PubMed

Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice. Sci Rep. 2016;6:26933 Authors: Trammell SA, Weidemann BJ, Chadda A, Yorek MS, Holmes A, Coppey LJ, Obrosov A, Kardon RH, Yorek MA, Brenner C Abstract Male C57BL/6J mice raised on high fat diet (HFD) become prediabetic and develop insulin resistance and sensory neuropathy. The same mice given low doses of streptozotocin are a model of type 2 diabetes (T2D), developing hyperglycemia, severe insulin resistance and diabetic peripheral neuropathy involving sensory and motor neurons. Because of suggestions that increased NAD(+) metabolism might address glycemic control and be neuroprotective, we treated prediabetic and T2D mice with nicotinamide riboside (NR) added to HFD. NR improved glucose tolerance, reduced weight gain, liver damage and the development of hepatic steatosis in prediabetic mice while protecting against sensory neuropathy. In T2D mice, NR greatly reduced non-fasting and fasting blood glucose, weight gain and hepatic steatosis while protecting against diabetic neuropathy. The neuroprotective effect of NR could not be explained by glycemic control alone. Corneal confocal microscopy was the most sensitive measure of neurodegeneration. This assay allowed detection of the protective effect of NR on small nerve structures in living mice. Quantitative metabolomics established that hepatic NADP(+) and NADPH levels were significantly degraded in prediabetes and T2D but were largely protected when mice were supplemented with NR. The data justify testing of NR in human models of obesity, T2D and associated neuropathies. PMID: 27230286 [PubMed - in process]

The use of mass spectrometry for analysing metabolite biomarkers in epidemiology: methodological and statistical considerations for application to large numbers of biological samples. Eur J Epidemiol. 2016 May 26; Authors: Lind MV, Savolainen OI, Ross AB Abstract Data quality is critical for epidemiology, and as scientific understanding expands, the range of data available for epidemiological studies and the types of tools used for measurement have also expanded. It is essential for the epidemiologist to have a grasp of the issues involved with different measurement tools. One tool that is increasingly being used for measuring biomarkers in epidemiological cohorts is mass spectrometry (MS), because of the high specificity and sensitivity of MS-based methods and the expanding range of biomarkers that can be measured. Further, the ability of MS to quantify many biomarkers simultaneously is advantageously compared to single biomarker methods. However, as with all methods used to measure biomarkers, there are a number of pitfalls to consider which may have an impact on results when used in epidemiology. In this review we discuss the use of MS for biomarker analyses, focusing on metabolites and their application and potential issues related to large-scale epidemiology studies, the use of MS "omics" approaches for biomarker discovery and how MS-based results can be used for increasing biological knowledge gained from epidemiological studies. Better understanding of the possibilities and possible problems related to MS-based measurements will help the epidemiologist in their discussions with analytical chemists and lead to the use of the most appropriate statistical tools for these data. PMID: 27230258 [PubMed - as supplied by publisher]

Metabolism, Metabolomics, and Nutritional Support of Patients with Sepsis. Clin Chest Med. 2016 Jun;37(2):321-31 Authors: Englert JA, Rogers AJ Abstract Sepsis is characterized by profound changes in systemic and cellular metabolism that disrupt normal metabolic homeostasis. These metabolic changes can serve as biomarkers for disease severity. Lactate, a metabolite of anaerobic metabolism, is the most widely used ICU biomarker and it is incorporated into multiple management algorithms. Technological advances now make broader metabolic profiling possible, with early studies identifying metabolic changes associated with sepsis mortality. Finally, given the marked changes in metabolism in sepsis and the association of worse prognosis in patients with severe metabolic derangements, we summarize the seminal trials conducted to optimize nutrition in the ICU. PMID: 27229648 [PubMed - in process]

Plasma metabolomic profile and potential biomarkers for missed abortion. Biomed Chromatogr. 2016 May 26; Authors: Fei H, Hou J, Wu Z, Zhang L, Zhao H, Dong X, Chen Y Abstract A missed abortion(MA)is an in utero death of the embryo or foetus before the 20th week of gestation with retained products of conception, and this condition is currently common in China. In order to discover novel biomarkers for MA, ultrahigh performance liquid chromatography (UHPLC-MS) was applied to study plasma metabolite profiles for 33 patients with MA and 29 control subjects. Thirty-seven differential plasma metabolites were found to discriminate between the two groups in the initial cohort (15 subjects with MA and 15 healthy controls). The feasibility of using these potential biomarkers to predict MA was further evaluated in the validation cohort (18 subjects with MA and 14 healthy controls) and 15 had an area under the receiver operating characteristic curve (AUC) of >0.80, making them satisfactory. Tryptophan metabolism and sphingolipid metabolism were identified as important potential target pathways for MA using metabolic pathway impact analysis. Furthermore, 3 of the 15 satisfactory metabolites (glyceric acid, indole and sphingosine) were combined to establish a predictive model with 100% sensitivity and 100% specificity in the validation cohort. Taken together, these results suggest that MA results in significant disturbance of metabolism and those various novel biomarkers have satisfactory diagnostic and predictive power for MA. PMID: 27229294 [PubMed - as supplied by publisher]

Related Articles Ancient Wheat Diet Delays Diabetes Development in a Type 2 Diabetes Animal Model. Rev Diabet Stud. 2014 Fall-Winter;11(3-4):245-57 Authors: Thorup AC, Gregersen S, Jeppesen PB Abstract AIM: The main objective was to investigate the physiological effects of ancient wheat whole grain flour diets on the development and progression of type 2 diabetes in Zucker diabetic fatty (ZDF) rats, and specifically to look at the acute glycemic responses. METHODS: An intervention study was conducted, involving 40 ZDF rats consuming one of 5 different diets (emmer, einkorn, spelt, rye and refined wheat) for 9 weeks. Refined wheat flour and whole grain rye flour were included as negative and positive controls, respectively. RESULTS: After 9 weeks of intervention, a downregulation of the hepatic genes PPAR-α, GLUT2, and SREBP-1c was observed in the emmer group compared to the control wheat group. Likewise, expression of hepatic SREBP-2 was lower for emmer, einkorn, and rye compared with the control group. Furthermore, spelt and rye induced a low acute glycemic response. The wheat group had higher HDL- and total cholesterol levels. CONCLUSIONS: Ancient wheat diets caused a downregulation of key regulatory genes involved in glucose and fat metabolism, equivalent to a prevention or delay of diabetes development. Spelt and rye induced a low acute glycemic response compared to wheat. PMID: 26177485 [PubMed - indexed for MEDLINE]

Related Articles Recent Advances and Understanding of Using Probiotic-Based Interventions to Restore Homeostasis of the Microbiome for the Prevention/Therapy of Bacterial Diseases. Microbiol Spectr. 2016 Apr;4(2) Authors: Suchodolski JS, Jergens AE Abstract The importance of the microbiome in health and disease has galvanized interest in using manipulations of the gastrointestinal ecosystem to prevent and/or combat gut bacterial infections and to restore mucosal homeostasis in patients with generalized microbial imbalances (i.e., dysbiosis), including the human inflammatory bowel diseases, Crohn's disease, and ulcerative colitis. Probiotics, prebiotics, or their combination use (i.e., synbiotics) are one mechanism for modifying the microbiota and exerting direct and indirect effects on the host immune responses and metabolomics profiles. These beneficial effects are transferred through various pathways, including the production of antimicrobial peptides, promoting the growth of beneficial microbes and enhancing immunomodulatory functions via various metabolites. While probiotic therapy has been used empirically for decades with mixed success, the recent advances in molecular and mass spectrophotometric techniques for the characterization of the complexity and diversity of the intestinal microbiome has aided in better understanding of host-microbe interactions. It is important to better understand the functional properties of the microbiome, because it is now clear that the microbiota secretes many metabolites that have a direct impact on host immune responses. This information will improve selection of the most appropriate probiotic strains that selectively target intestinal disease processes. PMID: 27227298 [PubMed - as supplied by publisher]

Related Articles Circadian regulation of lipid metabolism. Proc Nutr Soc. 2016 May 26;:1-11 Authors: Gooley JJ Abstract The circadian system temporally coordinates daily rhythms in feeding behaviour and energy metabolism. The objective of the present paper is to review the mechanisms that underlie circadian regulation of lipid metabolic pathways. Circadian rhythms in behaviour and physiology are generated by master clock neurons in the suprachiasmatic nucleus (SCN). The SCN and its efferent targets in the hypothalamus integrate light and feeding signals to entrain behavioural rhythms as well as clock cells located in peripheral tissues, including the liver, adipose tissue and muscle. Circadian rhythms in gene expression are regulated at the cellular level by a molecular clock comprising a core set of clock genes/proteins. In peripheral tissues, hundreds of genes involved in lipid biosynthesis and fatty acid oxidation are rhythmically activated and repressed by clock proteins, hence providing a direct mechanism for circadian regulation of lipids. Disruption of clock gene function results in abnormal metabolic phenotypes and impaired lipid absorption, demonstrating that the circadian system is essential for normal energy metabolism. The composition and timing of meals influence diurnal regulation of metabolic pathways, with food intake during the usual rest phase associated with dysregulation of lipid metabolism. Recent studies using metabolomics and lipidomics platforms have shown that hundreds of lipid species are circadian-regulated in human plasma, including but not limited to fatty acids, TAG, glycerophospholipids, sterol lipids and sphingolipids. In future work, these lipid profiling approaches can be used to understand better the interaction between diet, mealtimes and circadian rhythms on lipid metabolism and risk for obesity and metabolic diseases. PMID: 27225642 [PubMed - as supplied by publisher]

Related Articles Editorial on "Evaluation of steroidomics by liquid chromatography hyphenated to mass spectrometry as a powerful analytical strategy for measuring human steroid perturbations" by Fabienne Jeanneret, David Tonoli, Michel F. Rossier, Martial Saugy, Julien Boccard and S. Rudaz. J Chromatogr A. 2016 Jan 22;1430:96 Authors: Fanali S PMID: 26627585 [PubMed - indexed for MEDLINE]

Phamacometabolomics study identifies circulating spermidine and tryptophan as potential biomarkers associated with the complete pathological response to trastuzumab-paclitaxel neoadjuvant therapy in HER-2 positive breast cancer. Oncotarget. 2016 May 19; Authors: Miolo G, Muraro E, Caruso D, Crivellari D, Ash A, Scalone S, Lombardi D, Rizzolio F, Giordano A, Corona G Abstract Defining biomarkers that predict therapeutic effects and adverse events is a crucial mandate to guide patient selection for personalized cancer treatments. In the present study, we applied a pharmacometabolomics approach to identify biomarkers potentially associated with pathological complete response to trastuzumab-paclitaxel neoadjuvant therapy in HER-2 positive breast cancer patients. Based on histological response the 34 patients enrolled in the study were subdivided into two groups: good responders (n = 15) and poor responders (n = 19). The pre-treatment serum targeted metabolomics profile of all patients were analyzed by liquid chromatography tandem mass spectrometry and the differences in the metabolomics profile between the two groups was investigated by multivariate partial least squares discrimination analysis. The most relevant metabolites that differentiate the two groups of patients were spermidine and tryptophan. The Good responders showed higher levels of spermidine and lower amounts of tryptophan compared with the poor responders (p < 0.001, q < 0.05). The serum level of these two metabolites identified patients who achieved a pathological complete response with a sensitivity of 90% [0.79-1.00] and a specificity of 0.87% [0.67-1.00]. These preliminary results support the role played by the individual patients' metabolism in determining the response to cancer treatments and may be a useful tool to select patients that are more likely to benefit from the trastuzumab-paclitaxel treatment. PMID: 27223427 [PubMed - as supplied by publisher]

Use of Metabolomics to Trend Recovery and Therapy After Injury in Critically Ill Trauma Patients. JAMA Surg. 2016 May 25;:e160853 Authors: Parent BA, Seaton M, Sood RF, Gu H, Djukovic D, Raftery D, O'Keefe GE Abstract Importance: Metabolomics is the broad and parallel study of metabolites within an organism and provides a contemporaneous snapshot of physiologic state. Use of metabolomics in the clinical setting may help achieve precision medicine for those who have experienced trauma, where diagnosis and treatment are tailored to the individual patient. Objective: To examine whether metabolomics can (1) distinguish healthy volunteers from trauma patients and (2) quantify changes in catabolic metabolites over time after injury. Design, Setting, and Participants: Prospective cohort study with enrollment from September 2014 to May 2015 at an urban, level 1 trauma center. Included in the study were 10 patients with severe blunt trauma admitted within 12 hours of injury with systolic blood pressure less than 90 mm Hg or base deficit greater than 6 mEq/L and 5 healthy volunteers. Plasma samples (n = 35) were obtained on days 1, 3, and 7, and they were analyzed using mass spectrometry. Main Outcomes and Measures: Principal component analyses, multiple linear regression, and paired t tests were used to select biomarkers of interest. A broad-based metabolite profile comparison between trauma patients and healthy volunteers was performed. Specific biomarkers of interest were oxidative catabolites. Results: Trauma patients had a median age of 45 years and a median injury severity score of 43 (interquartile range, 34-50). Healthy fasting volunteers had a median age of 33 years. Compared with healthy volunteers, trauma patients showed oxidative stress on day 1: niacinamide concentrations were a mean (interquartile range) of 0.95 (0.30-1.45) relative units for trauma patients vs 1.06 (0.96-1.09) relative units for healthy volunteers (P = .02), biotin concentrations, 0.43 (0.27-0.58) relative units for trauma patients vs 1.21 (0.93-1.56) relative units for healthy volunteers (P = .049); and choline concentrations, 0.17 (0.09-0.22) relative units for trauma patients vs 0.21 (0.18-0.22) relative units for healthy volunteers (P = .004). Trauma patients showed lower nucleotide synthesis on day 1: adenylosuccinate concentrations were 0.08 (0.04-0.12) relative units for trauma patients vs 0.15 (0.14-0.17) relative units for healthy volunteers (P = .02) and cytidine concentrations were 1.44 (0.95-1.73) relative units for trauma patients vs 1.74 (1.62-1.98) relative units for healthy volunteers (P = .05). From trauma day 1 to day 7, trauma patients showed increasing muscle catabolism: serine levels increased from 42.03 (31.20-54.95) µM to 79.37 (50.29-106.37) µM (P = .002), leucine levels increased from 69.21 (48.36-99.89) µM to 114.16 (92.89-143.52) µM (P = .004), isoleucine levels increased from 20.43 (10.92-27.41) µM to 48.72 (36.28-64.84) µM (P < .001), and valine levels increased from 122.56 (95.63-140.61) µM to 190.52 (136.68-226.07) µM (P = .004). There was an incomplete reversal of oxidative stress. Conclusions and Relevance: Metabolomics can function as a serial, comprehensive, and potentially personalized tool to characterize metabolism after injury. A targeted metabolomics approach was associated with ongoing oxidative stress, impaired nucleotide synthesis, and initial suppression of protein metabolism followed by increased nitrogen turnover. This technique may provide new therapeutic and nutrition targets in critically injured patients. PMID: 27223119 [PubMed - as supplied by publisher]

Future paradigms for precision oncology. Oncotarget. 2016 May 19; Authors: Klement GL, Arkun K, Valik D, Roffidal T, Hashemi A, Klement C, Carmassi P, Rietman E, Slaby O, Mazanek P, Mudry P, Kovacs G, Kiss C, Norga K, Konstantinov D, André N, Slavc I, Berg HV, Kolenova A, Kren L, Tuma J, Skotakova J, Sterba J Abstract Research has exposed cancer to be a heterogeneous disease with a high degree of inter-tumoral and intra-tumoral variability. Individual tumors have unique profiles, and these molecular signatures make the use of traditional histology-based treatments problematic. The conventional diagnostic categories, while necessary for care, thwart the use of molecular information for treatment as molecular characteristics cross tissue types.This is compounded by the struggle to keep abreast the scientific advances made in all fields of science, and by the enormous challenge to organize, cross-reference, and apply molecular data for patient benefit. In order to supplement the site-specific, histology-driven diagnosis with genomic, proteomic and metabolomics information, a paradigm shift in diagnosis and treatment of patients is required.While most physicians are open and keen to use the emerging data for therapy, even those versed in molecular therapeutics are overwhelmed with the amount of available data. It is not surprising that even though The Human Genome Project was completed thirteen years ago, our patients have not benefited from the information. Physicians cannot, and should not be asked to process the gigabytes of genomic and proteomic information on their own in order to provide patients with safe therapies. The following consensus summary identifies the needed for practice changes, proposes potential solutions to the present crisis of informational overload, suggests ways of providing physicians with the tools necessary for interpreting patient specific molecular profiles, and facilitates the implementation of quantitative precision medicine. It also provides two case studies where this approach has been used. PMID: 27223079 [PubMed - as supplied by publisher]

Mechanisms of Diabetes Improvement Following Bariatric/Metabolic Surgery. Diabetes Care. 2016 Jun;39(6):893-901 Authors: Batterham RL, Cummings DE Abstract More than 20 years ago, Pories et al. published a seminal article, "Who Would Have Thought It? An Operation Proves to Be the Most Effective Therapy for Adult-Onset Diabetes Mellitus." This was based on their observation that bariatric surgery rapidly normalized blood glucose levels in obese people with type 2 diabetes mellitus (T2DM), and 10 years later, almost 90% remained diabetes free. Pories et al. suggested that caloric restriction played a key role and that the relative contributions of proximal intestinal nutrient exclusion, rapid distal gut nutrient delivery, and the role of gut hormones required further investigation. These findings of T2DM improvement/remission after bariatric surgery have been widely replicated, together with the observation that bariatric surgery prevents or delays incident T2DM. Over the ensuing two decades, important glucoregulatory roles of the gastrointestinal (GI) tract have been firmly established. However, the physiological and molecular mechanisms underlying the beneficial glycemic effects of bariatric surgery remain incompletely understood. In addition to the mechanisms proposed by Pories et al., changes in bile acid metabolism, GI tract nutrient sensing and glucose utilization, incretins, possible anti-incretin(s), and the intestinal microbiome are implicated. These changes, acting through peripheral and/or central pathways, lead to reduced hepatic glucose production, increased tissue glucose uptake, improved insulin sensitivity, and enhanced β-cell function. A constellation of factors, rather than a single overarching mechanism, likely mediate postoperative glycemic improvement, with the contributing factors varying according to the surgical procedure. Thus, different bariatric/metabolic procedures provide us with experimental tools to probe GI tract physiology. Embracing this approach through the application of detailed phenotyping, genomics, metabolomics, and gut microbiome studies will enhance our understanding of metabolic regulation and help identify novel therapeutic targets. PMID: 27222547 [PubMed - in process]

Screening of Intestinal Bacterial Metabolites of Platycodin D Using Ultra-Performance Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry. Am J Chin Med. 2016 May 24;:1-17 Authors: Zhang W, Qian SH, Qian DW, Li SL Abstract Platycodin D (PD), a bioactive triterpenoid saponin isolated from Platycodi Radix (PR), possesses a vast range of biological activities. Although the pharmacological activities and pharmacokinetics of PD have been well demonstrated, information regarding the intestinal metabolisms of PD is very limited. In this study, human and rat fecal microflora were prepared and anaerobically incubated with PD at 37(∘)C for 48 h, respectively. A highly sensitive and specific ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was developed for the analysis of PD and related metabolites in the reaction samples. A liquid-liquid extraction method was used for sample pretreatment and the chromatographic separation was performed on a 1.7 μm particle size Syncronis C18 column using gradient elution system. Finally, a total of seven metabolites were detected and tentatively identified, such as the demethylation metabolite (M1), deoxidation metabolites (M3, M7) and hydrolysis at the C-28 oligosaccharide metabolites (M5, M6), which were first discovered in this experiment. The results indicate that hydrolysis, demethylation, dehydroxylation, and acetylation were the major metabolic pathways of PDin vitro. Additionally, four bacterial strains from human feces including Enterococcus sp.41, Bacillus sp.46, Escherichia sp.49A andEscherichia sp.64 were detected and further identified with 16S rRNA gene sequencing due to their relatively strong metabolic capacity toward PD. The present study provides important information about the metabolism of PD, which will help elucidate the impact of intestinal bacteria on this active component. PMID: 27222071 [PubMed - as supplied by publisher]

Metabolomics as a tool in the identification of dietary biomarkers. Proc Nutr Soc. 2016 May 25;:1-12 Authors: Gibbons H, Brennan L Abstract Current dietary assessment methods including FFQ, 24-h recalls and weighed food diaries are associated with many measurement errors. In an attempt to overcome some of these errors, dietary biomarkers have emerged as a complementary approach to these traditional methods. Metabolomics has developed as a key technology for the identification of new dietary biomarkers and to date, metabolomic-based approaches have led to the identification of a number of putative biomarkers. The three approaches generally employed when using metabolomics in dietary biomarker discovery are: (i) acute interventions where participants consume specific amounts of a test food, (ii) cohort studies where metabolic profiles are compared between consumers and non-consumers of a specific food and (iii) the analysis of dietary patterns and metabolic profiles to identify nutritypes and biomarkers. The present review critiques the current literature in terms of the approaches used for dietary biomarker discovery and gives a detailed overview of the currently proposed biomarkers, highlighting steps needed for their full validation. Furthermore, the present review also evaluates areas such as current databases and software tools, which are needed to advance the interpretation of results and therefore enhance the utility of dietary biomarkers in nutrition research. PMID: 27221515 [PubMed - as supplied by publisher]

NMR detection in biofluid extracts at sub-μM concentrations via para-H2 induced hyperpolarization. Analyst. 2016 May 25; Authors: Reile I, Eshuis N, Hermkens NK, van Weerdenburg BJ, Feiters MC, Rutjes FP, Tessari M Abstract NMR spectroscopy is one of the most powerful techniques to simultaneously obtain qualitative and quantitative information in chemical analysis. Despite its versatility, the applications of NMR in the study of biofluids are often limited by the insensitivity of the technique, further aggravated by the poor signal dispersion in the (1)H spectra. Recent advances in para-H2 induced hyperpolarization have proven to address both these limitations for specific classes of compounds. Herein, this approach is for the first time applied for quantitative determination in biofluid extracts. We demonstrate that a combination of solid phase extraction, para-hydrogen induced hyperpolarization and selective NMR detection quickly reveals a doping substance, nikethamide, at sub-μM concentrations in urine. We suggest that this method can be further optimized for the detection of different analytes in various biofluids, anticipating a wider application of hyperpolarized NMR in metabolomics and pharmacokinetics studies in the near future. PMID: 27221513 [PubMed - as supplied by publisher]

Cytofluorometric Quantification of Cell Death Elicited by NLR Proteins. Methods Mol Biol. 2016;1417:231-45 Authors: Sica V, Manic G, Kroemer G, Vitale I, Galluzzi L Abstract Nucleotide-binding domain and leucine-rich repeat containing (NLR) proteins, also known as NOD-like receptors, are critical components of the molecular machinery that senses intracellular danger signals to initiate an innate immune response against invading pathogens or endogenous sources of hazard. The best characterized effect of NLR signaling is the secretion of various cytokines with immunostimulatory effects, including interleukin (IL)-1β and IL-18. Moreover, at least under specific circumstances, NLRs can promote regulated variants of cell death. Here, we detail two protocols for the cytofluorometric quantification of cell death-associated parameters that can be conveniently employed to assess the lethal activity of specific NLRs or their ligands. PMID: 27221495 [PubMed - in process]

Changes in serum metabolites with the stage of chronic kidney disease: Comparison of diabetes and non-diabetes. Clin Chim Acta. 2016 May 21; Authors: Lee J, Choi JY, Kwon YK, Lee D, Jung HY, Ryu HM, Cho JH, Ryu DH, Kim YL, Hwang GS Abstract BACKGROUND: The renal dysfunction of chronic kidney disease (CKD) alters serum metabolite levels, but it is not clear how diabetes mellitus (DM) affects the metabolic changes in CKD. METHODS: Serum metabolites from pre-dialysis CKD patients (n=291) with or without DM and from healthy controls (n=56) was measured using nuclear magnetic resonance. RESULTS: Initial principal components analysis and partial least squares-discriminant analysis score plots segregated the CKD patients according to CKD stage and separated DM from non-DM patients. In the CKD patients, associations were seen with clinical characteristics, hyperglycemia, altered amino acid metabolism, accumulated uremic toxins, and dyslipidemia. Of interest, diabetes more strongly affected the metabolic signature during early stage CKD. Furthermore, serum metabolite profiles were successfully applied to the PLS regression model to predict the estimated glomerular filtration rate. The R(2) values from the PLS models for CKD patients with DM were higher than those for CKD without DM. CONCLUSIONS: Metabolomics is useful clinically for providing a metabolic signature that is associated with the CKD phenotype and diabetes more seriously affects patients with early stage CKD compared to those with advanced CKD. PMID: 27221201 [PubMed - as supplied by publisher]

Non-targeted metabolomics by high resolution mass spectrometry in HPRT knockout mice. Life Sci. 2016 May 21; Authors: Tschirner SK, Bähre H, Kaever A, Schneider EH, Seifert R, Kaever V Abstract AIMS: Lesch-Nyhan disease (LND) is characterized by hyperuricemia as well as neurological and neuropsychiatric symptoms including repetitive self-injurious behavior. Symptoms are caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) as a result of a mutation on the X chromosome. To elucidate the pathophysiology of LND, we performed a metabolite screening for brain and serum extracts from HPRT knockout mice as an animal model for LND. MAIN METHODS: Analyses were performed by high performance liquid chromatography (HPLC)-coupled quadrupole time-of-flight mass spectrometry (QTOF-MS). KEY FINDINGS: In brain extracts, we found six metabolites with significantly different contents in wild-type and HPRT-deficient mice. Two compounds we could identify as 5-aminoimidazole-4-carboxamide ribotide (AICAR) and 1-methylimidazole-4-acetic acid (1-MI4AA). Whereas AICAR was accumulated in brains of HPRT knockout mice, 1-MI4AA was decreased in these mice. SIGNIFICANCE: Both metabolites play a role in histidine metabolism and, as a consequence, histamine metabolism. AICAR, in addition, is part of the purine metabolism. Our findings may help to better understand the mechanisms leading to the behavioral phenotype of LND. PMID: 27221022 [PubMed - as supplied by publisher]

Related Articles An Integrated Metabolic Atlas of Clear Cell Renal Cell Carcinoma. Cancer Cell. 2016 Jan 11;29(1):104-16 Authors: Hakimi AA, Reznik E, Lee CH, Creighton CJ, Brannon AR, Luna A, Aksoy BA, Liu EM, Shen R, Lee W, Chen Y, Stirdivant SM, Russo P, Chen YB, Tickoo SK, Reuter VE, Cheng EH, Sander C, Hsieh JJ Abstract Dysregulated metabolism is a hallmark of cancer, manifested through alterations in metabolites. We performed metabolomic profiling on 138 matched clear cell renal cell carcinoma (ccRCC)/normal tissue pairs and found that ccRCC is characterized by broad shifts in central carbon metabolism, one-carbon metabolism, and antioxidant response. Tumor progression and metastasis were associated with metabolite increases in glutathione and cysteine/methionine metabolism pathways. We develop an analytic pipeline and visualization tool (metabolograms) to bridge the gap between TCGA transcriptomic profiling and our metabolomic data, which enables us to assemble an integrated pathway-level metabolic atlas and to demonstrate discordance between transcriptome and metabolome. Lastly, expression profiling was performed on a high-glutathione cluster, which corresponds to a poor-survival subgroup in the ccRCC TCGA cohort. PMID: 26766592 [PubMed - indexed for MEDLINE]

Attention-deficit hyperactivity disorder in adults: A systematic review and meta-analysis of genetic, pharmacogenetic and biochemical studies. Mol Psychiatry. 2016 May 24; Authors: Bonvicini C, Faraone SV, Scassellati C Abstract The adult form of attention-deficit/hyperactivity disorder has a prevalence of up to 5% and is the most severe long-term outcome of this common disorder. Family studies in clinical samples as well as twin studies suggest a familial liability and consequently different genes were investigated in association studies. Pharmacotherapy with methylphenidate (MPH) seems to be the first-line treatment of choice in adults with attention-deficit hyperactive disorder (ADHD) and some studies were conducted on the genes influencing the response to this drug. Finally some peripheral biomarkers were identified in ADHD adult patients. We believe this work is the first systematic review and meta-analysis of candidate gene association studies, pharmacogenetic and biochemical (metabolomics) studies performed in adults with ADHD to identify potential genetic, predictive and peripheral markers linked specifically to ADHD in adults. After screening 5129 records, we selected 87 studies of which 61 were available for candidate gene association studies, 5 for pharmacogenetics and 21 for biochemical studies. Of these, 15 genetic, 2 pharmacogenetic and 6 biochemical studies were included in the meta-analyses. We obtained an association between adult ADHD and the gene BAIAP2 (brain-specific angiogenesis inhibitor 1-associated protein 2), even after Bonferroni correction, with any heterogeneity in effect size and no publication bias. If we did not apply the Bonferroni correction, a trend was found for the carriers allele 9R of dopamine transporter SLC6A3 40 bp variable tandem repeat polymorphism (VNTR) and for 6/6 homozygotes of SLC6A3 30 bp VNTR. Negative results were obtained for the 9-6 haplotype, the dopamine receptor DRD4 48 bp VNTR, and the enzyme COMT SNP rs4680. Concerning pharmacogenetic studies, no association was found for the SLC6A3 40 bp and response to MPH with only two studies selected. For the metabolomics studies, no differences between ADHD adults and controls were found for salivary cortisol, whereas lower serum docosahexaenoic acid (DHA) levels were found in ADHD adults. This last association was significant even after Bonferroni correction and in absence of heterogeneity. Other polyunsaturated fatty acids (PUFAs) such as AA (arachidonic acid), EPA (eicosapentaenoic acid) and DyLA (dihomogammalinolenic acid) levels were not different between patients and controls. No publication biases were observed for these markers. Genes linked to dopaminergic, serotoninergic and noradrenergic signaling, metabolism (DBH, TPH1, TPH2, DDC, MAOA, MAOB, BCHE and TH), neurodevelopment (BDNF and others), the SNARE system and other forty genes/proteins related to different pathways were not meta-analyzed due to insufficient data. In conclusion, we found that there were not enough genetic, pharmacogenetic and biochemical studies of ADHD in adults and that more investigations are needed. Moreover we confirmed a significant role of BAIAP2 and DHA in the etiology of ADHD exclusively in adults. Future research should be focused on the replication of these findings and to assess their specificity for ADHD.Molecular Psychiatry advance online publication, 24 May 2016; doi:10.1038/mp.2016.74. PMID: 27217152 [PubMed - as supplied by publisher]