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: 2 hours 2 min ago

Evidence from 3-month-old infants shows that a combination of postnatal feeding and exposures in utero shape lipid metabolism.

Sun, 06/10/2019 - 12:01
Related Articles Evidence from 3-month-old infants shows that a combination of postnatal feeding and exposures in utero shape lipid metabolism. Sci Rep. 2019 Oct 04;9(1):14321 Authors: Furse S, Snowden SG, Olga L, Prentice P, Ong KK, Hughes IA, Acerini CL, Dunger DB, Koulman A Abstract We tested the hypothesis that both postnatal feeding and conditions in utero affect lipid metabolism in infants. Infants who experienced restrictive growth conditions in utero and others exposed to maternal hyperglycaemia were compared to a control group with respect to feeding mode. Dried blood spots were collected from a pilot subset of infant participants of the Cambridge Baby Growth Study at 3mo. Groups: (a) a normal gestation (control, n = 40), (b) small for gestational age (SGA, n = 34) and (c) whose mothers developed hyperglycaemia (n = 59). These groups were further stratified by feeding mode; breastfed, formula-fed or received a mixed intake. Their phospholipid, glyceride and sterol fractions were profiled using direct infusion mass spectrometry. Statistical tests were used to identify molecular species that indicated differences in lipid metabolism. The abundance of several phospholipids identified by multivariate analysis, PC(34:1), PC(34:2) and PC-O(34:1), was 30-100% higher across all experimental groups. SM(39:1) was around half as abundant in in utero groups among breastfed infants only. The evidence from this pilot study shows that phospholipid metabolism is modulated by both conditions in utero and postnatal feeding in a cohort of 133 Caucasian infants, three months post partum. PMID: 31586083 [PubMed - in process]

Decreased ω6/ω3 PUFA ratio attenuates ethanol-induced alterations in intestinal homeostasis, microbiota and liver injury.

Sun, 06/10/2019 - 12:01
Related Articles Decreased ω6/ω3 PUFA ratio attenuates ethanol-induced alterations in intestinal homeostasis, microbiota and liver injury. J Lipid Res. 2019 Oct 04;: Authors: Warner DR, Warner JB, Hardesty JE, Song YL, King TN, Kang JX, Chen CY, Xie S, Yuan F, Prodhan MAI, Ma X, Zhang X, Rouchka EC, Maddipati KR, Whitlock J, Li EC, Wang GP, McClain CJ, Kirpich IA Abstract Ethanol-induced alterations in intestinal homeostasis lead to multi-system pathologies, including liver injury.  w6-PUFAs exert pro-inflammatory activity, while ω3-PUFAs promote anti-inflammatory activity that is mediated, in part, through specialized pro-resolving mediators (e.g. RvD1).  We tested the hypothesis that a decrease in ω6/ω3 PUFA ratio would attenuate ethanol-mediated alterations in the gut-liver axis.  fat-1 mice, which endogenously increase w3-PUFA levels, were protected against ethanol-mediated down-regulation of intestinal tight junction proteins in organoid cultures and in vivo.  Ethanol and LPS-induced expression of INF-g, Il-6, and Cxcl1 was attenuated in fat-1 and WT RvD1-treated mice. RNA-seq of ileum tissue revealed up-regulation of several genes involved in cell proliferation and stem cell renewal, and anti-microbial defense (including Alpi and Leap2) in fat-1 vs WT mice fed ethanol.  fat-1 mice were also resistant to ethanol-mediated down-regulation of genes important for xenobiotic/bile acid detoxification.  Further, gut microbiome and plasma metabolomics revealed several changes in fat-1 vs. WT mice that may contribute to a reduced inflammatory response.  Finally, these data correlated with a significant reduction in liver injury.  Our study suggests that w3-PUFA enrichment or treatment with resolvins can attenuate the disruption in alcohol-induced intestinal homeostasis caused by ethanol consumption and systemic inflammation with a concomitant reduction in liver injury. PMID: 31586017 [PubMed - as supplied by publisher]

The systems medicine of neonatal abstinence syndrome.

Sun, 06/10/2019 - 12:01
Related Articles The systems medicine of neonatal abstinence syndrome. Front Biosci (Landmark Ed). 2020 Jan 01;25:736-759 Authors: Stone WL, Wood DL, Justice NA, Shah DS, Olsen ME, Bharti D Abstract This review will focus on a systems medicine approach to neonatal abstinence syndrome (NAS). Systems medicine utilizes information gained from the application of "omics" technology and bioinformatics (1). The omic approaches we will emphasize include genomics, epigenomics, proteomics, and metabolomics. The goals of systems medicine are to provide clinically relevant and objective insights into disease diagnosis, prognosis, and stratification as well as pharmacological strategies and evidence-based individualized clinical guidance. Despite the increasing incidence of NAS and its societal and economic costs, there has been only a very modest emphasis on utilizing a systems medicine approach, and this has been primarily in the areas of genomics and epigenomics. As detailed below, proteomics and metabolomics hold great promise in advancing our knowledge of NAS and its treatment. Metabolomics, in particular, can provide a quantitative assessment of the exposome, which is a comprehensive picture of both internal and external environmental factors affecting health. PMID: 31585915 [PubMed - in process]

Metabolomics characterizes metabolic changes of Apocyni Veneti Folium in response to salt stress.

Sat, 05/10/2019 - 14:56
Related Articles Metabolomics characterizes metabolic changes of Apocyni Veneti Folium in response to salt stress. Plant Physiol Biochem. 2019 Sep 27;144:187-196 Authors: Chen C, Liu H, Wang C, Liu Z, Liu X, Zou L, Zhao H, Yan Y, Shi J, Chen S Abstract Apocyni Veneti Folium (AVF) has been raised great interest in the antioxidant properties recently for the preservation of human health. However, little research was found on the integrate metabolites except our previous investigation on the variations of the bioactive constituents. To understand the salt-tolerant mechanisms of the halophyte, metabolomic platform based on ultra-fast liquid chromatography tandem triple time-of-flight mass/mass spectrometer was applied in this study. The results showed that metabolic profiles were separated and differentiated among groups based on multivariate statistical analysis; different metabolites belonged to various chemical classes. Besides, phenylpropanoid pathway and terpenoid biosynthesis were disturbed in all salt-stressed AVF and low salt-treated group appeared to be better than other samples in terms of relative contents (peak areas) of the wide variety of bioactive components and physiological variations of photosynthetic pigments, osmotic homeostasis, lipid peroxidation product and antioxidative enzymes. This study may provide additional insight into the salt-tolerant mechanisms and the quality assessment of AVF in a holistic level based on the plant metabolomics. PMID: 31585397 [PubMed - as supplied by publisher]

Evaluation of Direct from Sample Metabolomics of Human Faeces using Rapid Evaporative Ionisation Mass Spectrometry (REIMS).

Sat, 05/10/2019 - 14:56
Related Articles Evaluation of Direct from Sample Metabolomics of Human Faeces using Rapid Evaporative Ionisation Mass Spectrometry (REIMS). Anal Chem. 2019 Oct 04;: Authors: Cameron SJS, Alexanders J, Bolt F, Burke A, Ashrafian H, Teare JP, Marchesi JR, Kinross JM, Li JV, Takats Z Abstract Mass spectrometry is a powerful tool in the investigation of the human faecal metabolome. However, current approaches require time-consuming sample preparation, chromatographic separations, and consequently long analytical run times. Rapid evaporative ionisation mass spectrometry (REIMS) is a method of ambient ionisation mass spectrometry and has been utilised in the metabolic profiling of a diverse range of biological materials, including human tissue, cell culture lines, and microorganisms. Here, we describe the use of an automated, high-throughput REIMS robotic platform for direct analysis of human faeces. Through the analysis of faecal samples from five healthy male participants, REIMS analytical parameters were optimised and used to assess the chemical information obtainable using REIMS. Within the faecal samples analysed, bile acids, including primary, secondary, and conjugate species were identified, and phospholipids of possible bacterial origin were detected. In addition, the effect of storage conditions and consecutive freeze/thaw cycles was determined. Within the REIMS mass spectra, the lower molecular weight metabolites, such as fatty acids, were shown to be significantly affected by storage conditions for prolonged periods at temperatures above -80°C, and consecutive freeze/thaw cycles. However, the complex lipid region was shown to be unaffected by these conditions. A further cohort of 50 faecal samples, collected from patients undergoing bariatric surgery, were analysed using the optimised REIMS parameters, and the complex lipid region mass spectra used for multivariate modelling. This analysis showed a predicted separation between pre- and post-surgery specimens, suggesting that REIMS analysis can detect biological differences, such as microbiome-level differences, which have traditionally been reliant upon methods utilising extensive sample preparations and chromatographic separations and/or DNA sequencing. PMID: 31584799 [PubMed - as supplied by publisher]

Precision medicine: The future of diagnostic approach to pulmonary hypertension?

Sat, 05/10/2019 - 14:56
Related Articles Precision medicine: The future of diagnostic approach to pulmonary hypertension? Anatol J Cardiol. 2019 Sep;22(4):168-171 Authors: Kedzierski P, Torbicki A Abstract Pulmonary hypertension (PH) is a common finding that can result from many different pathological conditions. Depending on the etiology, treatment may be quite different, but early diagnosis and correct classification of PH is difficult. With an aging population and recently suggested decreased pulmonary arterial pressure threshold defining PH, we are facing even more diagnostic uncertainties. A new approach to patients' phenotyping is needed. Here we present available data and future perspectives on employing an in-depth analysis of the omics cascade to allow an earlier and more reliable diagnosis and classification of PH. Indeed, with the help of super-fast computing, it became possible to simultaneously consider the levels of thousands of potential biomarkers to find patterns specific for clinically suspected disease. The omics cascade is an invaluable source of information. However, while the genome can be perceived as providing possibilities, transcriptome-as carving them this is metabolome that may tell us 'what is really going on' in an individual living organism. Metabolomics research requires blinded search for characteristic patterns of discreet changes in the levels of detectable metabolites. Since as many as 40,000 various substances are produced as a 'side effect of staying alive', metabolite profiling can be compared to fishing up for organized signals in a universe of chaos. Although difficult, such search for metabolic patterns that might lead to replacing the term biomarker by metabolic fingerprinting in the area of pulmonary circulation has already begun. PMID: 31584446 [PubMed - in process]

Metabolomics and many more….

Sat, 05/10/2019 - 14:56
Related Articles Metabolomics and many more…. Anatol J Cardiol. 2019;22(4):159 Authors: Erol Ç Abstract PMID: 31584439 [PubMed - in process]

Circulating metabolites and the risk of type 2 diabetes: a prospective study of 11,896 young adults from four Finnish cohorts.

Sat, 05/10/2019 - 14:56
Related Articles Circulating metabolites and the risk of type 2 diabetes: a prospective study of 11,896 young adults from four Finnish cohorts. Diabetologia. 2019 Oct 04;: Authors: Ahola-Olli AV, Mustelin L, Kalimeri M, Kettunen J, Jokelainen J, Auvinen J, Puukka K, Havulinna AS, Lehtimäki T, Kähönen M, Juonala M, Keinänen-Kiukaanniemi S, Salomaa V, Perola M, Järvelin MR, Ala-Korpela M, Raitakari O, Würtz P Abstract AIMS/HYPOTHESIS: Metabolomics technologies have identified numerous blood biomarkers for type 2 diabetes risk in case-control studies of middle-aged and older individuals. We aimed to validate existing and identify novel metabolic biomarkers predictive of future diabetes in large cohorts of young adults. METHODS: NMR metabolomics was used to quantify 229 circulating metabolic measures in 11,896 individuals from four Finnish observational cohorts (baseline age 24-45 years). Associations between baseline metabolites and risk of developing diabetes during 8-15 years of follow-up (392 incident cases) were adjusted for sex, age, BMI and fasting glucose. Prospective metabolite associations were also tested with fasting glucose, 2 h glucose and HOMA-IR at follow-up. RESULTS: Out of 229 metabolic measures, 113 were associated with incident type 2 diabetes in meta-analysis of the four cohorts (ORs per 1 SD: 0.59-1.50; p< 0.0009). Among the strongest biomarkers of diabetes risk were branched-chain and aromatic amino acids (OR 1.31-1.33) and triacylglycerol within VLDL particles (OR 1.33-1.50), as well as linoleic n-6 fatty acid (OR 0.75) and non-esterified cholesterol in large HDL particles (OR 0.59). The metabolic biomarkers were more strongly associated with deterioration in post-load glucose and insulin resistance than with future fasting hyperglycaemia. A multi-metabolite score comprised of phenylalanine, non-esterified cholesterol in large HDL and the ratio of cholesteryl ester to total lipid in large VLDL was associated with future diabetes risk (OR 10.1 comparing individuals in upper vs lower fifth of the multi-metabolite score) in one of the cohorts (mean age 31 years). CONCLUSIONS/INTERPRETATION: Metabolic biomarkers across multiple molecular pathways are already predictive of the long-term risk of diabetes in young adults. Comprehensive metabolic profiling may help to target preventive interventions for young asymptomatic individuals at increased risk. PMID: 31584131 [PubMed - as supplied by publisher]

Impact of matrix effects and ionization efficiency in non-quantitative untargeted metabolomics.

Sat, 05/10/2019 - 14:56
Related Articles Impact of matrix effects and ionization efficiency in non-quantitative untargeted metabolomics. Metabolomics. 2019 Oct 04;15(10):135 Authors: Chamberlain CA, Rubio VY, Garrett TJ Abstract INTRODUCTION: LC-MS-based untargeted metabolomics has become increasingly popular due to the vast amount of information gained in a single analysis. Many studies utilize metabolomics to profile metabolic changes in various representative biofluids, tissues, or other sample types. Most analyses are performed measuring changes in the metabolic pool of a single biological matrix due to an altered phenotype, such as disease versus normal. Measurements in such experiments are typically highly reproducible with little variation due to analytical and technological advancements in mass spectrometry. With the expanded application of metabolomics into various non-analytical scientific disciplines, the emergence of studies comparing the signal intensities of specific analytes across different biological matrices (e.g. plasma vs. urine) is becoming more common, but the matrix effect between sample types is often neglected. Additionally, the practice of comparing the signal intensities of different analytes and correlating to relative abundance is also increasingly prevalent, but the response ratio between analytes due to differences in ionization efficiency is not always accounted for in data analysis. This report serves to communicate and raise awareness of these two well-recognized issues to prevent improper data interpretation in the field of metabolomics. OBJECTIVES: We demonstrate the impact of matrix effects and ionization efficiency with labeled analytical standards in human plasma, serum, and urine and describe how the direct comparison of non-quantitative signal intensities between biofluids, as well as between different analytes in the same biofluid, in untargeted metabolomics is inaccurate without proper response corrections. METHODS: Human plasma, serum, and urine (n = 4 technical replicates per biofluid) were spiked with a panel of labeled internal standards all at identical concentrations, simultaneously extracted, and analyzed by UHPLC-HRMS. Signal intensities were compared for demonstration of the impact of matrix effects in untargeted metabolomics. A neat mixture of two co-eluting, structurally-similar labeled standards at the same concentration was also analyzed to demonstrate the effect of ionization efficiency on signal intensity. RESULTS: Despite being spiked at identical concentrations, labeled standards we examined in this study showed significant differences in their signal intensities between biofluids, as well as from each other in the same biofluid, due to matrix effects. Co-eluting standards were also found to yield significantly different signal intensities at identical concentrations due to differences in ionization efficiency. CONCLUSIONS: Due to the presence of matrix effects in untargeted, non-quantitative metabolomics, the signal intensity of any single analyte cannot be directly compared to the signal intensity of that same analyte (or any other analyte) between any two different matrices. Due to differences in ionization efficiency, the signal intensity of any single analyte cannot be directly compared to the signal intensity of any other analyte, even in the same matrix. PMID: 31584114 [PubMed - in process]

Multi-block PLS discriminant analysis for the joint analysis of metabolomic and epidemiological data.

Sat, 05/10/2019 - 14:56
Related Articles Multi-block PLS discriminant analysis for the joint analysis of metabolomic and epidemiological data. Metabolomics. 2019 Oct 03;15(10):134 Authors: Brandolini-Bunlon M, Pétéra M, Gaudreau P, Comte B, Bougeard S, Pujos-Guillot E Abstract INTRODUCTION: Metabolomics is a powerful phenotyping tool in nutrition and health research, generating complex data that need dedicated treatments to enrich knowledge of biological systems. In particular, to investigate relations between environmental factors, phenotypes and metabolism, discriminant statistical analyses are generally performed separately on metabolomic datasets, complemented by associations with metadata. Another relevant strategy is to simultaneously analyse thematic data blocks by a multi-block partial least squares discriminant analysis (MBPLSDA) allowing determining the importance of variables and blocks in discriminating groups of subjects, taking into account data structure. OBJECTIVE: The present objective was to develop a full open-source standalone tool, allowing all steps of MBPLSDA for the joint analysis of metabolomic and epidemiological data. METHODS: This tool was based on the mbpls function of the ade4 R package, enriched with functionalities, including some dedicated to discriminant analysis. Provided indicators help to determine the optimal number of components, to check the MBPLSDA model validity, and to evaluate the variability of its parameters and predictions. RESULTS: To illustrate the potential of this tool, MBPLSDA was applied to a real case study involving metabolomics, nutritional and clinical data from a human cohort. The availability of different functionalities in a single R package allowed optimizing parameters for an efficient joint analysis of metabolomics and epidemiological data to obtain new insights into multidimensional phenotypes. CONCLUSION: In particular, we highlighted the impact of filtering the metabolomic variables beforehand, and the relevance of a MBPLSDA approach in comparison to a standard PLS discriminant analysis method. PMID: 31583480 [PubMed - in process]

In vitro profiling of endothelial volatile organic compounds under resting and pro-inflammatory conditions.

Sat, 05/10/2019 - 14:56
Related Articles In vitro profiling of endothelial volatile organic compounds under resting and pro-inflammatory conditions. Metabolomics. 2019 Oct 03;15(10):132 Authors: Longo V, Forleo A, Capone S, Scoditti E, Carluccio MA, Siciliano P, Massaro M Abstract INTRODUCTION: The evaluation of volatile organic compounds(VOCs) emitted by human body offers a unique tool to set up new non-invasive devices for early diagnosis and long-lasting monitoring of most human diseases. However, their cellular origin and metabolic fate have not been completely elucidated yet, thus limiting their clinical application. Endothelium acts as an interface between blood and surrounding tissues. As such, it adapts its physiology in response to different environmental modifications thus playing a role in the pathogenesis of many metabolic and inflammatory diseases. OBJECTIVES: Since endothelium specifically reshapes its physiologic functions upon environmental changes the objective of this study was to evaluate if and how pro-inflammatory stimuli affect VOC metabolism in endothelial cell in culture. METHODS: Gas chromatography with mass spectrometric detection was applied to profile VOCs in the headspace of cultured endothelial cells (EC) in the absence or presence of the pro-inflammatory stimulus lipopolysaccharide (LPS). RESULTS: We observed that, under resting conditions, EC affected the amount of 58 VOCs belonging to aldehyde, alkane and ketone families. Among these, LPS significantly altered the amount of 15 VOCs. ROC curves show a perfect performance (AUC = 1) for 10 metabolites including 1-butanol, 3-methyl-1-butanol and 2-ethyl-1-hexanol. DISCUSSION: The emission and uptake of the aforementioned VOCs disclose potential unexplored metabolic pathways for EC that deserve to be investigated. Overall, we identified new candidate VOC potentially exploitable, upon experimental confirm in in vivo model of disease, as potential biomarkers of sepsis and pro-inflammatory clinical settings. PMID: 31583479 [PubMed - in process]

Predicting response to lisinopril in treating hypertension: a pilot study.

Sat, 05/10/2019 - 14:56
Related Articles Predicting response to lisinopril in treating hypertension: a pilot study. Metabolomics. 2019 Oct 03;15(10):133 Authors: Sonn BJ, Saben JL, McWilliams G, Shelton SK, Flaten HK, D'Alessandro A, Monte AA Abstract INTRODUCTION: Only ~ 50% of hypertensive patients will respond to treatment. OBJECTIVE: This pilot study aims to identify clinical and metabolite markers that predict response to lisinopril. METHODS: Hypertensive patients (n = 45) received lisinopril (10 mg) at their baseline visit. Blood pressures were reevaluated one week later. Responders to lisinopril (n = 19) were defined by a 10% decline in systolic blood pressure. Plasma metabolites were evaluated with mass spectrometry. RESULTS: BMI (p = 0.009), GFR (p = 0.015) and 2-oxoglutarate were included in a logistic regression model to predict response to lisinopril. CONCLUSIONS: Further validation cohorts are needed to confirm the predictive values of these clinical and metabolic markers. PMID: 31583478 [PubMed - in process]

Metabolomics analysis of children with autism, idiopathic-developmental delays, and Down syndrome.

Sat, 05/10/2019 - 14:56
Related Articles Metabolomics analysis of children with autism, idiopathic-developmental delays, and Down syndrome. Transl Psychiatry. 2019 Oct 03;9(1):243 Authors: Orozco JS, Hertz-Picciotto I, Abbeduto L, Slupsky CM Abstract Although developmental delays affect learning, language, and behavior, some evidence suggests the presence of disturbances in metabolism are associated with psychiatric disorders. Here, the plasma metabolic phenotype of children with autism spectrum disorder (ASD, n = 167), idiopathic-developmental delay (i-DD, n = 51), and Down syndrome (DS, n = 31), as compared to typically developed (TD, n = 193) controls was investigated in a subset of children from the case-control Childhood Autism Risk from Genetics and the Environment (CHARGE) Study. Metabolome profiles were obtained using nuclear magnetic resonance spectroscopy and analyzed in an untargeted manner. Forty-nine metabolites were identified and quantified in each sample that included amino acids, organic acids, sugars, and other compounds. Multiple linear regression analysis revealed significant associations between 11 plasma metabolites and neurodevelopmental outcome. Despite the varied origins of these developmental disabilities, we observed similar perturbation in one-carbon metabolism pathways among DS and ASD cases. Similarities were also observed in the DS and i-DD cases in the energy-related tricarboxylic acid cycle. Other metabolites and pathways were uniquely associated with DS or ASD. By comparing metabolic signatures between these conditions, the current study expands on extant literature demonstrating metabolic alterations associated with developmental disabilities and provides a better understanding of overlapping vs specific biological perturbations associated with these disorders. PMID: 31582732 [PubMed - in process]

MFF REGULATION OF MITOCHONDRIAL CELL DEATH IS A THERAPEUTIC TARGET IN CANCER.

Sat, 05/10/2019 - 14:56
Related Articles MFF REGULATION OF MITOCHONDRIAL CELL DEATH IS A THERAPEUTIC TARGET IN CANCER. Cancer Res. 2019 Oct 03;: Authors: Seo JH, Chae YC, Kossenkov AV, Lee YG, Tang HY, Agarwal E, Gabrilovich DI, Languino LR, Speicher DW, Shastrula PK, Storaci AM, Ferrero S, Gaudioso G, Caroli M, Tosi D, Giroda M, Vaira V, Rebecca VW, Herlyn M, Xiao M, Fingerman D, Martorella A, Skordalakes E, Altieri DC Abstract The regulators of mitochondrial cell death in cancer have remained elusive, hampering the development of new therapies. Here, we showed that protein isoforms of Mitochondrial Fission Factor (MFF1 and MFF2), a molecule that controls mitochondrial size and shape, i.e. mitochondrial dynamics, were overexpressed in patients with non-small cell lung cancer and formed homo- and heterodimeric complexes with the voltage-dependent anion channel-1 (VDAC1), a key regulator of mitochondrial outer membrane permeability. MFF inserted into the interior hole of the VDAC1 ring using Arg225, Arg236 and Gln241 as key contact sites. A cell-permeable MFF Ser223-Leu243 D-enantiomeric peptidomimetic disrupted the MFF-VDAC1 complex, acutely depolarized mitochondria and triggered cell death in heterogeneous tumor types, including drug-resistant melanoma, but had no effect on normal cells. In preclinical models, treatment with the MFF peptidomimetic was well-tolerated and demonstrated anticancer activity in patient-derived xenografts, primary breast and lung adenocarcinoma 3D organoids and glioblastoma neurospheres. These data identify the MFF-VDAC1 complex as a novel regulator of mitochondrial cell death and an actionable therapeutic target in cancer. PMID: 31582380 [PubMed - as supplied by publisher]

The Association between Alcohol Consumption and Serum Metabolites and the Modifying Effect of Smoking.

Sat, 05/10/2019 - 14:56
Related Articles The Association between Alcohol Consumption and Serum Metabolites and the Modifying Effect of Smoking. Nutrients. 2019 Oct 01;11(10): Authors: Langenau J, Boeing H, Bergmann MM, Nöthlings U, Oluwagbemigun K Abstract Alcohol consumption is an important lifestyle factor that is associated with several health conditions and a behavioral link with smoking is well established. Metabolic alterations after alcohol consumption have yet to be comprehensively investigated. We studied the association of alcohol consumption with metabolite patterns (MPs) among 2433 individuals from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study, and a potential modification by smoking. Alcohol consumption was self-reported through dietary questionnaires and serum metabolites were measured by a targeted approach. The metabolites were summarized as MPs using the treelet transform analysis (TT). We fitted linear models with alcohol consumption continuously and in five categories. We stratified the continuously modelled alcohol consumption by smoking status. All models were adjusted for potential confounders. Among men, alcohol consumption was positively associated with six MPs and negatively associated with one MP. In women, alcohol consumption was inversely associated with one MP. Heavy consumers differed from other consumers with respect to the "Long and short chain acylcarnitines" MP. Our findings suggest that long and short chain acylcarnitines might play an important role in the adverse effects of heavy alcohol consumption on chronic diseases. The relations seem to depend on gender and smoking status. PMID: 31581552 [PubMed - in process]

Bis-allylic Deuterated DHA Alleviates Oxidative Stress in Retinal Epithelial Cells.

Sat, 05/10/2019 - 14:56
Related Articles Bis-allylic Deuterated DHA Alleviates Oxidative Stress in Retinal Epithelial Cells. Antioxidants (Basel). 2019 Oct 01;8(10): Authors: Rosell M, Giera M, Brabet P, Shchepinov MS, Guichardant M, Durand T, Vercauteren J, Galano JM, Crauste C Abstract Oxidative stress plays a crucial role in developing and accelerating retinal diseases including age-related macular degeneration (AMD). Docosahexaenoic acid (DHA, C22:6, n-3), the main lipid constituent of retinal epithelial cell membranes, is highly prone to radical and enzymatic oxidation leading to deleterious or beneficial metabolites for retinal tissue. To inhibit radical oxidation while preserving enzymatic metabolism, deuterium was incorporated at specific positions of DHA, resulting in D2-DHA when incorporated at position 6 and D4-DHA when incorporated at the 6,9 bis-allylic positions. Both derivatives were able to decrease DHAs' toxicity and free radical processes involved in lipid peroxidation, in ARPE-19 cells (Adult Retinal Pigment Epithelial cell line), under pro-oxidant conditions. Our positive results encouraged us to prepare lipophenolic-deuterated-DHA conjugates as possible drug candidates for AMD treatment. These novel derivatives proved efficient in limiting lipid peroxidation in ARPE-19 cells. Finally, we evaluated the underlying mechanisms and the enzymatic conversion of both deuterated DHA. While radical abstraction was affected at the deuterium incorporation sites, enzymatic conversion by the lipoxygenase 15s-LOX was not impacted. Our results suggest that site-specifically deuterated DHA could be used in the development of DHA conjugates for treatment of oxidative stress driven diseases, or as biological tools to study the roles, activities and mechanisms of DHA metabolites. PMID: 31581525 [PubMed]

Development of an SNP-based parentage verification panel for lovebirds.

Fri, 04/10/2019 - 14:52
Related Articles Development of an SNP-based parentage verification panel for lovebirds. Anim Genet. 2019 Oct 03;: Authors: van der Zwan H, Visser C, Schoonen M, van der Sluis R Abstract The genus Agapornis, or lovebirds, are popular pet parrots worldwide. Currently, breeders are dependent on pedigree records as a selection tool as no molecular parentage verification test is available for any of the nine species. The A. roseicollis reference genome was recently assembled. This was followed by the sequencing of the whole genomes of the parents of the reference genome individual at 30× coverage. The parents' reads were mapped against the reference genome to identify SNPs. Over 1.6 million SNPs, shared between the parents, were discovered using the Genome Analysis Toolkit pipeline. SNPs were filtered to a panel of 480 SNPs based on Genome Analysis Toolkit parameters. The panel of 480 SNPs was genotyped in a population of 960 lovebirds across seven species. A panel of 262 SNPs was compiled that included SNPs successfully amplified across all species. The 262-SNP panel was reduced based on the observed heterozygosity (HO ) and minor allele frequency (MAF) values per SNP to include the lowest number of SNPs with the highest exclusion power for parentage verification. Two smaller panels consisting of 195 SNPs with MAF and HO values >0.1 and 40 SNPs with MAF and HO values >0.3, were constructed. The panels were verified using 43 families from different species with known relationships to evaluate the exclusion power of each panel. The 195 SNP panel with an average exclusion probability of 99.9% and MAF and HO values >0.1 was proposed as the routine Agapornis parentage verification panel. PMID: 31579954 [PubMed - as supplied by publisher]

A comparison of inducible, ontogenetic, and interspecific sources of variation in the foliar metabolome in tropical trees.

Fri, 04/10/2019 - 14:52
Related Articles A comparison of inducible, ontogenetic, and interspecific sources of variation in the foliar metabolome in tropical trees. PeerJ. 2019;7:e7536 Authors: Sedio BE, Durant Archibold A, Rojas Echeverri JC, Debyser C, Boya P CA, Wright SJ Abstract Plant interactions with other organisms are mediated by chemistry, yet chemistry varies among conspecific and within individual plants. The foliar metabolome-the suite of small-molecule metabolites found in the leaf-changes during leaf ontogeny and is influenced by the signaling molecule jasmonic acid. Species differences in secondary metabolites are thought to play an important ecological role by limiting the host ranges of herbivores and pathogens, and hence facilitating competitive coexistence among plant species in species-rich plant communities such as tropical forests. Yet it remains unclear how inducible and ontogenetic variation compare with interspecific variation, particularly in tropical trees. Here, we take advantage of novel methods to assemble mass spectra of all compounds in leaf extracts into molecular networks that quantify their chemical structural similarity in order to compare inducible and ontogenetic chemical variation to among-species variation in species-rich tropical tree genera. We ask (i) whether young and mature leaves differ chemically, (ii) whether jasmonic acid-inducible chemical variation differs between young and mature leaves, and (iii) whether interspecific exceeds intraspecific chemical variation for four species from four hyperdiverse tropical tree genera. We observed significant effects of the jasmonic acid treatment for three of eight combinations of species and ontogenetic stage evaluated. Three of the four species also exhibited large metabolomic differences with leaf ontogenetic stage. The profound effect of leaf ontogenetic stage on the foliar metabolome suggests a qualitative turnover in secondary chemistry with leaf ontogeny. We also quantified foliar metabolomes for 45 congeners of the four focal species. Chemical similarity was much greater within than between species for all four genera, even when within-species comparisons included leaves that differed in age and jasmonic acid treatment. Despite ontogenetic and inducible variation within species, chemical differences among congeneric species may be sufficient to partition niche space with respect to chemical defense. PMID: 31579568 [PubMed]

Systematic identification of metabolites controlling gene expression in E. coli.

Fri, 04/10/2019 - 14:52
Related Articles Systematic identification of metabolites controlling gene expression in E. coli. Nat Commun. 2019 Oct 02;10(1):4463 Authors: Lempp M, Farke N, Kuntz M, Freibert SA, Lill R, Link H Abstract Metabolism controls gene expression through allosteric interactions between metabolites and transcription factors. These interactions are usually measured with in vitro assays, but there are no methods to identify them at a genome-scale in vivo. Here we show that dynamic transcriptome and metabolome data identify metabolites that control transcription factors in E. coli. By switching an E. coli culture between starvation and growth, we induce strong metabolite concentration changes and gene expression changes. Using Network Component Analysis we calculate the activities of 209 transcriptional regulators and correlate them with metabolites. This approach captures, for instance, the in vivo kinetics of CRP regulation by cyclic-AMP. By testing correlations between all pairs of transcription factors and metabolites, we predict putative effectors of 71 transcription factors, and validate five interactions in vitro. These results show that combining transcriptomics and metabolomics generates hypotheses about metabolism-transcription interactions that drive transitions between physiological states. PMID: 31578326 [PubMed - in process]

Metabolic profiling of adolescent non-alcoholic fatty liver disease.

Fri, 04/10/2019 - 14:52
Related Articles Metabolic profiling of adolescent non-alcoholic fatty liver disease. Wellcome Open Res. 2018;3:166 Authors: Hartley A, Santos Ferreira DL, Anderson EL, Lawlor DA Abstract Background: Adolescent non-alcoholic fatty liver disease (NAFLD) is associated with cardiometabolic risk factors. The association between adolescent NAFLD and a wide range of metabolic biomarkers is unclear. We have attempted to determine the differences in metabolic profile of adolescents with and without markers of NAFLD. Methods: We performed cross-sectional analyses in a sample of 3,048 participants from the Avon Longitudinal Study of Parents and Children at age 17. We used three indicators of NAFLD: ALT >40 U/l; AST >40 U/l and ultrasound scan-assessed steatosis. Associations between each measure of NAFLD and 154 metabolic traits, assessed by Nuclear Magnetic Resonance, were analyzed by multivariable linear regression, adjusting for age, sex and BMI. Results: All three indicators of NAFLD were associated with ~0.5 standard deviation (SD) greater concentrations of all extremely large to small very low-density lipoproteins (VLDL) measures. ALT >40U/l was associated with ~0.5SD greater concentrations of very small VLDLs, intermediate-density lipoproteins and low-density lipoproteins. Concentrations of most cholesterols, including remnant cholesterol, all triglycerides and monounsaturated fatty acids, in addition to glycoprotein acetyls (inflammatory marker), were also higher in participants with NAFLD. Conclusions: We have identified differing metabolic profiles between adolescents with and without indicators of NAFLD. These results provide the foundations for future research to determine whether these differences persist and result in adverse future cardiometabolic health. PMID: 30687796 [PubMed]

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