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Metabolic Profile (metabolic + profile)
Selected AbstractsField Trial on Progesterone Cycles, Metabolic Profiles, Body Condition Score and their Relation to Fertility in Estonian Holstein Dairy CowsREPRODUCTION IN DOMESTIC ANIMALS, Issue 4 2008J Samarütel Contents Resumption of luteal activity postpartum and fertility were investigated in an Estonian Holstein high milk production and good fertility dairy herd. Body condition was scored after every 10 days in 54 multiparous dairy cows (71 lactations) calving inside from December to March during 4-year period. Blood samples were taken 1,14 days before calving and 1,14, 28,42 and 63,77 days after calving: analytes estimated were serum aspartate aminotransferase (AST), glucose, ketone bodies, total cholesterol, non-esterified fatty acids and triglycerides. The general linear mixed model was used to compare the data for cows with different characteristics in luteal activity postpartum based on their milk progesterone profiles. Forty-five per cent of cases had abnormal profiles; delayed resumption of ovarian cyclicity postpartum (DC) was the most prevalent abnormality. There was no difference in body condition scores between the groups. The DC and prolonged luteal phase groups had higher serum AST activity (p < 0.01) 1,14 days postpartum compared with normal group. The DC group also had higher cholesterol and triglyceride values (p < 0.05) 28,42 days postpartum and higher milk fat/protein ratio (p < 0.01) on the first month of lactation compared with normal profile group. Despite long post-calving anoestrous period (71 ± 5.0 days; mean ± SEM) DC group had 64.7% first service pregnancy rate (normal group 48.6% and PLP group 37.5%). This study did not find any detrimental effect of prolonged anovulatory period postpartum on subsequent fertility. [source] Metabolic profile of lettuce leaves by high-field NMR spectraMAGNETIC RESONANCE IN CHEMISTRY, Issue 8 2005Anatoli P. Sobolev Abstract A detailed analysis of the proton high-field NMR spectra of aqueous and organic extracts of lettuce leaves is reported for the first time. A combination of COSY, TOCSY, 1H,13C HSQC, 1H,13C HMBC bidimensional sequences and DOSY was used to assign each spin system and to separate the components of the complex patterns. A large number of water-soluble metabolites belonging to different classes such as carbohydrates, polyols, organic acids and amino acids were fully assigned. Moreover, the complex spectra of metabolites extracted in organic solvents belonging to sterols, fatty acids, diacylglycerophospholipids, galactosyldiacylglycerols, sulpholipids, pheophytins, carotenoids and hydrocarbons were also assigned. Copyright © 2005 John Wiley & Sons, Ltd. [source] FDB2 encodes a member of the arylamine N -acetyltransferase family and is necessary for biotransformation of benzoxazolinones by Fusarium verticillioidesJOURNAL OF APPLIED MICROBIOLOGY, Issue 2 2009A.E. Glenn Abstract Aims:, To clone and characterize genes from the mycotoxigenic fungus, Fusarium verticillioides, which are associated with its ability to biotransform allelopathic benzoxazolinones produced by maize, wheat, and rye. Methods and Results:, Suppression subtractive hybridization identified F. verticillioides genes up-regulated in response to 2-benzoxazolinone (BOA), including a cluster of genes along chromosome 3. One of these genes, putatively encoding an arylamine N -acetyltransferase (NAT), was highly represented in the subtracted library and was of particular interest since previous analyses identified the FDB2 locus as possibly encoding transferase activity. The gene was subcloned and complemented a natural fdb2 mutant. Conversely, disruption of the gene eliminated the ability of F. verticillioides to metabolize BOA. Other genes in the cluster also were assessed using a complementation assay. Metabolic profiles of fdb2 mutants suggest that minor acylation activity occurred independently of the NAT activity encoded by FDB2. Conclusions:, The previously defined FDB2 locus was functionally associated with the gene encoding putative NAT activity, and the FDB2 gene was essential for biotransformation of BOA. The flanking gene FDB3 encodes a putative Zn(II)2Cys6 transcription factor and contributes to efficient BOA biotransformation but was not essential. Significance and Impact of the Study:, Biotransformation of benzoxazolinones by F. verticillioides may enhance its ecological fitness in maize field environments and our results provide greater understanding of the genes that modulate the biotransformation process. Additionally, this is the first homologue of the NAT gene family to be characterized in a filamentous fungus. [source] Metabolomics in the assessment of chemical-induced reproductive and developmental outcomes using non-invasive biological fluids: application to the study of butylbenzyl phthalateJOURNAL OF APPLIED TOXICOLOGY, Issue 8 2009Susan Sumner Abstract This study was conducted to evaluate the use of metabolomics for improving our ability to draw correlations between early life exposures and reproductive and/or developmental outcomes. Pregnant CD rats were exposed by gavage daily during gestation to vehicle or to butylbenzyl phthalate (BBP) in vehicle at a level known to induce effects in the offspring and at a level previously not shown to induce effects. Urine was collected for 24,h (on dry ice using all glass metabolism chambers) from dams on gestational day 18 (during exposure) and on post natal day (pnd) 21, and from pnd 25 pups. Traditional phenotypic anchors were measured in pups (between pnd 0 and pnd 26). Metabolomics of urine collected from dams exposed to vehicle or BBP exhibited different patterns for endogenous metabolites. Even three weeks after gestational exposure, metabolic profiles of endogenous compounds in urine could differentiate dams that received the vehicle, low dose or high dose of BBP. Metabolic profiles could differentiate male from female pups, pups born to dams receiving the vehicle, low or high BBP dose, and pups with observable adverse reproductive effects from pups with no observed effects. Metabolites significant to the separation of dose groups and their relationship with effects measured in the study were mapped to biochemical pathways for determining mechanistic relevance. The application of metabolomics to understanding the mechanistic link between low levels of environmental exposure and disease/dysfunction holds huge promise, because this technology is ideal for the analysis of biological fluids in human populations. Copyright © 2009 John Wiley & Sons, Ltd. [source] Metabolic profiles of fat and glucose differ by gender in healthy 8-year-oldsACTA PAEDIATRICA, Issue 1 2010Susanne Eriksson Abstract Objective:, The aim was to investigate if metabolic markers were associated with anthropometry and weight increase in healthy 8-year-olds. Methods:, Ninety-seven healthy children, 66 of whom had been examined at the age of 4 years, were investigated. Dual energy X-ray absorptiometry was performed to determine fat (FM) and lean body mass (LBM). Plasma glucose and serum levels of insulin, cholesterol, triglycerides, adiponectin and leptin were analysed and HOMA-indices were calculated. Results:, Despite similar anthropometry, metabolic markers differed by gender. Sixteen % of the children were overweight or obese. Body mass index (BMI) was strongly correlated to FM. Anthropometric measures except LBM correlated to metabolic markers in the girls. Boys had higher concentrations of plasma glucose than girls. In overweight children, insulin was negatively associated with LBM. Leptin and the ratio between leptin and adiponectin, but not adiponectin, were significantly associated with HOMA-IR and body composition. Conclusion:, The metabolic profile of plasma glucose, serum leptin, fasting insulin and related HOMA indices differed by gender, despite no difference in BMI or FM. LBM, but not FM correlated to the insulin concentration in the overweight children. Leptin was the best marker of overweight. [source] A Phase III Study of Belatacept Versus Cyclosporine in Kidney Transplants from Extended Criteria Donors (BENEFIT-EXT Study)AMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2010A. Durrbach Recipients of extended criteria donor (ECD) kidneys are at increased risk for graft dysfunction/loss, and may benefit from immunosuppression that avoids calcineurin inhibitor (CNI) nephrotoxicity. Belatacept, a selective costimulation blocker, may preserve renal function and improve long-term outcomes versus CNIs. BENEFIT-EXT (Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial,EXTended criteria donors) is a 3-year, Phase III study that assessed a more (MI) or less intensive (LI) regimen of belatacept versus cyclosporine in adult ECD kidney transplant recipients. The coprimary endpoints at 12 months were composite patient/graft survival and a composite renal impairment endpoint. Patient/graft survival with belatacept was similar to cyclosporine (86% MI, 89% LI, 85% cyclosporine) at 12 months. Fewer belatacept patients reached the composite renal impairment endpoint versus cyclosporine (71% MI, 77% LI, 85% cyclosporine; p = 0.002 MI vs. cyclosporine; p = 0.06 LI vs. cyclosporine). The mean measured glomerular filtration rate was 4,7 mL/min higher on belatacept versus cyclosporine (p = 0.008 MI vs. cyclosporine; p = 0.1039 LI vs. cyclosporine), and the overall cardiovascular/metabolic profile was better on belatacept versus cyclosporine. The incidence of acute rejection was similar across groups (18% MI; 18% LI; 14% cyclosporine). Overall rates of infection and malignancy were similar between groups; however, more cases of posttransplant lymphoproliferative disorder (PTLD) occurred in the CNS on belatacept. ECD kidney transplant recipients treated with belatacept-based immunosuppression achieved similar patient/graft survival, better renal function, had an increased incidence of PTLD, and exhibited improvement in the cardiovascular/metabolic risk profile versus cyclosporine-treated patients. [source] Impact of substance use on the physical health of patients with bipolar disorderACTA PSYCHIATRICA SCANDINAVICA, Issue 6 2010M. P. Garcia-Portilla Garcia-Portilla MP, Saiz PA, Benabarre A, Florez G, Bascaran MT, Díaz EM, Bousońo M, Bobes J. Impact of substance use on the physical health of patients with bipolar disorder. Objective:, To describe the impact of tobacco, alcohol and cannabis on metabolic profile and cardiovascular risk in bipolar patients. Method:, Naturalistic, cross-sectional, multicenter Spanish study. Current use of tobacco, alcohol and cannabis was determined based on patient self-reports. Metabolic syndrome was defined using the National Health and Nutrition Examination Survey 1999,2000 and the American Heart Association/National Heart, Lung and Blood Institute criteria, and cardiovascular risk using the Framingham and the Systematic Coronary Risk Evaluation functions. Results:, Mean age was 46.6 years, 49% were male. Substance use: 51% tobacco, 13% alcohol and 12.5% cannabis. Patients who reported consuming any substance were significantly younger and a higher proportion was male. After controlling for confounding factors, tobacco was a risk factor for coronary heart disease (CHD) (unstandardized linear regression coefficient 3.47, 95% confidence interval 1.85,5.10). Conclusion:, Substance use, mainly tobacco, was common in bipolar patients. Tobacco use negatively impacted CHD risk. [source] Dipeptidyl peptidase-IV inhibitors: a major new class of oral antidiabetic drugDIABETES OBESITY & METABOLISM, Issue 2 2007Iskandar Idris Exploiting the incretin effect to develop new glucose-lowering treatments has become the focus of intense research. One successful approach has been the development of oral inhibitors of dipeptidyl peptidase-IV (DPP-IV). These drugs reversibly block DPP-IV-mediated inactivation of incretin hormones, for example, glucagon-like peptide 1 (GLP-1) and also other peptides that have alanine or proline as the penultimate N-terminal amino acid. DPP-IV inhibitors, therefore, increase circulating levels and prolong the biological activity of endogenous GLP-1, but whether this is sufficient to fully explain the substantial reduction in haemoglobin A1c (HbA1c) and associated metabolic profile remains open to further investigation. DPP-IV inhibitors such as vildagliptin and sitagliptin have been shown to be highly effective antihyperglycaemic agents that augment insulin secretion and reduce glucagon secretion via glucose-dependent mechanisms. This review summarizes the major clinical trials with DPP-IV inhibitors as monotherapy and as add-on therapy in patients with type 2 diabetes. The magnitude of HbA1c reduction with DPP-IV inhibitors depends upon the pretreatment HbA1c values, but there seems to be no change in body weight, and very low rates of hypoglycaemia and gastrointestinal disturbance with these agents. DPP-IV inhibitors represent a major new class of oral antidiabetic drug and their metabolic profile offers a number of unique clinical advantages for the management of type 2 diabetes. [source] Effect of a nutritional liquid supplement designed for the patient with diabetes mellitus (Glucerna SR) on the postprandial glucose state, insulin secretion and insulin sensitivity in healthy subjectsDIABETES OBESITY & METABOLISM, Issue 3 2006M. González-Ortiz Aim:, To identify the effect of a nutritional liquid supplement designed for the patient with diabetes mellitus (Glucerna SR) in single administration on the postprandial glucose state, insulin secretion and insulin sensitivity in healthy subjects. Methods:, A randomized, single-blind, cross-over, clinical trial was carried out in 14 young, healthy, non-obese, volunteers. A basal metabolic profile, which included glucose level, insulin, total cholesterol, high-density lipoprotein and low-density lipoprotein cholesterol, triglycerides, creatinine, and uric acid, was measured. Subjects received a single administration of 300 kcal, gauged with water at 350 ml, of each of the following (at least 3 days apart): glucose 75 g, polymeric supplement (Ensure high calcium) 315 ml or Glucerna SR 323 ml. At the beginning of each administration and 30, 60, 90 and 120 min later, glucose and insulin concentrations were measured. Areas under the curve of glucose and insulin were calculated. First-phase and total insulin secretions and insulin sensitivity were also estimated. Results:, Glucose level at 120 min was significantly lower after receiving Ensure high calcium or Glucerna SR. Administration of Glucerna SR resulted in a significant reduction in the areas under the curve of glucose and insulin, as well as in total insulin secretion with a tendency to be lower in their first phase. Insulin sensitivity was increased. Conclusions:, A single administration of Glucerna SR to healthy subjects decreased the postprandial glucose and insulin states, as well as the insulin secretion; insulin sensitivity increased. [source] Evaluation of CE methods for global metabolic profiling of urineELECTROPHORESIS, Issue 14 2010Rawi Ramautar Abstract In this study, the usefulness of noncovalently coated capillaries with layers of charged polymers is investigated to obtain global electrophoretic profiles of urinary metabolites covering a broad range of different compound classes in a highly repeatable way. Capillaries were coated with a bilayer of polybrene (PB) and poly(vinyl sulfonate) (PVS), or with a triple layer of PB, dextran sulfate (DS) and PB. The bilayer and triple layer coatings were evaluated at acidic (pH 2.0) and alkaline (pH 9.0) separation conditions, thereby providing separation conditions for basic and acidic compounds. A representative metabolite mixture and spiked urine samples were used for the evaluation of the four CE methods. Migration time repeatability (RSD<2%) and plate numbers (N, 100,000,400,000) were similar for the test compounds in all CE methods, except for some multivalent ions that may exhibit adsorption to oppositely charged coatings. The analysis of cationic compounds with the PB-DS-PB CE method at low pH (i.e. after the EOF time) provided a larger separation window and number of separated peaks in urine compared to the analysis with the PB-PVS CE method at low pH (i.e. before the EOF time). Approximately, 600 molecular features were detected in rat urine by the PB-DS-PB CE-MS method whereas about 300 features were found with the PB-PVS CE-MS method. This difference can be attributed to reduced comigration of compounds with the PB-DS-PB CE-MS method and a related decrease of ion suppression. With regard to the analysis of anionic compounds by CE-MS, in general analyte responses were significantly lower than that for cationic compounds, most probably due to less efficient ionization and to ion suppression effects caused by the background electrolyte. Hence, further optimization is required for the sensitive CE-MS analysis of anionic compounds in body fluids. It is concluded that the selection of a CE method for profiling of cationic metabolites in urine depends on the purpose of the study. For high-throughput analyses, the PB-PVS CE-MS method is favored whereas the PB-DS-PB CE-MS method provides a more information-rich metabolic profile, but at the cost of prolonged analysis time. [source] A phase I clinical trial of the histone deacetylase inhibitor belinostat in patients with advanced hematological neoplasiaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 3 2008Peter Gimsing Abstract Purpose:, To determine the safety, dose-limiting toxicity and maximum tolerated dose (MTD) of the novel hydroxamate histone deacetylase inhibitor belinostat (PXD101) in patients with advanced hematological neoplasms. Patients and methods:, Sequential dose-escalating cohorts of three to six patients with hematological malignancies received belinostat administered as a 30-min i.v. infusion on days 1,5 of a 21-d cycle. Experience from a parallel dose-finding study in patients with solid tumors influenced the selection of the final dose. Results:, Sixteen patients received belinostat at one of three dose levels: 600 mg/m2/d (three patients), 900 mg/m2/d (three patients) and 1000 mg/m2/d (10 patients), the dose determined to be the MTD in a phase I solid tumor study [Steele et al. (2008) Clin Cancer Res, 14, 804,10]. The most common treatment-related adverse events (all grades) were nausea (50%), vomiting (31%), fatigue (31%) and flushing (31%). No grade 3 or 4 hematological toxicity compared with baseline occurred except one case of grade 3 lymphopenia. There were two related grade 4 adverse events of renal failure observed. Both events occurred in patients with multiple myeloma and had similar characteristics, i.e. an acute episode of decrease in renal function (pre-existing nephropathy in one patient), with a metabolic profile and decrease in tumor burden consistent with tumor lysis syndrome. No other related grade 4 events were noted. The only related grade 3 events noticed in more than one patient were fatigue and neurological symptoms (one patient had status epilepticus in association with uremia and one patient had paresthesia), all other related grade 3 events occurred in single patients. No cardiac events were noted. No complete or partial remissions were noted in these heavily pre-treated (median of four prior regimens) patients. However, five patients, including two patients with diffuse large-cell lymphoma [including one patient with transformed chronic myelomcytic leukaemia (CLL)], two patients with CLL and one patient with multiple myeloma, achieved disease stabilization in of two to nine treatment cycles. Conclusions:, Intravenous belinostat at 600, 900 and 1000 mg/m2/d is well tolerated by patients with hematological malignancies. The study was carried out in parallel to a similar dose-finding study in patients with solid tumors, in which the MTD was determined to be 1000 mg/m2/d days 1,5 in a 21-d cycle. This dose can also be recommended for phase II studies in patients with hematological neoplasms. [source] Metabolism of methoxymorpholino-doxorubicin in rat, dog and monkey liver microsomes: comparison with human microsomesFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 6 2001Dominique Beulz-Riche The morpholino anthracycline, methoxymorpholino-doxorubicin (MMDx) is a novel anticancer agent. The metabolism of this highly lipophilic doxorubicin analogue is not fully elucidated. MMDx is metabolically activated in vivo, resulting in an 80-fold increase in potency over the parent drug. In this study, MMDx in vitro metabolism was compared in rat, dog, monkey and human liver microsomes. When microsomal fractions were incubated with MMDx, 6,8 metabolites were formed depending on the species and on the substrate concentrations. Among these eight metabolites, three comigrated with authentic standards, namely MMDx-ol, PNU156686 and PNU159682, and the five others are in the process of being characterized. Quantitatively, monkey and human metabolize MMDx with a higher rate than rat and dog. Qualitatively, MMDx metabolic profile in dog microsomes was different from the three other species. MMDx-ol was predominant in dog and only minor in other species. In conclusion, MMDx metabolism was species-different. Rat and monkey liver microsomes may be used as models to study MMDx metabolism in humans. Dog liver microsomes may be a good model for studying the formation of MMDx-ol. [source] The effect of weight loss by energy restriction on metabolic profile and glucose tolerance in poniesJOURNAL OF ANIMAL PHYSIOLOGY AND NUTRITION, Issue 5 2008S. Van Weyenberg Summary In nine initially obese ponies, a weekly weight loss according to 1% of their ideal body weight was evaluated for its impact on insulin sensitivity and metabolic profile. Weight loss was obtained solely through energy restriction, initially at 70% of maintenance energy requirements, but to maintain constant weight loss, feed amount had to be decreased to 50% and 35% of maintenance energy requirement during the course of the trial. An oral glucose tolerance test (OGTT) was performed at weeks 0, 10 and 17. Fasted blood samples were taken on weeks 0, 3, 10, 17 for analysis of triglycerides (TG), non-esterified fatty acids (NEFA), creatine phosphokinase (CPK), lactate dehydrogenase (LDH), T3, T4 and leptin. Total average weight loss was 18.2%. When the OGTT was performed at weeks 0, 10 and 17, ponies had lost 0.22%, 9.9% and 16.3% of their initial weight respectively. Weight loss was associated with a decreased AUC for glucose and insulin. Moreover, greater % weight loss was associated with a significantly lower glucose peak and a lower area under the curve (AUC glucose). The lower glucose response after an OGTT in lean ponies was not the result of an increased insulin secretion, but an improved insulin sensitivity. Restricted feeding led to mobilization of TG and NEFA and to a reduced basal metabolism, with lower LDH, CPK, T3 and leptin. In conclusion: in obese Shetland ponies, weight loss at a rate of 1% of ideal body weight per week through restricted energy intake, ameliorated insulin sensitivity. [source] Hydrocarbon degradation by thermophilic Nocardia otitidiscaviarum strain TSH1: physiological aspectsJOURNAL OF BASIC MICROBIOLOGY, Issue 6 2007Majid Zeinali Abstract Indigenous thermophilic hydrocarbon degraders are of special significance for the bioremediation of oil-contaminated desert soils with ambient temperature of 45,50 °C. The first objective of this study was to demonstrate the hydrocarbon-degrading capability of Nocardia otitidiscaviarum TSH1 (DSM 45036) which grows optimally at 50 °C. Analysis of the metabolic profile of the strain TSH1 showed that it could metabolize phenol, intermediate-chain-length n -alkanes and some polycyclic aromatic hydrocarbons (PAHs) ranging in size from two to four fused rings efficiently, but not toluene and xylene. N. otitidiscaviarum TSH1 was able to survive and grow at phenol concentrations up to 875 mg l,1. For the first time, the physiological response of a thermophilic Nocardia strain to poorly available hydrophobic compounds was also investigated. When grown on a mineral salt medium with hexadecane, N. otitidiscaviarum TSH1 showed very high affinity for the organic phase. Additionally, PAH-grown cells were considerably hydrophobic. The capacity of PAH-utilizing N. otitidiscaviarum TSH1 isolate to produce biosurfactants was also investigated. Fatty acids (C14,C18) were detected by GC-MS analysis during bacterial growth in PAH supplemented mineral media. High cell surface hydrophobicity and capability of N. otitidiscaviarum TSH1 to degrade different hydrocarbons at 50 °C may make it an ideal candidate to treat oil-contaminated desert soils. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [source] Use of the 1-mm micro-probe for metabolic analysis on small volume biological samplesJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 8b 2009Natalie J. Serkova Abstract Endogenous metabolites are promising diagnostic end-points in cancer research. Clinical application of high-resolution NMR spectroscopy is often limited by extremely low volumes of human specimens. In the present study, the use of the Bruker 1-mm high-resolution TXI micro-probe was evaluated in the elucidation of metabolic profiles for three different clinical applications with limited sample sizes (body fluids, isolated cells and tissue biopsies). Sample preparation and 1H-NMR metabolite quantification protocols were optimized for following oncology-oriented applications: (i) to validate the absolute concentrations of citrate and spermine in human expressed prostatic specimens (EPS volumes 5 to 10 ,l: prostate cancer application); (ii) to establish the metabolic profile of isolated human lymphocytes (total cell count 4 = 106: chronic myelogenous leukaemia application); (iii) to assess the metabolic composition of human head-and-neck cancers from mouse xenografts (biopsy weights 20 to 70 mg: anti-cancer treatment application). In this study, the use of the Bruker 1-mm micro-probe provides a convenient way to measure and quantify endogenous metabolic profiles of samples with a very low volume/weight/cell count. [source] Metabolomics-based systematic prediction of yeast lifespan and its application for semi-rational screening of ageing-related mutantsAGING CELL, Issue 4 2010Ryo Yoshida Summary Metabolomics , the comprehensive analysis of metabolites , was recently used to classify yeast mutants with no overt phenotype using raw data as metabolic fingerprints or footprints. In this study, we demonstrate the estimation of a complicated phenotype, longevity, and semi-rational screening for relevant mutants using metabolic profiles as strain-specific fingerprints. The fingerprints used in our experiments are profiled data consisting of individually identified and quantified metabolites rather than raw spectrum data. We chose yeast replicative lifespan as a model phenotype. Several yeast mutants that affect lifespan were selected for analysis, and they were subjected to metabolic profiling using mass spectrometry. Fingerprinting based on the profiles revealed a correlation between lifespan and metabolic profile. Amino acids and nucleotide derivatives were the main contributors to this correlation. Furthermore, we established a multivariate model to predict lifespan from a metabolic profile. The model facilitated the identification of putative longevity mutants. This work represents a novel approach to evaluate and screen complicated and quantitative phenotype by means of metabolomics. [source] Effect of a lifestyle intervention in patients with abnormal liver enzymes and metabolic risk factorsJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 3 2009Alexis St. George Abstract Background and Aim:, Non-alcoholic fatty liver disease associated with insulin resistance is the most common cause of abnormal liver tests in clinical practice. To date, practical and effective strategies to improve the metabolic profile of this large group of patients have not been well characterised. We sought to assess the effect at 3 months of a behavior change-based lifestyle intervention on the metabolic profile of patients characterised by elevated liver enzymes. Methods:, A total of 152 patients with elevated liver enzymes, central obesity and a range of metabolic risk factors were randomised to either a moderate- (6 sessions/10 weeks) or low-intensity (3 sessions/4 weeks) lifestyle counselling intervention or control group. Results:, There was improvement in all metabolic risk factors in the moderate-intensity group, versus a smaller number of changes in the low-intensity intervention group and no change in any metabolic risk factors in control subjects. Reduction in liver enzymes was greatest in the moderate-intensity intervention group and least in the control group. The likelihood of elevated alanine aminotransferase (ALT) levels in both the moderate and low-intensity groups was reduced by over 70% compared to controls. The proportion of subjects achieving weight loss (, 2%) was significantly higher in the moderate-intensity intervention group (66%) versus the low-intensity intervention group (39%; P < 0.05) and controls (29%; P < 0.001). Conclusions:, Moderate and even low-intensity lifestyle counselling interventions targeting improvement in physical activity and nutritional behaviors and modest weight loss are a practical and effective method for improving the health of patients with elevated liver enzymes and a range of metabolic risk factors. [source] Adenovirus-Mediated Leptin Expression Normalises Hypertension Associated with Diet-Induced ObesityJOURNAL OF NEUROENDOCRINOLOGY, Issue 3 2010W. Zhang In our previous study, moderate increases in plasma leptin levels achieved via administration of recombinant adenovirus containing the rat leptin cDNA were shown to correct the abnormal metabolic profile in rats with diet-induced obesity, suggesting that these animals had developed resistance to the metabolic effects of leptin, which could be reversed by leptin gene over-expression. However, the effect of this therapeutic strategy on blood pressure was not investigated. The present study aimed to determine whether a moderate increase of endogenous plasma leptin levels affected arterial blood pressure in rats with diet-induced obesity and hypertension. The major finding from the present study was that the natural rise in plasma leptin with weight-gain is insufficient to counterbalance high blood pressure associated with obesity, additional increases of circulating leptin levels with adenoviral leptin gene therapy led to normalisation of blood pressure in high-fat diet-induced obese and hypertensive rats. Mechanistically, the reduction of blood pressure by leptin in obese rats was likely independent of ,-adrenergic and acetylcholinergic receptor mediation. This is the first study to demonstrate that further increases in circulating leptin levels by leptin gene transfer during obesity could reduce blood pressure. [source] Differential Effects of Restricted Versus Unlimited High-Fat Feeding in Rats on Fat Mass, Plasma Hormones and Brain Appetite RegulatorsJOURNAL OF NEUROENDOCRINOLOGY, Issue 7 2009T. Shiraev The rapid rise in obesity has been linked to altered food consumption patterns. There is increasing evidence that, in addition to total energy intake, the macronutrient composition of the diet may influence the development of obesity. The present study aimed to examine the impact of high dietary fat content, under both isocaloric and hypercaloric conditions, compared with a low fat diet, on adiposity, glucose and lipid metabolism, and brain appetite regulators in rats. Male Sprague,Dawley rats were exposed to one of three diets: control (14% fat), ad lib high-fat palatable (HFD, 35% fat) or high-fat palatable restricted (HFD-R, matched to the energy intake of control) and were killed in the fasting state 11 weeks later. Body weight was increased by 28% in unrestricted HFD fed rats, with an almost tripling of caloric intake and fat mass (P < 0.001) and double the plasma triglycerides of controls. Glucose intolerance and increased insulin levels were observed. HFD-R animals calorie matched to control had double their fat mass, plasma insulin and triglycerides (P < 0.05). Only ad lib consumption of the HFD increased the hypothalamic mRNA expression of the appetite-regulating peptides, neuropeptide Y and pro-opiomelanocortin. Although restricted consumption of palatable HFD had no significant impact on hypothalamic appetite regulators or body weight, it increased adiposity and circulating triglycerides, suggesting that the proportion of dietary fat, independent of caloric intake, affects fat deposition and the metabolic profile. [source] Amelioration of disease severity by intraarticular hylan therapy in bilateral canine osteoarthritisJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 3 2000K. W. Marshall Because of its high molecular weight, the glycosaminoglycan molecule hyaluronan is responsible for the viscoelastic properties of normal synovial fluid. In osteoarthritis, the concentration and molecular weight of hyaluronan in synovial fluid is diminished; this impairs the ability of synovial fluid to effectively lubricate joints, absorb loads, and exert anti-inflammatory effects. Using a bilateral anterior cruciateligament transection and partial neurectomy canine model of osteoarthritis, this study examined the effect of viscosupplementation with hylan G-F 20 as a treatment for osteoarthritis, this study examined the effect of viscosupplementation with hylan G-F 20 as a treatment for osteoarthritis. Twelve dogs underwent bilateral arthroscopic anterior cruciate-ligament transections and partial neurectomy of the knee joints. Beginning 1 week after the operation, six dogs received three weekly 500-,l injections of hylan G-F 20 in one knee and a sham injection of saline solution in the contralateral knee (early-treatment group). The remaining six animals underwent the same treatment 2 months following the procedure (late-treatment group). All dogs were killed at 8 months, and both knees were evaluated for gross pathology, histology, and proteoglycan content. In addition, with use of 500-MHz [1H] magnetic resonance spectroscopy, the synovial fluid from both knees was assessed for changes in metabolic profile. Differences in outcome were analyzed with paired t tests. Gross pathological and histological examination revealed significantly less severe changes of osteoarthritis in knees treated with hylan G-F 20 2 months after surgery than in the contralateral untreated knees. Magnetic resonance spectroscopy of the specimens in this late-treatment group showed significantly decreased glucose concentrations and significantly elevated isoleucine levels in the synovial fluid from knees treated with hylan G-F 20 compared with the controls. Previous magnetic resonance spectroscopy had shown that glucose concentrations increase with the onset of osteoarthritis and eventually diminish in end-stage osteoarthritis. The three injections of hylan were given after osteoarthritis was established, and the severity of the disease was ameliorated in the treated knees 6 months after treatment. This occurred although hylan G-F 20 is almost certainly cleared from joints by lymphatics within 4 weeks of injection, suggesting that hylan therapy can retard the progression of osteoarthritis for periods of time extending beyond the intraarticular residence time of the injected molecules and that hylan injections given at relatively early stages of osteoarthritis may have a chondroprotective effect. No changes in outcome were noted in the animals that received hylan G-F 20 immediately following surgery. [source] Abnormal alterations in the metabolic patterns of patients on valproate therapyJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2002U. Kreher Four cases of abnormal metabolic patterns which were obtained from three infantile patients and one adult on valproate (valproic acid; 2-n-propyl-pentanoic acid) therapy are reported. Serum levels of valproate and 15 metabolites were measured by gas chromatography/mass spectrometry. A mentally retarded, 11-month-old boy developed an extremely altered metabolic profile after having been treated with valproate polytherapy for 3 months. The altered pattern included strongly elevated serum levels of the 4-ene as well as of the x-/x 1-metabolites, with the b-metabolites (2-ene; 2,3,-diene) being diminished. Two samples obtained previously had shown a common pattern. The infant died 3 weeks after the last sample had been taken. Two boys of the same age showed similar but less intense deviations in their metabolic profiles at the onset of valproate therapy. Within a few weeks they approached, in a step-wise fashion, the average pattern common for children under 3 years of age. The striking alterations were paralleled by the metabolic profiles of an adult patient who suffered from intrahepatic metastasis and renal insufficiency. From the close resemblance of the abnormal metabolic patterns it was concluded that liver dysfunction results in alteration of the whole metabolic system. Regular inspection of the entire profile of an individual might help to recognize conspicuous alterations in time to avoid severe side effects. [source] Comparative assessment of soybean meal with high and low glucosinolate rapeseed,mustard cake as protein supplement on performance of growing crossbred calvesJOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE, Issue 5 2008S Ravichandiran Abstract BACKGROUND: Feeding of high glucosinolate rapeseed,mustard cakes (RMCs) imparts adverse effects on dry matter (DM) intake, health and overall performance of animals. Recently, plant breeding efforts have resulted in many cultivars of RMCs containing low to moderate levels of glucosinolate in India. The feeding value of RMC cultivars with high and low glucosinolate was evaluated relative to commonly used soybean meal as a protein supplement in growing crossbred calves. RESULTS: Eighteen growing crossbred calves (62.9 ± 3.8 kg body weight) were randomly allocated to three dietary treatments SBM, LG and HG containing soybean meal, low glucosinolate B. napus (15 µmol glucosinolates g,1) and high glucosinolate B. juncea (135 µmol glucosinolates g,1), respectively. Although daily intake of total DM and wheat straw did not differ (P > 0.05) among the dietary treatments, intake (g/kgW0.75) of concentrate moiety decreased quadratically (P < 0.01) with increasing glucosinolate levels in diets. Nutrient digestibility and balances of N, Ca and P by calves were similar (P > 0.05) among dietary treatments. However, average daily gain (g) decreased and feed conversion ratio values increased quadratically (P < 0.05) with increasing glucosinolate levels. Serum metabolic profile and triiodothyronine remained within the normal range; however, thyroxine changed quadratically. CONCLUSION: The results suggested that while high glucosinolate RMCs may reduce the palatability and consequently growth rate in crossbred calves, SBM can be replaced completely by low glucosinolate rapeseed without compromising their performance. Copyright © 2008 Society of Chemical Industry [source] Characterization of oligodendrogliomas using short echo time 1H MR spectroscopic imagingNMR IN BIOMEDICINE, Issue 1 2003M. Rijpkema Abstract Oligodendroglial tumors may not be distinguished easily from other brain tumors based on clinical presentation and magnetic resonance imaging (MRI) alone. Identification of these tumors however may have therapeutic consequences. The purpose of this study was to characterize and identify oligodendrogliomas by their metabolic profile as measured by 1H MR spectroscopic imaging (MRSI). Fifteen patients with oligodendroglial tumors (eight high-grade oligodendrogliomas, seven low-grade oligodendrogliomas) underwent MRI and short echo time 1H MRSI examinations. Five main metabolites found in brain MR spectra were quantified and expressed as ratios of tumor to contralateral white matter tissue. The level of lipids plus lactate was also assessed in the tumor. For comparison six patients with a low grade astrocytoma were also included in the study. The metabolic profile of oligodendrogliomas showed a decreased level of N -acetylaspartate and increased levels of choline-containing compounds and glutamine plus glutamate compared with white matter. The level of glutamine plus glutamate was significantly higher in low-grade oligodendrogliomas than in low-grade astrocytomas and may serve as a metabolic marker in diagnosis and treatment planning. In high-grade oligodendrogliomas large resonances of lipids plus lactate were observed in contrast to low-grade tumors. Copyright © 2003 John Wiley & Sons, Ltd. [source] Metabolism of fungicidal cyanooximes, cymoxanil and analogues in various strains of Botrytis cinereaPEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 2 2009Frédérique Tellier Abstract BACKGROUND: The metabolism of cymoxanil [1-(2-cyano-2-methoxyiminoacetyl)-3-ethylurea] and fungicidal cyanooxime analogues was monitored on three phenotypes of Botrytis cinerea Pers. ex Fr. differing in their sensitivity towards cymoxanil. For this purpose, labelled [2- 14C]cymoxanil was added either to the culture medium of these strains or to its cell-free extract. RESULTS: In the culture medium of the most sensitive strain, four main metabolites were detected. Three were isolated and identified. Cymoxanil was quickly metabolised by at least three concurrent enzymatic pathways: (i) cyclisation leading, after hydrolysis, to ethylparabanic acid, (ii) reduction giving demethoxylated cymoxanil, (iii) hydrolysis followed by reduction and then acetylation leading to N -acetylcyanoglycine. In the cell-free extract of the same strain, only the first and the second of these enzymatic reactions occurred. By comparing the metabolic profile of the most sensitive strain with that of the less sensitive ones, it was shown that the decrease in sensitivity to cymoxanil correlates with a reduced acetylcyanoglycine formation. Among all metabolites, only N -acetylcyanoglycine is active against the most sensitive strain. Moreover, in a culture of this strain, two other fungicidal cyanooximes were also metabolised into this metabolite. CONCLUSION: The formation of N -acetylcyanoglycine may play an important role in the fungitoxicity of cymoxanil and cyanooxime derivatives. Copyright © 2008 Society of Chemical Industry [source] Evaluation of tramadol and its main metabolites in horse plasma by high-performance liquid chromatography/fluorescence and liquid chromatography/electrospray ionization tandem mass spectrometry techniquesRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 2 2009Marinella De Leo Tramadol is a centrally acting analgesic drug that has been used clinically for the last two decades to treat pain in humans. The clinical response of tramadol is strictly correlated to its metabolism, because of the different analgesic activity of its metabolites. O -Desmethyltramadol (M1), its major active metabolite, is 200 times more potent at the µ -receptor than the parent drug. In recent years tramadol has been widely introduced in veterinary medicine but its use has been questioned in some species. The aim of the present study was to develop a new sensible method to detect the whole metabolic profile of the drug in horses, through plasma analyses by high-performance liquid chromatography (HPLC) coupled with fluorimetric (FL) and photodiode array electrospray ionization mass spectrometric (PDA-ESI-MS) detection, after its sustained release by oral administration (5,mg/kg). In HPLC/FL experiments the comparison of the horse plasma chromatogram profile with that of a standard mixture suggested the identification of the major peaks as tramadol and its metabolites M1 and N,O -desmethyltramadol (M5). LC/PDA-ESI-MS/MS analysis confirmed the results obtained by HPLC/FL and also provided the identification of two more metabolites, N -desmethyltramadol (M2), and N,N -didesmethyltramadol (M3). Another metabolite, M6, was also detected and identified. The present findings demonstrate the usefulness and the advantage of LC/ESI-MS/MS techniques in a search for tramadol metabolites in horse plasma samples. Copyright © 2008 John Wiley & Sons, Ltd. [source] High-performance liquid chromatography/tandem mass spectrometry for the quantitative analysis of a novel taxane derivative (BAY59-8862) in biological samples and characterisation of its metabolic profile in rat bile samplesRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 19 2001Cristina Sottani A sensitive, specific, accurate and reproducible high-performance liquid chromatography (HPLC) analytical method was developed and validated for the quantification of the novel oral taxane analogue BAY59-8862 in mouse plasma and tissue samples. A fully automated solid-phase extraction procedure was applied to the plasma after internal standard (IS) addition, with only 0.2,mL volume of the sample loaded on a CN-Sep-pak cartridge. In the case of the tissues a very simple acetonitrile extraction was used to recover BAY59-8862 and its internal standard from liver. The procedure for the quantification of BAY59-8862 and its IS (IDN5127) is based on high-performance liquid chromatography/ion spray-tandem mass spectrometry, operating in selected ion monitoring mode. The retention times of BAY and IS were 7.21 and 10.36,min, respectively. In both plasma and tissue specimens the assay was linear in the range 50,5000,ng/mL (ng/g). The overall precision and accuracy were assessed on three different days. The results for plasma were within 6.1% (precision) and between 99 and 112% (accuracy), and for the liver samples within 7.3% and between 104 and 118%, respectively. The LOD was 5,ng/mL and 20,ng/g in the plasma and liver, respectively. In addition, the biliary excretion of the compound in rats was studied. The study showed that an oxidative chemical reaction was the preferred metabolic pathway for biliary excretion, and two sets of mono- and dihydroxylated metabolites were detected by LC/ISP-MS/MS experiments. With this method, BAY59-8862 pharmacokinetic was determined in mice. The combined results demonstrate that the methodology can be considered a valid approach to conduct pharmacokinetic and metabolic studies during preclinical and clinical investigations. Copyright © 2001 John7 Wiley & Sons, Ltd. [source] In vitro Metabolism of Genistein and Tangeretin by Human and Murine Cytochrome P450sBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 1 2003Vibeke M. Breinholt Analysis of the metabolic profile from incubations with genistein and human liver microsomes revealed the production of five different metabolites, of which three were obtained in sufficient amounts to allow a more detailed elucidation of the structure. One of these metabolites was identified as orobol, the 3,-hydroxylated metabolite of genistein. The remaining two metabolites were also hydroxylated metabolites as evidenced by LC/MS. Orobol was the only metabolite formed after incubation with CYP1A2. The two major product peaks after incubation of tangeretin with human microsomes were identical with 4,-hydroxy-5,6,7,8-tetramethoxyflavone and 5,6-dihydroxy-4,,7,8-trimethoxyflavone, previously identified in rat urine in our laboratory. By comparison with UV spectra and LC/MS fragmentation patterns of previously obtained standards, the remaining metabolites eluting after 14, 17 and 20 min. were found to be demethylated at the 4,,7-, 4,,6-positions or hydroxylated at the 3,- and demethylated at the 4,-positions, respectively. Metabolism of tangeretin by recombinant CYP1A2, 3A4, 2D6 and 2C9 resulted in metabolic profiles that qualitatively were identical to those observed in the human microsomes. Inclusion of the CYP1A2 inhibitor fluvoxamine in the incubation mixture with human liver microsomes resulted in potent inhibition of tangeretin and genistein metabolism. Other isozymes-selective CYP inhibitors had only minor effects on tangeretin or genistein metabolism. Overall the presented observations suggest major involvement of CYP1A2 in the hepatic metabolism of these two flavonoids. [source] Application of Multivariate Analysis to Optimize Function of Cultured HepatocytesBIOTECHNOLOGY PROGRESS, Issue 2 2003Christina Chan Understanding the metabolic and regulatory pathways of hepatocytes is important for biotechnological applications involving liver cells, including the development of bioartificial liver (BAL) devices. To characterize intermediary metabolism in the hepatocytes, metabolic flux analysis (MFA) was applied to elucidate the changes in intracellular pathway fluxes of primary rat hepatocytes exposed to human plasma and to provide a comprehensive snapshot of the hepatic metabolic profile. In the current study, the combination of preconditioning and plasma supplementation produced distinct metabolic states. Combining the metabolic flux distribution obtained by MFA with methodologies such as Fisher discriminant analysis (FDA) and partial least squares or projection to latent structures (PLS) provided insights into the underlying structure and causal relationship within the data. With the aid of these analyses, patterns in the cellular response of the hepatocytes that contributed to the separation of the different hepatic states were identified. Of particular interest was the recognition of distal pathways that strongly correlated with a particular hepatic function. The hepatic functions investigated were intracellular triglyceride accumulation and urea production. This study illustrates a framework for optimizing hepatic function and a possibility of identifying potential targets for improving hepatic functions. [source] Neural tube defects and maternal biomarkers of folate, homocysteine, and glutathione metabolism,BIRTH DEFECTS RESEARCH, Issue 4 2006Weizhi Zhao Abstract BACKGROUND Alterations in maternal folate and homocysteine metabolism are associated with neural tube defects (NTDs). The role played by specific micronutrients and metabolites in the causal pathway leading to NTDs is not fully understood. METHODS We conducted a case-control study to investigate the association between NTDs and maternal alterations in plasma micronutrients and metabolites in two metabolic pathways: methionine remethylation and glutathione transsulfuration. Biomarkers were measured in a population-based sample of women who had NTD-affected pregnancies (n = 43) and a control group of women who had a pregnancy unaffected by a birth defect (n = 160). We compared plasma concentrations of folate, vitamin B12, vitamin B6, methionine, S-adenosylmethionine (SAM), s-adenosylhomocysteine (SAH), adenosine, homocysteine, cysteine, and reduced and oxidized glutathione between cases and controls after adjusting for lifestyle and sociodemographic factors. RESULTS Women with NTD-affected pregnancies had significantly higher plasma concentrations of SAH (29.12 vs. 23.13 nmol/liter, P = .0011), adenosine (0.323 vs. 0.255 ,mol/liter; P = .0269), homocysteine (9.40 vs. 7.56 ,mol/liter; P < .001), and oxidized glutathione (0.379 vs. 0.262 ,mol/liter; P = .0001), but lower plasma SAM concentrations (78.99 vs. 83.16 nmol/liter; P = .0172) than controls. This metabolic profile is consistent with reduced methylation capacity and increased oxidative stress in women with affected pregnancies. CONCLUSIONS Increased maternal oxidative stress and decreased methylation capacity may contribute to the occurrence of NTDs. Further analysis of relevant genetic and environmental factors is required to define the basis for these observed alterations. Birth Defects Research (Part A), 2006. © 2006 Wiley-Liss, Inc. [source] Stereospecificity and stereoselectivity of flobufen metabolic profile in male rats in vitro and in vivo: Phase I of biotransformationCHIRALITY, Issue 10 2001Vladimír Wsól Abstract Flobufen (F) is the original nonsteroidal antiinflammatory drug (NSAID) containing two enantiomers. The aim of this investigation was to elucidate the biotransformation pathway of F at chiral level in phase I of biotransformation. Stereoselectivity and stereospecificity of the respective enzymes were studied in male rats in vitro (microsomal and cytosolic fractions, hepatocytes suspension) and in vivo. The rac -F, (+)-R-F and (,)-S-F were used as substrates. Amounts of F enantiomers, 4-dihydroflobufen diastereoisomers (DHF) and other metabolites (M-17203, UM) were determined with a chiral HPLC method in two chromatographic runs on R,R-ULMO and allyl-terguride bonded columns. Stereoselective biotransformation of the two enantiomers of F was observed at all tested levels and significant bidirectional chiral inversion of enantiomers of F was observed in hepatocytes. Mean enantiomeric ratios of F concentrations (S-/R-), after rac -F incubations, ranging from 1.09 in cytosolic fraction to 18.23 in hepatocytes. Stereospecificity of the respective F reductases was also observed. (2R;4S)-DHF and (2S;4S)-DHF are the principal metabolites of F in microsomes and hepatocytes. Neither DHF diastereoisomers nor M-17203 were found in cytosolic fraction. Only the nonchiral metabolite, M-17203, was found in all urine and feces samples after oral administration of F. Chirality 13:754,759, 2001. © 2001 Wiley-Liss, Inc. [source] | ||||||||||||||||||||||||||||