cells are subjected to a broad range of selective pressures. As a result of the imposed stress, subpopulations of surviving cells exhibit individual biochemical phenotypes that reflect metabolic reprograming. The present work aimed at investigating metabolic parameters of cells displaying increasing degrees of metastatic potential. The metabolites present in cell extracts fraction of tongue fibroblasts and of cell lines derived from human tongue squamous cell carcinoma lineages displaying increasing metastatic potential (SCC9 ZsG, LN1 and LN2) were analyzed by 1H NMR (nuclear magnetic resonance) spectroscopy. Living, intact cells were also examined by the non-invasive method of fluorescence lifetime imaging microscopy (FLIM) based on the auto fluorescence of endogenous NADH. The cell lines reproducibly exhibited distinct metabolic profiles confirmed by Partial Least-Square Discriminant Analysis (PLS-DA) of the spectra. Measurement of endogenous free and bound NAD(P)H relative concentrations in the intact cell lines showed that ZsG and LN1 cells displayed high heterogeneity in the energy metabolism, indicating that the cells would oscillate between glycolysis and oxidative metabolism depending on the microenvironment's composition. However, LN2 cells appeared to have more contributions to the oxidative status, displaying a lower NAD(P)H free/bound ratio. Functional experiments of energy metabolism, mitochondrial physiology, and proliferation assays revealed that all lineages exhibited similar energy features, although resorting to different bioenergetics strategies to face metabolic demands. These differentiated functions may also promote metastasis. We propose that lipid metabolism is related to the increased invasiveness as a result of the accumulation of malonate, methyl malonic acid, n-acetyl and unsaturated fatty acids (CH2)n in parallel with the metastatic potential progression, thus suggesting that the NAD(P)H reflected the lipid catabolic/anabolic pathways. PMID: 29456966 [PubMed]

Related Articles Growth and lipid accumulation by different nutrients in the microalga Chlamydomonas reinhardtii. Biotechnol Biofuels. 2018;11:40 Authors: Yang L, Chen J, Qin S, Zeng M, Jiang Y, Hu L, Xiao P, Hao W, Hu Z, Lei A, Wang J Abstract Background: Individual nutrient depletion is widely used to induce lipid accumulation in microalgae, which also causes cell growth inhibition and decreases the total biomass. Thus, improving the lipid accumulation without biomass loss in the nutrient deficiency cells becomes a potential cost-effective treatment for cheaper biofuels. Methods: In this study, the effects of different nutritional conditions on the growth and contents of lipids in Chlamydomonas reinhardtii were compared, and the metabolic profiles under different nutritional conditions were also investigated. Results: We showed that similar to other microalgae, nitrogen or phosphorus deficiency inhibited the growth of Chlamydomonas and combined nutrition deficiency reduced biomass by up to 31.7%, though lipid contents in cells (g/g dry weight [DW]) were significantly increased. The addition of sodium acetate countered this growth inhibition that resulted from nitrogen and phosphorus deficiency, with significantly increased biomass. Furthermore, the combination of 4 g/L sodium acetate supplementation with nitrogen and phosphorous deficiency increased total fatty acid yield (mg/L) by 93.0 and 150.1% compared to nutrient-depleted and normal culture conditions, respectively. Metabolite content was affected by the different nutritional conditions, especially metabolites that are involved in lipid metabolism, amino acid metabolism and metabolism of external substances. Conclusion: Further research into these metabolites could shed light onto the relationship between cell growth inhibition and fatty acid accumulation in Chlamydomonas. PMID: 29456627 [PubMed]

Related Articles The relevance of tyrosine kinase inhibitors for global metabolic pathways in cancer. Mol Cancer. 2018 Feb 19;17(1):27 Authors: Poliaková M, Aebersold DM, Zimmer Y, Medová M Abstract Tumor metabolism is a thrilling discipline that focuses on mechanisms used by cancer cells to earn crucial building blocks and energy to preserve growth and overcome resistance to various treatment modalities. At the same time, therapies directed specifically against aberrant signalling pathways driven by protein tyrosine kinases (TKs) involved in proliferation, metastasis and growth count for several years to promising anti-cancer approaches. In this respect, small molecule inhibitors are the most widely used clinically relevant means for targeted therapy, with a rising number of approvals for TKs inhibitors. In this review, we discuss recent observations related to TKs-associated metabolism and to metabolic feedback that is initialized as cellular response to particular TK-targeted therapies. These observations provide collective evidence that therapeutic responses are primarily linked to such pathways as regulation of lipid and amino acid metabolism, TCA cycle and glycolysis, advocating therefore the development of further effective targeted therapies against a broader spectrum of TKs to treat patients whose tumors display deregulated signalling driven by these proteins. PMID: 29455660 [PubMed - in process]

Related Articles Differentiation of Rums Produced from Sugar Cane Juice (Rhum Agricole) from Rums Manufactured from Sugar Cane Molasses by a Metabolomics Approach. J Agric Food Chem. 2018 Feb 17;: Authors: Franitza L, Nicolotti L, Granvogl M, Schieberle P Abstract A large set of volatiles (a metabolome) was isolated by SAFE distillation from twenty-five high priced rums prepared from sugar cane juice (SCJ) and twenty-six high priced rums manufactured from sugar cane molasses (SCM). The volatile fractions were first analyzed by comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry (GC×GC-TOF-MS) and the 'comprehensive template matching fingerprinting' was used to extract the entire features present in the respective set of volatile compounds. After raw data pre-treatment, chemometrics was used to locate marker compounds. Following, a sparse-partial-least-squares discriminant analysis (sPLS-DA) and a partial-least-squares discriminant analysis (PLS-DA) was applied to a training data set for creating a model. The model was validated using leave-one-out cross validation and tested over an independent data set to evaluate its predictive power. The characteristic fingerprint resulted in a 100% correct classification of sugar cane juice rums, thus achieving the first aim of locating markers for these higher quality rums. Then, past-processing identification within the discriminant features was done to characterize 12 significant marker compounds as 1-decanol, γ-dodecalactone, ethyl 3-methylbutanoate, ethyl nonanoate, 3-furancarboxaldehyde, 1-hexanol, β-ionone, 2- and 3-methylbutanol, methyl decanoate, 3-octanol, and 2-undecanone. Quantitation of eight selected markers by stable isotope dilution assays confirmed higher concentrations in SCJ compared to SCM and served as the final proof to differentiate both types of spirits. PMID: 29455529 [PubMed - as supplied by publisher]

Related Articles Nano-sized TiO2 (nTiO2) induces metabolic perturbations in Physarum polycephalum macroplasmodium to counter oxidative stress under dark conditions. Ecotoxicol Environ Saf. 2018 Feb 15;154:108-117 Authors: Zhang Z, Liang ZC, Zhang JH, Tian SL, Le Qu J, Tang JN, De Liu S Abstract Nano-sized TiO2 (nTiO2) exerts an oxidative effect on cells upon exposure to solar or UV irradiation and ecotoxicity of the nTiO2 is an urgent concern. Little information is available regarding the effect of TiO2 on cells under dark conditions. Metabolomics is a unique approach to the discovery of biomarkers of nTiO2 cytotoxicity, and leads to the identification of perturbed metabolic pathways and the mechanism underlying nTiO2 toxicity. In the present study, gas chromatography mass spectrometry (GC/MS)-based metabolomics was performed to investigate the effect of nTiO2 on sensitive cells (P. polycephalum macroplasmodium) under dark conditions. According to the multivariate pattern recognition analysis, at least 60 potential metabolic biomarkers related to sugar metabolism, amino acid metabolism, nucleotide metabolism, polyamine biosynthesis, and secondary metabolites pathways were significantly perturbed by nTiO2. Notably, many metabolic biomarkers and pathways were related to anti-oxidant mechanisms in the living organism, suggesting that nTiO2 may induce oxidative stress, even under dark conditions. This speculation was further validated by the biochemical levels of reactive oxygen species (ROS), 8-hydroxy-2-deoxyguanosine (8-OHdG), and total soluble phenols (TSP). We inferred that the oxidative stress might be related to nTiO2-induced imbalance of cellular ROS. To the best of our knowledge, the present study is the first to investigate the nTiO2-induced metabolic perturbations in slime mold, provide a new perspective of the mechanism underlying nTiO2 toxicity under dark conditions, and show that metabolomics can be employed as a rapid, reliable and powerful tool to investigate the interaction among organisms, the environment, and nanomaterials. PMID: 29454986 [PubMed - as supplied by publisher]

Related Articles First-line anti-tuberculosis drugs induce hepatotoxicity: A novel mechanism based on a urinary metabolomics platform. Biochem Biophys Res Commun. 2018 Feb 15;: Authors: Cao J, Mi Y, Shi C, Bian Y, Huang C, Ye Z, Liu L, Miao L Abstract Tuberculosis (TB) has become a global public health and social threat. As clinical first-line drugs, rifampicin and isoniazid used in combination with pyrazinamide and ethambutol (the HRZE regimen) usually induce hepatotoxicity. However, the mechanisms underlying this phenomenon remain unclear, and studying the metabolic impact of co-treating TB patients with the HRZE regimen can provide new hepatotoxicity evidence. In this study, urine metabolites from TB patients were profiled using a high-resolution ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) platform. The tricarboxylic acid circulation, arginine and proline metabolism and purine metabolic pathways were found to be affected by anti-TB drugs. The levels of pyroglutamate, isocitrate, citrate, and xanthine were significantly decreased after the administration of HRZE. The above mentioned pathways were also different between drug-induced liver injury (DILI) and non-DILI patients. Urate and cis-4-octenedioic acid levels in the DILI group were significantly increased compared to those in the non-DILI group, while the cis-aconitate and hypoxanthine levels were significantly decreased. These results highlight that superoxide generation can aggravate the hepatotoxic effects of the HRZE regimen. In addition, our metabolomic approach had the ability to predict hepatotoxicity for clinical applications. PMID: 29454961 [PubMed - as supplied by publisher]

Related Articles Metabolomic analysis uncovered an association of serum phospholipid levels with estrogen-induced mammary tumors in female ACI/Seg rats. Toxicol Lett. 2018 Feb 15;: Authors: Okamoto Y, Aoki A, Ueda K, Jinno H Abstract Estrogen is reported to be involved in mammary tumorigenesis. To unveil metabolic signatures for estrogen-induced mammary tumorigenesis, we carried out serum metabolomic analysis in an estrogen-induced mammary tumor model, female August Copenhagen-Irish/Segaloff (ACI/Seg) rats, using liquid chromatography-mass spectrometry. In contrast to the control group, all rats with an implanted 17β-estradiol (E2) pellet developed mammary tumors during this experiment. E2 treatment significantly suppressed body weight gain. But no significant differences in food consumption were observed between the two groups, suggesting that metabolic alteration depended on E2 treatment. Serum metabolomic analysis detected 116 features that were statistically different (p < 0.01) between the groups. Quantitation analysis revealed that several phospholipids such as phosphatidylcholines and lysophosphatidylcholines (LPCs) were identified as significantly different metabolites. E2-treated rat serum stimulated the proliferation of human breast cancer MDA-MB-231 cells. In addition, the proliferation effect was diminished by pretreating cells with either autotaxin inhibitor or antagonist for lysophosphatidic acid receptor whose ligands are metabolites of LPCs via autotaxin-mediated hydrolysis. In summary, our results suggest that not only are phospholipids potential biomarkers for mammary tumors but importantly, LPCs themselves could be associated with E2-induced mammary tumorigenesis in female ACI/Seg rats. PMID: 29454887 [PubMed - as supplied by publisher]

Related Articles Integrated metabolome and transcriptome analysis of Magnolia champaca identifies biosynthetic pathways for floral volatile organic compounds. BMC Genomics. 2017 Jun 14;18(1):463 Authors: Dhandapani S, Jin J, Sridhar V, Sarojam R, Chua NH, Jang IC Abstract BACKGROUND: Magnolia champaca, commonly known as champak is a well-known tree due to its highly fragrant flowers. Champak floral scent is attributed to a complex mix of volatile organic compounds (VOCs). These aromatic flowers are widely used in flavors and fragrances industry. Despite its commercial importance, the VOC biosynthesis pathways in these flowers are largely unknown. Here, we combine metabolite and RNA sequencing (RNA-seq) analyses of fully opened champak flowers to discover the active VOC biosynthesis pathways as well as floral scent-related genes. RESULTS: Volatile collection by headspace method and analysis by gas chromatography-mass spectrometry (GC-MS) identified a total of 43 VOCs from fully opened champak flowers, of which 46.9% were terpenoids, 38.9% were volatile esters and 5.2% belonged to phenylpropanoids/benzenoids. Sequencing and de novo assembly of champak flower transcriptome yielded 47,688 non-redundant unigenes. Transcriptome assembly was validated using standard polymerase chain reaction (PCR) based approach for randomly selected unigenes. The detailed profiles of VOCs led to the discovery of pathways and genes involved in floral scent biosynthesis from RNA-seq data. Analysis of expression levels of many floral-scent biosynthesis-related unigenes in flowers and leaves showed that most of them were expressed higher in flowers than in leaf tissues. Moreover, our metabolite-guided transcriptomics, in vitro and in vivo enzyme assays and transgenic studies identified (R)-linalool synthase that is essential for the production of major VOCs of champak flowers, (R)-linalool and linalool oxides. CONCLUSION: As our study is the first report on transcriptome analysis of Magnolia champaca, this transcriptome dataset that serves as an important public information for functional genomics will not only facilitate better understanding of ecological functions of champak floral VOCs, but also provide biotechnological targets for sustainable production of champak floral scent. PMID: 28615048 [PubMed - indexed for MEDLINE]

Related Articles Metabolic Flexibility in Health and Disease. Cell Metab. 2017 May 02;25(5):1027-1036 Authors: Goodpaster BH, Sparks LM Abstract Metabolic flexibility is the ability to respond or adapt to conditional changes in metabolic demand. This broad concept has been propagated to explain insulin resistance and mechanisms governing fuel selection between glucose and fatty acids, highlighting the metabolic inflexibility of obesity and type 2 diabetes. In parallel, contemporary exercise physiology research has helped to identify potential mechanisms underlying altered fuel metabolism in obesity and diabetes. Advances in "omics" technologies have further stimulated additional basic and clinical-translational research to further interrogate mechanisms for improved metabolic flexibility in skeletal muscle and adipose tissue with the goal of preventing and treating metabolic disease. PMID: 28467922 [PubMed - indexed for MEDLINE]

Related Articles Metabonomics-based analysis of Brachyspira pilosicoli's response to tiamulin reveals metabolic activity despite significant growth inhibition. Anaerobe. 2017 Jun;45:71-77 Authors: Le Roy CI, Passey JL, Woodward MJ, La Ragione RM, Claus SP Abstract Pathogenic anaerobes Brachyspira spp. are responsible for an increasing number of Intestinal Spirochaetosis (IS) cases in livestock against which few approved treatments are available. Tiamulin is used to treat swine dysentery caused by Brachyspira spp. and recently has been used to handle avian intestinal spirochaetosis (AIS). The therapeutic dose used in chickens requires further evaluation since cases of bacterial resistance to tiamulin have been reported. In this study, we evaluated the impact of tiamulin at varying concentrations on the metabolism of B. pilosicoli using a 1H-NMR-based metabonomics approach allowing the capture of the overall bacterial metabolic response to antibiotic treatment. Based on growth curve studies, tiamulin impacted bacterial growth even at very low concentration (0.008 μg/mL) although its metabolic activity was barely affected 72 h post exposure to antibiotic treatment. Only the highest dose of tiamulin tested (0.250 μg/mL) caused a major metabolic shift. Results showed that below this concentration, bacteria could maintain a normal metabolic trajectory despite significant growth inhibition by the antibiotic, which may contribute to disease reemergence post antibiotic treatment. Indeed, we confirmed that B. pilosicoli remained viable even after exposition to the highest antibiotic dose. This paper stresses the need to ensure new evaluation of bacterial viability post bacteriostatic exposure such as tiamulin to guarantee treatment efficacy and decrease antibiotic resistance development. PMID: 28373121 [PubMed - indexed for MEDLINE]

Related Articles Regulating dyslipidemia effect of polysaccharides from Pleurotus ostreatus on fat-emulsion-induced hyperlipidemia rats. Int J Biol Macromol. 2017 Aug;101:107-116 Authors: Zhang Y, Wang Z, Jin G, Yang X, Zhou H Abstract This study was conducted to evaluate the regulating dyslipidemia effect of polysaccharides from Pleurotus ostreatus (POP) on fat-emulsion-induced hyperlipidemia rats. A plasma metabonomics method based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry was applied to analyze the holistic mechanism of POP in a hyperlipidemia rat model. Multivariate statistical approaches such as principal component analysis and orthogonal projection to latent structure square-discriminant analysis revealed distinctions among the control, hyperlipidemia model, and POP groups.The results demonstrated that POP had an effect on regulating dyslipidemia. The mechanism of POP on regulating dyslipidemia was partially relevant with correcting the abnormal levels of fifteen potential biomarkers towards their normal levels. These biomarkers were belong to glycerophospholipids, fatty acids, prenol lipids, sphingolipids metabolism. PMID: 28322967 [PubMed - indexed for MEDLINE]

Related Articles Assessing Sertoli Cell Metabolic Activity. Methods Mol Biol. 2018;1748:157-171 Authors: Jarak I, Oliveira PF, Rindone G, Carvalho RA, Galardo MN, Riera MF, Meroni SB, Alves MG Abstract Nuclear magnetic resonance (NMR)-based metabolomics is widely used in the research of metabolic conditions of complex biological systems under various conditions, and its use has been found in the field of male fertility. Here we describe the implementation of total and targeted NMR-based metabolomics in the research on Sertoli cell metabolism. Main principles and techniques of cell medium, cellular extracts, and intact cells are explained, as well as some classical experiments that can give complementary information on the Sertoli cell metabolism. PMID: 29453571 [PubMed - in process]

Related Articles Next-generation metabolic screening: targeted and untargeted metabolomics for the diagnosis of inborn errors of metabolism in individual patients. J Inherit Metab Dis. 2018 Feb 16;: Authors: Coene KLM, Kluijtmans LAJ, van der Heeft E, Engelke UFH, de Boer S, Hoegen B, Kwast HJT, van de Vorst M, Huigen MCDG, Keularts IMLW, Schreuder MF, van Karnebeek CDM, Wortmann SB, de Vries MC, Janssen MCH, Gilissen C, Engel J, Wevers RA Abstract The implementation of whole-exome sequencing in clinical diagnostics has generated a need for functional evaluation of genetic variants. In the field of inborn errors of metabolism (IEM), a diverse spectrum of targeted biochemical assays is employed to analyze a limited amount of metabolites. We now present a single-platform, high-resolution liquid chromatography quadrupole time of flight (LC-QTOF) method that can be applied for holistic metabolic profiling in plasma of individual IEM-suspected patients. This method, which we termed "next-generation metabolic screening" (NGMS), can detect >10,000 features in each sample. In the NGMS workflow, features identified in patient and control samples are aligned using the "various forms of chromatography mass spectrometry (XCMS)" software package. Subsequently, all features are annotated using the Human Metabolome Database, and statistical testing is performed to identify significantly perturbed metabolite concentrations in a patient sample compared with controls. We propose three main modalities to analyze complex, untargeted metabolomics data. First, a targeted evaluation can be done based on identified genetic variants of uncertain significance in metabolic pathways. Second, we developed a panel of IEM-related metabolites to filter untargeted metabolomics data. Based on this IEM-panel approach, we provided the correct diagnosis for 42 of 46 IEMs. As a last modality, metabolomics data can be analyzed in an untargeted setting, which we term "open the metabolome" analysis. This approach identifies potential novel biomarkers in known IEMs and leads to identification of biomarkers for as yet unknown IEMs. We are convinced that NGMS is the way forward in laboratory diagnostics of IEMs. PMID: 29453510 [PubMed - as supplied by publisher]

Related Articles Integrated Metabolomics and Morphogenesis Reveals Volatile Signaling of the Nematode-Trapping Fungus Arthrobotrys oligospora. Appl Environ Microbiol. 2018 Feb 16;: Authors: Wang BL, Chen YH, He JN, Xue HX, Yan N, Zeng ZJ, Bennett JW, Zhang KQ, Niu XM Abstract The adjustment of metabolic patterns is fundamental to fungal biology and plays vital roles in adaption to diverse ecological challenges. Nematode trapping fungi can switch lifestyles from saprophytic to pathogenic by developing specific trapping devices induced by nematodes to infect their prey as a response to nutrient depletion in nature. However, the chemical identity of the specific fungal metabolites used during the switch remains poorly understood. We hypothesized that these important signal molecules might be volatile in nature. GC-MS was used to carry out comparative analysis of fungal metabolomics during saprophytic and pathogenic lifestyles of the model species Arthrobotrys oligospora Two media commonly used in research on this species, corn meal agar (CMA) and potato dextrose agar (PDA), were chosen in this study. The fungus produced a small group of volatile furanone and pyrone metabolites that were associated with the switch from saprophytic to pathogenic stages. A. oligospora grown on CMA tended to produce more traps and employ attractive furanones to improve utilization of traps, while fungus grown on PDA developed fewer traps and used nematodetoxic furanone metabolites to compensate for insufficient traps. Another volatile pyrone metabolite, maltol, was identified as a morphological regulator for enhancing trap formation. Deletion of gene AOL_s00079g496 in A. oligospora led to increased furanone attractant (2 folds) in mutants and enhanced attractive activity (1.5 fold) of the fungus, while resulted in decreased trap formation. This investigation provides new insights regarding the comprehensive tactics of fungal adaptation to environmental stress, integrating both morphological and metabolomic mechanisms.Importance Nematode-trapping fungi are a unique group of soil-living fungi that can switch from saprophytic to pathogenic lifestyle once in contact with nematodes as a response to nutrient depletion. In this study, we investigated the metabolic response during the switch and the key types of metabolites involved in the interaction between fungi and nematodes. Our findings indicated that A. oligospora develop multiple and flexible metabolic tactics corresponding to different morphological responses to nematodes. A. oligospora can use similar volatile furanone and pyrone metabolites with different ecological functions to help capture nematodes in the fungal switch from saprophytic to pathogenic lifestyles. Furthermore, A. oligospora mutants with increased furanone and pyrone metabolites confirmed the results. This investigation reveals the importance of volatile signaling in the comprehensive tactics used by nematode trapping fungi, integrating both morphological and metabolomic mechanisms. PMID: 29453265 [PubMed - as supplied by publisher]

Related Articles 1H NMR-based metabolomics reveals interactive effects between the carrier solvent methanol and a pharmaceutical mixture in an amphibian developmental bioassay with Limnodynastes peronii. Chemosphere. 2018 Feb 10;199:372-381 Authors: Melvin SD, Jones OAH, Carroll AR, Leusch FDL Abstract Organic carrier solvents are used in aquatic toxicity testing to improve chemical solubility and facilitate the exploration of dose-response relationships. Both water- and solvent-control groups are normally included in these scenarios to ensure that the solvent itself has no effect on the test organism, but this fails to consider possible interactive effects between carrier solvents and contaminants of interest. We explored this topic by exposing Limnodynastes peronii tadpoles to a mixture of common water-soluble pharmaceuticals (diclofenac, metformin and valproic acid) in the presence and absence of the carrier solvent methanol, according to standard developmental bioassay methodology. Nuclear Magnetic Resonance (NMR) spectroscopy was applied as a platform for untargeted metabolomics, to compare broad sub-lethal hepatotoxicity in solvent- and solvent-free exposure scenarios. Considerable interactive effects were identified between the pharmaceutical mixture and a typical dose of methanol (0.003%). Specifically, pronounced differences were observed between the solvent- and solvent-free exposure groups for leucine, acetate, glutamine, citrate, glycogen, tyrosine, arginine, purine nucleotides and an unidentified metabolite at 6.53 ppm. Various other metabolites exhibited similar disparity related to the use of carrier solvent, but the interactions were non-significant. These results raise important questions about the use of carrier solvents for chemical exposures in aquatic ecotoxicology, and particularly for studies interested in sub-lethal mechanistic information and/or biomarker discovery. PMID: 29453063 [PubMed - as supplied by publisher]

Related Articles Evaluation of the anti-hypertensive effect of Tengfu Jiangya tablet by combination of UPLC-Q-exactive-MS-based metabolomics and iTRAQ-based proteomics technology. Biomed Pharmacother. 2018 Feb 13;100:324-334 Authors: Tian Y, Jiang F, Li Y, Jiang H, Chu Y, Zhu L, Guo W Abstract OBJECTIVE: Tengfu Jiangya tablet (TJT) is a traditional Chinese medicine formulation composed of Uncaria rhynchophylla and Semen raphani. It is a hospital preparation that is widely used in clinics for treating hypertension. A previous metabolomics study reported that TJT exerted a protective effect on hypertension by restoring impaired NO production, ameliorating the inflammatory state, and vascular remodeling. A clinical proteomics study also revealed five key target proteins during TJT intervention. This study aimed to integrate proteome and metabolome data sets for a holistic view of the molecular mechanisms of TJT in treating hypertension. METHODS: Serum samples from spontaneously hypertensive rats and Wistar Kyoto rats were analyzed using ultra-high performance liquid chromatography coupled to Q Exactive hybrid quadrupole-Orbitrap mass spectrometry (UPLC-Q-Exactive-MS)-based metabolomics technology and isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomics technology. Moreover, we selected two candidate proteins and determined their expression levels in rat serum using an enzyme-linked immunosorbent assay (ELISA). RESULTS: A total of 20 potential biomarkers and 14 differential proteins in rat serum were identified. These substances were mainly involved in three biological pathways: the kallikrein-kinin pathway, the lipid metabolism pathway, and the PPARγ signaling pathway. CONCLUSIONS: The results suggested that TJT could effectively treat hypertension, partially by regulating the above three metabolic pathways. The combination of proteomics and metabolomics provided a feasible method to uncover the underlying interventional effect and therapeutic mechanism of TJT on spontaneously hypertensive rats. PMID: 29453042 [PubMed - as supplied by publisher]

Related Articles Metabolomic profiling of Campylobacter jejuni with resistance gene ermB by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry and tandem quadrupole mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2018 Feb 10;1079:62-68 Authors: Fu Q, Liu D, Wang Y, Li X, Wang L, Yu F, Shen J, Xia X Abstract The metabolome changes of Campylobacter jejuni with resistant gene ermB remain unclear. Here, we described an untargeted metabolomic workflow based on ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry to investigate the metabolites perturbations mediated by ermB in C. jejuni. After optimization of extractants and chromatographic conditions, the combination of 100% methanol extraction with a 12 min gradient by C18 column was adopted for untargeted metabolomic profiling in reversed phase separation. Meanwhile, 60% methanol extraction followed by a 14 min separation using hydrophilic interaction chromatography column was suitable to complementally expand the metabolite coverage of C. jejuni. Multivariate statistical analysis was performed by means of orthogonal projection to latent structures-discriminant analysis to select metabolic features. The selected features were further confirmed by ultra-high performance liquid chromatography-tandem quadrupole mass spectrometry. A total of thirty-six differential metabolites between the susceptible strain (C. jejuni NCTC 11168) and resistant stain (C. jejuni NCTC 11168 with ermB) were identified. These pivotal metabolites were primarily participated in biological processes as cell signaling, membrane integrity/stability, fuel and energy source/storage and nutrient. The biofilm formation capability of resistant strain was inferior to that of susceptible strain, confirming the influence of ermB on membrane integrity/stability of C. jejuni. Our findings revealed important metabolic regulatory pathways associated with resistant C. jejuni with ermB. PMID: 29453015 [PubMed - as supplied by publisher]

Related Articles Metabolic and Lipidomic Reprogramming in Renal Cell Carcinoma Subtypes Reflects Regions of Tumor Origin. Eur Urol Focus. 2018 Feb 13;: Authors: Schaeffeler E, Büttner F, Reustle A, Klumpp V, Winter S, Rausch S, Fisel P, Hennenlotter J, Kruck S, Stenzl A, Wahrheit J, Sonntag D, Scharpf M, Fend F, Agaimy A, Hartmann A, Bedke J, Schwab M Abstract BACKGROUND: Renal cell carcinoma (RCC) consists of prognostic distinct subtypes derived from different cells of origin (eg, clear cell RCC [ccRCC], papillary RCC [papRCC], and chromophobe RCC [chRCC]). ccRCC is characterized by lipid accumulation and metabolic alterations, whereas data on metabolic alterations in non-ccRCC are limited. OBJECTIVE: We assessed metabolic alterations and the lipid composition of RCC subtypes and ccRCC-derived metastases. Moreover, we elucidated the potential of metabolites/lipids for subtype classification and identification of therapeutic targets. DESIGN, SETTING, AND PARTICIPANTS: Metabolomic/lipidomic profiles were quantified in ccRCC (n=58), chRCC (n=19), papRCC (n=14), corresponding nontumor tissues, and metastases (n=9) through a targeted metabolomic approach. Transcriptome profiling was performed in corresponding samples and compared with expression data of The Cancer Genome Atlas cohorts (patients with ccRCC, n=452; patients with papRCC, n=260; and patients with chRCC, n=59). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: In addition to cluster analyses, metabolomic/transcriptomic data were analyzed to evaluate metabolic differences of ccRCC and chRCC using Welch's t test or paired t test as appropriate. Where indicated, p values were adjusted for multiple testing using Bonferroni or Benjamini-Hochberg correction. RESULTS AND LIMITATIONS: Based on their metabolic profiles, RCC subtypes clustered into two groups separating ccRCC and papRCC from chRCC, which mainly reflected the different cells of origin. ccRCC-derived metastases clustered with primary ccRCCs. In addition to differences in certain lipids (lysophosphatidylcholines and sphingomyelins), the coregulation network of lipids differed between ccRCC and chRCC. Consideration of metabolic gene expression indicated, for example, alterations of the polyamine pathway at metabolite and transcript levels. In vitro treatment of RCC cells with the ornithine-decarboxylase inhibitor difluoromethylornithine resulted in reduced cell viability and mitochondrial activity. Further evaluation of clinical utility was limited by the retrospective study design and cohort size. CONCLUSIONS: In summary, we provide novel insight into the metabolic profiles of ccRCC and non-ccRCC, thereby confirming the different ontogeny of RCC subtypes. Quantification of differentially regulated metabolites/lipids improves classification of RCC with an impact on the identification of novel therapeutic targets. PATIENT SUMMARY: Several subtypes of renal cell carcinoma (RCC) with different metastatic potentials and prognoses exist. In the present study, we provide novel insight into the metabolism of these different subtypes, which improves classification of subtypes and helps identify novel targets for RCC therapy. PMID: 29452772 [PubMed - as supplied by publisher]