Integrative Molecular Phenotyping
INTEGRATIVE MOLECULAR
PHENOTYPING
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

PubMed

PubMed
NCBI: db=pubmed; Term=metabolomics
Updated: 1 hour 51 min ago

Serum Metabolomic Profiling in a Rat Model Reveals Protective Function of Paeoniflorin Against ANIT Induced Cholestasis.

Tue, 26/01/2016 - 14:03
Serum Metabolomic Profiling in a Rat Model Reveals Protective Function of Paeoniflorin Against ANIT Induced Cholestasis. Phytother Res. 2016 Jan 25; Authors: Chen Z, Zhu Y, Zhao Y, Ma X, Niu M, Wang J, Su H, Wang R, Li J, Liu L, Wei Z, Zhao Q, Chen H, Xiao X Abstract Cholestasis is a leading cause of hepatic accumulation of bile acids resulting in liver injury, fibrosis, and liver failure. Paeoniflorin displays bright prospects in liver protective effect. However, its molecular mechanism has not been well-explored. This study was designed to assess the effects and possible mechanisms of paeoniflorin against alpha-naphthylisothiocyanate-induced liver injury. Ultraperformance liquid chromatography coupled with quadrupole time-of-flight combined with principle component analysis and partial least squares discriminant analysis were integrated to obtain differentiating metabolites for the pathways and clarify mechanisms of disease. The results indicated that paeoniflorin could remarkably downregulate serum biochemical indexes and alleviate the histological damage of liver tissue. Different expression of 14 metabolites demonstrated that paeoniflorin mainly regulated the dysfunctions of glycerophospholipid metabolism and primary bile acid biosynthesis. Moreover, several pathways such as arginine and proline metabolism, ether lipid metabolism, and arachidonic acid metabolism were also related to the efficacy. In conclusion, paeoniflorin has indicated favorable pharmacological effect on serum biochemical indexes and pathological observation on cholestatic model. And metabolomics is a promising approach to unraveling hepatoprotective effects by partially regulating the perturbed pathways, which provide insights into mechanisms of cholestasis. Copyright © 2016 John Wiley & Sons, Ltd. PMID: 26806614 [PubMed - as supplied by publisher]

Metabolomics study on the effects of Buchang Naoxintong capsules for treating cerebral ischemia in rats using UPLC-Q/TOF-MS.

Tue, 26/01/2016 - 14:03
Metabolomics study on the effects of Buchang Naoxintong capsules for treating cerebral ischemia in rats using UPLC-Q/TOF-MS. J Ethnopharmacol. 2016 Jan 19; Authors: Liu M, Liu X, Wang H, Xiao H, Jing F, Tang L, Li D, Zhang Y, Wu H, Yang H Abstract ETHNOPHARMACOLOGICAL RELEVANCE: Buchang Naoxintong Capsules (BNC) are widely prescribed in Chinese medicine for the treatment of cerebrovascular and cardiovascular diseases. However, the therapeutic effects and mechanisms are not yet well understood. MATERIALS AND METHODS: In this study, a UPLC/TOF-MS-based metabolomic study was conducted to explore potential biomarkers that will increase our understanding of cerebral ischemia and to assess the integral efficacy of BNC in a middle cerebral artery occlusion (MCAO) rat model. Plasma metabolic profiles were analyzed and metabolic biomarkers were identified through multivariate data analysis. RESULTS: Clear separations were observed between the sham, MCAO and BNC-treated groups. We identified twenty-eight biomarkers in the MCAO rats using variable importance for the projections (VIP) values (VIP>1) and a t-test (P<0.05). The identified biomarkers were mainly related to disturbances in monoamine neurotransmitter metabolism, amino acid metabolism, energy metabolism and lipid metabolism. Moreover, a correlation network diagram of the plasma biomarkers perturbed by MCAO was constructed. Some biomarkers, such as glutamine, PE (17:0), LysoPE (20:1), LysoPE (24:0), and the ratios of LysoPE (24:1) to LysoPE (24:0), LysoPE (24:2) to LysoPE (24:0), showed obvious changes and a tendency for returning to baseline values in BNC-treated MCAO rats. In addition, MCAO rats receiving BNC treatment had improved neurological deficits and reduced cerebral infarct size demonstrating the therapeutic potential of BNC for treating cerebral ischemia. CONCLUSION: This study provides a useful approach for exploring the mechanism of MCAO-induced cerebral ischemia and evaluating the efficacy of BNC. PMID: 26806568 [PubMed - as supplied by publisher]

Homocysteine in embryo culture media as a predictor of pregnancy outcome in assisted reproductive technology.

Tue, 26/01/2016 - 14:03
Homocysteine in embryo culture media as a predictor of pregnancy outcome in assisted reproductive technology. Gynecol Endocrinol. 2016 Jan 24;:1-3 Authors: Boyama BA, Cepni I, Imamoglu M, Oncul M, Tuten A, Yuksel MA, Kervancioglu ME, Kaleli S, Ocal P Abstract The aim of this study was to determine whether homocysteine (hcy) concentrations in embryo culture media correlate with pregnancy outcome in assisted reproductive technology (ART) cycles. Forty patients who underwent single embryo transfer at the infertility clinic of a tertiary care center were recruited for this case-control study. Spent embryo culture media from all patients were collected after single embryo transfer on day 3 (n = 40). Hcy concentrations in embryo culture media were analyzed by enzyme cycling method. Patients were grouped according to the diagnosis of a clinical pregnancy. Sixteen patients were pregnant while 24 patients failed to achieve conception. Mean Hcy levels in the culture media were significantly different between the groups (p < 0.003), as 4.58 ± 1.31 μmol/l in the non-pregnant group and 3.37 ± 0.92 μmol/l in the pregnant group. Receiver operator curve analysis for determining the diagnostic potential of Hcy for pregnancy revealed an area under the curve of 0.792 (confidence interval: 0.65-0.94; p < 0.05). A cut-off value of 3.53 μmol/l was determined with a sensitivity of 83.3%, and a specificity of 68.8%. Lower hcy levels were associated with a better chance of pregnancy and better embryo grades. Hcy may be introduced as an individual metabolomic profiling marker for embryos. PMID: 26806445 [PubMed - as supplied by publisher]

Blood metabolite markers of preclinical Alzheimer's disease in two longitudinally followed cohorts of older individuals.

Tue, 26/01/2016 - 14:03
Blood metabolite markers of preclinical Alzheimer's disease in two longitudinally followed cohorts of older individuals. Alzheimers Dement. 2016 Jan 21; Authors: Casanova R, Varma S, Simpson B, Kim M, An Y, Saldana S, Riveros C, Moscato P, Griswold M, Sonntag D, Wahrheit J, Klavins K, Jonsson PV, Eiriksdottir G, Aspelund T, Launer LJ, Gudnason V, Quigley CL, Thambisetty M Abstract Recently, quantitative metabolomics identified a panel of 10 plasma lipids that were highly predictive of conversion to Alzheimer's disease (AD) in cognitively normal older individuals (n = 28, area under the curve [AUC] = 0.92, sensitivity/specificity of 90%/90%). We failed to replicate these findings in a substantially larger study from two independent cohorts-the Baltimore Longitudinal Study of Aging ([BLSA], n = 93, AUC = 0.642, sensitivity/specificity of 51.6%/65.7%) and the Age, Gene/Environment Susceptibility-Reykjavik Study ([AGES-RS], n = 100, AUC = 0.395, sensitivity/specificity of 47.0%/36.0%). In analyses applying machine learning methods to all 187 metabolite concentrations assayed, we find a modest signal in the BLSA with distinct metabolites associated with the preclinical and symptomatic stages of AD, whereas the same methods gave poor classification accuracies in the AGES-RS samples. We believe that ours is the largest blood biomarker study of preclinical AD to date. These findings underscore the importance of large-scale independent validation of index findings from biomarker studies with relatively small sample sizes. PMID: 26806385 [PubMed - as supplied by publisher]

Serum Metabolomic Characterization of Liver Fibrosis in Rats and Anti-Fibrotic Effects of Yin-Chen-Hao-Tang.

Tue, 26/01/2016 - 14:03
Serum Metabolomic Characterization of Liver Fibrosis in Rats and Anti-Fibrotic Effects of Yin-Chen-Hao-Tang. Molecules. 2016;21(1) Authors: Zhang H, Wang X, Hu P, Zhou W, Zhang M, Liu J, Wang Y, Liu P, Luo G Abstract Yin-Chen-Hao-Tang (YCHT) is a famous Chinese medicine formula which has long been used in clinical practice for treating various liver diseases, such as liver fibrosis. However, to date, the mechanism for its anti-fibrotic effects remains unclear. In this paper, an ultra-performance liquid chromatography-time-of-flight mass spectrometry (UPLC-TOF-MS)-based metabolomic study was performed to characterize dimethylnitrosamine (DMN)-induced liver fibrosis in rats and evaluate the therapeutic effects of YCHT. Partial least squares-discriminant analysis (PLS-DA) showed that the model group was well separated from the control group, whereas the YCHT-treated group exhibited a tendency to restore to the controls. Seven significantly changed fibrosis-related metabolites, including unsaturated fatty acids and lysophosphatidylcholines (Lyso-PCs), were identified. Moreover, statistical analysis demonstrated that YCHT treatment could reverse the levels of most metabolites close to the normal levels. These results, along with histological and biochemical examinations, indicate that YCHT has anti-fibrotic effects, which may be due to the suppression of oxidative stress and resulting lipid peroxidation involved in hepatic fibrogenesis. This study offers new opportunities to improve our understanding of liver fibrosis and the anti-fibrotic mechanisms of YCHT. PMID: 26805802 [PubMed - in process]

OXIDATIVE AND NON-OXIDATIVE METABOLOMICS OF ETHANOL.

Tue, 26/01/2016 - 14:03
OXIDATIVE AND NON-OXIDATIVE METABOLOMICS OF ETHANOL. Curr Drug Metab. 2016 Jan 24; Authors: Dinis-Oliveira RJ Abstract It is well known that ethanol can cause significant morbidity and mortality, and much of the related toxic effects can be explained by its metabolic profile. The main pathway of metabolism is catalyzed by cytosolic alcohol dehydrogenase, which exhibits multiple isoenzymes and genetic polymorphisms with clinical and forensic implications. Another two oxidative routes, the highly inducible CYP2E1 system and peroxisomal catalase may acquire relevance under specific circumstances. In addition to oxidative metabolism, ethanol also originates minor metabolites such as ethyl glucuronide, ethyl sulfate, ethyl phosphate, ethyl nitrite, phosphatidylethanol and fatty acid ethyl esters. These metabolites represent alternative biomarkers since they can be detected several hours or days after ethanol exposure. This work performs a complete review of the metabolism of ethanol focusing on both major and minor metabolites. PMID: 26805730 [PubMed - as supplied by publisher]

A longitudinal analysis of the effects of age on the blood plasma metabolome in the common marmoset, Callithrix jacchus.

Tue, 26/01/2016 - 14:03
A longitudinal analysis of the effects of age on the blood plasma metabolome in the common marmoset, Callithrix jacchus. Exp Gerontol. 2016 Jan 21; Authors: Hoffman JM, Tran V, Wachtman LM, Green CL, Jones DP, Promislow DE Abstract Primates tend to be long-lived for their size with humans being the longest lived of all primates. There are compelling reasons to understand the underlying age-related processes that shape human lifespan. But the very fact of our long lifespan that makes it so compelling, also makes it especially difficult to study. Thus, in studies of aging, researchers have turned to non-human primate models, including chimpanzees, baboons, and rhesus macaques. More recently, the common marmoset, Callithrix jacchus, has been recognized as a particularly valuable model in studies of aging, given its small size, ease of housing in captivity, and relatively short lifespan. However, little is known about the physiological changes that occur as marmosets age. To begin to fill in this gap, we utilized high sensitivity metabolomics to define the longitudinal biochemical changes associated with age in the common marmoset. We measured 2104 metabolites from blood plasma at three separate time points over a 17-month period, and we completed both a cross-sectional and longitudinal analysis of the metabolome. We discovered hundreds of metabolites associated with age and body weight in both male and female animals. Our longitudinal analysis identified age-associated metabolic pathways that were not found in our cross-sectional analysis. Pathways enriched for age-associated metabolites included tryptophan, nucleotide, and xenobiotic metabolism, suggesting these biochemical pathways might play an important role in the basic mechanisms of aging in primates. Moreover, we found that many metabolic pathways associated with age were sex specific. Our work illustrates the power of longitudinal approaches, even in a short time frame, to discover novel biochemical changes that occur with age. PMID: 26805607 [PubMed - as supplied by publisher]

Phenotypic Characterization Analysis of Human Hepatocarcinoma by Urine Metabolomics Approach.

Tue, 26/01/2016 - 14:03
Phenotypic Characterization Analysis of Human Hepatocarcinoma by Urine Metabolomics Approach. Sci Rep. 2016;6:19763 Authors: Liang Q, Liu H, Wang C, Li B Abstract Hepatocarcinoma (HCC) is one of the deadliest cancers in the world and represents a significant disease burden. Better biomarkers are needed for early detection of HCC. Metabolomics was applied to urine samples obtained from HCC patients to discover noninvasive and reliable biomarkers for rapid diagnosis of HCC. Metabolic profiling was performed by LC-Q-TOF-MS in conjunction with multivariate data analysis, machine learning approaches, ingenuity pathway analysis and receiver-operating characteristic curves were used to select the metabolites which were used for the noninvasive diagnosis of HCC. Fifteen differential metabolites contributing to the complete separation of HCC patients from matched healthy controls were identified involving several key metabolic pathways. More importantly, five marker metabolites were effective for the diagnosis of human HCC, achieved a sensitivity of 96.5% and specificity of 83% respectively, could significantly increase the diagnostic performance of the metabolic biomarkers. Overall, these results illustrate the power of the metabolomics technology which has the potential as a non-invasive strategies and promising screening tool to evaluate the potential of the metabolites in the early diagnosis of HCC patients at high risk and provides new insight into pathophysiologic mechanisms. PMID: 26805550 [PubMed - in process]

CoA protects against the deleterious effects of caloric overload in Drosophila.

Tue, 26/01/2016 - 14:03
CoA protects against the deleterious effects of caloric overload in Drosophila. J Lipid Res. 2016 Jan 24; Authors: Musselman LP, Fink JL, Baranski TJ Abstract We developed a Drosophila model of type 2 diabetes in which high sugar (HS) feeding leads to insulin resistance. In this model, adipose triglyceride storage is protective against fatty acid toxicity and diabetes. Initial biochemical and gene expression studies suggested that deficiency in CoA might underlie reduced triglyceride synthesis in animals during chronic HS feeding. Focusing on the Drosophila fat body, which is specialized for triglyceride storage and lipolysis, we undertook a series of experiments to test the hypothesis that CoA could protect against the deleterious effects of caloric overload. Quantitative metabolomics revealed a reduction in substrate availability for CoA synthesis in the face of an HS diet. Further reducing CoA synthetic capacity by expressing fat body-specific RNAi targeting pantothenate kinase (fumble) or phosphopantothenoylcysteine decarboxylase (PPCS) exacerbated HS-diet-induced accumulation of free fatty acids. Dietary supplementation with pantothenic acid (vitamin B5, a precursor of CoA) was able to ameliorate HS-diet-induced free fatty acid accumulation and hyperglycemia while increasing triglyceride synthesis. Taken together, our data support a model where free CoA is required to support fatty acid esterification and to protect against the toxicity of HS diets. PMID: 26805007 [PubMed - as supplied by publisher]

Biomarkers in bladder cancer: A metabolomic approach using in vitro and ex vivo model systems.

Tue, 26/01/2016 - 14:03
Biomarkers in bladder cancer: A metabolomic approach using in vitro and ex vivo model systems. Int J Cancer. 2016 Jan 25; Authors: Rodrigues D, Jerónimo C, Henrique R, Belo L, de Lourdes Bastos M, de Pinho PG, Carvalho M Abstract Metabolomics has recently proved to be useful in the area of biomarker discovery for cancers in which early diagnostic and prognostic biomarkers are urgently needed, as is the case of bladder cancer (BC). This paper presents a comprehensive review of the literature on the metabolomic studies on BC, highlighting metabolic pathways perturbed in this disease and the altered metabolites as potential biomarkers for BC detection. Current disease model systems used in the study of BC metabolome include in vitro cultured cancer cells, ex vivo neoplastic bladder tissues, and biological fluids, mainly urine but also blood serum/plasma, from BC patients. The major advantages and drawbacks of each model system are discussed. Based on available data, it seems that BC metabolic signature is mainly characterized by alterations in metabolites related to energy metabolic pathways, particularly glycolysis, amino acid and fatty acid metabolism, known to be crucial for cell proliferation, as well as glutathione metabolism, known to be determinant in maintaining cellular redox balance. In addition, purine and pyrimidine metabolism as well as carnitine species were found to be altered in BC. Finally, it is emphasized that, despite the progress made in respect to novel biomarkers for BC diagnosis, there are still some challenges and limitations that should be addressed in future metabolomic studies to ensure their translatability to clinical practice. This article is protected by copyright. All rights reserved. PMID: 26804544 [PubMed - as supplied by publisher]

Metabolic analysis of antibody producing Chinese hamster ovary cell culture under different stresses conditions.

Mon, 25/01/2016 - 13:43
Metabolic analysis of antibody producing Chinese hamster ovary cell culture under different stresses conditions. J Biosci Bioeng. 2016 Jan 20; Authors: Badsha MB, Kurata H, Onitsuka M, Oga T, Omasa T Abstract Chinese hamster ovary (CHO) cells are commonly used as the host cell lines concerning their ability to produce therapeutic proteins with complex post-translational modifications. In this study, we have investigated the time course extra- and intracellular metabolome data of the CHO-K1 cell line, under a control and stress conditions. The addition of NaCl and trehalose greatly suppressed cell growth, where the maximum viable cell density of NaCl and trehalose cultures were 2.2-fold and 2.8-fold less than that of a control culture. Contrariwise, the antibody production of both the NaCl and trehalose cultures was sustained for a longer time to surpass that of the control culture. The NaCl and trehalose cultures showed relatively similar dynamics of cell growth, antibody production, and substrate/product concentrations, while they indicated different dynamics from the control culture. The principal component analysis of extra- and intracellular metabolome dynamics indicated that their dynamic behaviors were consistent with biological functions. The qualitative pattern matching classification and hierarchical clustering analyses for the intracellular metabolome identified the metabolite clusters whose dynamic behaviors depend on NaCl and trehalose. The volcano plot revealed several reporter metabolites whose dynamics greatly change between in the NaCl and trehalose cultures. The elastic net identified some critical, intracellular metabolites that are distinct between the NaCl and trehalose. While a relatively small number of intracellular metabolites related to the cell growth, glucose, glutamine, lactate and ammonium ion concentrations, the mechanism of antibody production was suggested to be very complicated or not to be explained by elastic net regression analysis. PMID: 26803706 [PubMed - as supplied by publisher]

Metabolomics study of fatigue in patients with rheumatoid arthritis naïve to biological treatment.

Mon, 25/01/2016 - 13:43
Metabolomics study of fatigue in patients with rheumatoid arthritis naïve to biological treatment. Rheumatol Int. 2016 Jan 23; Authors: Surowiec I, Gjesdal CG, Jonsson G, Norheim KB, Lundstedt T, Trygg J, Omdal R Abstract Fatigue occurs in all chronic inflammatory diseases, in cancer, and in some neurological conditions. Patients often regard fatigue as one of their most debilitating problems, but currently there is no established treatment and the mechanisms that lead to and regulate fatigue are incompletely understood. Our objective was to more completely understand the physiology of this phenomenon. Twenty-four patients with rheumatoid arthritis (RA) naïve to treatment with biological drugs were enrolled for the study. Fatigue was measured with a fatigue visual analogue scale (fVAS). Ethylenediaminetetraacetic acid (EDTA) plasma samples were subjected to gas chromatography-time-of-flight mass spectrometry (GC/MS-TOF)-based metabolite profiling. Obtained metabolite data were evaluated by multivariate data analysis with orthogonal projections to latent structures (OPLS) method to pinpoint metabolic changes related to fatigue severity. A significant multivariate OPLS model was obtained between the fVAS scores and the measured metabolic levels. Increasing fatigue scores were associated with a metabolic pattern characterized by down-regulation of metabolites from the urea cycle, fatty acids, tocopherols, aromatic amino acids, and hypoxanthine. Uric acid levels were increased. Apart from fatigue, we found no other disease-related variables that might be responsible for these changes. Our MS-based metabolomic approach demonstrated strong associations between fatigue and several biochemical patterns related to oxidative stress. PMID: 26803313 [PubMed - as supplied by publisher]

Personalized medicine in diabetes: the role of 'omics' and biomarkers.

Sun, 24/01/2016 - 13:03
Personalized medicine in diabetes: the role of 'omics' and biomarkers. Diabet Med. 2016 Jan 23; Authors: Pearson E Abstract Personalized medicine, otherwise called stratified or precision medicine, aims to better target intervention to the individual to maximize benefit and minimize harm. This review discusses how diabetes aetiology, pathophysiology and patient genotype influence response to or side effects of the commonly used diabetes treatments. C-peptide is a useful biomarker that is underused to guide treatment choice, severe insulin deficiency predicts non-response to glucagon-like peptide-1 receptor agonists, and thiazolidinediones are more effective in insulin-resistant patients. The field of pharmacogenetics is now yielding clinically important results, with three examples outlined: sulphonylurea sensitivity in patients with HNF1A maturity-onset diabetes of the young; sulphonylurea sensitivity in patients with Type 2 diabetes with reduced function alleles at CYP2C9, resulting in reduced metabolism of sulphonylureas; and severe metformin intolerance associated with reduced function organic cation transporter 1 (OCT1) variants, exacerbated by drugs that also inhibit OCT1. Genome-wide approaches and the potential of other 'omics', including metagenomics and metabolomics, are then outlined, highlighting the complex interacting networks that we need to understand before we can truly personalize diabetes treatments. This article is protected by copyright. All rights reserved. PMID: 26802434 [PubMed - as supplied by publisher]

Metabolic profiling of residents in the vicinity of a petrochemical complex.

Sun, 24/01/2016 - 13:03
Metabolic profiling of residents in the vicinity of a petrochemical complex. Sci Total Environ. 2016 Jan 20;548-549:260-269 Authors: Yuan TH, Chung MK, Lin CY, Chen ST, Wu KY, Chan CC Abstract No previous studies have simultaneously measured the biomarkers of environmental exposure and metabolome perturbation in residents affected by industrial pollutants. This study aimed to investigate the metabolic effects of environmental pollutants such as vanadium and polycyclic aromatic hydrocarbons (PAHs) on residents in the vicinity of a petrochemical complex. The study subjects were 160 residents, including 80 high-exposure subjects exposed to high levels of vanadium and PAHs and 80 age- and gender-matched low-exposure subjects living within a 40-km radius of a petrochemical complex. The exposure biomarkers vanadium and 1-hydroxypyrene and four oxidative/nitrosative stress biomarkers were measured in these subjects. Plasma samples from the study subjects were also analyzed using (1)H NMR spectroscopy for metabolic profiling. The results showed that the urinary levels of vanadium and 1-hydroxypyrene in the high-exposure subjects were 40- and 20-fold higher, respectively, than those in the low-exposure subjects. Higher urinary levels of stress biomarkers, including 8-OHdG, HNE-MA, 8-isoPF2α, and 8-NO2Gua, were also observed among the high-exposure subjects compared with the low-exposure subjects. Partial least squares discriminant analysis of the plasma metabolome demonstrated a clear separation between the high- and low-exposure subjects; the intensities of amino acids and carbohydrate metabolites were lower in the high-exposure subjects compared with the low-exposure subjects. The exposure to vanadium and PAHs may cause a reduction in the levels of amino acids and carbohydrates by elevating PPAR and insulin signaling, as well as oxidative/nitrosative stress. PMID: 26802354 [PubMed - as supplied by publisher]

Metabolomics of Neurotransmitters and Related Metabolites in Post-Mortem Tissue from the Dorsal and Ventral Striatum of Alcoholic Human Brain.

Sun, 24/01/2016 - 13:03
Metabolomics of Neurotransmitters and Related Metabolites in Post-Mortem Tissue from the Dorsal and Ventral Striatum of Alcoholic Human Brain. Neurochem Res. 2016 Jan 22; Authors: Kashem MA, Ahmed S, Sultana N, Ahmed EU, Pickford R, Rae C, Šerý O, McGregor IS, Balcar VJ Abstract We report on changes in neurotransmitter metabolome and protein expression in the striatum of humans exposed to heavy long-term consumption of alcohol. Extracts from post mortem striatal tissue (dorsal striatum; DS comprising caudate nucleus; CN and putamen; P and ventral striatum; VS constituted by nucleus accumbens; NAc) were analysed by high performance liquid chromatography coupled with tandem mass spectrometry. Proteomics was studied in CN by two-dimensional gel electrophoresis followed by mass-spectrometry. Proteomics identified 25 unique molecules expressed differently by the alcohol-affected tissue. Two were dopamine-related proteins and one a GABA-synthesizing enzyme GAD65. Two proteins that are related to apoptosis and/or neuronal loss (BiD and amyloid-β A4 precursor protein-binding family B member 3) were increased. There were no differences in the levels of dopamine (DA), 3,4-dihydrophenylacetic acid (DOPAC), serotonin (5HT), homovanillic acid (HVA), 5-hydroxyindoleacetic acid (HIAA), histamine, L-glutamate (Glu), γ-aminobutyric acid (GABA), tyrosine (Tyr) and tryptophan (Tryp) between the DS (CN and P) and VS (NAc) in control brains. Choline (Ch) and acetylcholine (Ach) were higher and norepinephrine (NE) lower, in the VS. Alcoholic striata had lower levels of neurotransmitters except for Glu (30 % higher in the alcoholic ventral striatum). Ratios of DOPAC/DA and HIAA/5HT were higher in alcoholic striatum indicating an increase in the DA and 5HT turnover. Glutathione was significantly reduced in all three regions of alcohol-affected striatum. We conclude that neurotransmitter systems in both the DS (CN and P) and the VS (NAc) were significantly influenced by long-term heavy alcohol intake associated with alcoholism . PMID: 26801172 [PubMed - as supplied by publisher]

Fusarium oxysporum mediates systems metabolic reprogramming of chickpea roots as revealed by a combination of proteomics and metabolomics.

Sun, 24/01/2016 - 13:03
Fusarium oxysporum mediates systems metabolic reprogramming of chickpea roots as revealed by a combination of proteomics and metabolomics. Plant Biotechnol J. 2016 Jan 23; Authors: Kumar Y, Zhang L, Panigrahi P, Dholakia BB, Dewangan V, Chavan SG, Kunjir SM, Wu X, Li N, Rajmohanan PR, Kadoo NY, Giri AP, Tang H, Gupta VS Abstract Molecular changes elicited by plants in response to fungal attack and how this affects plant-pathogen interaction, including susceptibility or resistance, remain elusive. We studied the dynamics in root metabolism during compatible and incompatible interactions between chickpea and Fusarium oxysporum f. sp. ciceri (Foc), using quantitative label-free proteomics and NMR-based metabolomics. Results demonstrated differential expression of proteins and metabolites upon Foc inoculations in the resistant plants compared with the susceptible ones. Additionally, expression analysis of candidate genes supported the proteomic and metabolic variations in the chickpea roots upon Foc inoculation. In particular, we found that the resistant plants revealed significant increase in the carbon and nitrogen metabolism; generation of reactive oxygen species (ROS), lignification and phytoalexins. The levels of some of the pathogenesis-related proteins were significantly higher upon Foc inoculation in the resistant plant. Interestingly, results also exhibited the crucial role of altered Yang cycle, which contributed in different methylation reactions and unfolded protein response in the chickpea roots against Foc. Overall, the observed modulations in the metabolic flux as outcome of several orchestrated molecular events are determinant of plant's role in chickpea-Foc interactions. PMID: 26801007 [PubMed - as supplied by publisher]

Intracrine Androgens and AKR1C3 Activation Confer Resistance to Enzalutamide in Prostate Cancer.

Sun, 24/01/2016 - 13:03
Related Articles Intracrine Androgens and AKR1C3 Activation Confer Resistance to Enzalutamide in Prostate Cancer. Cancer Res. 2015 Apr 1;75(7):1413-22 Authors: Liu C, Lou W, Zhu Y, Yang JC, Nadiminty N, Gaikwad NW, Evans CP, Gao AC Abstract The introduction of enzalutamide and abiraterone has led to improvement in the treatment of metastatic castration-resistant prostate cancer. However, acquired resistance to enzalutamide and abiraterone therapies frequently develops within a short period in many patients. In the present study, we developed enzalutamide-resistant prostate cancer cells in an effort to understand the mechanisms of resistance. Global gene-expression analysis showed that the steroid biosynthesis pathway is activated in enzalutamide-resistant prostate cancer cells. One of the crucial steroidogenic enzymes, AKR1C3, was significantly elevated in enzalutamide-resistant cells. In addition, AKR1C3 is highly expressed in metastatic and recurrent prostate cancer and in enzalutamide-resistant prostate xenograft tumors. LC/MS analysis of the steroid metabolites revealed that androgen precursors such as cholesterol, DHEA and progesterone, as well as androgens are highly upregulated in enzalutamide-resistant prostate cancer cells compared to the parental cells. Knockdown of AKR1C3 expression by shRNA or inhibition of AKR1C3 enzymatic activity by indomethacin resensitized enzalutamide-resistant prostate cancer cells to enzalutamide treatment both in vitro and in vivo. In contrast, overexpression of AKR1C3 confers resistance to enzalutamide. Furthermore, the combination of indomethacin and enzalutamide resulted in significant inhibition of enzalutamide-resistant tumor growth. These results suggest that AKR1C3 activation is a critical resistance mechanism associated with enzalutamide resistance; targeting intracrine androgens and AKR1C3 will overcome enzalutamide resistance and improve survival of advanced prostate cancer patients. PMID: 25649766 [PubMed - indexed for MEDLINE]

ECERIFERUM2-LIKE proteins have unique biochemical and physiological functions in very-long-chain fatty acid elongation.

Sun, 24/01/2016 - 13:03
Related Articles ECERIFERUM2-LIKE proteins have unique biochemical and physiological functions in very-long-chain fatty acid elongation. Plant Physiol. 2015 Mar;167(3):682-92 Authors: Haslam TM, Haslam R, Thoraval D, Pascal S, Delude C, Domergue F, Fernández AM, Beaudoin F, Napier JA, Kunst L, Joubès J Abstract The extension of very-long-chain fatty acids (VLCFAs) for the synthesis of specialized apoplastic lipids requires unique biochemical machinery. Condensing enzymes catalyze the first reaction in fatty acid elongation and determine the chain length of fatty acids accepted and produced by the fatty acid elongation complex. Although necessary for the elongation of all VLCFAs, known condensing enzymes cannot efficiently synthesize VLCFAs longer than 28 carbons, despite the prevalence of C28 to C34 acyl lipids in cuticular wax and the pollen coat. The eceriferum2 (cer2) mutant of Arabidopsis (Arabidopsis thaliana) was previously shown to have a specific deficiency in cuticular waxes longer than 28 carbons, and heterologous expression of CER2 in yeast (Saccharomyces cerevisiae) demonstrated that it can modify the acyl chain length produced by a condensing enzyme from 28 to 30 carbon atoms. Here, we report the physiological functions and biochemical specificities of the CER2 homologs CER2-LIKE1 and CER2-LIKE2 by mutant analysis and heterologous expression in yeast. We demonstrate that all three CER2-LIKEs function with the same small subset of condensing enzymes, and that they have different effects on the substrate specificity of the same condensing enzyme. Finally, we show that the changes in acyl chain length caused by each CER2-LIKE protein are of substantial importance for cuticle formation and pollen coat function. PMID: 25596184 [PubMed - indexed for MEDLINE]

Phosphoenolpyruvate Carboxylase in Arabidopsis Leaves Plays a Crucial Role in Carbon and Nitrogen Metabolism.

Sun, 24/01/2016 - 13:03
Related Articles Phosphoenolpyruvate Carboxylase in Arabidopsis Leaves Plays a Crucial Role in Carbon and Nitrogen Metabolism. Plant Physiol. 2015 Mar;167(3):671-81 Authors: Shi J, Yi K, Liu Y, Xie L, Zhou Z, Chen Y, Hu Z, Zheng T, Liu R, Chen Y, Chen J Abstract Phosphoenolpyruvate carboxylase (PEPC) is a crucial enzyme that catalyzes an irreversible primary metabolic reaction in plants.Previous studies have used transgenic plants expressing ectopic PEPC forms with diminished feedback inhibition to examine the role of PEPC in carbon and nitrogen metabolism. To date, the in vivo role of PEPC in carbon and nitrogen metabolism has not been analyzed in plants. In this study, we examined the role of PEPC in plants, demonstrating that PPC1 and PPC2 were highly expressed genes encoding PEPC in Arabidopsis (Arabidopsis thaliana) leaves and that PPC1 and PPC2 accounted for approximately 93% of total PEPC activity in the leaves. A double mutant, ppc1/ppc2, was constructed that exhibited a severe growth-arrest phenotype. The ppc1/ppc2 mutant accumulated more starch and sucrose than wild-type plants when seedlings were grown under normal conditions. Physiological and metabolic analysis revealed that decreased PEPC activity in the ppc1/ppc2 mutant greatly reduced the synthesis of malate and citrate and severely suppressed ammonium assimilation. Furthermore, nitrate levels in the ppc1/ppc2 mutant were significantly lower than those in wild-type plants due to the suppression of ammonium assimilation. Interestingly, starch and sucrose accumulation could be prevented and nitrate levels could be maintained by supplying the ppc1/ppc2 mutant with exogenous malate and glutamate, suggesting that low nitrogen status resulted in the alteration of carbon metabolism and prompted the accumulation of starch and sucrose in the ppc1/ppc2 mutant. Our results demonstrate that PEPC in leaves plays a crucial role in modulating the balance of carbon and nitrogen metabolism in Arabidopsis. PMID: 25588735 [PubMed - indexed for MEDLINE]

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Sat, 23/01/2016 - 12:47
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