PubMed

Related Articles MyCompoundID MS/MS Search: Metabolite Identification Using a Library of Predicted Fragment-Ion-Spectra of 383,830 Possible Human Metabolites. Anal Chem. 2015 Oct 20;87(20):10619-26 Authors: Huan T, Tang C, Li R, Shi Y, Lin G, Li L Abstract We report an analytical tool to facilitate metabolite identification based on an MS/MS spectral match of an unknown to a library of predicted MS/MS spectra of possible human metabolites. To construct the spectral library, the known endogenous human metabolites in the Human Metabolome Database (HMDB) (8,021 metabolites) and their predicted metabolic products via one metabolic reaction in the Evidence-based Metabolome Library (EML) (375,809 predicted metabolites) were subjected to in silico fragmentation to produce the predicted MS/MS spectra. This spectral library is hosted at the public MCID Web site ( www.MyCompoundID.org ), and a spectral search program, MCID MS/MS, has been developed to allow a user to search one or a batch of experimental MS/MS spectra against the library spectra for possible match(s). Using MS/MS spectra generated from standard metabolites and a human urine sample, we demonstrate that this tool is very useful for putative metabolite identification. It allows a user to narrow down many possible structures initially found by using an accurate mass search of an unknown metabolite to only one or a few candidates, thereby saving time and effort in selecting or synthesizing metabolite standard(s) for eventual positive metabolite identification. PMID: 26415007 [PubMed - indexed for MEDLINE]

Related Articles Effects of metformin on metabolite profiles and LDL cholesterol in patients with type 2 diabetes. Diabetes Care. 2015 Oct;38(10):1858-67 Authors: Xu T, Brandmaier S, Messias AC, Herder C, Draisma HH, Demirkan A, Yu Z, Ried JS, Haller T, Heier M, Campillos M, Fobo G, Stark R, Holzapfel C, Adam J, Chi S, Rotter M, Panni T, Quante AS, He Y, Prehn C, Roemisch-Margl W, Kastenmüller G, Willemsen G, Pool R, Kasa K, van Dijk KW, Hankemeier T, Meisinger C, Thorand B, Ruepp A, Hrabé de Angelis M, Li Y, Wichmann HE, Stratmann B, Strauch K, Metspalu A, Gieger C, Suhre K, Adamski J, Illig T, Rathmann W, Roden M, Peters A, van Duijn CM, Boomsma DI, Meitinger T, Wang-Sattler R Abstract OBJECTIVE: Metformin is used as a first-line oral treatment for type 2 diabetes (T2D). However, the underlying mechanism is not fully understood. Here, we aimed to comprehensively investigate the pleiotropic effects of metformin. RESEARCH DESIGN AND METHODS: We analyzed both metabolomic and genomic data of the population-based KORA cohort. To evaluate the effect of metformin treatment on metabolite concentrations, we quantified 131 metabolites in fasting serum samples and used multivariable linear regression models in three independent cross-sectional studies (n = 151 patients with T2D treated with metformin [mt-T2D]). Additionally, we used linear mixed-effect models to study the longitudinal KORA samples (n = 912) and performed mediation analyses to investigate the effects of metformin intake on blood lipid profiles. We combined genotyping data with the identified metformin-associated metabolites in KORA individuals (n = 1,809) and explored the underlying pathways. RESULTS: We found significantly lower (P < 5.0E-06) concentrations of three metabolites (acyl-alkyl phosphatidylcholines [PCs]) when comparing mt-T2D with four control groups who were not using glucose-lowering oral medication. These findings were controlled for conventional risk factors of T2D and replicated in two independent studies. Furthermore, we observed that the levels of these metabolites decreased significantly in patients after they started metformin treatment during 7 years' follow-up. The reduction of these metabolites was also associated with a lowered blood level of LDL cholesterol (LDL-C). Variations of these three metabolites were significantly associated with 17 genes (including FADS1 and FADS2) and controlled by AMPK, a metformin target. CONCLUSIONS: Our results indicate that metformin intake activates AMPK and consequently suppresses FADS, which leads to reduced levels of the three acyl-alkyl PCs and LDL-C. Our findings suggest potential beneficial effects of metformin in the prevention of cardiovascular disease. PMID: 26251408 [PubMed - indexed for MEDLINE]

Related Articles Isolation of Vaginal Lactobacilli and Characterization of Anti-Candida Activity. PLoS One. 2015;10(6):e0131220 Authors: Parolin C, Marangoni A, Laghi L, Foschi C, Ñahui Palomino RA, Calonghi N, Cevenini R, Vitali B Abstract Healthy vaginal microbiota is dominated by Lactobacillus spp., which form a critical line of defence against pathogens, including Candida spp. The present study aims to identify vaginal lactobacilli exerting in vitro activity against Candida spp. and to characterize their antifungal mechanisms of action. Lactobacillus strains were isolated from vaginal swabs of healthy premenopausal women. The isolates were taxonomically identified to species level (L. crispatus B1-BC8, L. gasseri BC9-BC14 and L. vaginalis BC15-BC17) by sequencing the 16S rRNA genes. All strains produced hydrogen peroxide and lactate. Fungistatic and fungicidal activities against C. albicans, C. glabrata, C. krusei, C. tropicalis, C. parapsilosis and C. lusitaniae were evaluated by broth micro-dilution method. The broadest spectrum of activity was observed for L. crispatus BC1, BC4, BC5 and L. vaginalis BC15, demonstrating fungicidal activity against all isolates of C. albicans and C. lusitaniae. Metabolic profiles of lactobacilli supernatants were studied by 1H-NMR analysis. Metabolome was found to be correlated with both taxonomy and activity score. Exclusion, competition and displacement experiments were carried out to investigate the interference exerted by lactobacilli toward the yeast adhesion to HeLa cells. Most Lactobacillus strains significantly reduced C. albicans adhesion through all mechanisms. In particular, L. crispatus BC2, L. gasseri BC10 and L. gasseri BC11 appeared to be the most active strains in reducing pathogen adhesion, as their effects were mediated by both cells and supernatants. Inhibition of histone deacetylases was hypothesised to support the antifungal activity of vaginal lactobacilli. Our results are prerequisites for the development of new therapeutic agents based on probiotics for prophylaxis and adjuvant therapy of Candida infection. PMID: 26098675 [PubMed - indexed for MEDLINE]

Related Articles Compartment resolved reference proteome map from highly purified naïve, activated, effector, and memory CD8⁺ murine immune cells. Proteomics. 2015 Jun;15(11):1808-12 Authors: Zanker D, Otto W, Chen W, von Bergen M, Tomm JM Abstract Differentiation of CD8(+) T lymphocytes into effector and memory cells is key for an adequate immune response and relies on complex interplay of pathways that convey signals from the cell surface to the nucleus. In this study, we investigated the proteome of four cytotoxic T-cell subtypes; naïve, recently activated effector, effector, and memory cells. Cells were fractionated into membrane, cytosol, soluble nuclear, chromatin-bound, and cytoskeletal compartments. Following LC-MS/MS analysis, identified peptides were analyzed via MaxQuant. Compartment fractionation and gel-LC-MS separation resulted in 2399 proteins identified in total. Comparison between the different subsets resulted in 146 significantly regulated proteins for naïve and effector cells, followed by 116 for activated, and 55 for memory cells. Besides Granzyme B signaling (for activated and/ or effector cells vs. naïve cells), the most prominent changes occurred in the TCA cycle and aspartate degradation. These changes suggest that correct balancing of metabolism is key for differentiation processes. All MS data have been deposited in the ProteomeXchange with identifier PXD001065 (http://proteomecentral.proteomexchange.org/dataset/PXD001065). PMID: 25643623 [PubMed - indexed for MEDLINE]

Related Articles Use of metabotyping for the delivery of personalised nutrition. Mol Nutr Food Res. 2015 Mar;59(3):377-85 Authors: O'Donovan CB, Walsh MC, Nugent AP, McNulty B, Walton J, Flynn A, Gibney MJ, Gibney ER, Brennan L Abstract SCOPE: Personalised nutrition can be defined as dietary advice that is tailored to an individual. In recent years, the concept of targeted nutrition has evolved, which involves delivering specific dietary advice to a group of phenotypically similar individuals or metabotypes. This study examined whether cluster analysis could be used to define metabotypes and developed a strategy for the delivery of targeted dietary advice. METHOD AND RESULTS: K-means clustering was employed to identify clusters based on four markers of metabolic health (triacylglycerols, total cholesterol, direct HDL cholesterol and glucose) (n = 896) using data from the National Adult Nutrition Survey. A decision tree approach was developed for the delivery of targeted dietary advice per cluster based on biochemical characteristics, anthropometry and blood pressure. The appropriateness of the advice was tested by comparison with individualised dietary advice manually compiled (n = 99). A mean match of 89.1% between the methods was demonstrated with a 100% match for two-thirds of participants. CONCLUSION: Good agreement was found between the individualised and targeted methods demonstrating the ability of this framework to deliver targeted dietary advice. This approach has the potential to be a fast and novel method for the delivery of targeted nutrition in clinical settings. PMID: 25410729 [PubMed - indexed for MEDLINE]

Related Articles Effects of dietary betaine supplementation subjected to heat stress on milk performances and physiology indices in dairy cow. Genet Mol Res. 2014;13(3):7577-86 Authors: Zhang L, Ying SJ, An WJ, Lian H, Zhou GB, Han ZY Abstract This study aimed to determine whether feeding betaine to cows elevates their production performance during summer heat stress. Thirty-two lactating Holstein cows were randomly divided into 4 groups: the control group, which received a total mixed ration (TMR), and 3 experimental groups that received TMR blended with 10 g/day (group I), 15 g/day (group II), and 20 g/day (group III) betaine for 8 weeks. Milk and blood were sampled throughout the experimental period. The average maximum and minimum air temperatures were 28.3 and 24.1°C, respectively. The average temperature-humidity index was 78.6 units. The results showed that feeding betaine to cows increased feed intake, milk yield, milk lactose, milk protein, plasma cortisol, glutathione peroxidase, superoxide dismutase, and malondialdehyde levels (P<0.05); however, it caused HSP70 levels to decrease (P<0.05). The milk performance of group II was significantly affected. These results indicate that supplementing betaine to the diet of dairy cows increases their milk performance and improves their antioxidant capacity; these processes help relieve the cow from heat stress. In conclusion, supplementing dairy cows with 15 g/day betaine generated the most positive influence on performance and productivity, and hence caused the greatest reduction in heat stress. PMID: 25222258 [PubMed - indexed for MEDLINE]

Related Articles Detection of Apoptotic Versus Autophagic Cell Death by Flow Cytometry. Methods Mol Biol. 2016;1419:1-16 Authors: Sica V, Maiuri MC, Kroemer G, Galluzzi L Abstract Different modes of regulated cell death (RCD) can be initiated by distinct molecular machineries and their morphological manifestations can be difficult to discriminate. Moreover, cells responding to stress often activate an adaptive response centered around autophagy, and whether such a response is cytoprotective or cytotoxic cannot be predicted based on morphological parameters only. Molecular definitions are therefore important to understand various RCD subroutines from a mechanistic perspective. In vitro, various forms of RCD including apoptosis and autophagic cell death can be easily discriminated from each other with assays that involve chemical or pharmacological interventions targeting key components of either pathway. Here, we detail a straightforward method to discriminate apoptosis from autophagic cell death by flow cytometry, based on the broad-spectrum caspase inhibitor Z-VAD-fmk and the genetic inhibition of ATG5. PMID: 27108427 [PubMed - as supplied by publisher]

Related Articles Neuronal metabolomics by ion mobility mass spectrometry in cocaine self-administering rats after early and late withdrawal. Anal Bioanal Chem. 2016 Apr 23; Authors: Zhang X, Chiu VM, Todd RP, Sorg BA, Hill HH Abstract The neuronal metabolomes in rat striatum (STR), prefrontal cortex (PFC), and nucleus accumbens (NAC) were analyzed by Hadamard transform ion mobility mass spectrometry (HT-IMMS) in order to reveal global and specific metabolic changes induced by cocaine self-administration after 1-day or 3-week withdrawal. Metabolite features were comprehensively separated and detected using HPLC-IMMS within minutes. Global metabolic differences were observed by PCA for comparisons between cocaine and saline treatments at 1-day withdrawal time. Metabolite features that were significantly changed were selected using PCA loadings' plot and unpaired LLL test and then tentatively identified by accurate m/z, yielding a complete profile of metabolic changes induced by cocaine self-administration. The majority of these changes were found at the 1-day withdrawal time, but several of them endured even after 3-week withdrawal from cocaine, and these changes were generally brain region specific. Putatively identified metabolites associated with oxidative stress and energy metabolism were also specifically investigated. We discovered that the dysregulation of creatine/creatinine was different between the STR and NAC, demonstrating that metabolic alterations are brain region specific. Glutathione and adenosine were also changed in their abundance, and the results agreed with previous studies. In general, this study provided a high-throughput analytical platform to perform metabolomics analyses with putative identifications for altered metabolite features induced by cocaine treatment, therefore revealing additional metabolic targets of cocaine-induced changes after early and extended withdrawal times. PMID: 27108279 [PubMed - as supplied by publisher]

Related Articles Integrative functional genomic analysis unveils the differing dysregulated metabolic processes across hepatocellular carcinoma stages. Gene. 2016 Apr 20; Authors: Ramesh V, Ganesan K Abstract Hepatocellular carcinoma (HCC) is a highly heterogeneous disease and the development of targeted therapeutics is still at an early stage. The 'omics' based genome-wide profiling comprising the transcriptome, miRNome and proteome are highly useful in identifying the deregulated molecular processes involved in hepatocarcinogenesis. One of the end products and processes of the central dogma being the metabolites and metabolic processes mediate the cellular functions. In recent years, metabolomics based investigations have revealed the major deregulated metabolic processes involved in carcinogenesis. However, the integrative analysis of the holistic metabolic processes with genomics is at an early stage. Since the gene-sets are highly useful in assessing the biological processes and pathways, we made an attempt to infer the deregulated cellular metabolic processes involved in HCC by employing metabolism associated gene-set enrichment analysis. Further, the metabolic process enrichment scores were integrated with the transcriptome profiles of HCC. Integrative analysis shows three distinct metabolic deregulations: i) hepatocyte function related molecular processes involving lipid/ fatty acid/ bile acid synthesis, ii) inflammatory processes with cytokine, sphingolipid & chondriotin sulphate metabolism and iii) enriched nucleotide metabolic process involving purine/pyrimidine & glucose mediated catabolic process, in hepatocarcinogenesis. The three distinct metabolic processes were found to occur both in tumor and liver cancer cell line profiles. Unsupervised hierarchical clustering of the metabolic processes along with clinical sample information has identified two major clusters based on AFP (alpha-fetoprotein) and metastasis. The study reveals the three major regulatory processes involved in HCC stages. PMID: 27107678 [PubMed - as supplied by publisher]

Related Articles Metabolomics to identify biomarkers and as a predictive tool in inflammatory diseases. Best Pract Res Clin Rheumatol. 2015 Dec;29(6):770-782 Authors: Jutley GS, Young SP Abstract There is an overwhelming need for a simple, reliable tool that aids clinicians in diagnosing, assessing disease activity and treating rheumatic conditions. Identification of biomarkers in partially understood inflammatory disorders has long been sought after as the Holy Grail of Rheumatology. Given the complex nature of inflammatory conditions, it has been difficult to earmark the potential biomarkers. Metabolomics, however, is promising in providing new insights into inflammatory conditions and also identifying such biomarkers. Metabolomic studies have generally revealed increased energy requirements for by-products of a hypoxic environment, leading to a characteristic metabolic fingerprint. Here, we discuss the significance of such studies and their potential as a biomarker. PMID: 27107512 [PubMed - as supplied by publisher]

Related Articles NMR-based fecal metabolomics fingerprinting as predictors of earlier diagnosis in patients with colorectal cancer. Oncotarget. 2016 Apr 16; Authors: Lin Y, Ma C, Liu C, Wang Z, Yang J, Liu X, Shen Z, Wu R Abstract Colorectal cancer (CRC) is a growing cause of mortality in developing countries, warranting investigation into its earlier detection for optimal disease management. A metabolomics based approach provides potential for noninvasive identification of biomarkers of colorectal carcinogenesis, as well as dissection of molecular pathways of pathophysiological conditions. Here, proton nuclear magnetic resonance spectroscopy (1HNMR) -based metabolomic approach was used to profile fecal metabolites of 68 CRC patients (stage I/II=20; stage III=25 and stage IV=23) and 32 healthy controls (HC). Pattern recognition through principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) was applied on 1H-NMR processed data for dimension reduction. OPLS-DA revealed that each stage of CRC could be clearly distinguished from HC based on their metabolomic profiles. Successive analyses identified distinct disturbances to fecal metabolites of CRC patients at various stages, compared with those in cancer free controls, including reduced levels of acetate, butyrate, propionate, glucose, glutamine, and elevated quantities of succinate, proline, alanine, dimethylglycine, valine, glutamate, leucine, isoleucine and lactate. These altered fecal metabolites potentially involved in the disruption of normal bacterial ecology, malabsorption of nutrients, increased glycolysis and glutaminolysis. Our findings revealed that the fecal metabolic profiles of healthy controls can be distinguished from CRC patients, even in the early stage (stage I/II), highlighting the potential utility of NMR-based fecal metabolomics fingerprinting as predictors of earlier diagnosis in CRC patients. PMID: 27107423 [PubMed - as supplied by publisher]

Related Articles Evaluation of the technical variations and the suitability of a hydrophilic interaction liquid chromatography-high resolution mass spectrometry (ZIC-pHILIC-Exactive orbitrap) for clinical urinary metabolomics study. J Chromatogr B Analyt Technol Biomed Life Sci. 2016 Apr 13;1022:199-205 Authors: Zhang T, Watson DG Abstract Although many hydrophilic interaction liquid chromatography-high resolution mass spectrometry (HILIC-HRMS) methods have been developed and applied for untargeted metabolite profiling in clinical metabolomics, according to the literature, the suitability of these HILIC-HRMS methods has not been fully evaluated with respect to their performance when they are subjected to statistical analysis. In this study, using a series of human urine samples we investigated the effect of technical variations on multivariate and univariate analysis of the data collected using a previously developed HILIC-HRMS method for untargeted urinary metabolite profiling in clinical metabolomics. The technical variation introduced by sample preparation was more significant than that produced by the HILIC-HRMS method. By using an orthogonal partial least squares (OPLS) model, subtle fold-changes were accurately measured in the urine samples spiked with (13)C and (15)N isotope labelled amino acids at different concentrations. The robustness of this HILIC method was also evaluated by analysing the obtained data from a single urine sample following manipulation of several primary LC parameters. High reproducibility in the chromatographic performance of three ZIC-pHILIC columns with different batch numbers indicated the reliability of the polymer based zwitterionic stationary phase allowing column replacement without compromising the performance of the method. PMID: 27107246 [PubMed - as supplied by publisher]

Related Articles Identification of a polyketide synthase involved in sorbicillin biosynthesis by Penicillium chrysogenum. Appl Environ Microbiol. 2016 Apr 22; Authors: Salo O, Guzmán-Chávez F, Ries MI, Lankhorst PP, Bovenberg RA, Vreeken RJ, Driessen AJ Abstract Secondary metabolism in Penicillium chrysogenum was intensively subjected to classical strain improvement (CSI) resulting industrial strains producing high levels of β-lactams. During this process, the production of yellow pigments including sorbicillinoids was eliminated as part of a strategy to enable the rapid purification of β-lactams. Here we report the identification of the polyketide synthase (PKS) gene essential for sorbicillinoids biosynthesis in P. chrysogenum We demonstrate that the production of polyketide precursors like sorbicillinol and dihydrosorbicillinol as well as their derivatives bisorbicillinoids require the function of a highly reducing PKS encoded by the gene Pc21g05080 (pks13). This gene belongs to the cluster that was mutated and transcriptionally silenced during the strain improvement program. Using an improved β-lactam producing strain, repair of the mutation in pks13 led to the restoration of sorbicillinoids production. This now enable genetic studies on the mechanism of sorbicillinoid biosynthesis in P. chrysogenum and opens new perspectives for pathway engineering. IMPORTANCE: Sorbicillinoids are secondary metabolites with anti-viral, anti-inflammatory and anti-microbial activity produced by filamentous fungi. This study identified the gene cluster responsible for sorbicillinoids formation in Penicillium chrysogenum now allow engineering of this diverse group of compounds. PMID: 27107123 [PubMed - as supplied by publisher]

Related Articles High-resolution magic angle spinning (1)H nuclear magnetic resonance spectroscopy metabolomics of hyperfunctioning parathyroid glands. Surgery. 2016 Apr 20; Authors: Battini S, Imperiale A, Taïeb D, Elbayed K, Cicek AE, Sebag F, Brunaud L, Namer IJ Abstract BACKGROUND: Primary hyperparathyroidism (PHPT) may be related to a single gland disease or multiglandular disease, which requires specific treatments. At present, an operation is the only curative treatment for PHPT. Currently, there are no biomarkers available to identify these 2 entities (single vs. multiple gland disease). The aims of the present study were to compare (1) the tissue metabolomics profiles between PHPT and renal hyperparathyroidism (secondary and tertiary) and (2) single gland disease with multiglandular disease in PHPT using metabolomics analysis. METHODS: The method used was (1)H high-resolution magic angle spinning nuclear magnetic resonance spectroscopy. Forty-three samples from 32 patients suffering from hyperparathyroidism were included in this study. RESULTS: Significant differences in the metabolomics profile were assessed according to PHPT and renal hyperparathyroidism. A bicomponent orthogonal partial least square-discriminant analysis showed a clear distinction between PHPT and renal hyperparathyroidism (R(2)Y = 0.85, Q(2) = 0.63). Interestingly, the model also distinguished single gland disease from multiglandular disease (R(2)Y = 0.96, Q(2) = 0.55). A network analysis was also performed using the Algorithm to Determine Expected Metabolite Level Alterations Using Mutual Information (ADEMA). Single gland disease was accurately predicted by ADEMA and was associated with higher levels of phosphorylcholine, choline, glycerophosphocholine, fumarate, succinate, lactate, glucose, glutamine, and ascorbate compared with multiglandular disease. CONCLUSION: This study shows for the first time that (1)H high-resolution magic angle spinning nuclear magnetic resonance spectroscopy is a reliable and fast technique to distinguish single gland disease from multiglandular disease in patients with PHPT. The potential use of this method as an intraoperative tool requires specific further studies. PMID: 27106795 [PubMed - as supplied by publisher]

Amino acid deprivation promotes intestinal homeostasis through autophagy. Oncotarget. 2016 Apr 19; Authors: Galluzzi L, Kroemer G PMID: 27105494 [PubMed - as supplied by publisher]

Posttranslational modulation of FoxO1 contributes to cardiac remodeling in post-ischemic heart failure. Atherosclerosis. 2016 Apr 7;249:148-156 Authors: Kappel BA, Stöhr R, De Angelis L, Mavilio M, Menghini R, Federici M Abstract OBJECTIVE: Forkhead box protein O1 (FoxO1) plays a key role in energy homeostasis, stress response and autophagy and is dysregulated in diabetes and ischemia. We investigated cardiac FoxO1 expression and posttranstranslational modifications after myocardial infarction (MI) and further tested if active posttranstranslational modulation of FoxO1 can alter cardiac remodeling in postischemic heart failure. METHODS: Non-diabetic and diabetic C57BL/6 mice were subjected to MI by ligation of left anterior descending artery. In selected experiments we combined this model with intramyocardial injection of adenovirus expressing different isoforms of FoxO1. We used Millar catheter, histology, Western blot and metabolomics for further analyses. RESULTS: We show that after MI total cardiac FoxO1 is downregulated and partly recovers after 7 days. This downregulation is accompanied by fundamental posttranslational modifications of FoxO1, particularly acetylation. Adenovirus experiments revealed smaller infarction size and improved heart function in mice expressing a constitutively deacetylated variant of FoxO1 compared to a wild type variant of FoxO1 in both non-diabetic (MI size: -13.4 ± 3.5%; LVDP: +29.1 ± 9.4  mmHg; p < 0.05) and diabetic mice (MI size: -17.6 ± 3.7%; LVDP: +10.9 ± 3.6  mmHg; p < 0.05). Metabolomics analyses showed alterations in metabolites connected to muscle breakdown, collagen/elastin and energy metabolism between the two groups. CONCLUSION: First, our results demonstrate that myocardial ischemia is associated with downregulation and posttranslational modification of cardiac FoxO1. Second, we show in a mouse model of postischemic heart failure that posttranslational modulation of FoxO1 alters heart function involving collagen and protein metabolism. Therefore, posttranslational modifications of FoxO1 could be an option to target remodeling processes in postischemic heart failure. PMID: 27105158 [PubMed - as supplied by publisher]

Precision Medicine for psychopharmacology: a general introduction. Expert Rev Neurother. 2016 Apr 22; Authors: Shin C, Han C, Pae CU, Patkar AA Abstract INTRODUCTION: Precision medicine is an emerging medical model that can provide accurate diagnoses and tailored therapeutic strategies for patients based on data pertaining to genes, microbiomes, environment, family history and lifestyle. Areas covered: Here, we provide basic information about precision medicine and newly introduced concepts, such as the precision medicine ecosystem and big data processing, and omics technologies including pharmacogenomics, pharamacometabolomics, pharmacoproteomics, pharmacoepigenomics, connectomics and exposomics. The authors review the current state of omics in psychiatry and the future direction of psychopharmacology as it moves towards precision medicine. Expert Commentary: Advances in precision medicine have been facilitated by achievements in multiple fields, including large-scale biological databases, powerful methods for characterizing patients (such as genomics, proteomics, metabolomics, diverse cellular assays, and even social networks and mobile health technologies), and computer-based tools for analyzing large amounts of data. PMID: 27104961 [PubMed - as supplied by publisher]

A Chemo-Enzymatic Road Map to the Synthesis of CoA Esters. Molecules. 2016;21(4) Authors: Peter DM, Vögeli B, Cortina NS, Erb TJ Abstract Coenzyme A (CoA) is a ubiquitous cofactor present in every known organism. The thioesters of CoA are core intermediates in many metabolic processes, such as the citric acid cycle, fatty acid biosynthesis and secondary metabolism, including polyketide biosynthesis. Synthesis of CoA-thioesters is vital for the study of CoA-dependent enzymes and pathways, but also as standards for metabolomics studies. In this work we systematically tested five chemo-enzymatic methods for the synthesis of the three most abundant acyl-CoA thioester classes in biology; saturated acyl-CoAs, α,β-unsaturated acyl-CoAs (i.e., enoyl-CoA derivatives), and α-carboxylated acyl-CoAs (i.e., malonyl-CoA derivatives). Additionally we report on the substrate promiscuity of three newly described acyl-CoA dehydrogenases that allow the simple conversion of acyl-CoAs into enoyl-CoAs. With these five methods, we synthesized 26 different CoA-thioesters with a yield of 40% or higher. The CoA esters produced range from short- to long-chain, include branched and α,β-unsaturated representatives as well as other functional groups. Based on our results we provide a general guideline to the optimal synthesis method of a given CoA-thioester in respect to its functional group(s) and the commercial availability of the precursor molecule. The proposed synthetic routes can be performed in small scale and do not require special chemical equipment, making them convenient also for biological laboratories. PMID: 27104508 [PubMed - as supplied by publisher]

Translational and emerging clinical applications of metabolomics in cardiovascular disease diagnosis and treatment. Eur J Prev Cardiol. 2016 Apr 21; Authors: Dona AC, Coffey S, Figtree G Abstract Numerous molecular screening strategies have recently been developed to measure the chemical diversity of a population's biofluids with the ultimate aim to provide clinicians, medical scientists and epidemiologists with a clearer picture of the presence and severity of cardiovascular disease; prognosis; and response to treatment. Current cardiology practice integrates clinical history and examination with state-of-the-art imaging, invasive measures, and electrical interrogation. Biomarkers in common clinical use are relatively limited to troponin and brain natriuretic peptide, dependent on damage to heart muscle, or myocyte 'stretch' respectively. Although they have been recently applied to risk stratification in asymptomatic individuals at higher risk, the development of markers capable of detecting earlier phases of disease development would facilitate targeted strategies to prevent pathological complications in the general community. Metabolomics is the systematic study of small molecules in biological fluids. Profiling strategies aim to comprehensively measure and quantify such biomarkers in a fast, cost-effective and clinically informative manner. Techniques tend to be applied in an unbiased fashion, with advanced statistical methods allowing for identification of signature profiles in particular cohorts. In this manner, metabolomics has the potential to identify new pathophysiological pathways, and thus therapeutic targets, as well as assist in improved risk-stratification and personalized cardiovascular medicine. The latter has great potential in the primary and secondary cardiovascular disease prevention settings, integrating known and as yet unidentified host and environmental factors. The current review discusses applications of metabolomic techniques relevant to both the research and the clinical cardiologist. PMID: 27103630 [PubMed - as supplied by publisher]

Metabolic changes may precede proteostatic dysfunction in a Drosophila model of amyloid beta peptide toxicity. Neurobiol Aging. 2016 May;41:39-52 Authors: Ott S, Vishnivetskaya A, Malmendal A, Crowther DC Abstract Amyloid beta (Aβ) peptide aggregation is linked to the initiation of Alzheimer's disease; accordingly, aggregation-prone isoforms of Aβ, expressed in the brain, shorten the lifespan of Drosophila melanogaster. However, the lethal effects of Aβ are not apparent until after day 15. We used shibire(TS) flies that exhibit a temperature-sensitive paralysis phenotype as a reporter of proteostatic robustness. In this model, we found that increasing age but not Aβ expression lowered the flies' permissive temperature, suggesting that Aβ did not exert its lethal effects by proteostatic disruption. Instead, we observed that chemical challenges, in particular oxidative stressors, discriminated clearly between young (robust) and old (sensitive) flies. Using nuclear magnetic resonance spectroscopy in combination with multivariate analysis, we compared water-soluble metabolite profiles at various ages in flies expressing Aβ in their brains. We observed 2 genotype-linked metabolomic signals, the first reported the presence of any Aβ isoform and the second the effects of the lethal Arctic Aβ. Lethality was specifically associated with signs of oxidative respiration dysfunction and oxidative stress. PMID: 27103517 [PubMed - in process]