PubMed

Related Articles Differential Amino Acid, Carbohydrate and Lipid Metabolism Perpetuations Involved in a Subtype of Rheumatoid Arthritis with Chinese Medicine Cold Pattern. Int J Mol Sci. 2016 Oct 21;17(10): Authors: Guo H, Niu X, Gu Y, Lu C, Xiao C, Yue K, Zhang G, Pan X, Jiang M, Tan Y, Kong H, Liu Z, Xu G, Lu A Abstract Pattern classification is a key approach in Traditional Chinese Medicine (TCM), and it is used to classify the patients for intervention selection accordingly. TCM cold and heat patterns, two main patterns of rheumatoid arthritis (RA) had been explored with systems biology approaches. Different regulations of apoptosis were found to be involved in cold and heat classification in our previous works. For this study, the metabolic profiling of plasma was explored in RA patients with typical TCM cold or heat patterns by integrating liquid chromatography/mass spectrometry (LC/MS) and gas chromatography/mass spectrometry (GC/MS) platforms in conjunction with the Ingenuity Pathway Analysis (IPA) software. Three main processes of metabolism, including amino acid, carbohydrate and lipid were focused on for function analysis. The results showed that 29 and 19 differential metabolites were found in cold and heat patterns respectively, compared with healthy controls. The perturbation of amino acid metabolism (increased essential amino acids), carbohydrate metabolism (galactose metabolism) and lipid metabolism, were found to be involved in both cold and heat pattern RA. In particular, more metabolic perturbations in protein and collagen breakdown, decreased glycolytic activity and aerobic oxidation, and increased energy utilization associated with RA cold pattern patients. These findings may be useful for obtaining a better understanding of RA pathogenesis and for achieving a better efficacy in RA clinical practice. PMID: 27775663 [PubMed - indexed for MEDLINE]

Related Articles The effects of early postnatal exposure to a low dose of decabromodiphenyl ether (BDE-209) on serum metabolites in male mice. J Toxicol Sci. 2016;41(5):667-75 Authors: Eguchi A, Miyaso H, Mori C Abstract The toxicity of decabromodiphenyl ether (BDE-209) has been reported in several studies. However, there is not much known about the toxicological biomarkers that characterize BDE-209 exposure. In this study, we subcutaneously exposed mice to 0.025 mg/kg/day BDE-209 on postnatal days 1‑5 and sacrificed the animals at 12 weeks of age (day 84). Flow injection analysis and hydrophilic interaction chromatography-triple quadrupole mass spectrometry were used to determine the serum metabolomes of these mice in order to characterize the effects of BDE-209 exposure. Data analysis showed a good separation between control and exposed mice (R(2) = 0.953, Q(2) = 0.728, and ANOVA of the cross‑validated residuals (CV‑ANOVA): P‑value = 0.0317) and 54 metabolites were identified as altered in the exposed animals. These were selected using variable importance (VIP) and loadings scaled by a correlation coefficient criteria and orthogonal partial least squares discriminant analysis (OPLS‑DA). BDE‑209‑exposed mice showed lower levels of long-chain acylcarnitines and citrate cycle-related metabolites, and higher levels of some amino acids, long-chain phospholipids, and short-chain acylcarnitines. The disruption of fatty acid, carbohydrate, and amino acid metabolism observed in the serum metabolome might be related to the previously observed impaired spermatogenesis in mice with early postnatal exposure to a low dose of BDE-209. PMID: 27665776 [PubMed - indexed for MEDLINE]

Related Articles Effects of potato spindle tuber viroid infection on tomato metabolic profile. J Plant Physiol. 2016 Aug 20;201:42-53 Authors: Bagherian SA, Hamzehzarghani H, Izadpanah K, Djavaheri M Abstract Viroids are the smallest plant pathogens consisting of a single stranded circular RNA molecule with a strong secondary structure, lacking a coat protein or any other proteins. The mechanism of viroid pathogenicity has remained unclear. Recent advances in instrumentation and data mining have made it possible to study the effects of various stresses on primary and secondary metabolisms. Here, we have utilized metabolic profiling approach to show how PSTVd infection alters tomato metabolic profile and the related pathways. Three terminal leaflets of third true leaf of 20-day-old tolerant tomato cultivar 'Moneymaker' were mechanically inoculated by PSTVd intermediate variant cDNAs and samples were taken from eighth leaf, 19days post-inoculation. Metabolites were extracted and analyzed by gas chromatography/mass spectrometry (GC/MS) and subjected to statistical data analysis. Affected pathways were identified by Pathway Tools program and were compared with microarray data previously reported. The study showed that 79 metabolites changed significantly and 23 pathways were identified in relation to these metabolites. Fourteen of these pathways were similar to those reported in other works. The altered pathways in PSTVd infected tomato leaves included, eight cutin and wax biosynthesis, seven pathways that produce defense related compounds, two energy generator pathways, three hormone biosynthesis pathways, two signal transduction pathways, and one nucleotide biosynthesis pathway. Our data on up/down-regulation of pathways supported the data produced on their corresponding gene(s) up/down-regulation. PMID: 27393919 [PubMed - indexed for MEDLINE]

Related Articles Urinary nuclear magnetic resonance spectroscopy of a Bangladeshi cohort with hepatitis-B hepatocellular carcinoma: A biomarker corroboration study. World J Gastroenterol. 2016 Apr 28;22(16):4191-200 Authors: Cox IJ, Aliev AE, Crossey MM, Dawood M, Al-Mahtab M, Akbar SM, Rahman S, Riva A, Williams R, Taylor-Robinson SD Abstract AIM: To establish if a distinct urinary metabolic profile could be identified in Bangladeshi hepatitis-B hepatocellular carcinoma (HCC) patients compared to cirrhosis patients and controls. METHODS: Urine samples from 42 Bangladeshi patients with HCC (39 patients with hepatitis-B HCC), 47 with cirrhosis on a background of hepatitis B, 46 with chronic hepatitis B, and seven ethnically-matched healthy controls were analyzed using nuclear magnetic resonance (NMR) spectroscopy. A full dietary and medication history was recorded for each subject. The urinary NMR data were analyzed using principal component analysis (PCA) and orthogonal partial least squared discriminant analysis (OPLS-DA) techniques. Differences in relative signal levels of the most discriminatory metabolites identified by PCA and OPLS-DA were compared between subject groups using an independent samples Kruskal-Wallis one-way analysis of variance (ANOVA) test with all pairwise multiple comparisons. Within the patient subgroups, the Mann-Whitney U test was used to compare metabolite levels depending on hepatitis B e-antigen (HBeAg) status and treatment with anti-viral therapy. A Benjamini-Hochberg adjustment was applied to acquire the level of significance for multiple testing, with a declared level of statistical significance of P < 0.05. RESULTS: There were significant differences in age (P < 0.001), weight (P < 0.001), and body mass index (P < 0.001) across the four clinical subgroups. Serum alanine aminotransferase (ALT) was significantly higher in the HCC group compared to controls (P < 0.001); serum α-fetoprotein was generally markedly elevated in HCC compared to controls; and serum creatinine levels were significantly reduced in the HCC group compared to the cirrhosis group (P = 0.004). A three-factor PCA scores plot showed clustering of the urinary NMR spectra from the four subgroups. Metabolites that contributed to the discrimination between the subgroups included acetate, creatine, creatinine, dimethyamine (DMA), formate, glycine, hippurate, and trimethylamine-N-oxide (TMAO). A comparison of relative metabolite levels confirmed that carnitine was significantly increased in HCC; and creatinine, hippurate, and TMAO were significantly reduced in HCC compared to the other subgroups. HBeAg negative patients showed a significant increase in creatinine (P = 0.001) compared to HBeAg positive patients in the chronic hepatitis B subgroup, whilst HBeAg negative patients showed a significant decrease in DMA (P = 0.004) in the cirrhosis subgroup compared to HBeAg positive patients. There were no differences in metabolite levels in HCC patients who did or did not receive antiviral treatment. CONCLUSION: Urinary NMR changes in Bangladeshi HCC were identified, corroborating previous findings from Egypt and West Africa. These findings could form the basis for the development of a cost-effective HCC dipstick screening test. PMID: 27122669 [PubMed - indexed for MEDLINE]

Related Articles Profiling of acidic (amino and phenolic acids) and phenylpropanoids production in response to methyl jasmonate-induced oxidative stress in Scrophularia striata suspension cells. Planta. 2016 Jul;244(1):75-85 Authors: Sadeghnezhad E, Sharifi M, Zare-Maivan H Abstract MAIN CONCLUSION: A metabolic profiling including calculation of energy cost of amino acids biosynthesis in cultured cells of Scrophularia striata showed that methyl jasmonate-inducible oxidative stress elicited secondary metabolites formation derived from phenylalanine and tyrosine and increased energy cost for these amino acids biosynthesis. Understanding of the metabolic pathways in cell culture of Scrophularia striata, an aromatic plant species, facilitates means of production of pharmaceutical metabolites under oxidative stress. In this study, we evaluated the effects of MeJA on the S. striata metabolic pathway and the responses to oxidative stress. Exposure to methyl jasmonate (MeJA) affects plant growth, effectively induces production of reactive oxygen species (ROS) and inserts oxidative stress at the cellular level which results in alteration of primary metabolites and production of phenylepropanoid compounds. Cells treated with MeJA indicated increase in the activities of three antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT), guaiacol peroxidase (GPx) as well as intracellular H2O2 and MDA contents compared with mock-treated cells. High performance liquid chromatography (HPLC)-based metabolome analysis revealed dynamic metabolic changes in oxidatively stressed S. striata cells, e.g., general phenylpropanoid pathway, phenylethanoid-glycosides, lignans, and increased energy cost of biosynthesis and accumulation of amino acids. Furthermore, principal component analysis (PCA)-derived score plots demonstrated that MeJA affects cellular metabolism in S. striata cells and significantly alters metabolite composition under MeJA-inducible oxidative stress. These observations suggest that MeJA-elicited cell suspension cultures of S. striata balanced the production of primary and secondary metabolites in coordination with ROS-scavenging system. PMID: 26945858 [PubMed - indexed for MEDLINE]

Related Articles Increased p-cresyl sulfate level is independently associated with poor outcomes in patients with heart failure. Heart Vessels. 2016 Jul;31(7):1100-8 Authors: Wang CH, Cheng ML, Liu MH, Shiao MS, Hsu KH, Huang YY, Lin CC, Lin JF Abstract Amino acid-derived metabolites, including protein-bound uremic toxins, may have prognostic value for patients with heart failure (HF). The aim of this study was to investigate whether p-cresyl sulfate (PCS), indoxyl sulfate (IS), and arginine metabolites provided prognostic values in addition to the traditional biomarker, B-type natriuretic peptide (BNP), in patients with HF. Chromatography mass spectrometry was performed to measure tyrosine, tryptophan, arginine, PCS, IS, and asymmetric (ADMA) and symmetric dimethylarginine (SDMA) in the plasma from 51 normal controls and 136 HF patients. Compared to the normal controls, PCS levels significantly increased in HF patients (p = 0.003). During the follow-up (2.3 ± 1.1 years), 35 (25.7 %) patients experienced a composite event of death or HF-related re-hospitalization. In univariable analysis, PCS, estimated glomerular filtration rate (eGFR), BNP, DMA/arginine ratio, and ADMA/arginine ratio were associated with a higher rate of composite events. In the multivariable analysis, PCS was the only independent predictor of composite events [hazard ratio (HR) 1.06 (per 10 μM), 95 % confidence interval (CI) 1.01-1.11, p = 0.02]. Kaplan-Meier curves showed that a PCS level of ≥50 μM was significantly associated with a higher composite event rate than those with a PCS level of <50 μM (Log rank = 5.11, p = 0.024; HR 2.13, 95 % CI 1.09-4.16, p = 0.02). In conclusion, among protein-bound uremic toxins, eGFR, and DMA metabolites, increased PCS is the only independent predictor of HF-related events in patients with HF. A combination of PCS and BNP should better risk-stratify patients with HF. PMID: 26135926 [PubMed - indexed for MEDLINE]

Related Articles Strategy for comparative untargeted metabolomics reveals honey markers of different floral and geographic origins using ultrahigh-performance liquid chromatography-hybrid quadrupole-orbitrap mass spectrometry. J Chromatogr A. 2017 Mar 28;: Authors: Li Y, Jin Y, Yang S, Zhang W, Zhang J, Zhao W, Chen L, Wen Y, Zhang Y, Lu K, Zhang Y, Zhou J, Yang S Abstract Honey discrimination based on floral and geographic origins is limited by the ability to determine reliable markers because developing hypothetical substances in advance considerably limits the throughput of metabolomics studies. Here, we present a novel approach to screen and elucidate honey markers based on comparative untargeted metabolomics using ultrahigh-performance liquid chromatography-hybrid quadrupole-orbitrap mass spectrometry (UHPLC-Q-Orbitrap). To reduce metabolite information losses during sample preparation, the honey samples were dissolved in water and centrifuged to remove insoluble particles prior to UHPLC-Q-Orbitrap analysis in positive and negative electrospray ionization modes. The data were pretreated using background subtraction, chromatographic peak extraction, normalization, transformation and scaling to remove interferences from unwanted biases and variance in the experimental data. The pretreated data were further processed using principal component analysis (PCA) and a three-stage approach (t-test, volcano plot and variable importance in projection (VIP) plot) to ensure marker authenticity. A correlation between the molecular and fragment ions with a mass accuracy of less than 1.0ppm was used to annotate and elucidate the marker structures, and the marker responses in real samples were used to confirm the effectiveness of the honey discrimination. Moreover, we evaluated the data quality using blank and quality control (QC) samples based on PCA clustering, retention times, normalized levels and peak areas. This strategy will help guide standardized, comparative untargeted metabolomics studies of honey and other agro-products from different floral and geographic origins. PMID: 28390668 [PubMed - as supplied by publisher]

Related Articles ASN1-encoded asparagine synthetase in floral organs contributes to nitrogen filling in Arabidopsis seeds. Plant J. 2017 Apr 08;: Authors: Gaufichon L, Marmagne A, Belcram K, Yoneyama T, Sakakibara Y, Hase T, Grandjean O, Gilles C, Citerne S, Boutet-Mercey S, Masclaux-Daubresse C, Chardon F, Soulay F, Xu X, Trassaert M, Shakiebaei M, Najihi A, Suzuki A Abstract Despite a general view that asparagine synthetase generates asparagine as a long-distance nitrogen transport amino acid to sink organs, its role in nitrogen metabolic pathways in floral organs during seed nitrogen filling has remained undefined. We demonstrate that onset of pollination in Arabidopsis induces selected genes of asparagine metabolism particularly at ovule stage (stage 0): ASN1 (At3g47340), GLN2 (At5g35630), GLU1 (At5g04140), AapAT2 (At5g19950), ASPGA1 (At5g08100) and ASPGB1 (At3g16150), which accompanies enhanced asparagine synthetase protein, asparagine and total amino acids. Immunolocalization confined asparagine synthetase to the vascular cells of silique cell wall and septum, but also to the outer and inner seed integuments, pointing out the post-phloem transport asparagine supply in these cells to developing embryos. In asn1 mutant, aberrant embryo cell divisions in upper suspensor cell layers from globular to heart stages assign a role of nitrogen in differentiating embryos within ovary. Light/dark- and nitrate-induction of asparagine metabolic genes supports fine shifts of nitrogen metabolic pathways. In transgenic Arabidopsis expressing promoterCaMV35S ::ASN1 fusion, marked metabolomics changes at stage 0 including several-fold increase in free asparagine are correlated to enhanced seed nitrogen. Whereas specific promoterNapin2S ::ASN1 expression during seed formation and a 6-fold asparagine increase toward desiccation stage result in wild-type seed nitrogen, which underlines that the delayed asparagine accumulation impairs the timing of its use by releasing the amide- and amino-nitrogen. Transcript and metabolite profiles in floral organs match the carbon and nitrogen partitioning to generate energy via the TCA cycle, GABA shunt and phosphorylated serine synthetic pathway. This article is protected by copyright. All rights reserved. PMID: 28390103 [PubMed - as supplied by publisher]

Related Articles Understanding the role of the gut ecosystem in Diabetes Mellitus. J Diabetes Investig. 2017 Apr 08;: Authors: Aw W, Fukuda S Abstract Diabetes mellitus is a type of metabolic disorder patients are unable to regulate glycemia. It is currently worldwide public health issue and is a burden to society due to its disabling and common complications. Diabetes is multi-factorial and also induces the onset of other diseases. In this report, we will review the labyrinth encompassing the gut microbiota and gut microbiota derived metabolites on type 1 diabetes and type 2 diabetes pathogenesis. There has been exceptional improvements in Deoxyribonucleic acid (DNA) sequencing and mass spectrometry technologies throughout these years and this has allowed the comprehensive collection of information on our unique gut ecosystem. We would like to advocate incorporating metagenome and metabolome information for comprehensive perspective of the complex interrelationships between the gut environment, host metabolism and diabetes pathogenesis. We hope that with this improved understanding we would be able to provide exciting novel therapeutic approaches to engineer an ideal gut ecosystem for optimal health. This article is protected by copyright. All rights reserved. PMID: 28390093 [PubMed - as supplied by publisher]

Related Articles Single vagus nerve stimulation reduces early postprandial C-peptide levels but not other hormones or postprandial metabolism. Clin Rheumatol. 2017 Apr 08;: Authors: Tang MW, van Nierop FS, Koopman FA, Eggink HM, Gerlag DM, Chan MW, Zitnik R, Vaz FM, Romijn JA, Tak PP, Soeters MR Abstract A recent study in rheumatoid arthritis (RA) patients using electrical vagus nerve stimulation (VNS) to activate the inflammatory reflex has shown promising effects on disease activity. Innervation by the autonomic nerve system might be involved in the regulation of many endocrine and metabolic processes and could therefore theoretically lead to unwanted side effects. Possible effects of VNS on secretion of hormones are currently unknown. Therefore, we evaluated the effects of a single VNS on plasma levels of pituitary hormones and parameters of postprandial metabolism. Six female patients with RA were studied twice in balanced assignment (crossover design) to either VNS or no stimulation. The patients selected for this substudy had been on VNS therapy daily for at least 3 months and at maximum of 24 months. We compared 10-, 20-, and 30-min poststimulus levels to baseline levels, and a 4-h mixed meal test was performed 30 min after VNS. We also determined energy expenditure (EE) by indirect calorimetry before and after VNS. VNS did not affect pituitary hormones (growth hormone, thyroid stimulating hormone, adrenocorticotropic hormone, prolactin, follicle-stimulating hormone, and luteinizing hormone), postprandial metabolism, or EE. Of note, VNS reduced early postprandial insulin secretion, but not AUC of postprandial plasma insulin levels. Cortisol and catecholamine levels in serum did not change significantly. Short stimulation of vagal activity by VNS reduces early postprandial insulin secretion, but not other hormone levels and postprandial response. This suggests VNS as a safe treatment for RA patients. PMID: 28389989 [PubMed - as supplied by publisher]

Related Articles Metabolic profiling and novel plasma biomarkers for predicting survival in epithelial ovarian cancer. Oncotarget. 2017 Mar 31;: Authors: Xie H, Hou Y, Cheng J, Openkova MS, Xia B, Wang W, Li A, Yang K, Li J, Xu H, Yang C, Ma L, Li Z, Fan X, Li K, Lou G Abstract Epithelial ovarian cancer (EOC) is one of the most lethal gynecological malignancies around the world, and patients with ovarian cancer always have an extremely poor chance of survival. Therefore, it is meaningful to develop a highly efficient model that can predict the overall survival for EOC. In order to investigate whether metabolites could be used to predict the survival of EOC, we performed a metabolic analysis of 98 plasma samples with follow-up information, based on the ultra-performance liquid chromatography mass spectrometry (UPLC/MS) systems in both positive (ESI+) and negative (ESI-) modes. Four metabolites: Kynurenine, Acetylcarnitine, PC (42:11), and LPE(22:0/0:0) were selected as potential predictive biomarkers. The AUC value of metabolite-based risk score, together with pathological stages in predicting three-year survival rate was 0.80. The discrimination performance of these four biomarkers between short-term mortality and long-term survival was excellent, with an AUC value of 0.82. In conclusion, our plasma metabolomics study presented the dysregulated metabolism related to the survival of EOC, and plasma metabolites could be utilized to predict the overall survival and discriminate the short-term mortality and long-term survival for EOC patients. These results could provide supplementary information for further study about EOC survival mechanism and guiding the appropriate clinical treatment. PMID: 28389631 [PubMed - as supplied by publisher]

Related Articles Metabolomics for biomarker discovery in the diagnosis, prognosis, survival and recurrence of colorectal cancer: a systematic review. Oncotarget. 2017 Mar 30;: Authors: Zhang F, Zhang Y, Zhao W, Deng K, Wang Z, Yang C, Ma L, Openkova MS, Hou Y, Li K Abstract Colorectal cancer (CRC) remains an incurable disease. There are no effective noninvasive techniques that have achieved colorectal cancer (CRC) diagnosis, prognosis, survival and recurrence in clinic. To investigate colorectal cancer metabolism, we perform an electronic literature search, from 1998 to January 2016, for studies evaluating the metabolomic profile of patients with CRC regarding the diagnosis, recurrence, prognosis/survival, and systematically review the twenty-three literatures included. QUADOMICS tool was used to assess the quality of them. We highlighted the metabolism perturbations based on metabolites and pathway. Metabolites related to cellular respiration, carbohydrate, lipid, protein and nucleotide metabolism were significantly altered in CRC. Altered metabolites were also related to prognosis, survival and recurrence of CRC. This review could represent the most comprehensive information and summary about CRC metabolism to date. It certificates that metabolomics had great potential on both discovering clinical biomarkers and elucidating previously unknown mechanisms of CRC pathogenesis. PMID: 28389626 [PubMed - as supplied by publisher]

Related Articles Microbial Metabolites in Health and Disease: Navigating the Unknown in Search of Function. J Biol Chem. 2017 Apr 07;: Authors: Martinez KB, Leone VA, Chang EB Abstract The gut microbiota has been implicated in the development of a number of chronic gastrointestinal and systemic diseases. These include inflammatory bowel diseases, irritable bowel syndrome, metabolic (i.e. obesity, non-alcoholic fatty liver disease, diabetes), and neurological diseases. The advanced understanding of host-microbe interactions has largely been due to new technologies such as 16S rRNA sequencing to identify previously unknown microbial communities and more importantly their functional characteristics through metagenomic sequencing, and other multi-omic technologies such as metatranscriptomics, metaproteomics, and metabolomics. Given the vast array of newly acquired knowledge in the field and technological advances, it is expected that mechanisms underlying several disease states involving the interactions between microbes, their metabolites, and the host will be discovered. The identification of these mechanisms will allow for the development of more precise therapies to prevent or manage chronic disease. This review discusses the functional characterization of the microbiome, highlighting the advances in identifying bioactive microbial metabolites that have been directly linked to gastrointestinal and peripheral diseases. PMID: 28389566 [PubMed - as supplied by publisher]

Related Articles Introduction to the Thematic Minireview Series: Host-Microbiome Metabolic Interplay. J Biol Chem. 2017 Apr 07;: Authors: Banerjee R Abstract Long before the recent thrust of scientific research on the microbiome, the importance of its interface with the host was being acknowledged by practices such as probiotic supplementation e.g., after a course of antibiotics, which has the unwanted side effect of depleting commensal bacteria. The shared metabolite capital between the host and the microbiome is extensive and tightly controlled. However, despite the influence of microbial-derived metabolites on many aspects of host physiology, behavior and pathology, our understanding of this metabolic interface is still in its infancy and its therapeutic targeting is largely untapped. In this thematic minireview series, JBC presents six exciting articles discussing a range of approaches for identifying microbial natural products, and elucidating their biosynthetic pathways and their physiological effects, which could potentially be leveraged for developing new therapeutics. PMID: 28389560 [PubMed - as supplied by publisher]

Related Articles Targeting of Microbe-Derived Metabolites to Improve Human Health: The Next Frontier for Drug Discovery. J Biol Chem. 2017 Apr 07;: Authors: Brown JM, Hazen SL Abstract Recent advances in metabolomic and genome mining approaches have uncovered a poorly understood metabolome that originates solely or in part from bacterial enzyme sources. Whether living on exposed surfaces or within our intestinal tract, our microbial inhabitants produce a remarkably diverse set of natural products and small molecule metabolites that can impact human health and disease. Highlighted here, the gut microbe-derived metabolite trimethylamine N-oxide (TMAO) has been causally linked to the development of cardiovascular diseases. Recent studies reveal drugging this pathway can inhibit atherosclerosis development in mice. Building on this example, we discuss challenges and untapped potential of targeting bacterial enzymology for improvements in human health. PMID: 28389555 [PubMed - as supplied by publisher]

Related Articles Robust identification of metabolic control for microbial l-methionine production following an easy-to-use puristic approach. Metab Eng. 2017 Apr 04;: Authors: Teleki A, Rahnert M, Bungart O, Gann B, Ochrombel I, Takors R Abstract The identification of promising metabolic engineering targets is a key issue in metabolic control analysis (MCA). Conventional approaches make intensive use of model-based studies, such as exploiting post-pulse metabolic dynamics after proper perturbation of the microbial system. Here, we present an easy-to-use, purely data-driven approach, defining pool efflux capacities (PEC) for identifying reactions that exert the highest flux control in linear pathways. Comparisons with linlog-based MCA and data-driven substrate elasticities (DDSE) showed that similar key control steps were identified using PEC. Using the example of l-methionine production with recombinant Escherichia coli, PEC consistently and robustly identified main flux controls using perturbation data after a non-labeled (12)C-l-serine stimulus. Furthermore, the application of full-labeled (13)C-l-serine stimuli yielded additional insights into stimulus propagation to l-methionine. PEC analysis performed on the (13)C data set revealed the same targets as the (12)C data set. Notably, the typical drawback of metabolome analysis, namely, the omnipresent leakage of metabolites, was excluded using the (13)C PEC approach. PMID: 28389396 [PubMed - as supplied by publisher]

Related Articles Induced Pluripotent Stem Cell Differentiation Enables Functional Validation of GWAS Variants in Metabolic Disease. Cell Stem Cell. 2017 Apr 06;20(4):547-557.e7 Authors: Warren CR, O'Sullivan JF, Friesen M, Becker CE, Zhang X, Liu P, Wakabayashi Y, Morningstar JE, Shi X, Choi J, Xia F, Peters DT, Florido MH, Tsankov AM, Duberow E, Comisar L, Shay J, Jiang X, Meissner A, Musunuru K, Kathiresan S, Daheron L, Zhu J, Gerszten RE, Deo RC, Vasan RS, O'Donnell CJ, Cowan CA Abstract Genome-wide association studies (GWAS) have highlighted a large number of genetic variants with potential disease association, but functional analysis remains a challenge. Here we describe an approach to functionally validate identified variants through differentiation of induced pluripotent stem cells (iPSCs) to study cellular pathophysiology. We collected peripheral blood cells from Framingham Heart Study participants and reprogrammed them to iPSCs. We then differentiated 68 iPSC lines into hepatocytes and adipocytes to investigate the effect of the 1p13 rs12740374 variant on cardiometabolic disease phenotypes via transcriptomics and metabolomic signatures. We observed a clear association between rs12740374 and lipid accumulation and gene expression in differentiated hepatocytes, in particular, expression of SORT1, CELSR2, and PSRC1, consistent with previous analyses of this variant using other approaches. Initial investigation of additional SNPs also highlighted correlations with gene expression. These findings suggest that iPSC-based population studies hold promise as tools for the functional validation of GWAS variants. PMID: 28388431 [PubMed - in process]

Related Articles Physiologic Medium Rewires Cellular Metabolism and Reveals Uric Acid as an Endogenous Inhibitor of UMP Synthase. Cell. 2017 Apr 06;169(2):258-272.e17 Authors: Cantor JR, Abu-Remaileh M, Kanarek N, Freinkman E, Gao X, Louissaint A, Lewis CA, Sabatini DM Abstract A complex interplay of environmental factors impacts the metabolism of human cells, but neither traditional culture media nor mouse plasma mimic the metabolite composition of human plasma. Here, we developed a culture medium with polar metabolite concentrations comparable to those of human plasma (human plasma-like medium [HPLM]). Culture in HPLM, relative to that in traditional media, had widespread effects on cellular metabolism, including on the metabolome, redox state, and glucose utilization. Among the most prominent was an inhibition of de novo pyrimidine synthesis-an effect traced to uric acid, which is 10-fold higher in the blood of humans than of mice and other non-primates. We find that uric acid directly inhibits uridine monophosphate synthase (UMPS) and consequently reduces the sensitivity of cancer cells to the chemotherapeutic agent 5-fluorouracil. Thus, media that better recapitulates the composition of human plasma reveals unforeseen metabolic wiring and regulation, suggesting that HPLM should be of broad utility. PMID: 28388410 [PubMed - in process]

Related Articles Improved Quantum Chemical NMR Chemical Shift Prediction of Metabolites in Aqueous Solution Toward the Validation of Unknowns. J Phys Chem A. 2017 Apr 07;: Authors: Hoffmann F, Li DW, Sebastiani D, Bruschweiler R Abstract A quantum-chemistry based protocol, termed MOSS-DFT, is presented for the prediction of 13C and 1H NMR chemical shifts of a wide range of organic molecules in aqueous solution, including metabolites. Molecular motif-specific linear scaling parameters are reported for five different density functional theory (DFT) methods (B97-2/pcS-1, B97-2/pcS-2, B97-2/pcS-3, B3LYP/pcS-2 and BLYP/pcS-2), which were applied to a large set of 176 metabolite molecules. The chemical shift root-mean-square deviations (RMSD) for the best method, B97-2/pcS-3, are 1.93 ppm and 0.154 ppm for 13C and 1H chemical shifts, respectively. Excellent results have been obtained for chemical shifts of methyl and aromatic 13C and 1H that are not directly bonded to a heteroatom (O, N, S, or P) with RMSD values of 1.15/0.079 ppm and 1.31/0.118 ppm, respectively. This study not only demonstrates how NMR chemical shift predictions can be improved over the commonly used global linear scaling approach, but also allows for motif-specific error estimates, which are useful for an improved chemical shift-based verification of metabolite candidates of metabolomics samples containing unknown components. PMID: 28388058 [PubMed - as supplied by publisher]

Related Articles Translocator Protein-18 kDa (TSPO) Positron Emission Tomography (PET) Imaging and Its Clinical Impact in Neurodegenerative Diseases. Int J Mol Sci. 2017 Apr 07;18(4): Authors: Dupont AC, Largeau B, Santiago Ribeiro MJ, Guilloteau D, Tronel C, Arlicot N Abstract In vivo exploration of activated microglia in neurodegenerative diseases is achievable by Positron Emission Tomography (PET) imaging, using dedicated radiopharmaceuticals targeting the translocator protein-18 kDa (TSPO). In this review, we emphasized the major advances made over the last 20 years, thanks to TSPO PET imaging, to define the pathophysiological implication of microglia activation and neuroinflammation in neurodegenerative diseases, including Parkinson's disease, Huntington's disease, dementia, amyotrophic lateral sclerosis, multiple sclerosis, and also in psychiatric disorders. The extent and upregulation of TSPO as a molecular biomarker of activated microglia in the human brain is now widely documented in these pathologies, but its significance, and especially its protective or deleterious action regarding the disease's stage, remains under debate. Thus, we exposed new and plausible suggestions to enhance the contribution of TSPO PET imaging for biomedical research by exploring microglia's role and interactions with other cells in brain parenchyma. Multiplex approaches, associating TSPO PET radiopharmaceuticals with other biomarkers (PET imaging of cellular metabolism, neurotransmission or abnormal protein aggregates, but also other imaging modalities, and peripheral cytokine levels measurement and/or metabolomics analysis) was considered. Finally, the actual clinical impact of TSPO PET imaging as a routine biomarker of neuroinflammation was put into perspective regarding the current development of diagnostic and therapeutic strategies for neurodegenerative diseases. PMID: 28387722 [PubMed - in process]