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

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PubMed
NCBI: db=pubmed; Term=metabolomics
Updated: 12 min 31 sec ago

Sebaceous gland abnormalities in fatty acyl CoA reductase 2 (Far2) null mice result in primary cicatricial alopecia.

Tue, 30/10/2018 - 11:20
Sebaceous gland abnormalities in fatty acyl CoA reductase 2 (Far2) null mice result in primary cicatricial alopecia. PLoS One. 2018;13(10):e0205775 Authors: Sundberg JP, Shen T, Fiehn O, Rice RH, Silva KA, Kennedy VE, Gott NE, Dionne LA, Bechtold LS, Murray SA, Kuiper R, Pratt CH Abstract In a large scale screen for skin, hair, and nail abnormalities in null mice generated by The Jackson Laboratory's KOMP center, homozygous mutant Far2tm2b(KOMP)Wtsi/2J (hereafter referrred to as Far2-/-) mice were found to develop focal areas of alopecia as they aged. As sebocytes matured in wildtype C57BL/NJ mice they became pale with fine, uniformly sized clear lipid containing vacuoles that were released when sebocytes disintegrated in the duct. By contrast, the Far2-/- null mice had sebocytes that were similar within the gland but become brightly eosinophilic when the cells entered the sebaceous gland duct. As sebocytes disintegrated, their contents did not readily dissipate. Scattered throughout the dermis, and often at the dermal hypodermal fat junction, were dystrophic hair follicles or ruptured follicles with a foreign body granulomatous reaction surrounding free hair shafts (trichogranuloma). The Meibomian and clitoral glands (modified sebaceous glands) of Far2-/- mice showed ducts dilated to various degrees that were associated with mild changes in the sebocytes as seen in the truncal skin. Skin surface lipidomic analysis revealed a lower level of wax esters, cholesterol esters, ceramides, and diacylglycerols compared to wildtype control mice. Similar changes were described in a number of other mouse mutations that affected the sebaceous glands resulting in primary cicatricial alopecia. PMID: 30372477 [PubMed - in process]

Chromosome 3p Loss-Orchestrated VHL, HIF, and Epigenetic Deregulation in Clear Cell Renal Cell Carcinoma.

Tue, 30/10/2018 - 11:20
Chromosome 3p Loss-Orchestrated VHL, HIF, and Epigenetic Deregulation in Clear Cell Renal Cell Carcinoma. J Clin Oncol. 2018 Oct 29;:JCO2018792549 Authors: Hsieh JJ, Le VH, Oyama T, Ricketts CJ, Ho TH, Cheng EH Abstract Clear cell renal cell carcinoma (ccRCC) is the most common renal cell carcinoma subtype, and metastatic ccRCC is associated with 5-year survival rates of 10% to 20%. Genetically, ccRCC originates from sequential losses of multiple tumor suppressor genes. Remarkably, chromosome 3p loss occurs in more than 90% of sporadic ccRCCs. This results in concurrent one-copy loss of four tumor suppressor genes that are also mutated individually at high frequency in ccRCC (ie, VHL, 80%; PBRM1, 29% to 46%; BAP1, 6% to 19%; and SETD2, 8% to 30%). Pathogenically, 3p loss probably represents the first genetic event that occurs in sporadic ccRCC and the second genetic event in VHL-mutated hereditary ccRCC. VHL constitutes the substrate recognition module of the VCB-Cul2 E3 ligase that degrades HIF1/2α, whereas PBRM1, BAP1, and SETD2 are epigenetic modulators that regulate gene transcription. Because 3p loss and VHL inactivation are nearly universal truncal events in ccRCC, the resulting HIF1/2 signaling overdrive and accompanied tumor hypervascularization probably underlie the therapeutic benefits observed with vascular endothelial growth factor receptor inhibitors, including sorafenib, sunitinib, pazopanib, axitinib, bevacizumab, cabozantinib, and lenvatinib. Furthermore, recent marked advances in ccRCC genomics, transcriptomics, proteomics, metabolomics, molecular mechanisms, mouse models, prognostic and predictive biomarkers, and clinical trials have rendered invaluable translational insights concerning precision kidney cancer therapeutics. With an armamentarium encompassing 13 drugs that exploit seven unique therapeutic mechanisms (ie, cytokines, vascular endothelial growth factor receptor, mTORC1, cMET/AXL, fibroblast growth factor receptor, programmed cell death-1 and programmed death-ligand 1, and cytotoxic T-cell lymphocyte associated-4) to treat metastatic renal cell carcinoma, one of the imminent clinical questions concerning care of patients with metastatic ccRCC is how a personalized treatment strategy, through rationally combining and sequencing different therapeutic modalities, can be formulated to offer the best clinical outcome for individual patients. Here, we attempt to integrate recent discoveries of immediate translational impacts and discuss future translational challenges and opportunities. PMID: 30372397 [PubMed - as supplied by publisher]

Epidemiology and Risk Factors for Kidney Cancer.

Tue, 30/10/2018 - 11:20
Epidemiology and Risk Factors for Kidney Cancer. J Clin Oncol. 2018 Oct 29;:JCO2018791905 Authors: Scelo G, Larose TL Abstract The purpose of this narrative review is to summarize evidence of the epidemiology of and risk factors for kidney cancer with a focus on renal cell carcinoma in adults. The etiology of kidney cancer is largely unknown and the main epidemiologic determinants are large geographic and temporal variations in incidence rates. Established risk factors include tobacco smoking, body size, and history of hypertension and chronic kidney disease. Other suspected risk factors require additional investigation, as do the underlying biologic mechanisms that are responsible for disease occurrence. Opportunities to prevent kidney cancer include targeting modifiable risk factors-for example, smoking abstinence/cessation and body weight control-as well as interventions along the diagnostic pathway to improve early diagnosis. Molecular epidemiology, including, but not limited to, metabolomics and tumor genomics, are new areas of research that promise to play important roles in identifying some of the underlying causes of kidney cancer. PMID: 30372394 [PubMed - as supplied by publisher]

Lethal toxicity and sub-lethal metabolic interference effects of sulfoxaflor on the earthworm ( Eisenia fetida).

Tue, 30/10/2018 - 11:20
Lethal toxicity and sub-lethal metabolic interference effects of sulfoxaflor on the earthworm ( Eisenia fetida). J Agric Food Chem. 2018 Oct 29;: Authors: Fang S, Zhang Y, You X, Sun P, Qiu J, Kong F Abstract Testing for effects of pesticides on non-target organisms is an integral part of ecological risk assessment. In the present study, the acute toxicity of sulfoxaflor to earthworms was evaluated using an artificial soil toxicity test, and sub-lethal effects were assessed through oxidative stress and metabolomics. Sulfoxaflor is a super toxic pollutant to earthworms that easily bioaccumulates in earthworms, and contains LC2, LC10, and LC50 value of 0.08 (0.04 - 0.13), 0.19 (0.11 - 0.25) and 0.54 (0.45 - 0.65) mg/kg respectively. Sub-lethal doses of sulfoxaflor resulted in oxidative damage to earthworms in which antioxidant enzymatic activities including SOD, CAT, GST were significantly inhibited, and MDA content accumulated. Metabolomics analysis suggested the energy metabolism and the urea cycle in earthworms were significantly activated, while nucleotide metabolism was depressed which could cause DNA damage. Results suggest earthworms have the potential to be a new entry point for sulfoxaflor into the wildlife food chain. Since earthworms significantly contribute to soil function and ecosystems, the high safety risks of sulfoxaflor to the earthworm could extend to the environment. In view of these findings, more attention should be given to the risks sulfoxaflor poses on the environment through its effects on earthworms. PMID: 30372061 [PubMed - as supplied by publisher]

Habitual sleep quality, plasma metabolites and risk of coronary heart disease in post-menopausal women.

Tue, 30/10/2018 - 11:20
Habitual sleep quality, plasma metabolites and risk of coronary heart disease in post-menopausal women. Int J Epidemiol. 2018 Oct 26;: Authors: Huang T, Zeleznik OA, Poole EM, Clish CB, Deik AA, Scott JM, Vetter C, Schernhammer ES, Brunner R, Hale L, Manson JE, Hu FB, Redline S, Tworoger SS, Rexrode KM Abstract Background: Epidemiologic studies suggest a strong link between poor habitual sleep quality and increased cardiovascular disease risk. However, the underlying mechanisms are not entirely clear. Metabolomic profiling may elucidate systemic differences associated with sleep quality that influence cardiometabolic health. Methods: We explored cross-sectional associations between sleep quality and plasma metabolites in a nested case-control study of coronary heart disease (CHD) in the Women's Health Initiative (WHI; n = 1956) and attempted to replicate the results in an independent sample from the Nurses' Health Study II (NHSII; n = 209). A sleep-quality score (SQS) was derived from self-reported sleep problems asked in both populations. Plasma metabolomics were assayed using LC-MS with 347 known metabolites. General linear regression was used to identify individual metabolites associated with continuous SQS (false-discovery rate <0.05). Using least absolute shrinkage and selection operator (LASSO) algorithms, a metabolite score was created from replicated metabolites and evaluated with CHD risk in the WHI. Results: After adjusting for age, race/ethnicity, body mass index (BMI) and smoking, we identified 69 metabolites associated with SQS in the WHI (59 were lipids). Of these, 16 were replicated in NHSII (15 were lipids), including 6 triglycerides (TAGs), 4 phosphatidylethanolamines (PEs), 3 phosphatidylcholines (PCs), 1 diglyceride (DAG), 1 lysophosphatidylcholine and N6-acetyl-L-lysine (a product of histone acetylation). These metabolites were consistently higher among women with poorer sleep quality. The LASSO selection resulted in a nine-metabolite score (TAGs 45: 1, 48: 1, 50: 4; DAG 32: 1; PEs 36: 4, 38: 5; PCs 30: 1, 40: 6; N6-acetyl-L-lysine), which was positively associated with CHD risk (odds ratio per SD increase in the score: 1.16; 95% confidence interval: 1.05, 1.28; p = 0.0003) in the WHI after adjustment for matching factors and conventional CHD risk factors. Conclusions: Differences in lipid metabolites may be an important pathogenic pathway linking poor habitual sleep quality and CHD risk. PMID: 30371783 [PubMed - as supplied by publisher]

Molecular Atlas of Postnatal Mouse Heart Development.

Tue, 30/10/2018 - 11:20
Molecular Atlas of Postnatal Mouse Heart Development. J Am Heart Assoc. 2018 Oct 16;7(20):e010378 Authors: Talman V, Teppo J, Pöhö P, Movahedi P, Vaikkinen A, Karhu ST, Trošt K, Suvitaival T, Heikkonen J, Pahikkala T, Kotiaho T, Kostiainen R, Varjosalo M, Ruskoaho H Abstract Background The molecular mechanisms mediating postnatal loss of cardiac regeneration in mammals are not fully understood. We aimed to provide an integrated resource of mRNA , protein, and metabolite changes in the neonatal heart for identification of metabolism-related mechanisms associated with cardiac regeneration. Methods and Results Mouse ventricular tissue samples taken on postnatal day 1 (P01), P04, P09, and P23 were analyzed with RNA sequencing and global proteomics and metabolomics. Gene ontology analysis, KEGG pathway analysis, and fuzzy c-means clustering were used to identify up- or downregulated biological processes and metabolic pathways on all 3 levels, and Ingenuity pathway analysis (Qiagen) was used to identify upstream regulators. Differential expression was observed for 8547 mRNA s and for 1199 of 2285 quantified proteins. Furthermore, 151 metabolites with significant changes were identified. Differentially regulated metabolic pathways include branched chain amino acid degradation (upregulated at P23), fatty acid metabolism (upregulated at P04 and P09; downregulated at P23) as well as the HMGCS ( HMG -CoA [hydroxymethylglutaryl-coenzyme A] synthase)-mediated mevalonate pathway and ketogenesis (transiently activated). Pharmacological inhibition of HMGCS in primary neonatal cardiomyocytes reduced the percentage of BrdU-positive cardiomyocytes, providing evidence that the mevalonate and ketogenesis routes may participate in regulating the cardiomyocyte cell cycle. Conclusions This study is the first systems-level resource combining data from genomewide transcriptomics with global quantitative proteomics and untargeted metabolomics analyses in the mouse heart throughout the early postnatal period. These integrated data of molecular changes associated with the loss of cardiac regeneration may open up new possibilities for the development of regenerative therapies. PMID: 30371266 [PubMed - in process]

Mass spectrometry dataset for LC-MS metabolomics analysis of Garcinia mangostana L. seed development.

Tue, 30/10/2018 - 11:20
Related Articles Mass spectrometry dataset for LC-MS metabolomics analysis of Garcinia mangostana L. seed development. Data Brief. 2018 Dec;21:548-551 Authors: Mazlan O, Aizat WM, Baharum SN, Azizan KA, Noor NM Abstract Garcinia mangostana L. (mangosteen) seed is recalcitrant, prone to low temperature and drying which limit its long-term storage. Therefore, it is imperative to understand the metabolic changes throughout its development, to shed some light into the recalcitrant nature of this seed. We performed metabolomics analysis on mangosteen seed at different stages of development; six, eight, ten, twelve and fourteen weeks after anthesis. Seed samples were subjected to methanol extraction prior analysis using liquid chromatography - mass spectrometry (LC-MS). The MS data acquired were analyzed using ProfileAnalysis (version 2.1). This data article refers to the article entitled "Metabolomics analysis of developing Garcinia mangostana seed reveals modulated levels of sugars, organic acids and phenylpropanoid compounds" (Mazlan et al., 2018) [1]. PMID: 30370325 [PubMed]

Metabolic Characterization of Antifolate Responsiveness and Non-responsiveness in Malignant Pleural Mesothelioma Cells.

Tue, 30/10/2018 - 11:20
Related Articles Metabolic Characterization of Antifolate Responsiveness and Non-responsiveness in Malignant Pleural Mesothelioma Cells. Front Pharmacol. 2018;9:1129 Authors: Sato Y, Matsuda S, Maruyama A, Nakayama J, Miyashita T, Udagawa H, Umemura S, Yanagihara K, Ochiai A, Tomita M, Soga T, Tsuchihara K, Makinoshima H Abstract Antifolates are a class of drugs effective for treating malignant pleural mesothelioma (MPM). The majority of antifolates inhibit enzymes involved in purine and pyrimidine synthesis such as dihydrofolate reductase (DHFR), thymidylate synthase (TYMS), and glycinamide ribonucleotide formyltransferase (GART). In order to select the most suitable patients for effective therapy with drugs targeting specific metabolic pathways, there is a need for better predictive metabolic biomarkers. Antifolates can alter global metabolic pathways in MPM cells, yet the metabolic profile of treated cells has not yet been clearly elucidated. Here we found that MPM cell lines could be categorized into two groups according to their sensitivity or resistance to pemetrexed treatment. We show that pemetrexed susceptibility could be reversed and DNA synthesis rescued in drug-treated cells by the exogenous addition of the nucleotide precursors hypoxanthine and thymidine (HT). We observed that the expression of pemetrexed-targeted enzymes in resistant MPM cells was quantitatively lower than that seen in pemetrexed-sensitive cells. Metabolomic analysis revealed that glycine and choline, which are involved in one-carbon metabolism, were altered after drug treatment in pemetrexed-sensitive but not resistant MPM cells. The addition of HT upregulated the concentration of inosine monophosphate (IMP) in pemetrexed-sensitive MPM cells, indicating that the nucleic acid biosynthesis pathway is important for predicting the efficacy of pemetrexed in MPM cells. Our data provide evidence that may link therapeutic response to the regulation of metabolism, and points to potential biomarkers for informing clinical decisions regarding the most effective therapies for patients with MPM. PMID: 30369878 [PubMed]

Infliximab ameliorates tumor necrosis factor-alpha-induced insulin resistance by attenuating PTP1B activation in 3T3L1 adipocytes in vitro.

Tue, 30/10/2018 - 11:20
Related Articles Infliximab ameliorates tumor necrosis factor-alpha-induced insulin resistance by attenuating PTP1B activation in 3T3L1 adipocytes in vitro. Scand J Immunol. 2018 Nov;88(5):e12716 Authors: Méndez-García LA, Trejo-Millán F, Martínez-Reyes CP, Manjarrez-Reyna AN, Esquivel-Velázquez M, Melendez-Mier G, Islas-Andrade S, Rojas-Bernabé A, Kzhyshkowska J, Escobedo G Abstract Insulin resistance is the inability to respond to insulin and is considered a key pathophysiological factor in the development of type 2 diabetes. Tumor necrosis factor-alpha (TNF-alpha) can directly contribute to insulin resistance by disrupting the insulin signalling pathway via protein-tyrosine phosphatase 1B (PTP1B) activation, especially in adipocytes. Infliximab (Remicade® ) is a TNF-alpha-neutralizing antibody that has not been fully studied in insulin resistance. We investigated the effect of infliximab on TNF-alpha-induced insulin resistance in 3T3L1 adipocytes in vitro, and examined the possible molecular mechanisms involved. Once differentiated, adipocytes were cultured with 5 mmol L-1 2-deoxy-D-glucose-3 H and stimulated twice with 2 μmol L-1 insulin, in the presence or absence of 5 ng/mL TNF-alpha and/or 10 ng/mL infliximab. Glucose uptake was measured every 20 minutes for 2 hour, and phosphorylated forms of insulin receptor (IR), insulin receptor substrate-2 (IRS-2), protein kinase B (AKT) and PTP1B were determined by Western blotting. TNF-alpha-treated adipocytes showed a significant 64% decrease in insulin-stimulated glucose uptake as compared with control cells, whereas infliximab reversed TNF-alpha actions by significantly improving glucose incorporation. Although IR phosphorylation remained unaltered, TNF-alpha was able to increase PTP1B activation and decrease phosphorylation of IRS-2 and AKT. Notably, infliximab restored phosphorylation of IRS-2 and AKT by attenuating PTP1B activation. This work demonstrates for the first time that infliximab ameliorates TNF-alpha-induced insulin resistance in 3T3L1 adipocytes in vitro by restoring the insulin signalling pathway via PTP1B inhibition. Further clinical research is needed to determine the potential benefit of using infliximab for treating insulin resistance in patients. PMID: 30260514 [PubMed - indexed for MEDLINE]

Pentose sugars inhibit metabolism and increase expression of an AgrD-type cyclic pentapeptide in Clostridium thermocellum.

Tue, 30/10/2018 - 11:20
Related Articles Pentose sugars inhibit metabolism and increase expression of an AgrD-type cyclic pentapeptide in Clostridium thermocellum. Sci Rep. 2017 02 23;7:43355 Authors: Verbeke TJ, Giannone RJ, Klingeman DM, Engle NL, Rydzak T, Guss AM, Tschaplinski TJ, Brown SD, Hettich RL, Elkins JG Abstract Clostridium thermocellum could potentially be used as a microbial biocatalyst to produce renewable fuels directly from lignocellulosic biomass due to its ability to rapidly solubilize plant cell walls. While the organism readily ferments sugars derived from cellulose, pentose sugars from xylan are not metabolized. Here, we show that non-fermentable pentoses inhibit growth and end-product formation during fermentation of cellulose-derived sugars. Metabolomic experiments confirmed that xylose is transported intracellularly and reduced to the dead-end metabolite xylitol. Comparative RNA-seq analysis of xylose-inhibited cultures revealed several up-regulated genes potentially involved in pentose transport and metabolism, which were targeted for disruption. Deletion of the ATP-dependent transporter, CbpD partially alleviated xylose inhibition. A putative xylitol dehydrogenase, encoded by Clo1313_0076, was also deleted resulting in decreased total xylitol production and yield by 41% and 46%, respectively. Finally, xylose-induced inhibition corresponds with the up-regulation and biogenesis of a cyclical AgrD-type, pentapeptide. Medium supplementation with the mature cyclical pentapeptide also inhibits bacterial growth. Together, these findings provide new foundational insights needed for engineering improved pentose utilizing strains of C. thermocellum and reveal the first functional Agr-type cyclic peptide to be produced by a thermophilic member of the Firmicutes. PMID: 28230109 [PubMed - indexed for MEDLINE]

Alterations in the carnitine cycle in a mouse model of Rett syndrome.

Tue, 30/10/2018 - 11:20
Related Articles Alterations in the carnitine cycle in a mouse model of Rett syndrome. Sci Rep. 2017 02 02;7:41824 Authors: Mucerino S, Di Salle A, Alessio N, Margarucci S, Nicolai R, Melone MA, Galderisi U, Peluso G Abstract Rett syndrome (RTT) is a neurodevelopmental disease that leads to intellectual deficit, motor disability, epilepsy and increased risk of sudden death. Although in up to 95% of cases this disease is caused by de novo loss-of-function mutations in the X-linked methyl-CpG binding protein 2 gene, it is a multisystem disease associated also with mitochondrial metabolic imbalance. In addition, the presence of long QT intervals (LQT) on the patients' electrocardiograms has been associated with the development of ventricular tachyarrhythmias and sudden death. In the attempt to shed light on the mechanism underlying heart failure in RTT, we investigated the contribution of the carnitine cycle to the onset of mitochondrial dysfunction in the cardiac tissues of two subgroups of RTT mice, namely Mecp2+/- NQTc and Mecp2+/- LQTc mice, that have a normal and an LQT interval, respectively. We found that carnitine palmitoyltransferase 1 A/B and carnitine acylcarnitine translocase were significantly upregulated at mRNA and protein level in the heart of Mecp2+/- mice. Moreover, the carnitine system was imbalanced in Mecp2+/- LQTc mice due to decreased carnitine acylcarnitine transferase expression. By causing accumulation of intramitochondrial acylcarnitines, this imbalance exacerbated incomplete fatty acid oxidation, which, in turn, could contribute to mitochondrial overload and sudden death. PMID: 28150739 [PubMed - indexed for MEDLINE]

MPLEx: a method for simultaneous pathogen inactivation and extraction of samples for multi-omics profiling.

Tue, 30/10/2018 - 11:20
Related Articles MPLEx: a method for simultaneous pathogen inactivation and extraction of samples for multi-omics profiling. Analyst. 2017 Jan 26;142(3):442-448 Authors: Burnum-Johnson KE, Kyle JE, Eisfeld AJ, Casey CP, Stratton KG, Gonzalez JF, Habyarimana F, Negretti NM, Sims AC, Chauhan S, Thackray LB, Halfmann PJ, Walters KB, Kim YM, Zink EM, Nicora CD, Weitz KK, Webb-Robertson BM, Nakayasu ES, Ahmer B, Konkel ME, Motin V, Baric RS, Diamond MS, Kawaoka Y, Waters KM, Smith RD, Metz TO Abstract The continued emergence and spread of infectious agents is of great concern, and systems biology approaches to infectious disease research can advance our understanding of host-pathogen relationships and facilitate the development of new therapies and vaccines. Molecular characterization of infectious samples outside of appropriate biosafety containment can take place only subsequent to pathogen inactivation. Herein, we describe a modified Folch extraction using chloroform/methanol that facilitates the molecular characterization of infectious samples by enabling simultaneous pathogen inactivation and extraction of proteins, metabolites, and lipids for subsequent mass spectrometry-based multi-omics measurements. This single-sample metabolite, protein and lipid extraction (MPLEx) method resulted in complete inactivation of clinically important bacterial and viral pathogens with exposed lipid membranes, including Yersinia pestis, Salmonella Typhimurium, and Campylobacter jejuni in pure culture, and Yersinia pestis, Campylobacter jejuni, and West Nile, MERS-CoV, Ebola, and influenza H7N9 viruses in infection studies. In addition, >99% inactivation, which increased with solvent exposure time, was also observed for pathogens without exposed lipid membranes including community-associated methicillin-resistant Staphylococcus aureus, Clostridium difficile spores and vegetative cells, and adenovirus type 5. The overall pipeline of inactivation and subsequent proteomic, metabolomic, and lipidomic analyses was evaluated using a human epithelial lung cell line infected with wild-type and mutant influenza H7N9 viruses, thereby demonstrating that MPLEx yields biomaterial of sufficient quality for subsequent multi-omics analyses. Based on these experimental results, we believe that MPLEx will facilitate systems biology studies of infectious samples by enabling simultaneous pathogen inactivation and multi-omics measurements from a single specimen with high success for pathogens with exposed lipid membranes. PMID: 28091625 [PubMed - indexed for MEDLINE]

Human White Adipose Tissue Metabolome: Current Perspective.

Mon, 29/10/2018 - 13:55
Related Articles Human White Adipose Tissue Metabolome: Current Perspective. Obesity (Silver Spring). 2018 Oct 28;: Authors: Kučera J, Spáčil Z, Friedecký D, Novák J, Pekař M, Bienertová-Vašků J Abstract OBJECTIVE: Interest in metabolites produced by adipose tissue has increased substantially in the past several decades. Previously regarded as an inert energy storage depot, adipose tissue is now viewed as a complex metabolically active organ with considerable impact on human health. The emerging field of mass spectrometry-based metabolomics presents a powerful tool for the study of processes in complex biological matrices including adipose tissue. RESULTS: A large number of structurally distinct metabolites can be analyzed to facilitate the investigation of differences between physiological and pathophysiological metabolic profiles associated with adipose tissue. Understanding the molecular basis of adipose tissue regulation can thereby provide insight into the monitoring of obesity-related metabolic disorders and lead to the development of novel diagnostic and prognostic biomarkers. CONCLUSIONS: This review provides the current state of knowledge, recent progress, and critical evaluation of metabolomics approaches in the context of white adipose tissue and obesity. An overview of basic principles and resources describing individual groups of metabolites analyzed in white adipose tissue and biological fluids is given. The focus is on metabolites that can serve as reliable biomarkers indicative of metabolic alterations associated with obesity. PMID: 30369078 [PubMed - as supplied by publisher]

Extensive exploration of a novel rat model of Parkinson's disease using partial 6-hydroxydopamine lesion of dopaminergic neurons suggests new therapeutic approaches.

Mon, 29/10/2018 - 13:55
Related Articles Extensive exploration of a novel rat model of Parkinson's disease using partial 6-hydroxydopamine lesion of dopaminergic neurons suggests new therapeutic approaches. Synapse. 2018 Oct 28;: Authors: Vetel S, Sérrière S, Vercouillie J, Vergote J, Chicheri G, Deloye JB, Dollé F, Bodard S, Tronel C, Nadal-Desbarats L, Lefèvre A, Emond P, Chalon S Abstract Parkinson's disease (PD) is characterized by the degeneration of dopaminergic (DA) neurons constituting the nigrostriatal pathway. Neuroinflammation, related to microglial activation, plays an important role in this process. Exploration of animal models of PD using neuroimaging modalities allows to better understand the pathophysiology of the disease. Here, we fully explored a moderate lesion model in the rat in which 6-hydroxydopamine was unilaterally delivered in 3 sites along the striatum. The degenerative process was assessed through in vivo Positron Emission Tomography (PET) imaging and in vitro autoradiographic quantitation of the striatal dopamine transporter (DAT) and immunostaining of tyrosine hydroxylase (TH). The microglial activation was studied through in vitro autoradiographic quantitation of the 18 kDa translocator protein (TSPO) in the striatum and CD11b staining in the SN. In addition, a targeted metabolomics exploration was performed in both these structures using mass spectrometry coupled to HPLC. Our results showed a reproducible decrease in the striatal DAT density associated with a reduction in the number of TH-positive cells in the SN and striatum, reflecting a robust moderate degeneration of nigrostriatal DA neurons. In addition, we observed strong microglia activation in both the striatum and SN ipsilateral to the lesion, highlighting that this moderate degeneration of DA neurons was associated with a marked neuroinflammation. Our metabolomics studies revealed alterations of specific metabolites and metabolic pathways such as carnitine, arginine/proline and histidine metabolisms. These results bring new insights in the PD mechanism knowledge and new potential targets for future therapeutic strategies. This article is protected by copyright. All rights reserved. PMID: 30368914 [PubMed - as supplied by publisher]

Integrated proteomic and metabolomic analysis of a reconstructed three-species microbial consortium for one-step fermentation of 2-keto-L-gulonic acid, the precursor of vitamin C.

Mon, 29/10/2018 - 13:55
Related Articles Integrated proteomic and metabolomic analysis of a reconstructed three-species microbial consortium for one-step fermentation of 2-keto-L-gulonic acid, the precursor of vitamin C. J Ind Microbiol Biotechnol. 2018 Oct 27;: Authors: Ma Q, Bi YH, Wang EX, Zhai BB, Dong XT, Qiao B, Ding MZ, Yuan YJ Abstract Microbial consortia, with the merits of strong stability, robustness, and multi-function, played critical roles in human health, bioenergy, and food manufacture, etc. On the basis of 'build a consortium to understand it', a novel microbial consortium consisted of Gluconobacter oxydans, Ketogulonicigenium vulgare and Bacillus endophyticus was reconstructed to produce 2-keto-L-gulonic acid (2-KGA), the precursor of vitamin C. With this synthetic consortium, 73.7 g/L 2-KGA was obtained within 30 h, which is comparable to the conventional industrial method. A combined time-series proteomic and metabolomic analysis of the fermentation process was conducted to further investigate the cell-cell interaction. The results suggested that the existence of B. endophyticus and G. oxydans together promoted the growth of K. vulgare by supplying additional nutrients, and promoted the 2-KGA production by supplying more substrate. Meanwhile, the growth of B. endophyticus and G. oxydans was compromised from the competition of the nutrients by K. vulgare, enabling the efficient production of 2-KGA. This study provides valuable guidance for further study of synthetic microbial consortia. PMID: 30368638 [PubMed - as supplied by publisher]

Phenotyping analysis of the Japanese Kampo medicine maoto in healthy human subjects using wide-targeted plasma metabolomics.

Sun, 28/10/2018 - 13:19
Related Articles Phenotyping analysis of the Japanese Kampo medicine maoto in healthy human subjects using wide-targeted plasma metabolomics. J Pharm Biomed Anal. 2018 Oct 22;164:119-127 Authors: Kitagawa H, Ohbuchi K, Munekage M, Fujisawa K, Kawanishi Y, Namikawa T, Kushida H, Matsumoto T, Shimobori C, Nishi A, Sadakane C, Watanabe J, Yamamoto M, Hanazaki K Abstract Traditional herbal medicine (THM) consists of a vast number of compounds that exert pharmacological effects throughout the body. Comprehensive phenotyping analysis using omics is essential for understanding the nature of THM in detail. We previously reported that the Japanese Kampo medicine maoto ameliorated flu-like symptoms in a rat infection model and dynamically changed plasma metabolites as indicated by metabolome analysis. The aim of this study was to apply wide-targeted plasma metabolomics with quantitative analysis of maoto compounds in a human clinical trial to evaluate the effect of maoto on plasma metabolites. Four healthy human subjects were recruited. Plasma samples were collected before and 0.25, 0.5, 1, 2, 4 and 8 h after maoto treatment. Wide-targeted metabolomics and quantitative analysis of the main chemical constituents of maoto were then performed. Plasma metabolome analysis revealed that maoto administration decreased essential amino acids including branched-chain amino acids (BCAAs) and increased various kinds of ω-3 fatty acids including eicosapentaenoic acid and docosahexaenoic acid, consistent with previous studies in rats. Fifteen of the major compounds in maoto were identified in the systemic circulation. Finally, the correlation between endogenous metabolites and maoto compounds in plasma was analyzed and the results indicated that the decrease in plasma BCAAs might be caused by ephedrines present in maoto. The present study demonstrated that plasma metabolomic studies of endogenous and exogenous metabolites are useful for elucidating the mechanism of action of THM. PMID: 30368117 [PubMed - as supplied by publisher]

Hepatic metabolite profiling of polychlorinated biphenyl (PCB)-resistant and sensitive populations of Atlantic killifish (Fundulus heteroclitus).

Sun, 28/10/2018 - 13:19
Related Articles Hepatic metabolite profiling of polychlorinated biphenyl (PCB)-resistant and sensitive populations of Atlantic killifish (Fundulus heteroclitus). Aquat Toxicol. 2018 Oct 16;205:114-122 Authors: Glazer L, Kido Soule MC, Longnecker K, Kujawinski EB, Aluru N Abstract Atlantic killifish inhabiting polluted sites along the east coast of the U.S. have evolved resistance to toxic effects of contaminants. One such contaminated site is the Acushnet River estuary, near New Bedford Harbor (NBH), Massachusetts, which is characterized by very high PCB concentrations in the sediments and in the tissues of resident killifish. Though killifish at this site appear to be thriving, the metabolic costs of survival in a highly contaminated environment are not well understood. In this study we compared the hepatic metabolite profiles of resistant (NBH) and sensitive populations (Scorton Creek (SC), Sandwich, MA) using a targeted metabolomics approach in which polar metabolites were extracted from adult fish livers and quantified. Our results revealed differences in the levels of several metabolites between fish from the two sites. The majority of these metabolites are associated with one-carbon metabolism, an important pathway that supports multiple physiological processes including DNA and protein methylation, nucleic acid biosynthesis and amino acid metabolism. We measured the gene expression of DNA methylation (DNA methyltransferase 1, dnmt1) and demethylation genes (Ten-Eleven Translocation (TET) genes) in the two populations, and observed lower levels of dnmt1 and higher levels of TET gene expression in the NBH livers, suggesting possible differences in DNA methylation profiles. Consistent with this, the two populations differed significantly in the levels of 5-methylcytosine and 5-hydroxymethylcytosine nucleotides. Overall, our results suggest that the unique hepatic metabolite signatures observed in NBH and SC reflect the adaptive mechanisms for survival in their respective habitats. PMID: 30368057 [PubMed - as supplied by publisher]

Application of Proteomics Technologies in Oil Palm Research.

Sun, 28/10/2018 - 13:19
Related Articles Application of Proteomics Technologies in Oil Palm Research. Protein J. 2018 Oct 26;: Authors: Lau BYC, Othman A, Ramli US Abstract Proteomics technologies were first applied in the oil palm research back in 2008. Since proteins are the gene products that are directly correspond to phenotypic traits, proteomic tools hold a strong advantage above other molecular tools to comprehend the biological and molecular mechanisms in the oil palm system. These emerging technologies have been used as non-overlapping tools to link genome-wide transcriptomics and metabolomics-based studies to enhance the oil palm yield and quality through sustainable plant breeding. Many efforts have also been made using the proteomics technologies to address the oil palm's Ganoderma disease; the cause and management. At present, the high-throughput screening technologies are being applied to identify potential biomarkers involved in metabolism and cellular development through determination of protein expression changes that correlate with oil production and disease. This review highlights key elements in proteomics pipeline, challenges and some examples of their implementations in plant studies in the context of oil palm in particular. We foresee that the proteomics technologies will play more significant role to address diverse issues related to the oil palm in the effort to improve the oil crop. PMID: 30367348 [PubMed - as supplied by publisher]

An automated framework for NMR chemical shift calculations of small organic molecules.

Sun, 28/10/2018 - 13:19
Related Articles An automated framework for NMR chemical shift calculations of small organic molecules. J Cheminform. 2018 Oct 26;10(1):52 Authors: Yesiltepe Y, Nuñez JR, Colby SM, Thomas DG, Borkum MI, Reardon PN, Washton NM, Metz TO, Teeguarden JG, Govind N, Renslow RS Abstract When using nuclear magnetic resonance (NMR) to assist in chemical identification in complex samples, researchers commonly rely on databases for chemical shift spectra. However, authentic standards are typically depended upon to build libraries experimentally. Considering complex biological samples, such as blood and soil, the entirety of NMR spectra required for all possible compounds would be infeasible to ascertain due to limitations of available standards and experimental processing time. As an alternative, we introduce the in silico Chemical Library Engine (ISiCLE) NMR chemical shift module to accurately and automatically calculate NMR chemical shifts of small organic molecules through use of quantum chemical calculations. ISiCLE performs density functional theory (DFT)-based calculations for predicting chemical properties-specifically NMR chemical shifts in this manuscript-via the open source, high-performance computational chemistry software, NWChem. ISiCLE calculates the NMR chemical shifts of sets of molecules using any available combination of DFT method, solvent, and NMR-active nuclei, using both user-selected reference compounds and/or linear regression methods. Calculated NMR chemical shifts are provided to the user for each molecule, along with comparisons with respect to a number of metrics commonly used in the literature. Here, we demonstrate ISiCLE using a set of 312 molecules, ranging in size up to 90 carbon atoms. For each, calculation of NMR chemical shifts have been performed with 8 different levels of DFT theory, and with solvation effects using the implicit solvent Conductor-like Screening Model. The DFT method dependence of the calculated chemical shifts have been systematically investigated through benchmarking and subsequently compared to experimental data available in the literature. Furthermore, ISiCLE has been applied to a set of 80 methylcyclohexane conformers, combined via Boltzmann weighting and compared to experimental values. We demonstrate that our protocol shows promise in the automation of chemical shift calculations and, ultimately, the expansion of chemical shift libraries. PMID: 30367288 [PubMed]

Microbial structure and function in infant and juvenile rhesus macaques are primarily affected by age, not vaccination status.

Sun, 28/10/2018 - 13:19
Related Articles Microbial structure and function in infant and juvenile rhesus macaques are primarily affected by age, not vaccination status. Sci Rep. 2018 Oct 26;8(1):15867 Authors: Hasegawa Y, Curtis B, Yutuc V, Rulien M, Morrisroe K, Watkins K, Ferrier C, English C, Hewitson L, Slupsky CM Abstract Although thimerosal, an ethylmercury-based preservative, has been removed from most pediatric vaccines in the United States, some multidose vaccines, such as influenza vaccines, still contain thimerosal. Considering that a growing number of studies indicate involvement of the gut microbiome in infant immune development and vaccine responses, it is important to elucidate the impact of pediatric vaccines, including thimerosal-containing vaccines, on gut microbial structure and function. Here, a non-human primate model was utilized to assess how two vaccine schedules affect the gut microbiome in infants (5-9 days old) and juveniles (77-88 weeks old) through 16S ribosomal RNA sequencing and metabolomics analyses of the fecal samples. Two treatment groups (n = 12/group) followed either the vaccine schedule that was in place during the 1990s (intensive exposure to thimerosal) or an expanded schedule administered in 2008 (prenatal and postnatal exposure to thimerosal mainly via influenza vaccines), and were compared with a control group (n = 16) that received saline injections. The primary impact on gut microbial structure and function was age. Although a few statistically significant impacts of the two common pediatric vaccine schedules were observed when confounding factors were considered, the magnitude of the differences was small, and appeared to be positive with vaccination. PMID: 30367140 [PubMed - in process]

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