PubMed

Related Articles Di-(2-Ethylhexyl)-Phthalate (DEHP) Causes Impaired Adipocyte Function and Alters Serum Metabolites. PLoS One. 2015;10(12):e0143190 Authors: Klöting N, Hesselbarth N, Gericke M, Kunath A, Biemann R, Chakaroun R, Kosacka J, Kovacs P, Kern M, Stumvoll M, Fischer B, Rolle-Kampczyk U, Feltens R, Otto W, Wissenbach DK, von Bergen M, Blüher M Abstract Di-(2-ethylhexyl)-phthalate (DEHP), an ubiquitous environmental contaminant, has been shown to cause adverse effects on glucose homeostasis and insulin sensitivity in epidemiological studies, but the underlying mechanisms are still unknown. We therefore tested the hypothesis that chronic DEHP exposure causes impaired insulin sensitivity, affects body weight, adipose tissue (AT) function and circulating metabolic parameters of obesity resistant 129S6 mice in vivo. An obesity-resistant mouse model was chosen to reduce a potential obesity bias of DEHP effects on metabolic parameters and AT function. The metabolic effects of 10-weeks exposure to DEHP were tested by insulin tolerance tests and quantitative assessment of 183 metabolites in mice. Furthermore, 3T3-L1 cells were cultured with DEHP for two days, differentiated into mature adipocytes in which the effects on insulin stimulated glucose and palmitate uptake, lipid content as well as on mRNA/protein expression of key adipocyte genes were investigated. We observed in female mice that DEHP treatment causes enhanced weight gain, fat mass, impaired insulin tolerance, changes in circulating adiponectin and adipose tissue Pparg, adiponectin and estrogen expression. Serum metabolomics indicated a general increase in phospholipid and carnitine concentrations. In vitro, DEHP treatment increases the proliferation rate and alters glucose uptake in adipocytes. Taken together, DEHP has significant effects on adipose tissue (AT) function and alters specific serum metabolites. Although, DEHP treatment led to significantly impaired insulin tolerance, it did not affect glucose tolerance, HOMA-IR, fasting glucose, insulin or triglyceride serum concentrations. This may suggest that DEHP treatment does not cause impaired glucose metabolism at the whole body level. PMID: 26630026 [PubMed - as supplied by publisher]

Related Articles Circulating Unsaturated Fatty Acids Delineate the Metabolic Status of Obese Individuals. EBioMedicine. 2015 Oct;2(10):1513-22 Authors: Ni Y, Zhao L, Yu H, Ma X, Bao Y, Rajani C, Loo LW, Shvetsov YB, Yu H, Chen T, Zhang Y, Wang C, Hu C, Su M, Xie G, Zhao A, Jia W, Jia W Abstract BACKGROUND: Obesity is not a homogeneous condition across individuals since about 25-40% of obese individuals can maintain healthy status with no apparent signs of metabolic complications. The simple anthropometric measure of body mass index does not always reflect the biological effects of excessive body fat on health, thus additional molecular characterizations of obese phenotypes are needed to assess the risk of developing subsequent metabolic conditions at an individual level. METHODS: To better understand the associations of free fatty acids (FFAs) with metabolic phenotypes of obesity, we applied a targeted metabolomics approach to measure 40 serum FFAs from 452 individuals who participated in four independent studies, using an ultra-performance liquid chromatograph coupled to a Xevo G2 quadruple time-of-flight mass spectrometer. FINDINGS: FFA levels were significantly elevated in overweight/obese subjects with diabetes compared to their healthy counterparts. We identified a group of unsaturated fatty acids (UFAs) that are closely correlated with metabolic status in two groups of obese individuals who underwent weight loss intervention and can predict the recurrence of diabetes at two years after metabolic surgery. Two UFAs, dihomo-gamma-linolenic acid and palmitoleic acid, were also able to predict the future development of metabolic syndrome (MS) in a group of obese subjects. INTERPRETATION: These findings underscore the potential role of UFAs in the MS pathogenesis and also as important markers in predicting the risk of developing diabetes in obese individuals or diabetes remission after a metabolic surgery. PMID: 26629547 [PubMed - in process]

Related Articles Evidence that 2-hydroxyglutarate is not readily metabolized in colorectal carcinoma cells. Cancer Metab. 2015;3:13 Authors: Gelman SJ, Mahieu NG, Cho K, Llufrio EM, Wencewicz TA, Patti GJ Abstract BACKGROUND: Two-hydroxyglutarate (2HG) is present at low concentrations in healthy mammalian cells as both an L and D enantiomer. Both the L and D enantiomers have been implicated in regulating cellular physiology by mechanisms that are only partially characterized. In multiple human cancers, the D enantiomer accumulates due to gain-of-function mutations in the enzyme isocitrate dehydrogenase (IDH) and has been hypothesized to drive malignancy through mechanisms that remain incompletely understood. While much attention has been dedicated to identifying the route of 2HG synthesis, the metabolic fate of 2HG has not been studied in detail. Yet the metabolism of 2HG may have important mechanistic consequences influencing cell function and cancer pathogenesis, such as modulating redox potential or producing unknown products with unique modes of action. RESULTS: By applying our isotope-based metabolomic platform, we unbiasedly and comprehensively screened for products of L- and D-2HG in HCT116 colorectal carcinoma cells harboring a mutation in IDH1. After incubating HCT116 cells in uniformly (13)C-labeled 2HG for 24 h, we used liquid chromatography/mass spectrometry to track the labeled carbons in small molecules. Strikingly, we did not identify any products of 2HG metabolism from the thousands of metabolomic features that we screened. Consistent with these results, we did not detect any significant changes in the labeling patterns of tricarboxylic acid cycle metabolites from wild type or IDH1 mutant cells cultured in (13)C-labeled glucose upon the addition of L, D, or racemic mixtures of 2HG. A more sensitive, targeted analysis revealed trace levels of isotopic enrichment (<1 %) in some central carbon metabolites from (13)C-labeled 2HG. However, we found that cells do not deplete 2HG from the media at levels above our detection limit over a 48 h time period. CONCLUSIONS: Taken together, we conclude that 2HG carbon is not readily transformed in the HCT116 cell line. These data indicate that the phenotypic alterations induced by 2HG are not a result of its metabolic products. PMID: 26629338 [PubMed - as supplied by publisher]

Related Articles Integrative molecular profiling indicates a central role of transitory starch breakdown in establishing a stable C/N homeostasis during cold acclimation in two natural accessions of Arabidopsis thaliana. BMC Plant Biol. 2015;15:284 Authors: Nagler M, Nukarinen E, Weckwerth W, Nägele T Abstract BACKGROUND: The variation of growth and cold tolerance of two natural Arabidopsis accessions, Cvi (cold sensitive) and Rschew (cold tolerant), was analysed on a proteomic, phosphoproteomic and metabolomic level to derive characteristic information about genotypically distinct strategies of metabolic reprogramming and growth maintenance during cold acclimation. RESULTS: Growth regulation before and after a cold acclimation period was monitored by recording fresh weight of leaf rosettes. Significant differences in the shoot fresh weight of Cvi and Rschew were detected both before and after acclimation to low temperature. During cold acclimation, starch levels were found to accumulate to a significantly higher level in Cvi compared to Rschew. Concomitantly, statistical analysis revealed a cold-induced decrease of beta-amylase 3 (BAM3; AT4G17090) in Cvi but not in Rschew. Further, only in Rschew we observed an increase of the protein level of the debranching enzyme isoamylase 3 (ISA3; AT4G09020). Additionally, the cold response of both accessions was observed to severely affect ribosomal complexes, but only Rschew showed a pronounced accumulation of carbon and nitrogen compounds. The abundance of the Cold Regulated (COR) protein COR78 (AT5G52310) as well as its phosphorylation was observed to be positively correlated with the acclimation state of both accessions. In addition, transcription factors being involved in growth and developmental regulation were found to characteristically separate the cold sensitive from the cold tolerant accession. Predicted protein-protein interaction networks (PPIN) of significantly changed proteins during cold acclimation allowed for a differentiation between both accessions. The PPIN revealed the central role of carbon/nitrogen allocation and ribosomal complex formation to establish a new cold-induced metabolic homeostasis as also observed on the level of the metabolome and proteome. CONCLUSION: Our results provide evidence for a comprehensive multi-functional molecular interaction network orchestrating growth regulation and cold acclimation in two natural accessions of Arabidopsis thaliana. The differential abundance of beta-amylase 3 and isoamylase 3 indicates a central role of transitory starch degradation in the coordination of growth regulation and the development of stress tolerance. Finally, our study indicates naturally occurring differential patterns of C/N balance and protein synthesis during cold acclimation. PMID: 26628055 [PubMed - in process]

Related Articles Anaplerotic Accumulation of Tricarboxylic Acid Cycle Intermediates As Well As Changes in Other Key Metabolites During Heterotopic Ossification. J Cell Biochem. 2015 Dec 2; Authors: Davis EL, Salisbury EA, Olmsted-Davis E, Davis AR Abstract Heterotopic ossification (HO) is the de novo formation of bone that occurs in soft tissue, through recruitment, expansion, and differentiation of multiple cells types including transient brown adipocytes, osteoblasts, chondrocytes, mast cells, and platelets to name a few. Much evidence is accumulating that suggests changes in metabolism may be required to accomplish this bone formation. Recent work using a mouse model of heterotopic bone formation reliant on delivery of adenovirus-transduced cells expressing low levels of BMP2 showed the immediate expansion of a unique brown adipocyte-like cell. These cells are undergoing robust uncoupled oxidative phosphorylation to a level such that oxygen in the microenvironment is dramatically lowered creating areas of hypoxia. It is unclear how these oxygen changes ultimately affect metabolism and bone formation. To identify the processes and changes occurring over the course of bone formation, HO was established in the mice, and tissues isolated at early and late times were subjected to a global metabolomic screen. Results show that there are significant changes in both glucose levels, as well as TCA cycle intermediates. Additionally, metabolites necessary for oxidation of stored lipids were also found to be significantly elevated. The complete results of this screen are presented here, and provide a unique picture of the metabolic changes occurring during heterotopic bone formation. This article is protected by copyright. All rights reserved. PMID: 26627193 [PubMed - as supplied by publisher]

Related Articles Improved motor and cognitive performance with sodium nitrite supplementation is related to small metabolite signatures: a pilot trial in middle-aged and older adults. Aging (Albany NY). 2015 Nov 20; Authors: Justice JN, Johnson LC, DeVan AE, Cruickshank-Quinn C, Reisdorph N, Bassett CJ, Evans TJ, Brooks FA, Bryan NS, Chonchol MB, Giordano T, McQueen MB, Seals DB Abstract Advancing age is associated with reductions in nitric oxide bioavailability and changes in metabolic activity, which are implicated in declines in motor and cognitive function. In preclinical models, sodium nitrite supplementation (SN) increases plasma nitrite and improves motor function, whereas other nitric oxide-boosting agents improve cognitive function. This pilot study was designed to translate these findings to middle-aged and older (MA/O) humans to provide proof-of-concept support for larger trials. SN (10 weeks, 80 to 160 mg/day capsules, TheraVasc, Inc.) acutely and chronically increased plasma nitrite and improved performance on measures of motor and cognitive outcomes (all p<0.05 or better) in healthy MA/O adults (62 ± 7 years). Untargeted metabolomics analysis revealed that SN significantly altered 33 (160 mg/day) to 45 (80 mg/day) different metabolites, 13 of which were related to changes in functional outcomes; baseline concentrations of 99 different metabolites predicted functional improvements with SN. This pilot study provides the first evidence that SN improves aspects of motor and cognitive function in healthy MA/O adults, and that these improvements are associated with, and predicted by, the plasma metabolome. Our findings provide the necessary support for larger clinical trials on this promising pharmacological strategy for preserving physiological function with aging. PMID: 26626856 [PubMed - as supplied by publisher]

Related Articles Effects of glucagon-like peptide-1 on glucagon secretion in patients with non-alcoholic fatty liver disease. J Hepatol. 2015 Nov 25; Authors: Junker AE, Gluud LL, van Hall G, Holst JJ, Knop FK, Vilsbøll T Abstract BACKGROUND & AIMS: We evaluated the glucagon-suppressive effect of glucagon-like peptide-1 (GLP-1) and its potential effects on endogenous glucose production and whole body lipolysis in non-diabetic patients with non-alcoholic fatty liver disease (NAFLD). METHODS: On two separate days 10 non-diabetic patients with liver biopsy-verified NAFLD (NAFLD activity score 2.5±1.0) and 10 matched controls underwent a 2-hour intravenous infusions of GLP-1 (0.8 pmol × kg(-1) × min(-1)) and placebo. Since GLP-1-mediated glucagon suppression has been shown to be glucose-dependent, plasma glucose was clamped at fasting level during the first hour, and then raised and clamped at 'postprandial level' (fasting plasma glucose level plus 3 mmol/L) for the remaining hour. We evaluated relative plasma levels of glucagon, endogenous glucose production and whole body lipolysis rates with stable isotopes and respiratory quotient using indirect calorimety. RESULTS: Compared to controls, patients with NAFLD were insulin resistant (homeostasis model assessment (HOMAIR): 3.8±2.2 vs. 1.6±1.5, p=0.003) and had fasting hyperglucagonaemia (7.5±5.3 vs. 5.8±1.5 mmol/L, p=0.045). Similar relative glucagon suppression was seen in both groups during GLP-1 infusion at fasting (-97±75 vs. -93±41 pmol/L × min(-1)p=0.566) and 'postprandial' plasma glucose levels (-108±101 vs. -97±53 pmol/L × min(-1), p=0.196). Increased insulinotropic effects of GLP-1 was observed in NAFLD patients. No effect of GLP-1 on endogenous glucose production was observed in any of the groups. CONCLUSIONS: Patients with NAFLD exhibited fasting hyperglucagonaemia, but intact GLP-1-mediated glucagon suppression independently of plasma glucose concentrations. Preserved glucagonostatic effect and increased insulinotropic effects of GLP-1 in NAFLD may be important to maintain normoglycaemia in these patients. PMID: 26626496 [PubMed - as supplied by publisher]

Related Articles A standardized kit for automated quantitative assessment of candidate protein biomarkers in human plasma. Bioanalysis. 2015 Dec 2; Authors: Percy AJ, Mohammed Y, Yang J, Borchers CH Abstract BACKGROUND: An increasingly popular mass spectrometry-based quantitative approach for health-related research in the biomedical field involves the use of stable isotope-labeled standards (SIS) and multiple/selected reaction monitoring (MRM/SRM). To improve inter-laboratory precision and enable more widespread use of this 'absolute' quantitative technique in disease-biomarker assessment studies, methods must be standardized. Results/methodology: Using this MRM-with-SIS-peptide approach, we developed an automated method (encompassing sample preparation, processing and analysis) for quantifying 76 candidate protein markers (spanning >4 orders of magnitude in concentration) in neat human plasma. DISCUSSION/CONCLUSION: The assembled biomarker assessment kit - the 'BAK-76' - contains the essential materials (SIS mixes), methods (for acquisition and analysis), and tools (Qualis-SIS software) for performing biomarker discovery or verification studies in a rapid and standardized manner. PMID: 26626236 [PubMed - as supplied by publisher]

Related Articles The authenticity and quality of Rhodiola rosea products. Phytomedicine. 2015 Oct 31; Authors: Booker A, Jalil B, Frommenwiler D, Reich E, Zhai L, Kulic Z, Heinrich M Abstract BACKGROUND: Rhodiola rosea L. Crassulaceae, root (Golden Root, Arctic Root) is a high-value herbal medicinal product, registered in the UK for the treatment of stress-induced fatigue, exhaustion and anxiety based on traditional use and used throughout Europe as a herbal medicinal product for similar indications. Numerous unregistered supplements are also available. There are several Chinese species used in traditional Chinese medicine (TCM), including Rhodiola crenulata (Hook.f. & Thomoson) that is believed to be a common adulterant in the R. rosea value chain. AIMS: The project is embedded in a larger study aiming to investigate the diverse value chains that lead to the production of R. rosea as an herbal medicinal product or supplement. Here we focus on a comparison of the quality of the finished products and assess any phytochemical variation between products registered under the Traditional Herbal Medicine Products Directive (THMPD) and products obtained from the market without any registration (i.e. generally unlicensed supplements). Our key aim is to establish the extent of the problem in terms of adulteration of consumer products claiming to contain R. rosea (or R. crenulata). METHODS: Approximately 40 commercial products (granulated powders and extracts) were sourced from different suppliers. We analysed these samples using high performance thin layer chromatography (HPTLC), mass spectrometry (MS) and (1)H NMR spectroscopy coupled with multi-variate analysis software following a method previously developed by our group for the analysis of turmeric products. RESULTS: We investigate the phytochemistry of the different species and assess the potential of R. crenulata as an adulterant at the end of the R. rosea value chains. The consistency of the products varies significantly. Approximately one fifth of commercial products that claimed to be R. rosea did not contain rosavin (the key reference markers used to distinguish R. rosea from related species). Moreover some products appeared not to contain salidroside, another marker compound found in other Rhodiola species. Approximately 80% of the remaining commercial products were lower in rosavin content than the registered products and appeared to be adulterated with other Rhodiola species. CONCLUSIONS: The variation in phytochemical constituents present in Rhodiola products available to European buyers via the internet and other sources is a major cause for concern. Adulteration with different species, and other sometimes unknown adulterants, appears to be commonplace. Good quality systems and manufacturing practices, including those required under the THMPD, enable consumers to have confidence that products are authentic and meet a high specification for quality and safety. PMID: 26626192 [PubMed - as supplied by publisher]

Related Articles Ginseng alleviates cyclophosphamide-induced hepatotoxicity via reversing disordered homeostasis of glutathione and bile acid. Sci Rep. 2015;5:17536 Authors: Zhu H, Long MH, Wu J, Wang MM, Li XY, Shen H, Xu JD, Zhou L, Fang ZJ, Luo Y, Li SL Abstract Cyclophosphamide (CP), a chemotherapeutic agent, is restricted due to its side effects, especially hepatotoxicity. Ginseng has often been clinically used with CP in China, but whether and how ginseng reduces the hepatotoxicity is unknown. In this study, the hepatoprotective effects and mechanisms under the combined usage were investigated. It was found that ginseng could ameliorate CP-induced elevations of ALP, ALT, ALS, MDA and hepatic deterioration, enhance antioxidant enzymes' activities and GSH's level. Metabolomics study revealed that 33 endogenous metabolites were changed by CP, 19 of which were reversed when ginseng was co-administrated via two main pathways, i.e., GSH metabolism and primary bile acids synthesis. Furthermore, ginseng could induce expression of GCLC, GCLM, GS and GST, which associate with the disposition of GSH, and expression of FXR, CYP7A1, NTCP and MRP 3, which play important roles in the synthesis and transport of bile acids. In addition, NRF 2, one of regulatory elements on the expression of GCLC, GCLM, GS, GST, NTCP and MRP3, was up-regulated when ginseng was co-administrated. In conclusion, ginseng could alleviate CP-induced hepatotoxicity via modulating the disordered homeostasis of GSH and bile acid, which might be mediated by inducing the expression of NRF 2 in liver. PMID: 26625948 [PubMed - in process]

Related Articles Integration of tissue metabolomics, transcriptomics and immunohistochemistry reveals ERG- and gleason score- specific metabolomic alterations in prostate cancer. Oncotarget. 2015 Nov 23; Authors: Meller S, Meyer HA, Bethan B, Dietrich D, González Maldonado S, Lein M, Montani M, Reszka R, Schatz P, Peter E, Stephan C, Jung K, Kamlage B, Kristiansen G Abstract Integrated analysis of metabolomics, transcriptomics and immunohistochemistry can contribute to a deeper understanding of biological processes altered in cancer and possibly enable improved diagnostic or prognostic tests. In this study, a set of 254 metabolites was determined by gas-chromatography/liquid chromatography-mass spectrometry in matched malignant and non-malignant prostatectomy samples of 106 prostate cancer (PCa) patients. Transcription analysis of matched samples was performed on a set of 15 PCa patients using Affymetrix U133 Plus 2.0 arrays. Expression of several proteins was immunohistochemically determined in 41 matched patient samples and the association with clinico-pathological parameters was analyzed by an integrated data analysis. These results further outline the highly deregulated metabolism of fatty acids, sphingolipids and polyamines in PCa. For the first time, the impact of the ERG translocation on the metabolome was demonstrated, highlighting an altered fatty acid oxidation in TMPRSS2-ERG translocation positive PCa specimens. Furthermore, alterations in cholesterol metabolism were found preferentially in high grade tumors, enabling the cells to create energy storage. With this integrated analysis we could not only confirm several findings from previous metabolomic studies, but also contradict others and finally expand our concepts of deregulated biological pathways in PCa. PMID: 26623558 [PubMed - as supplied by publisher]

Related Articles Microbial, host and xenobiotic diversity in the cystic fibrosis sputum metabolome. ISME J. 2015 Dec 1; Authors: Quinn RA, Phelan VV, Whiteson KL, Garg N, Bailey BA, Lim YW, Conrad DJ, Dorrestein PC, Rohwer FL Abstract Cystic fibrosis (CF) lungs are filled with thick mucus that obstructs airways and facilitates chronic infections. Pseudomonas aeruginosa is a significant pathogen of this disease that produces a variety of toxic small molecules. We used molecular networking-based metabolomics to investigate the chemistry of CF sputa and assess how the microbial molecules detected reflect the microbiome and clinical culture history of the patients. Metabolites detected included xenobiotics, P. aeruginosa specialized metabolites and host sphingolipids. The clinical culture and microbiome profiles did not correspond to the detection of P. aeruginosa metabolites in the same samples. The P. aeruginosa molecules that were detected in sputum did not match those from laboratory cultures. The pseudomonas quinolone signal (PQS) was readily detectable from cultured strains, but absent from sputum, even when its precursor molecules were present. The lack of PQS production in vivo is potentially due to the chemical nature of the CF lung environment, indicating that culture-based studies of this pathogen may not explain its behavior in the lung. The most differentially abundant molecules between CF and non-CF sputum were sphingolipids, including sphingomyelins, ceramides and lactosylceramide. As these highly abundant molecules contain the inflammatory mediator ceramide, they may have a significant role in CF hyperinflammation. This study demonstrates that the chemical makeup of CF sputum is a complex milieu of microbial, host and xenobiotic molecules. Detection of a bacterium by clinical culturing and 16S rRNA gene profiling do not necessarily reflect the active production of metabolites from that bacterium in a sputum sample. PMID: 26623545 [PubMed - as supplied by publisher]

Related Articles Metabolomic analysis of riboswitch containing E. coli recombinant expression system. Mol Biosyst. 2015 Dec 1; Authors: Muhamadali H, Xu Y, Morra R, Trivedi DK, Rattray NJ, Dixon N, Goodacre R Abstract In this study we have employed metabolomics approaches to understand the metabolic effects of producing enhanced green fluorescent protein (eGFP) as a recombinant protein in Escherichia coli cells. This metabolic burden analysis was performed against a number of recombinant expression systems and control strains and included: (i) standard transcriptional recombinant expression control system BL21(DE3) with the expression plasmid pET-eGFP, (ii) the recently developed dual transcriptional-translational recombinant expression control strain BL21(IL3), with pET-eGFP, (iii) BL21(DE3) with an empty expression plasmid pET, (iv) BL21(IL3) with an empty expression plasmid, and (v) BL21(DE3) without an expression plasmid; all strains were cultured under various induction conditions. The growth profiles of all strains together with the results gathered by the analysis of the Fourier transform infrared (FT-IR) spectroscopy data, identified IPTG-dependent induction as the dominant factor hampering cellular growth and metabolism, which was in general agreement with the findings of GC-MS analysis of cell extracts and media samples. In addition, the exposure of host cells to the synthetic inducer ligand, pyrimido[4,5-d] pyrimidine-2,4-diamine (PPDA), of the orthogonal riboswitch containing expression system (BL21(IL3)) did not display any detrimental effects, and its detected levels in all the samples were at similar levels, emphasising the inability of the cells to metabolise PPDA. The overall results obtained in this study suggested that although the BL21(DE3)-EGFP and BL21(IL3)-EGFP strains produced comparable levels of recombinant eGFP, the presence of the orthogonal riboswitch seemed to be moderating the metabolic burden of eGFP production in the cells enabling higher biomass yield, whilst providing a greater level of control over protein expression. PMID: 26621574 [PubMed - as supplied by publisher]

Related Articles System-wide assembly of pathways and modules hierarchically reveal metabolic mechanism of cerebral ischemia. Sci Rep. 2015;5:17068 Authors: Zhu Y, Guo Z, Zhang L, Zhang Y, Chen Y, Nan J, Zhao B, Xiao H, Wang Z, Wang Y Abstract The relationship between cerebral ischemia and metabolic disorders is poorly understood, which is partly due to the lack of comparative fusing data for larger complete systems and to the complexity of metabolic cascade reactions. Based on the fusing maps of comprehensive serum metabolome, fatty acid and amino acid profiling, we identified 35 potential metabolic biomarkers for ischemic stroke. Our analyses revealed 8 significantly altered pathways by MetPA (Metabolomics Pathway Analysis, impact score >0.10) and 15 significantly rewired modules in a complex ischemic network using the Markov clustering (MCL) method; all of these pathways became more homologous as the number of overlapping nodes was increased. We then detected 24 extensive pathways based on the total modular nodes from the network analysis, 12 of which were new discovery pathways. We provided a new perspective from the viewpoint of abnormal metabolites for the overall study of ischemic stroke as well as a new method to simplify the network analysis by selecting the more closely connected edges and nodes to build a module map of stroke. PMID: 26621314 [PubMed - in process]

Related Articles A systematic approach to expound the variations in taxane production under different dissolved oxygen conditions in Taxus chinensis cells. Plant Cell Rep. 2015 Nov 30; Authors: Zhao C, Song G, Fu C, Dong Y, Xu H, Zhang H, Yu LJ Abstract KEY MESSAGE: Our results provide an evidence that the changes in taxane production caused by dissolved oxygen shifts could be associated with the global variations in the cell central carbon metabolism. Taxol is an important taxane synthesized by the Taxus plant. A two-stage culture of Taxus in vitro has been considered as an attractive alternative approach to produce Taxol and its precursors. To investigate the consequences of dissolved oxygen (DO) shifts for cell primary and secondary metabolism, we conducted metabolomic and transcriptomic profiling analyses under low dissolved oxygen (LDO), medium dissolved oxygen (MDO), and high dissolved oxygen (HDO) conditions in a suspension culture of Taxus chinensis cells. Under LDO, the results indicate a significant increase in the production of Taxol and its main precursors by 3.4- to 1.4-fold compared with those under MDO and HDO on 9th day. Multiple acyl taxanes (MAT) are abundant taxanes in the cells, and exhibited only a slight increase under the same conditions. Metabolomic analysis based on 209 primary metabolites indicated that several pathways in central carbon metabolism were involved, including the enhancement of the glycolysis pathway of glucose-6-phosphate to fructose-6-phosphate and pyruvate and the mevalonate pathway of terpene biosynthesis, and decline in the tricarboxylic acid pathway under LDO. These results indicate the mechanism by which related taxanes accumulate through enhancing the supplies of substrates and expression levels of hydroxylases. Excess acetyl-CoA supply induced by high oxygen stress was found to be correlated with high productivity of MAT. Our results provide an evidence that the changes in taxane production caused by DO shifts could be associated with the global variations in the cell central carbon metabolism. PMID: 26620815 [PubMed - as supplied by publisher]

Related Articles (1) H NMR Metabolomics analysis of renal cell carcinoma cells: Effect of VHL inactivation on metabolism. Int J Cancer. 2015 Dec 1; Authors: Cuperlovic-Culf M, Cormier K, Touaibia M, Reyjal J, Robichaud S, Belbraouet M, Turcotte S Abstract Von Hippel-Lindau (VHL) is an onco-suppressor involved in oxygen and energy-dependent promotion of protein ubiquitination and proteosomal degradation. Loss of function mutations of VHL (VHL- cells) result in organ specific cancers with the best studied example in renal cell carcinomas. VHL has a well-established role in deactivation of hypoxia-inducible factor (HIF-1) and in regulation of PI3K/AKT/mTOR activity. Cell culture metabolomics analysis was utilized to determined effect of VHL and HIF-1α or HIF-2α on metabolism of renal cell carcinomas (RCC). RCC cells were stably transfected with VHL or shRNA designed to silence HIF-1α or HIF-2α genes. Obtained metabolic data was analysed qualitatively, searching for overall effects on metabolism as well as quantitatively, using methods developed in our group in order to determine specific metabolic changes. Analysis of the effect of VHL and HIF silencing on cellular metabolic footprints and fingerprints provided information about the metabolic pathways affected by VHL through HIF function as well as independently of HIF. Through correlation network analysis as well as statistical analysis of significant metabolic changes we have determined effects of VHL and HIF on energy production, amino acid metabolism, choline metabolism as well as cell regulation and signaling. VHL was shown to influence cellular metabolism through its effect on HIF proteins as well as by affecting activity of other factors. This article is protected by copyright. All rights reserved. PMID: 26620126 [PubMed - as supplied by publisher]

Related Articles Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics of Immunosuppressants in Allogeneic Hematopoietic Cell Transplantation: Part II. Clin Pharmacokinet. 2015 Nov 30; Authors: McCune JS, Bemer MJ, Long-Boyle J Abstract Part I of this article included a pertinent review of allogeneic hematopoietic cell transplantation (alloHCT), the role of postgraft immunosuppression in alloHCT, and the pharmacokinetics, pharmacodynamics, and pharmacogenomics of the calcineurin inhibitors and methotrexate. In this article (Part II), we review the pharmacokinetics, pharmacodynamics, and pharmacogenomics of mycophenolic acid (MPA), sirolimus, and the antithymocyte globulins (ATG). We then discuss target concentration intervention (TCI) of these postgraft immunosuppressants in alloHCT patients, with a focus on current evidence for TCI and on how TCI may improve clinical management in these patients. Currently, TCI using trough concentrations is conducted for sirolimus in alloHCT patients. Several studies demonstrate that MPA plasma exposure is associated with clinical outcomes, with an increasing number of alloHCT patients needing TCI of MPA. Compared with MPA, there are fewer pharmacokinetic/dynamic studies of rabbit ATG and horse ATG in alloHCT patients. Future pharmacokinetic/dynamic research of postgraft immunosuppressants should include '-omics'-based tools: pharmacogenomics may be used to gain an improved understanding of the covariates influencing pharmacokinetics as well as proteomics and metabolomics as novel methods to elucidate pharmacodynamic responses. PMID: 26620047 [PubMed - as supplied by publisher]

Related Articles Molecular Aspects of Conifer Zygotic and Somatic Embryo Development: A Review of Genome-Wide Approaches and Recent Insights. Methods Mol Biol. 2016;1359:167-207 Authors: Trontin JF, Klimaszewska K, Morel A, Hargreaves C, Lelu-Walter MA Abstract Genome-wide profiling (transcriptomics, proteomics, metabolomics) is providing unprecedented opportunities to unravel the complexity of coordinated gene expression during embryo development in trees, especially conifer species harboring "giga-genome." This knowledge should be critical for the efficient delivery of improved varieties through seeds and/or somatic embryos in fluctuating markets and to cope with climate change. We reviewed "omics" as well as targeted gene expression studies during both somatic and zygotic embryo development in conifers and tentatively puzzled over the critical processes and genes involved at the specific developmental and transition stages. Current limitations to the interpretation of these large datasets are going to be lifted through the ongoing development of comprehensive genome resources in conifers. Nevertheless omics already confirmed that master regulators (e.g., transcription and epigenetic factors) play central roles. As in model angiosperms, the molecular regulation from early to late embryogenesis may mainly arise from spatiotemporal modulation of auxin-, gibberellin-, and abscisic acid-mediated responses. Omics also showed the potential for the development of tools to assess the progress of embryo development or to build genotype-independent, predictive models of embryogenesis-specific characteristics. PMID: 26619863 [PubMed - in process]

The first protocol of stable isotope ratio assessment in tumor tissues based on original research. Pol J Pathol. 2015;66(3):288-295 Authors: Taran K, Frączek T, Kamiński R, Sitkiewicz A, Kobos J, Paneth P Abstract Thanks to proteomics and metabolomics, for the past several years there has been a real explosion of information on the biology of cancer, which has been achieved by spectroscopic methods, including mass spectrometry. These modern techniques can provide answers to key questions about tissue structure and mechanisms of its pathological changes. However, despite the thousands of spectroscopic studies in medicine, there is no consensus on issues ranging from the choice of research tools, acquisition and preparation of test material to the interpretation and validation of the results, which greatly reduces the possibility of transforming the achieved knowledge to progress in the treatment of individual patients. The aim of this study was to verify the utility of isotope ratio mass spectrometry in the evaluation of tumor tissues. Based on experimentation on animal tissues and human neoplasms, the first protocol of stable isotope ratio assessment of carbon and nitrogen isotopes in tumor tissues was established. PMID: 26619108 [PubMed - as supplied by publisher]

The essential role of coumarin secretion for Fe acquisition from alkaline soil. Plant Signal Behav. 2015 Nov 30;:0 Authors: Clemens S, Weber M Abstract Plant productivity is limited by the scarcity of the essential micronutrient iron particularly in alkaline soils. The root secretion of phenolics has long been recognized as a component of the acidification-reduction strategy to acquire iron (strategy I). However, very little molecular insight into this process was available until recently several research groups independently discovered the important role of coumarins for the growth of Arabidopsis thaliana under Fe-limited conditions. Genome-wide analyses of iron deficiency responses, mutant screening and metabolomics experiments all converged on the finding that the synthesis and root exudation of scopoletin, esculetin and other coumarins is essential for iron uptake from substrates with low iron availability. Here we describe the evidence supporting this conclusion and discuss important questions that now have to be addressed in order to better understand the mechanistic basis of coumarin-dependent iron uptake and its significance within the plant kingdom. PMID: 26618918 [PubMed - as supplied by publisher]