PubMed

Related Articles Age at diagnosis and C-peptide level are associated with diabetic retinopathy in Chinese. PLoS One. 2014;9(3):e91174 Authors: Cai X, Han X, Zhang S, Luo Y, Chen Y, Ji L Abstract OBJECTIVE: To find the associations between diabetic retinopathy and age at diagnosis, C-peptide level and thyroid-stimulating hormone (TSH) level in Chinese type 2 diabetes mellitus. METHODS: 3100 hospitalized type 2 diabetic patients in Peking University People's Hospital were included in this retrospective study. Their medical history and the laboratory data were collected. All the patients received examination of diabetic retinopathy (DR) by professional ophthalmologist. RESULTS: Comparisons among patients with NDR, NPDR and PDR showed that with the progression of diabetic retinopathy, patients turned to have older age but younger age at diagnosis of diabetes, and have higher SBP, longer duration of diabetes, higher mean HbA1c but lower fasting and 2 hours postprandial C-peptide level. Moreover, with the progression of diabetic retinopathy, patients turned to have higher prevalence of primary hypertension, higher prevalence of peripheral vascular sclerosis, higher proportion with insulin treatment. TSH level was comparable among the three groups of patients. Association analysis showed that after adjusting for age, sex, duration of diabetes, body mass index, HbA1c, blood pressure and albuminurea creatinine ratio and insulin treatment, age at diagnosis (OR 0.888, 95%CI 0.870-0.907, p = 0.00) and postprandial C-peptide (OR 0.920, 95%CI 0.859-0.937, p = 0.00) are the independent associated factors of DR in Chinese type 2 diabetes. CONCLUSIONS: According to the results, postprandial C-peptide level and age at diabetes may be two independent associated factors with DR in Chinese type 2 diabetes. The lower level of postprandial C-peptide, the younger age at diagnosis, may indicate the higher prevalence of DR. PMID: 24614131 [PubMed - indexed for MEDLINE]

Gut microbiota profiling of pediatric NAFLD and obese patients unveiled by an integrated meta-omics based approach. Hepatology. 2016 Mar 29; Authors: Del Chierico F, Nobili V, Vernocchi P, Russo A, De Stefanis C, Gnani D, Furlanello C, Zandonà A, Paci P, Capuani G, Dallapiccola B, Miccheli A, Alisi A, Putignani L Abstract There is evidence that non-alcoholic fatty liver disease (NAFLD) is affected by gut microbiota. Therefore, we investigated its modifications in paediatric NAFLD patients using targeted-metagenomics (MG) and metabolomics (MB). Stools were collected from 61 consecutive patients diagnosed with NAFL, NASH, or obesity and 54 healthy subjects (CTRLs), matched in a case-control fashion. Operational taxonomic units were pyrosequenced targeting 16S ribosomal RNA and volatile organic compounds (VOCs) determined by solid-phase micro-extraction GC-MS. The α-diversity was highest in CTRLs followed by obese, NASH, NAFL patients and β-diversity distinguished between patients and CTRLs, but not NAFL and NASH. Compared to CTRLs, in NAFLD patients Actinobacteria were significantly increased and Bacteroidetes reduced. There were no significant differences amongst NAFL, NASH, and obese groups. Overall NAFLD patients had increased levels of Bradyrhizobium, Anaerococcus, Peptoniphilus, Propionibacterium acnes, Dorea, Ruminococcus and reduced proportions of Oscillospira and Rikenellaceae compared to CTRLs. After reducing MG and MB data dimensionality, multivariate analyses indicated Oscillospira decrease in NAFL and NASH groups, and Ruminococcus, Blautia, and Dorea increase in NASH patients compared to CTRLs. Of the 292 VOCs, 26 were up- and 2 down-regulated in NAFLD patients. Multivariate analyses found that combination of Oscillospira, Rickenellaceae, Parabacteroides, Bacteroides fragilis, Sutterella, Lachnospiraceae, 4-methyl-2-pentanone, 1-butanol, and 2-butanone could discriminate NAFLD patients from CTRLs. Univariate analyses found significantly lower levels of Oscillospira and higher levels of 1-pentanol and 2-butanone in NAFL compared to CTRLs. In NASH, lower levels of Oscillospira were associated with higher abundance of Dorea, Ruminococcus and higher levels of 2-butanone, 4-methyl-2-pentanone compared to CTRLs. CONCLUSION: Oscillospira decrease coupled to 2-butanone up-regulation and Ruminococcus, Dorea increase were identified as gut microbiota signatures of NAFL onset and NAFL-NASH progression, respectively. This article is protected by copyright. All rights reserved. PMID: 27028797 [PubMed - as supplied by publisher]

Linking field-based metabolomics and chemical analyses to prioritize contaminants of emerging concern in the Great Lakes basin. Environ Toxicol Chem. 2016 Mar 30; Authors: Davis JM, Ekman DR, Teng Q, Ankley GT, Berninger JP, Cavallin JE, Jensen KM, Kahl MD, Schroeder AL, Villeneuve DL, Jorgenson ZG, Lee KE, Collette TW Abstract The ability to focus on the most biologically relevant contaminants affecting aquatic ecosystems can be challenging because toxicity assessment programs have not kept pace with the growing number of contaminants requiring testing. Because it has proven effective in assessing biological impacts of potentially toxic contaminants, profiling of endogenous metabolites (metabolomics) may help screen out contaminants with a lower likelihood of eliciting biological impacts, thereby prioritizing the most biologically-important contaminants. We present results from a study that utilized cage-deployed fathead minnows (Pimephales promelas) at 18 sites across the Great Lakes basin. We measured water temperature and contaminant concentrations in water samples (132 contaminants targeted; 86 detected), and used (1) H-NMR spectroscopy to measure endogenous metabolites in polar extracts of livers. We used partial least-squares (PLS) regression to compare relative abundances of endogenous metabolites with contaminant concentrations and temperature. Results indicated that profiles of endogenous polar metabolites covaried with at most 49 contaminants. Thus, we identified up to 52% of detected contaminants as not significantly covarying with changes in endogenous metabolites, suggesting they likely were not eliciting measureable impacts at these sites. This represents a first step in screening for the biological-relevance of detected contaminants by shortening lists of contaminants potentially affecting these sites. Such information may allow risk assessors to prioritize contaminants and focus toxicity testing on the most biologically-relevant contaminants. This article is protected by copyright. All rights reserved. PMID: 27027868 [PubMed - as supplied by publisher]

"Omics" of Selenium Biology: A Prospective Study of Plasma Proteome Network Before and After Selenized-Yeast Supplementation in Healthy Men. OMICS. 2016 Mar 30; Authors: Sinha I, Karagoz K, Fogle RL, Hollenbeak CS, Zea AH, Arga KY, Stanley AE, Hawkes WC, Sinha R Abstract Low selenium levels have been linked to a higher incidence of cancer and other diseases, including Keshan, Chagas, and Kashin-Beck, and insulin resistance. Additionally, muscle and cardiovascular disorders, immune dysfunction, cancer, neurological disorders, and endocrine function have been associated with mutations in genes encoding for selenoproteins. Selenium biology is complex, and a systems biology approach to study global metabolomics, genomics, and/or proteomics may provide important clues to examining selenium-responsive markers in circulation. In the current investigation, we applied a global proteomics approach on plasma samples collected from a previously conducted, double-blinded placebo controlled clinical study, where men were supplemented with selenized-yeast (Se-Yeast; 300 μg/day, 3.8 μmol/day) or placebo-yeast for 48 weeks. Proteomic analysis was performed by iTRAQ on 8 plasma samples from each arm at baseline and 48 weeks. A total of 161 plasma proteins were identified in both arms. Twenty-two proteins were significantly altered following Se-Yeast supplementation and thirteen proteins were significantly changed after placebo-yeast supplementation in healthy men. The differentially expressed proteins were involved in complement and coagulation pathways, immune functions, lipid metabolism, and insulin resistance. Reconstruction and analysis of protein-protein interaction network around selected proteins revealed several hub proteins. One of the interactions suggested by our analysis, PHLD-APOA4, which is involved in insulin resistance, was subsequently validated by Western blot analysis. Our systems approach illustrates a viable platform for investigating responsive proteomic profile in 'before and after' condition following Se-Yeast supplementation. The nature of proteins identified suggests that selenium may play an important role in complement and coagulation pathways, and insulin resistance. PMID: 27027327 [PubMed - as supplied by publisher]

Real-time bilinear rotation decoupling in absorptive mode J-spectroscopy: Detecting low-intensity metabolite peak close to high-intensity metabolite peak with convenience. J Magn Reson. 2016 Mar 10;266:51-58 Authors: Verma A, Baishya B Abstract "Pure shift" NMR spectra display singlet peak per chemical site. Thus, high resolution is offered at the cost of valuable J-coupling information. In the present work, real-time BIRD (BIlinear Rotation Decoupling) is applied to the absorptive-mode 2D J-spectroscopy to provide pure shift spectrum in the direct dimension and J-coupling information in the indirect dimension. Quite often in metabolomics, proton NMR spectra from complex bio-fluids display tremendous signal overlap. Although conventional J-spectroscopy in principle overcomes this problem by separating the multiplet information from chemical shift information, however, only magnitude mode of the experiment is practical, sacrificing much of the potential high resolution that could be achieved. Few J-spectroscopy methods have been reported so far that produce high-resolution pure shift spectrum along with J-coupling information for crowded spectral regions. In the present work, high-quality J-resolved spectrum from important metabolomic mixture such as tissue extract from rat cortex is demonstrated. Many low-intensity metabolite peaks which are obscured by the broad dispersive tails from high-intensity metabolite peaks in regular magnitude mode J-spectrum can be clearly identified in real-time BIRD J-resolved spectrum. The general practice of removing such spectral overlap is tedious and time-consuming as it involves repeated sample preparation to change the pH of the tissue extract sample and subsequent spectra recording. PMID: 27026651 [PubMed - as supplied by publisher]

Diastolic Left Ventricular Function in Relation to Circulating Metabolic Biomarkers in a General Population. J Am Heart Assoc. 2016;5(3) Authors: Zhang ZY, Marrachelli VG, Thijs L, Yang WY, Wei FF, Monleon D, Jacobs L, Nawrot T, Verhamme P, Voigt JU, Kuznetsova T, Redón J, Staessen JA Abstract BACKGROUND: The metabolic signature associated with subclinical diastolic left ventricular (LV) dysfunction in the population remains ill defined. METHODS AND RESULTS: In 711 randomly recruited Flemish (50.8% women; mean age, 50.8 years), we assessed echocardiographic Doppler indexes of diastolic LV function in relation to 44 circulating metabolites determined by nuclear magnetic resonance spectroscopy. In multivariable-adjusted regression analysis with Bonferroni correction of significance levels applied, peak a' decreased (P≤0.048) and e'/a' increased (P≤0.044) with circulating tyrosine, high-density lipoprotein apolipoproteins, glucose+glutamine, and an unidentified molecule. Effect sizes expressed per 1-SD increment in the metabolite ranged from -0.277 to -0.203 cm/s for peak a' and from +0.047 to +0.054 for e'/a'. In addition, peak a' decreased (P≤0.031) with glucose+2-aminobutyrate (-0.261 cm/s) and glucose+2-phosphoglycerate (-0.209 cm/s). In partial least square discriminant analysis (PLS-DA), metabolites associated with normal diastolic LV function (n=538) included glucose+glutamine, glucose+2-aminobutyrate, and glucose+2-phosphoglycerate, whereas those siding with abnormal function encompassed 4-aminobutyrate, 4-hydroxybutyrate, creatinine, and phosphocholine. In receiver operating characteristics plots, adding 3 latent factors identified by PLS-DA to prohormone brain natriuretic peptide increased (P<0.0001) the area under the curve from 0.64 (95% CI, 0.58-0.68) to 0.73 (0.68-0.78). CONCLUSIONS: In a general population, circulating metabolites indicative of energy substrate utilization and protection against oxidative stress differentiated normal from abnormal diastolic LV function. These findings improve our understanding of the pathophysiology underlying deterioration of diastolic LV function and potentially point to new targets for prevention and treatment of this condition. PMID: 27025885 [PubMed - in process]

Plasma Metabolomics of Common Marmosets (Callithrix jacchus) to Evaluate Diet and Feeding Husbandry. J Am Assoc Lab Anim Sci. 2016;55(2):137-46 Authors: Banton SA, Soltow QA, Liu KH, Uppal K, Promislow DE, Power ML, Tardif SD, Wachtman LM, Jones DP Abstract Common marmosets (Callithrix jacchus) are an important NHP model for the study of human aging and age-related diseases. However, the full potential of marmosets as a research model has not been realized due to a lack of evidence-based, standardized procedures for their captive management, especially regarding diet and feeding husbandry. In the present study, we conducted a high-resolution metabolomics analysis of plasma from marmosets from a 3-mo dietary crossover study to determine whether significant metabolic differences occur with a semisynthetic chemically defined (purified) diet as needed for controlled nutrition research. Marmosets were fed a standard, diverse-ingredient diet, followed by a semisynthetic purified diet, and then were switched back to the standard diet. The standard diet used in this analysis was specific to the animal facility, but it is similar in content to the diets currently used for other marmoset colonies. High-resolution metabolomics of plasma with liquid chromatography-mass spectrometry and bioinformatics was used to measure metabolic differences. The concentration of the essential amino acids methionine, leucine/isoleucine, lysine, and threonine were higher when marmosets were fed the purified diet. In contrast, phenylalanine concentrations were higher during exposure to the standard diet. In addition, metabolic pathway enrichment and analysis revealed differences among metabolites associated with dopamine metabolism and the carnitine shuttle. These results show that diet-associated differences in metabolism occur in marmosets and suggest that additional nutritional studies with detailed physiologic characterization are needed to optimize standard and purified diets for common marmosets. PMID: 27025803 [PubMed - in process]

Urine metabonomic study for blood-replenishing mechanism of Angelica sinensis in a blood-deficient mouse model. Chin J Nat Med. 2016 Mar;14(3):210-9 Authors: Wang T, Sun HG, Hua YL, Li PL, Wei YM Abstract This study aimed at determining the effects of Angelica sinensis (AS) on urinary metabolites in blood deficiency mice and exploring its replenishing blood mechanism. Gas chromatography-mass spectrometry (GC-MS) was applied to detect metabolites in the urine samples in different collection periods. Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were used to investigate the differences in metabolic profiles among control group (CG), blood deficiency model group (MG), AS groups, and Colla Corii Asini group (CCAG). The potential biomarkers were identified based on the variable importance in the projection (VIP), T-test, and National Institute of Standards and Technology (NIST) and mass spectra library. The metabolites were analyzed using metabolomics pathway analysis (MetPA) to build the metabolic pathways. Our results indicated that, on the seventh day, the levels of glucose, lactic acid, pyruvic acid, alanine, acetoacetic acid, and citric acid changed significantly in blood deficiency mice. However, these metabolic deviations came to closer to normal levels after AS intervention. The reversing blood-deficiency mechanism of AS might involve regulating synthesis and degradation of ketone bodies, Pyruvate metabolism, TCA cycle, and Glycolysis/Gluconeogenesis. In conclusion, metabonomics is a robust and promising means for the identification of biomarkers and elucidation of the mechanisms of a disease, thereby highlighting its importance in drug discovery. PMID: 27025368 [PubMed - in process]

Related Articles Comparative Metabolomic Analysis of the Neuroprotective Effects of Scutellarin and Scutellarein against Ischemic Insult. PLoS One. 2015;10(7):e0131569 Authors: Tang H, Tang Y, Li NG, Lin H, Li W, Shi Q, Zhang W, Zhang P, Dong Z, Shen M, Gu T, Duan JA Abstract For more than thirty years, scutellarin (Scu) has been used in China to clinically treat acute cerebral infarction and paralysis. Scutellarein (Scue), the major Scu metabolite in vivo, exhibits heightened neuroprotective effects when compared to Scu. To explore the neuroprotective role of these compounds, we performed ultra-high-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UHPLC-QTOF/MS) coupled with a pattern recognition approach to investigate metabolomic differences in a rat model of ischemia after treatment with each compound. We examined metabolites in urine, hippocampal tissue, and plasma, and we tentatively identified 23 endogenous metabolites whose levels differed significantly between sham-operated and model groups. Upon pathway analysis, we found an additional 11 metabolic pathways in urine, 14 metabolic pathways in the hippocampal tissue, and 3 metabolic pathways in plasma. These endogenous metabolites were mainly involved in sphingolipid metabolism, lysine biosynthesis, and alanine, aspartate, and glutamate metabolism. We found that metabolic changes after ischemic injury returned to near-normal levels after Scue intervention, unlike Scu treatment, further validating the heightened protective effects exerted by Scue compared to Scu. These results demonstrate that Scue is a potential drug for treatment of ischemic insult. PMID: 26147971 [PubMed - indexed for MEDLINE]

Related Articles Urine and serum metabolomic profiling reveals that bile acids and carnitine may be potential biomarkers of primary biliary cirrhosis. Int J Mol Med. 2015 Aug;36(2):377-85 Authors: Tang YM, Wang JP, Bao WM, Yang JH, Ma LK, Yang J, Chen H, Xu Y, Yang LH, Li W, Zhu YP, Cheng JB Abstract In order to provide non-invasive, reliable and sensitive laboratory parameters for the diagnosis of primary biliary cirrhosis (PBC), metabolic technology of ultraperformance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UPLC/Q-TOF MS) was used to compare small molecule metabolites in blood and urine from patients with PBC and healthy controls. We then screened for bio-markers in the blood and urine of the patients with PBC. Data were processed by Bruker ProfileAnalysis metabonomic software and imported to SIMCA-P software, which utilized principal component analysis (PCA) to create models of patients with PBC and healthy controls. In total, 18 urinary markers were found and the levels of 11 of these urinary markers were elevated in the patients with PBC, whereas the levels of the remaining 7 markers were lower in the PBC group compared to the control group. We also identified 20 blood-based biomarkers in the patients with PBC and the levels of 9 of these markers were higher in the PBC group, whereas the levels of the remaining 11 markers were lower in the patients with PBC compared to the controls. Among these biomarkers, the levels of bile acids increased with the progression of PBC, while the levels of carnitines, such as propionyl carnitine and butyryl carnitine, decreased with the progression of PBC. In conclusion, the findings of the present study suggest that the circulating levels of bile acids and carnitine are differentially altered in patients with PBC. PMID: 26046127 [PubMed - indexed for MEDLINE]

Related Articles Identification and mode of inheritance of quantitative trait loci for secondary metabolite abundance in tomato. Plant Cell. 2015 Mar;27(3):485-512 Authors: Alseekh S, Tohge T, Wendenberg R, Scossa F, Omranian N, Li J, Kleessen S, Giavalisco P, Pleban T, Mueller-Roeber B, Zamir D, Nikoloski Z, Fernie AR Abstract A large-scale metabolic quantitative trait loci (mQTL) analysis was performed on the well-characterized Solanum pennellii introgression lines to investigate the genomic regions associated with secondary metabolism in tomato fruit pericarp. In total, 679 mQTLs were detected across the 76 introgression lines. Heritability analyses revealed that mQTLs of secondary metabolism were less affected by environment than mQTLs of primary metabolism. Network analysis allowed us to assess the interconnectivity of primary and secondary metabolism as well as to compare and contrast their respective associations with morphological traits. Additionally, we applied a recently established real-time quantitative PCR platform to gain insight into transcriptional control mechanisms of a subset of the mQTLs, including those for hydroxycinnamates, acyl-sugar, naringenin chalcone, and a range of glycoalkaloids. Intriguingly, many of these compounds displayed a dominant-negative mode of inheritance, which is contrary to the conventional wisdom that secondary metabolite contents decreased on domestication. We additionally performed an exemplary evaluation of two candidate genes for glycolalkaloid mQTLs via the use of virus-induced gene silencing. The combined data of this study were compared with previous results on primary metabolism obtained from the same material and to other studies of natural variance of secondary metabolism. PMID: 25770107 [PubMed - indexed for MEDLINE]

Effect of Genotype and Environment on Salvia miltiorrhiza Roots Using LC/MS-Based Metabolomics. Molecules. 2016;21(4) Authors: Zhao Q, Song Z, Fang X, Pan Y, Guo L, Liu T, Wang J Abstract Salvia miltiorrhiza (S. miltiorrhiza) Bunge is broadly used as herbal medicine for the clinical treatments of cardiovascular and cerebrovascular diseases. Despite its commercial and medicinal values, few systematic studies on the metabolome of S. miltiorrhiza roots have been carried out so far. We systematically described the metabolic profiles of S. miltiorrhiza using high pressure liquid chromatography mass spectrometry (LC/MS) in conjunction with multivariate statistical analyses, aimed at monitoring their biological variations of secondary metabolites related to three locations and four S. miltiorrhiza genotypes. A total of 40 bioactive constituents were putatively annotated in S. miltiorrhiza root samples. This study found that both the same S. miltiorrhiza genotype growing at three different locations and four S. miltiorrhiza genotypes growing at the same location had significant metabonomic differences identified by the principal component analysis (PCA) approach. By using orthogonal projection to latent structure with discriminant analysis (OPLS-DA), 16 and 14 secondary metabolites can be used as potential location-specific and genotype-specific markers in S. miltiorrhiza, respectively. The specificity of LC/MS profiles offered a powerful tool to discriminate S. miltiorrhiza samples according to genotypes or locations. PMID: 27023512 [PubMed - as supplied by publisher]

Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer. J Vis Exp. 2016;(109) Authors: Zhao YC, Madak Erdogan Z Abstract With the advent of the -omics approaches our understanding of the chronic diseases like cancer and metabolic syndrome has improved. However, effective mining of the information in the large-scale datasets that are obtained from gene expression microarrays, deep sequencing experiments or metabolic profiling is essential to uncover and then effectively target the critical regulators of diseased cell phenotypes. Estrogen Receptor α (ERα) is one of the master transcription factors regulating the gene programs that are important for estrogen responsive breast cancers. In order to understand to role of ERα signaling in breast cancer metabolism we utilized transcriptomic, cistromic and metabolomic data from MCF-7 cells treated with estradiol. In this report we described generation of samples for RNA-Seq, ChIP-Seq and metabolomics experiments and the integrative computational analysis of the obtained data. This approach is useful in delineating novel molecular mechanisms and gene regulatory circuits that are regulated by a particular transcription factor which impacts metabolism of normal or diseased cells. PMID: 27023311 [PubMed - as supplied by publisher]

Multiomic candidate biomarkers for clinical manifestations of sickle cell severity: Early steps to precision medicine. Exp Biol Med (Maywood). 2016 Mar 27; Authors: Goodman SR, Pace BS, Hansen KC, D'alessandro A, Xia Y, Daescu O, Glatt SJ Abstract In this review, we provide a description of those candidate biomarkers which have been demonstrated by multiple-omics approaches to vary in correlation with specific clinical manifestations of sickle cell severity. We believe that future clinical analyses of severity phenotype will require a multiomic analysis, or an omics stack approach, which includes integrated interactomics. It will also require the analysis of big data sets. These candidate biomarkers, whether they are individual or panels of functionally linked markers, will require future validation in large prospective and retrospective clinical studies. Once validated, the hope is that informative biomarkers will be used for the identification of individuals most likely to experience severe complications, and thereby be applied for the design of patient-specific therapeutic approaches and response to treatment. This would be the beginning of precision medicine for sickle cell disease. PMID: 27022133 [PubMed - as supplied by publisher]

Delineation of molecular pathways involved in cardiomyopathies caused by troponin T mutations. Mol Cell Proteomics. 2016 Mar 28; Authors: Gilda JE, Lai X, Witzmann FA, Gomes AV Abstract Familial hypertrophic cardiomyopathy (FHC) is associated with mild to severe cardiac problems and is the leading cause of sudden death in young people and athletes. Although the genetic basis for FHC is well-established, the molecular mechanisms that ultimately lead to cardiac dysfunction are not well understood. To obtain important insights into the molecular mechanism(s) involved in FHC, hearts from two FHC troponin T (TnT) models (I79N and R278C) were investigated using label-free proteomics and metabolomics. Mutations in TnT are the third most common cause of FHC, and the I79N mutation is associated with a high risk of sudden cardiac death. Most FHC-causing mutations, including I79N, increase the Ca2+ sensitivity of the myofilament; however the R278C mutation does not alter Ca2+ sensitivity and is associated with a better prognosis than most FHC mutations. Out of more than 1200 identified proteins, 53 and 76 proteins were differentially expressed in I79N and R278C hearts, respectively, when compared to wild-type hearts. Interestingly, more than 400 proteins were differentially expressed when the I79N and R278C hearts were directly compared. The three major pathways affected in I79N hearts relative to R278C and WT hearts were the ubiquitin-proteasome system, antioxidant systems, and energy production pathways. Further investigation of the proteasome system using western blotting and activity assays showed that proteasome dysfunction occurs in I79N hearts. Metabolomic results corroborate the proteomic data and suggest the glycolytic, citric acid, and electron transport chain pathways are important pathways that are altered in I79N hearts relative to R278C or WT hearts. Our findings suggest that impaired energy production and protein degradation dysfunction are important mechanisms in FHCs associated with poor prognosis and that cardiac hypertrophy is not likely needed for a switch from fatty acid to glucose metabolism. PMID: 27022107 [PubMed - as supplied by publisher]

Characterizing novel metabolic pathways of melatonin receptors agonist agomelatine using metabolomic approaches. Biochem Pharmacol. 2016 Mar 25; Authors: Liu X, Lu YF, Guan X, Zhao M, Wang J, Li F Abstract Agomelatine (AGM), an analogue of melatonin, is a potential agonist at melatonin receptors 1/2 and a selective antagonist at 5-hydroxytryptamine 2C receptors. AGM is widely used for the treatment of major depressive episodes in adults. However, multiple adverse effects associated with AGM have been reported in clinical practice. It is little known about AGM metabolism in vitro and in vivo, although metabolism plays a pivotal role in its efficacy and safety. To elucidate metabolic pathways of AGM, we systemically investigated AGM metabolism and its bioactivation in human liver microsomes (HLM) and mice using metabolomic approaches. We identified thirty eight AGM metabolites and adducts, among which thirty two are novel. In HLM, we uncovered five GSH-trapped adducts and two semicarbazide-trapped aldehydes. Moreover, we characterized three N-acetyl cysteine conjugated-AGM adducts in mouse urine and feces, which were formed from the degradation of AGM_GSH adducts. Using recombinant CYP450 isoenzymes and chemical inhibitors, we demonstrated that CYP1A2 and CYP3A4 are primary enzymes contributing to the formation of AGM_GSH adducts and AGM_hydrazones. This study provided a global view of AGM metabolism and identified the novel pathways of AGM bioactivation, which could be utilized for further understanding the mechanism of adverse effects related to AGM and possible drug-drug interactions. PMID: 27021842 [PubMed - as supplied by publisher]

Changes in fecal microbiota and metabolomics in a child with juvenile idiopathic arthritis (JIA) responding to two treatment periods with exclusive enteral nutrition (EEN). Clin Rheumatol. 2016 Mar 29; Authors: Berntson L, Agback P, Dicksved J Abstract The microbiome and immune system of the digestive tract are highly important in both health and disease. Exclusive enteral nutrition (EEN) is a common anti-inflammatory treatment in children with Crohn's disease in the European countries, and the mechanism is most likely linked to changes in the intestinal microbiome. In the present study, EEN was given in two treatment periods several months apart to a patient with very severe, disabling juvenile idiopathic arthritis (JIA), with a remarkable clinical response as the result. The aim of the present study was to study how the EEN treatment influenced the microbiome and metabolome of this patient. Fecal samples from before, during, and between treatments with EEN were studied. The microbiome was analyzed by sequencing of 16S rRNA amplicons using Illumina MiSeq, and the metabolome was analyzed using nuclear magnetic resonance. The microbiome changed markedly from treatment with EEN, with a strong reduction of the Bacteroidetes phylum. Metabolic profiles showed clear differences before, during, and between treatment with EEN, where butyrate, propionate, and acetate followed a cyclic pattern with the lowest levels at the end of each treatment period. This patient with JIA showed remarkable clinical improvement after EEN treatment, and we found corresponding changes in both the fecal microbiome and the metabolome. Further studies are needed to explore the pathophysiological role of the intestinal canal in children with JIA. PMID: 27021336 [PubMed - as supplied by publisher]

Optimization of metabolomics of defined in vitro gut microbial ecosystems. Int J Med Microbiol. 2016 Mar 16; Authors: Wissenbach DK, Oliphant K, Rolle-Kampczyk U, Yen S, Höke H, Baumann S, Haange SB, Verdu EF, Allen-Vercoe E, von Bergen M Abstract The metabolic functionality of a microbial community is a key to the understanding of its inherent ecological processes and the interaction with the host. However, the study of the human gut microbiota is hindered by the complexity of this ecosystem. One way to resolve this issue is to derive defined communities that may be cultured ex vivo in bioreactor systems and used to approximate the native ecosystem. Doing so has the advantage of experimental reproducibility and ease of sampling, and furthermore, in-depth analysis of metabolic processes becomes highly accessible. Here, we review the use of bioreactor systems for ex vivo modelling of the human gut microbiota with respect to analysis of the metabolic output of the microbial ecosystem, and discuss the possibility of mechanistic insights using these combined techniques. We summarize the different platforms currently used for metabolomics and suitable for analysis of gut microbiota samples from a bioreactor system. With the help of representative datasets obtained from a series of bioreactor runs, we compare the outputs of both NMR and mass spectrometry based approaches in terms of their coverage, sensitivity and quantification. We also discuss the use of untargeted and targeted analyses in mass spectroscopy and how these techniques can be combined for optimal biological interpretation. Potential solutions for linking metabolomic and phylogenetic datasets with regards to active, key species within the ecosystem will be presented. PMID: 27020116 [PubMed - as supplied by publisher]

Related Articles Genomes to natural products PRediction Informatics for Secondary Metabolomes (PRISM). Nucleic Acids Res. 2015 Nov 16;43(20):9645-62 Authors: Skinnider MA, Dejong CA, Rees PN, Johnston CW, Li H, Webster AL, Wyatt MA, Magarvey NA Abstract Microbial natural products are an invaluable source of evolved bioactive small molecules and pharmaceutical agents. Next-generation and metagenomic sequencing indicates untapped genomic potential, yet high rediscovery rates of known metabolites increasingly frustrate conventional natural product screening programs. New methods to connect biosynthetic gene clusters to novel chemical scaffolds are therefore critical to enable the targeted discovery of genetically encoded natural products. Here, we present PRISM, a computational resource for the identification of biosynthetic gene clusters, prediction of genetically encoded nonribosomal peptides and type I and II polyketides, and bio- and cheminformatic dereplication of known natural products. PRISM implements novel algorithms which render it uniquely capable of predicting type II polyketides, deoxygenated sugars, and starter units, making it a comprehensive genome-guided chemical structure prediction engine. A library of 57 tailoring reactions is leveraged for combinatorial scaffold library generation when multiple potential substrates are consistent with biosynthetic logic. We compare the accuracy of PRISM to existing genomic analysis platforms. PRISM is an open-source, user-friendly web application available at http://magarveylab.ca/prism/. PMID: 26442528 [PubMed - indexed for MEDLINE]

Related Articles Bovine yolk sac: from morphology to metabolomic and proteomic profiles. Genet Mol Res. 2015;14(2):6223-38 Authors: Galdos-Riveros AC, Favaron PO, Will SE, Miglino MA, Maria DA Abstract In several species, placentation involves the presence of two different membranes responsible for maternal-fetal exchanges: the yolk sac and the chorioallantoic placenta. The yolk sac plays important roles in embryonic survival, mainly during the early stages of gestation. In bovine, it is a transitional membrane that is present until day 50-70 of pregnancy. Herein, we evaluated the morphological and molecular aspects of the yolk sac of bovine embryos during 24 to 52 days of gestation. A total of 69 embryos were allocated into three groups according to the crown-rump length and estimated ages. Yolk sac samples were then subjected to morphological and molecular analysis using mass spectrometry and nuclear magnetic resonance techniques. In contrast to alanine, which was observed only in Group I, during all gestational stages, we identified important metabolites such as aspartate, taurine, glycerophosphocholine, creatinine, creatine, hydrouracil, glutamate, glutamine, lactate, lysine, valine, myo-inositol, cadaverine, and choline. In addition, 314 random sequences of proteins were identified in the bovine yolk sac, and 47 of these were considered to be specific. Changes in alpha-fetoprotein and carcinoembryonic antigen concentrations during gestation were also evaluated. In conclusion, the majority of these proteins are related to the development of secondary metabolites that are involved in the activation of other proteins and metabolites, and in signaling pathways that are responsible for maternal-fetal exchanges, activation of programmed cell death mechanisms, and cellular differentiation, and also in proteins that are responsible for the yolk sac involution that is required to establish chorioallantoic placentation. PMID: 26125823 [PubMed - indexed for MEDLINE]