PubMed

Related Articles Recent developments in software tools for high-throughput in vitro ADME support with high-resolution MS. Bioanalysis. 2016 Aug;8(16):1723-33 Authors: Paiva A, Shou WZ Abstract The last several years have seen the rapid adoption of the high-resolution MS (HRMS) for bioanalytical support of high throughput in vitro ADME profiling. Many capable software tools have been developed and refined to process quantitative HRMS bioanalysis data for ADME samples with excellent performance. Additionally, new software applications specifically designed for quan/qual soft spot identification workflows using HRMS have greatly enhanced the quality and efficiency of the structure elucidation process for high throughput metabolite ID in early in vitro ADME profiling. Finally, novel approaches in data acquisition and compression, as well as tools for transferring, archiving and retrieving HRMS data, are being continuously refined to tackle the issue of large data file size typical for HRMS analyses. PMID: 27487387 [PubMed - indexed for MEDLINE]

Related Articles Metabonomic study of the fruits of Alpinia oxyphylla as an effective treatment for chronic renal injury in rats. J Pharm Biomed Anal. 2016 May 30;124:236-45 Authors: Li YH, Tan YF, Cai HD, Zhang JQ Abstract Alpinia oxyphylla (Zingiberaceae) is a well-known medicinal plant. Its fruit ("Yi-Zhi-Ren" in Chinese) is used as an anti-diuretic and traditionally used for the treatment of enuresis and reduce urination. Chronic kidney disease (CKD) is a disease with the characteristic of the slowly loss of kidney function and has a prevalence of up to 7-10% in adults. Recent advances in its etiology and pathogenesis are providing more speculative hypotheses focused on integral systems. Using a UPLC-QTOF-MS/MS-based metabolomic platform, we explored the changes of metabolic profiling in plasma/urine simultaneously between chronic kidney disease (CKD) induced from adenine excess and the protective effects of A. oxyphylla extract (AOE). The total twenty-one metabolites (twelve in urine and nine in plasma), up-regulated or down-regulated, were identified and contributed to CKD progress. Among these biomarkers, agmatine, CAMP, 7-methylguanine, hippuric acid, indoxyl sulfate, asparagines, kynurenic acid and p-cresol sulfate were restored back to the control-like level after the treatment of AOE (p<0.05 or 0.01), These findings may be promising to yield a valuable insight into the pathophysiology of CKD and serve as characteristics to explain the mechanisms of AOE. PMID: 26966897 [PubMed - indexed for MEDLINE]

Related Articles Analytical strategies to assess the functional metabolome of vitamin E. J Pharm Biomed Anal. 2016 May 30;124:399-412 Authors: Torquato P, Ripa O, Giusepponi D, Galarini R, Bartolini D, Wallert M, Pellegrino R, Cruciani G, Lorkowski S, Birringer M, Mazzini F, Galli F Abstract After more than 90 years from its discovery and thousands of papers published, the physiological roles of vitamin E (tocopherols and tocotrienols) are still not fully clarified. In the last few decades, the enzymatic metabolism of this vitamin has represented a stimulating subject of research. Its elucidation has opened up new horizons to the interpretation of the biological function of that class of molecules. The identification of specific properties for some of the physiological metabolites and the definition of advanced analytical techniques to assess the human metabolome of this vitamin in vivo, have paved the way to a series of hypotheses on the functional implications that this metabolism may have far beyond its catabolic role. The present review collects the available information on the most relevant analytical strategies employed to assess the status and metabolism of vitamin E in humans as well as in other model systems. A particular focus is dedicated to the analytical methods used to measure vitamin E metabolites, and particularly long-chain metabolites, in biological fluids and tissues. Preliminary information on a new LC-APCI-MS/MS method to measure these metabolites in human serum is reported. PMID: 26947319 [PubMed - indexed for MEDLINE]

1H NMR Metabolomics Reveals Association of High Expression of Inositol 1, 4, 5 Trisphosphate Receptor and Metabolites in Breast Cancer Patients. PLoS One. 2017;12(1):e0169330 Authors: Singh A, Sharma RK, Chagtoo M, Agarwal G, George N, Sinha N, Godbole MM Abstract 1H NMR is used to detect alterations in metabolites and their linkage to metabolic processes in a number of pathological conditions including breast cancer. Inositol 1, 4, 5 trisphosphate (IP3R) receptor is an intracellular calcium channel known to regulate metabolism and cellular bioenergetics. Its expression is up regulated in a number of cancers. However, its linkage to metabolism in disease conditions has not been evaluated. This study was designed to determine the association if any, of these metabolites with altered expression of IP3R in breast cancer. We used 1H NMR to identify metabolites in the serum of breast cancer patients (n = 27) and performed Real-time Polymerase Chain Reaction analysis for quantifying the expression of IP3R type 3 and type 2 in tissues from breast cancer patients (n = 40). Principal Component Analysis (PCA) and Partial Least Square-Discriminant Analysis (PLS-DA) clearly distinguished patients with high/low IP3R expression from healthy subjects. The present study revealed high expression of IP3R type 2 and type 3 in human breast tumor tissue compared to adjacent non-tumorous tissue. Moreover, patients with ≥ 2-fold increase in IP3R (high IP3R group) had significantly higher concentration of metabolic intermediates compared to those with < 2-fold increase in IP3R (low IP3R group). We observed an increase in lipoprotein content and the levels of metabolites like lactate, lysine and alanine and a decrease in the levels of pyruvate and glucose in serum of high IP3R group patients when compared to those in healthy subjects. Receiver operating characteristic (ROC) curve analysis was performed to show the clinical utility of metabolites. In addition to the human studies, functional relevance of IP3Rs in causing metabolic disruption was observed in MCF-7 and MDA MB-231 cells. Results from our studies bring forth the importance of metabolic (or metabolomics) profiling of serum by 1H NMR in conjunction with tissue expression studies for characterizing breast cancer patients. The results from this study provide new insights into relationship of breast cancer metabolites with IP3R. PMID: 28072864 [PubMed - in process]

Protective Effects of Dexrazoxane against Doxorubicin-Induced Cardiotoxicity: A Metabolomic Study. PLoS One. 2017;12(1):e0169567 Authors: QuanJun Y, GenJin Y, LiLi W, YongLong H, Yan H, Jie L, JinLu H, Jin L, Run G, Cheng G Abstract Cardioprotection of dexrazoxane (DZR) against doxorubicin (DOX)-induced cardiotoxicity is contentious and the indicator is controversial. A pairwise comparative metabolomics approach was used to delineate the potential metabolic processes in the present study. Ninety-six BALB/c mice were randomly divided into two supergroups: tumor and control groups. Each supergroup was divided into control, DOX, DZR, and DOX plus DZR treatment groups. DOX treatment resulted in a steady increase in 5-hydroxylysine, 2-hydroxybutyrate, 2-oxoglutarate, 3-hydroxybutyrate, and decrease in glucose, glutamate, cysteine, acetone, methionine, asparate, isoleucine, and glycylproline.DZR treatment led to increase in lactate, 3-hydroxybutyrate, glutamate, alanine, and decrease in glucose, trimethylamine N-oxide and carnosine levels. These metabolites represent potential biomarkers for early prediction of cardiotoxicity of DOX and the cardioprotective evaluation of DZR. PMID: 28072830 [PubMed - in process]

Systematic Analysis of Transcriptional and Post-transcriptional Regulation of Metabolism in Yeast. PLoS Comput Biol. 2017 Jan;13(1):e1005297 Authors: Gonçalves E, Raguz Nakic Z, Zampieri M, Wagih O, Ochoa D, Sauer U, Beltrao P, Saez-Rodriguez J Abstract Cells react to extracellular perturbations with complex and intertwined responses. Systematic identification of the regulatory mechanisms that control these responses is still a challenge and requires tailored analyses integrating different types of molecular data. Here we acquired time-resolved metabolomics measurements in yeast under salt and pheromone stimulation and developed a machine learning approach to explore regulatory associations between metabolism and signal transduction. Existing phosphoproteomics measurements under the same conditions and kinase-substrate regulatory interactions were used to in silico estimate the enzymatic activity of signalling kinases. Our approach identified informative associations between kinases and metabolic enzymes capable of predicting metabolic changes. We extended our analysis to two studies containing transcriptomics, phosphoproteomics and metabolomics measurements across a comprehensive panel of kinases/phosphatases knockouts and time-resolved perturbations to the nitrogen metabolism. Changes in activity of transcription factors, kinases and phosphatases were estimated in silico and these were capable of building predictive models to infer the metabolic adaptations of previously unseen conditions across different dynamic experiments. Time-resolved experiments were significantly more informative than genetic perturbations to infer metabolic adaptation. This difference may be due to the indirect nature of the associations and of general cellular states that can hinder the identification of causal relationships. This work provides a novel genome-scale integrative analysis to propose putative transcriptional and post-translational regulatory mechanisms of metabolic processes. PMID: 28072816 [PubMed - in process]

Identification of altered brain metabolites associated with TNAP activity in a mouse model of hypophosphatasia using untargeted NMR-based metabolomics analysis. J Neurochem. 2017 Jan 10;: Authors: Cruz T, Gleizes M, Balayssac S, Mornet E, Marsal G, Millán JL, Malet-Martino M, Nowak LG, Gilard V, Fonta C Abstract Tissue Nonspecific Alkaline Phosphatase (TNAP) is a key player of bone mineralization and TNAP gene (ALPL) mutations in human are responsible for hypophosphatasia (HPP), a rare heritable disease affecting the mineralization of bones and teeth. Moreover, TNAP is also expressed by brain cells and the severe forms of HPP are associated with neurological disorders, including epilepsy and brain morphological anomalies. However TNAP's role in the nervous system remains poorly understood. In order to investigate its neuronal functions, we aimed to identify without any a priori the metabolites regulated by TNAP in the nervous tissue. For this purpose we used (1) H- and (31) P NMR to analyze the brain metabolome of Alpl (Akp2) mice null for TNAP function, a well-described model of infantile HPP. Among 39 metabolites identified in brain extracts of one week-old animals, 8 displayed significantly different concentration in Akp2(-/-) compared to Akp2(+/+) and Akp2(+/-) mice: cystathionine, adenosine, GABA, methionine, histidine, 3-methylhistidine, N-acetylaspartate (NAA) and N-acetyl-aspartyl-glutamate (NAAG), with cystathionine and adenosine levels displaying the strongest alteration. These metabolites identify several biochemical processes that directly or indirectly involve TNAP function, in particular through the regulation of ecto-nucleotide levels and of pyridoxal phosphate-dependent enzymes. Some of these metabolites are involved in neurotransmission (GABA, adenosine), in myelin synthesis (NAA, NAAG), and in the methionine cycle and transsulfuration pathway (cystathionine, methionine). Their disturbances may contribute to the neurodevelopmental and neurological phenotype of HPP. This article is protected by copyright. All rights reserved. PMID: 28072448 [PubMed - as supplied by publisher]

Plasma Amino Acid Profile in Patients with Aortic Dissection. Sci Rep. 2017 Jan 10;7:40146 Authors: Wang L, Liu S, Yang W, Yu H, Zhang L, Ma P, Wu P, Li X, Cho K, Xue S, Jiang B Abstract Aortic dissection (AD), a severe cardiovascular disease with the characteristics of high mortality, is lack of specific clinical biomarkers. In order to facilitate the diagnosis of AD, we investigated plasma amino acid profile through metabolomics approach. Total 33 human subjects were enrolled in the study: 11 coronary heart disease (CHD) patients without aortic lesion and 11 acute AD and 11 chronic AD. Amino acids were identified in plasma using liquid chromatography and mass spectrometry (LC-MS/MS), and were further subjected to multiple logistic regression analysis. The score plots of principal component analysis (PCA) and partial least squares-discriminate analysis (PLS-DA) showed clear discrimination of CHD patients with AD, acute AD or chronic AD patients, respectively. The contents of histidine, glycine, serine, citrate, ornithine, hydroxyproline, proline and sarcosine were significant different in acute AD patients comparing with CHD patients. The levels of citrate, GABA, glutamate and cysteine were significant different in chronic AD patients comparing with CHD patients. The contents of glutamate and phenylalanine were significant changed in acute AD patients comparing with chronic AD patients. Plasma aminograms were significantly altered in patients with AD comparing with CHD, especially in acute AD, suggesting amino acid profile is expected to exploit a novel, non-invasive, objective diagnosis for AD. PMID: 28071727 [PubMed - in process]

Related Articles NMR-based metabolomics reveals brain region-specific metabolic alterations in streptozotocin-induced diabetic rats with cognitive dysfunction. Metab Brain Dis. 2017 Jan 09;: Authors: Zheng H, Lin Q, Wang D, Xu P, Zhao L, Hu W, Bai G, Yan Z, Gao H Abstract Diabetes mellitus (DM) can result in cognitive dysfunction, but its potential metabolic mechanisms remain unclear. In the present study, we analyzed the metabolite profiling in eight different brain regions of the normal rats and the streptozotocin (STZ)-induced diabetic rats accompanied by cognitive dysfunction using a (1)H NMR-based metabolomic approach. A mixed linear model analysis was performed to assess the effects of DM, brain region and their interaction on metabolic changes. We found that different brain regions in rats displayed significant metabolic differences. In addition, the hippocampus was more susceptible to DM compared with other brain regions in rats. More interestingly, significant interaction effects of DM and brain region were observed on alanine, creatine/creatine-phosphate, lactate, succinate, aspartate, glutamate, glutamine, γ-aminobutyric acid, glycine, choline, N-acetylaspartate, myo-inositol and taurine. Based on metabolic pathway analysis, we speculate that cognitive dysfunction in the STZ-induced diabetic rats may be associated with brain region-specific metabolic alterations involving energy metabolism, neurotransmitters, membrane metabolism and osmoregulation. PMID: 28070703 [PubMed - as supplied by publisher]

Related Articles Stable isotope profiles reveal active production of VOCs from human-associated microbes. J Breath Res. 2017 Jan 10;: Authors: Phan J, Meinardi S, Barletta B, Blake D, Whiteson K Abstract Volatile organic compounds (VOCs) measured from exhaled breath have great promise for the diagnosis of bacterial infections. However, determining human or microbial origin of VOCs detected in breath remains a great challenge. For example, the microbial fermentation product 2,3-butanedione was recently found in the breath of CF patients; parallel culture-independent metagenomic sequencing of the same samples revealed that Streptococcus and Rothia spp. have the genetic capacity to produce 2,3-butanedione. To investigate whether the genetic capacity found in metagenomes translates to bacterial production of a VOC of interest such as 2,3-butanedione, we fed stable isotopes to three bacterial strains isolated from Cystic Fibrosis (CF) patients: two Gram-positive bacteria, Rothia mucilaginosa and Streptococcus salivarius, and a dominant opportunistic Gram-negative pathogen, Pseudomonas aeruginosa. Culture headspaces were collected and analyzed using a gas chromatographic system to quantify the abundance of VOCs of interest; mass spectroscopy was used to determine whether the stable isotope label had been incorporated. Our results show that R. mucilaginosa and S. salivarius consumed D-Glucose-13C6 to produce labeled 2,3-butanedione. R. mucilaginosa and S. salivarius also produced labeled acetaldehyde and ethanol when grown with 2H2O. Additionally, we find that P. aeruginosa growth and dimethyl sulfide production are increased when exposed to lactic acid in culture. These results highlight the importance VOCs produced by P. aeruginosa, R. mucilaginosa, and S. salivarius as nutrients and signals in microbial communities, and as potential biomarkers in a CF infection. PMID: 28070022 [PubMed - as supplied by publisher]

Related Articles Analytes related to erythrocyte metabolism are reliable biomarkers for preanalytical error due to delayed plasma processing in metabolomics studies. Clin Chim Acta. 2017 Jan 06;: Authors: Jain M, Kennedy AD, Elsea SH, Miller MJ Abstract INTRODUCTION: Delaying plasma separation after phlebotomy (processing delay) can cause perturbations of numerous small molecule analytes. This poses a major challenge to the clinical application of metabolomics analyses. We define the analyte changes that occur during processing delays and generate a model for the post hoc detection of this preanalytical error. METHODS: Using an untargeted metabolomics platform we analyzed EDTA-preserved plasma specimens harvested after processing delays lasting from minutes to days. Identified biomarkers were tested on (i) a test-set of samples exposed to either minimal (n=28) or long delays (n=40) and (ii) samples collected in a clinical setting for metabolomics analysis (n=141). RESULTS: A total of 149 of 803 plasma analytes changed significantly during processing delays lasting 0-20h. Biomarkers related to erythrocyte metabolism, e.g., 5-oxoproline, lactate, and an ornithine/arginine ratio, were the strongest predictors of plasma separation delays, providing 100% diagnostic accuracy in the test set.Together these biomarkers could accurately predict processing delays >2h in a pilot study and we found evidence of sample mishandling in 4 of 141 clinically derived specimens. CONCLUSIONS: Due to the widespread effects of processing delays, we propose that erythrocyte metabolism creates a reproducible signal that can identify mishandled specimens in metabolomics studies. PMID: 28069401 [PubMed - as supplied by publisher]

Related Articles Proteomics as an innovative tool to investigate frontotemporal disorders. Proteomics Clin Appl. 2016 Apr;10(4):457-69 Authors: Agresta AM, De Palma A, Bardoni A, Salvini R, Iadarola P, Mauri PL Abstract Neurodegenerative diseases are characterized by slow progressive loss of one or more functions of the CNS. Worldwide, the number of people affected by neurodegeneration is dramatically high and the social impact is upsetting. While being a heterogeneous group of diseases, most of these pathologies manifest similar clinical features and illness progression, thus making their diagnosis elusive. With its ability to meet the needs of neurodegenerative research, proteomics could help facilitate the diagnosis of these disorders. This strategy, recently emerged as complementary to genomics, has led in the last years to substantial achievements in deciphering molecular mechanisms and the follow-up of neurodegenerative diseases. Specifically, aim of this review is to cover the main proteomic investigations realized in the field of familial frontotemporal dementias. This disorder is less common than Alzheimer's disease and disproportionately affects younger individuals, thus representing a major psychological and economic burden for both patients and families. Although early and accurate differential diagnosis of frontotemporal dementias is crucial because of its implications for heritability, prognosis, therapeutics, and environmental management of patients, the investigative methods currently available to clinicians are incomplete. Certainly, the development of a focused therapy cannot be separated from the investigation of biochemical pathways involved in the pathogenesis. PMID: 27061321 [PubMed - indexed for MEDLINE]

Related Articles A metabonomic investigation on the biochemical perturbation in post-stroke patients with depressive disorder (PSD). Metab Brain Dis. 2016 Apr;31(2):279-87 Authors: Ding X, Liu R, Li W, Ni H, Liu Y, Wu D, Yang S, Liu J, Xiao B, Liu S Abstract A metabonomics study based on GC/MS and multivariate statistical analysis was performed involving 28 post stroke depressed (PSD) patients, 27 post-stroke non-depressed (PSND) patients and 33 healthy subjects to investigate the biochemical perturbation in their plasma samples. The outcome of this study showed that there was distinctive metabolic profile for PSD patients. Seven sentinel metabolites showed marked perturbations in PSD patients' blood. The introduction of metabonomics approach may provide a novel metabonomic insight about PSD and the sentinel metabolites for classifying PSD. PMID: 26537495 [PubMed - indexed for MEDLINE]

Related Articles Bacterial spoilers of food: behavior, fitness and functional properties. Food Microbiol. 2015 Feb;45(Pt A):45-53 Authors: Remenant B, Jaffrès E, Dousset X, Pilet MF, Zagorec M Abstract Most food products are highly perishable as they constitute a rich nutrient source for microbial development. Among the microorganisms contaminating food, some present metabolic activities leading to spoilage. In addition to hygienic rules to reduce contamination, various treatments are applied during production and storage to avoid the growth of unwanted microbes. The nature and appearance of spoilage therefore depend on the physiological state of spoilers and on their ability to resist the processing/storage conditions and flourish on the food matrix. Spoilage also relies on the interactions between the microorganisms composing the ecosystems encountered in food. The recent rapid increase in publicly available bacterial genome sequences, as well as the access to high-throughput methods, should lead to a better understanding of spoiler behavior and to the possibility of decreasing food spoilage. This review lists the main bacterial species identified as food spoilers, their ability to develop during storage and/or processing, and the functions potentially involved in spoilage. We have also compiled an inventory of the available genome sequences of species encompassing spoilage strains. Combining in silico analysis of genome sequences with experimental data is proposed in order to understand and thus control the bacterial spoilage of food better. PMID: 25481061 [PubMed - indexed for MEDLINE]

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Related Articles Dose-response characteristics of Clematis triterpenoid saponins and clematichinenoside AR in rheumatoid arthritis rats by liquid chromatography/mass spectrometry-based serum and urine metabolomics. J Pharm Biomed Anal. 2016 Dec 29;136:81-91 Authors: Li R, Guo LX, Li Y, Chang WQ, Liu JQ, Liu LF, Xin GZ Abstract Clematidis Radix et Rhizoma is a traditional Chinese medicine widely used for treating arthritic disease. Clematis triterpenoid saponins (TS) and clematichinenoside AR (C-AR) have been considered to be responsible for its antiarthritic effects. However, the underling mechanism is still unclear because of their low bioavailability. To address of this issue, metabolomics tools were performed to determine metabolic variations associated with rheumatoid arthritis (RA) and responses to Clematis TS, C-AR and positive drug (Triptolide, TP) treatments. This metabolomics investigation of RA was conducted in collagen-induced arthritis (CIA) rats. Liquid chromatography/mass spectrometry and multivariate statistical tools were used to identify the alteration of serum and urine metabolites associated with RA and responses to drug treatment. As a result, 45 potential metabolites associated with RA were identified. After treatment, a total of 24 biomarkers were regulated to normal like levels. Among these, PC(18:0/20:4), 9,11-octadecadienoic acid, arachidonic acid, 1-methyladenosine, valine, hippuric acid and pantothenic acid etc, were reversed in Clematis TS and C-AR groups. Tetrahydrocortisol was regulated to normal levels in Clematis TS and TP groups, while 3,7,12-trihydroxycholan-24-oic acid was regulated in C-AR and TP groups. Biomarkers like citric acid, p-cresol glucuronide, creatinine, cortolone were reversed in TP group. PMID: 28064091 [PubMed - as supplied by publisher]

Related Articles Frontiers of high-throughput metabolomics. Curr Opin Chem Biol. 2017 Jan 05;36:15-23 Authors: Zampieri M, Sekar K, Zamboni N, Sauer U Abstract Large scale metabolomics studies are increasingly used to investigate genetically different individuals and time-dependent responses to environmental stimuli. New mass spectrometric approaches with at least an order of magnitude more rapid analysis of small molecules within the cell's metabolome are now paving the way towards true high-throughput metabolomics, opening new opportunities in systems biology, functional genomics, drug discovery, and personalized medicine. Here we discuss the impact and advantages of the progress made in profiling large cohorts and dynamic systems with high temporal resolution and automated sampling. In both areas, high-throughput metabolomics is gaining traction because it can generate hypotheses on molecular mechanisms and metabolic regulation. We conclude with the current status of the less mature single cell analyses where high-throughput analytics will be indispensable to resolve metabolic heterogeneity in populations and compartmentalization of metabolites. PMID: 28064089 [PubMed - as supplied by publisher]

Related Articles Cerebrospinal fluid metabolomic profiling in tuberculous and viral meningitis: Screening potential markers for differential diagnosis. Clin Chim Acta. 2017 Jan 04;: Authors: Li Z, Du B, Li J, Zhang J, Zheng X, Jia H, Xing A, Sun Q, Liu F, Zhang Z Abstract BACKGROUND: Tuberculous meningitis (TBM) is the most severe and frequent form of central nervous system tuberculosis. The current lack of efficient diagnostic tests makes it difficult to differentiate TBM from other common types of meningitis, especially viral meningitis (VM). Metabolomics is an important tool to identify disease-specific biomarkers. However, little metabolomic information is available on adult TBM. METHODS: We used (1)H nuclear magnetic resonance-based metabolomics to investigate the metabolic features of the CSF from 18 TBM and 20 VM patients. Principal component analysis and orthogonal signal correction-partial least squares-discriminant analysis (OSC-PLS-DA) were applied to analyze profiling data. Metabolites were identified using the Human Metabolome Database and pathway analysis was performed with MetaboAnalyst 3.0. RESULTS: The OSC-PLS-DA model could distinguish TBM from VM with high reliability. A total of 25 key metabolites that contributed to their discrimination were identified, including some, such as betaine and cyclohexane, rarely reported before in TBM. Pathway analysis indicated that amino acid and energy metabolism was significantly different in the CSF of TBM compared with VM. CONCLUSIONS: Twenty-five key metabolites identified in our study may be potential biomarkers for TBM differential diagnosis and are worthy of further investigation. PMID: 28063937 [PubMed - as supplied by publisher]

Related Articles Trichloroethylene-induced formic aciduria in the male C57 Bl/6 mouse. Toxicology. 2017 Jan 04;: Authors: Lock EA, Keane P, Rowe PH, Foster JR, Antoine D, Morris CM Abstract 1, 1, 2-Trichloroethylene (TCE) is of environmental concern, due to evaporation while handling, chemical processing and leakage from chemical waste sites, leading to its contamination of ground water and air. For several decades there has been issues about possible long term health effects of TCE but recently the International Agency for Research on Cancer (IARC) and the US Environmental Protection Agency classified TCE as a human carcinogen. Links having been established between occupational exposures and kidney cancer and possible links to non-Hodgkin lymphoma and liver cancer, but there is more still more to learn. In male rats, TCE produces a small increase in the incidence of renal tubule tumours but not in female rats or mice of either sex. However, chronic renal injury was seen in these bioassays in both sexes of rats and mice. The mechanism of kidney injury from TCE is thought to be due to reductive metabolism forming a cysteine conjugate that is converted to a reactive metabolite via the enzyme cysteine conjugate β-lyase. However, TCE also produces a marked and sustained formic aciduria in male rats and it has been suggested that long term exposure to formic acid could lead to renal tubule injury and regeneration. In this study we have determined if TCE produces formic aciduria in male mice following a single and repeat dosing. Male C57 Bl/6OlaHsd mice were dosed with 1000mg/kg by ip injection and urine collected overnight 24, 48, 72 and 96h after dosing. Formic acid was present in urine 24h after dosing, peaked around 48h at 8mg formic acid excreted/mouse, and remained constant over the next 24h and was not back to normal 96h after dosing. This was associated with a marked acidification of the urine. Plasma creatinine and renal pathology was normal. Plasma kinetics of formic acid showed it was readily cleared with an initial half-life of 2.42h followed by a slower rate with a half-life of 239h. Male mice were then dosed twice/week at 1000mg/kg TCE for 56 days, as anticipated there was a marked and sustained formic aciduria over the duration of the study. This was associated with acidification of the urine, mild diuresis and a marked fall in urinary ammonia. Six biomarkers of renal injury KIM-1, NGAL, NAG, Cystatin-c, Albumin and IL-18 were measured in urine over time and they all showed a small increase at the later time points indicative of early markers of renal injury. However, there was no histological evidence of renal damage or renal tubule cell proliferation after 8 weeks' exposure to TCE. The concentration of formic acid in plasma at the end of the study was 1.05±0.61mM compared to control, 0.39±0.17mM. In the liver, formic acid was present at a concentration of 1mM in both control and treated mice while in the kidney it was higher at 2mM in both treated and controls. We also report that trichloroacetic acid (TCA) a metabolite of TCE also causes formic aciduria, at doses likely to arise in vivo after 1000mg/kg TCE namely 16 and 32mg/kg. Urinary formic acid peaked 24h after dosing at 4mg formic acid excreted/mouse. Thus, as in male and female rats (Yaqoob et al., 2013) male mice show a marked formic aciduria following TCE which after 8 weeks' exposure did not produce renal injury, but the small rise in renal biomarkers suggest renal damage may occur following longer exposure. Thus, TCE-induced formic aciduria may be a contributor factor in the chronic renal injury seen in male and female rats and mice. PMID: 28063905 [PubMed - as supplied by publisher]

(1)H NMR-based metabolomics study of liver damage induced by ginkgolic acid (15:1) in mice. J Pharm Biomed Anal. 2016 Dec 29;136:44-54 Authors: Jiang L, Si ZH, Li MH, Zhao H, Fu YH, Xing YX, Hong W, Ruan LY, Li PM, Wang JS Abstract Ginkgolic acid (15:1) is a major toxic component in extracts obtained from Ginkgo biloba (EGb) that has allergic and genotoxic effects. This study is the first to explore the hepatotoxicity of ginkgolic acid (15:1) using a NMR (nuclear magnetic resonance)-based metabolomics approach in combination with biochemistry assays. Mice were orally administered two doses of ginkgolic acid (15:1), and mouse livers and serum were then collected for NMR recordings and biochemical assays. The levels of activity of alanine aminotransferase (ALT) and glutamic aspartate transaminase (AST) observed in the ginkgolic acid (15:1)-treated mice suggested that it had induced severe liver damage. An orthogonal signal correction partial least-squares discriminant analysis (OSC-PLSDA) performed to determine the metabolomic profile of mouse liver tissues indicated that many metabolic disturbances, especially oxidative stress and purine metabolism, were induced by ginkgolic acid (15:1). A correlation network analysis combined with information related to structural similarities further confirmed that purine metabolism was disturbed by ginkgolic acid (15:1). This mechanism might represent the link between the antitumour activity and the liver injury-inducing effect of ginkgolic acid (15:1). A SUS (Shared and Unique Structure) plot suggested that a two-dose treatment of ginkgolic acid (15:1) had generally the same effect on metabolic variations but that its effects were dose-dependent, revealing some of the common features of ginkgolic acid (15:1) dosing. This integrated metabolomics approach helped us to characterise ginkgolic acid (15:1)-induced liver damage in mice. PMID: 28063335 [PubMed - as supplied by publisher]