PubMed

Related Articles Metabolomic Profiling of Human Urine as a Screen for Multiple Inborn Errors of Metabolism. Genet Test Mol Biomarkers. 2016 Sep;20(9):485-95 Authors: Kennedy AD, Miller MJ, Beebe K, Wulff JE, Evans AM, Miller LA, Sutton VR, Sun Q, Elsea SH Abstract AIMS: We wished to determine the efficacy of using urine as an analyte to screen for a broad range of metabolic products associated with multiple different types of inborn errors of metabolism (IEMs), using an automated mass spectrometry-based assay. Urine was compared with plasma samples from a similar cohort analyzed using the same assay. Specimens were analyzed using two different commonly utilized urine normalization methods based on creatinine and osmolality, respectively. METHODS: Biochemical profiles for each sample (from both affected and unaffected subjects) were obtained using a mass spectrometry-based platform and population-based statistical analyses. RESULTS: We identified over 1200 biochemicals from among 100 clinical urine samples and identified clear biochemical signatures for 16 of 18 IEM diseases tested. The two diseases that did not result in clear signatures, X-linked creatine transporter deficiency and ornithine transcarbamylase deficiency, were from individuals under treatment, which masked biomarker signatures. Overall the process variability and coefficient of variation for isolating and identifying biochemicals by running technical replicates of each urine sample was 10%. CONCLUSIONS: A single urine sample analyzed with our integrated metabolomic platform can identify signatures of IEMs that are traditionally identified using many different assays and multiple sample types. Creatinine and osmolality-normalized data were robust to the detection of the disorders and samples tested here. PMID: 27448163 [PubMed - indexed for MEDLINE]

Related Articles DNA hypomethylation upregulates expression of the MGAT3 gene in HepG2 cells and leads to changes in N-glycosylation of secreted glycoproteins. Sci Rep. 2016 Apr 13;6:24363 Authors: Klasić M, Krištić J, Korać P, Horvat T, Markulin D, Vojta A, Reiding KR, Wuhrer M, Lauc G, Zoldoš V Abstract Changes in N-glycosylation of plasma proteins are observed in many types of cancer, nevertheless, few studies suggest the exact mechanism involved in aberrant protein glycosylation. Here we studied the impact of DNA methylation on the N-glycome in the secretome of the HepG2 cell line derived from hepatocellular carcinoma (HCC). Since the majority of plasma glycoproteins originate from the liver, the HepG2 cells represent a good model for glycosylation changes in HCC that are detectable in blood, which is an easily accessible analytic material in a clinical setting. Two different concentrations of 5-aza-2'-deoxycytidine (5-aza-2dC) differentially affected global genome methylation and induced different glycan changes. Around twenty percent of 84 glyco-genes analysed changed expression level after the 5-aza-2dC treatment as a result of global genome hypomethylation. A correlation study between the changes in glyco-gene expression and the HepG2 glycosylation profile suggests that the MGAT3 gene might be responsible for the glycan changes consistently induced by both doses of 5-aza-2dC. Core-fucosylated tetra-antennary structures were decreased in quantity likely as a result of hypomethylated MGAT3 gene promoter followed by increased expression of this gene. PMID: 27073020 [PubMed - indexed for MEDLINE]

25 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 2017/04/04PubMed comprises more than millions of 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 Metabolomics analysis of anaphylactoid reaction reveals its mechanism in a rat model. Asian Pac J Allergy Immunol. 2017 Apr 01;: Authors: Xu Y, Guo N, Dou D, Ran X, Liu C Abstract BACKGROUND: Anaphylactoid reactions, accounting for more than 77% of all immune-mediated immediate hypersensitivity reactions, have become a serious threat to public health, but their effect mechanism is not clear and diagnostic tests are limited. Comprehensive metabolite analysis may reveal the anaphylactoid effect mechanism systematically and provide reference for future diagnostic purposes. METHODS: Plasma from Brown Norway rats given intravenous injection of saline, compound 48/80 (2.5 mL/kg) or ovalbumin (20 mL/kg) in 20 s for the first time was used to study the effect mechanism of anaphylactoid reactions through metabolomics (UPLC-qTOF-MS/MS). Metabolomics integrated with proteomics data were used to analyze the anaphylactoid pathways by MetaboAnalyst followed by integrated pathway analysis. RESULTS: Thirty metabolites were identified through the METLIN database by MS/MS and 18 of them were confirmed by authentic standards. The results showed that adenosine, histamine, N-acetylhistamine, N(α)-γ-glutamylhistamine, malate and xanthine are important indices for anaphylactoid reactions. It could be concluded that the effect mechanism is mainly composed of histidine metabolism, arachidonic acid metabolism, energy metabolism, purine metabolism and other small molecules through 30 metabolites. Multiple linear regression analysis indicated that not only histamine but also N(α)-γ-glutamylhistamine and arachidonic acid could be used to evaluate anaphylactoid symptoms of animals. Furthermore, the citrate cycle, histidine metabolism and arachidonic acid metabolism could be the main pathways of anaphylactoid reactions as determined by MetaboAnalyst. CONCLUSION: The results may provide a reference to improve diagnostic accuracy and predict and monitor treatment efficacy in anaphylactoid reactions in the clinical setting. PMID: 28364409 [PubMed - as supplied by publisher]

Related Articles Comparison of Ambient and Atmospheric Pressure Ion Sources for Cystic Fibrosis Exhaled Breath Condensate Ion Mobility-Mass Spectrometry Metabolomics. J Am Soc Mass Spectrom. 2017 Mar 31;: Authors: Zang X, Pérez JJ, Jones CM, Monge ME, McCarty NA, Stecenko AA, Fernández FM Abstract Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The vast majority of the mortality is due to progressive lung disease. Targeted and untargeted CF breath metabolomics investigations via exhaled breath condensate (EBC) analyses have the potential to expose metabolic alterations associated with CF pathology and aid in assessing the effectiveness of CF therapies. Here, transmission-mode direct analysis in real time traveling wave ion mobility spectrometry time-of-flight mass spectrometry (TM-DART-TWIMS-TOF MS) was tested as a high-throughput alternative to conventional direct infusion (DI) electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) methods, and a critical comparison of the three ionization methods was conducted. EBC was chosen as the noninvasive surrogate for airway sampling over expectorated sputum as EBC can be collected in all CF subjects regardless of age and lung disease severity. When using pooled EBC collected from a healthy control, ESI detected the most metabolites, APCI a log order less, and TM-DART the least. TM-DART-TWIMS-TOF MS was used to profile metabolites in EBC samples from five healthy controls and four CF patients, finding that a panel of three discriminant EBC metabolites, some of which had been previously detected by other methods, differentiated these two classes with excellent cross-validated accuracy. Graphical Abstract ᅟ. PMID: 28364225 [PubMed - as supplied by publisher]

Related Articles X-Linked Cobalamin Disorder (HCFC1) Mimicking Nonketotic Hyperglycinemia With Increased Both Cerebrospinal Fluid Glycine and Methylmalonic Acid. Pediatr Neurol. 2017 Jan 07;: Authors: Scalais E, Osterheld E, Weitzel C, De Meirleir L, Mataigne F, Martens G, Shaikh TH, Coughlin CR, Yu HC, Swanson M, Friederich MW, Scharer G, Helbling D, Wendt-Andrae J, Van Hove JL Abstract BACKGROUND: Autosomal recessive or X-linked inborn errors of intracellular cobalamin metabolism can lead to methylmalonic aciduria and homocystinuria. In neonates, both increased cerebrospinal fluid glycine and cerebrospinal fluid/plasma glycine ratio are biochemical features of nonketotic hyperglycinemia. METHODS: We describe a boy presenting in the neonatal period with hypotonia, tonic, clonic, and later myoclonic seizures, subsequently evolving into refractory epilepsy and severe neurocognitive impairment. RESULTS: Increased cerebrospinal fluid glycine and cerebrospinal fluid to plasma glycine ratio were indicative of nonketotic hyperglycinemia. Early magnetic resonance imaging showed restricted diffusion and decreased apparent diffusion coefficient values in posterior limb of internal capsules and later in entire internal capsules and posterior white matter. Sequencing did not show a mutation in AMT, GLDC, or GCSH. Biochemical analysis identified persistently increased cerebrospinal fluid levels of glycine and methylmalonic acid and increased urinary methylmalonic acid and plasma homocysteine levels, which improved on higher parenteral hydroxocobalamin dose. Exome sequencing identified a known pathogenic sequence variant in X-linked cobalamin (HCFC1), c.344C>T, p. Ala115Val. In addition, a hemizygous mutation was found in the ATRX (c. 2728A>G, p. Lys910Glu). Retrospective review of two other patients with X-linked cobalamin deficiency also identified increased cerebrospinal fluid glycine levels. CONCLUSIONS: This boy had X-linked cobalamin deficiency (HCFC1) with increased cerebrospinal fluid glycine and methylmalonic acid and increased cerebrospinal fluid to plasma glycine ratio suggesting a brain hyperglycinemia. Putative binding sites for HCFC1 and its binding partner THAP11 were identified near genes of the glycine cleavage enzyme, providing a potential mechanistic link between HCFC1 mutations and increased glycine. PMID: 28363510 [PubMed - as supplied by publisher]

Effect of Major Royal Jelly Proteins on Spatial Memory in Aged Rats: Metabolomics Analysis in Urine. J Agric Food Chem. 2017 Mar 31;: Authors: Chen D, Liu F, Wan JB, Lai CQ, Shen L Abstract Royal jelly (RJ) produced by worker honeybees is the sole food for the queen bee throughout her life as well as the larvae of worker bees for the first three days after hatching. Supplementation of RJ in the diet has been shown to increase spatial memory in rodents. However, the key constituents in RJ responsible for improvement of cognitive function are unknown. Our objective was to find out if the major royal-jelly proteins (MRJPs) extracted from RJ can improve the spatial memory of aged rats. The spatial memory assay using the Morris Water Maze test was administrated once to all the rats after 14-week feeding. Metabolomics analysis based on quadrupole time-of-flight mass spectrometry was conducted to examine the differences in compounds from urine. Aged male rats fed MRJPs were improved for spatial memory up to 48.5% when compared to the control male aged rats fed with distilled water. Metabolite pattern of the MRJPs-fed aged rats was regressed to that of the young rats. Compounds altered by MRJPs were mapped to nicotinate and nicotinamide metabolism, cysteine taurine metabolism and energy metabolism pathways. In summary, MRJPs may improve spatial memory and possess the potential for prevention of cognitive impairment via the cysteine and taurine metabolism and energy metabolism pathways in aged rats. PMID: 28362493 [PubMed - as supplied by publisher]

The genetic basis of obesity complications. Acta Sci Pol Technol Aliment. 2017 Jan-Mar;16(1):83-91 Authors: Skrypnik K, Suliburska J, Skrypnik D, Pilarski Ł, Reguła J, Bogdański P Abstract Intensive research is currently being performed into the genetic background of excess body mass compli- cations such as diabetes, cardiovascular disorders, especially atherosclerosis and coronary heart disease. Chronic inflammation is an important process in the pathogenesis of obesity, wherein there is an aberrant ex- pression of genes encoding adipokines. Visceral tissue is characterized by a higher expression and secretion of interleukin-8, interleukin-1ß and plasminogen activator inhibitor 1 in the subcutaneous tissue secretion of leptin prevails. An important complication of obesity is obstructive sleep apnea, often observed in Prader- Willi syndrome. The genetic background of sleep apnea may be a polymorphism of the SREBF1 gene. The consequence of excess body mass is metabolic syndrome, which may be related to the occurrence of the rs926198 variant of gene encoding caveolin-1. The genes of transcription factor TCF7L2 and PPAR-γ2 take part in the pathogenesis of diabetes development. It has been demonstrated that oncogenes FOS, FOSB, and JUN may be co-responsible not only for obesity but also for osteoporosis and colorectal cancer. It has been shown that weight loss causes a modification in the expression of about 100 genes involvedt in the production of substances such as cytokines and other responsible for chronic inflammation in obesity. In future studies on the complications of obesity, such scientific disciplines as proteomics, peptidomics, metabolomics and transcriptomics should be used. The aim of this study is to present the current state of knowledge about the genetic basis of obesity complications. PMID: 28362475 [PubMed - in process]

Discrimination of Four Marine Biofilm-Forming Bacteria by LC-MS Metabolomics and Influence of Culture Parameters. J Proteome Res. 2017 Mar 31;: Authors: Favre L, Ortalo-Magné A, Greff S, Pérez T, Thomas OP, Martin JC, Culioli G Abstract Most of the marine bacteria can form biofilms and they are the main components of biofilms observed on marine surfaces. Biofilms constitute a widespread life strategy, as growing in such structures offers many important biological benefits. The molecular compounds expressed in biofilms and, more generally, the metabolomes of marine bacteria remain poorly studied. In this context, a non-targeted LC-MS metabolomics approach of marine biofilm-forming bacterial strains was developed. Four marine bacteria, Persicivirga (Nonlabens) mediterranea TC4 and TC7, Pseudoalteromonas lipolytica TC8 and Shewanella sp. TC11, were used as model organisms. The main objective was to search for some strain-specific bacterial metabolites and to determine how culture parameters (culture medium, phase growth and mode of culture) may affect the cellular metabolism of each strain and thus the global inter-strain metabolic discrimination. LC-MS profiling and statistical partial least-square discriminant analyses showed that the four strains could be differentiated at the species level whatever the medium, the growth phase or the mode of culture (planktonic vs biofilm). A MS/MS molecular network was subsequently built and allowed the identification of putative bacterial biomarkers. TC8 was discriminated by a series of ornithine lipids while the P. mediterranea strains produced hydroxylated ornithine and glycine lipids. Among the P. mediterranea strains, TC7 extracts were distinguished by the occurrence of diamine derivatives, such as putrescine amides. PMID: 28362105 [PubMed - as supplied by publisher]

Spontaneous DNA damage propels tumorigenicity. Cell Res. 2017 Mar 31;: Authors: Vitale I, Kroemer G Abstract High levels of endogenously generated DNA damage drive oncogenesis, sustain malignant progression and increase therapy resistance. In a paper recently published in Cell Research, Liu and colleagues added additional insights into this topic by uncovering a novel intrinsic source of double-strand breaks that fosters the aggressiveness and stemness of malignant cells. PMID: 28361897 [PubMed - as supplied by publisher]

Related Articles A molecular analysis of the GBA gene in Caucasian South Africans with Parkinson's disease. Mol Genet Genomic Med. 2017 Mar;5(2):147-156 Authors: Barkhuizen M, Anderson DG, van der Westhuizen FH, Grobler AF Abstract BACKGROUND: The molecular basis of Parkinson's disease in South African population groups remains elusive. To date, substitutions in the GBA gene are the most common large-effect genetic risk factor for Parkinson's disease. The primary objective of this study was to determine the prevalence of GBA substitutions in South Africans with idiopathic Parkinson's disease. METHODS: Participants were recruited from tertiary hospitals in the Gauteng Province in South Africa. All participants were screened for substitutions in GBA exon 8-11 and the full coding region was analysed in 20 participants. Peripheral β-glucocerebrosidase enzymatic activity of GBA-carriers was measured in mixed leukocytes. RESULTS: Of 105 Caucasian Parkinson's disease participants (82.7% Afrikaner) with an average age of disease onset of 61.9 ± 12.2 years and 40 controls (age 73.4 ± 12.4 years) were included. Heterozygous GBA substitutions were identified in 12.38% of affected participants (p.G35A, p.E326K, p.I368T, p.T369M, p.N370S, p.P387L and p.K441N) and 5.00% of controls (p.E326K and p.T369M). The substitutions ranged from predicted benign to moderately damaging; with p.E326K and p.T369M most prevalent, followed by the Afrikaner Gaucher disease substitution p.P387L. Severe Gaucher disease mutations, like p.L444P, were absent in this cohort. Enzyme activity analysis revealed a nonsignificant reduction in the GBA-Parkinson's disease individuals (14.49 ± 2.30 nmol/h/mg protein vs. 15.98 ± 3.06 nmol/h/mg in control samples). GBA substitutions occur in both young-onset and late-onset Parkinson's cases in the cohort. CONCLUSION: Mild GBA substitutions that may not cause Gaucher disease were a common risk factor for Parkinson's disease in the participant group. PMID: 28361101 [PubMed - in process]

Related Articles Sex differences in the association of phospholipids with components of the metabolic syndrome in young adults. Biol Sex Differ. 2017;8:10 Authors: Rauschert S, Uhl O, Koletzko B, Mori TA, Beilin LJ, Oddy WH, Hellmuth C Abstract BACKGROUND: There are differences in the prevalence and severity of diseases between males, females not taking hormonal contraceptives (non-HC females) and females taking hormonal contraceptives (HC females). The aim of this study was to identify sex-specific differences in the metabolome and its relation to components of the metabolic syndrome in a young adult population. METHODS: The subjects analysed are from the 20-year follow-up of the Western Australian Pregnancy Cohort (Raine) Study. Two hundred fifteen plasma metabolites were analysed in 1021 fasted plasma samples by a targeted liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) metabolomics approach. Principal component analysis between males (n = 550), non-HC females (n = 199) and HC females (n = 269) was applied. Regression analysis with a sex × metabolite concentration interaction was performed on components of the MetS, namely waist circumference, systolic blood pressure, and plasma HDL-C, triglycerides and glucose concentration, as outcome to select the significant metabolites of the interaction. Those selected metabolites were used as predictors in a sex group stratified analysis to compare the different β coefficients and therefore the sex group-dependent associations. RESULTS: Principal component analysis between males, non-HC females, and HC females showed a general discriminating trend between males and HC females. One hundred twenty-seven metabolites were significantly different between males and non-HC females, whereas 97 differed between non-HC females and HC females. Males and non-HC females mainly differed in sphingomyelin, lyso-phosphatidylcholine, acyl-carnitine and amino acid species, whilst non-HC females and HC females mainly differed in phosphatidylcholine, lyso-phosphatidylcholine and acyl-carnitine concentrations. Forty-one metabolites (phosphatidylcholines, sphingomyelines, lyso-phosphatidylcholine) were significantly differently associated with the MetS factors in the different groups. CONCLUSIONS: We have shown clear differences between plasma metabolite concentrations in males, and HC or non-HC females, especially in lyso-phosphatidylcholine, sphingomyelin and phosphatidylcholine, which have been shown to associate with obesity in other studies. The association of these metabolites differed between sexes with components of the metabolic syndrome, which means that development of diseases like obesity and diabetes may differ between the sexes. Our findings highlight the importance of considering sex differences when conducting a metabolomics study and the need to account for the effect of HC usage in females in future studies. PMID: 28360990 [PubMed - in process]

Related Articles Potential Impact and Study Considerations of Metabolomics in Cardiovascular Health and Disease: A Scientific Statement From the American Heart Association. Circ Cardiovasc Genet. 2017 Apr;10(2): Authors: Cheng S, Shah SH, Corwin EJ, Fiehn O, Fitzgerald RL, Gerszten RE, Illig T, Rhee EP, Srinivas PR, Wang TJ, Jain M, American Heart Association Council on Functional Genomics and Translational Biology; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; and Stroke Council Abstract Through the measure of thousands of small-molecule metabolites in diverse biological systems, metabolomics now offers the potential for new insights into the factors that contribute to complex human diseases such as cardiovascular disease. Targeted metabolomics methods have already identified new molecular markers and metabolomic signatures of cardiovascular disease risk (including branched-chain amino acids, select unsaturated lipid species, and trimethylamine-N-oxide), thus in effect linking diverse exposures such as those from dietary intake and the microbiota with cardiometabolic traits. As technologies for metabolomics continue to evolve, the depth and breadth of small-molecule metabolite profiling in complex systems continue to advance rapidly, along with prospects for ongoing discovery. Current challenges facing the field of metabolomics include scaling throughput and technical capacity for metabolomics approaches, bioinformatic and chemoinformatic tools for handling large-scale metabolomics data, methods for elucidating the biochemical structure and function of novel metabolites, and strategies for determining the true clinical relevance of metabolites observed in association with cardiovascular disease outcomes. Progress made in addressing these challenges will allow metabolomics the potential to substantially affect diagnostics and therapeutics in cardiovascular medicine. PMID: 28360086 [PubMed - in process]

Related Articles In silico analysis of nonsynonymous single nucleotide polymorphisms of the human adiponectin receptor 2 (ADIPOR2) gene. Comput Biol Chem. 2017 Mar 14;68:175-185 Authors: Solayman M, Saleh MA, Paul S, Khalil MI, Gan SH Abstract Polymorphisms of the ADIPOR2 gene are frequently linked to a higher risk of developing diseases including obesity, type 2 diabetes and cardiovascular diseases. Though mutations of the ADIPOR2 gene are detrimental, there is a lack of comprehensive in silico analyses of the functional and structural impacts at the protein level. Considering the involvement of ADIPOR2 in glucose uptake and fatty acid oxidation, an in silico functional analysis was conducted to explore the possible association between genetic mutations and phenotypic variations. A genomic analysis of 82 nonsynonymous SNPs in ADIPOR2 was initiated using SIFT followed by the SNAP2, nsSNPAnalyzer, PolyPhen-2, SNPs&GO, FATHMM and PROVEAN servers. A total of 10 mutations (R126W, L160Q, L195P, F201S, L235R, L235P, L256R, Y328H, E334K and Q349H) were predicted to have deleterious effects on the ADIPOR2 protein and were therefore selected for further analysis. Theoretical models of the variants were generated by comparative modeling via MODELLER 9.16. A protein structural analysis of these amino acid variants was performed using SNPeffect, I-Mutant, ConSurf, Swiss-PDB Viewer and NetSurfP to explore their solvent accessibility, molecular dynamics and energy minimization calculations. In addition, FTSite was used to predict the ligand binding sites, while NetGlycate, NetPhos2.0, UbPerd and SUMOplot were used to predict post-translational modification sites. All of the variants showed increased free energy, though F201S exhibited the highest energy increase. The root mean square deviation values of the modeled mutants strongly indicated likely pathogenicity. Remarkably, three binding sites were detected on ADIPOR2, and two mutations at positions 328 and 201 were found in the first and second binding pockets, respectively. Interestingly, no mutations were found at the post-translational modification sites. These genetic variants can provide a better understanding of the wide range of disease susceptibility associated with ADIPOR2 and aid the development of new molecular diagnostic markers for these diseases. The findings may also facilitate the development of novel therapeutic elements for associated diseases. PMID: 28359874 [PubMed - as supplied by publisher]

16 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 2017/03/31PubMed comprises more than millions of 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.

23 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 2017/03/30PubMed comprises more than millions of 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.

27 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 2017/03/28PubMed comprises more than millions of 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.

Studying the effects of natural extracts with metabolomics: A longitudinal study on the supplementation of healthy rats with Polygonum cuspidatum Sieb. et Zucc. J Pharm Biomed Anal. 2017 Mar 16;140:62-70 Authors: Peron G, Uddin J, Stocchero M, Mammi S, Schievano E, Dall'Acqua S Abstract BACKGROUND: A longitudinal study was performed to evaluate the effects of Polygonum cuspidatum extract (standardized at 20% resveratrol) supplementation on healthy rats. The effects were explored by monitoring urinary metabolome changes using UPLC-HRMS and (1)H NMR-based approaches. The aim of the study was to explore the effects of P. cuspidatum supplementation on a healthy animal model using metabolomics, in order to determine possible modes of action and obtain information on bioactivity. METHODS: Healthy Sprague-Dawley rats were orally supplemented with 100mg/kg of dried P. cuspidatum extract for 49days and 24-h urinary outputs were collected. Samples were analysed by untargeted UPLC-HRMS and (1)H NMR approaches and the obtained data sets were modelled by an adaptation of post-transformation of PLS2 to longitudinal studies. Putative markers were discovered by a stability selection procedure and specific oxidative stress markers were monitored by a targeted HPLC-MS/MS analysis to assess the in vivo antioxidant activity of P. cuspidatum extract. RESULTS: UPLC-HRMS and (1)H NMR platforms showed two different but complementary patterns of metabolites describing the changes ascribable to P. cuspidatum supplementation and using both approaches, a comprehensive resveratrol metabolism and urinary excretion could be observed. Markers of P. cuspidatum supplementation effects identified by UPLC-HRMS were mainly related to its antioxidant activity and to a possible "adaptogenic" activity. Urinary changes observed by (1)H NMR were mainly related to energy metabolism. UPLC-HRMS and (1)H NMR metabolomics approaches allowed the effects of a prolonged supplementation with P. cuspidatum on healthy rats to be observed. The statistical models built from both data sets showed metabolic changes in urines related to rat aging. PMID: 28340474 [PubMed - as supplied by publisher]

The link between phenotype and fatty acid metabolism in advanced chronic kidney disease. Nephrol Dial Transplant. 2017 Mar 01;: Authors: Chen DQ, Chen H, Chen L, Vaziri ND, Wang M, Li XR, Zhao YY Abstract Background.: The kidney plays a central role in elimination of metabolic waste products and regulation of low-molecular weight metabolites via glomerular filtration, tubular secretion and reabsorption. Disruption of these processes results in profound changes in the biochemical milieu of the body fluids, which contribute to complications of chronic kidney disease (CKD) by inducing cytotoxicity and inflammation. Insight into the changes of the composition of metabolites and dysregulation of target genes and proteins enhances the understanding of the pathophysiology of CKD and its complications, and the development of novel therapeutic strategies. Chronic interstitial nephropathy is a common cause of CKD. The present study was designed to determine the effect of chronic interstitial nephropathy on the composition of serum metabolites and regulation of oxidative, inflammatory, fibrotic and cytoprotective pathways. Methods.: Male Sprague-Dawley rats were randomized to the CKD and control groups ( n  = 8/group). CKD was induced by administration of adenine (200 mg/kg body weight/day) by oral gavage for 3 weeks. The control group was treated with the vehicle alone. The animals were then observed for an additional 3 weeks, at which point they were sacrificed and kidney and serum samples were collected. Serum metabolomic and lipidomic analyses were performed using ultra-performance liquid chromatography-quadrupole time-of-flight high-definition mass spectrometry. Kidney tissues were processed for histological and molecular biochemical analyses. Results.: CKD rats exhibited increased plasma urea and creatinine concentrations, renal interstitial fibrosis, tubular damage and up-regulation of pro-inflammatory, pro-oxidant and pro-fibrotic pathways. Comparison of serum from CKD and control rats revealed significant differences in concentrations of amino acids and lipids including 33 metabolites and 35 lipid species. This was associated with marked abnormalities of fatty acid oxidation, and γ-linolenic acid and linoleic acid metabolism in CKD rats. Logistic regression analysis identified tetracosanoic acid, docosatrienoic acid, PC(18:3/14:1) and l -aspartic acid, tetracosanoic acid and docosatrienoic acid as novel biomarkers of chronic interstitial nephropathy. Conclusions.: Advanced CKD in rats with adenine-induced chronic interstitial nephropathy results in profound changes in the serum metabolome, activation of inflammatory, oxidative and fibrotic pathways, and suppression of cytoprotective and antioxidant pathways. PMID: 28339984 [PubMed - as supplied by publisher]

Specialized Information Processing Deficits and Distinct Metabolomic Profiles Following TM-Domain Disruption of Nrg1. Schizophr Bull. 2017 Mar 11;: Authors: O'Tuathaigh CM, Mathur N, O'Callaghan MJ, MacIntyre L, Harvey R, Lai D, Waddington JL, Pickard BS, Watson DG, Moran PM Abstract Although there is considerable genetic and pathologic evidence for an association between neuregulin 1 (NRG1) dysregulation and schizophrenia, the underlying molecular and cellular mechanisms remain unclear. Mutant mice containing disruption of the transmembrane (TM) domain of the NRG1 gene constitute a heuristic model for dysregulation of NRG1-ErbB4 signaling in schizophrenia. The present study focused on hitherto uncharacterized information processing phenotypes in this mutant line. Using a mass spectrometry-based metabolomics approach, we also quantified levels of unique metabolites in brain. Across 2 different sites and protocols, Nrg1 mutants demonstrated deficits in prepulse inhibition, a measure of sensorimotor gating, that is, disrupted in schizophrenia; these deficits were partially reversed by acute treatment with second, but not first-, generation antipsychotic drugs. However, Nrg1 mutants did not show a specific deficit in latent inhibition, a measure of selective attention that is also disrupted in schizophrenia. In contrast, in a "what-where-when" object recognition memory task, Nrg1 mutants displayed sex-specific (males only) disruption of "what-when" performance, indicative of impaired temporal aspects of episodic memory. Differential metabolomic profiling revealed that these behavioral phenotypes were accompanied, most prominently, by alterations in lipid metabolism pathways. This study is the first to associate these novel physiological mechanisms, previously independently identified as being abnormal in schizophrenia, with disruption of NRG1 function. These data suggest novel mechanisms by which compromised neuregulin function from birth might lead to schizophrenia-relevant behavioral changes in adulthood. PMID: 28338897 [PubMed - as supplied by publisher]