PubMed

Related Articles Multi-level systems biology modeling characterized the atheroprotective efficiencies of modified dairy fats in a hamster model. Am J Physiol Heart Circ Physiol. 2015 Jun 12;:ajpheart.00032.2015 Authors: Martin JC, Berton A, Ginies C, Bott R, Scheercousse P, Saddi A, Gripois D, Landrier JF, Dalemans D, Alessi MC, Delplanque B Abstract We assessed the atheroprotective efficiency of modified dairy fats in hyperlipidemic hamsters. A systems biology approach was implemented to reveal and quantify the dietary fat-related components of the disease. Three modified dairy fats (40% energy) were prepared from regular butter by mixing with a plant oil mixture, by removing cholesterol alone or by removing cholesterol in combination with reducing saturated fatty acids. A plant oil mixture with regular butter was used as the control diet. The atherosclerosis severity (aortic cholesteryl-ester level) was higher in the regular butter-fed hamsters than in the other four groups (P < 0.05). Eighty-seven of the 1666 variables measured from multi-platform analysis were found to be strongly associated with the disease. When aggregated into 10 biological clusters combined into a multivariate predictive equation, these 87 variables explained 81% of the disease variability. The biological cluster "regulation of lipid transport and metabolism" appeared central to atherogenic development relative to diets. The "vitamin E metabolism" cluster was the main driver of atheroprotection with the best performing transformed dairy fat. Under conditions that promote atherosclerosis, the impact of dairy fats on atherogenesis could be greatly ameliorated by technological modifications. Our modeling approach allowed for identifying and quantifying the contribution of complex factors to atherogenic development in each dietary setup. PMID: 26071539 [PubMed - as supplied by publisher]

Related Articles Phenolic amides are potent inhibitors of de novo nucleotide biosynthesis. Appl Environ Microbiol. 2015 Jun 12; Authors: Pisithkul T, Jacobson TB, O'Brien TJ, Stevenson DM, Amador-Noguez D Abstract An outstanding challenge towards efficient production of biofuels and value-added chemicals from plant biomass is the impact that lignocellulose-derived inhibitors have on microbial fermentations. Elucidating the mechanisms that underlie their toxicity is critical for developing strategies to overcome them. Here, using E. coli as a model system, we investigated the metabolic effects and toxicity mechanisms of feruloyl and coumaroyl amide, the predominant phenolic compounds in ammonia-pretreated biomass hydrolysates. Using metabolomics, isotope tracers, and biochemical assays, we show that these two phenolic amides act as potent and fast-acting inhibitors of purine and pyrimidine biosynthetic pathways. Feruloyl or coumaroyl amide exposure leads to: 1) rapid buildup of 5-phosphoribosylpyrophosphate (PRPP), a key precursor in nucleotide biosynthesis; 2) rapid decrease in the levels of pyrimidine biosynthetic intermediates; and 3) long-term generalized decrease in nucleotide and deoxynucleotide levels. Tracer experiments using (13)C-sugars and (15)N-ammonia demonstrated that carbon and nitrogen flux into nucleotides and deoxynucleotides are inhibited by these phenolic amides. We found that these effects are mediated via direct inhibition of glutamine amidotransferases that participate in nucleotide biosynthetic pathways. In particular, feruloyl amide is a competitive inhibitor of glutamine PRPP amidotransferase (PurF), which catalyzes the first committed step in de novo purine biosynthesis. Finally, external nucleoside supplementation prevents phenolic amide-mediated growth inhibition by allowing nucleotide biosynthesis via salvage pathways. The results presented here will help develop strategies to overcome toxicity of phenolic compounds and facilitate engineering of more efficient microbial producers of biofuels and chemicals. PMID: 26070680 [PubMed - as supplied by publisher]

Related Articles Compartmentation of metabolism of the C12-, C9-, and C5-n-dicarboxylates in rat liver, investigated by mass isotopomer analysis: Anaplerosis from dodecanedioate. J Biol Chem. 2015 Jun 12; Authors: Jin Z, Bian F, Tomcik K, Kelleher JK, Zhang GF, Brunengraber H Abstract We investigated the compartmentation of the catabolism of dodecanedioate (DODA), azelate and glutarate in perfused rat livers, using a combination of metabolomics and mass isotopomer analyses. Livers were perfused with recirculating or nonrecirculating buffer containing one fully (13)C-labeled dicarboxylate. Information on the peroxisomal vs mitochondrial catabolism was gathered from the labeling patterns of acetyl-CoA proxies, i.e., total acetyl-CoA, the acetyl moiety of citrate, C-1+2 of β-hydroxybutyrate, malonyl-CoA and acetylcarnitine. Additional information was obtained from the labeling patterns of citric acid cycle intermediates and related compounds. The data characterize the partial oxidation of DODA and azelate in peroxisomes, with terminal oxidation in mitochondria. We did not find evidence of peroxisomal oxidation of glutarate. Unexpectedly, DODA contributes a substantial fraction to anaplerosis of the citric acid cycle. This opens the possibility to use water-soluble DODA in nutritional or pharmacological anaplerotic therapy when other anaplerotic substrates are impractical or contraindicated, e.g., in propionic acidemia and methylmalonic acidemia. PMID: 26070565 [PubMed - as supplied by publisher]

17 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 2015/06/13PubMed comprises more than 24 million 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.

Related Articles p53 attenuates AKT signaling by modulating membrane phospholipid composition. Oncotarget. 2015 Jun 3; Authors: Rueda-Rincon N, Bloch K, Derua R, Vyas R, Harms A, Hankemeier T, Khan NA, Dehairs J, Bagadi M, Binda MM, Waelkens E, Marine JC, Swinnen JV Abstract The p53 tumor suppressor is the central component of a complex network of signaling pathways that protect organisms against the propagation of cells carrying oncogenic mutations. Here we report a previously unrecognized role of p53 in membrane phospholipids composition. By repressing the expression of stearoyl-CoA desaturase 1, SCD, the enzyme that converts saturated to mono-unsaturated fatty acids, p53 causes a shift in the content of phospholipids with mono-unsaturated acyl chains towards more saturated phospholipid species, particularly of the phosphatidylinositol headgroup class. This shift affects levels of phosphatidylinositol phosphates, attenuates the oncogenic AKT pathway, and contributes to the p53-mediated control of cell survival. These findings expand the p53 network to phospholipid metabolism and uncover a new molecular pathway connecting p53 to AKT signaling. PMID: 26061814 [PubMed - as supplied by publisher]

Related Articles Pyrimidine Metabolism: Dynamic and Versatile Pathways in Pathogens and Cellular Development. J Genet Genomics. 2015 May 20;42(5):195-205 Authors: Garavito MF, Narváez-Ortiz HY, Zimmermann BH Abstract The importance of pyrimidines lies in the fact that they are structural components of a broad spectrum of key molecules that participate in diverse cellular functions, such as synthesis of DNA, RNA, lipids, and carbohydrates. Pyrimidine metabolism encompasses all enzymes involved in the synthesis, degradation, salvage, interconversion and transport of these molecules. In this review, we summarize recent publications that document how pyrimidine metabolism changes under a variety of conditions, including, when possible, those studies based on techniques of genomics, transcriptomics, proteomics, and metabolomics. First, we briefly look at the dynamics of pyrimidine metabolism during nonpathogenic cellular events. We then focus on changes that pathogen infections cause in the pyrimidine metabolism of their host. Next, we discuss the effects of antimetabolites and inhibitors, and finally we consider the consequences of genetic manipulations, such as knock-downs, knock-outs, and knock-ins, of pyrimidine enzymes on pyrimidine metabolism in the cell. PMID: 26059768 [PubMed - as supplied by publisher]

Related Articles Determination of the in vivo NAD/NADH ratio in S. cerevisiae under anaerobic conditions using alcohol dehydrogenase as sensor reaction. Yeast. 2015 Jun 9; Authors: Bekers KM, Heijnen JJ, van Gulik WM Abstract With the current quantitative metabolomics techniques only whole cell concentrations of NAD and NADH can be quantified. These measurements cannot provide information on the in vivo redox state of the cells, which is determined by the ratio of the free forms only. In this work we quantified the free NAD/NADH ratio in yeast under anaerobic conditions using alcohol dehydrogenase (ADH) and the lumped reaction of glyceraldehyde-3-phosphate dehydrogenase and 3-phosphoglycerate kinase as sensor reactions. We show that with an alternative accurate acetaldehyde determination method, based on rapid sampling, instantaneous derivatization with 2,4 diaminophenol hydrazine (DNPH) and quantification with HPLC, the ADH catalyzed oxidation of ethanol to acetaldehyde can be applied as a relatively fast and simple sensor reaction to quantify the free NAD/NADH ratio under anaerobic conditions. We evaluated the applicability of ADH as a sensor reaction in the yeast Saccharomyces cerevisiae grown in anaerobic glucose limited chemostats during steady state and dynamic conditions. The results found in this study show that the cytosolic redox status (NAD/NADH ratio) of yeast is at least one order of magnitude lower, and thus much more reduced, under anaerobic conditions compared to aerobic glucose-limited steady state conditions. The more reduced state of the cytosol under anaerobic conditions has major implications for (central) metabolism. Accurate determination of the free NAD/NADH ratio is therefore of importance for the unravelling of in vivo enzyme kinetics and to judge accurately the thermodynamic reversibility of each redox reaction. PMID: 26059529 [PubMed - as supplied by publisher]

Related Articles Meta-analysis of organ-specific differences in the structure of the immune infiltrate in major malignancies. Oncotarget. 2015 May 20;6(14):11894-909 Authors: Stoll G, Bindea G, Mlecnik B, Galon J, Zitvogel L, Kroemer G Abstract Anticancer immunosurveillance is one of the major endogenous breaks of tumor progression. Here, we analyzed gene expression pattern indicative of the presence of distinct leukocyte subtypes within four cancer types (breast cancer, colorectal carcinoma, melanoma, and non-small cell lung cancer) and 20 different microarray datasets corresponding to a total of 3471 patients. Multiple metagenes reflecting the presence of such immune cell subtypes were highly reproducible across distinct cohorts. Nonetheless, there were sizable differences in the correlation patterns among such immune-relevant metagenes across distinct malignancies. The reproducibility of the correlations among immune-relevant metagenes was highest in breast cancer (followed by colorectal cancer, non-small cell lung cancer and melanoma), reflecting the fact that mammary carcinoma has an intrinsically better prognosis than the three other malignancies. Among breast cancer patients, we found that the expression of a lysosomal enzyme-related metagene centered around ASAH1 (which codes for N-acylsphingosine amidohydrolase-1, also called acid ceramidase) exhibited a higher correlation with multiple immune-relevant metagenes in patients that responded to neoadjuvant chemotherapy than in non-responders. Altogether, this meta-analysis revealed novel organ-specific features of the immune infiltrate in distinct cancer types, as well as a strategy for defining new prognostic biomarkers. PMID: 26059437 [PubMed - in process]

Related Articles The Use of 'Omics Technology to Rationally Improve Industrial Mammalian Cell Line Performance. Biotechnol Bioeng. 2015 Jun 9; Authors: Lewis AM, Abu-Absi NR, Borys MC, Li ZJ Abstract Biologics represent an increasingly important class of therapeutics, with 7 of the 10 top selling drugs from 2013 being in this class. Furthermore, health authority approval of biologics in the immuno-oncology space is expected to transform treatment of patients with debilitating and deadly diseases. The growing importance of biologics in the healthcare field has also resulted in the recent approvals of several biosimilars. These recent developments, combined with pressure to provide treatments at lower costs to payers, are resulting in increasing need for the industry to quickly and efficiently develop high yielding, robust processes for the manufacture of biologics with the ability to control quality attributes within narrow distributions. Achieving this level of manufacturing efficiency and the ability to design processes capable of regulating growth, death and other cellular pathways through manipulation of media, feeding strategies and other process parameters will undoubtedly be facilitated through systems biology tools generated in academic and public research communities. Here we discuss the intersection of systems biology, 'Omics technologies, and mammalian bioprocess sciences. Specifically, we address how these methods in conjunction with traditional monitoring techniques represent a unique opportunity to better characterize and understand host cell culture state, shift from an empirical to rational approach to process development and optimization of bioreactor cultivation processes. We summarize six key areas: 1) research applied to parental, non-recombinant cell lines, 2) systems level datasets generated with recombinant cell lines, 3) datasets linking phenotypic traits to relevant biomarkers, 4) data depositories and bioinformatics tools, 5) in silico model development, and 6) examples where these approaches have been used to rationally improve cellular processes. We critically assess relevant and state of the art research being conducted in academic, government and industrial laboratories. Furthermore, we apply our expertise in bioprocess to define a potential model for integration of these systems biology approaches into biologics development. This article is protected by copyright. All rights reserved. PMID: 26059229 [PubMed - as supplied by publisher]

Related Articles Combinatorial chemistry in nematodes: modular assembly of primary metabolism-derived building blocks. Nat Prod Rep. 2015 Jun 10; Authors: von Reuss SH, Schroeder FC Abstract Covering: up to 2015The nematode Caenorhabditis elegans was the first animal to have its genome fully sequenced and has become an important model organism for biomedical research. However, like many other animal model systems, its metabolome remained largely uncharacterized, until recent investigations demonstrated the importance of small molecule-based signalling cascades for virtually every aspect of nematode biology. These studies have revealed that nematodes are amazingly skilled chemists: using simple building blocks from conserved primary metabolism and a strategy of modular assembly, C. elegans and other nematode species create complex molecular architectures to regulate their development and behaviour. These nematode-derived modular metabolites (NDMMs) are based on the dideoxysugars ascarylose or paratose, which serve as scaffolds for attachment of moieties from lipid, amino acid, carbohydrate, citrate, and nucleoside metabolism. Mutant screens and comparative metabolomics based on NMR spectroscopy and MS have so-far revealed several 100 different ascarylose ("ascarosides") and a few paratose ("paratosides") derivatives, many of which represent potent signalling molecules that can be active at femtomolar levels, regulating development, behaviour, body shape, and many other life history traits. NDMM biosynthesis appears to be carefully regulated as assembly of different modules proceeds with very high specificity. Preliminary biosynthetic studies have confirmed the primary metabolism origin of some NDMM building blocks, whereas the mechanisms that underlie their highly specific assembly are not understood. Considering their functions and biosynthetic origin, NDMMs represent a new class of natural products that cannot easily be classified as "primary" or "secondary". We believe that the identification of new variants of primary metabolism-derived structures that serve important signalling functions in C. elegans and other nematodes provides a strong incentive for a comprehensive re-analysis of metabolism in higher animals, including humans. PMID: 26059053 [PubMed - as supplied by publisher]

Related Articles Crosstalk between branched chain amino acids and hepatic mitochondria is compromised in nonalcoholic fatty liver disease. Am J Physiol Endocrinol Metab. 2015 Jun 9;:ajpendo.00161.2015 Authors: Sunny NE, Kalavalapalli S, Bril F, Garrett TJ, Nautiyal M, Mathew JT, Williams CM, Cusi K Abstract Elevated plasma branched chain amino acids (BCAA) in the setting of insulin resistance have been relevant in predicting type 2 diabetes mellitus (T2DM) onset, but their role in the etiology of hepatic insulin resistance remains uncertain. We determined the link between BCAA and dysfunctional hepatic tri-carboxylic acid (TCA) cycle, which is a central feature of hepatic insulin resistance and nonalcoholic fatty liver disease (NAFLD). Plasma metabolites under basal fasting and euglycemic hyperinsulinemic clamps (insulin stimulation) were measured in 94 human subjects with varying degrees of insulin sensitivity, to identify their relationships with insulin resistance. Further, the impact of elevated BCAA on hepatic TCA cycle was determined in a diet induced mouse model of NAFLD, utilizing targeted metabolomics and nuclear magnetic resonance (NMR) based metabolic flux analysis. Insulin stimulation revealed robust relationships between human plasma BCAA and indices of insulin resistance, indicating chronic metabolic overload from BCAA. Human plasma BCAA and long chain acylcarnitines also showed a positive correlation, suggesting modulation of mitochondrial metabolism by BCAA. Concurrently, mice with NAFLD failed to optimally induce hepatic mTORC1, plasma ketones and hepatic long chain acylcarnitines, following acute elevation of plasma BCAA. Furthermore, elevated BCAA failed to induce multiple fluxes through hepatic TCA cycle in mice with NAFLD. Our data suggest that BCAA are essential to mediate efficient channeling of carbon substrates for oxidation through mitochondrial TCA cycle. Impairment of BCAA-mediated up-regulation of TCA cycle could be a significant contributor to mitochondrial dysfunction in NAFLD. PMID: 26058864 [PubMed - as supplied by publisher]

Related Articles Metabolite profiling in plasma and tissues of ob/ob and db/db mice identifies novel markers of obesity and type 2 diabetes. Diabetologia. 2015 Jun 10; Authors: Giesbertz P, Padberg I, Rein D, Ecker J, Höfle AS, Spanier B, Daniel H Abstract AIMS/HYPOTHESIS: Metabolomics approaches in humans have identified around 40 plasma metabolites associated with insulin resistance (IR) and type 2 diabetes, which often coincide with those for obesity. We aimed to separate diabetes-associated from obesity-associated metabolite alterations in plasma and study the impact of metabolically important tissues on plasma metabolite concentrations. METHODS: Two obese mouse models were studied; one exclusively with obesity (ob/ob) and another with type 2 diabetes (db/db). Both models have impaired leptin signalling as a cause for obesity, but the different genetic backgrounds determine the susceptibility to diabetes. In these mice, we profiled plasma, liver, skeletal muscle and adipose tissue via semi-quantitative GC-MS and quantitative liquid chromatography (LC)-MS/MS for a wide range of metabolites. RESULTS: Metabolite profiling identified 24 metabolites specifically associated with diabetes but not with obesity. Among these are known markers such as 1,5-anhydro-D-sorbitol, 3-hydroxybutyrate and the recently reported marker glyoxylate. New metabolites in the diabetic model were lysine, O-phosphotyrosine and branched-chain fatty acids. We also identified 33 metabolites that were similarly altered in both models, represented by branched-chain amino acids (BCAA) as well as glycine, serine, trans-4-hydroxyproline, and various lipid species and derivatives. Correlation analyses showed stronger associations for plasma amino acids with adipose tissue metabolites in db/db mice compared with ob/ob mice, suggesting a prominent contribution of adipose tissue to changes in plasma in a diabetic state. CONCLUSIONS/INTERPRETATION: By studying mice with metabolite signatures that resemble obesity and diabetes in humans, we have found new metabolite entities for validation in appropriate human cohorts and revealed their possible tissue of origin. PMID: 26058503 [PubMed - as supplied by publisher]

Related Articles Glucose and glycerol concentrations and their tracer enrichment measurements using liquid chromatography tandem mass spectrometry. J Mass Spectrom. 2014 Oct;49(10):980-8 Authors: Bornø A, Foged L, van Hall G Abstract The present study describes a new liquid chromatography tandem mass spectrometry method for high-throughput quantification of glucose and glycerol in human plasma using stable isotopically labeled internal standards and is suitable for simultaneous measurements of glucose and glycerol enrichments in connection to in vivo metabolic studies investigating glucose turnover and lipolytic rate. Moreover, in order to keep up with this new fast analysis, simple derivatization procedures have been developed. Prior to analysis, glucose and glycerol were derivatized using benzoyl chloride in order to form benzoylated derivatives via new simplified fast procedures. For glucose, two internal standards were evaluated, [U-(13) C(6)]glucose and [U-(13) C(6), D(7)]glucose, and for glycerol, [U-(13) C(3), D(8)]glycerol was used. The method was validated by means of calibration curves, quality control samples, and plasma samples spiked with [6,6-D(2)]glucose, [U-(13) C(6)]glucose, and [1,1,2,3,3-D(5)]glycerol in order to test accuracy, precision, and recovery of the method. Moreover, post preparative and freeze-thaw sample stability were tested. The correlation of calibration curves for the glucose concentration were r(2) = 0.9998 for [U-(13) C(6)]glucose and r(2) = 0.9996 for [U-(13) C(6), D(7)]glucose, and r(2) = 0.9995 for the glycerol concentration. Interday accuracy for glucose using [U-(13) C(6)]glucose and glycerol determined in spiked plasma were respectively 103.5% and 106.0%, and the coefficients of variation were 2.0% and 9.7%, respectively. After derivatization, plasma samples were stable for at least 14 days. In conclusion, we have developed and validated a novel, accurate, and sensitive high-throughput liquid chromatography tandem mass spectrometry method for simultaneous determination of glucose and glycerol concentrations and enrichment of infused tracers most commonly used in human metabolic kinetic studies. PMID: 25303387 [PubMed - indexed for MEDLINE]

Related Articles Combined mass spectrometry-based metabolite profiling of different pigmented rice (Oryza sativa L.) seeds and correlation with antioxidant activities. Molecules. 2014;19(10):15673-86 Authors: Kim GR, Jung ES, Lee S, Lim SH, Ha SH, Lee CH Abstract Nine varieties of pigmented rice (Oryza sativa L.) seeds that were black, red, or white were used to perform metabolite profiling by using ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF-MS) and gas chromatography (GC) TOF-MS, to measure antioxidant activities. Clear grouping patterns determined by the color of the rice seeds were identified in principle component analysis (PCA) derived from UPLC-Q-TOF-MS. Cyanidin-3-glucoside, peonidin-3-glucoside, proanthocyanidin dimer, proanthocyanidin trimer, apigenin-6-C-glugosyl-8-C-arabiboside, tricin-O-rhamnoside-O-hexoside, and lipids were identified as significantly different secondary metabolites. In PCA score plots derived from GC-TOF-MS, Jakwangdo (JKD) and Ilpoom (IP) species were discriminated from the other rice seeds by PC1 and PC2. Valine, phenylalanine, adenosine, pyruvate, nicotinic acid, succinic acid, maleic acid, malonic acid, gluconic acid, xylose, fructose, glucose, maltose, and myo-inositol were significantly different primary metabolites in JKD species, while GABA, asparagine, xylitol, and sucrose were significantly distributed in IP species. Analysis of antioxidant activities revealed that black and red rice seeds had higher activity than white rice seeds. Cyanidin-3-glucoside, peonidin-3-glucoside, proanthocyanidin dimers, proanthocyanidin trimers, and catechin were highly correlated with antioxidant activities, and were more plentiful in black and red rice seeds. These results are expected to provide valuable information that could help improve and develop rice-breeding techniques. PMID: 25268721 [PubMed - indexed for MEDLINE]

Related Articles Novel genetic associations with serum level metabolites identified by phenotype set enrichment analyses. Hum Mol Genet. 2014 Nov 1;23(21):5847-57 Authors: Ried JS, Shin SY, Krumsiek J, Illig T, Theis FJ, Spector TD, Adamski J, Wichmann HE, Strauch K, Soranzo N, Suhre K, Gieger C Abstract Availability of standardized metabolite panels and genome-wide single-nucleotide polymorphism data endorse the comprehensive analysis of gene-metabolite association. Currently, many studies use genome-wide association analysis to investigate the genetic effects on single metabolites (mGWAS) separately. Such studies have identified several loci that are associated not only with one but with multiple metabolites, facilitated by the fact that metabolite panels often include metabolites of the same or related pathways. Strategies that analyse several phenotypes in a combined way were shown to be able to detect additional genetic loci. One of those methods is the phenotype set enrichment analysis (PSEA) that tests sets of metabolites for enrichment at genes. Here we applied PSEA on two different panels of serum metabolites together with genome-wide data. All analyses were performed as a two-step identification-validation approach, using data from the population-based KORA cohort and the TwinsUK study. In addition to confirming genes that were already known from mGWAS, we were able to identify and validate 12 new genes. Knowledge about gene function was supported by the enriched metabolite sets. For loci with unknown gene functions, the results suggest a function that is interrelated with the metabolites, and hint at the underlying pathways. PMID: 24927737 [PubMed - indexed for MEDLINE]

Related Articles Tuning intracellular homeostasis of human uroporphyrinogen III synthase by enzyme engineering at a single hotspot of congenital erythropoietic porphyria. Hum Mol Genet. 2014 Nov 1;23(21):5805-13 Authors: ben Bdira F, González E, Pluta P, Laín A, Sanz-Parra A, Falcon-Perez JM, Millet O Abstract Congenital erythropoietic porphyria (CEP) results from a deficiency in uroporphyrinogen III synthase enzyme (UROIIIS) activity that ultimately stems from deleterious mutations in the uroS gene. C73 is a hotspot for these mutations and a C73R substitution, which drastically reduces the enzyme activity and stability, is found in almost one-third of all reported CEP cases. Here, we have studied the structural basis, by which mutations in this hotspot lead to UROIIIS destabilization. First, a strong interdependency is observed between the volume of the side chain at position 73 and the folded protein. Moreover, there is a correlation between the in vitro half-life of the mutated proteins and their expression levels in eukaryotic cell lines. Molecular modelling was used to rationalize the results, showing that the mutation site is coupled to the hinge region separating the two domains. Namely, mutations at position 73 modulate the inter-domain closure and ultimately affect protein stability. By incorporating residues capable of interacting with R73 to stabilize the hinge region, catalytic activity was fully restored and a moderate increase in the kinetic stability of the enzyme was observed. These results provide an unprecedented rationale for a destabilizing missense mutation and pave the way for the effective design of molecular chaperones as a therapy against CEP. PMID: 24925316 [PubMed - indexed for MEDLINE]

Related Articles The future of the laboratory information system - what are the requirements for a powerful system for a laboratory data management? Clin Chem Lab Med. 2014 Nov;52(11):e225-30 Authors: Kammergruber R, Robold S, Karliç J, Durner J PMID: 24897404 [PubMed - indexed for MEDLINE]

Metabolism alteration in follicular niche: The nexus between intermediary metabolism, mitochondrial function, and classic polycystic ovary syndrome. Free Radic Biol Med. 2015 Jun 6; Authors: Zhao H, Zhao Y, Li T, Li M, Li J, Li R, Liu P, Yu Y, Qiao J Abstract Classic polycystic ovary syndrome (PCOS) is a high-risk phenotype accompanied by increased risks of reproductive and metabolic abnormalities; however, the local metabolism characteristics of the ovaries and their effects on germ cell development are unclear. The present study used targeted metabolomics to detect alterations in the intermediate metabolites of follicular fluid from classic PCOS patients, and the results indicated hyperandrogenism, but not obesity induced the changed intermediate metabolites in classic PCOS patients. Regarding the direct contact, we identified mitochondrial function, redox potential and oxidative stress in cumulus cells which werenecessary to support oocyte growth before fertilization, and suggested dysfunction of mitochondria, imbalanced redox potential and increased oxidative stress in cumulus cells of classic PCOS patients. Follicular fluid intermediary metabolic profiles provide signatures of classic PCOS ovary local metabolism and establish close link with mitochondria dyfunction of cumulus cells and highlighting the role of metabolic signal and mitochondrial crosstalk involved in the pathogenesis of classic PCOS. PMID: 26057937 [PubMed - as supplied by publisher]

Metabolome strategy against Edwardsiella tarda infection through glucose-enhanced metabolic modulation in tilapias. Fish Shellfish Immunol. 2015 Jun 6; Authors: Peng B, Ma YM, Zhang JY, Li H Abstract Edwardsiella tarda causes fish disease and great economic loss. However, metabolic strategy against the pathogen remains unexplored. In the present study, GC-MS based metabolomics was used to investigate the metabolic profile from tilapias infected by sublethal dose of E. tarda. The metabolic differences between the dying group and survival group allow the identification of key pathways and crucial metabolites during infections. More importantly, those metabolites may modulate the survival-related metabolome to enhance the anti-infective ability. Our data showed that tilapias generated two different strategies, survival-metabolome and death-metabolome, to encounter EIB202 infection, leading to differential outputs of the survival and dying. Glucose was the most crucial biomarker, which was upregulated and downregulated in the survival and dying groups, respectively. Exogenous glucose by injection or oral administration enhanced hosts' ability against EIB202 infection and increased the chances of survival. These findings highlight that host mounts the metabolic strategy to cope with bacterial infection, from which crucial biomarkers may be identified to enhance the metabolic strategy. PMID: 26057462 [PubMed - as supplied by publisher]

Related Articles Tissue lipid metabolism and hepatic metabolomic profiling in response to supplementation of fermented cottonseed meal in the diets of broiler chickens. J Zhejiang Univ Sci B. 2015 Jun;16(6):447-55 Authors: Nie CX, Zhang WJ, Wang YQ, Liu YF, Ge WX, Liu JC Abstract This study investigated the effects of fermented cottonseed meal (FCSM) on lipid metabolites, lipid metabolism-related gene expression in liver tissues and abdominal adipose tissues, and hepatic metabolomic profiling in broiler chickens. One hundred and eighty 21-d-old broiler chickens were randomly divided into three diet groups with six replicates of 10 birds in each group. The three diets consisted of a control diet supplemented with unfermented cottonseed meal, an experimental diet of cottonseed meal fermented by Candida tropicalis, and a second experimental diet of cottonseed meal fermented by C. tropicalis plus Saccharomyces cerevisae. The results showed that FCSM intake significantly decreased the levels of abdominal fat and hepatic triglycerides (P<0.05 for both). Dietary FCSM supplementation down-regulated the mRNA expression of fatty acid synthase and acetyl CoA carboxylase in liver tissues and the lipoprotein lipase expression in abdominal fat tissues (P<0.05 for both). FCSM intake resulted in significant metabolic changes of multiple pathways in the liver involving the tricarboxylic acid cycle, synthesis of fatty acids, and the metabolism of glycerolipid and amino acids. These findings indicated that FCSM regulated lipid metabolism by increasing or decreasing the expression of the lipid-related gene and by altering multiple endogenous metabolites. Lipid metabolism regulation is a complex process, this discovery provided new essential information about the effects of FCSM diets in broiler chickens and demonstrated the great potential of nutrimetabolomics in researching complex nutrients added to animal diets. PMID: 26055906 [PubMed - in process]