PubMed

Global serum metabolomics profiling of colorectal cancer. Mol Clin Oncol. 2019 Jul;11(1):3-14 Authors: Hashim NAA, Ab-Rahim S, Suddin LS, Saman MSA, Mazlan M Abstract Accurate diagnosis of colorectal cancer (CRC) relies on the use of invasive tools such as colonoscopy and sigmoidoscopy. Non-invasive tools are less sensitive in detecting the disease, particularly in the early stage. A number of researchers have used metabolomics analyses on serum/plasma samples of patients with CRC compared with normal healthy individuals in an effort to identify biomarkers for CRC. The aim of the present review is to compare reported serum metabolomics profiles of CRC and to identify common metabolites affected among these studies. A literature search was performed to include any experimental studies on global metabolomics profile of CRC using serum/plasma samples published up to March 2018. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool was used to assess the quality of the studies reviewed. In total, nine studies were included. The studies used various analytical platforms and were performed on different populations. A pathway enrichment analysis was performed using the data from all the studies under review. The most affected pathways identified were protein biosynthesis, urea cycle, ammonia recycling, alanine metabolism, glutathione metabolism and citric acid cycle. The metabolomics analysis revealed levels of metabolites of glycolysis, tricarboxylic acid cycle, anaerobic respiration, protein, lipid and glutathione metabolism were significantly different between cancer and control samples. Although the majority of differentiating metabolites identified were different in the different studies, there were several metabolites that were common. These metabolites include pyruvic acid, glucose, lactic acid, malic acid, fumaric acid, 3-hydroxybutyric acid, tryptophan, phenylalanine, tyrosine, creatinine and ornithine. The consistent dysregulation of these metabolites among the different studies suggest the possibility of common diagnostic biomarkers for CRC. PMID: 31289671 [PubMed]

Ectopic defense gene expression is associated with growth defects in Medicago truncatula lignin pathway mutants. Plant Physiol. 2019 Jul 09;: Authors: Ha CM, Fine D, Bhatia A, Rao X, Martin M, Engle N, Wherritt DJ, Tschaplinski T, Sumner L, Dixon RA Abstract Lignin provides essential mechanical support for plant cell walls but decreases the digestibility of forage crops and increases the recalcitrance of biofuel crops. Attempts to modify lignin content and/or composition by genetic modification often result in negative growth effects. Although several studies have attempted to address the basis for such effects in individual transgenic lines, no common mechanism linking lignin modification with perturbations in plant growth and development has yet been identified. To address whether a common mechanism exists, we have analyzed transposon insertion mutants resulting in independent loss of function of five enzymes of the monolignol pathway, as well as one double mutant, in the model legume Medicago truncatula. These plants exhibit growth phenotypes from essentially wild-type to severely retarded. Extensive phenotypic, transcriptomic, and metabolomics analyses, including structural characterization of differentially expressed compounds, revealed diverse phenotypic consequences of lignin pathway perturbation that were perceived early in plant development, but were not predicted by lignin content or composition alone. Notable phenotypes among the mutants with severe growth impairment were increased trichome numbers, accumulation of a variety of triterpene saponins, and extensive but differential ectopic expression of defense response genes. No currently proposed model explains the observed phenotypes across all lines. We propose that re-allocation of resources into defense pathways is linked to the severity of the final growth phenotype in monolignol pathway mutants of Medicago, although it remains unclear as to whether this is a cause or an effect of the growth impairment. PMID: 31289215 [PubMed - as supplied by publisher]

Novel pyrrolo[3,2-d]pyrimidine compounds target mitochondrial and cytosolic one-carbon metabolism with broad-spectrum antitumor efficacy. Mol Cancer Ther. 2019 Jul 09;: Authors: Dekhne AS, Shah K, Ducker GS, Katinas JM, Wong-Roushar J, Nayeen MJ, Doshi A, Ning C, Bao X, Frühauf J, Liu J, Wallace-Povirk A, O'Connor C, Dzinic SH, White K, Kushner J, Kim S, Hüttemann M, Polin L, Rabinowitz JD, Li J, Hou Z, Dann CE, Gangjee A, Matherly LH Abstract Folate-dependent one-carbon (C1) metabolism is compartmentalized into the mitochondria and cytosol and supports cell growth through nucleotide and amino acid biosynthesis. Mitochondrial C1 metabolism, including serine hydroxymethyltransferase (SHMT) 2, provides glycine, NAD(P)H, ATP, and C1 units for cytosolic biosynthetic reactions, and is implicated in the oncogenic phenotype across a wide range of cancers. Whereas multi-targeted inhibitors of cytosolic C1 metabolism such as pemetrexed are used clinically, there are currently no anticancer drugs that specifically target mitochondrial C1 metabolism. We used molecular modeling to design novel small-molecule pyrrolo[3,2-d]pyrimidine inhibitors targeting mitochondrial C1 metabolism at SHMT2. In vitro antitumor efficacy was established with the lead compounds (AGF291, AGF320, AGF347) toward lung, colon, and pancreatic cancer cells. Intracellular targets were identified by metabolic rescue with glycine and nucleosides, and by targeted metabolomics using a stable isotope tracer, with confirmation by in vitro assays with purified enzymes. In addition to targeting SHMT2, inhibition of the cytosolic purine biosynthetic enzymes, β-glycinamide ribonucleotide formyltransferase and/or 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase, and SHMT1 was also established. AGF347 generated significant in vivo antitumor efficacy with potential for complete responses against both early stage and upstage MIA PaCa-2 pancreatic tumor xenografts, providing compelling proof-of-concept for therapeutic targeting of SHMT2 and cytosolic C1 enzymes by this series. Our results establish structure-activity relationships and identify exciting new drug prototypes for further development as multi-targeted antitumor agents. PMID: 31289137 [PubMed - as supplied by publisher]

Comparison and Discrimination of Artemisia argyi and Artemisia lavandulifolia by Gas Chromatography-Mass Spectrometry-Based Metabolomic Approach. J AOAC Int. 2019 Jul 09;: Authors: Guo L, Zhang D, Wang L, Xue Z, Guo M, Duan L, Zheng Y Abstract Background: Artemisia argyi and A. lavandulifolia are two morphologically similar herbal medicines derived from the Artemisia genus. Although the two Artemisia herbs have been used as herbal medicines for a long time, studies on their phytochemicals and bioactive compositions are still limited, and no research has been devoted to compare the volatile compounds in A. argyi and A. lavandulifolia. Objective: To compare the volatile constituents in A. argyi and A. lavandulifolia and to explore chemical markers for discrimination and quality evaluation of the two Artemisia herbal medicines. Methods: A GC-MS-based metabolomic approach was employed to compare and discriminate A. argyi and A. lavandulifolia from the aspect of volatile compounds. Multivariate statistical methods, including principal component analysis and orthogonal partial least-squares discriminate analysis, were applied to explore chemical markers for discrimination of the two Artemisia herbal medicines. Results: Thirty volatile compounds were identified, and the chemical profiles of volatile compounds in A. argyi and A. lavandulifolia were quite similar. Principal component analysis and orthogonal partial least-squares discrimination analysis results indicated that the two Artemisia herbal medicines could be distinguished effectively from each other. Ten volatile compounds were selected as potential chemical markers for discrimination of the two Artemisia herbal medicines. Conclusions: The GC-MS-based metabolomics could be an acceptable strategy for comparison and discrimination of A. argyi and A. lavandulifolia as well as authentication of herbal medicines derived from other closely related species. Highlights: GC-MS based metabolomic approach was firstly applied to compare and discriminate Artemisia argyi and Artemisia lavandulifolia. PMID: 31288892 [PubMed - as supplied by publisher]

Metabolic Perturbations from Step Reduction in Older Persons at Risk for Sarcopenia: Plasma Biomarkers of Abrupt Changes in Physical Activity. Metabolites. 2019 Jul 08;9(7): Authors: Saoi M, Li A, McGlory C, Stokes T, von Allmen MT, Phillips SM, Britz-McKibbin P Abstract Sarcopenia is the age-related loss of skeletal muscle mass, strength and function, which may be accelerated during periods of physical inactivity. Declines in skeletal muscle and functionality not only impacts mobility but also increases chronic disease risk, such as type 2 diabetes. The aim of this study was to measure adaptive metabolic responses to acute changes in habitual activity in a cohort of overweight, pre-diabetic older adults (age = 69 ± 4 years; BMI = 27 ± 4 kg/m2, n = 17) when using non-targeted metabolite profiling by multisegment injection-capillary electrophoresis-mass spectrometry. Participants completed two weeks of step reduction (<1000 steps/day) followed by a two week recovery period, where fasting plasma samples were collected at three time intervals at baseline, after step reduction and following recovery. Two weeks of step reduction elicited increases in circulatory metabolites associated with a decline in muscle energy metabolism and protein degradation, including glutamine, carnitine and creatine (q < 0.05; effect size > 0.30), as well as methionine and deoxycarnitine (p < 0.05; effect size ≈ 0.20) as compared to baseline. Similarly, decreases in uremic toxins in plasma that promote muscle inflammation, indoxyl sulfate and hippuric acid, as well as oxoproline, a precursor used for intramuscular glutathione recycling, were also associated with physical inactivity (p < 0.05; effect size > 0.20). Our results indicate that older persons are susceptible to metabolic perturbations due to short-term step reduction that were not fully reversible with resumption of normal ambulatory activity over the same time period. These plasma biomarkers may enable early detection of inactivity-induced metabolic dysregulation in older persons at risk for sarcopenia not readily measured by current imaging techniques or muscle function tests, which is required for the design of therapeutic interventions to counter these deleterious changes in support of healthy ageing. PMID: 31288431 [PubMed]

Related Articles Deletion of TSPO Resulted in Change of Metabolomic Profile in Retinal Pigment Epithelial Cells. Int J Mol Sci. 2019 Mar 19;20(6): Authors: Alamri A, Biswas L, Watson DG, Shu X Abstract Age-related macular degeneration is the main cause of vision loss in the aged population worldwide. Drusen, extracellular lesions formed underneath the retinal pigment epithelial (RPE) cells, are a clinical feature of AMD and associated with AMD progression. RPE cells support photoreceptor function by providing nutrition, phagocytosing outer segments and removing metabolic waste. Dysfunction and death of RPE cells are early features of AMD. The translocator protein, TSPO, plays an important role in RPE cholesterol efflux and loss of TSPO results in increased intracellular lipid accumulation and reactive oxygen species (ROS) production. This study aimed to investigate the impact of TSPO knockout on RPE cellular metabolism by identifying the metabolic differences between wildtype and knockout RPE cells, with or without treatment with oxidized low density lipoprotein (oxLDL). Using liquid chromatography mass spectrometry (LC/MS), we differentiated several metabolic pathways among wildtype and knockout cells. Lipids amongst other intracellular metabolites were the most influenced by loss of TSPO and/or oxLDL treatment. Glucose, amino acid and nucleotide metabolism was also affected. TSPO deletion led to up-regulation of fatty acids and glycerophospholipids, which in turn possibly affected the cell membrane fluidity and stability. Higher levels of glutathione disulphide (GSSG) were found in TSPO knockout RPE cells, suggesting TSPO regulates mitochondrial-mediated oxidative stress. These data provide biochemical insights into TSPO-associated function in RPE cells and may shed light on disease mechanisms in AMD. PMID: 30893912 [PubMed - indexed for MEDLINE]

Related Articles The biology of ageing and the omics revolution. Biogerontology. 2018 12;19(6):435-436 Authors: Harries L, Goljanek-Whysall K Abstract PMID: 30288632 [PubMed - indexed for MEDLINE]

Related Articles Transcription factor repertoire in Ashwagandha (Withania somnifera) through analytics of transcriptomic resources: Insights into regulation of development and withanolide metabolism. Sci Rep. 2017 11 30;7(1):16649 Authors: Tripathi S, Sangwan RS, Narnoliya LK, Srivastava Y, Mishra B, Sangwan NS Abstract Transcription factors (TFs) are important regulators of cellular and metabolic functions including secondary metabolism. Deep and intensive RNA-seq analysis of Withania somnifera using transcriptomic databases provided 3532 annotated transcripts of transcription factors in leaf and root tissues, belonging to 90 different families with major abundance for WD-repeat (174 and 165 transcripts) and WRKY (93 and 80 transcripts) in root and leaf tissues respectively, followed by that of MYB, BHLH and AP2-ERF. Their detailed comparative analysis with Arabidopsis thaliana, Capsicum annum, Nicotiana tabacum and Solanum lycopersicum counterparts together gave interesting patterns. However, no homologs for WsWDR representatives, LWD1 and WUSCHEL, were observed in other Solanaceae species. The data extracted from the sequence read archives (SRA) in public domain databases were subjected to re-annotation, re-mining, re-analysis and validation for dominant occurrence of WRKY and WD-repeat (WDR) gene families. Expression of recombinant LWD1 and WUSCHEL proteins in homologous system led to enhancements in withanolide content indicating their regulatory role in planta in the biosynthesis. Contrasting expression profiles of WsLWD1 and WsWUSCHEL provided tissue-specific insights for their participation in the regulation of developmental processes. The in-depth analysis provided first full-spectrum and comparative characteristics of TF-transcripts across plant species, in the perspective of integrated tissue-specific regulation of metabolic processes including specialized metabolism. PMID: 29192149 [PubMed - indexed for MEDLINE]

46 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 2019/07/10PubMed 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.

Related Articles Metabolomic Status of The Oral Cavity in Chronic Periodontitis. In Vivo. 2019 Jul-Aug;33(4):1165-1174 Authors: Gawron K, Wojtowicz W, Łazarz-Bartyzel K, Łamasz A, Qasem B, Mydel P, Chomyszyn-Gajewska M, Potempa J, Mlynarz P Abstract Chronic periodontitis is an inflammatory disease of tooth-supporting tissues associated with Porphyromonas gingivalis. Expansion and invasion of this bacterium into the periodontium is associated with changes in the metabolome of the oral cavity. MATERIALS AND METHODS: Metabolomics analysis of mouth washout and tongue swab samples based on proton nuclear magnetic resonance (1H-NMR) method was employed to determine metabolic status of the oral cavity in chronic periodontal disease. RESULTS: Mouth washout extracts contained a total of 23 metabolites and tongue swab extracts contained 17. Identified metabolites partially overlap with the content of saliva and gingival crevicular fluid. The colonization of the oral cavity of patients with periodontitis by bacteria was manifested in the change in levels of eight metabolites. CONCLUSION: NMR-based metabolomics analysis is a potentially useful methodological approach for monitoring the pathological processes observed in the oral cavity in the course of periodontitis. PMID: 31280206 [PubMed - in process]

Related Articles Untargeted liquid chromatography coupled with mass spectrometry reveals metabolic changes in nitrogen-deficient Isatis indigotica Fortune. Phytochemistry. 2019 Jul 04;166:112058 Authors: Cao YW, Qu RJ, Miao YJ, Tang XQ, Zhou Y, Wang L, Geng L Abstract Isatis indigotica Fortune is a popular herb in traditional Chinese medicine, and various types of metabolites are the basis for its pharmacological efficacy. The biosynthesis and accumulation of these metabolites are closely linked to nitrogen availability; the benefits of low nitrogen application on the environment and herb quality are increasingly prominent. To analyze metabolic changes in the leaves and roots of I.indigotica in nitrogen deficiency conditions, and to identify the pathways and metabolites induced by low nitrogen availability, we used untargeted liquid chromatography coupled with mass spectrometry (UHPLC-TripleTOF) to obtain metabolomics profiling of I.indigotica under two N-deficiency treatments (0 kg/hm2; 337.5 kg/hm2) and normal nitrogen treatment (675 kg/hm2). A total of 447 metabolites were annotated. Principal component analysis separated the three nitrogen treatments. A greater diversity of metabolites was observed in roots than in leaves under N-deficiency treatments, suggesting that roots have a more important function in low N tolerance. Differential metabolites were mainly enriched in purine metabolism, phenylpropanoid biosynthesis, the shikimate pathway, tryptophan metabolism, and flavonoid biosynthesis that notably induced only in leaves in low nitrogen stress. Moderate N-deficiency benefits carbohydrate accumulation, whereas accumulation of most amino acids decreases. Uniquely, L-tryptophan was maintained at a high concentration in N-deficiency conditions. Low nitrogen stress induced the accumulation of some specialized metabolites (matairesinol, dictamnine, 5-hydroxyindoleacetate (serotonin) in roots and vitexin, xanthohumol, sinapyl alcohol in leaves). N-deficiency also increased the accumulation of adenosine and quality indicators of I.indigotica (indirubin-indigo, epigoitrin and anthranilic acid) in a certain degree. Our findings showed that nitrogen deficiency modified roots and leaves conditions of I.indigotica, affecting both the primary and secondary metabolism. Moderate nitrogen reduction was beneficial to the accumulation of active ingredients. Our methods and analysis are expected to provide an insight regarding the diversity of metabolites and regulation of their synthesis in low nitrogen application, and better investigate the nitrogen deficiency effect on I.indigotica. PMID: 31280093 [PubMed - as supplied by publisher]

Related Articles Application of metabolomics for unveiling the therapeutic role of traditional Chinese medicine in metabolic diseases. J Ethnopharmacol. 2019 Jul 04;:112057 Authors: Wu G, Zhang W, Li H Abstract ETHNOPHARMACOLOGICAL RELEVANCE: Traditional medicine has been practiced for thousands of years in China and some Asian countries. Traditional Chinese Medicine (TCM) is characterized as multi-component and multiple targets in disease therapy, and it is a great challenge for elucidating the mechanisms of TCM. AIM OF THE REVIEW: Comprehensively summarize the application of metabolomics in biomarker discovery, stratification of TCM syndromes, and mechanism underlying TCM therapy on metabolic diseases. METHODS: This review systemically searched the publications with key words such as metabolomics, traditional Chinese medicine, metabolic diseases, obesity, cardiovascular disease, diabetes mellitus in "Title OR Abstract" in major databases including PubMed, the Web of Science, Google Scholar, Science Direct, CNKI from 2010 to 2019. RESULTS: A total of 135 papers was searched and included in this review. An overview of articles indicated that metabolic characteristics may be a hallmark of different syndromes/models of metabolic diseases, which provides a new perspective for disease diagnosis and therapeutic optimization. Moreover, TCM treatment has significantly altered the metabolic perturbations associated with metabolic diseases, which may be an important mechanism for the therapeutic effect of TCM. CONCLUSIONS: Until now, many metabolites and differential biomarkers related to the pathogenesis of metabolic diseases and TCM therapy have been discovered through metabolomics research. Unfortunately, the biological role and mechanism of disease-related metabolites were largely unclarified so far, which warrants further investigation. PMID: 31279867 [PubMed - as supplied by publisher]

Related Articles A 1H-NMR based study of hemolymph metabonomics in different resistant silkworms, Bombyx mori (Lepidotera), after BmNPV inoculation. J Insect Physiol. 2019 Jul 04;:103911 Authors: Wang XY, Shao ZM, Zhang YJ, Vu TT, Wu YC, Xu JP, Deng MJ Abstract Bombyx mori nucleopolyhedrovirus (BmNPV) is a primary silkworm pathogen, and the molecular mechanism of silkworm defense to BmNPV infection is still unclear. Herein, comparative metabolomics was adopted to analyze the variations in the hemolymph metabolites of different resistant silkworm strains following BmNPV inoculation using a 1H-NMR method. Trehalose, as an instant source of energy, plays a crucial role in the response to pathogen infections in insects. The level of trehalose was persistently upregulated in the hemolymph of the resistant silkworm strain YeA following infection with BmNPV, compared to that of the susceptible strain YeB, indicating that trehalose metabolism plays a vital role in the response to BmNPV infection. The significant upregulation of TCA cycle relevant metabolites, including malate, fumarate, citrate, succinate, and α-ketoglutarate, was identified at 0 h, 12 h, 48 h, and 96 h post-infection in YeA hemolymph, whereas a significant upregulation in YeB hemolymph was only detected at an early stage of infection (0 h-24 h). The expression level of selected key metabolic enzymes, determined using RT-qPCR, validated the differences in trehalose and TCA cycle relevant metabolite levels. The variations in branched-chain amino acid (BCAA) pathway relevant metabolites in resistant silkworm strains following BmNPV infection showed a regular undulation at different times after infection. A significant accumulation of phenylalanine and tyrosine was observed in YeA following BmNPV infection compared to YeB. The glycolysis and gluconeogenesis pathways showed a relatively low activity in YeA following BmNPV infection. Moreover, the levels of other metabolites related to fat metabolism, transamination, energy metabolism, and glycometabolism, such as glycine, threonine, glutamine, and glutamate, were unstable in the two silkworm strains following BmNPV infection. Thus, our study provides an overview of the metabolic response of the silkworm in response to BmNPV infection, which lays the foundation for clarifying the mechanism of silkworm resistance to BmNPV infection. PMID: 31279633 [PubMed - as supplied by publisher]

Related Articles Metabolomics reveals plausible interactive effects between dairy product consumption and metabolic syndrome in humans. Clin Nutr. 2019 Jun 26;: Authors: Capel F, Bongard V, Malpuech-Brugère C, Karoly E, Michelotti GA, Rigaudière JP, Jouve C, Ferrières J, Marmonier C, Sébédio JL Abstract BACKGROUND & AIMS: Metabolic syndrome (MetS) induces major disturbances in plasma metabolome, reflecting abnormalities of several metabolic pathways. Recent evidences have demonstrated that the consumption of dairy products may protect from MetS, but the mechanisms remains unknown. The present study aimed at identify how the consumption of different types of dairy products could modify the changes in plasma metabolome during MetS. METHODS: In this observational study, we analyzed how the consumption of dairy products could modify the perturbations in the plasma metabolome induced by MetS in a sample of 298 participants (61 with MetS) from the French MONA LISA survey. Metabolomic profiling was analyzed with UPLC-MS/MS. RESULTS: Subjects with MetS exhibited major changes in plasma metabolome. Significant differences in plasma levels of branched chain amino acids, gamma-glutamyl amino acids, and metabolites from arginine and proline metabolism were observed between healthy control and Mets subjects. Plasma levels of many lipid species were increased with MetS (mono- and diacylglycerols, eicosanoids, lysophospholipids and lysoplasmalogens), with corresponding decreases in short chain fatty acids and plasmalogens. The consumption of dairy products, notably with a low fat content (milk and fresh dairy products), altered metabolite profiles in plasma from MetS subjects. Specifically, increasing consumption of dairy products promoted accumulation of plasma C15:0 fatty acid and was inversely associated to some circulating lysophospholipids, sphingolipids, gamma-glutamyl amino acids, leukotriene B4 and lysoplasmalogens. CONCLUSIONS: the consumption of low fat dairy products could mitigate some of the variations induced by MetS. PMID: 31279616 [PubMed - as supplied by publisher]

Related Articles Genetic variance of metabolomic features and their relationship with body weight and body weight gain in Holstein cattle. J Anim Sci. 2019 Jul 05;: Authors: Aliakbari A, Ehsani A, Vaez Torshizi R, Løvendahl P, Esfandyari H, Jensen J, Sarup P Abstract In recent years, metabolomics has been used to clarify the biology underlying biological samples. In the field of animal breeding, investigating the magnitude of genetic control on the metabolomic profiles of animals and their relationships with quantitative traits adds valuable information to animal improvement schemes. In this study, we analyzed metabolomic features (MFs) extracted from the metabolomic profiles of 843 male Holstein calves. The metabolomic profiles were obtained using nuclear magnetic resonance (NMR) spectroscopy. We investigated two alternative methods to control for peak shifts in the NMR spectra, binning and aligning, to determine which approach was the most efficient for assessing genetic variance. Series of univariate analyses were implemented to elucidate the heritability of each MF. Furthermore, records on body weight (BW) and average daily gains from 154 to 294 days of age (ADG154-294), 294 to 336 days of age (ADG294-336), and 154 to 336 days of age (ADG154-336) were used in a series of bivariate analyses to establish the genetic and phenotypic correlations with MFs. Bivariate analyses were only performed for MFs that had a heritability significantly different from zero. The heritabilities obtained in the univariate analyses for the MFs in the binned dataset were low (< 0.2). In contrast, in the aligned dataset, we obtained moderate heritability (0.2 to 0.5) for 3.5% of MFs and high heritability (more than 0.5) for 1% of MFs. The bivariate analyses showed that ~12 %, ~3 %, ~9 %, and ~9 % of MFs had significant additive genetic correlations with BW, ADG154-294, ADG294-336, and ADG154-336, respectively. In all of the bivariate analyses, the percentage of significant additive genetic correlations was higher than the percentage of significant phenotypic correlations of the corresponding trait. Our results provided insights into the influence of the underlying genetic mechanisms on MFs. Further investigations in this field are needed for better understanding of the genetic relationship among the MFs and quantitative traits. PMID: 31278866 [PubMed - as supplied by publisher]

Related Articles Systems Genetics for Evolutionary Studies. Methods Mol Biol. 2019;1910:635-652 Authors: Prins P, Smant G, Arends D, Mulligan MK, Williams RW, Jansen RC Abstract Systems genetics combines high-throughput genomic data with genetic analysis. In this chapter, we review and discuss application of systems genetics in the context of evolutionary studies, in which high-throughput molecular technologies are being combined with quantitative trait locus (QTL) analysis in segregating populations.The recent explosion of high-throughput data-measuring thousands of RNAs, proteins, and metabolites, using deep sequencing, mass spectrometry, chromatin, methyl-DNA immunoprecipitation, etc.-allows the dissection of causes of genetic variation underlying quantitative phenotypes of all types. To deal with the sheer amount of data, powerful statistical tools are needed to analyze multidimensional relationships and to extract valuable information and new modes and mechanisms of changes both within and between species. In the context of evolutionary computational biology, a well-designed experiment and the right population can help dissect complex traits likely to be under selection using proven statistical methods for associating phenotypic variation with chromosomal locations.Recent evolutionary expression QTL (eQTL) studies focus on gene expression adaptations, mapping the gene expression landscape, and, tentatively, define networks of transcripts and proteins that are jointly modulated sets of eQTL networks. Here, we discuss the possibility of introducing an evolutionary "prior" in the form of gene families displaying evidence of positive selection, and using that prior in the context of an eQTL experiment for elucidating host-pathogen protein-protein interactions.Here we review one exemplar evolutionairy eQTL experiment and discuss experimental design, choice of platforms, analysis methods, scope, and interpretation of results. In brief we highlight how eQTL are defined; how they are used to assemble interacting and causally connected networks of RNAs, proteins, and metabolites; and how some QTLs can be efficiently converted to reasonably well-defined sequence variants. PMID: 31278680 [PubMed - in process]

Related Articles MCEE 2.0: more options and enhanced performance. Anal Bioanal Chem. 2019 Jul 05;: Authors: Li Y, Zheng X, Liang D, Zhao A, Jia W, Chen T Abstract A confounding factor is an unstudied factor that affects one or more of the variables that are being studied in an investigation, so the presence of a confounder may lead to inaccurate or biased results. It is well recognized that physiological and environmental factors such as race, diet, age, gender, blood pressure, and diurnal cycle affect mammalian metabolism. To eliminate the noise introduced by confounders into metabolomics studies, a GUI-based method denoted metabolic confounding effect elimination (MCEE) was developed and has since been applied successfully in a wide range of metabolomics studies. To keep up with recent developments in computational metabolomics and a growing number of user requests, an upgraded version of MCEE with more options and enhanced performance was designed and developed. Besides the generalized linear model (GLM) method, a multivariate method for selecting affected metabolites-canonical correlation analysis (CCA)-was introduced, which accounts for complicated correlations and collinearity within the metabolome. Multiple confounders are acceptable and can be identified and processed separately or simultaneously. The effectiveness of this new version of MCEE as well as the pros and cons of the two methodological options were examined using three simulated data sets (a basic model, a model with different sample size ratios, and a sparse model) and two real-world data sets (a human type 2 diabetes mellitus data set and a human arthritis data set). As well as presenting the results of this examination of the new version of MCEE, some instructions on appropriate method selection and parameter setting are provided here. The freely available MATLAB code for MCEE with a GUI has also been updated accordingly at https://github.com/chentianlu/MCEE-2.0 . Graphical abstract. PMID: 31278548 [PubMed - as supplied by publisher]

Related Articles Erythrocyte Adenosine A2B Receptor-Mediated AMPK Activation: A Missing Component Counteracting CKD by Promoting Oxygen Delivery. J Am Soc Nephrol. 2019 Jul 05;: Authors: Peng Z, Luo R, Xie T, Zhang W, Liu H, Wang W, Tao L, Kellems RE, Xia Y Abstract BACKGROUND: Oxygen deprivation or hypoxia in the kidney drives CKD and contributes to end organ damage. The erythrocyte's role in delivery of oxygen (O2) is regulated by hypoxia, but the effects of CKD are unknown. METHODS: We screened all of the metabolites in the whole blood of mice infused with angiotensin II (Ang II) at 140 ng/kg per minute up to 14 days to simulate CKD and compared their metabolites with those from untreated mice. Mice lacking a receptor on their erythrocytes called ADORA2B, which increases O2 delivery, and patients with CKD were studied to assess the role of ADORA2B-mediated O2 delivery in CKD. RESULTS: Untargeted metabolomics showed increased production of 2,3-biphosphoglycerate (2,3-BPG), an erythrocyte-specific metabolite promoting O2 delivery, in mice given Ang II to induce CKD. Genetic studies in mice revealed that erythrocyte ADORA2B signaling leads to AMPK-stimulated activation of BPG mutase, promoting 2,3-BPG production and O2 delivery to counteract kidney hypoxia, tissue damage, and disease progression in Ang II-induced CKD. Enhancing AMPK activation in mice offset kidney hypoxia by triggering 2,3-BPG production and O2 delivery. Patients with CKD had higher 2,3-BPG levels, AMPK activity, and O2 delivery in their erythrocytes compared with controls. Changes were proportional to disease severity, suggesting a protective effect. CONCLUSIONS: Mouse and human evidence reveals that ADORA2B-AMPK signaling cascade-induced 2,3-BPG production promotes O2 delivery by erythrocytes to counteract kidney hypoxia and progression of CKD. These findings pave a way to novel therapeutic avenues in CKD targeting this pathway. PMID: 31278195 [PubMed - as supplied by publisher]

Related Articles Leveraging -omics for asthma endotyping. J Allergy Clin Immunol. 2019 Jul;144(1):13-23 Authors: Tyler SR, Bunyavanich S Abstract Asthma is a highly heterogeneous disease, often manifesting with wheeze, dyspnea, chest tightness, and cough as prominent symptoms. The eliciting factors, natural history, underlying molecular biology, and clinical management of asthma vary highly among affected subjects. Because of this variation, many efforts have gone into subtyping asthma. Endotypes are subtypes of disease based on distinct pathophysiologic mechanisms. Endotypes can be clinically useful because they organize our mechanistic understanding of heterogeneous diseases and can direct treatment toward modalities that are likely to be the most effective. Asthma endotyping can be shaped by clinical features, laboratory parameters, and/or -omics approaches. We discuss the application of -omics approaches, including transcriptomics, epigenomics, microbiomics, metabolomics, and proteomics, to asthma endotyping. -Omics approaches have provided supporting evidence for many existing endotyping paradigms and also suggested novel ways to conceptualize asthma endotypes. Although endotypes based on single -omics approaches are relatively common, their integrated multi-omics application to asthma endotyping has been more limited thus far. We discuss paths forward to integrate multi-omics with clinical features and laboratory parameters to achieve the goal of precise asthma endotypes. PMID: 31277743 [PubMed - in process]

Related Articles Impaired branched chain amino acid oxidation contributes to cardiac insulin resistance in heart failure. Cardiovasc Diabetol. 2019 Jul 05;18(1):86 Authors: Uddin GM, Zhang L, Shah S, Fukushima A, Wagg CS, Gopal K, Al Batran R, Pherwani S, Ho KL, Boisvenue J, Karwi QG, Altamimi T, Wishart DS, Dyck JRB, Ussher JR, Oudit GY, Lopaschuk GD Abstract BACKGROUND: Branched chain amino acids (BCAA) can impair insulin signaling, and cardiac insulin resistance can occur in the failing heart. We, therefore, determined if cardiac BCAA accumulation occurs in patients with dilated cardiomyopathy (DCM), due to an impaired catabolism of BCAA, and if stimulating cardiac BCAA oxidation can improve cardiac function in mice with heart failure. METHOD: For human cohorts of DCM and control, both male and female patients of ages between 22 and 66 years were recruited with informed consent from University of Alberta hospital. Left ventricular biopsies were obtained at the time of transplantation. Control biopsies were obtained from non-transplanted donor hearts without heart disease history. To determine if stimulating BCAA catabolism could lessen the severity of heart failure, C57BL/6J mice subjected to a transverse aortic constriction (TAC) were treated between 1 to 4-week post-surgery with either vehicle or a stimulator of BCAA oxidation (BT2, 40 mg/kg/day). RESULT: Echocardiographic data showed a reduction in ejection fraction (54.3 ± 2.3 to 22.3 ± 2.2%) and an enhanced formation of cardiac fibrosis in DCM patients when compared to the control patients. Cardiac BCAA levels were dramatically elevated in left ventricular samples of patients with DCM. Hearts from DCM patients showed a blunted insulin signalling pathway, as indicated by an increase in P-IRS1ser636/639 and its upstream modulator P-p70S6K, but a decrease in its downstream modulators P-AKT ser473 and in P-GSK3β ser9. Cardiac BCAA oxidation in isolated working hearts was significantly enhanced by BT2, compared to vehicle, following either acute or chronic treatment. Treatment of TAC mice with BT2 significantly improved cardiac function in both sham and TAC mice (63.0 ± 1.8 and 56.9 ± 3.8% ejection fraction respectively). Furthermore, P-BCKDH and BCKDK expression was significantly decreased in the BT2 treated groups. CONCLUSION: We conclude that impaired cardiac BCAA catabolism and insulin signaling occur in human heart failure, while enhancing BCAA oxidation can improve cardiac function in the failing mouse heart. PMID: 31277657 [PubMed - in process]