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: 26 min 31 sec ago

metabolomics; +22 new citations

Sat, 14/09/2019 - 14:05
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 2019/09/14PubMed 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; +19 new citations

Fri, 13/09/2019 - 13:47
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 2019/09/13PubMed 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; +17 new citations

Thu, 12/09/2019 - 13:37
17 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/09/12PubMed 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.

metabolomics; +24 new citations

Wed, 11/09/2019 - 16:30
24 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 2019/09/11PubMed 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; +29 new citations

Tue, 10/09/2019 - 16:16
29 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 2019/09/10PubMed 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; +29 new citations

Tue, 10/09/2019 - 13:13
29 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 2019/09/10PubMed 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.

Impact of Left Ventricular Assist Device Therapy on the Cardiac Proteome and Metabolome Composition in Ischemic Cardiomyopathy.

Mon, 09/09/2019 - 13:06
Impact of Left Ventricular Assist Device Therapy on the Cardiac Proteome and Metabolome Composition in Ischemic Cardiomyopathy. Artif Organs. 2019 Sep 08;: Authors: Shahinian JH, Rog-Zielinska EA, Schlimpert M, Mayer B, Tholen S, Kammerer B, Biniossek ML, Beyersdorf F, Schilling O, Siepe M Abstract BACKGROUND: The changes in the myocardial proteome and metabolome associated with left ventricular assist device (LVAD) therapy in patients with ischemic cardiomyopathy (ICM) are poorly characterized. We investigated the impact of mechanical unloading following LVAD therapy on the myocardial proteome and metabolome. METHODS: Matched samples of 5 patients' myocardial tissue, harvested at time of LVAD implant ("pre-LVAD") or heart transplant ("post-LVAD") were studied by quantitative proteomics and metabolomics as well as being probed for T-tubule structure and connexin-43 distribution. Moreover, pre-LVAD proteome profiles of ICM context were bioinformatically compared to pre-LVAD proteome profiles of dilate cardiac myopathy (DCM). RESULTS: More than 2120 proteins were reliably identified and quantified in paired patient samples. LVAD therapy led to proteomic remodelling, including reduced levels of α-1-antichymotrypsin together with an overall decrease of immune response proteins and an increase of proteins involved in membrane biology. Metabolomics highlighted increased glucose and glucose-6-phosphate levels in the left ventricle upon LVAD therapy. Wheat germ agglutinin staining demonstrated improved T-tubule structure. Connexin-43 displayed a trend for more pronounced intercalated disc localization. In comparing pre-LVAD proteome profiles of ICM context with pre-LVAD proteome profiles of dilate cardiac myopathy (DCM) we noticed an overrepresentation in ICM of proteins accosiated with humoral immune response. CONCLUSIONS: Our findings underline an impact of LVAD therapy on left ventricular biology in ICM. The proteomic, metabolomic, and structural alterations described here are typically associated with cardiac recovery. On the molecular level, our findings indicate the possibility of cardiac remodeling under LVAD therapy in ICM. This article is protected by copyright. All rights reserved. PMID: 31494943 [PubMed - as supplied by publisher]

Metabolic signature of methylone in primary mouse hepatocytes, at subtoxic concentrations.

Mon, 09/09/2019 - 13:06
Metabolic signature of methylone in primary mouse hepatocytes, at subtoxic concentrations. Arch Toxicol. 2019 Sep 07;: Authors: Araújo AM, Carvalho M, Bastos ML, Carvalho F, de Pinho PG Abstract Methylone (3,4-methylenedioxymethcathinone) is one of the most popular new psychoactive drugs worldwide. Although advertised as a safe drug, its use has been associated to several cases of liver damage. In this work, a metabolomics approach based on gas chromatography-mass spectrometry (GC-MS) combined with chemometric analyses was used to characterize the disturbances occurring in the intra- and extracellular metabolome of primary mouse hepatocytes exposed to two subtoxic concentrations (LC01 and LC10) of methylone to better understand the early hepatotoxic events. Results showed a characteristic metabolic fingerprint for methylone, where aspartate, cysteine, 2-methyl-1-pentanol, 4-methylheptane, dodecane, 2,4-dimethyl-1-heptene, 1,3-di-tert-butylbenzene, acetophenone, formaldehyde and glyoxal levels were significantly changed at both concentrations tested. Furthermore, subtoxic concentrations of methylone caused profound changes in several biochemical pathways, suggesting adaptations in energy production processes (TCA cycle, amino acids metabolism and pyruvate metabolism), cellular antioxidant defenses (glutamate, cysteine and glutathione metabolism) and hepatic enzymes (associated to hydrocarbons, alcohols, aldehydes and ketones metabolism). This metabolic response to the initial methylone challenge most probably reflects the activation of protective mechanisms to restore cellular homeostasis. Overall, this study highlights the potential of untargeted metabolomic analysis to reveal the hepatic metabolic signature of methylone at subtoxic concentrations, and also provides clues to clarify the early mechanisms underlying the toxicity triggered by this new psychoactive substance, opening a new perspective for the study of toxicity mechanisms of new xenobiotics. PMID: 31494693 [PubMed - as supplied by publisher]

The Current State of Omics Technologies in the Clinical Management of Asthma and Allergic Diseases.

Mon, 09/09/2019 - 13:06
The Current State of Omics Technologies in the Clinical Management of Asthma and Allergic Diseases. Ann Allergy Asthma Immunol. 2019 Sep 05;: Authors: Donovan BM, Bastarache L, Turi KN, Zutter MM, Hartert TV Abstract OBJECTIVE: To review the state of omics science specific to asthma and allergic diseases and discuss the current and potential applicability of omics in clinical disease prediction, treatment, and management DATA SOURCES: Studies and reviews focused on the use of omics technologies in asthma and allergic disease research and clinical management were identified using PubMed STUDY SELECTIONS: Publications were included based on relevance, with emphasis placed on the most recent findings RESULTS: Omics-based research is increasingly being used to differentiate asthma and allergic disease subtypes, identify biomarkers and pathological mediators, predict patient responsiveness to specific therapies, and monitor disease control. While most studies have focused on genomics and transcriptomics approaches, increasing attention is being placed on omics technologies that assess the effect of environmental exposures on disease initiation and progression. Studies utilizing omics data to identify biological targets and pathways involved in asthma and allergic disease pathogenesis have primarily focused on a specific omics subtype, providing only a partial view of the disease process. CONCLUSIONS: While omics technologies have advanced our understanding of the molecular mechanisms underlying asthma and allergic disease pathology, omics testing for these diseases are not standard of care at this point. Several important factors need to be addressed before these technologies can be effectively utilized in clinical practice. Use of clinical decision support systems and integration of these systems within electronic medical records will become increasingly. PMID: 31494234 [PubMed - as supplied by publisher]

Plasma metabolomics of depressed patients and treatment with Xiaoyaosan based on mass spectrometry technique.

Mon, 09/09/2019 - 13:06
Plasma metabolomics of depressed patients and treatment with Xiaoyaosan based on mass spectrometry technique. J Ethnopharmacol. 2019 Sep 05;:112219 Authors: Liu X, Liu C, Tian J, Gao X, Li K, Du G, Qin X Abstract ETHNOPHARMACOLOGICAL RELEVANCE: Xiaoyaosan (XYS), a famous and classic traditional Chinese prescription, has been used for long time in treating depressive disorders. XYS consists of Radix Bupleuri (Bupleurum chinense DC.), Radix Angelicae Sinensis (Angelica sinensis (Oliv.) Diels), Radix PaeoniaeAlba (Paeonia lactiflora Pall.), Rhizoma Atractylodis Macrocepha lae (Atractylodes macrocephala Koidz.), Poria (Poria cocos (Schw.)Wolf), Radix Glycyrrhizae (Glycyrrhiza uralensis Fisch.), Herba Menthae Haplocalycis (Mentha haplocalyx Briq.), and Rhizoma Zin-giberis Recens (Zingiber officinale Rosc.). AIM OF THE STUDY: A GC-MS based metabolomics approach was applied to discover the potential biomarkers that were related to metabolic differences between healthy volunteers and depression cohort diagnosed by HAMD and CGI, and to demonstrate the potential utility of these biomarkers in the diagnosis of depression and pharmaceutical efficacy of XYS. MATERIALS AND METHODS: A total of 17 depressed patients and the 17 age- and gender-matched healthy subjects were served as the primary cohort. The depressed patients were screened according to the Chinese Classification of Mental Disorder (CCMD-3) and the Hamilton Depression Scale (HAMD). In addition, five other depressed patients were also enrolled as the primary cohort when the final step of sample collection was conducted. Plasma samples were analyzed by Gas Chromatography-Mass Spectrometry (GC-MS). Clinical and metabolomics data were analyzed by multivariate statistics analysis, Receiver Operating Characteristic (ROC) curve and MetaboAnalyst. RESULTS: We observed significant differences between depression cohort and healthy volunteers, and between patients before and after the treatment of XYS. The method was then clinically validated in an independent validation cohort. Levels of oxalic and stearic acids significantly increased in depressed patients' plasma while valine and urea significantly decreased, as compared with healthy controls. Of note, XYS reversed these metabolite changes in terms of regulating dysfunctions in glyoxylate and dicarboxylate metabolism, fatty acid biosynthesis, valine, leucine and isoleucine biosynthesis, and arginine and proline metabolism. Importantly, the combination of oxalic and stearic acids is in prospect as diagnose biomarkers. CONCLUSIONS: This study highlights the clinical application of metabolomics in disease diagnose and therapy evaluation, which will help in improving our understanding of depression and will lay solid foundation for the clinic application of TCMs. In addition, it suggests that the combination of the two potential biomarkers had also achieved a high diagnostic value, which consequently could be used a diagnose biomarkers. PMID: 31494201 [PubMed - as supplied by publisher]

Kidney harvesting and metabolite extraction for metabolomics studies in rodents.

Mon, 09/09/2019 - 13:06
Kidney harvesting and metabolite extraction for metabolomics studies in rodents. Methods Cell Biol. 2019;154:15-29 Authors: Maksimovic I, Zhang S, Vuckovic I, Irazabal MV Abstract Elucidating the metabolic changes that accompany disease states via metabolomics analysis of tissues has become an important avenue of exploration in biomarker and therapeutic target discovery. Conventional harvesting techniques rely on post-euthanasia tissue harvest which introduces ischemic conditions and subsequent metabolome changes that may ultimately introduce artifacts into final analyses. In this chapter, we present protocols for low-ischemia time rapid kidney tissue harvest followed by metabolite extraction for metabolomics studies in rodents. PMID: 31493816 [PubMed - in process]

Single glomerular proteomics: A novel tool for translational glomerular cell biology.

Mon, 09/09/2019 - 13:06
Single glomerular proteomics: A novel tool for translational glomerular cell biology. Methods Cell Biol. 2019;154:1-14 Authors: Rinschen MM Abstract The glomerulus harbors the renal filtration barrier and needs to be precisely maintained. In this chapter, the concept of single glomerular proteomics is described. Single glomerular proteomics has recently been enabled by advances in glomerular isolation, ultrasensitive peptide sample preparation and mass spectrometry based technology and acquisition strategies. It generates protein content information on a single glomerulus that can be overlaid with morphological and other multi-layered omics analyses. The novel method consists of four essential steps: preparation of single glomeruli-by microdissection, glomerular preparation, or laser microdissection-followed by proteomic sample preparation, mass spectrometry analysis and bioinformatics analysis. It enables for the first time the generation of sub-biopsy level proteomics data. In perspective, comprehensive data from individual glomeruli could be used in order to pinpoint novel druggable targets in animal models of kidney disease or in patients with proteinuria and glomerular disease. PMID: 31493812 [PubMed - in process]

Age-specific urinary metabolite signatures and functions in patients with major depressive disorder.

Sun, 08/09/2019 - 12:44
Age-specific urinary metabolite signatures and functions in patients with major depressive disorder. Aging (Albany NY). 2019 Sep 06;11: Authors: Chen JJ, Xie J, Li WW, Bai SJ, Wang W, Zheng P, Xie P Abstract Major depressive disorder (MDD) patients in different age ranges might have different urinary metabolic phenotypes, because age could significantly affect the physiological and psychological status of person. Therefore, it was very important to take age into consideration when studying MDD. Here, a dual platform metabolomic approach was performed to profile urine samples from young and middle-aged MDD patients. In total, 18 and 15 differential metabolites that separately discriminated young and middle-aged MDD patients, respectively, from their respective HC were identified. Only ten metabolites were significantly disturbed in both young and middle-aged MDD patients. Meanwhile, two different biomarker panels for diagnosing young and middle-aged MDD patients, respectively, were identified. Additionally, the TCA cycle was significantly affected in both young and middle-aged MDD patients, but the Glyoxylate and dicarboxylate metabolism and phenylalanine metabolism were only significantly affected in young and middle-aged MDD patients, respectively. Our results would be helpful for developing age-specific diagnostic method for MDD and further investigating the pathogenesis of this disease. PMID: 31493765 [PubMed - as supplied by publisher]

An integrated metabolomics strategy to reveal dose-effect relationship and therapeutic mechanisms of different efficacy of rhubarb in constipation rats.

Sun, 08/09/2019 - 12:44
An integrated metabolomics strategy to reveal dose-effect relationship and therapeutic mechanisms of different efficacy of rhubarb in constipation rats. J Pharm Biomed Anal. 2019 Aug 26;177:112837 Authors: Chen JQ, Chen YY, Tao HJ, Pu ZJ, Shi XQ, Zhang J, Tan YJ, Yue SJ, Zhou GS, Shang EX, Tang YP, Duan JA Abstract The ambiguity of dose-effect relationship of many traditional Chinese medicines (TCMs) has always influenced their rational use in TCM clinic. Rhubarb, a preferred representative of cathartic TCM, is currently widely used that results in a diversity of its dosage. The aim of this study was to use an integrated metabolomics strategy to simultaneously reveal dose-effect relationship and therapeutic mechanisms of different efficacy of rhubarb in constipation rats. Six doses of rhubarb (0.135, 0.27, 0.81, 1.35, 4.05, and 8.1 g/kg) were examined to elucidate the laxative and fire-purging effects by pathological sections and UPLC-Q-TOF/MSE. The results showed that there existed serious lesions in the stomach and colon of model rats. And conditions were basically improved to some extent in rhubarb-treated groups. Through relative distance calculation based on metabolomics score plots, it suggested that the effective dose threshold (EC20-EC80 range) of rhubarb was from 0.31 to 4.5 g/kg (corresponding to 3.44-50.00 g in the clinic) in rat serum and 0.29-2.1 g/kg (corresponding to 3.22-23.33 g in the clinic) in feces. Then, 33 potential biomarkers were identified in total. Functional pathway analysis revealed that the alterations of these biomarkers were associated with 15 metabolic pathways, mainly including arachidonic acid metabolism, glycerophospholipid metabolism, steroid biosynthesis, primary bile acid biosynthesis and sphingolipid metabolism. Of note, different doses of rhubarb could alleviate endogenous disorders to varying degrees through regulating multiple perturbed pathways to the normal state, which might be in a dose-dependent manner and involved in therapeutic mechanisms. To sum up, integrated serum and fecal metabolomics obtained that rhubarb ranging from 0.31 to 2.1 g/kg is safe and effective for constipation treatment. Also, our findings showed that the robust metabolomics techniques would be promising to be more accurately used in the dose-effect studies of complex TCM, and to clarify syndrome pathogenesis and action mechanisms in Chinese medicine. PMID: 31493746 [PubMed - as supplied by publisher]

Phytotoxicity induced by engineered nanomaterials as explored by metabolomics: Perspectives and challenges.

Sun, 08/09/2019 - 12:44
Phytotoxicity induced by engineered nanomaterials as explored by metabolomics: Perspectives and challenges. Ecotoxicol Environ Saf. 2019 Sep 04;184:109602 Authors: Li X, Peng T, Mu L, Hu X Abstract Given the wide applications of engineered nanomaterials (ENMs) in various fields, the ecotoxicology of ENMs has attracted much attention. The traditional plant physiological activity (e.g., reactive oxygen species and antioxidant enzymes) are limited in that they probe one specific process of nanotoxicity, which may result in the loss of understanding of other important biological reactions. Metabolites, which are downstream of gene and protein expression, are directly related to biological phenomena. Metabolomics is an easily performed and efficient tool for solving the aforementioned problems because it involves the comprehensive exploration of metabolic profiles. To understand the roles of metabolomics in phytotoxicity, the analytical methods for metabolomics should be organized and discussed. Moreover, the dominant metabolites and metabolic pathways are similar in different plants, which determines the universal applicability of metabolomics analysis. The analysis of regulated metabolism will globally and scientifically help determine the ecotoxicology that is induced by ENMs. In the past several years, great developments in nanotoxicology have been achieved using metabolomics. However, many knowledge gaps remain, such as the relationships between biological responses that are induced by ENMs and the regulation of metabolism (e.g., carbohydrate, energy, amino acid, lipid and secondary metabolism). The phytotoxicity that is induced by ENMs has been explored by metabolomics, which is still in its infancy. The detrimental and defence mechanisms of plants in their response to ENMs at the level of metabolomics also deserve much attention. In addition, owing to the regulation of metabolism in plants by ENMs affected by multiple factors, it is meaningful to uniformly identify the key influencing factor. PMID: 31493589 [PubMed - as supplied by publisher]

Ion Mobility Spectrometry: Fundamental Concepts, Instrumentation, Applications, and the Road Ahead.

Sun, 08/09/2019 - 12:44
Related Articles Ion Mobility Spectrometry: Fundamental Concepts, Instrumentation, Applications, and the Road Ahead. J Am Soc Mass Spectrom. 2019 Sep 06;: Authors: Dodds JN, Baker ES Abstract Ion mobility spectrometry (IMS) is a rapid separation technique that has experienced exponential growth as a field of study. Interfacing IMS with mass spectrometry (IMS-MS) provides additional analytical power as complementary separations from each technique enable multidimensional characterization of detected analytes. IMS separations occur on a millisecond timescale, and therefore can be readily nested into traditional GC and LC/MS workflows. However, the continual development of novel IMS methods has generated some level of confusion regarding the advantages and disadvantages of each. In this critical insight, we aim to clarify some common misconceptions for new users in the community pertaining to the fundamental concepts of the various IMS instrumental platforms (i.e., DTIMS, TWIMS, TIMS, FAIMS, and DMA), while addressing the strengths and shortcomings associated with each. Common IMS-MS applications are also discussed in this review, such as separating isomeric species, performing signal filtering for MS, and incorporating collision cross-section (CCS) values into both targeted and untargeted omics-based workflows as additional ion descriptors for chemical annotation. Although many challenges must be addressed by the IMS community before mobility information is collected in a routine fashion, the future is bright with possibilities. PMID: 31493234 [PubMed - as supplied by publisher]

Role of purines in regulation of metabolic reprogramming.

Sun, 08/09/2019 - 12:44
Related Articles Role of purines in regulation of metabolic reprogramming. Purinergic Signal. 2019 Sep 06;: Authors: Tang Z, Ye W, Chen H, Kuang X, Guo J, Xiang M, Peng C, Chen X, Liu H Abstract Purines, among most influential molecules, are reported to have essential biological function by regulating various cell types. A large number of studies have led to the discovery of many biological functions of the purine nucleotides such as ATP, ADP, and adenosine, as signaling molecules that engage G protein-coupled or ligand-gated ion channel receptors. The role of purines in the regulation of cellular functions at the gene or protein level has been well documented. With the advances in multiomics, including those from metabolomic and bioinformatic analyses, metabolic reprogramming was identified as a key mechanism involved in the regulation of cellular function under physiological or pathological conditions. Recent studies suggest that purines or purine-derived products contribute to important regulatory functions in many fundamental biological and pathological processes related to metabolic reprogramming. Therefore, this review summarizes the role and potential mechanism of purines in the regulation of metabolic reprogramming. In particular, the molecular mechanisms of extracellular purine- and intracellular purine-mediated metabolic regulation in various cells during disease development are discussed. In summary, our review provides an extensive resource for studying the regulatory role of purines in metabolic reprogramming and sheds light on the utilization of the corresponding peptides or proteins for disease diagnosis and therapy. PMID: 31493132 [PubMed - as supplied by publisher]

Genome-wide association studies of 74 plasma metabolites of German shepherd dogs reveal two metabolites associated with genes encoding their enzymes.

Sun, 08/09/2019 - 12:44
Related Articles Genome-wide association studies of 74 plasma metabolites of German shepherd dogs reveal two metabolites associated with genes encoding their enzymes. Metabolomics. 2019 Sep 06;15(9):123 Authors: Soh PXY, Marin Cely JM, Mortlock SA, Jara CJ, Booth R, Natera S, Roessner U, Crossett B, Cordwell S, Singh Khatkar M, Williamson P Abstract INTRODUCTION: German shepherd dogs (GSDs) are a popular breed affected by numerous disorders. Few studies have explored genetic variations that influence canine blood metabolite levels. OBJECTIVES: To investigate genetic variants affecting the natural metabolite variation in GSDs. METHODS: A total of 82 healthy GSDs were genotyped on the Illumina CanineHD Beadchip, assaying 173,650 markers. For each dog, 74 metabolites were measured through liquid and gas chromatography mass spectrometry (LC-MS and GC-MS) and were used as phenotypes for genome-wide association analyses (GWAS). Sliding window and homozygosity analyses were conducted to fine-map regions of interest, and to identify haplotypes and gene dosage effects. RESULTS: Summary statistics for 74 metabolites in this population of GSDs are reported. Forty-one metabolites had significant associations at a false discovery rate of 0.05. Two associations were located around genes which encode for enzymes for the relevant metabolites: 4-hydroxyproline was significantly associated to D-amino acid oxidase (DAO), and threonine to L-threonine 3-dehydrogenase (LOC477365). Three of the top ten haplotypes associated to 4-hydroxyproline included at least one SNP on DAO. These haplotypes occurred only in dogs with the highest 15 measurements of 4-hydroxyproline, ranging in frequency from 16.67 to 20%. None of the dogs were homozygous for these haplotypes. The top two haplotypes associated to threonine included SNPs on LOC477365 and were also overrepresented in dogs with the highest 15 measurements of threonine. These haplotypes occurred at a frequency of 90%, with 80% of these dogs homozygous for the haplotypes. In dogs with the lowest 15 measurements of threonine, the haplotypes occurred at a frequency of 26.67% and 0% homozygosity. CONCLUSION: DAO and LOC477365 were identified as candidate genes affecting the natural plasma concentration of 4-hydroxyproline and threonine, respectively. Further investigations are needed to validate the effects of the variants on these genes. PMID: 31493001 [PubMed - in process]

Serotonin is elevated in risk-genotype carriers of TCF7L2 - rs7903146.

Sun, 08/09/2019 - 12:44
Related Articles Serotonin is elevated in risk-genotype carriers of TCF7L2 - rs7903146. Sci Rep. 2019 Sep 06;9(1):12863 Authors: Leiherer A, Muendlein A, Saely CH, Fraunberger P, Drexel H Abstract The transcription factor 7-like 2 (TCF7L2) polymorphism rs7903146 is known to be tightly associated with an elevated risk for type 2 diabetes, whereas the molecular mechanisms remain elusive. We evaluated the metabolic profile of a total of 394 patients' serum samples with respect to their rs7903146 genotype using targeted metabolomics in a discovery (n = 154) and a validation (n = 240) study. We have identified serotonin as the top metabolite being increased in carriers of the risk allele. Serotonin was significantly associated with the rs7903146 genotype after full adjustment including type 2 diabetes and further top ranked metabolites. Given the role of peripheral serotonin in metabolic homeostasis and type 2 diabetes, this finding provides a first hint that the well-known impact of the TCF7L2 polymorphism on type 2 diabetes risk may involve a serotonin-dependent pathway. PMID: 31492908 [PubMed - in process]

Prognostic Relevance of Steroid Sulfation in Adrenocortical Carcinoma Revealed by Molecular Phenotyping Using High-Resolution Mass Spectrometry Imaging.

Sun, 08/09/2019 - 12:44
Related Articles Prognostic Relevance of Steroid Sulfation in Adrenocortical Carcinoma Revealed by Molecular Phenotyping Using High-Resolution Mass Spectrometry Imaging. Clin Chem. 2019 Sep 06;: Authors: Sun N, Kunzke T, Sbiera S, Kircher S, Feuchtinger A, Aichler M, Herterich S, Ronchi CL, Weigand I, Schlegel N, Waldmann J, Fragoso MCV, Whitsett TG, Gill AJ, Fassnacht M, Walch A, Kroiss M Abstract BACKGROUND: Adrenocortical carcinoma (ACC) is a rare tumor with variable prognosis even within the same tumor stage. Cancer-related sex hormones and their sulfated metabolites in body fluids can be used as tumor markers. The role of steroid sulfation in ACC has not yet been studied. MALDI mass spectrometry imaging (MALDI-MSI) is a novel tool for tissue-based chemical phenotyping. METHODS: We performed phenotyping of formalin-fixed, paraffin-embedded tissue samples from 72 ACC by MALDI-MSI at a metabolomics level. RESULTS: Tumoral steroid hormone metabolites- estradiol sulfate [hazard ratio (HR) 0.26; 95% CI, 0.10-0.69; P = 0.005] and estrone 3-sulfate (HR 0.22; 95% CI, 0.07-0.63; P = 0.003)-were significantly associated with prognosis in Kaplan-Meier analyses and after multivariable adjustment for age, tumor stage, and sex (HR 0.29; 95% CI, 0.11-0.79; P = 0.015 and HR 0.30; 95% CI, 0.10-0.91; P = 0.033, respectively). Expression of sulfotransferase SULT2A1 was associated with prognosis to a similar extent and was validated to be a prognostic factor in two published data sets. We discovered the presence of estradiol-17β 3,17-disulfate (E2S2) in a subset of tumors with particularly poor overall survival. Electron microscopy revealed novel membrane-delimited organelles in only these tumors. By applying cluster analyses of metabolomic data, 3 sulfation-related phenotypes exhibited specific metabolic features unrelated to steroid metabolism. CONCLUSIONS: MALDI-MSI provides novel insights into the pathophysiology of ACC. Steroid hormone sulfation may be used for prognostication and treatment stratification. Sulfation-related metabolic reprogramming may be of relevance also in conditions beyond the rare ACC and can be directly investigated by the use of MALDI-MSI. PMID: 31492715 [PubMed - as supplied by publisher]

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