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

PubMed

PubMed
NCBI: db=pubmed; Term=metabolomics
Updated: 1 hour 40 min ago

Identification of Metabolites in Coriander seeds (Coriandrum Sativum L.) Aided by Ultrahigh Resolution Total Correlation NMR Spectroscopy.

Fri, 15/02/2019 - 12:00
Identification of Metabolites in Coriander seeds (Coriandrum Sativum L.) Aided by Ultrahigh Resolution Total Correlation NMR Spectroscopy. Magn Reson Chem. 2019 Feb 14;: Authors: Verma A, Parihar R, Baishya B Abstract NMR is a fast method for obtaining a holistic snapshot of the metabolome and also offers quantitative information without separating the compounds present in a complex mixture. Identification of the metabolites present in a plant extract sample is a crucial step for all plant metabolomics studies. In the present work, we used various two dimensional (2D) NMR methods such as J-Resolved NMR, TOCSY, and HSQC NMR spectroscopy for the identification of thirty-six common metabolites present in Coriandrum sativum L. seed extract. The identified metabolites belong to the following classes: organic acids, amino acids, and carbohydrates. 1 H NMR spectra of such complex mixtures in general display tremendous signal overlap due to the presence of a large number of metabolites with closely resonating multiplet signals. This signal overlapping leads to ambiguity in an assignment and hence identification of metabolites becomes tedious or impossible in many cases. Therefore, the utility of pure-shift proton spectrum along the indirect (F1 ) dimension of the F1 -PSYCHE-TOCSY spectrum is demonstrated for overcoming ambiguity in assignment of metabolites in crowded spectral regions from Coriandrum sativum L. seed extract sample. Since pure-shift NMR methods yield ultra-high resolution spectrum (i.e., a singlet peak per chemical site) along one or more dimensions, such spectra provide better identification of metabolites compared to regular 2D TOCSY where signal overlap and peak distortions lead to ambiguity in the assignment. Nine metabolite peaks were unambiguously assigned by pure-shift F1 -PSYCHE-TOCSY spectrum which was unresolved in regular TOCSY spectrum. PMID: 30762898 [PubMed - as supplied by publisher]

Targeted metabolomic analysis of plasma metabolites in patients with coronary heart disease in southern China.

Fri, 15/02/2019 - 12:00
Targeted metabolomic analysis of plasma metabolites in patients with coronary heart disease in southern China. Medicine (Baltimore). 2019 Feb;98(7):e14309 Authors: Zhong Z, Liu J, Zhang Q, Zhong W, Li B, Li C, Liu Z, Yang M, Zhao P Abstract Coronary heart disease (CHD), one of the leading causes of death in the world, is a complex metabolic disorder due to genetic and environmental interactions. The potential mechanisms and diagnostic biomarkers for different types of coronary heart disease remain unclear. Metabolomics is increasingly considered to be a promising technology with the potential to identify metabolomic features in an attempt to distinguish the different stages of CHD.We aimed to investigate serum metabolite profiling between CHD patients and normal coronary artery (NCA) subjects and identify metabolic biomarkers associated with CHD progression in an ethnic Hakka population in southern China.Using a novel targeted metabolomics approach, we explored the metabolic characteristics of CHD patients. Blood samples from 302 patients with CHD and 59 NCA subjects were collected that analyses using targeted liquid-chromatography coupled with tandem mass spectrometry (LC-MS).A total of 361 blood samples were determined using targeted LC-MS. Plasma concentrations for trimetlylamine oxide (TMAO), choline, creatinine, and carnitine were significantly higher in patients with CHD compared to the NCA cohort. Further, we observed that the concentration of the 4 metabolites were higher than that of the NCA group in any group of CHD, which including acute myocardial infarction (AMI), unstable angina (UA), and stable angina (SA). In addition, the diagnostic model was constructed based on the metabolites identified and the ROC curve of the NCA subjects and CHD patients were performed. For choline and creatinine, the AUCs ranged from 0.720 to 0.733. For TMAO and carnitine, the AUCs ranged from 0.568 to 0.600.In conclusion, the current study illustrates the distribution of 4 metabolites between CHD patients and NCA subjects. Metabolomics analysis may yield novel predictive biomarkers that will potentially provide value for clinical diagnosis of CHD. PMID: 30762730 [PubMed - in process]

An in silico design of bioavailability for kinase inhibitors evaluating the mechanistic rationale in the CYP metabolism of erlotinib.

Fri, 15/02/2019 - 12:00
An in silico design of bioavailability for kinase inhibitors evaluating the mechanistic rationale in the CYP metabolism of erlotinib. J Mol Model. 2019 Feb 14;25(3):65 Authors: Chelli SM, Gupta P, Belliraj SK Abstract Soft spot analysis helps evaluate the site of the metabolic lability that impacts the bio-availability of the drug. However, given its laborious and time consuming experimentation, we propose a reliable and cheap in silico strategy. In this context, we hypothesized a mechanistic rationale for metabolism of erlotinib by the CYP3A4 enzyme. The comparison of the 3D conformations of the target CYP class of enzymes using MD simulations with GROMACS helped evaluate its impact on the metabolism. The molecular docking studies using Autodock-Vina ascertained the explicit role of the Fe ion present in the Heme moiety in this process. This mechanism was confirmed with respect to 13 other popular approved FDA kinase inhibitors using ab initio DFT calculations using Gaussian 09 (G09), molecular docking studies with Autodock-Vina, and MD simulations with GROMACS. We then developed a quantitative (Q-Met) metabolic profile of these soft spots in the molecules and demonstrated the lack of a linear relationship between the extent of metabolism and drug efficacy. We thus propose an economic in silico strategy for the early prediction of the lability in kinase inhibitors to help model their bio-availability and activity simultaneously, prior to clinical testing. PMID: 30762124 [PubMed - in process]

Personalization of therapies in rare diseases: a translational approach for the treatment of cystic fibrosis.

Fri, 15/02/2019 - 12:00
Related Articles Personalization of therapies in rare diseases: a translational approach for the treatment of cystic fibrosis. Minerva Pediatr. 2019 Feb 13;: Authors: Villella VR, Tosco A, Esposito S, Ferrari E, Bona G, Kroemer G, Raia V, Maiuri L Abstract High variability in the response rates to treatments can make the interpretation of data from clinical trials very difficult, particularly in rare genetic diseases in which the enrolment of thousands of patients is problematic. Personalized medicine largely depends on the establishment of appropriate early detectors of drug efficacy that may guide the administration (or discontinuation) of specific treatments. Such biomarkers should be capable of predicting the therapeutic response of individual patients and of monitoring early benefits of candidate drugs before late clinical benefits become evident. The identification of these biomarkers implies a rigorous stepwise process of translation from preclinical evaluation in cultured cells, suitable animal models or patient-derived freshly isolated cells to clinical application. In this review, we will discuss how a process of research translation can lead to the implementation of functional and mechanistic disease-relevant biomarkers. Moreover, we will address how preclinical data can be translated into the clinic in a personalized medical approach that can provide the right drug to the right patient within the right timeframe. PMID: 30761822 [PubMed - as supplied by publisher]

The Role of Glycosphingolipids in Immune Cell Functions.

Fri, 15/02/2019 - 12:00
Related Articles The Role of Glycosphingolipids in Immune Cell Functions. Front Immunol. 2019;10:90 Authors: Zhang T, de Waard AA, Wuhrer M, Spaapen RM Abstract Glycosphingolipids (GSLs) exhibit a variety of functions in cellular differentiation and interaction. Also, they are known to play a role as receptors in pathogen invasion. A less well-explored feature is the role of GSLs in immune cell function which is the subject of this review article. Here we summarize knowledge on GSL expression patterns in different immune cells. We review the changes in GSL expression during immune cell development and differentiation, maturation, and activation. Furthermore, we review how immune cell GSLs impact membrane organization, molecular signaling, and trans-interactions in cellular cross-talk. Another aspect covered is the role of GSLs as targets of antibody-based immunity in cancer. We expect that recent advances in analytical and genome editing technologies will help in the coming years to further our knowledge on the role of GSLs as modulators of immune cell function. PMID: 30761148 [PubMed - in process]

Metabolites predict cardiovascular disease events in persons living with HIV: a pilot case-control study.

Fri, 15/02/2019 - 12:00
Related Articles Metabolites predict cardiovascular disease events in persons living with HIV: a pilot case-control study. Metabolomics. 2018 Mar;14(3): Authors: Okeke NL, Craig DM, Muehlbauer MJ, Ilkayeva O, Clement ME, Naggie S, Shah SH Abstract Introduction: Persons living with HIV (PLWH) are at higher risk for cardiovascular disease (CVD) events than uninfected persons. Current risk-stratification methods to define PLWH at highest risk for CVD events are lacking. Methods: Using tandem flow injection mass spectrometry, we quantified plasma levels of 60 metabolites in 24 matched pairs of PLWH [1:1 with and without known coronary artery disease (CAD)]. Metabolite levels were reduced to interpretable factors using principal components analysis. Results: Factors derived from short-chain dicarboxylacylcarnitines (SCDA) (p = 0.08) and glutamine/valine (p = 0.003) were elevated in CAD cases compared to controls. Conclusion: SCDAs and glutamine/valine may be valuable markers of cardiovascular risk among persons living with HIV in the future, pending validation in larger cohorts. PMID: 30760970 [PubMed - in process]

Epigenetic findings in periodontitis in UK twins: a cross-sectional study.

Fri, 15/02/2019 - 12:00
Related Articles Epigenetic findings in periodontitis in UK twins: a cross-sectional study. Clin Epigenetics. 2019 Feb 13;11(1):27 Authors: Kurushima Y, Tsai PC, Castillo-Fernandez J, Couto Alves A, El-Sayed Moustafa JS, Le Roy C, Spector TD, Ide M, Hughes FJ, Small KS, Steves CJ, Bell JT Abstract BACKGROUND: Genetic and environmental risk factors contribute to periodontal disease, but the underlying susceptibility pathways are not fully understood. Epigenetic mechanisms are malleable regulators of gene function that can change in response to genetic and environmental stimuli, thereby providing a potential mechanism for mediating risk effects in periodontitis. The aim of this study is to identify epigenetic changes across tissues that are associated with periodontal disease. METHODS: Self-reported gingival bleeding and history of gum disease, or tooth mobility, were used as indicators of periodontal disease. DNA methylation profiles were generated using the Infinium HumanMethylation450 BeadChip in whole blood, buccal, and adipose tissue samples from predominantly older female twins (mean age 58) from the TwinsUK cohort. Epigenome-wide association scans (EWAS) of gingival bleeding and tooth mobility were conducted in whole blood in 528 and 492 twins, respectively. Subsequently, targeted candidate gene analysis at 28 genomic regions was carried out testing for phenotype-methylation associations in 41 (tooth mobility) and 43 (gingival bleeding) buccal, and 501 (tooth mobility) and 556 (gingival bleeding) adipose DNA samples. RESULTS: Epigenome-wide analyses in blood identified one CpG-site (cg21245277 in ZNF804A) associated with gingival bleeding (FDR = 0.03, nominal p value = 7.17e-8) and 58 sites associated with tooth mobility (FDR < 0.05) with the top signals in IQCE and XKR6. Epigenetic variation at 28 candidate regions (247 CpG-sites) for chronic periodontitis showed an enrichment for association with periodontal traits, and signals in eight genes (VDR, IL6ST, TMCO6, IL1RN, CD44, IL1B, WHAMM, and CXCL1) were significant in both traits. The methylation-phenotype association signals validated in buccal samples, and a subset (25%) also validated in adipose tissue. CONCLUSIONS: Epigenome-wide analyses in adult female twins identified specific DNA methylation changes linked to self-reported periodontal disease. Future work will explore the environmental basis and functional impact of these results to infer potential for strategic personalized treatments and prevention of chronic periodontitis. PMID: 30760334 [PubMed - in process]

Elevated Plasma Ceramides Are Associated With Antiretroviral Therapy Use and Progression of Carotid Artery Atherosclerosis in HIV Infection.

Fri, 15/02/2019 - 12:00
Related Articles Elevated Plasma Ceramides Are Associated With Antiretroviral Therapy Use and Progression of Carotid Artery Atherosclerosis in HIV Infection. Circulation. 2019 Feb 14;: Authors: Zhao W, Wang X, Deik AA, Hanna DB, Wang T, Haberlen SA, Shah SJ, Lazar JM, Hodis HN, Landay AL, Yu B, Gustafson D, Anastos K, Post WS, Clish CB, Kaplan RC, Qi Q Abstract BACKGROUND: Ceramides have been implicated in the pathophysiology of HIV infection and cardiovascular disease (CVD). However, no study, to our knowledge, has evaluated circulating ceramide levels in association with subclinical CVD risk among HIV-infected individuals. METHODS: Plasma levels of four ceramide species (C16:0, C22:0, C24:0 and C24:1) were measured among 398 women (73% HIV+) and 339 men (68% HIV+) without carotid artery plaques at baseline from the Women's Interagency HIV Study and the Multicenter AIDS Cohort Study. We examined associations between baseline plasma ceramides and risk of carotid artery plaque formation, assessed by repeated B-mode carotid artery ultrasound imaging over a median 7 year follow-up. RESULTS: Plasma levels of C16:0, C22:0 and C24:1 ceramides were significantly higher in HIV-infected individuals compared to those without HIV infection (all P<0.001), and further analysis indicated that elevated ceramide levels were associated with antiretroviral therapy (ART) use, particularly protease inhibitor use, in HIV-infected individuals (all P<0.001). All four ceramides were highly correlated with each other (r=0.70 to 0.94; all P < 0.001) and significantly correlated with total-cholesterol (r=0.42 to 0.58; all P<0.001) and LDL-cholesterol (r=0.24 to 0.42; all P< 0.001) levels. Of note, C16:0 and C24:1 ceramides, rather than C22:0 and C24:0 ceramides, were more closely correlated with specific monocyte activation and inflammation markers (e.g., r=0.30 between C16:0 ceramide and soluble CD14; P<0.001) and surface markers of CD4+ T cell activation. A total of 112 participants developed carotid artery plaques over 7 years, and higher levels of C16:0 and C24:1 ceramides were significantly associated with increased risk of carotid artery plaques (relative risk [95% CI]=1.55 [1.29, 1.86] and 1.51 [1.26, 1.82] per standard deviation increment, respectively; both P<0.001), after adjusting for demographic and behavioral factors. After further adjustment for CVD risk factors and immune activation markers, these associations were attenuated but remained significant. Results were consistent between men and women, and between HIV-infected and HIV-uninfected participants. CONCLUSIONS: In two HIV cohorts, elevated plasma levels of C16:0 and C24:1 ceramides, correlating with immune activation and inflammation, were associated with ART use and progression of carotid artery atherosclerosis. PMID: 30759995 [PubMed - as supplied by publisher]

Towards rapid prediction of drug-resistant cancer cell phenotypes: single cell mass spectrometry combined with machine learning.

Fri, 15/02/2019 - 12:00
Related Articles Towards rapid prediction of drug-resistant cancer cell phenotypes: single cell mass spectrometry combined with machine learning. Chem Commun (Camb). 2019 Jan 10;55(5):616-619 Authors: Liu R, Zhang G, Yang Z Abstract Combined single cell mass spectrometry and machine learning methods is demonstrated for the first time to achieve rapid and reliable prediction of the phenotype of unknown single cells based on their metabolomic profiles, with experimental validation. This approach can be potentially applied towards prediction of drug-resistant phenotypes prior to chemotherapy. PMID: 30525135 [PubMed - indexed for MEDLINE]

MZmine 2 Data-Preprocessing To Enhance Molecular Networking Reliability.

Fri, 15/02/2019 - 12:00
Related Articles MZmine 2 Data-Preprocessing To Enhance Molecular Networking Reliability. Anal Chem. 2017 08 01;89(15):7836-7840 Authors: Olivon F, Grelier G, Roussi F, Litaudon M, Touboul D Abstract Molecular networking is becoming more and more popular into the metabolomic community to organize tandem mass spectrometry (MS2) data. Even though this approach allows the treatment and comparison of large data sets, several drawbacks related to the MS-Cluster tool routinely used on the Global Natural Product Social Molecular Networking platform (GNPS) limit its potential. MS-Cluster cannot distinguish between chromatography well-resolved isomers as retention times are not taken into account. Annotation with predicted chemical formulas is also not implemented and semiquantification is only based on the number of MS2 scans. We propose to introduce a data-preprocessing workflow including the preliminary data treatment by MZmine 2 followed by a homemade Python script freely available to the community that clears the major previously mentioned GNPS drawbacks. The efficiency of this workflow is exemplified with the analysis of six fractions of increasing polarities obtained from a sequential supercritical CO2 extraction of Stillingia lineata leaves. PMID: 28644610 [PubMed - indexed for MEDLINE]

metabolomics; +22 new citations

Thu, 14/02/2019 - 14:55
22 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 2019/02/14PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

metabolomics; +35 new citations

Wed, 13/02/2019 - 14:43
35 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 2019/02/13PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

metabolomics; +19 new citations

Tue, 12/02/2019 - 14:26
19 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/02/12PubMed 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.

Microbial metabolomics: essential definitions and the importance of cultivation conditions for utilizing Bacillus species as bionematicides.

Mon, 11/02/2019 - 14:14
Related Articles Microbial metabolomics: essential definitions and the importance of cultivation conditions for utilizing Bacillus species as bionematicides. J Appl Microbiol. 2019 Feb 10;: Authors: Horak I, Engelbrecht G, Jansen van Rensburg PJ, Claassens S Abstract Root-knot nematodes are destructive phytopathogens that damage agricultural crops globally and there is growing interest in the use of biocontrol based on rhizobacteria such as Bacillus to combat Meloidogyne species. It is hypothesized that nematicidal activity of Bacillus can be attributed to the production of secondary metabolites and hydrolytic enzymes. Yet, few studies have characterized these metabolites and their identities remain unknown. Others are speculative or fail to elaborate on how secondary metabolites were detected or distinguished from primary metabolites. Metabolites can be classified based on their origin as either intracellular or extracellular and based on their function, as either primary or secondary. Although this classification is in general use, the boundaries are not always well defined. An understanding of the secondary metabolite and hydrolytic enzyme classification of Bacillus species will facilitate investigations aimed at bionematicide development. This review summarizes the significance of Bacillus hydrolytic enzymes and secondary metabolites in bionematicide research and provides an overview of known classifications. The importance of appropriate cultivation conditions for optimum metabolite and enzyme production are also discussed. Finally, the use of metabolomics for the detection and identification of nematicidal compounds is considered. This article is protected by copyright. All rights reserved. PMID: 30739384 [PubMed - as supplied by publisher]

The importance of BRAF-V600E mutation to ameloblastoma metabolism.

Mon, 11/02/2019 - 14:14
Related Articles The importance of BRAF-V600E mutation to ameloblastoma metabolism. J Oral Pathol Med. 2019 Feb 09;: Authors: Duarte-Andrade FF, Silva AMB, Vitório JG, Canuto GAB, Costa SFS, Diniz MG, Fernandes AP, de Toledo JS, André LC, Gomes CC, Gomez RS, Fonseca FP Abstract BACKGROUND: Ameloblastoma is a locally infiltrative, aggressive epithelial odontogenic neoplasm. BRAF-V600E mutation is frequently found in this tumor and has a pivotal role in its pathogenesis, but the consequences of this alteration need to be addressed. An untargeted metabolomics approach was applied to verify whether metabolic disturbances are related to tumor biology and whether BRAF-V600E mutation contributes to these alterations. METHODS: Formalin-fixed and paraffin-embedded tissue specimens from thirteen ameloblastoma and six dental follicles were included in this study. BRAF mutational status was determined by competitive allele-specific real-time PCR. Metabolite extracts were analyzed using gas chromatography coupled to mass spectrometry. Univariate and multivariate statistical methods were employed to compare the metabolic profiles of the samples. RESULTS: The abundance of eleven metabolites were significantly higher in ameloblastoma in relation to dental follicles, including amino acids, fatty acids, carbohydrates, inorganic acids, and organoheterocyclic compounds. The presence of BRAF-V600E mutations in ameloblastoma was related to decreased levels of glycerol in comparison to tumors carrying only wild-type alleles of this gene. No metabolic differences were observed between recurrent and primary manifestations of ameloblastoma. CONCLUSIONS: Ameloblastoma exhibits a distinct metabolic profile from normal odontogenic epithelium. BRAF-V600E may contribute to metabolic alterations in ameloblastoma. Collectively, our findings suggest that metabolic alterations might play a role in tumor pathogenesis. This article is protected by copyright. All rights reserved. PMID: 30739334 [PubMed - as supplied by publisher]

Comprehensive kinetic and substrate specificity analysis of an arylsulfatase from Helix pomatia using mass spectrometry.

Mon, 11/02/2019 - 14:14
Related Articles Comprehensive kinetic and substrate specificity analysis of an arylsulfatase from Helix pomatia using mass spectrometry. Bioorg Med Chem. 2019 Jan 30;: Authors: Correia MSP, Ballet C, Meistermann H, Conway LP, Globisch D Abstract Sulfatases hydrolyze sulfated metabolites to their corresponding alcohols and are present in all domains of life. These enzymes have found major application in metabolic investigation of drugs, doping control analysis and recently in metabolomics. Interest in sulfatases has increased due to a link between metabolic processes involving sulfated metabolites and pathophysiological conditions in humans. Herein, we present the first comprehensive substrate specificity and kinetic analysis of the most commonly used arylsulfatase extracted from the snail Helix pomatia. In the past, this enzyme has been used in the form of a crude mixture of enzymes, however, recently we have purified this sulfatase for a new application in metabolomics-driven discovery of sulfated metabolites. To evaluate the substrate specificity of this promiscuous sulfatase, we have synthesized a series of new sulfated metabolites of diverse structure and employed a mass spectrometric assay for kinetic substrate hydrolysis evaluation. Our analysis of the purified enzyme revealed that the sulfatase has a strong preference for metabolites with a bi- or tricyclic aromatic scaffold and to a lesser extent for monocyclic aromatic phenols. This metabolite library and mass spectrometric method can be applied for the characterization of other sulfatases from humans and gut microbiota to investigate their involvement in disease development. PMID: 30738652 [PubMed - as supplied by publisher]

Pushing arterial-venous plasma biomarkers to new heights: A model for personalised redox metabolomics?

Sun, 10/02/2019 - 13:46
Related Articles Pushing arterial-venous plasma biomarkers to new heights: A model for personalised redox metabolomics? Redox Biol. 2019 Jan 22;21:101113 Authors: Cumpstey AF, Minnion M, Fernandez BO, Mikus-Lelinska M, Mitchell K, Martin DS, Grocott MPW, Feelisch M, Xtreme Alps research group Abstract The chemical and functional interactions between Reactive Oxygen (ROS), Nitrogen (RNS) and Sulfur (RSS) species allow organisms to detect and respond to metabolic and environmental stressors, such as exercise and altitude exposure. Whether redox markers and constituents of this 'Reactive Species Interactome' (RSI) differ in concentration between arterial and venous blood is unknown. We hypothesised that such measurements may provide useful insight into metabolic/redox regulation at the whole-body level and would be consistent between individuals exposed to identical challenges. An exploratory study was performed during the Xtreme Alps expedition in 2010 in which four healthy individuals (2 male, 2 female) underwent paired arterial and central venous blood sampling before, during and after performance of a constant-work-rate cardiopulmonary exercise test, at sea level and again at 4559 m. Unexpectedly, plasma total free thiol and free cysteine concentrations remained substantially elevated at altitude throughout exercise with minimal arteriovenous gradients. Free sulfide concentrations changed only modestly upon combined altitude/exercise stress, whereas bound sulfide levels were lower at altitude than sea-level. No consistent signal indicative of the expected increased oxidative stress and nitrate→nitrite→NO reduction was observed with 4-hydroxynonenal, isoprostanes, nitrate, nitrite, nitroso species and cylic guanosine monophosphate. However, the observed arteriovenous concentration differences revealed a dynamic pattern of response that was unique to each participant. This novel redox metabolomic approach of obtaining quantifiable 'metabolic signatures' to a defined physiological challenge could potentially offer new avenues for personalised medicine. PMID: 30738322 [PubMed - as supplied by publisher]

Comparative analysis of the gut microbiota in centenarians and young adults shows a common signature across genotypically non-related populations.

Sun, 10/02/2019 - 13:46
Related Articles Comparative analysis of the gut microbiota in centenarians and young adults shows a common signature across genotypically non-related populations. Mech Ageing Dev. 2019 Feb 06;: Authors: Tuikhar N, Keisam S, Labala RK, Imrat, Ramakrishnan P, Arunkumar MC, Ahmed G, Biagi E, Jeyaram K Abstract Gut microbiota is among the factors that may be involved in healthy aging. Broader and geographically spread studies on gut microbiota of centenarians can help in identifying a common signature of longevity. We identified an endogamous Indian population with high centenarian prevalence. Here, we compared the gut microbiota composition and fecal metabolites of a centenarians group (˜100 years) with young people (25-45 years) of the region with the high centenarian prevalence and the nearby region of low centenarian prevalence to decipher microbial-related longevity signatures. Also, we compared our results with publicly available datasets of similar groups including 125 centenarians from three countries (Italy, Japan, China). Our comparative analysis resulted in higher biodiversity within Ruminococcaceae in centenarians, with respect to younger adults, irrespective of their nationality. We observed bacterial signatures that are common among extremely old people of different nationality. Comparative metabolites profiling identified the fecal metabolic signature of extreme aging in the Indian study population. Our analysis of the co-occurrence network and bimodal distribution of several taxa suggested the establishment of a pervasive change in the gut ecology during extreme aging. Our study might pave the way to develop gut microbiota based biomarkers for healthy aging. PMID: 30738080 [PubMed - as supplied by publisher]

Defective proteostasis in celiac disease as a new therapeutic target.

Sun, 10/02/2019 - 13:46
Related Articles Defective proteostasis in celiac disease as a new therapeutic target. Cell Death Dis. 2019 Feb 08;10(2):114 Authors: Maiuri L, Villella VR, Piacentini M, Raia V, Kroemer G Abstract Cystic fibrosis (CF) is a disease caused by loss-of-function mutations affecting the CF transmembrane conductance regulator (CFTR), a chloride channel. Recent evidence indicates that CFTR is inhibited by a gluten/gliadin-derived peptide (P31-43), causing an acquired state of CFTR inhibition within the gut that contributes to the pathogenesis of celiac disease (CD). Of note, CFTR inhibition does not only cause intra- and extracellular ion imbalances but also affects proteostasis by activating transglutaminase-2 (TGM2) and by disabling autophagy. These three phenomena (CFTR inhibition, TGM2 activation, and autophagy impairment) engage in multiple self-amplifying circuitries, thus forming an "infernal trio". The trio hinders enterocytes from returning to homeostasis and instead locks them in an irreversible pro-inflammatory state that ultimately facilitates T lymphocyte-mediated immune responses against another gluten/gliadin-derived peptide (P57-68), which,upon deamidation by activated TGM2, becomes fully antigenic. Hence, the pathogenic protein gliadin exemplifies a food constituent the exceptional immunogenicity of which arises from a combination of antigenicity (conferred by deaminated P57-68) and adjuvanticity (conferred by P31-43). CF can be treated by agents targeting the "infernal trio" including CFTR potentiators, TGM2 inhibitors, and autophagy enhancers. We speculate that such agents may also be used for CD therapy and indeed could constitute close-to-etiological treatments of this enteropathy. PMID: 30737369 [PubMed - in process]

The Detection of Natural Products and Their Producers in Ocean Sediments.

Sun, 10/02/2019 - 13:46
Related Articles The Detection of Natural Products and Their Producers in Ocean Sediments. Appl Environ Microbiol. 2019 Feb 08;: Authors: Tuttle RN, Demko AM, Patin N, Kapono CA, Donia MS, Dorrestein P, Jensen PR Abstract Thousands of natural products have been identified from cultured microorganisms yet evidence of their production in the environment has proven elusive. Technological advances in mass spectrometry combined with public databases now make it possible to address this disparity by detecting compounds directly from environmental samples. Here we used adsorbent resins, tandem mass spectrometry, and next generation sequencing to assess the metabolome of marine sediments and its relationship to bacterial community structure. We identified natural products previously reported from cultured bacteria, providing evidence they are produced in situ, and compounds of anthropogenic origin, suggesting this approach can be used as an indicator of environmental impact. The bacterial metabolite staurosporine was quantified and shown to reach physiologically relevant concentrations, indicating it may influence sediment community structure. Staurosporine concentrations were correlated with the relative abundance of the staurosporine producing bacterial genus Salinispora and production confirmed in strains cultured from the same location, providing a link between compound and candidate producer. Metagenomic analyses revealed numerous biosynthetic gene clusters related to indolocarbazole biosynthesis, providing evidence for non-canonical sources of staurosporine and a path forward to assess the relationships between natural products and the organisms that produce them. Untargeted environmental metabolomics circumvents the need for laboratory cultivation and represents a promising approach to understanding the functional roles of natural products in shaping microbial community structure in marine sediments.ImportanceNatural products are readily isolated from cultured bacteria and exploited for useful purposes including drug discovery. However, these compounds are rarely detected in the environments from which the bacteria are obtained thus limiting our understanding of their ecological significance. Here we used environmental metabolomics to assess chemical diversity directly in marine sediments. We identified numerous metabolites and, in one case, isolated strains of bacteria capable of producing one of the compounds detected. Coupling environmental metabolomics with community and metagenomic analyses provides opportunities to link compounds and producers and begin to assess the complex interactions mediated by specialized metabolites in marine sediments. PMID: 30737349 [PubMed - as supplied by publisher]

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