PubMed

Related Articles Multi-level glyco-engineering techniques to generate IgG with defined Fc-glycans. Sci Rep. 2016 Nov 22;6:36964 Authors: Dekkers G, Plomp R, Koeleman CA, Visser R, von Horsten HH, Sandig V, Rispens T, Wuhrer M, Vidarsson G Abstract Immunoglobulin G (IgG) mediates its immune functions through complement and cellular IgG-Fc receptors (FcγR). IgG contains an evolutionary conserved N-linked glycan at position Asn297 in the Fc-domain. This glycan consists of variable levels of fucose, galactose, sialic acid, and bisecting N-acetylglucosamine (bisection). Of these variations, the lack of fucose strongly enhances binding to the human FcγRIII, a finding which is currently used to improve the efficacy of therapeutic monoclonal antibodies. The influence of the other glycan traits is largely unknown, mostly due to lack of glyco-engineering tools. We describe general methods to produce recombinant proteins of any desired glycoform in eukaryotic cells. Decoy substrates were used to decrease the level of fucosylation or galactosylation, glycosyltransferases were transiently overexpressed to enhance bisection, galactosylation and sialylation and in vitro sialylation was applied for enhanced sialylation. Combination of these techniques enable to systematically explore the biological effect of these glycosylation traits for IgG and other glycoproteins. PMID: 27872474 [PubMed - in process]

Related Articles Molecular details on gilthead sea bream (Sparus aurata) sensitivity to low water temperatures from (1)H NMR metabolomics. Comp Biochem Physiol A Mol Integr Physiol. 2016 Nov 18;: Authors: Melis R, Sanna R, Braca A, Bonaglini E, Cappuccinelli R, Slawski H, Roggio T, Uzzau S, Anedda R Abstract Biometric and metabolic responses of gilthead sea bream to cold challenge are described following a growth trial divided into three water temperature steps, namely cooling, cold maintenance and recovery. Experimental data provide a useful description of fish response to thermal stress at both zootechnical and molecular level. Although no mortality has been observed, Nuclear Magnetic Resonance-based metabolomics confirms the marked sensitivity of this fish species to low water temperature, and explains some key molecular events associated to fish response to cold. Increase in hepatosomatic index is associated to liver fat accumulation, as a consequence of lipid mobilization from muscle and other extrahepatic tissues, and metabolic rearrangements linked to homeoviscous adaptation of cellular membranes are observed. Following primary responses to descending temperature from 18°C to 11°C, the energetic metabolism (insulin signaling, glycolysis) is first clearly affected; then, at constant low water temperature (11°C), the most perturbed metabolic pathways are related to methionine cycle in liver, while osmoregulatory function is exerted by TMAO in muscle. Water temperature recovery from 11°C to 18°C stimulates gluconeogenesis and glycogen synthesis activities at hepatic level, although the rate of a thermo-compensatory response seems to be slower than that of the cooling phase. The obtained results are intended to guide novel high-performance feed formulations for gilthead sea bream reared during winter. PMID: 27872009 [PubMed - as supplied by publisher]

Related Articles Pso p27, a SERPINB3/B4-derived protein, is most likely a common autoantigen in chronic inflammatory diseases. Clin Immunol. 2016 Nov 15;: Authors: Iversen OJ, Lysvand H, Slupphaug G Abstract Autoimmune diseases are characterized by chronic inflammatory reactions localized to an organ or organ-system. They are caused by loss of immunologic tolerance toward self-antigens, causing formation of autoantibodies that mistakenly attack their own body. Psoriasis is a chronic inflammatory autoimmune skin disease in which the underlying molecular mechanisms remain elusive. In this review, we present evidence accumulated through more than three decades that the serpin-derived protein Pso p27 is an autoantigen in psoriasis and probably also in other chronic inflammatory diseases. Pso p27 is derived from the serpin molecules SERPINB3 and SERPINB4 through non-canonical cleavage by mast cell chymase. In psoriasis, it is exclusively found in skin lesions and not in uninvolved skin. The serpins are cleaved into three fragments that remain associated as a Pso p27 complex with novel immunogenic properties and increased tendency to form large aggregates compared to native SERPINB3/B4. The amount of Pso p27 is directly correlated to disease activity, and through formation of complement activating immune-complexes, Pso p27 contribute to the inflammation in the skin lesions. SERPINB3/B4 are expressed in skin fibroblasts and keratinocytes, but normally absent in mast cells. Overexpression of the serpins may be induced by inflammation and hypoxia, resulting in mast cell uptake via yet unknown mechanisms. Here the generation and subsequent release of Pso p27 aggregates may promote an inflammatory loop that contributes to the chronicity of psoriasis and other autoimmune diseases. PMID: 27871892 [PubMed - as supplied by publisher]

Integrated Proteomics and Metabolomics Suggests Symbiotic Metabolism and Multimodal Regulation in a Fungal-Endobacterial System. Environ Microbiol. 2016 Nov 21;: Authors: Li Z, Yao Q, Dearth SP, Entler MR, Castro Gonzalez HF, Uehling JK, Vilgalys RJ, Hurst GB, Campagna SR, Labbé JL, Pan C Abstract Many plant-associated fungi host endosymbiotic endobacteria with reduced genomes. While endobacteria play important roles in these tri-partite plant-fungal-endobacterial systems, the active physiology of fungal endobacteria has not been characterized extensively by systems biology approaches. Here, we use integrated proteomics and metabolomics to characterize the relationship between the endobacterium Mycoavidus sp. and the root-associated fungus Mortierella elongata. In nitrogen-poor media, M. elongata had decreased growth but hosted a large and growing endobacterial population. The active endobacterium likely extracted malate from the fungal host as the primary carbon substrate for energy production and biosynthesis of phospho-sugars, nucleobases, peptidoglycan, and some amino acids. The endobacterium obtained nitrogen by importing a variety of nitrogen-containing compounds. Further, nitrogen limitation significantly perturbed the carbon and nitrogen flows in the fungal metabolic network. M. elongata regulated many pathways by concordant changes on enzyme abundances, post-translational modifications, reactant concentrations, and allosteric effectors. Such multimodal regulations may be a general mechanism for metabolic modulation. This article is protected by copyright. All rights reserved. PMID: 27871150 [PubMed - as supplied by publisher]

Metabolic response of Agrobacterium tumefaciens 5A to arsenite. Environ Microbiol. 2016 Nov 21;: Authors: Tokmina-Lukaszewska M, Shi Z, Tripet B, McDermott TR, Copié V, Bothner B, Wang G Abstract Wide-spread abundance in soil and water, coupled with high toxicity have put arsenic at the top of the list of environmental contaminants. Early studies demonstrated that both concentration and the valence state of inorganic arsenic (arsenite, As(III) vs. arsenate As(V)) can be modulated by microbes. Using genetics, transcriptomic and proteomic techniques, microbe-arsenic detoxification, respiratory As(V) reduction, and As(III) oxidation have since been examined. The effect of arsenic exposure on whole-cell intracellular microbial metabolism, however, has not been extensively studied. We combined LC-MS and (1) H NMR to quantify metabolic changes in Agrobacterium tumefaciens (strain 5A) upon exposure to sub-lethal concentrations of As(III). Metabolomics analysis reveals global differences in metabolite concentrations between control and As(III) exposure groups, with significant perturbations to intermediates shuttling into and cycling within the TCA cycle. These data are most consistent with the disruption of two key TCA cycle enzymes, pyruvate dehydrogenase and α-ketoglutarate dehydrogenase. Glycolysis also appeared altered following As(III) stress, with carbon accumulating as complex saccharides. These observations suggest that an important consequence of As(III) contamination in nature will be to alter microbial carbon metabolism at the microbial community level and thus has the potential to foundationally impact all biogeochemical cycles in the environment. This article is protected by copyright. All rights reserved. PMID: 27871140 [PubMed - as supplied by publisher]

A novel amino acid and metabolomics signature in mice overexpressing muscle uncoupling protein 3. FASEB J. 2016 Nov 10;: Authors: Aguer C, Piccolo BD, Fiehn O, Adams SH, Harper ME Abstract Uncoupling protein 3 (UCP3) is highly selectively expressed in skeletal muscle and is known to lower mitochondrial reactive oxygen species and promote fatty acid oxidation; however, the global impact of UCP3 activity on skeletal muscle and whole-body metabolism have not been extensively studied. We utilized untargeted metabolomics to identify novel metabolites that distinguish mice overexpressing UCP3 in muscle, both at rest and after exercise regimens that challenged muscle metabolism, to potentially unmask subtle phenotypes. Male wild-type (WT) and muscle-specific UCP3-overexpressing transgenic (UCP3 Tg) C57BL/6J mice were compared with or without a 5 wk endurance training protocol at rest or after an acute exercise bout (EB). Skeletal muscle, liver, and plasma samples were analyzed by gas chromatography time-of-flight mass spectrometry. Discriminant metabolites were considered if within the top 99th percentile of variable importance measurements obtained from partial least-squares discriminant analysis models. A total of 80 metabolites accurately discriminated UCP3 Tg mice from WT when modeled within a specific exercise condition (i.e., untrained/rested, endurance trained/rested, untrained/EB, and endurance trained/EB). Results revealed that several amino acids and amino acid derivatives in skeletal muscle and plasma of UCP3 Tg mice (e.g., Asp, Glu, Lys, Tyr, Ser, Met) were significantly reduced after an EB; that metabolites associated with skeletal muscle glutathione/Met/Cys metabolism (2-hydroxybutanoic acid, oxoproline, Gly, and Glu) were altered in UCP3 Tg mice across all training and exercise conditions; and that muscle metabolite indices of dehydrogenase activity were increased in UCP3 Tg mice, suggestive of a shift in tissue NADH/NAD(+) ratio. The results indicate that mitochondrial UCP3 activity affects metabolism well beyond fatty acid oxidation, regulating biochemical pathways associated with amino acid metabolism and redox status. That select metabolites were altered in liver of UCP3 Tg mice highlights that changes in muscle UCP3 activity can also affect other organ systems, presumably through changes in systemic metabolite trafficking.-Aguer, C., Piccolo, B. D., Fiehn, O., Adams, S. H., Harper, M.-E. A novel amino acid and metabolomics signature in mice overexpressing muscle uncoupling protein 3. PMID: 27871066 [PubMed - as supplied by publisher]

Supporting metabolomics with adaptable software: design architectures for the end-user. Curr Opin Biotechnol. 2016 Nov 18;43:110-117 Authors: Sarpe V, Schriemer DC Abstract Large and disparate sets of LC-MS data are generated by modern metabolomics profiling initiatives, and while useful software tools are available to annotate and quantify compounds, the field requires continued software development in order to sustain methodological innovation. Advances in software development practices allow for a new paradigm in tool development for metabolomics, where increasingly the end-user can develop or redeploy utilities ranging from simple algorithms to complex workflows. Resources that provide an organized framework for development are described and illustrated with LC-MS processing packages that have leveraged their design tools. Full access to these resources depends in part on coding experience, but the emergence of workflow builders and pluggable frameworks strongly reduces the skill level required. Developers in the metabolomics community are encouraged to use these resources and design content for uptake and reuse. PMID: 27870998 [PubMed - as supplied by publisher]

Metabolomics, a Powerful Tool for Agricultural Research. Int J Mol Sci. 2016 Nov 17;17(11): Authors: Tian H, Lam SM, Shui G Abstract Metabolomics, which is based mainly on nuclear magnetic resonance (NMR), gas-chromatography (GC) or liquid-chromatography (LC) coupled to mass spectrometry (MS) analytical technologies to systematically acquire the qualitative and quantitative information of low-molecular-mass endogenous metabolites, provides a direct snapshot of the physiological condition in biological samples. As complements to transcriptomics and proteomics, it has played pivotal roles in agricultural and food science research. In this review, we discuss the capacities of NMR, GC/LC-MS in the acquisition of plant metabolome, and address the potential promise and diverse applications of metabolomics, particularly lipidomics, to investigate the responses of Arabidopsis thaliana, a primary plant model for agricultural research, to environmental stressors including heat, freezing, drought, and salinity. PMID: 27869667 [PubMed - in process]

Insight into the metabolic mechanism of scoparone on biomarkers for inhibiting Yanghuang syndrome. Sci Rep. 2016 Nov 21;6:37519 Authors: Fang H, Zhang A, Yu J, Wang L, Liu C, Zhou X, Sun H, Song Q, Wang X Abstract Scoparone (6,7-dimethoxycoumarin) is the representative ingredient of Yinchenhao (Artemisia capillaris Thunb.) which is a famous Chinese medicinal herb and shows favorable efficacy for all kinds of liver disease, specifically for the treatment of Yanghuang syndrome (YHS). The precise molecular mechanism concerning the action of scoparone on YHS is yet to be fully elucidated. The aim of the present study was to determine the mechanism of scoparone and evaluate its efficacy on metabolite levels. The differential expression of metabolites responsible for the pharmacological effects of scoparone was characterized and the protection effect of scoparone against this disease. Using multivariate statistical analysis, 33 biomarkers were identified using precise MS/MS and play an important role in the regulation of key metabolic pathways associated with liver disease. In addition, pathological results also showed consistent changes in the YHS model group and after treatment with scoparone, both the metabolic profile and histopathology resembled that of normal level, which suggesting favorable efficacy over the observed time period. The present work indicated that a metabolomics platform provided a new insight into understanding the mechanisms of action of natural medicines such as scoparone. PMID: 27869223 [PubMed - in process]

Related Articles A Comparison of Molecular Biology Mechanism of Shewanella putrefaciens between Fresh and Terrestrial Sewage Wastewater. Front Bioeng Biotechnol. 2016;4:86 Authors: Xu J, He W, Wang Z, Zhang D, Sun J, Zhou J, Li Y, Su X Abstract Municipal and industrial wastewater is often discharged into the environment without appropriate treatment, especially in developing countries. As a result, many rivers and oceans are contaminated. It is urgent to control and administer treatments to these contaminated rivers and oceans. However, most mechanisms of bacterial colonization in contaminated rivers and oceans were unknown, especially in sewage outlets. We found Shewanella putrefaciens to be the primary bacteria in the terrestrial sewage wastewater outlets around Ningbo City, China. Therefore, in this study, we applied a combination of differential proteomics, metabolomics, and real-time fluorescent quantitative PCR techniques to identify bacteria intracellular metabolites. We found S. putrefaciens had 12 different proteins differentially expressed in freshwater culture than when grown in wastewater, referring to the formation of biological membranes (Omp35, OmpW), energy metabolism (SOD, deoxyribose-phosphate pyrophosphokinase), fatty acid metabolism (beta-ketoacyl synthase), secondary metabolism, TCA cycle, lysine degradation (2-oxoglutarate reductase), and propionic acid metabolism (succinyl coenzyme A synthetase). The sequences of these 12 differentially expressed proteins were aligned with sequences downloaded from NCBI. There are also 27 differentially concentrated metabolites detected by NMR, including alcohols (ethanol, isopropanol), amines (dimethylamine, ethanolamine), amino acids (alanine, leucine), amine compounds (bilinerurine), nucleic acid compounds (nucleosides, inosines), and organic acids (formate, acetate). Formate and ethanolamine show significant difference between the two environments and are possibly involved in energy metabolism, glycerophospholipid and ether lipids metabolism to provide energy supply, and material basis for engraftment in sewage. Because understanding S. putrefaciens's biological mechanism of colonization (protein, gene express, and metabolites) in terrestrial sewage outlets is so important to administering and improving contaminated river and to predicting and steering performance, we delved into the biological mechanism that sheds light on the effect of environmental conditions on metabolic pathways. PMID: 27867934 [PubMed - in process]

Related Articles Combined (13)C-assisted metabolomics and metabolic flux analysis reveals the impacts of glutamate on the central metabolism of high β-galactosidase-producing Pichia pastoris. Bioresour Bioprocess. 2016;3(1):47 Authors: Liu P, Huang M, Guo M, Qian J, Lin W, Chu J, Zhuang Y, Zhang S Abstract BACKGROUND: Pichia pastoris is a popular recombinant protein expression system for its accessibility of efficient gene manipulation and high protein production. Sufficient supply of precursors, energy, and redox cofactors is crucial for high recombinant protein production. In our present work, we found that the addition of glutamate improved the recombinant β-galactosidase (β-gal) production by P. pastoris G1HL. METHODS: To elucidate the impacts of glutamate on the central metabolism in detail, a combined (13)C-assisted metabolomics and (13)C metabolic flux analysis was conducted based on LC-MS/MS and GC-MS data. RESULTS: The pool sizes of intracellular amino acids were obviously higher on glucose/glutamate (Glc/Glu). The fluxes in EMP entry reaction and in downstream TCA cycle were 50 and 67% higher on Glc/Glu than on Glc, respectively. While the fluxes in upstream TCA cycle kept almost unaltered, the fluxes in PPP oxidative branch decreased. CONCLUSION: The addition of glutamate leads to a remarkable change on the central metabolism of high β-galactosidase-producing P. pastoris G1HL. To meet the increased demands of redox cofactors and energy for higher β-galactosidase production on Glc/Glu, P. pastoris G1HL redistributes the fluxes in central metabolism through the inhibitions and/or activation of the enzymes in key nodes together with the energy and redox status. PMID: 27867835 [PubMed - in process]

Related Articles ClassyFire: automated chemical classification with a comprehensive, computable taxonomy. J Cheminform. 2016;8:61 Authors: Djoumbou Feunang Y, Eisner R, Knox C, Chepelev L, Hastings J, Owen G, Fahy E, Steinbeck C, Subramanian S, Bolton E, Greiner R, Wishart DS Abstract BACKGROUND: Scientists have long been driven by the desire to describe, organize, classify, and compare objects using taxonomies and/or ontologies. In contrast to biology, geology, and many other scientific disciplines, the world of chemistry still lacks a standardized chemical ontology or taxonomy. Several attempts at chemical classification have been made; but they have mostly been limited to either manual, or semi-automated proof-of-principle applications. This is regrettable as comprehensive chemical classification and description tools could not only improve our understanding of chemistry but also improve the linkage between chemistry and many other fields. For instance, the chemical classification of a compound could help predict its metabolic fate in humans, its druggability or potential hazards associated with it, among others. However, the sheer number (tens of millions of compounds) and complexity of chemical structures is such that any manual classification effort would prove to be near impossible. RESULTS: We have developed a comprehensive, flexible, and computable, purely structure-based chemical taxonomy (ChemOnt), along with a computer program (ClassyFire) that uses only chemical structures and structural features to automatically assign all known chemical compounds to a taxonomy consisting of >4800 different categories. This new chemical taxonomy consists of up to 11 different levels (Kingdom, SuperClass, Class, SubClass, etc.) with each of the categories defined by unambiguous, computable structural rules. Furthermore each category is named using a consensus-based nomenclature and described (in English) based on the characteristic common structural properties of the compounds it contains. The ClassyFire webserver is freely accessible at http://classyfire.wishartlab.com/. Moreover, a Ruby API version is available at https://bitbucket.org/wishartlab/classyfire_api, which provides programmatic access to the ClassyFire server and database. ClassyFire has been used to annotate over 77 million compounds and has already been integrated into other software packages to automatically generate textual descriptions for, and/or infer biological properties of over 100,000 compounds. Additional examples and applications are provided in this paper. CONCLUSION: ClassyFire, in combination with ChemOnt (ClassyFire's comprehensive chemical taxonomy), now allows chemists and cheminformaticians to perform large-scale, rapid and automated chemical classification. Moreover, a freely accessible API allows easy access to more than 77 million "ClassyFire" classified compounds. The results can be used to help annotate well studied, as well as lesser-known compounds. In addition, these chemical classifications can be used as input for data integration, and many other cheminformatics-related tasks. PMID: 27867422 [PubMed - in process]

Related Articles Draft Genome Sequence of Mentha longifolia (L.) and Development of Resources for Mint Cultivar Improvement. Mol Plant. 2016 Nov 17;: Authors: Vining KJ, Johnson SR, Ahkami A, Lange I, Parrish AN, Trapp SC, Croteau RB, Straub SC, Pandelova I, Lange BM Abstract The genus Mentha encompasses species cultivated for their essential oils, which are formulated into a vast array of consumer products. Desirable oil characteristics and resistance to the fungal disease Verticillium wilt are top priorities for the mint industry. However, cultivated mints have complex polyploid genomes and are sterile. Breeding efforts, therefore, require the development of genomic resources for fertile mint species. Here, we present draft de novo genome and plastome assemblies for a wilt-resistant South African accession of Mentha longifolia (L.) Huds., a diploid species ancestral to cultivated peppermint and spearmint. The 353 Mb contained 35,597 predicted protein-coding genes, including 292 disease resistance gene homologs, and nine genes determining essential oil characteristics. A genetic linkage map ordered 1,397 genome scaffolds on 12 pseudochromosomes. Over two million simple sequence repeats were identified, which will aid molecular marker development. The M. longifolia genome is a valuable resource for both metabolic engineering and molecular breeding. This is exemplified by employing the genome sequence to clone and functionally characterize promoters in a peppermint cultivar, and demonstrating the utility of a glandular trichome-specific promoter to increase expression of a biosynthetic gene, thereby modulating essential oil composition. PMID: 27867107 [PubMed - as supplied by publisher]

Related Articles Inhibition of the Glycolytic Activator PFKFB3 in Endothelium Induces Tumor Vessel Normalization, Impairs Metastasis, and Improves Chemotherapy. Cancer Cell. 2016 Nov 8;: Authors: Cantelmo AR, Conradi LC, Brajic A, Goveia J, Kalucka J, Pircher A, Chaturvedi P, Hol J, Thienpont B, Teuwen LA, Schoors S, Boeckx B, Vriens J, Kuchnio A, Veys K, Cruys B, Finotto L, Treps L, Stav-Noraas TE, Bifari F, Stapor P, Decimo I, Kampen K, De Bock K, Haraldsen G, Schoonjans L, Rabelink T, Eelen G, Ghesquière B, Rehman J, Lambrechts D, Malik AB, Dewerchin M, Carmeliet P Abstract Abnormal tumor vessels promote metastasis and impair chemotherapy. Hence, tumor vessel normalization (TVN) is emerging as an anti-cancer treatment. Here, we show that tumor endothelial cells (ECs) have a hyper-glycolytic metabolism, shunting intermediates to nucleotide synthesis. EC haplo-deficiency or blockade of the glycolytic activator PFKFB3 did not affect tumor growth, but reduced cancer cell invasion, intravasation, and metastasis by normalizing tumor vessels, which improved vessel maturation and perfusion. Mechanistically, PFKFB3 inhibition tightened the vascular barrier by reducing VE-cadherin endocytosis in ECs, and rendering pericytes more quiescent and adhesive (via upregulation of N-cadherin) through glycolysis reduction; it also lowered the expression of cancer cell adhesion molecules in ECs by decreasing NF-κB signaling. PFKFB3-blockade treatment also improved chemotherapy of primary and metastatic tumors. PMID: 27866851 [PubMed - as supplied by publisher]

Related Articles Untargeted serum metabolomics reveals Fu-Zhu-Jiang-Tang tablet and its optimal combination improve an impaired glucose and lipid metabolism in type II diabetic rats. J Chromatogr B Analyt Technol Biomed Life Sci. 2016 Nov 13;: Authors: Tao Y, Chen X, Cai H, Li W, Cai B, Chai C, Di L, Shi L, Hu L Abstract Fu-Zhu-Jiang-Tang tablet, a six-herb preparation, was proved to show beneficial effects on type II diabetes patients in clinical. This study aims to optimize the component proportion of the six-herb preparation and explore the serum metabolic signatures of type II diabetes rats after treatment with Fu-Zhu-Jiang-Tang tablet and its optimal combination. The component proportion of the preparation was optimized using uniform experimental design and machine learning techniques. Untargeted GC-MS metabolomic experiments were carried out with serum samples from model group and treatment groups. Data were normalized, multivariate and univariate statistical analysis performed and metabolites of interest putatively identified. 23 metabolites were significantly changed by Fu-Zhu-Jiang-Tang tablet treatment and the majority of these were decreased, including various carbohydrates (glucose, mannose, fructose, allose and gluconic acid), unsaturated fatty acids (palmitic acid, 9-octadecenoic acid, oleic acid, arachidonic acid), alanine, valine, propanoic acid, 3-hydroxybutyrate, along with pyrimidine and cholesterol. Increased concentrations of oxalic acid, leucine, glycine, serine, threonine, proline, lysine and citrate were observed. In the optimal combination-fed group, 21 metabolites were significantly affected and strikingly, the magnitudes of changes here were generally much greater than that of Fu-Zhu-Jiang-Tang tablet treated rats. 18 metabolites affected in both groups included various carbohydrates (mannose, glucose, allose, fructose and gluconic acid), unsaturated fatty acids (palmitic acid, 9-octadecenoic acid, oleic acid and arachidonic acid), short-chain fatty acids (oxalic acid, 3-hydroxybutyrate), and amino acids (alanine, valine, leucine, glycine, proline and lysine), as well as pyrimidine. Metabolites exclusively affected in optimal combination treated rat included succinic acid, cysteine and phenylalanine, whilst four metabolites (propanoic acid, citrate, serine and threonine) were only altered in Fu-Zhu-Jiang-Tang tablet treated rat. Our investigation demonstrated Fu-Zhu-Jiang-Tang tablet and its optimal combination treatments were able to ameliorate impaired glucose and lipid metabolism, down- regulate the high level of glucose to a lower level and reverse abnormal levels of metabolites in serum of type II diabetes rats. However, the optimal combination treatment was able to maximize the magnitudes of changes in some metabolites. These findings may be helpful in clarifying the anti-diabetic mechanism of FZJT tablet and its optimal combination. PMID: 27866845 [PubMed - as supplied by publisher]

Related Articles Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity. Cell Metab. 2016 Nov 16;: Authors: Arts RJ, Novakovic B, Ter Horst R, Carvalho A, Bekkering S, Lachmandas E, Rodrigues F, Silvestre R, Cheng SC, Wang SY, Habibi E, Gonçalves LG, Mesquita I, Cunha C, van Laarhoven A, van de Veerdonk FL, Williams DL, van der Meer JW, Logie C, O'Neill LA, Dinarello CA, Riksen NP, van Crevel R, Clish C, Notebaart RA, Joosten LA, Stunnenberg HG, Xavier RJ, Netea MG Abstract Induction of trained immunity (innate immune memory) is mediated by activation of immune and metabolic pathways that result in epigenetic rewiring of cellular functional programs. Through network-level integration of transcriptomics and metabolomics data, we identify glycolysis, glutaminolysis, and the cholesterol synthesis pathway as indispensable for the induction of trained immunity by β-glucan in monocytes. Accumulation of fumarate, due to glutamine replenishment of the TCA cycle, integrates immune and metabolic circuits to induce monocyte epigenetic reprogramming by inhibiting KDM5 histone demethylases. Furthermore, fumarate itself induced an epigenetic program similar to β-glucan-induced trained immunity. In line with this, inhibition of glutaminolysis and cholesterol synthesis in mice reduced the induction of trained immunity by β-glucan. Identification of the metabolic pathways leading to induction of trained immunity contributes to our understanding of innate immune memory and opens new therapeutic avenues. PMID: 27866838 [PubMed - as supplied by publisher]

Related Articles TP53 and 53BP1 Reunited. Trends Cell Biol. 2016 Nov 17;: Authors: Soussi T, Kroemer G Abstract Identified as a TP53-binding protein, 53BP1 is a key regulator of the cellular response to double-strand breaks, a TP53-independent activity. Recent data have established a new TP53-dependent function for 53BP1 in mitotic surveillance after centrosome loss. PMID: 27866833 [PubMed - as supplied by publisher]

Related Articles Metabolomics evaluation of the in vivo toxicity of bromoacetonitriles: One class of high-risk nitrogenous disinfection byproducts. Sci Total Environ. 2016 Nov 17;: Authors: Deng Y, Zhang Y, Lu Y, Lu K, Bai H, Ren H Abstract Bromoacetonitriles (BANs), one class of nitrogenous disinfection byproducts (N-DBPs), have frequently been detected in drinking water. The cytotoxicity and genotoxicity of BANs have been demonstrated in mammalian cells. However, a systematic study of the in vivo toxicity of BANs is rare. In this study, metabolomics combined with histopathology and oxidative stress analysis were used to evaluate the toxicity of BANs in mice. The results indicated that BAN exposure induced liver and kidney injury in mice. Furthermore, the superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities decreased, and the level of malonaldehyde (MDA) increased in mice livers due to BANs exposure, which indicated that hepatic oxidative stress was induced. These toxicities increased with an increasing number of bromine at the α carbon. In addition, BAN exposure disrupted the metabolic pathways of amino acid, energy and lipid metabolism in mice. Our results provide evidence for the comprehensive omics endpoints of the in vivo toxicity of BANs. PMID: 27866740 [PubMed - as supplied by publisher]

Related Articles Dysregulated fatty acid metabolism in coronary ectasia: An extended lipidomic analysis. Int J Cardiol. 2016 Nov 11;228:303-308 Authors: Boles U, Pinto RC, David S, Abdullah AS, Henein MY Abstract BACKGROUND: Coronary artery ectasia (CAE) is not an uncommon clinical condition, which could be associated with adverse outcome. The exact pathophysiology of the disease is poorly understood and is commonly interpreted as a variant of atherosclerosis. In this study, we sought to undertake lipidomic profiling of a group of CAE patients in an attempt to achieve better understanding of its disturbed metabolism. METHODS: Untargeted lipid profiling and complementary modelling strategies were employed to compare serum samples from 16 patients with CAE (mean age 63.5±10.1years, 6 female) and 26 controls with normal smooth coronary arteries (mean age 59.2±6.6years and 7 female). Sample preparation, LC-MS analysis and metabolite identification were performed at the Swedish Metabolomics Centre, Umeå, Sweden. RESULTS: Phosphatidylcholine levels were significantly distorted in the CAE patients (p=0.001-0.04). Specifically, 16-carbon fatty acyl chain phosphatidylcholines (PC) were detected in lower levels. Similarly, 11 meioties of Sphyngomyelin (SM) species were detected at lower concentrations (p=0.000001-0.01) in the same group. However, only three metabolites were significantly higher in the pure CAE subgroup (6 patients) when compared with the 10 mixed CAE patients (two meioties of SM species and one of PC). Atherosclerosis risk factors were not different between groups. CONCLUSION: This is the first lipid profiling study reported in coronary artery ectasia. While the lower concentration and dysregulation of sphyngomyelin suggests an evidence for premature apoptosis, that of phosphatidylcholines suggests perturbed fatty acid elongation/desaturation, thus may be indicative of non-atherogenic process in CAE. PMID: 27866019 [PubMed - as supplied by publisher]

Related Articles Role for Human arylamine N-acetyltransferase 1 in the methionine salvage pathway. Biochem Pharmacol. 2016 Nov 16;: Authors: Witham KL, Minchin RF, Butcher NJ Abstract The Phase II drug metabolizing enzyme arylamine N-acetyltransferase 1 (NAT1) has been implicated in the growth and survival of cancer cells, although the mechanisms that underlies these effects are unknown. Here, a focused metabolomics approach was used to identify changes in folate catabolism as well as the S-adenosylmethionine (SAM) cycle following NAT1 knockdown with shRNA. Although acetylation of the folate catabolite p-aminobenzoylglutamate (pABG) was significantly decreased, there were no changes in intracellular pABG or the various components of the SAM cycle. By contrast, the flux of homocysteine in the medium was different following NAT1 knockdown after the methionine content was exhausted suggesting a need for this metabolite in methionine synthesis. Analysis of the growth of various cancer cells in methylthioadenosine-supplemented medium showed that NAT1 knockdown inhibited the methionine salvage pathway in HT-29 cells but not in HeLa or MDA-MB-436 cells. The cause of this was a low level of expression of the isomerase MRI-1 in the HT-29 cells. Knocking down both NAT1 and MRI-1 in HeLa cells with siRNA further demonstrated a redundancy between these 2 enzymes, although direct isomerase activity by NAT1 could not be demonstrated. The present study has identified a novel endogenous role for human NAT1 that might explain some of its effects in cancer cell growth and survival. PMID: 27865712 [PubMed - as supplied by publisher]