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1.
Development of biomarkers based on diet-dependent metabolic serotypes: characteristics of component-based models of metabolic serotypes 总被引:2,自引:0,他引:2
Paolucci U Vigneau-Callahan KE Shi H Matson WR Kristal BS 《Omics : a journal of integrative biology》2004,8(3):221-238
Our research seeks to identify a serum profile, or serotype, that reflects the systemic physiologic modifications resultant from dietary restriction (DR), in part such that this knowledge can be applied for biomarker studies. Direct comparison suggests that component-based classification algorithms consistently out-perform distance-based metrics for studies of nutritional modulation of metabolic serotype, but are subject to over-fitting concerns. Intercohort differences in the sera metabolome could partially obscure the effects of DR. Further analysis now shows that implementation of component-based approaches (also called projection methods) optimized for class separation and controlled for over-fitting have >97% accuracy for distinguishing sera from control or DR rats. DR's effect on the metabolome is shown to be robust across cohorts, but differs in males and females (although some metabolites are affected in both). We demonstrate the utility of projection-based methods for both sample and variable diagnostics, including identification of critical metabolites and samples that are atypical with respect to both class and variable models. Inclusion of non-statistically different variables enhances classification models. Variables that contribute to these models are sharply dependent on mathematical processing techniques; some variables that do not contribute under one paradigm are powerful under alternative mathematical paradigms. In practical terms, this information may find purpose in other endeavors, such as mechanistic studies of DR. Application of these approaches confirms the utility of megavariate data analysis techniques for optimal generation of biomarkers based on nutritional modulation of physiological processes. 相似文献
2.
The effects of age and dietary restriction on the tissue‐specific metabolome of Drosophila
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Matthew J. Laye ViLinh Tran Dean P. Jones Pankaj Kapahi Daniel E. L. Promislow 《Aging cell》2015,14(5):797-808
Dietary restriction (DR) is a robust intervention that extends lifespan and slows the onset of age‐related diseases in diverse organisms. While significant progress has been made in attempts to uncover the genetic mechanisms of DR, there are few studies on the effects of DR on the metabolome. In recent years, metabolomic profiling has emerged as a powerful technology to understand the molecular causes and consequences of natural aging and disease‐associated phenotypes. Here, we use high‐resolution mass spectroscopy and novel computational approaches to examine changes in the metabolome from the head, thorax, abdomen, and whole body at multiple ages in Drosophila fed either a nutrient‐rich ad libitum (AL) or nutrient‐restricted (DR) diet. Multivariate analysis clearly separates the metabolome by diet in different tissues and different ages. DR significantly altered the metabolome and, in particular, slowed age‐related changes in the metabolome. Interestingly, we observed interacting metabolites whose correlation coefficients, but not mean levels, differed significantly between AL and DR. The number and magnitude of positively correlated metabolites was greater under a DR diet. Furthermore, there was a decrease in positive metabolite correlations as flies aged on an AL diet. Conversely, DR enhanced these correlations with age. Metabolic set enrichment analysis identified several known (e.g., amino acid and NAD metabolism) and novel metabolic pathways that may affect how DR effects aging. Our results suggest that network structure of metabolites is altered upon DR and may play an important role in preventing the decline of homeostasis with age. 相似文献
3.
Shi H Paolucci U Vigneau-Callahan KE Milbury PE Matson WR Kristal BS 《Omics : a journal of integrative biology》2004,8(3):197-208
Dietary restriction (DR)-induced changes in the serum metabolome may be biomarkers for physiological status (e.g., relative risk of developing age-related diseases such as cancer). Megavariate analysis (unsupervised hierarchical cluster analysis [HCA]; principal components analysis [PCA]) of serum metabolites reproducibly distinguish DR from ad libitum fed rats. Component-based approaches (i.e., PCA) consistently perform as well as or better than distance-based metrics (i.e., HCA). We therefore tested the following: (A) Do identified subsets of serum metabolites contain sufficient information to construct mathematical models of class membership (i.e., expert systems)? (B) Do component-based metrics out-perform distance-based metrics? Testing was conducted using KNN (k-nearest neighbors, supervised HCA) and SIMCA (soft independent modeling of class analogy, supervised PCA). Models were built with single cohorts, combined cohorts or mixed samples from previously studied cohorts as training sets. Both algorithms over-fit models based on single cohort training sets. KNN models had >85% accuracy within training/test sets, but were unstable (i.e., values of k could not be accurately set in advance). SIMCA models had 100% accuracy within all training sets, 89 % accuracy in test sets, did not appear to over-fit mixed cohort training sets, and did not require post-hoc modeling adjustments. These data indicate that (i) previously defined metabolites are robust enough to construct classification models (expert systems) with SIMCA that can predict unknowns by dietary category; (ii) component-based analyses outperformed distance-based metrics; (iii) use of over-fitting controls is essential; and (iv) subtle inter-cohort variability may be a critical issue for high data density biomarker studies that lack state markers. 相似文献
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HPLC separations coupled with coulometric electrode-based detectors offer potential to evaluate complex biological samples, but analytical approaches to such samples are still being defined. Coulometric electrode array systems use response ratio (as ratio conformity), for quantitation and qualitative characterization. We investigated the influence of changing the ratio conformity requirement (ratio window, RW) on quantitative consistency of the system. Sixty-one serum metabolites were analyzed in three cohorts of ad libitum/dietary restricted rats with two RW settings. RW 30 uses channels with <30% ratio variation (vs standard) to quantitate, whereas RW 100 generally uses all channels. Quantitation between the two approaches differed in 29/671, 61/976, and 264/976 metabolites in cohorts A, B, and C, respectively. The changes were 23.0 +/- 16.6, 31.9 +/- 28.6, and 23.6 +/- 17.1% (+/- SD). Correlation analysis showed that 11, 7, and 21% of the 61 metabolites had r(2) < 0.9 in cohorts A, B, and C, respectively. Inspection of HPLC chromatograms revealed that most of the metabolites with changed levels possessed common characteristics (e.g., shoulder peaks, low signal/noise ratios, coeluting peaks). Analysis demonstrated that RW 30 provided precise quantitation, whereas RW 100 did not. These data suggest that narrow ratio window increases quantitative accuracy in coulometric electrode array analysis of the metabolome(s) of complex biological samples (e.g., sera, mitochondria). 相似文献
6.
Untargeted metabolic profiling reveals geography as the strongest predictor of metabolic phenotypes of a cosmopolitan weed
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Natalie Iwanycki Ahlstrand Nicoline Havskov Reghev Bo Markussen Hans Christian Bruun Hansen Finnur F. Eiriksson Margrét Thorsteinsdóttir Nina Rønsted Christopher J. Barnes 《Ecology and evolution》2018,8(13):6812-6826
Plants produce a multitude of metabolites that contribute to their fitness and survival and play a role in local adaptation to environmental conditions. The effects of environmental variation are particularly well studied within the genus Plantago; however, previous studies have largely focused on targeting specific metabolites. Studies exploring metabolome‐wide changes are lacking, and the effects of natural environmental variation and herbivory on the metabolomes of plants growing in situ remain unknown. An untargeted metabolomic approach using ultra‐high‐performance liquid chromatography–mass spectrometry, coupled with variation partitioning, general linear mixed modeling, and network analysis was used to detect differences in metabolic phenotypes of Plantago major in fifteen natural populations across Denmark. Geographic region, distance, habitat type, phenological stage, soil parameters, light levels, and leaf area were investigated for their relative contributions to explaining differences in foliar metabolomes. Herbivory effects were further investigated by comparing metabolomes from damaged and undamaged leaves from each plant. Geographic region explained the greatest number of significant metabolic differences. Soil pH had the second largest effect, followed by habitat and leaf area, while phenological stage had no effect. No evidence of the induction of metabolic features was found between leaves damaged by herbivores compared to undamaged leaves on the same plant. Differences in metabolic phenotypes explained by geographic factors are attributed to genotypic variation and/or unmeasured environmental factors that differ at the regional level in Denmark. A small number of specialized features in the metabolome may be involved in facilitating the success of a widespread species such as Plantago major into such wide range of environmental conditions, although overall resilience in the metabolome was found in response to environmental parameters tested. Untargeted metabolomic approaches have great potential to improve our understanding of how specialized plant metabolites respond to environmental change and assist in adaptation to local conditions. 相似文献
7.
Elena Cubero-Leon Christophe Minier Jeanette M. Rotchell Elizabeth M. Hill 《Comparative biochemistry and physiology. Part D, Genomics & proteomics》2012,7(2):212-219
Marine mussels have been used as sentinel organisms to monitor exposure to a variety of chemical contaminants, including endocrine disrupting chemicals, in the aquatic environment. Although they are an important species for use in ecotoxicology investigations, information on their reproductive physiology and biochemistry is fragmentary. Mass spectrometry-based profiling techniques are increasingly being used to study how the metabolome of an organism changes as a result of tissue differentiation, disease or in response to environmental stressors. In this study, ultraperformance liquid chromatography–time-of-flight-mass spectrometry (UPLC–TOFMS) was used to investigate sex specific differences in the mussel metabolome in order to further investigate the reproductive physiology of this species. Using this method, a comparison of female and male mantle tissues containing mature gonad, revealed significant differences in glycerophosphatidylcholine (PC) and lysophosphatidylcholine (LPC) metabolites. A number of other unidentified metabolites, including those putatively identified as conjugated sterols, were also differentially expressed between male and female mantle/gonadal tissue. 相似文献
8.
《Animal : an international journal of animal bioscience》2021,15(4):100180
Bovine colostrum is important for neonates' health due to its nutritive and non-nutritive components. Heat treatment of colostrum is a well-established management tool, but it may influence colostrum components and affect the health status of calves. In our previous studies, we had shown that colostrum proteome and serum proteome of calves were altered by heat treatment to different degrees. Our objectives in this study were to investigate the effects of heat treatment on colostrum metabolome and the effect of feeding heat-treated colostrum on the serum metabolome of newborn calves. Further, the changes in serum metabolome from before to after colostrum feeding were characterized. Newborn Holstein female calves (n = 10) were randomized within pairs and fed heat-treated (n = 5; 60 °C, 60 min) or raw (n = 5) colostrum at 8.5% of birth BW by esophageal feeder within 1 h of birth. After a single colostrum feeding, calves were not fed until after the 8 h time point. Blood samples were taken immediately prior to feeding (0 h) and 8 h after feeding. The colostrum and serum metabolome were first analyzed using reverse-phase chromatography and tandem MS, and serum metabolome was then further analyzed using hydrophilic interaction chromatography and tandem MS. In colostrum metabolome, 458 features were identified and 328 were annotated and a trend of separation between raw and heat-treated colostrum could be observed through multivariate analysis. In serum metabolome, 3 360 features were identified and 1 439 were annotated, but no trend of separation was observed between the two groups of calves fed raw colostrum vs. heat-treated colostrum. The serum metabolome presented substantial differences comparing before (0 h) and after colostrum feeding (8 h); in particular, a tripeptide, β-homovaline-β-homoalanine-β-homoleucine, and 1-(2-acetamido-2-deoxy-α-d-glucopyranosyl)-1D-myo-inositol had higher concentrations after colostrum feeding than before, along with other metabolites that were not fully annotated. Based on a relatively small sample size, our findings point to the effect of heat treatment on the change of colostrum metabolome, but not on the change of serum metabolome of calves fed raw colostrum vs. heat-treated colostrum. Further studies using larger sample size and complementary analytical techniques are warranted to further explore potential heat treatment-induced alterations in colostrum metabolome. 相似文献
9.
Morten Rahr Clausen Xumin Zhang Christian C. Yde Ditte B. Ditlev Haldis H. Lillefosse Lise Madsen Karsten Kristiansen Bj?rn Liaset Hanne C. Bertram 《PloS one》2015,10(3)
The amount and form of dietary casein have been shown to affect energy metabolism and lipid accumulation in mice, but the underlying mechanisms are not fully understood. We investigated 48 hrs urinary metabolome, hepatic lipid composition and gene expression in male C57BL/6J mice fed Western diets with 16 or 32 energy% protein in the form of extensively hydrolyzed or intact casein. LC-MS based metabolomics revealed a very strong impact of casein form on the urinary metabolome. Evaluation of the discriminatory metabolites using tandem mass spectrometry indicated that intake of extensively hydrolyzed casein modulated Phase II metabolism associated with an elevated urinary excretion of glucuronic acid- and sulphate conjugated molecules, whereas glycine conjugated molecules were more abundant in urine from mice fed the intact casein diets. Despite the differences in the urinary metabolome, we observed no differences in hepatic expression of genes involved in Phase II metabolism, but it was observed that expression of Abcc3 encoding ATP binding cassette c3 (transporter of glucuronic acid conjugates) was increased in livers of mice fed hydrolyzed casein. As glucuronic acid is derived from glucose and sulphate is derived from cysteine, our metabolomic data provided evidence for changes in carbohydrate and amino acid metabolism and we propose that this modulation of metabolism was associated with the reduced glucose and lipid levels observed in mice fed the extensively hydrolyzed casein diets. 相似文献
10.
《生物化学与生物物理学报:疾病的分子基础》2021,1867(12):166266
Sexual dimorphism exists in the onset and development of type 1 diabetes (T1D), but its potential pathological mechanism is poorly understood. In the present study, we examined sex-specific changes in the gut microbiome and host metabolome of T1D mice via 16S rRNA gene sequencing and nuclear magnetic resonance (NMR)-based metabolomics approach, and aimed to investigate potential mechanism of the gut microbiota-host metabolic interaction in the sexual dimorphism of T1D. Our results demonstrate that female mice had a greater shift in the gut microbiota than male mice during the development of T1D; however, host metabolome was more susceptible to T1D in male mice. The correlation network analysis indicates that T1D-induced host metabolic changes may be regulated by the gut microbiota in a sex-specific manner, mainly involving short-chain fatty acids (SCFAs) metabolism, energy metabolism, amino acid metabolism, and choline metabolism. Therefore, our study suggests that sex-dependent “gut microbiota-host metabolism axis” may be implicated in the sexual dimorphism of T1D, and the link between microbes and metabolites might contribute to the prevention and treatment of T1D. 相似文献
11.
Lijuan Han Ling Zhao Yong Zhou Chao Yang Teng Xiong Lin Lu Yusheng Deng Wen Luo Yang Chen Qinwei Qiu Xiaoxiao Shang Li Huang Zongchao Mo Shaogang Huang Suiping Huang Zhi Liu Wei Yang Lixiang Zhai Ziwan Ning Chengyuan Lin Tao Huang Chungwah Cheng Linda L. D. Zhong Shuaicheng Li Zhaoxiang Bian Xiaodong Fang 《The ISME journal》2022,16(4):983
Irritable bowel syndrome (IBS) is one of the functional gastrointestinal disorders characterized by chronic and/or recurrent symptoms of abdominal pain and irregular defecation. Changed gut microbiota has been proposed to mediate IBS; however, contradictory results exist, and IBS-specific microbiota, metabolites, and their interactions remain poorly understood. To address this issue, we performed metabolomic and metagenomic profiling of stool and serum samples based on discovery (n = 330) and validation (n = 101) cohorts. Fecal metagenomic data showed moderate dysbiosis compared with other diseases, in contrast, serum metabolites showed significant differences with greater power to distinguish IBS patients from healthy controls. Specifically, 726 differentially abundant serum metabolites were identified, including a cluster of fatty acyl-CoAs enriched in IBS. We further identified 522 robust associations between differentially abundant gut bacteria and fecal metabolites, of which three species including Odoribacter splanchnicus, Escherichia coli, and Ruminococcus gnavus were strongly associated with the low abundance of dihydropteroic acid. Moreover, dysregulated tryptophan/serotonin metabolism was found to be correlated with the severity of IBS depression in both fecal and serum metabolomes, characterized by a shift in tryptophan metabolism towards kynurenine production. Collectively, our study revealed serum/fecal metabolome alterations and their relationship with gut microbiome, highlighted the massive alterations of serum metabolites, which empower to recognize IBS patients, suggested potential roles of metabolic dysregulation in IBS pathogenesis, and offered new clues to understand IBS depression comorbidity. Our study provided a valuable resource for future studies, and would facilitate potential clinical applications of IBS featured microbiota and/or metabolites.Subject terms: Clinical microbiology, Colitis, Metagenomics 相似文献
12.
Louise Vida Traill Shepherd Christine Anne Hackett Colin James Alexander Julia Anne Sungurtas Simon David Alexander Pont Derek Stewart James William McNicol Stephen Joseph Wilcockson Carlo Leifert Howard Vivian Davies 《Metabolomics : Official journal of the Metabolomic Society》2014,10(2):212-224
Potato (Solanum tuberosum L.) cv. Santé was grown over 2 years under both conventional and organic fertiliser and crop protection regimes. The tuber metabolome was analysed using mass-spectrometry (MS) based approaches, principally liquid chromatography (LC)–MS and gas chromatography (GC)–MS. Data were analysed using Principal Components Analysis (PCA) and Analysis of Variance (ANOVA) to assess any differences between production practices. GC–MS analysis of non-polar metabolites did not detect any statistically significant differences, but GC–MS analysis of polar compounds identified 83 metabolites showing significant differences in the metabolome between the fertiliser treatments. Of the 62 metabolites that were less abundant in tuber samples from organic compared with conventionally fertilised crops, consistent year on year differences were dominated by free amino acids. The effect on free amino acids is associated with the lower nitrogen (N) content of the organically grown potatoes in this instance (50 % lower than for conventional production). LC–MS provided indications that levels of certain glycoalkaloids may be lower under the organic fertiliser regime in one growing season. Differences associated with the crop protection measures used were much less consistent, and relatively small, compared with the fertiliser effects found. 相似文献
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Robert E. Brown Mahmoud A. Ghannoum Pranab K. Mukherjee Patrick M. Gillevet Masoumeh Sikaroodi 《PloS one》2015,10(4)
We implemented a Systems Biology approach using Correlation Difference Probability Network (CDPN) analysis to provide insights into the statistically significant functional differences between HIV-infected patients and uninfected individuals. The analysis correlates bacterial microbiome (“bacteriome”), fungal microbiome (“mycobiome”), and metabolome data to model the underlying biological processes comprising the Human Oral Metabiome. CDPN highlights the taxa-metabolite-taxa differences between the cohorts that frequently capture quorum-sensing modifications that reflect communication disruptions in the dysbiotic HIV cohort. The results also highlight the significant role of cyclic mono and dipeptides as quorum-sensing (QS) mediators between oral bacteria and fungal genus. The developed CDPN approach allowed us to model the interactions of taxa and key metabolites, and hypothesize their possible contribution to the etiology of Oral Candidiasis (OC). 相似文献
15.
Manuel Liebeke 《Analytical biochemistry》2010,401(2):312-314
Analysis of metabolome samples by gas chromatography/mass spectrometry requires a comprehensive derivatization method to afford quantitative and qualitative information of a complex biological sample. Here we describe an extremely time-effective microwave-assisted protocol for the commonly used methoxyamine and N-methyl-N-trimethylsilylfluoracetamide silylation method of primary metabolites. Our studies show that microwave irradiation can decrease the sample preparation time from approximately 120 min to 6 min without loss of either qualitative or quantitative information for the tested synthetic metabolite mixtures and microbial-derived metabolome samples collected from Bacillus subtilis and Staphylococcus aureus. Comparisons of metabolic fingerprints and selected metabolites show no noticeable differences compared with the commonly used heating block methods. 相似文献
16.
Women have an increased incidence of whiplash injury and neck pain compared to men. Physical and numerical models represent one avenue to explore and potentially explain these gender differences, but a valid model of the female neck does not yet exist. A fundamental question in the development of a female neck model is whether female necks are simply scaled versions of male necks, or whether there are significant inter-gender geometrical differences. The goal of this study was to quantify differences in head and neck geometry and neck strength in pairs of male and female subjects matched for standing height and neck length. Based on 14 matched pairs of men and women, we found that most head and neck anthropometric parameters were significantly smaller in females compared to males. Moreover, gender differences in a number of neck anthropometry parameters (an average of 9-16% smaller in females) were larger than differences in head anthropometry parameters (an average of 3-6% smaller in females). Female vertebrae between C3 and C7 were significantly smaller than male vertebrae in the anterior-posterior dimension (p < 0.012) but not in the medial-lateral dimension (p > 0.07). Female necks were also significantly weaker than male necks (32% weaker in flexion and 20% weaker in extension; p < 0.001), and these strength differences corresponded well to those predicted solely from the observed geometric differences. These results demonstrate that male and female necks are not geometrically similar and indicate that a female-specific model will be necessary to study gender differences in neck-related disorders. 相似文献
17.
Annika Haugeneder Johanna Trinkl Katja Härtl Thomas Hoffmann James William Allwood Wilfried Schwab 《Metabolomics : Official journal of the Metabolomic Society》2018,14(11):145
Background
The qualitative and quantitative analysis of all low molecular weight metabolites within a biological sample, known as the metabolome, provides powerful insights into their roles in biological systems and processes. The study of all the chemical structures, concentrations, and interactions of the thousands of metabolites is called metabolomics. However present state of the art methods and equipment can only analyse a small portion of the numerous, structurally diverse groups of chemical substances found in biological samples, especially with respect to samples of plant origin with their huge diversity of secondary metabolites. Nevertheless, metabolite profiling and fingerprinting techniques have been applied to the analysis of the strawberry metabolome since their early beginnings.Aim
The application of metabolomics and metabolite profiling approaches within strawberry research was last reviewed in 2011. Here, we aim to summarize the latest results from research of the strawberry metabolome since its last review with a special emphasis on studies that address specific biological questions.Key scientific concepts
Analysis of strawberry, and other fruits, requires a plethora of analytical methods and approaches encompassing the analysis of primary and secondary metabolites, as well as capturing and quantifying volatile compounds that are related to aroma as well as fruit development, function and plant-to-plant communication. The success and longevity of metabolite and volatile profiling approaches in fruit breeding relies upon the ability of the approach to uncover biologically meaningful insights. The key concepts that must be addressed and are reviewed include: gene function analysis and genotype comparison, analysis of environmental effects and plant protection, screening for bioactive compounds for food and non-food uses, fruit development and physiology as well as fruit sensorial quality. In future, the results will facilitate fruit breeding due to the identification of metabolic QTLs and candidate genes for fruit quality and consumer preference.18.
Background/Aim
The changes in the cerebrospinal fluid (CSF) metabolome associated with the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS) are poorly understood and earlier smaller studies have shown conflicting results. The metabolomic methodology is suitable for screening large cohorts of samples. Global metabolomics can be used for detecting changes of metabolite concentrations in samples of fluids such as CSF.Methodology
Using gas chromatography coupled to mass spectrometry (GC/TOFMS) and multivariate statistical modeling, we simultaneously studied the metabolome signature of ∼120 small metabolites in the CSF of patients with ALS, stratified according to hereditary disposition and clinical subtypes of ALS in relation to controls.Principal Findings
The study is the first to report data validated over two sub-sets of ALS vs. control patients for a large set of metabolites analyzed by GC/TOFMS. We find that patients with sporadic amyotrophic lateral sclerosis (SALS) have a heterogeneous metabolite signature in the cerebrospinal fluid, in some patients being almost identical to controls. However, familial amyotrophic lateral sclerosis (FALS) without superoxide dismutase-1 gene (SOD1) mutation is less heterogeneous than SALS. The metabolome of the cerebrospinal fluid of 17 ALS patients with a SOD1 gene mutation was found to form a separate homogeneous group. Analysis of metabolites revealed that glutamate and glutamine were reduced, in particular in patients with a familial predisposition. There are significant differences in the metabolite profile and composition among patients with FALS, SALS and patients carrying a mutation in the SOD1 gene suggesting that the neurodegenerative process in different subtypes of ALS may be partially dissimilar.Conclusions/Significance
Patients with a genetic predisposition to amyotrophic lateral sclerosis have a more distinct and homogeneous signature than patients with a sporadic disease. 相似文献19.
Metabolomics is the study of metabolite profiles in biological samples, particularly urine, saliva, blood plasma and fat biopsies. The metabolome is now considered by some to be the most predictive phenotype: consequently, the comprehensive and quantitative study of metabolites is a desirable tool for diagnosing disease, identifying new therapeutic targets and enabling appropriate treatments. A wealth of information about metabolites has been accumulated with global profiling tools and several candidate technologies for metabolomic studies are now available. Many high-throughput metabolomics methodologies are currently under development and have yet to be applied in clinical practice on a routine basis. In the cardiovascular field, few recent metabolomic studies have been reported so far. This minireview provides an updated overview of alternative technical approaches for metabolomics studies and reviews initial applications of metabolomics that relate to both cardiovascular disease and lipid metabolism research. 相似文献
20.
William J. Fasano Lisa M. Sweeney Diane L. Nabb Robert C. Buck 《Chemico-biological interactions》2009,180(2):281-52
Fluorotelomer alcohols (FTOHs) are raw materials used in the manufacture of polymeric and surfactant products. Based on previous findings from single oral dosing in rats with radiolabeled 8-2 FTOH, glutathione (GSH) depletion and/or the presence of perfluorinated/polyfluorinated acids and aldehyde metabolites was hypothesized to account for the hepatocellular lesions observed in male rats from a 90-day subchronic oral dosing study. Further, the reported nephropathy in female rats from the subchronic experiment was hypothesized to have been initiated by a thiol metabolite produced by degradation of GSH conjugates. In the current investigation, the kinetics of 8-2 FTOH and its metabolites along with liver GSH status were evaluated in the rat following daily oral dosing with 8-2 FTOH for 45 days at 5 and 125 mg/kg/day. Liver GSH stores 1-2 h after dosing were unaffected, suggesting that GSH depletion is not likely a relevant mode of action in the liver. The tissue metabolite data indicate that the liver toxicity mode of action is likely associated with elevated levels of perfluoroalkyl acids found in males, since other polyfluorinated metabolites and 8-2 FTOH were present in livers from female rats at comparable or higher levels. Detection of the N-acetyl cysteine conjugate of the unsaturated parent telomer alcohol in urine from female rats and not male rats provides some evidence to support the mechanistic basis for the observed kidney effects. Further, the increasing levels of perfluorooctanoic acid (PFOA) in plasma from female rats over the 45-day dosing phase, while unexpected, may reflect an increased net absorption of 8-2 FTOH, slow elimination of intermediates in the metabolic pathway between 8-2 FTOH and PFOA, or altered kidney clearance. The results of this study have enhanced our understanding of 8-2 FTOH kinetics and metabolism and potential modes of action in the rat, which will guide the design of future studies for FTOHs and our need to define the mechanistic basis for the observed effects. 相似文献