PubMed

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]

Related Articles Proteomics and comparative genomics of Nitrososphaera viennensis reveal the core genome and adaptations of archaeal ammonia oxidizers. Proc Natl Acad Sci U S A. 2016 Nov 18;: Authors: Kerou M, Offre P, Valledor L, Abby SS, Melcher M, Nagler M, Weckwerth W, Schleper C Abstract Ammonia-oxidizing archaea (AOA) are among the most abundant microorganisms and key players in the global nitrogen and carbon cycles. They share a common energy metabolism but represent a heterogeneous group with respect to their environmental distribution and adaptions, growth requirements, and genome contents. We report here the genome and proteome of Nitrososphaera viennensis EN76, the type species of the archaeal class Nitrososphaeria of the phylum Thaumarchaeota encompassing all known AOA. N. viennensis is a soil organism with a 2.52-Mb genome and 3,123 predicted protein-coding genes. Proteomic analysis revealed that nearly 50% of the predicted genes were translated under standard laboratory growth conditions. Comparison with genomes of closely related species of the predominantly terrestrial Nitrososphaerales as well as the more streamlined marine Nitrosopumilales [Candidatus (Ca.) order] and the acidophile "Ca. Nitrosotalea devanaterra" revealed a core genome of AOA comprising 860 genes, which allowed for the reconstruction of central metabolic pathways common to all known AOA and expressed in the N. viennensis and "Ca Nitrosopelagicus brevis" proteomes. Concomitantly, we were able to identify candidate proteins for as yet unidentified crucial steps in central metabolisms. In addition to unraveling aspects of core AOA metabolism, we identified specific metabolic innovations associated with the Nitrososphaerales mediating growth and survival in the soil milieu, including the capacity for biofilm formation, cell surface modifications and cell adhesion, and carbohydrate conversions as well as detoxification of aromatic compounds and drugs. PMID: 27864514 [PubMed - as supplied by publisher]

Related Articles Metabolites profiling reveals for antimicrobial compositional differences and action mechanism in the toothbrushing stick "miswak" Salvadora persica. J Pharm Biomed Anal. 2016 Nov 11;: Authors: Farag MA, Fahmy S, Choucry MA, Wahdan MO, Elsebai MF Abstract Among many plant species suitable for preparing toothbrushing sticks, miswak (Salvadora persica, family Salvadoraceae) is found the most effective tool for oral hygiene. S. persica possesses antibacterial, antiviral and antifungal effects against oral microbes, mostly due to its benzyl isothiocyanate content. To provide insight into S. persica chemical composition, volatile constituents from roots and stems of S. persica grown in Egypt and Saudi Arabia were profiled using solid-phase microextraction (SPME) coupled to gas chromatography-mass spectrometry (GC-MS). A total of 21 volatiles were identified with sulfur compounds amounting for the major volatile class. Orthogonal projection to latent structures-discriminant analysis (OPLS-DA) revealed for benzyl isothiocyanate (BITC) enrichment in roots versus stems. Primary metabolites contributing to S. persica taste viz. sugars and organic acids were profiled using GC-MS with silylation. Polyols (sugars) viz. arabitol, meso-erythritol, and mannitol were found to predominate sugars composition in S. persica stems being most enriched in meso-erythritol. The impact of saliva on S. persica aroma profile was further assessed and revealing for no enhancement in BITC production with salivation, and further not being detected in toothpaste preparation claimed to contain S. persica extract. This study provides the most complete profile of volatiles, sugars, and organic acids in S. persica organs and more rationalizing its use as a toothbrush. PMID: 27863835 [PubMed - as supplied by publisher]

Related Articles Chromatographic determination of some biomarkers of liver cirrhosis and hepatocellular carcinoma in Egyptian patients. Biomed Chromatogr. 2016 Nov 10;: Authors: Osman D, Ali O, Obada M, El-Mezayen H, El-Said H Abstract Metabolomics has been shown to be an effective tool for disease diagnosis, biomarker screening and characterization of biological pathways. A total of 140 subjects were included in this study; urine metabolomes of patients with liver cirrhosis (LC, n = 40), patients with HCC (n = 55) and healthy male subjects (n = 45); as control group, were studied. Gas chromatography/mass spectrometry based urine metabolomics profile was investigated for all participants. Diagnostic models were constructed with a combination of marker metabolites, using principal components analysis (PCA) and receiver operator characteristic curves. A total of 57 peaks could be auto-identified of which 13 marker metabolites (glycine, serine, threonine, proline, urea, phosphate, pyrimidine, arabinose, xylitol, hippuric acid, citric acid, xylonic acid, and glycerol) were responsible for the separation of HCC group from healthy subjects. Also, 8 markers metabolites (glycine, serine, threonine, proline, citric acid, urea, xylitol and arabinose) showed significant difference between LC group and healthy subjects. No significant difference was detected between HCC and LC groups regarding all these metabolites. Metabolomic profile using GC-MS established an optimized diagnostic model to discriminate between HCC patients and healthy subjects; also it could be useful for diagnosis of LC patients. However, it failed to differentiate between HCC and LC patients. PMID: 27862090 [PubMed - as supplied by publisher]

Related Articles Rule-Mining for the Early Prediction of Chronic Kidney Disease Based on Metabolomics and Multi-Source Data. PLoS One. 2016;11(11):e0166905 Authors: Luck M, Bertho G, Bateson M, Karras A, Yartseva A, Thervet E, Damon C, Pallet N Abstract 1H Nuclear Magnetic Resonance (NMR)-based metabolic profiling is very promising for the diagnostic of the stages of chronic kidney disease (CKD). Because of the high dimension of NMR spectra datasets and the complex mixture of metabolites in biological samples, the identification of discriminant biomarkers of a disease is challenging. None of the widely used chemometric methods in NMR metabolomics performs a local exhaustive exploration of the data. We developed a descriptive and easily understandable approach that searches for discriminant local phenomena using an original exhaustive rule-mining algorithm in order to predict two groups of patients: 1) patients having low to mild CKD stages with no renal failure and 2) patients having moderate to established CKD stages with renal failure. Our predictive algorithm explores the m-dimensional variable space to capture the local overdensities of the two groups of patients under the form of easily interpretable rules. Afterwards, a L2-penalized logistic regression on the discriminant rules was used to build predictive models of the CKD stages. We explored a complex multi-source dataset that included the clinical, demographic, clinical chemistry, renal pathology and urine metabolomic data of a cohort of 110 patients. Given this multi-source dataset and the complex nature of metabolomic data, we analyzed 1- and 2-dimensional rules in order to integrate the information carried by the interactions between the variables. The results indicated that our local algorithm is a valuable analytical method for the precise characterization of multivariate CKD stage profiles and as efficient as the classical global model using chi2 variable section with an approximately 70% of good classification level. The resulting predictive models predominantly identify urinary metabolites (such as 3-hydroxyisovalerate, carnitine, citrate, dimethylsulfone, creatinine and N-methylnicotinamide) as relevant variables indicating that CKD significantly affects the urinary metabolome. In addition, the simple knowledge of the concentration of urinary metabolites classifies the CKD stage of the patients correctly. PMID: 27861591 [PubMed - in process]

Related Articles Homozygous variants in pyrroline-5-carboxylate reductase 2 (PYCR2) in patients with progressive microcephaly and hypomyelinating leukodystrophy. Am J Med Genet A. 2016 Nov 11;: Authors: Meng L, Donti T, Xia F, Niu Z, Al Shamsi A, Hertecant J, Al-Jasmi F, Gibson JB, Nagakura H, Zhang J, He W, Eng C, Yang Y, Elsea SH Abstract Pyrroline-5-carboxylate reductase 2, encoded by PYCR2, is one of the three homologous enzymes that catalyze the last step of proline synthesis. Homozygous variants in PYCR2 have been reported in patients from multiple consanguineous families with hypomyelinating leukodystrophy 10 (HLD10) (MIM: 616420). Here, we report five additional patients from three families with homozygous nonsense or missense variants in PYCR2, identified through clinical exome sequencing. All patients presented with postnatally acquired microcephaly, moderate to profound global developmental delay, and failure to thrive. Brain MRI in these patients showed thin corpus callosum, delayed myelination, and generalized white-matter volume loss. Additional phenotypes that were less consistent among patients included seizures or seizure-like movements, spasticity and ataxic gait, recurrent vomiting, cortical blindness, dysmorphic features, joint contractures, and irritability. Exome sequencing identified homozygous variants in PYCR2 in the proband from each family: c.28C>T (p.(Glu10Ter)), c.796C>T (p.(Arg266Ter)), and c.577G>A (p.(Val193Met)). Subsequent targeted analyses demonstrated co-segregation of the disease with the variant in the family. Despite the metabolic role of PYCR2, routine serum metabolic test in these patients were normal. To further understand the disease etiology and functions of PYCR2, small molecule metabolomics profiling was performed in plasma from three severely affected patients. No significant changes were identified in proline biosynthesis pathway or related metabolites. Studying the clinical features and the metabolic profiles of the PYCR2-deficient patients provides a more comprehensive picture for this newly identified disorder and facilitates further research on the gene function and disease etiology. © 2016 Wiley Periodicals, Inc. PMID: 27860360 [PubMed - as supplied by publisher]

Related Articles Mediterranean diet-gene interactions: a targeted metabolomics study in Greek-Cypriot women. Mol Nutr Food Res. 2016 Nov 18;: Authors: Kakkoura MG, Sokratous K, Demetriou CA, Loizidou MA, Loucaides G, Kakouri E, Hadjisavvas A, Kyriacou K Abstract SCOPE: A high adherence to the Mediterranean diet (MD) was previously associated with a decreased risk of breast cancer (BC) among Greek-Cypriot women. Additionally, particular polymorphisms were shown to modulate this MD-BC association. Herein, we aimed to investigate the effect of polymorphisms-MD interactions on the levels of specific metabolites that could be related to dietary adherence or enzymatic activity, which is itself modulated by polymorphisms. METHODS AND RESULTS: Greek-Cypriot women who were BC controls and had the lowest or the highest MD adherence (vegetables, fruit, legumes, fish) as assessed by principal component analysis (n = 564) were included. Participants were previously genotyped for 9 polymorphisms of the one-carbon metabolism, oxidative stress and xenobiotic metabolism. The serum levels of 14 metabolites that are key players in the aforementioned pathways were measured by UPLC-MS/MS. ANCOVA was used to assess polymorphism-MD interactions on metabolites' levels within a multivariate linear regression model. Statistically significant interactions between GSTM1 deletion polymorphism and MD on flavin mononucleotide (FMN) and on 5-methyltetrahydrofolate (5-MTHF) concentrations were observed. The MTHFR rs1801133 interacted significantly with MD on 5-MTHF concentration. CONCLUSION: Serum levels of FMN and 5-MTHF were shown to be influenced by interactions between GSTM1 deletion or MTHFR (rs1801133) polymorphisms and a dietary pattern, characteristic of MD. This article is protected by copyright. All rights reserved. PMID: 27860207 [PubMed - as supplied by publisher]

Related Articles Peptidome characterization of the antipyretic fraction of Bubali Cornu aqueous extract by nano liquid chromatography with orbitrap mass spectrum detection. J Sep Sci. 2016 Nov 9;: Authors: Liu R, Huang Q, Duan JA, Zhu Z, Liu P, Bian Y, Tao J, Qian D Abstract In the present study, the antipyretic activity of Bubali Cornu (water buffalo horn) fraction and its metabolomics were investigated. The fraction decreased rat rectal temperature, and 13 endogenous metabolites were identified as potential biomarkers. Selected metabolites were involved in arachidonic acid metabolism and glycerophospholipid metabolism etc. Following treatment with the fraction, four metabolites, pyroglutamic acid, palmitelaidic acid, leukotriene A4, and prostaglandin A2 were reversed. In addition, the levels of interleukin-1β, tumor necrosis factor-α, prostaglandin E2 , and cyclic adenosine monophosphate in plasma were also reversed after treatment as determined by enzyme linked immunosorbent assay. Furthermore, nano-flow liquid chromatography with orbitrap mass spectrometry detection was used to analyze the peptides in the fraction. In total, 824 peptide sequences mainly from keratins were determined, with Keratin 14, Keratin 34, and Keratin 86 representing the three main types of keratin hydrolysis in water buffalo horn based on peptide heat maps. Of the identified peptides, 81.2% were hydrophilic and the molecular weight of 70.3% of identified peptides was lower than 2000 Da. According to the metabolomics- and peptidomics-based approach used in the present study, it is feasible to identify and analyze the active peptide matrix from animal-horn-derived traditional Chinese medicines. This article is protected by copyright. All rights reserved. PMID: 27860201 [PubMed - as supplied by publisher]

Related Articles Metabolite profiling of whole murine embryos reveals metabolic perturbations associated with maternal valproate-induced neural tube closure defects. Birth Defects Res A Clin Mol Teratol. 2016 Nov 18;: Authors: Akimova D, Wlodarczyk BJ, Lin Y, Ross ME, Finnell RH, Chen Q, Gross SS Abstract BACKGROUND: Valproic acid (VPA) is prescribed therapeutically for multiple conditions, including epilepsy. When taken during pregnancy, VPA is teratogenic, increasing the risk of several birth and developmental defects including neural tube defects (NTDs). The mechanism by which VPA causes NTDs remains controversial and how VPA interacts with folic acid (FA), a vitamin commonly recommended for the prevention of NTDs, remains uncertain. We sought to address both questions by applying untargeted metabolite profiling analysis to neural tube closure (NTC) stage mouse embryos. METHODS: Pregnant SWV dams on either a 2 ppm or 10 ppm FA supplemented diet were injected with a single dose of VPA on gestational day E8.5. On day E9.5, the mouse embryos were collected and evaluated for NTC status. Liquid chromatography coupled to mass spectrometry metabolomics analysis was performed to compare metabolite profiles of NTD-affected VPA-exposed whole mouse embryos with profiles from embryos that underwent normal NTC from control dams. RESULTS: NTDs were observed in all embryos from VPA-treated dams and penetrance was not diminished by dietary FA supplementation. The most profound metabolic perturbations were found in the 10ppm FA VPA-exposed mouse embryos, compared with the other three treatment groups. Affected metabolites included amino acids, nucleobases and related phosphorylated nucleotides, lipids, and carnitines. CONCLUSION: Maternal VPA treatment markedly perturbed purine and pyrimidine metabolism in E9.5 embryos. In combination with a high FA diet, VPA treatment resulted in gross metabolic changes, likely caused by a multiplicity of mechanisms, including an apparent disruption of mitochondrial beta-oxidation. Birth Defects Research (Part A), 2016. © 2016 Wiley Periodicals, Inc. PMID: 27860192 [PubMed - as supplied by publisher]

Related Articles Quantitative Method to Investigate the Balance between Metabolism and Proteome Biomass: Starting from Glycine. Angew Chem Int Ed Engl. 2016 Nov 15;: Authors: Gu H, Carroll PA, Du J, Zhu J, Neto FC, Eisenman RN, Raftery D Abstract The balance between metabolism and biomass is very important in biological systems; however, to date there has been no quantitative method to characterize the balance. In this methodological study, we propose to use the distribution of amino acids in different domains to investigate this balance. It is well known that endogenous or exogenous amino acids in a biological system are either metabolized or incorporated into free amino acids (FAAs) or proteome amino acids (PAAs). Using glycine (Gly) as an example, we demonstrate a novel method to accurately determine the amounts of amino acids in various domains using serum, urine, and cell samples. As expected, serum and urine had very different distributions of FAA- and PAA-Gly. Using Tet21N human neuroblastoma cells, we also found that Myc(oncogene)-induced metabolic reprogramming included a higher rate of metabolizing Gly, which provides additional evidence that the metabolism of proliferating cells is adapted to facilitate producing new cells. It is therefore anticipated that our method will be very valuable for further studies of the metabolism and biomass balance that will lead to a better understanding of human cancers. PMID: 27860107 [PubMed - as supplied by publisher]

Related Articles Metabolic characterization of the early stage of hepatic fibrosis in rat using GC-TOF/MS and multivariate data analyses. Biomed Chromatogr. 2016 Nov 17;: Authors: Jiang H, Song JM, Gao PF, Qin XJ, Xu SZ, Zhang JF Abstract The aim of this study was to explore the changes in the urine metabolic spectrum in rats with the early stage of liver fibrosis using gas chromatography-time of flight/mass spectrometry (GC-TOF/MS), try to search for potential biomarkers and elucidate the probably metabonomic pathogenesis. The early stage of liver fibrosis was established with a single subcutaneously injection carbon tetrachloride (CCl4 ) twice each week for 4 weeks continuously. At the end of the experiment, GC-TOF/MS technology with multivariate statistical approaches such as principal component analysis (PCA), partial least squares-discriminant analysis (PLS-DA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) was used to analyze the changes in the metabolic spectrum trajectory and identify potential biomarkers. The results showed that twelve potential biomarkers in the model group such as succinic acid, threonine, lactose and so on were selected, which indicate that the metabonomic pathogenesis of the early stage of liver fibrosis may be related to disorders of energy metabolism, amino acid metabolism, fatty acid metabolism. PMID: 27859443 [PubMed - as supplied by publisher]