PubMed

Identification of novel metabolomic biomarkers in an experimental model of septic acute kidney injury. Am J Physiol Renal Physiol. 2018 Oct 31;: Authors: Izquierdo-Garcia JL, Nin N, Cardinal-Fernandez P, Rojas Y, de Paula M, Granados R, Martínez-Caro L, Ruiz-Cabello J, Lorente JÁ Abstract The aim of this study is the identification of metabolomic biomarkers of sepsis and sepsis-induced acute kidney injury (AKI) in an experimental model. Pigs were anesthetized and monitored to measure mean arterial pressure (MAP), systemic blood flow (QT), mean pulmonary arterial pressure (MPAP), renal artery blood flow (QRA), renal cortical blood flow (QRC), and urine output (UO). Sepsis was induced at t=0 min by the administration of live Escherichia coli (n=6) or saline (n=8). At t=300 min, animals were sacrificed. Renal tissue, urine and serum samples were analyzed by Nuclear Magnetic Resonance (NMR) spectroscopy. Principal component analyses were performed on the processed NMR spectra to highlight kidney injury biomarkers. Sepsis was associated with decreased QT and MAP, and decreased QRA, QRC and urine output. Creatinine serum concentration and neutrophil gelatinase-associated lipocalin serum and urine concentrations increased. NMR-based metabolomics analysis found metabolic differences between control and septic animals: (i) in kidney tissue, increased lactate and nicotinuric acid, and decreased valine, aspartate, glucose and threonine; (ii) in urine, increased isovaleroglycine, aminoadipic acid, N-acetylglutamine, N-acetylaspartate and ascorbic acid, and decreased myoinositol and phenylacetylglycine; (iii) in serum, increased lactate, alanine, pyruvate and glutamine, and decreased valine, glucose and betaine concentrations. The concentration of several metabolites altered in renal tissue and urine samples from septic animals showed a significant correlation with markers of AKI (i.e., creatinine and NGAL serum concentrations). NMR-based metabolomics is a potentially useful tool for biomarker identification of sepsis-induced AKI. PMID: 30379100 [PubMed - as supplied by publisher]

Flow Injection-Traveling Wave Ion Mobility-Mass Spectrometry for Rapid Prostate Cancer Metabolomics. Anal Chem. 2018 Oct 31;: Authors: Zang X, Monge ME, Gaul DA, Fernandez FM Abstract Flow injection-traveling wave ion mobility-mass spectrometry (FI-TWIM-MS) was applied to the non-targeted metabolic profiling of serum extracts from 61 prostate cancer (PCa) patients and 42 controls with an analysis speed of 6 minutes per sample, including a wash run. Comprehensive data mining of the mobility-mass domain was used to discriminate species with various charge states and filter matrix salt cluster ions. Specific criteria were developed to ensure correct grouping of adducts, in-source fragments, and impurities in the dataset. Endogenous metabolites were identified with high confidence using FI-TWIM-MS/MS and collision cross-section (CCS) matching with chemical standards or CCS databases. PCa patient samples were distinguished from control samples with good accuracies (88.3-89.3%), sensitivities (88.5-90.2%), and specificities (88.1%) using supervised multivariate classification methods. Although largely underutilized in metabolomics studies, FI-TWIM-MS proved advantageous in terms of analysis speed, separation of ions in complex mixtures, improved signal-to-noise ratio, and reduction of spectral congestion. Results from this study showcase the potential of FI-TWIM-MS as a high throughput metabolic profiling tool for large scale metabolomics studies. PMID: 30379062 [PubMed - as supplied by publisher]

The protective effects of Poria cocos-derived polysaccharide CMP33 against IBD in mice and its molecular mechanism. Food Funct. 2018 Oct 31;: Authors: Liu X, Yu X, Xu X, Zhang X, Zhang X Abstract In this study, the protective effects of a carboxymethyl polysaccharide CMP33 from Poria cocos against inflammatory bowel disease (IBD) were investigated using TNBS-induced colitis in mice. The results showed that CMP33 markedly ameliorated the severity of colitis, including a 2-fold decrease in the mortality rate, a 50% decrease in disease activity index, and a 36%-44% decrease in macro- or microscopic histopathological score, compared with TNBS administration. Moreover, CMP33 decreased the levels of pro-inflammatory cytokines and increased the levels of anti-inflammatory cytokines in the colon tissue and serum of colitic mice. Using iTRAQ-coupled- nano-HPLC-MS/MS-based proteomics, the protein profiles after TNBS, high- or low-dose CMP33 and salazosulfapyridine (SASP) treatments were compared and many differentially expressed proteins were identified. Among them, 7 proteins (Hmgcs2, Fabp2, Hp, B4galnt2, B3gnt6, Sap and Ca1) were proposed to be the common targeting protein group (TPG) of CMP33 and drug SASP. Particularly, some targeting proteins were CMP33-dose-specific: high-dose-specific TPG (Mtco3, Gal-6, Mptx, S100 g and Hpx) and low-dose-specific TPG (Zg16, Hexb, Insl5, Cept1, Hspb6 and Ifi27l2b), suggesting the complex acting mechanism of CMP33. GC-TOF-MS-based metabolomics revealed that oleic acid and dihydrotestosterone could be the common targets of CMP33 and SASP. By integrative analysis of proteomics and metabolomics, key protein-metabolite pathways (PMP) were identified, PMP for high-dose: 2-hydroxybutyric acid - (GPT, GGH) - glutathione - ALB - testosterone - TTR - dihydrotestosterone; PMP for low-dose: (PYY, FABP2, HMGCS2) - oleic acid - TTR - dihydrotestosterone. In total, these results demonstrated the protective effects of CMP33 against IBD in mice through the potential TPG and PMP. PMID: 30378628 [PubMed - as supplied by publisher]

Nanoparticle microarray for high-throughput microbiome metabolomics using matrix-assisted laser desorption ionization mass spectrometry. Anal Bioanal Chem. 2018 Oct 30;: Authors: Hansen RL, Dueñas ME, Looft T, Lee YJ Abstract A high-throughput matrix-assisted laser desorption/ionization mass spectrometry (MALDI)-MS-based metabolomics platform was developed using a pre-fabricated microarray of nanoparticles and organic matrices. Selected organic matrices, inorganic nanoparticle (NP) suspensions, and sputter coated metal NPs, as well as various additives, were tested for metabolomics analysis of the turkey gut microbiome. Four NPs and one organic matrix were selected as the optimal matrix set: α-cyano-4-hydroycinnamic acid, Fe3O4 and Au NPs in positive ion mode with 10 mM sodium acetate, and Cu and Ag NPs in negative ion mode with no additive. Using this set of five matrices, over two thousand unique metabolite features were reproducibly detected across intestinal samples from turkeys fed a diet amended with therapeutic or sub-therapeutic antibiotics (200 g/ton or 50 g/ton bacitracin methylene disalicylate (BMD), respectively), or non-amended feed. Among the thousands of unique features, 56 of them were chemically identified using MALDI-MS/MS, with the help of in-parallel liquid chromatography (LC)-MS/MS analysis. Lastly, as a proof of concept application, this protocol was applied to 52 turkey cecal samples at three different time points from the antibiotic feed trial. Statistical analysis indicated variations in the metabolome of turkeys with different ages or treatments. Graphical abstract ᅟ. PMID: 30377739 [PubMed - as supplied by publisher]

Identification of TMAO-producer phenotype and host-diet-gut dysbiosis by carnitine challenge test in human and germ-free mice. Gut. 2018 Oct 30;: Authors: Wu WK, Chen CC, Liu PY, Panyod S, Liao BY, Chen PC, Kao HL, Kuo HC, Kuo CH, Chiu THT, Chen RA, Chuang HL, Huang YT, Zou HB, Hsu CC, Chang TY, Lin CL, Ho CT, Yu HT, Sheen LY, Wu MS Abstract OBJECTIVE: The gut microbiota-derived metabolite, trimethylamine N-oxide (TMAO) plays an important role in cardiovascular disease (CVD). The fasting plasma TMAO was shown as a prognostic indicator of CVD incident in patients and raised the interest of intervention targeting gut microbiota. Here we develop a clinically applicable method called oral carnitine challenge test (OCCT) for TMAO-related therapeutic drug efforts assessment and personalising dietary guidance. DESIGN: A pharmacokinetic study was performed to verify the design of OCCT protocol. The OCCT was conducted in 23 vegetarians and 34 omnivores to validate gut microbiota TMAO production capacity. The OCCT survey was integrated with gut microbiome, host genotypes, dietary records and serum biochemistry. A humanised gnotobiotic mice study was performed for translational validation. RESULTS: The OCCT showed better efficacy than fasting plasma TMAO to identify TMAO producer phenotype. The omnivores exhibited a 10-fold higher OR to be high TMAO producer than vegetarians. The TMAO-associated taxa found by OCCT in this study were consistent with previous animal studies. The TMAO producer phenotypes were also reproduced in humanised gnotobiotic mice model. Besides, we found the faecal CntA gene was not associated with TMAO production; therefore, other key relevant microbial genes might be involved. Finally, we demonstrated the urine TMAO exhibited a strong positive correlation with plasma TMAO (r=0.92, p<0.0001) and improved the feasibility of OCCT. CONCLUSION: The OCCT can be used to identify TMAO-producer phenotype of gut microbiota and may serve as a personal guidance in CVD prevention and treatment. TRIAL REGISTRATION NUMBER: NCT02838732; Results. PMID: 30377191 [PubMed - as supplied by publisher]

Distinct microbes, metabolites, and ecologies define the microbiome in deficient and proficient mismatch repair colorectal cancers. Genome Med. 2018 Oct 31;10(1):78 Authors: Hale VL, Jeraldo P, Chen J, Mundy M, Yao J, Priya S, Keeney G, Lyke K, Ridlon J, White BA, French AJ, Thibodeau SN, Diener C, Resendis-Antonio O, Gransee J, Dutta T, Petterson XM, Sung J, Blekhman R, Boardman L, Larson D, Nelson H, Chia N Abstract BACKGROUND: Links between colorectal cancer (CRC) and the gut microbiome have been established, but the specific microbial species and their role in carcinogenesis remain an active area of inquiry. Our understanding would be enhanced by better accounting for tumor subtype, microbial community interactions, metabolism, and ecology. METHODS: We collected paired colon tumor and normal-adjacent tissue and mucosa samples from 83 individuals who underwent partial or total colectomies for CRC. Mismatch repair (MMR) status was determined in each tumor sample and classified as either deficient MMR (dMMR) or proficient MMR (pMMR) tumor subtypes. Samples underwent 16S rRNA gene sequencing and a subset of samples from 50 individuals were submitted for targeted metabolomic analysis to quantify amino acids and short-chain fatty acids. A PERMANOVA was used to identify the biological variables that explained variance within the microbial communities. dMMR and pMMR microbial communities were then analyzed separately using a generalized linear mixed effects model that accounted for MMR status, sample location, intra-subject variability, and read depth. Genome-scale metabolic models were then used to generate microbial interaction networks for dMMR and pMMR microbial communities. We assessed global network properties as well as the metabolic influence of each microbe within the dMMR and pMMR networks. RESULTS: We demonstrate distinct roles for microbes in dMMR and pMMR CRC. Bacteroides fragilis and sulfidogenic Fusobacterium nucleatum were significantly enriched in dMMR CRC, but not pMMR CRC. These findings were further supported by metabolic modeling and metabolomics indicating suppression of B. fragilis in pMMR CRC and increased production of amino acid proxies for hydrogen sulfide in dMMR CRC. CONCLUSIONS: Integrating tumor biology and microbial ecology highlighted distinct microbial, metabolic, and ecological properties unique to dMMR and pMMR CRC. This approach could critically improve our ability to define, predict, prevent, and treat colorectal cancers. PMID: 30376889 [PubMed - in process]

Related Articles Progress in Metabonomics of Type 2 Diabetes Mellitus. Molecules. 2018 Jul 23;23(7): Authors: Ma Q, Li Y, Wang M, Tang Z, Wang T, Liu C, Wang C, Zhao B Abstract With the improvement of living standards and a change in lifestyle, the incidence of type 2 diabetes mellitus (T2DM) is increasing. Its etiology is too complex to be completely understand yet. Metabonomics techniques are used to study the changes of metabolites and metabolic pathways before and after the onset of diabetes and make it more possible to further understand the pathogenesis of T2DM and improve its prediction, early diagnosis, and treatment. In this review, we summarized the metabonomics study of T2DM in recent years and provided a theoretical basis for the study of pathogenesis and the effective prevention and treatment of T2DM. PMID: 30041493 [PubMed - indexed for MEDLINE]

Related Articles The interaction between the proliferating macroalga Asparagopsis taxiformis and the coral Astroides calycularis induces changes in microbiome and metabolomic fingerprints. Sci Rep. 2017 02 20;7:42625 Authors: Greff S, Aires T, Serrão EA, Engelen AH, Thomas OP, Pérez T Abstract Mediterranean Sea ecosystems are considered as hotspots of biological introductions, exposed to possible negative effects of non-indigenous species. In such temperate marine ecosystems, macroalgae may be dominant, with a great percentage of their diversity represented by introduced species. Their interaction with temperate indigenous benthic organisms have been poorly investigated. To provide new insights, we performed an experimental study on the interaction between the introduced proliferative red alga Asparagopsis taxiformis and the indigenous Mediterranean coral Astroides calycularis. The biological response measurements included meta-barcoding of the associated microbial communities and metabolomic fingerprinting of both species. Significant changes were detected among both associated microbial communities, the interspecific differences decreasing with stronger host interaction. No short term effects of the macroalga on the coral health, neither on its polyp activity or its metabolism, were detected. In contrast, the contact interaction with the coral induced a change in the macroalgal metabolomic fingerprint with a significant increase of its bioactivity against the marine bacteria Aliivibrio fischeri. This induction was related to the expression of bioactive metabolites located on the macroalgal surface, a phenomenon which might represent an immediate defensive response of the macroalga or an allelopathic offense against coral. PMID: 28218290 [PubMed - indexed for MEDLINE]

21 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 2018/10/31PubMed 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.

21 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 2018/10/31PubMed 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.

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. 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. 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). 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. 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. 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]

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]

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]

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]

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]