PubMed

Assessment of dietary exposure and effect in humans: The role of NMR. Prog Nucl Magn Reson Spectrosc. 2016 Aug;96:58-72 Authors: van Duynhoven JP, Jacobs DM Abstract In human nutritional science progress has always depended strongly on analytical measurements for establishing relationships between diet and health. This field has undergone significant changes as a result of the development of NMR and mass spectrometry methods for large scale detection, identification and quantification of metabolites in body fluids. This has allowed systematic studies of the metabolic fingerprints that biological processes leave behind, and has become the research field of metabolomics. As a metabolic profiling technique, NMR is at its best when its unbiased nature, linearity and reproducibility are exploited in well-controlled nutritional intervention and cross-sectional population screening studies. Although its sensitivity is less good than that of mass spectrometry, NMR has maintained a strong position in metabolomics through implementation of standardisation protocols, hyphenation with mass spectrometry and chromatographic techniques, accurate quantification and spectral deconvolution approaches, and high-throughput automation. Thus, NMR-based metabolomics has contributed uniquely to new insights into dietary exposure, in particular by unravelling the metabolic fates of phytochemicals and the discovery of dietary intake markers. NMR profiling has also contributed to the understanding of the subtle effects of diet on central metabolism and lipoprotein metabolism. In order to hold its ground in nutritional metabolomics, NMR will need to step up its performance in sensitivity and resolution; the most promising routes forward are the analytical use of dynamic nuclear polarisation and developments in microcoil construction and automated fractionation. PMID: 27573181 [PubMed - in process]

Metabolomics-based screening of the Malaria Box reveals both novel and established mechanisms of action. Antimicrob Agents Chemother. 2016 Aug 29; Authors: Creek DJ, Chua HH, Cobbold SA, Nijagal B, Macrae JI, Dickerman BK, Gilson PR, Ralph SA, McConville MJ Abstract High-throughput phenotypic screening of chemical libraries has resulted in the identification of thousands of compounds with potent antimalarial activity, although in most cases, the mechanism(s) of action of these compounds remain unknown. Here we have investigated the mode of action of 90 antimalarial compounds derived from the Malaria Box collection using high-coverage, untargeted metabolomics analysis. Approximately half of the tested compounds induced significant metabolic perturbations in in vitro cultures of P. falciparum In most cases, the metabolic profiles were highly correlated with known antimalarials, in particular artemisinin, the 4-aminoquinolines, or atovaquone. Select Malaria Box compounds also induced changes in intermediates in essential metabolic pathways such as isoprenoid biosynthesis (i.e. 2-C-methyl-D-erythritol 2,4-cyclodiphosphate), and linolenic acid metabolism (i.e. traumatic acid). This study provides a comprehensive database of the metabolic perturbations induced by chemically diverse inhibitors and highlights the utility of metabolomics for triaging new lead compounds and defining specific modes of action, which will assist with the development and optimization of new antimalarial drugs. PMID: 27572396 [PubMed - as supplied by publisher]

Metabolomic responses to sub-lethal contaminant exposure in neonate and adult Daphnia magna. Environ Toxicol Chem. 2016 Aug 30; Authors: Wagner ND, Simpson AJ, Simpson MJ Abstract The use of consumer products and pharmaceuticals that act as contaminants entering waterways through runoff and wastewater effluents alter aquatic ecosystem health. Traditional toxicological end points may underestimate the toxicity of contaminants as lethal concentrations are often orders of magnitude higher than that found within freshwater ecosystems. While newer techniques examine the metabolic responses of sub-lethal contaminant exposure, there has been no direct comparison with ontogeny in Daphnia. We hypothesize that Daphnia magna will have distinct metabolic changes to 3 different sub-lethal contaminant exposures caused by differences in the toxic mode of action and ontogeny. To test this hypothesis, we measured the proton nuclear magnetic resonance metabolomic profiles in D. magna aged day 0 and 18 after exposure to 28% of the lethal concentration of 50% of organisms tested (LC50) of atrazine, propranolol and perfluorooctanesulfonic acid (PFOS) for 48 hours. Principal component analysis revealed significant separation of contaminants from the control daphnids in both neonates and adults exposed to propranolol and PFOS. In contrast, atrazine exposure caused separation from the controls in only the adult D. magna. Propranolol exposure displayed minimal ontogenetic changes in the targeted metabolites. For both atrazine and PFOS exposures ontogeny exhibited unique changes in the targeted metabolites. These results indicate that depending on the contaminant studied, neonates and adults respond uniquely to sub-lethal contaminant exposure. This article is protected by copyright. All rights reserved. PMID: 27571995 [PubMed - as supplied by publisher]

Urinary biomarker and treatment mechanism of Rhizoma Alismatis on hyperlipidemia. Biomed Chromatogr. 2016 Aug 29; Authors: Miao H, Zhang L, Chen DQ, Chen H, Zhao YY, Ma SC Abstract Rhizoma Alismatis (RA), a diuretic in Asia and Europe, was found to possess anti-hyperlipidemic activity. Since the biomarkers and mechanisms of RA in the treatment of hyperlipidemia is inadequate, ultra performance liquid chromatography coupled with quadrupole time-of-flight synapt high-definition mass spectrometry and multivariate data analysis were employed to investigate the urinary metabolomics of RA on hyperlipidemic rats induced by high fat diet. The metabolic profile of RA-treated hyperlipidemic group located between control and diet-induced hyperlipidemic groups. Nineteen metabolites with significant fluctuations were identified as potential biomarkers related to the hyperlipidemia and anti-hyperlipidemia of RA using partial least-squares-discriminate analysis, heatmap analysis and correlation coefficient analysis. The fluctuations of these biomarkers represented the disturbances in amino acid metabolism, purine metabolism, pyrimidine metabolism and energy metabolism. After RA treatment, these perturbed metabolites were restored to normal or nearly normal levels. RA can alleviate high fat diet-induced dysfunctions in these metabolic pathways. This article is protected by copyright. All rights reserved. PMID: 27571931 [PubMed - as supplied by publisher]

The WEIZMASS spectral library for high-confidence metabolite identification. Nat Commun. 2016;7:12423 Authors: Shahaf N, Rogachev I, Heinig U, Meir S, Malitsky S, Battat M, Wyner H, Zheng S, Wehrens R, Aharoni A Abstract Annotation of metabolites is an essential, yet problematic, aspect of mass spectrometry (MS)-based metabolomics assays. The current repertoire of definitive annotations of metabolite spectra in public MS databases is limited and suffers from lack of chemical and taxonomic diversity. Furthermore, the heterogeneity of the data prevents the development of universally applicable metabolite annotation tools. Here we present a combined experimental and computational platform to advance this key issue in metabolomics. WEIZMASS is a unique reference metabolite spectral library developed from high-resolution MS data acquired from a structurally diverse set of 3,540 plant metabolites. We also present MatchWeiz, a multi-module strategy using a probabilistic approach to match library and experimental data. This strategy allows efficient and high-confidence identification of dozens of metabolites in model and exotic plants, including metabolites not previously reported in plants or found in few plant species to date. PMID: 27571918 [PubMed - in process]

Related Articles Circulating mitochondrial biomarkers for drug-induced liver injury. Biomark Med. 2015;9(11):1215-23 Authors: Shi Q, Yang X, Mattes WB, Mendrick DL, Harrill AH, Beger RD Abstract Liver mitochondria affected by drugs can be released into circulation and serve as biomarkers for drug-induced liver injury (DILI). The tissue specificity of ALT was improved by differentiating cytosolic ALT1 and mitochondrial ALT2 isoforms released in circulation. Prior to ALT elevation, mitochondrial cytochrome c, OCT, GLDH, CPS1 and DNA were increased in circulation following DILI. The baseline expression of mt-Nd6 was predictive of individual DILI susceptibility in animals. As mitochondrial DILI biomarkers appeared to be drug or species dependent, they might have value in clinical scenarios when culprit drugs are established, but may not be ideal tools to assess DILI potentials of new drugs. PMID: 26507261 [PubMed - indexed for MEDLINE]

Plasma Biomarkers for Monitoring Brain Pathophysiology in FMR1 Premutation Carriers. Front Mol Neurosci. 2016;9:71 Authors: Giulivi C, Napoli E, Tassone F, Halmai J, Hagerman R Abstract Premutation carriers have a 55-200 CGG expansion in the fragile X mental retardation 1 (FMR1) gene. Currently, 1.5 million individuals are affected in the United States, and carriers are at risk of developing the late-onset neurodegenerative disorder Fragile X-associated tremor ataxia syndrome (FXTAS). Limited efforts have been made to develop new methods for improved early patient monitoring, treatment response, and disease progression. To this end, plasma metabolomic phenotyping was obtained for 23 premutation carriers and 16 age- and sex-matched controls. Three biomarkers, phenylethylamine normalized by either aconitate or isocitrate and oleamide normalized by isocitrate, exhibited excellent model performance. The lower phenylethylamine and oleamide plasma levels in carriers may indicate, respectively, incipient nigrostriatal degeneration and higher incidence of substance abuse, anxiety and sleep disturbances. Higher levels of citrate, isocitrate, aconitate, and lactate may reflect deficits in both bioenergetics and neurotransmitter metabolism (Glu, GABA). This study lays important groundwork by defining the potential utility of plasma metabolic profiling to monitor brain pathophysiology in carriers before and during the progression of FXTAS, treatment efficacy and evaluation of side effects. PMID: 27570505 [PubMed]

Quantitative Metabolomic Profiling of Plasma, Urine and Liver Extracts by 1H NMR Spectroscopy Characterizes Different Stages of Atherosclerosis in Hamsters. J Proteome Res. 2016 Aug 29; Authors: Guo W, Jiang C, Yang L, Li T, Liu X, Jin M, Qu K, Chen H, Jin X, Liu H, Zhu H, Wang Y Abstract Atherosclerosis (AS) is a progressive disease that contributes to cardiovascular disease and shows a complex etiology, including genetic and environmental factors. To understand systemic metabolic changes and to identify potential biomarkers correlated with the occurrence and perpetuation of diet-induced AS, we applied 1H NMR-based metabolomics to detect the time-related metabolic profiles of plasma, urine and liver extracts from male hamsters fed a high fat/high cholesterol (HFHC) diet. Conventional biochemical assays and histopathological examinations as well as protein expression analyses were performed to provide complementary information. We found that diet treatment caused obvious aortic lesions, lipid accumulation and inflammatory infiltration in hamsters. Down-regulation of proteins related to cholesterol metabolism, including hepatic SREBP2, LDL-R, CYP7A1, SR-BI, HMGCR, LCAT and SOAT1 was detected, which elucidated the perturbation of cholesterol homeostasis during the HFHC diet challenge. Using "targeted analysis", we quantified 40 plasma, 80 urine and 60 liver hydrophilic extract metabolites. Multivariate analyses of the identified metabolites elucidated sophisticated metabolic disturbances in multiple matrices, including energy homeostasis, inflammation, oxidative stress and intestinal microbiota functions coupled with the metabolism of saccharides, fatty acids, choline, amino acids and nucleotides. For the first time, our results demonstrate a time-dependent metabolic progression of multiple biological matrices in hamsters from physiological status to early AS and further to late-stage AS, demonstrating that 1H NMR-based metabolomics is a reliable tool for early diagnosis and monitoring of the progression of AS. PMID: 27570155 [PubMed - as supplied by publisher]

Metabolomic determination of pathogenesis of late-onset preeclampsia. J Matern Fetal Neonatal Med. 2016 Aug 28;:1-7 Authors: Bahado-Singh RO, Syngelaki A, Mandal R, Graham SF, Akolekar R, Han B, Bjondahl TC, Dong E, Bauer S, Alpay-Savasan Z, Turkoglu O, Ogunyemi D, Poon LC, Wishart DS, Nicolaides KH Abstract OBJECTIVE: Our primary objective was to apply metabolomic pathway analysis of first trimester maternal serum to provide an insight into the pathogenesis of late-onset preeclampsia (late-PE) and thereby identify plausible therapeutic targets for PE. METHODS: NMR-based metabolomics analysis was performed on 29 cases of late-PE and 55 unaffected controls. In order to achieve sufficient statistical power to perform the pathway analysis, these cases were combined with a group of previously analyzed specimens, 30 late-PE cases and 60 unaffected controls. Specimens from both groups of cases and controls were collected in the same clinical centers during the same time period. In addition, NMR analyses were performed in the same lab and using the same techniques. RESULTS: We identified abnormalities in branch chain amino acids (valine, leucine and isoleucine) and propanoate, glycolysis, gluconeogenesis and ketone body metabolic pathways. The results suggest insulin resistance and metabolic syndrome, mitochondrial dysfunction and disturbance of energy metabolism, oxidative stress and lipid dysfunction in the pathogenesis of late PE and suggest a potential role for agents that reduce insulin resistance in PE. CONCLUSIONS: Branched chain amino acids are known markers of insulin resistance and strongly predict future diabetes development. The analysis provides independent evidence linking insulin resistance and late-PE and suggests a potentially important therapeutic role for pharmacologic agents that reduce insulin resistance for late-PE. PMID: 27569705 [PubMed - as supplied by publisher]

Association of maternal pre-pregnancy BMI with metabolomic profile across gestation. Int J Obes (Lond). 2016 Aug 29; Authors: Hellmuth C, Lindsay KL, Uhl O, Buss C, Wadhwa PD, Koletzko B, Entringer S Abstract BACKGROUND/OBJECTIVES: Elevated pre-pregnancy BMI (pBMI) and excess gestational weight gain (GWG) constitute important prenatal exposures which may program adiposity and disease risk in offspring. The objective of this study is to investigate the influence of pBMI and GWG on the maternal metabolomic profile across pregnancy, and to identify associations with birthweight. SUBJECTS/METHODS: This is a longitudinal prospective study of 167 non-diabetic women carrying a singleton pregnancy. Women were recruited between March 2011-December 2013 from antenatal clinics affiliated to the University of California, Irvine, Medical Center. Seven women were excluded from analyses due to a diagnosis of diabetes during pregnancy. A total of 254 plasma metabolites known to be related to obesity in non-pregnant populations were analyzed in each trimester using targeted metabolomics. The effects of pBMI and GWG on metabolites were tested through linear regression and principle component analysis, adjusting for maternal sociodemographic factors, diet, and insulin resistance. A Bonferroni correction was applied for multiple comparison testing. RESULTS: pBMI was significantly associated with 40 metabolites. Non-esterified fatty acids (NEFA) showed a strong positive association with pBMI, with specificity for mono-unsaturated and omega-6 NEFA. Among phospholipids, sphingomyelins with two double bonds and phosphatidylcholines containing 20:3 fatty acid chain, indicative of omega-6 NEFA, were positively associated with pBMI. Few associations between GWG, quality and quantity of the diet, insulin resistance and the maternal metabolome throughout gestation were detected. NEFA levels in the first and, to a lesser degree, in the second trimester were positively associated with birthweight percentiles. CONCLUSION: Pre-conception obesity appears to have a stronger influence on the maternal metabolic milieu than gestational factors such as weight gain, dietary intake and insulin resistance, highlighting the critical importance of pre-conception health. NEFA in general, as well as particular mono-unsaturated and omega-6 fatty acid species, represent key metabolites for a potential mechanism of intergenerational transfer of obesity risk.International Journal of Obesity accepted article preview online, 29 August 2016. doi:10.1038/ijo.2016.153. PMID: 27569686 [PubMed - as supplied by publisher]

The antiandrogen flutamide is a novel aryl hydrocarbon receptor ligand that disrupts bile acid homeostasis in mice through induction of Abcc4. Biochem Pharmacol. 2016 Aug 25; Authors: Gao X, Xie C, Wang Y, Luo Y, Yagai T, Sun D, Qin X, Krausz KW, Gonzalez FJ Abstract Flutamide (FLU), an oral, nonsteroidal antiandrogen drug used in the treatment of prostate cancer, is associated with idiosyncratic hepatotoxicity that sometimes causes severe liver damage, including cholestasis, jaundice, and liver necrosis. To understand the mechanism of toxicity, a combination of aryl hydrocarbon receptor (Ahr)-deficient (Ahr(-/-)) mice, primary hepatocytes, luciferase reporter gene assays, in silico ligand docking and ultra-performance chromatography-quadrupole time-of-flight mass spectrometry-based metabolomics were used. A significant increase of liver weights, and liver and serum bile acid levels was observed after FLU treatment, indicating hepatomegaly and disrupted bile acid homeostasis. Expression of the AhR gene battery was markedly increased in livers of wild-type mice Ahr(+/+) treated with FLU, while no change was noted in Ahr(-/-) mice. Messenger RNAs encoded by AhR target genes were induced in primary mouse hepatocytes cultured with FLU, which confirmed the in vivo results. Ligand-docking analysis further predicted that FLU is an AhR agonist ligand which was confirmed by luciferase reporter gene assays. Multivariate data analysis showed that bile acids were responsible for the separation of vehicle- and FLU-treated Ahr(+/+) mice, while there was no separation in Ahr(-/-) mice. Expression of mRNA encoding the bile acid transporter ABCC4 was increased and farnesoid X receptor signaling was inhibited in the livers of Ahr(+/+) mice, but not in Ahr(-/-) mice treated with FLU, in agreement with the observed downstream metabolic alterations. These findings provide new insights into the mechanism of liver injury caused by FLU treatment involving activation of AhR and the alterations of bile acid homeostasis, which could guide clinical application. PMID: 27569425 [PubMed - as supplied by publisher]

Tumor eradication by cisplatin is sustained by CD80/86-mediated costimulation of CD8+ T cells. Cancer Res. 2016 Aug 28; Authors: Beyranvand Nejad E, van der Sluis TC, van Duikeren S, Yagita H, Janssen GM, van Veelen PA, Melief CJ, van der Burg SH, Arens R Abstract Certain cytotoxic chemotherapeutic drugs are immunogenic, stimulating tumor immunity through mechanisms that are not completely understood. Here we show how the DNA damaging drug cisplatin modulates tumor immunity. At the maximum tolerated dose (MTD), cisplatin cured 50% of mice with established murine TC-1 or C3 tumors, which are preclinical models of human papilloma virus (HPV)-associated cancer. Notably, the curative benefit of cisplatin relied entirely upon induction of tumor-specific CD8+ T cells. Mechanistic investigations showed that cisplatin stimulated tumor infiltration of inflammatory antigen-presenting cells (APCs) expressing relatively higher levels of the T-cell costimulatory ligands CD70, CD80 and CD86. Cell death triggered by cisplatin was associated with the release of at least 19 proteins in the tumor environment that could act as damage-related molecular patterns (DAMPs) and upregulate costimulatory molecules, either alone or in concert, but the responsible proteins remain unknown. Essentially, the curative effect of cisplatin was abrogated in mice lacking expression of CD80 and CD86 on APCs. Further, cisplatin treatment was improved by CTLA-4 blockade, which increases the availability of CD80/86 to bind to CD28. In contrast, there was no effect of CD27 stimulation, which replaces CD70 interaction. At the cisplatin MTD, cure rates could also be increased by vaccination with synthetic long peptides, whereas cures could also be achieved at similar rates at 80% of the MTD with reduced side effects. Our findings reveal an essential basis for the immunogenic properties of cisplatin, which are mediated by induction of costimulatory signals for CD8+ T cell-dependent tumor destruction. PMID: 27569212 [PubMed - as supplied by publisher]

Related Articles Five omic technologies are concordant in differentiating the biochemical characteristics of the berries of five grapevine (Vitis vinifera L.) cultivars. BMC Genomics. 2015;16:946 Authors: Ghan R, Van Sluyter SC, Hochberg U, Degu A, Hopper DW, Tillet RL, Schlauch KA, Haynes PA, Fait A, Cramer GR Abstract BACKGROUND: Grape cultivars and wines are distinguishable by their color, flavor and aroma profiles. Omic analyses (transcripts, proteins and metabolites) are powerful tools for assessing biochemical differences in biological systems. RESULTS: Berry skins of red- (Cabernet Sauvignon, Merlot, Pinot Noir) and white-skinned (Chardonnay, Semillon) wine grapes were harvested near optimum maturity (°Brix-to-titratable acidity ratio) from the same experimental vineyard. The cultivars were exposed to a mild, seasonal water-deficit treatment from fruit set until harvest in 2011. Identical sample aliquots were analyzed for transcripts by grapevine whole-genome oligonucleotide microarray and RNAseq technologies, proteins by nano-liquid chromatography-mass spectroscopy, and metabolites by gas chromatography-mass spectroscopy and liquid chromatography-mass spectroscopy. Principal components analysis of each of five Omic technologies showed similar results across cultivars in all Omic datasets. Comparison of the processed data of genes mapped in RNAseq and microarray data revealed a strong Pearson's correlation (0.80). The exclusion of probesets associated with genes with potential for cross-hybridization on the microarray improved the correlation to 0.93. The overall concordance of protein with transcript data was low with a Pearson's correlation of 0.27 and 0.24 for the RNAseq and microarray data, respectively. Integration of metabolite with protein and transcript data produced an expected model of phenylpropanoid biosynthesis, which distinguished red from white grapes, yet provided detail of individual cultivar differences. The mild water deficit treatment did not significantly alter the abundance of proteins or metabolites measured in the five cultivars, but did have a small effect on gene expression. CONCLUSIONS: The five Omic technologies were consistent in distinguishing cultivar variation. There was high concordance between transcriptomic technologies, but generally protein abundance did not correlate well with transcript abundance. The integration of multiple high-throughput Omic datasets revealed complex biochemical variation amongst five cultivars of an ancient and economically important crop species. PMID: 26573226 [PubMed - indexed for MEDLINE]

Related Articles Editorial: Would You Like A Hypothesis With Those Data? Omics and the Age of Discovery Science. Mol Endocrinol. 2015 Nov;29(11):1531-4 Authors: Kraus WL PMID: 26524008 [PubMed - indexed for MEDLINE]

Quality evaluation of green tea leaf cultured under artificial light condition using gas chromatography/mass spectrometry. J Biosci Bioeng. 2016 Aug 24; Authors: Miyauchi S, Yonetani T, Yuki T, Tomio A, Bamba T, Fukusaki E Abstract For an experimental model to elucidate the relationship between light quality during plant culture conditions and plant quality of crops or vegetables, we cultured tea plants (Camellia sinensis) and analyzed their leaves as tea material. First, metabolic profiling of teas from a tea contest in Japan was performed with gas chromatography/mass spectrometry (GC/MS), and then a ranking predictive model was made which predicted tea rankings from their metabolite profile. Additionally, the importance of some compounds (glutamine, glutamic acid, oxalic acid, epigallocatechin, phosphoric acid, and inositol) was elucidated for measurement of the quality of tea leaf. Subsequently, tea plants were cultured in artificial conditions to control these compounds. From the result of prediction by the ranking predictive model, the tea sample supplemented with ultraviolet-A (315-399 nm) showed the highest ranking. The improvement in quality was thought to come from the high amino-acid and decreased epigallocatechin content in tea leaves. The current study shows the use and value of metabolic profiling in the field of high-quality crops and vegetables production that has been conventionally evaluated by human sensory analysis. Metabolic profiling enables us to form hypothesis to understand and develop high quality plant cultured under artificial condition. PMID: 27568369 [PubMed - as supplied by publisher]

Metabolic adaptations to HFHS overfeeding: how whole body and tissues postprandial metabolic flexibility adapt in Yucatan mini-pigs. Eur J Nutr. 2016 Aug 27; Authors: Polakof S, Rémond D, Bernalier-Donadille A, Rambeau M, Pujos-Guillot E, Comte B, Dardevet D, Savary-Auzeloux I Abstract PURPOSE: In the present study, we aimed to metabolically characterize the postprandial adaptations of the major tissues involved in energy, lipids and amino acids metabolisms in mini-pigs. METHOD: Mini-pigs were fed on high-fat-high-sucrose (HFHS) diet for 2 months and several tissues explored for metabolic analyses. Further, the urine metabolome was followed over the time to picture the metabolic adaptations occurring at the whole body level following overfeeding. RESULTS: After 2 months of HFHS consumption, mini-pigs displayed an obese phenotype characterized by high circulating insulin, triglycerides and cholesterol levels. At the tissue level, a general (muscle, adipose tissue, intestine) reduction in the capacity to phosphorylate glucose was observed. This was also supported by the enhanced hepatic gluconeogenesis potential, despite the concomitant normoglycaemia, suggesting that the high circulating insulin levels would be enough to maintain glucose homoeostasis. The HFHS feeding also resulted in a reduced capacity of two other pathways: the de novo lipogenesis, and the branched-chain amino acids transamination. Finally, the follow-up of the urine metabolome over the time allowed determining breaking points in the metabolic trajectory of the animals. CONCLUSIONS: Several features confirmed the pertinence of the animal model, including increased body weight, adiposity and porcine obesity index. At the metabolic level, we observed a perturbed glucose and amino acid metabolism, known to be related to the onset of the obesity. The urine metabolome analyses revealed several metabolic pathways potentially involved in the obesity onset, including TCA (citrate, pantothenic acid), amino acids catabolism (cysteine, threonine, leucine). PMID: 27568059 [PubMed - as supplied by publisher]

Biomarker Discovery in Human Prostate Cancer: an Update in Metabolomics Studies. Transl Oncol. 2016 Aug;9(4):357-370 Authors: Lima AR, Bastos ML, Carvalho M, Guedes de Pinho P Abstract Prostate cancer (PCa) is the most frequently diagnosed cancer and the second leading cause of cancer death among men in Western countries. Current screening techniques are based on the measurement of serum prostate specific antigen (PSA) levels and digital rectal examination. A decisive diagnosis of PCa is based on prostate biopsies; however, this approach can lead to false-positive and false-negative results. Therefore, it is important to discover new biomarkers for the diagnosis of PCa, preferably noninvasive ones. Metabolomics is an approach that allows the analysis of the entire metabolic profile of a biological system. As neoplastic cells have a unique metabolic phenotype related to cancer development and progression, the identification of dysfunctional metabolic pathways using metabolomics can be used to discover cancer biomarkers and therapeutic targets. In this study, we review several metabolomics studies performed in prostatic fluid, blood plasma/serum, urine, tissues and immortalized cultured cell lines with the objective of discovering alterations in the metabolic phenotype of PCa and thus discovering new biomarkers for the diagnosis of PCa. Encouraging results using metabolomics have been reported for PCa, with sarcosine being one of the most promising biomarkers identified to date. However, the use of sarcosine as a PCa biomarker in the clinic remains a controversial issue within the scientific community. Beyond sarcosine, other metabolites are considered to be biomarkers for PCa, but they still need clinical validation. Despite the lack of metabolomics biomarkers reaching clinical practice, metabolomics proved to be a powerful tool in the discovery of new biomarkers for PCa detection. PMID: 27567960 [PubMed - as supplied by publisher]

Discrimination of wild types and hybrids of Duboisia myoporoides and Duboisia leichhardtii at different growth stages using (1)H NMR-based metabolite profiling and tropane alkaloids-targeted HPLC-MS analysis. Phytochemistry. 2016 Aug 23; Authors: Ullrich SF, Averesch NJ, Castellanos L, Choi YH, Rothauer A, Kayser O Abstract Duboisia species, which belong to the family of Solanaceae, are commercially cultivated in large scale, as they are main source of the pharmaceutically-used active compound scopolamine. In this study, (1)H NMR-based metabolite profiling linking primary with secondary metabolism and additional quantification via HPCL-MS with special focus on the tropane alkaloids were applied to compare leaf and root extracts of three wild types and two hybrids of Duboisia myoporoides and D. leichhardtii at different developmental stages grown under controlled conditions in climate chambers and under agricultural field plantation. Based on the leaf extracts, a clear distinction between the Duboisia hybrids and the wild types Duboisia myoporoides and D. leichhardtii using principal component analysis of (1)H NMR data was observed. The average content in scopolamine in the hybrids of Duboisia cultivated in climate chambers increased significantly from month 3-6 after potting of the rooted cuttings, however not so for the examined wild types. The Duboisia hybrids grown in climate chambers showed higher growth and contained more sugars and amino acids than Duboisia hybrids grown in the field, which in contrast showed an enhanced flux towards tropane alkaloids as well as flavonoids. For a more detailed analysis of tropane alkaloids, an appropriate HPLC-MS method was developed and validated. The measurements revealed large differences in the alkaloid pattern within the different genotypes under investigation, especially regarding the last enzymatic step, the conversion from hyoscamine to scopolamine by the hyoscyamine 6β-hydroxylase. Scopolamine was found in highest concentrations in Duboisia hybrids (20.04 ± 4.05 and 17.82 ± 3.52 mg/g dry wt) followed by Duboisia myoporoides (12.71 ± 2.55 mg/g dry wt), both showing a high selectivity for scopolamine in contrast to Duboisia leichhardtii (3.38 ± 0.59 and 5.09 ± 1.24 mg/g dry wt) with hyoscyamine being the predominant alkaloid. PMID: 27567452 [PubMed - as supplied by publisher]

Non-targeted and targeted metabolomics approaches to diagnosing lung cancer and predicting patient prognosis. Oncotarget. 2016 Aug 23; Authors: Zhang X, Zhu X, Wang C, Zhang H, Cai Z Abstract Lung cancer is the most common cause of cancer death in China. We characterized metabolic alterations in lung cancer using two analytical platforms: a non-targeted metabolic profiling strategy based on proton nuclear magnetic resonance (1H-NMR) spectroscopy and a targeted metabolic profiling strategy based on rapid resolution liquid chromatography (RRLC). Changes in serum metabolite levels during oncogenesis were evaluated in 25 stage I lung cancer patients and matched healthy controls. We identified 25 metabolites that were differentially regulated between the lung cancer patients and matched controls. Of those, 16 were detected using the non-targeted approach and 9 were identified using the targeted approach. Both groups of metabolites could differentiate between lung cancer patients and healthy controls with 100% sensitivity and specificity. The principal metabolic alternations in lung cancer included changes in glycolysis, lipid metabolism, choline phospholipid metabolism, one-carbon metabolism, and amino acid metabolism. The targeted metabolomics approach was more sensitive, accurate, and specific than the non-targeted metabolomics approach. However, our data suggest that both metabolomics strategies could be used to detect early-stage lung cancer and predict patient prognosis. PMID: 27566571 [PubMed - as supplied by publisher]

Exploration of Candidate Biomarkers for Human Psoriasis Based on GC-MS Serum Metabolomics. Br J Dermatol. 2016 Aug 26; Authors: Kang H, Li X, Zhou Q, Quan S, Xue F, Zheng J, Yu Y Abstract BACKGROUND: Recent studies have shown that dysregulated metabolic pathways are linked to psoriasis pathogenesis. However, an extensive, unbiased metabolic analysis in psoriatic patients has not been completely explored. The metabolome represents the end products of proteomics or cellular processes which may be closely associated with the pathogenesis of psoriasis. OBJECTIVES: To determine the differences in serum metabolomic profiles among psoriasis patients and healthy controls with the goal of identifying potential biomarkers in patients with psoriasis. METHODS: Serum metabolomic profiles from 29 subjects (14 psoriasis patients and 15 age and gender matched healthy controls). The serum metabolites were analyzed by gas chromatography mass spectrometry based on a combined full scan and selected-ion monitoring mode. RESULTS: Multivariate statistical analysis of metabolomics data revealed altered serum metabolites between the patients with psoriasis and healthy individuals. Compared to healthy individuals, psoriasis patients had higher levels of amino acids including asparagine, aspartic acid, isoleucine, phenylalanine, ornithine and proline, and higher levels of lactic acid and urea; while a lower level of crotonic acid, azelaic acid, ethanolamine and cholesterol. CONCLUSIONS: It appears that glycolysis pathway and amino acid metabolic activity are increased in psoriasis patients. These metabolic perturbations may stem from increased demand for protein biosynthesis and keratinocyte hyperproliferation. Our findings may help elucidate the pathogenesis of psoriasis and provide insights into early diagnosis and therapeutic intervention. This article is protected by copyright. All rights reserved. PMID: 27564527 [PubMed - as supplied by publisher]