PubMed

Priorities for future research into asthma diagnostic tools: A PAN-EU Consensus exercise from the European asthma research innovation partnership (EARIP). Clin Exp Allergy. 2017 Dec 31;: Authors: Garcia-Marcos L, Edwards J, Kennington E, Aurora P, Baraldi E, Carraro S, Gappa M, Louis R, Moreno-Galdo A, Peroni DG, Pijnenburg M, Priftis KN, Sanchez-Solis M, Schuster A, Walker S, EARIP collaboration Abstract The diagnosis of asthma is currently based on clinical history, physical examination and lung function; and to date there are no accurate objective tests either to confirm the diagnosis or to discriminate between different types of asthma. This consensus exercise reviews the state-of-the-art in asthma diagnosis to identify opportunities for future investment based on the likelihood of their successful development, potential for widespread adoption and their perceived impact on asthma patients. Using a two-stage e-Delphi process and a summarising workshop, a group of European asthma experts including health professionals, researchers, people with asthma and industry representatives ranked the potential impact of research investment in each technique or tool for asthma diagnosis and monitoring. After a systematic review of the literature, 21 statements were extracted and were subject of the two-stage Delphi process. Eleven statements were scored 3 or more and were further discussed and ranked in a face to face workshop. The three most important diagnostic/predictive tools ranked were: "New biological markers of asthma (e.g. genomics, proteomics and metabolomics) as a tool for diagnosis and/or monitoring", "Prediction of future asthma in preschool children with reasonable accuracy" and "Tools to measure volatile organic compounds (VOCs) in exhaled breath". This article is protected by copyright. All rights reserved. PMID: 29290104 [PubMed - as supplied by publisher]

A multi-omics analysis reveals metabolic reprogramming in THP-1 cells upon treatment with the contact allergen DNCB. Toxicol Appl Pharmacol. 2017 Dec 28;: Authors: Mussotter F, Potratz S, Budczies J, Luch A, Haase A Abstract Dendritic cell (DC) activation by contact allergens is one of the key steps in the development of allergic contact dermatitis (ACD). Recent evidence suggests that metabolic reprogramming is a prerequisite for the activation of DCs, macrophages and monocytes. Therefore, we used an integrated approach by combining proteomics and metabolomics to investigate the metabolism of human THP-1 cells in response to the strong contact allergen, 2,4-dinitrochlorobenzene (DNCB). Cells were treated with 5, 10 and 20μM DNCB for 4, 8, and 24h, respectively. Using a targeted metabolomics approach, we quantified levels of 188 endogenous metabolites, among them phospholipids, acylcarnitines, amino acids and hexoses. In addition, proteomic changes were analyzed using an untargeted quantitative approach based on stable isotope labeling with amino acids in cell culture (SILAC). We detected several alterations in the metabolome and consistently in the proteome indicating metabolic reprogramming of THP-1 cells by DNCB. In particular, we found an increase in phospholipids that was accompanied by an up-regulation of fatty acid synthase (FAS), a key enzyme in lipid synthesis. PMID: 29289672 [PubMed - as supplied by publisher]

Construction, immune protection and innate immune response of shuffled polyvalent ompAs vaccines. Fish Shellfish Immunol. 2017 Dec 28;: Authors: Wang SN, Cheng ZX, Ling XP, Chu X, Peng XX, Li H Abstract Our previous studies demonstrated that molecular breeding via DNA shuffling directs the evolution of polyvalent vaccines with desired traits, which leads to generation of polyvalent ompA vaccines using Vibrio alginolyticus VA0764 primers. Here, we replaced VA0764 primers with Edwardsiella tarda ompA primers to generate new polyvalent ompA vaccines by DNA shuffling of the same five ompA genes from four species of bacteria E. tarda, V. parahaemolyticus, V. alginolyticus and Escherichia coli. We identified four polyvalent vaccine candidates from a eukaryotic expressing library EompAs-FE containing 82 ompAs using active immune protection against V. alginolyticus and E. tarda. Furthermore, we explored mechanisms of polyvalent vaccine candidates by investigation of the innate immune response to these ompAs, and found that expression of IL-1β, IL-8, IL-15, COX-2, IFN-γ, TLR-1, TLR-3 and C3b genes was elevated as a characteristic feature of these polyvalent vaccine candidates. These results indicate that use of different primers to construct a DNA library selects new evolution of polyvalent vaccines with desired traits, and polyvalent ompA vaccines elicit high innate immune response. PMID: 29289655 [PubMed - as supplied by publisher]

Mass spectrometry based analytical approaches and pitfalls for toxicometabolomics of arsenic in mammals: A tutorial review. Anal Chim Acta. 2018 Feb 13;1000:41-66 Authors: García-Barrera T, Rodríguez-Moro G, Callejón-Leblic B, Arias-Borrego A, Gómez-Ariza JL Abstract The present review focus on the analytical platforms and the workflow for toxicometabolomics with a special emphasis on their strengths and pitfalls presenting as a case study the toxicometabolomics of arsenic in mammals. Although powerful analytical methods and techniques are currently available for metabolomics, the main "bottleneck" is still the absence of unified protocols for sample preparation (e.g. quenching, solvents used) as well as several important factors in toxicometabolomics, which drastically affect the metabolism (e.g. selection of model organisms, xenobiotic doses, chemical form of the xenobiotic, exposure route, biological sample). In this context, the applicability to complex samples, higher sensitivity, specificity and the possibility to perform quantitative analysis offered by MS is crucial to probe xenobiotic induced metabolic changes to evaluate the stress responses. Nowadays, the use of different metabolomic platforms allowed determining important changes in the metabolism induced by arsenic in mammals such as alterations in the energy (e.g. Glycolysis, Kreb's cycle), amino acid, lipid, nucleotide and androgen metabolisms. PMID: 29289324 [PubMed - in process]

Related Articles Effect of pomegranate based marinades on the microbiological, chemical and sensory quality of chicken meat: A metabolomics approach. Int J Food Microbiol. 2017 Dec 21;267:42-53 Authors: Lytou AE, Nychas GE, Panagou EZ Abstract Pomegranate juice is a product with enhanced functional properties that could be used as an alternative to traditional marination ingredients and effectively retard microbial growth along with providing an improved sensory result. In this study, two pomegranate based marinades were prepared for the marination of chicken breast fillets and the marinated samples were aerobically stored at 4 and 10°C for 9days. Raw, non-marinated chicken samples were used as control. Levels of total viable counts (TVC), Pseudomonas spp., Brochothrix thermosphacta, Enterobacteriaceae and lactic acid bacteria (LAB) were determined together with sensory assessment to evaluate the evolution of spoilage. The profile of organic acids and volatile compounds was also analyzed during storage. The shelf life of marinated samples was significantly extended compared to control samples at both storage temperatures (e.g., up to 5 and 6days for the pomegranate/lemon marinated samples stored at 4 and 10°C, respectively) as evaluated by both microbiological and sensory analyses. The profile of the organic acids and the volatilome of marinated and control samples were remarkably differentiated according to storage time, microbial load and sensory score. The findings of this study suggest that pomegranate juice could be used as a novel ingredient in marinades to improve the sensory attributes, while prolonging the shelf life of chicken meat. PMID: 29288907 [PubMed - as supplied by publisher]

Related Articles Untargeted metabolic profiling reveals distinct patterns of thermal sensitivity in two related notothenioids. Comp Biochem Physiol A Mol Integr Physiol. 2017 Dec 27;: Authors: Rebelein A, Pörtner HO, Bock C Abstract Antarctic marine ectothermal animals may be affected more than temperate species by rising temperatures due to ongoing climate change. Their specialisation on stable cold temperatures make them vulnerable to even small degrees of warming. Thus, addressing the impacts of warming on Antarctic organisms and identifying their potentially limited capacities to respond is of interest. The objective of the study was to determine changes in metabolite profiles related to temperature acclimation. In a long-term experiment adult fish of two Antarctic sister species Notothenia rossii and Notothenia coriiceps were acclimated to 0 °C and 5 °C for three months. Impacts and indicators of acclimation at the cellular level were determined from metabolite profiles quantified in gill tissue extracts using nuclear magnetic resonance (NMR) spectroscopy. Furthermore, the metabolite profiles of the two con-generic species were compared. NMR spectroscopy identified 37 metabolites that were present in each sample, but varied in their absolute concentration between species and between treatments. A decrease in amino acid levels indicated an increased amino acid catabolism after incubation to 5°C. In addition, long term warming initiated shifts in organic osmolyte concentrations and modified membrane structure observed by altered levels of phospholipid compounds. Differences in the metabolite profile between the two notothenioid species can be related to their divergent lifestyles, especially their different rates of motor activity. Increased levels of the Krebs cycle intermediate succinate and a higher reduction of amino acid concentrations in warm-acclimated N. rossii showed that N. rossii is more affected by warming than N. coriiceps. PMID: 29288768 [PubMed - as supplied by publisher]

Related Articles Cohort profile: the Emory Cardiovascular Biobank (EmCAB). BMJ Open. 2017 Dec 29;7(12):e018753 Authors: Ko YA, Hayek S, Sandesara P, Samman Tahhan A, Quyyumi A Abstract PURPOSE: The Emory Cardiovascular Biobank (EmCAB) is an ongoing prospective registry of patients undergoing cardiac catheterisation, which was established to identify novel factors associated with the pathobiological process and treatment of cardiovascular disease. PARTICIPANTS: Individuals aged 18 years and older undergoing cardiac catheterisation at three Emory Healthcare sites in Atlanta are asked to participate in this prospective registry. Around 95% agree to participate. Around 7000 unique patients have been enrolled. The current data set contains detailed phenotyping, patient outcomes, genomics, protein biomarkers, regenerative markers, transcriptomic analysis, metabolomics profiling and longitudinal follow-up for adverse cardiovascular outcomes. FINDINGS TO DATE: Thus far, the EmCAB has approximately 3000 major cardiovascular events. About 48% of the EmCAB participants have more than 5 years of follow-up. It is a great resource for discovery of novel predictive factors for cardiovascular disease outcomes, including genomics, transcriptomics, protein biomarkers, oxidative stress markers and circulating progenitor cells. Several circulating inflammatory markers have shown to improve risk prediction metrics beyond standard risk factors. FUTURE PLANS: Future integrative -omics analyses will provide the cardiovascular research community opportunities for subsequent mechanistic confirmation studies, which will promote the development of effective personalised therapy that leads to clinical care tailored to the individual patient. PMID: 29288185 [PubMed - in process]

Related Articles Sphingolipid Metabolic Pathway Impacts Thiazide Diuretics Blood Pressure Response: Insights From Genomics, Metabolomics, and Lipidomics. J Am Heart Assoc. 2017 Dec 29;7(1): Authors: Shahin MH, Gong Y, Frye RF, Rotroff DM, Beitelshees AL, Baillie RA, Chapman AB, Gums JG, Turner ST, Boerwinkle E, Motsinger-Reif A, Fiehn O, Cooper-DeHoff RM, Han X, Kaddurah-Daouk R, Johnson JA Abstract BACKGROUND: Although hydrochlorothiazide (HCTZ) is a well-established first-line antihypertensive in the United States, <50% of HCTZ treated patients achieve blood pressure (BP) control. Thus, identifying biomarkers that could predict the BP response to HCTZ is critically important. In this study, we utilized metabolomics, genomics, and lipidomics to identify novel pathways and biomarkers associated with HCTZ BP response. METHODS AND RESULTS: First, we conducted a pathway analysis for 13 metabolites we recently identified to be significantly associated with HCTZ BP response. From this analysis, we found the sphingolipid metabolic pathway as the most significant pathway (P=5.8E-05). Testing 78 variants, within 14 genes involved in the sphingolipid metabolic canonical pathway, with the BP response to HCTZ identified variant rs6078905, within the SPTLC3 gene, as a novel biomarker significantly associated with the BP response to HCTZ in whites (n=228). We found that rs6078905 C-allele carriers had a better BP response to HCTZ versus noncarriers (∆SBP/∆DBP: -11.4/-6.9 versus -6.8/-3.5 mm Hg; ∆SBP P=6.7E-04; ∆DBP P=4.8E-04). Additionally, in blacks (n=148), we found genetic signals in the SPTLC3 genomic region significantly associated with the BP response to HCTZ (P<0.05). Last, we observed that rs6078905 significantly affects the baseline level of 4 sphingomyelins (N24:2, N24:3, N16:1, and N22:1; false discovery rate <0.05), from which N24:2 sphingomyelin has a significant correlation with both HCTZ DBP-response (r=-0.42; P=7E-03) and SBP-response (r=-0.36; P=2E-02). CONCLUSIONS: This study provides insight into potential pharmacometabolomic and genetic mechanisms underlying HCTZ BP response and suggests that SPTLC3 is a potential determinant of the BP response to HCTZ. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00246519. PMID: 29288159 [PubMed - in process]

Related Articles 17,18-EpETE-GPR40 axis ameliorates contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques. J Allergy Clin Immunol. 2017 Dec 26;: Authors: Nagatake T, Shiogama Y, Inoue A, Kikuta J, Honda T, Tiwari P, Kishi T, Yanagisawa A, Isobe Y, Matsumoto N, Shimojou M, Morimoto S, Suzuki H, Hirata S, Steneberg P, Edlund H, Aoki J, Arita M, Kiyono H, Yasutomi Y, Ishii M, Kabashima K, Kunisawa J Abstract BACKGROUND: Metabolites of eicosapentaenoic acid (EPA) exert various physiological actions. 17,18-epoxyeicosatetraenoic acid (17,18-EpETE) is a recently identified new class of anti-allergic and anti-inflammatory lipid metabolite of EPA, but its effects on skin inflammation and the underlying mechanisms remain to be investigated. OBJECTIVE: We evaluated the effectiveness of 17,18-EpETE for the control of contact hypersensitivity in mouse and cynomolgus macaques. We further sought to reveal underlying mechanisms by identifying the responsible receptor and cellular target of 17,18-EpETE. METHODS: Contact hypersensitivity was induced by topical application of 2,4-dinitrofluorobenzene. Skin inflammation and immune cell populations were analyzed by flow cytometric, immunohistologic and quantitative RT-PCR analyses. Neutrophil mobility was examined by imaging analysis in vivo and neutrophil culture in vitro. The receptor for 17,18-EpETE was identified by using the TGFα-shedding assay and receptor's involvement in the anti-inflammatory effects of 17,18-EpETE was examined by using KO mice and specific inhibitor treatment. RESULTS: We found that preventive or therapeutic treatment with 17,18-EpETE ameliorated contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques. 17,18-EpETE was recognized by GPR40 (also known as free fatty acid receptor 1) and inhibited chemoattractant-induced Rac activation and pseudopod formation in neutrophils. Indeed, the anti-allergic inflammatory effect of 17,18-EpETE was abolished in the absence or inhibition of GPR40. CONCLUSION: 17,18-EpETE inhibits neutrophil mobility through the activation of GPR40, which is a potential therapeutic target to control allergic inflammatory diseases. PMID: 29288079 [PubMed - as supplied by publisher]

Related Articles Bioaccessibility of phenolic compounds following in vitro large intestine fermentation of nuts for human consumption. Food Chem. 2018 Apr 15;245:633-640 Authors: Rocchetti G, Chiodelli G, Giuberti G, Lucini L Abstract A bioaccessibility study of polyphenols after in vitro simulated large intestine fermentation was carried out on edible nuts. Raw nuts were also analysed for total phenolic content and antioxidant potential, considering both bound and free phenolics. The highest phenolic content was found in walnuts, followed by pistachios extracts (596.9 and 410.1 mg gallic acid equivalents 100 g-1, respectively). Consistently, the total antioxidant capacity was highest in walnuts (3689.7 μM trolox equivalents 100 g-1) followed by peanuts and pistachios (3169.6 and 2990.1 μM trolox equivalents 100 g-1, respectively). Data showed high correlations between total phenolics and both antioxidant activities. The metabolomics-based phenolic profile depicted during in vitro fermentation showed a degradation of higher-molecular-weight phenolics over 48 hours of faecal fermentation, with a concurrent increase in low-molecular-weight compounds (hydroxybenzoic and hydroxycinnamic acids, alkylphenols, and tyrosols). Our findings indicate that nuts deliver polyphenols into the colon, with bioaccessibility values not negligible for alkylphenols, tyrosols and phenolic acids. PMID: 29287419 [PubMed - in process]

Related Articles Metabolomics fingerprint of coffee species determined by untargeted-profiling study using LC-HRMS. Food Chem. 2018 Apr 15;245:603-612 Authors: Souard F, Delporte C, Stoffelen P, Thévenot EA, Noret N, Dauvergne B, Kauffmann JM, Van Antwerpen P, Stévigny C Abstract Coffee bean extracts are consumed all over the world as beverage and there is a growing interest in coffee leaf extracts as food supplements. The wild diversity in Coffea (Rubiaceae) genus is large and could offer new opportunities and challenges. In the present work, a metabolomics approach was implemented to examine leaf chemical composition of 9 Coffea species grown in the same environmental conditions. Leaves were analyzed by LC-HRMS and a comprehensive statistical workflow was designed. It served for univariate hypothesis testing and multivariate modeling by PCA and partial PLS-DA on the Workflow4Metabolomics infrastructure. The first two axes of PCA and PLS-DA describes more than 40% of variances with good values of explained variances. This strategy permitted to investigate the metabolomics data and their relation with botanic and genetic informations. Finally, the identification of several key metabolites for the discrimination between species was further characterized. PMID: 29287415 [PubMed - in process]

Related Articles Statistical modelling coupled with LC-MS analysis to predict human upper intestinal absorption of phytochemical mixtures. Food Chem. 2018 Apr 15;245:353-363 Authors: Selby-Pham SNB, Howell KS, Dunshea FR, Ludbey J, Lutz A, Bennett L Abstract A diet rich in phytochemicals confers benefits for health by reducing the risk of chronic diseases via regulation of oxidative stress and inflammation (OSI). For optimal protective bio-efficacy, the time required for phytochemicals and their metabolites to reach maximal plasma concentrations (Tmax) should be synchronised with the time of increased OSI. A statistical model has been reported to predict Tmax of individual phytochemicals based on molecular mass and lipophilicity. We report the application of the model for predicting the absorption profile of an uncharacterised phytochemical mixture, herein referred to as the 'functional fingerprint'. First, chemical profiles of phytochemical extracts were acquired using liquid chromatography mass spectrometry (LC-MS), then the molecular features for respective components were used to predict their plasma absorption maximum, based on molecular mass and lipophilicity. This method of 'functional fingerprinting' of plant extracts represents a novel tool for understanding and optimising the health efficacy of plant extracts. PMID: 29287381 [PubMed - in process]

Related Articles NMR based metabolomic comparison of the antitussive and expectorant effect of Farfarae Flos collected at different stages. J Pharm Biomed Anal. 2017 Dec 13;150:377-385 Authors: Li J, Zhang ZZ, Lei ZH, Qin XM, Li ZY Abstract Farfarae Flos (FF) is widely used for the treatment of cough, bronchitis, and asthmatic disorders in the Traditional Chinese Medicine (TCM). According to the experience of TCM, only the flower bud can be used as herbal drug, and its medicinal quality becomes lower after blooming. However, the underlying scientific basis for this phenomenon is not fully understood. In this study, the chemical components and the bioactivities of the FF collected at three different development stages were compared systematically. NMR based fingerprint coupled with multivariate analysis showed that the flower buds differed greatly from the fully opened flower both on the secondary and primary metabolites, and the animal experiments showed that the fully opened flower exhibited no antitussive or expectorant effect. In addition, the endogenous metabolites correlated with the antitussive and expectorant effect of FF were also identified. These findings are useful for understanding the rationality of the traditional use of FF, and also suggested the components responsible for the antitussive and expectorant effect of FF. PMID: 29287265 [PubMed - as supplied by publisher]

Related Articles A combination of NMR and liquid chromatography to characterize the protective effects of Rhus tripartita extracts on ethanol-induced toxicity and inflammation on intestinal cells. J Pharm Biomed Anal. 2017 Dec 19;150:347-354 Authors: Ben Barka Z, Grintzalis K, Polet M, Heude C, Sommer U, Ben Miled H, Ben Rhouma K, Mohsen S, Tebourbi O, Schneider YJ Abstract Consumption of ethanol may have severe effects on human organs and tissues and lead to acute and chronic inflammation of internal organs. The present study aims at investigating the potential protective effects of three different extracts prepared from the leaves, root, and stem of the sumac, Rhus tripartita, against ethanol-induced toxicity and inflammation using intestinal cells as a cell culture system, in vitro model of the intestinal mucosa. The results showed an induction of cytotoxicity by ethanol, which was partially reversed by co-administration of the plant extracts. As part of investigating the cellular response and the mechanism of toxicity, the role of reduced thiols and glutathione-S-transferases were assessed. In addition, intestinal cells were artificially imposed to an inflammation state and the anti-inflammatory effect of the extracts was estimated by determination of interleukin-8. Finally, a detailed characterization of the contents of the three plant extracts by high resolution Nuclear Magnetic Resonance (NMR) spectroscopy and mass spectrometry revealed significant differences in their chemical compositions. PMID: 29287261 [PubMed - as supplied by publisher]

Related Articles Improving the discovery of secondary metabolite natural products using ion mobility-mass spectrometry. Curr Opin Chem Biol. 2017 Dec 26;42:160-166 Authors: Schrimpe-Rutledge AC, Sherrod SD, McLean JA Abstract Secondary metabolite discovery requires an unbiased, comprehensive workflow to detect unknown unknowns for which little to no molecular knowledge exists. Untargeted mass spectrometry-based metabolomics is a powerful platform, particularly when coupled with ion mobility for high-throughput gas-phase separations to increase peak capacity and obtain gas-phase structural information. Ion mobility data are described by the amount of time an ion spends in the drift cell, which is directly related to an ion's collision cross section (CCS). The CCS parameter describes the size, shape, and charge of a molecule and can be used to characterize unknown metabolomic species. Here, we describe current and emerging applications of ion mobility-mass spectrometry for prioritization, discovery and structure elucidation, and spatial/temporal characterization. PMID: 29287234 [PubMed - as supplied by publisher]

Related Articles Microprobe Capillary Electrophoresis Mass Spectrometry for Single-cell Metabolomics in Live Frog (Xenopus laevis) Embryos. J Vis Exp. 2017 Dec 22;(130): Authors: Onjiko RM, Portero EP, Moody SA, Nemes P Abstract The quantification of small molecules in single cells raises new potentials for better understanding the basic processes that underlie embryonic development. To enable single-cell investigations directly in live embryos, new analytical approaches are needed, particularly those that are sensitive, selective, quantitative, robust, and scalable to different cell sizes. Here, we present a protocol that enables the in situ analysis of metabolism in single cells in freely developing embryos of the South African clawed frog (Xenopus laevis), a powerful model in cell and developmental biology. This approach uses a capillary microprobe to aspirate a defined portion from single identified cells in the embryo, leaving neighboring cells intact for subsequent analysis. The collected cell content is analyzed by a microscale capillary electrophoresis electrospray ionization (CE-ESI) interface coupled to a high-resolution tandem mass spectrometer. This approach is scalable to various cell sizes and compatible with the complex three-dimensional structure of the developing embryo. As an example, we demonstrate that microprobe single-cell CE-ESI-MS enables the elucidation of metabolic cell heterogeneity that unfolds as a progenitor cell gives rise to descendants during development of the embryo. Besides cell and developmental biology, the single-cell analysis protocols described here are amenable to other cell sizes, cell types, or animal models. PMID: 29286491 [PubMed - in process]

Related Articles Metabolomic Analysis of 92 Pulmonary Embolism Patients from a Nested Case-control Study Identifies Metabolites Associated with Adverse Clinical Outcomes. J Thromb Haemost. 2017 Dec 29;: Authors: Zeleznik OA, Poole EM, Lindstrom S, Kraft P, Van Hylckama Vlieg A, Lasky-Su JA, Harrington LB, Hagan K, Kim J, Parry BA, Giordano N, Kabrhel C Abstract BACKGROUND: Patients with acute pulmonary embolism (PE) exhibit wide variation in clinical presentation and outcomes. Our understanding of the pathophysiologic mechanisms differentiating low-risk and high-risk PE is limited, so current risk-stratification efforts often fail to predict clinical deterioration and are insufficient to guide management. OBJECTIVES: To improve our understanding of the physiology differentiating low-risk from high-risk PE, we conducted the first-ever high-throughput metabolomics analysis (843 named metabolites) comparing PE patients across risk strata within a nested case-control study. PATIENTS/METHODS: We enrolled 92 patients diagnosed with acute PE and collected plasma within 24 hours of PE diagnosis. We used linear regression and pathway analysis to identify metabolites and pathways associated with PE risk-strata. RESULTS: When we compared 46 low-risk to 46 intermediate/high-risk PE, 50 metabolites were significantly different after multiple testing correction. These metabolites were enriched in the following pathways: TCA Cycle, Fatty Acid Metabolism (Acyl Carnitine), and Purine Metabolism, (Hypo)Xanthine/Inosine Containing. Additionally, Energy, Nucleotide, and Amino Acid pathways were down-regulated in intermediate/high-risk PE patients. When we compared 28 intermediate-risk to 18 high-risk PE patients, 41 metabolites differed at a nominal p-value level. These metabolites were enriched in Fatty Acid Metabolism (Acyl Cholines), and Hemoglobin and Porphyrin Metabolism. CONCLUSION: Our results suggest that high-throughput metabolomics can provide insight into the pathophysiology of PE. Specifically, changes in circulating metabolites reflect compromised energy metabolism in intermediate/high-risk PE patients. These findings demonstrate the important role metabolites play in the pathophysiology of PE and highlight metabolomics as a potential tool for risk stratification of PE. This article is protected by copyright. All rights reserved. PMID: 29285876 [PubMed - as supplied by publisher]

Related Articles MALDI-Imaging detects endogenous Digoxin in glioblastoma cells infected by Zika virus - would it be the oncolytic key? J Mass Spectrom. 2017 Dec 28;: Authors: de O Lima E, Guerreiro TM, Melo CFOR, de Oliveira DN, Machado D, Lancelloti M, Catharino RR Abstract Recently, microcephaly cases have increased in Americas and have been matter of concern due to Zika virus (ZIKV) recent outbreak. Previous studies have shown that ZIKV-infected progenitor neuronal cells present morphological abnormalities and increased rates of cell death, which may be indicators of microcephaly causes. As recent studies indicate Zika virus' tropism for brain cells, how would a glioblastoma (GBM) lineage behave under ZIKV infection, considering GBM the most common and malignant brain tumor in adults, presenting extreme chemoresistance and high morbidity and mortality rates? The current trend of using genetically engineered oncolytic pathogens as a safe way to eliminate tumors is under development, with trials already in course. Therefore, the present study evaluated the possible oncolytic effects and metabolomic alterations of Zika virus infection at human malignant M059J glioblastoma cells. Microscopic evaluation was performed using optical microscopy, which showed cytopathic effects induced by ZIKV at GBM cells. For the metabolomics study, both control and infected cell cultures were submitted to MALDI-MSI analysis. Mass spectrometry data were submitted to PLS-DA statistical analysis, and distinct biomarkers were elected for each infected groups. This study brings light to unexpectedly induced metabolic changes, as endogenous Digoxin as important biomarker for ZIKV-GBM group, associated with cytopathic effects induced by viral infection. These results evidences that genetically engineered ZIKV might be a potential new strategy for neural cancer management through the induction of endogenous digoxin synthesis in glioblastoma cells. PMID: 29285820 [PubMed - as supplied by publisher]

Related Articles Endogenous metabolites-mediated communication between OAT1/OAT3 and OATP1B1 may explain the association between SLCO1B1 SNPs and methotrexate toxicity. Clin Pharmacol Ther. 2017 Dec 29;: Authors: Martinez D, Muhrez K, Woillard JB, Berthelot A, Gyan E, Choquet S, Andrès CR, Marquet P, Barin-Le Guellec C Abstract Although OATP1B1 is not expressed in the kidney, polymorphisms in SLCO1B1 have been associated with methotrexate clearance or toxicity. This unexpected pharmacogenetic association may reflect remote communication between liver and kidney transporters. This study confirms the pharmacogenetic association with methotrexate toxicity in adult patients with hematological malignancies. Using a targeted urinary metabolomics approach, we identified 38 and 34 metabolites which were differentially excreted between wild-type and carriers of the c.388A>G or c.521T>C variant alleles, respectively, half of them being associated with methotrexate toxicity. These metabolites mainly consisted of fatty acid derivatives and microbiota catabolites, including glycine conjugates and other uremic toxins, all known OATs substrates. These results suggest that dysfunction of a transporter affects the excretion profile of endogenous or exogenous substrates, possibly through metabolite-mediated interactions involving other transport systems, even in distant organs. This opens the way for better comprehension of complex pharmacokinetics and transporter-mediated drug-drug or nutrient-drug interactions. This article is protected by copyright. All rights reserved. PMID: 29285751 [PubMed - as supplied by publisher]

Related Articles Renal oncocytoma characterized by the defective complex I of the respiratory chain boosts the synthesis of the ROS scavenger glutathione. Oncotarget. 2017 Dec 01;8(62):105882-105904 Authors: Kürschner G, Zhang Q, Clima R, Xiao Y, Busch JF, Kilic E, Jung K, Berndt N, Bulik S, Holzhütter HG, Gasparre G, Attimonelli M, Babu M, Meierhofer D Abstract Renal oncocytomas are rare benign tumors of the kidney and characterized by a deficient complex I (CI) enzyme activity of the oxidative phosphorylation (OXPHOS) system caused by mitochondrial DNA (mtDNA) mutations. Yet, little is known about the underlying molecular mechanisms and alterations of metabolic pathways in this tumor. We compared renal oncocytomas with adjacent matched normal kidney tissues on a global scale by multi-omics approaches, including whole exome sequencing (WES), proteomics, metabolomics, and metabolic pathway simulation. The abundance of proteins localized to mitochondria increased more than 2-fold, the only exception was a strong decrease in the abundance for CI subunits that revealed several pathogenic heteroplasmic mtDNA mutations by WES. We also observed renal oncocytomas to dysregulate main metabolic pathways, shunting away from gluconeogenesis and lipid metabolism. Nevertheless, the abundance of energy carrier molecules such as NAD+, NADH, NADP, ATP, and ADP were significantly higher in renal oncocytomas. Finally, a substantial 5000-fold increase of the reactive oxygen species scavenger glutathione can be regarded as a new hallmark of renal oncocytoma. Our findings demonstrate that renal oncocytomas undergo a metabolic switch to eliminate ATP consuming processes to ensure a sufficient energy supply for the tumor. PMID: 29285300 [PubMed]