Publications
197 results found
Fletcher ME, Boshier PR, Wakabayashi K, et al., 2015, Influence of glutathione-S-transferase (GST) inhibition on lung epithelial cell injury: role of oxidative stress and metabolism, AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, Vol: 308, Pages: L1274-L1285, ISSN: 1040-0605
Oxidant-mediated tissue injury is key to the pathogenesis of acute lung injury. Glutathione-S-transferases (GSTs) are important detoxifying enzymes that catalyze the conjugation of glutathione with toxic oxidant compounds and are associated with acute and chronic inflammatory lung diseases. We hypothesized that attenuation of cellular GST enzymes would augment intracellular oxidative and metabolic stress and induce lung cell injury. Treatment of murine lung epithelial cells with GST inhibitors, ethacrynic acid (EA), and caffeic acid compromised lung epithelial cell viability in a concentration-dependent manner. These inhibitors also potentiated cell injury induced by hydrogen peroxide (H2O2), tert-butyl-hydroperoxide, and hypoxia and reoxygenation (HR). SiRNA-mediated attenuation of GST-π but not GST-μ expression reduced cell viability and significantly enhanced stress (H2O2/HR)-induced injury. GST inhibitors also induced intracellular oxidative stress (measured by dihydrorhodamine 123 and dichlorofluorescein fluorescence), caused alterations in overall intracellular redox status (as evidenced by NAD+/NADH ratios), and increased protein carbonyl formation. Furthermore, the antioxidant N-acetylcysteine completely prevented EA-induced oxidative stress and cytotoxicity. Whereas EA had no effect on mitochondrial energetics, it significantly altered cellular metabolic profile. To explore the physiological impact of these cellular events, we used an ex vivo mouse-isolated perfused lung model. Supplementation of perfusate with EA markedly affected lung mechanics and significantly increased lung permeability. The results of our combined genetic, pharmacological, and metabolic studies on multiple platforms suggest the importance of GST enzymes, specifically GST-π, in the cellular and whole lung response to acute oxidative and metabolic stress. These may have important clinical implications.
Valbuena GN, Rizzardini M, Cimini S, et al., 2015, Metabolomic Analysis Reveals Increased Aerobic Glycolysis and Amino Acid Deficit in a Cellular Model of Amyotrophic Lateral Sclerosis, Molecular Neurobiology, Vol: 53, Pages: 2222-2240, ISSN: 1559-1182
Defects in energy metabolism are potential pathogenic mechanisms in amyotrophic lateral sclerosis (ALS), a rapidly fatal disease with no cure. The mechanisms through which this occurs remain elusive and their understanding may prove therapeutically useful. We used metabolomics and stable isotope tracers to examine metabolic changes in a well-characterized cell model of familial ALS, the motor neuronal NSC-34 line stably expressing human wild-type Cu/Zn superoxide dismutase (wtSOD1) or mutant G93A (G93ASOD1). Our findings indicate that wt and G93ASOD1 expression both enhanced glucose metabolism under serum deprivation. However, in wtSOD1 cells, this phenotype increased supply of amino acids for protein and glutathione synthesis, while in G93ASOD1 cells it was associated with death, aerobic glycolysis, and a broad dysregulation of amino acid homeostasis. Aerobic glycolysis was mainly due to induction of pyruvate dehydrogenase kinase 1. Our study thus provides novel insight into the role of deranged energy metabolism as a cause of poor adaptation to stress and a promoter of neural cell damage in the presence of mutant SOD1. Furthermore, the metabolic alterations we report may help explain why mitochondrial dysfunction and impairment of the endoplasmic reticulum stress response are frequently seen in ALS.
Hendrickx DM, Aerts HJWL, Caiment F, et al., 2015, diXa: a data infrastructure for chemical safety assessment, Bioinformatics, Vol: 31, Pages: 1505-1507, ISSN: 1367-4803
Motivation: The field of toxicogenomics (the application of ‘-omics’ technologies to risk assessment of compound toxicities) has expanded in the last decade, partly driven by new legislation, aimed at reducing animal testing in chemical risk assessment but mainly as a result of a paradigm change in toxicology towards the use and integration of genome wide data. Many research groups worldwide have generated large amounts of such toxicogenomics data. However, there is no centralized repository for archiving and making these data and associated tools for their analysis easily available.Results: The Data Infrastructure for Chemical Safety Assessment (diXa) is a robust and sustainable infrastructure storing toxicogenomics data. A central data warehouse is connected to a portal with links to chemical information and molecular and phenotype data. diXa is publicly available through a user-friendly web interface. New data can be readily deposited into diXa using guidelines and templates available online. Analysis descriptions and tools for interrogating the data are available via the diXa portal.Availability and implementation:http://www.dixa-fp7.euContact:d.hendrickx@maastrichtuniversity.nl; info@dixa-fp7.euSupplementary information:Supplementary data are available at Bioinformatics online.
Pomyen Y, Segura M, Ebbels TMD, et al., 2015, Over-representation of correlation analysis (ORCA): a method for identifying associations between variable sets, BIOINFORMATICS, Vol: 31, Pages: 102-108, ISSN: 1367-4803
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- Citations: 6
Miller JA, Pappan K, Thompson PA, et al., 2015, Plasma Metabolomic Profiles of Breast Cancer Patients after Short-term Limonene Intervention, CANCER PREVENTION RESEARCH, Vol: 8, ISSN: 1940-6207
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- Citations: 30
Trousil S, Lee P, Pinato DJ, et al., 2014, Alterations of choline phospholipid metabolism in endometrial cancer are caused by choline kinase alpha overexpression and a hyperactivated deacylation pathway, Cancer Research, Vol: 74, Pages: 6867-6877, ISSN: 0008-5472
Metabolic rearrangements subsequent to malignant transformation are not well characterized in endometrial cancer. Identification of altered metabolites could facilitate imaging-guided diagnosis, treatment surveillance, and help to identify new therapeutic options. Here, we used high-resolution magic angle spinning magnetic resonance mass spectroscopy on endometrial cancer surgical specimens and normal endometrial tissue to investigate the key modulators that might explain metabolic changes, incorporating additional investigations using qRT-PCR, Western blotting, tissue microarrays (TMA), and uptake assays of [3H]-labeled choline. Lipid metabolism was severely dysregulated in endometrial cancer with various amino acids, inositols, nucleobases, and glutathione also altered. Among the most important lipid-related alterations were increased phosphocholine levels (increased 70% in endometrial cancer). Mechanistic investigations revealed that changes were not due to altered choline transporter expression, but rather due to increased expression of choline kinase α (CHKA) and an activated deacylation pathway, as indicated by upregulated expression of the catabolic enzymes LYPLA1, LYPLA2, and GPCPD1. We confirmed the significance of CHKA overexpression on a TMA, including a large series of endometrial hyperplasia, atypical hyperplasia, and adenocarcinoma tissues, supporting a role for CHKA in malignant transformation. Finally, we documented several-fold increases in the uptake of [3H]choline in endometrial cancer cell lines compared with normal endometrial stromal cells. Our results validate deregulated choline biochemistry as an important source of noninvasive imaging biomarkers for endometrial cancer. Cancer Res; 74(23); 6867–77. ©2014 AACR.
Maitre L, 2014, Urinary metabolic profiles in early pregnancy are associated with preterm birth and fetal growth restriction in the Rhea mother–child cohort study, BMC Medicine, Vol: 12, ISSN: 1741-7015
BackgroundPreterm birth (PB) and fetal growth restriction (FGR) convey the highest risk of perinatal mortality and morbidity, as well as increasing the chance of developing chronic disease in later life. Identifying early in pregnancy the unfavourable maternal conditions that can predict poor birth outcomes could help their prevention and management. Here we used an exploratory metabolic profiling approach (metabolomics) to investigate the association between birth outcomes and metabolites in maternal urine collected early in pregnancy as part of the prospective mother–child cohort Rhea study. Metabolomic techniques can simultaneously capture information about genotype and its interaction with the accumulated exposures experienced by an individual from their diet, environment, physical activity or disease (the exposome). As metabolic syndrome has previously been shown to be associated with PB in this cohort, we sought to gain further insight into PB-linked metabolic phenotypes and to define new predictive biomarkers.MethodsOur study was a case–control study nested within the Rhea cohort. Major metabolites (n = 34) in maternal urine samples collected at the end of the first trimester (n = 438) were measured using proton nuclear magnetic resonance spectroscopy. In addition to PB, we used FGR in weight and small for gestational age as study endpoints.ResultsWe observed significant associations between FGR and decreased urinary acetate (interquartile odds ratio (IOR) = 0.18 CI 0.04 to 0.60), formate (IOR = 0.24 CI 0.07 to 0.71), tyrosine (IOR = 0.27 CI 0.08 to 0.81) and trimethylamine (IOR = 0.14 CI 0.04 to 0.40) adjusting for maternal education, maternal age, parity, and smoking during pregnancy. These metabolites were inversely correlated with blood insulin. Women with clinically induced PB (IPB) had a significant increase in a glycoprotein N-acetyl resonance (IOR =&
Marchan R, Lesjak MS, Buettner B, et al., 2014, EDI3, a glycerophosphodiesterase linking metabolism to cellular migration and attachment
Chadeau-Hyam M, Vermeulen RCH, Hebels DGAJ, et al., 2014, Prediagnostic transcriptomic markers of Chronic lymphocytic leukemia reveal perturbations 10 years before diagnosis, Annals of Oncology, Vol: 25, Pages: 1065-1072, ISSN: 0923-7534
BackgroundB-cell lymphomas are a diverse group of hematological neoplasms with differential etiology and clinical trajectories. Increased insights in the etiology and the discovery of prediagnostic markers have the potential to improve the clinical course of these neoplasms.MethodsWe investigated in a prospective study global gene expression in peripheral blood mononuclear cells of 263 incident B-cell lymphoma cases, diagnosed between 1 and 17 years after blood sample collection, and 439 controls, nested within two European cohorts.ResultsOur analyses identified only transcriptomic markers for specific lymphoma subtypes; few markers of multiple myeloma (N = 3), and 745 differentially expressed genes in relation to future risk of chronic lymphocytic leukemia (CLL). The strongest of these associations were consistently found in both cohorts and were related to (B-) cell signaling networks and immune system regulation pathways. CLL markers exhibited very high predictive abilities of disease onset even in cases diagnosed more than 10 years after blood collection.ConclusionsThis is the first investigation on blood cell global gene expression and future risk of B-cell lymphomas. We mainly identified genes in relation to future risk of CLL that are involved in biological pathways, which appear to be mechanistically involved in CLL pathogenesis. Many but not all of the top hits we identified have been reported previously in studies based on tumor tissues, therefore suggesting that a mixture of preclinical and early disease markers can be detected several years before CLL clinical diagnosis.
Chan PH, Zhang WL, Lau C-H, et al., 2014, Metabonomic analysis of water extracts from different angelica roots by H-1-nuclear magnetic resonance spectroscopy, Molecules, Vol: 19, Pages: 3460-3470, ISSN: 1420-3049
Angelica Radix, the roots of the genus Angelica, has been used for more than 2,000 years as a traditional medicine in Eastern Asia. The Chinese Pharmacopoeia records more than 100 herbal formulae containing Angelica roots. There are two common sources of Angelica roots, Angelica sinensis from China and A. gigas from Korea. The two species of Angelica roots differ in their chemical compositions, pharmacological properties and clinical efficacy. 1H-NMR metabolic profiling has recently emerged as a promising quality control method for food and herbal chemistry. We explored the use of 1H-NMR metabolic profiling for the quality control of Angelica Radix. Unlike previous work, we performed the metabolic profiling on hot water extracts, so as to mimic the clinically relevant preparation method. Unsupervised principle component analyses of both the full spectral profile and a selection of targeted molecules revealed a clear differentiation of three types of Angelica roots. In addition, the levels of 13 common metabolites were measured. Statistically significant differences in the levels of glucose, fructose and threonine were found between different sources of Angelica. Ferulic acid, a marker commonly used to evaluate Angelica root, was detected in our samples, but the difference in ferulic acid levels between the samples was not statistically significant. Overall, we successfully applied 1H-NMR metabolic profiling with water extraction to discriminate all three sources of Angelica roots, and obtained quantitative information of many common metabolites.
Tredwell GD, Miller JA, Chow H-HS, et al., 2014, Metabolomic Characterization of Nipple Aspirate Fluid by <SUP>1</SUP>H NMR Spectroscopy and GC-MS, JOURNAL OF PROTEOME RESEARCH, Vol: 13, Pages: 883-889, ISSN: 1535-3893
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- Citations: 17
Vrijheid M, Slama R, Robinson O, et al., 2014, The human early-life exposome (HELIX): project rationale and design, Environ Health Perspect, Vol: 122, Pages: 535-544, ISSN: 0091-6765
BACKGROUND: Developmental periods in early life may be particularly vulnerable to impacts of environmental exposures. Human research on this topic has generally focused on single exposure-health effect relationships. The "exposome" concept encompasses the totality of exposures from conception onward, complementing the genome. OBJECTIVES: The Human Early-Life Exposome (HELIX) project is a new collaborative research project that aims to implement novel exposure assessment and biomarker methods to characterize early-life exposure to multiple environmental factors and associate these with omics biomarkers and child health outcomes, thus characterizing the "early-life exposome." Here we describe the general design of the project. METHODS: In six existing birth cohort studies in Europe, HELIX will estimate prenatal and postnatal exposure to a broad range of chemical and physical exposures. Exposure models will be developed for the full cohorts totaling 32,000 mother-child pairs, and biomarkers will be measured in a subset of 1,200 mother-child pairs. Nested repeat-sampling panel studies (n = 150) will collect data on biomarker variability, use smartphones to assess mobility and physical activity, and perform personal exposure monitoring. Omics techniques will determine molecular profiles (metabolome, proteome, transcriptome, epigenome) associated with exposures. Statistical methods for multiple exposures will provide exposure-response estimates for fetal and child growth, obesity, neurodevelopment, and respiratory outcomes. A health impact assessment exercise will evaluate risks and benefits of combined exposures. CONCLUSIONS: HELIX is one of the first attempts to describe the early-life exposome of European populations and unravel its relation to omics markers and health in childhood. As proof of concept, it will form an important first step toward the life-course exposome.
Keun H, 2014, Metabolomic Studies of Patient Material by High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance Spectroscopy, CELL-WIDE METABOLIC ALTERATIONS ASSOCIATED WITH MALIGNANCY, Vol: 543, Pages: 297-313, ISSN: 0076-6879
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- Citations: 5
Athersuch TJ, Wilson ID, Keun HC, et al., 2013, Development of quantitative structure-metabolism (QSMR) relationships for substituted anilines based on computational chemistry, XENOBIOTICA, Vol: 43, Pages: 792-802, ISSN: 0049-8254
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- Citations: 5
Hosnijeh FS, Pechlivanis A, Keun HC, et al., 2013, Serum metabolomic pertubations among workers exposed to 2,3,7,8-tetrachlorodibenzo-<i>p</i>-dioxin (TCDD), ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Vol: 54, Pages: 558-565, ISSN: 0893-6692
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- Citations: 18
Athersuch TJ, Malik S, Weljie A, et al., 2013, Evaluation of <SUP>1</SUP>H NMR Metabolic Profiling Using Biofluid Mixture Design, ANALYTICAL CHEMISTRY, Vol: 85, Pages: 6674-6681, ISSN: 0003-2700
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- Citations: 4
Ramirez T, Daneshian M, Kamp H, et al., 2013, Metabolomics in toxicology and preclinical research, ALTEX : Alternatives to Animal Experimentation, Vol: 30, Pages: 209-225, ISSN: 0946-7785
Metabolomics, the comprehensive analysis of metabolites in a biological system, provides detailed information about the biochemical/physiological status of a biological system, and about the changes caused by chemicals. Metabolomics analysis is used in many fields, ranging from the analysis of the physiological status of genetically modified organisms in safety science to the evaluation of human health conditions. In toxicology, metabolomics is the -omics discipline that is most closely related to classical knowledge of disturbed biochemical pathways. It allows rapid identification of the potential targets of a hazardous compound. It can give information on target organs and often can help to improve our understanding regarding the mode-of-action of a given compound. Such insights aid the discovery of biomarkers that either indicate pathophysiological conditions or help the monitoring of the efficacy of drug therapies. The first toxicological applications of metabolomics were for mechanistic research, but different ways to use the technology in a regulatory context are being explored. Ideally, further progress in that direction will position the metabolomics approach to address the challenges of toxicology of the 21st century. To address these issues, scientists from academia, industry, and regulatory bodies came together in a workshop to discuss the current status of applied metabolomics and its potential in the safety assessment of compounds. We report here on the conclusions of three working groups addressing questions regarding 1) metabolomics for in vitro studies 2) the appropriate use of metabolomics in systems toxicology, and 3) use of metabolomics in a regulatory context.
Blazquez M, Carretero A, Ellis JK, et al., 2013, A Combination of Transcriptomics and Metabolomics Uncovers Enhanced Bile Acid Biosynthesis in HepG2 Cells Expressing CCAAT/Enhancer-Binding Protein β (C/EBPβ), Hepatocyte Nuclear Factor 4α (HNF4α), and Constitutive Androstane Receptor (CAR), Journal of proteome research, Pages: 130515154744008-130515154744008
Hebels DGAJ, Georgiadis P, Keun HC, et al., 2013, Performance in Omics Analyses of Blood Samples in Long-Term Storage: Opportunities for the Exploitation of Existing Biobanks in Environmental Health Research, ENVIRONMENTAL HEALTH PERSPECTIVES, Vol: 121, Pages: 480-487, ISSN: 0091-6765
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- Citations: 117
Jimenez B, Mirnezami R, Kinross J, et al., 2013, <SUP>1</SUP>H HR-MAS NMR Spectroscopy of Tumor-Induced Local Metabolic "Field-Effects" Enables Colorectal Cancer Staging and Prognostication, JOURNAL OF PROTEOME RESEARCH, Vol: 12, Pages: 959-968, ISSN: 1535-3893
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- Citations: 88
Cantor GH, Beckonert O, Bollard ME, et al., 2013, Integrated Histopathological and Urinary Metabonomic Investigation of the Pathogenesis of Microcystin-LR Toxicosis, VETERINARY PATHOLOGY, Vol: 50, Pages: 159-171, ISSN: 0300-9858
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- Citations: 13
Vinken M, Maes M, Cavill R, et al., 2012, Proteomic and metabolomic responses to connexin43 silencing in primary hepatocyte cultures, Archives of Toxicology, Vol: 87, Pages: 883-894
Shariff MIF, Keun HC, Beckonert O, et al., 2012, PLASMA METABOLITE PROFILING IN A RAT MODEL OF HEPATOCELLULAR CARCINOMA AND THE EFFECTS OF CO-ADMINISTERED ANTIBIOTICS, GUT, Vol: 61, Pages: A405-A406, ISSN: 0017-5749
Shariff MIF, Lewis MR, Want EJ, et al., 2012, BLOOD LIPIDOMIC PROFILING OF HEPATOCELLULAR CARCINOMA IN HUMAN AND ANIMAL STUDIES IDENTIFIES LYSOPHOSPHATIDYLCHOLINE (24,0,0), A DISCRIMINATORY BIOMARKER
Lamour SD, Choi B, Keun HC, et al., 2012, Metabolic characterization of leishmania major infection in activated and nonactivated macrophages., Journal of Proteome Research, Vol: 11, Pages: 4211-4222, ISSN: 1535-3907
Infection with Leishmania spp. can lead to a range of symptoms in the affected individual, depending on underlying immune-metabolic processes. The macrophage activation state hereby plays a key role. Whereas the l-arginine pathway has been described in detail as the main biochemical process responsible for either nitric oxide mediated parasite killing (classical activation) or amplification of parasite replication (alternative activation), we were interested in a wider characterization of metabolic events in vitro. We therefore assessed cell growth medium, parasite extract, and intra- and extracellular metabolome of activated and nonactivated macrophages, in presence and absence of Leishmania major. A metabolic profiling approach was applied combining (1)H NMR spectroscopy with multi- and univariate data treatment. Metabolic changes were observed along both conditional axes, that is, infection state and macrophage activation, whereby significantly higher levels of potential parasite end products were found in parasite exposed samples including succinate, acetate, and alanine, compared to uninfected macrophages. The different macrophage activation states were mainly discriminated by varying glucose consumption. The presented profiling approach allowed us to obtain a metabolic snapshot of the individual biological compartments in the assessed macrophage culture experiments and represents a valuable read out system for further multiple compartment in vitro studies.
Stewart JD, Marchan R, Lesjak MS, et al., 2012, Choline-releasing glycerophosphodiesterase EDI3 drives tumor cell migration and metastasis, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 109, Pages: 8155-8160, ISSN: 0027-8424
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- Citations: 89
Patel NR, McPhail MJ, Shariff MI, et al., 2012, Biofluid metabonomics using (1)H NMR spectroscopy: the road to biomarker discovery in gastroenterology and hepatology., Expert Rev Gastroenterol Hepatol, Vol: 6, Pages: 239-251
Metabolic profiling or 'metabonomics' is an investigatory method that allows metabolic changes associated with the presence of an underlying pathological process to be investigated. Various biofluids can be utilized in the process but urine, serum and fecal extract are most pertinent to the investigation of gastrointestinal and hepatological disease. Nuclear magnetic resonance spectroscopy-based metabonomic research has the potential to generate novel noninvasive diagnostic tests, based on biomarkers of disease, which are simple and cost effective yet retain high sensitivity and specificity characteristics. The process involves a number of key steps, including sample collection, data acquisition, chemometric techniques and, finally, validation. This technique-driven review aims to demystify the metabonomics pathway, while also illustrating the potential of this technique with recent examples of its application in hepato-gastroenterological disease.
Stebbing J, Sharma A, North B, et al., 2012, A metabolic phenotyping approach to understanding relationships between metabolic syndrome and breast tumour responses to chemotherapy, ANNALS OF ONCOLOGY, Vol: 23, Pages: 860-U2, ISSN: 0923-7534
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- Citations: 39
Patel NR, McPhail MJW, Shariff MIF, et al., 2012, Biofluid metabonomics using <SUP>1</SUP>H NMR spectroscopy: the road to biomarker discovery in gastroenterology and hepatology, EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY, Vol: 6, Pages: 239-251, ISSN: 1747-4124
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- Citations: 20
Perez-Trujillo M, Lindon JC, Parella T, et al., 2012, Chiral Metabonomics: <SUP>1</SUP>H NMR-Based Enantiospecific Differentiation of Metabolites in Human Urine via Direct Cosolvation with β-Cyclodextrin, ANALYTICAL CHEMISTRY, Vol: 84, Pages: 2868-2874, ISSN: 0003-2700
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- Citations: 29
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