Publications
263 results found
Wu Q, Li JV, Seyfried F, et al., 2015, Metabolic phenotype-microRNA data fusion analysis of the systemic consequences of Roux-en-Y gastric bypass surgery., International Journal of Obesity, Vol: 2015, Pages: 1126-1134, ISSN: 1476-5497
Background/Objectives: Bariatric surgery offers sustained dramatic weight loss and often remission of type 2 diabetes, yet the mechanisms of establishment of these health benefits are not clear.Subjects/MethodsWe mapped the co-ordinated systemic responses of gut hormones, the circulating miRNAome and the metabolome in a rat model of Roux-en-Y gastric bypass (RYGB) surgery. Results: The response of circulating miRNAs to RYGB was striking and selective. Analysis of 14 significantly altered circulating miRNAs within a pathway context was suggestive of modulation of signalling pathways including G protein signalling, neurodegeneration, inflammation, and growth and apoptosis responses. Concomitant alterations in the metabolome indicated increased glucose transport, accelerated glycolysis and inhibited gluconeogenesis in the liver. Of particular significance, we show significantly decreased circulating miRNA-122 levels and a more modest decline in hepatic levels, following surgery. In mechanistic studies, manipulation of miRNA-122 levels in a cell model induced changes in the activity of key enzymes involved in hepatic energy metabolism, glucose transport, glycolysis, TCA cycle, pentose phosphate shunt, fatty acid oxidation and gluconeogenesis, consistent with the findings of the in vivo surgery-mediated responses, indicating the powerful homeostatic activity of the miRNAs. Conclusions: The close association between energy metabolism, neuronal signalling and gut microbial metabolites derived from the circulating miRNA, plasma, urine and liver metabolite and gut hormone correlations further supports an enhanced gut-brain signaling, which we suggest is hormonally mediated by both traditional gut hormones and miRNAs. This transomic approach to map the crosstalk between the circulating miRNAome and metabolome offers opportunities to understand complex systems biology within a disease and interventional treatment setting.International Journal of Obesity accepted article previe
Saleh AF, Priestley CC, Gooderham NJ, et al., 2015, Re-evaluation of the Mutagenic Response to Phosphorothioate Nucleotides in Human Lymphoblastoid TK6 Cells., Toxicological Sciences, Vol: 145, Pages: 169-176, ISSN: 1096-6080
The degradation of phosphorothioate oligonucleotides (PS-ONDs) and the release of potentially genotoxic modified mononucleotides raise a safety concern for OND-based therapeutics. Deoxyadenosine monophosphorothioate (dAMPαS), a PS nucleotide analog, has been reported to be a potent in vitro mutagen at the thymidine kinase (TK) locus in human TK6 lymphoblastoid cells. This led us to explore the mechanism behind the apparent positive response induced by dAMPαS in the TK gene-mutation assay in TK6 cells. In this work, treatment of TK6 cells with dAMPαS produced a dose-dependent increase in cytotoxicity and mutant frequency at the TK locus. Surprisingly, when the colonies from dAMPαS were re-challenged with the selective agent trifluorothymidine (TFT), the TFT-resistant phenotype was lost. Moreover, dAMPαS-induced colonies displayed distinct growth kinetics and required longer incubation time than 4-nitroquinoline-1-oxide-induced colonies to start growing. Treatment of TK6 cells with dAMPαS induced cell cycle arrest at the G1 phase, enabling cells to grow, and form a colony after the efficacy of TFT in the culture medium was lost. Our findings suggest that a fraction of parental "nonmutant" TK6 cells escaped the toxicity of TFT, possibly via G1 arrest, and resumed growth after the degradation of TFT. We conclude that dAMPαS did not induce real TFT-resistant mutants and caution should be taken with interpretation of mutation data from TK gene-mutation assay in TK6 cells when assessing modified nucleotides.
Cohen SM, Flikushima S, Gooderham NJ, et al., 2015, GRAS 27 Flavoring Substances, Food Technology, Vol: 69, Pages: 41-59, ISSN: 0015-6639
The 27th publication by the Expert Panel of the Flavor and Extract Manufacturers Association provides an update on recent progress in the consideration of flavoring ingredients generally recognized as safe under the Food Additives Amendment.
Patel SAA, Bhambra U, Charalambous MP, et al., 2014, Interleukin-6 mediated upregulation of CYP1B1 and CYP2E1 in colorectal cancer involves DNA methylation, miR27b and STAT3, BRITISH JOURNAL OF CANCER, Vol: 111, Pages: 2287-2296, ISSN: 0007-0920
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- Citations: 68
Kirkland D, Zeiger E, Madia F, et al., 2014, Can <i>in vitro</i> mammalian cell genotoxicity test results be used to complement positive results in the Ames test and help predict carcinogenic or <i>in vivo</i> genotoxic activity? I. Reports of individual databases presented at an EURL ECVAM Workshop, MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS, Vol: 775, Pages: 55-68, ISSN: 1383-5718
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- Citations: 45
Kadir NHA, Rossiter JT, Gooderham N, 2014, Glucosinolate hydrolysis products of cruciferous vegetables inhibit cytochrome P450 1A activity and mediate oxidative stress, 50th Congress of the European-Societies-of-Toxicology, Publisher: ELSEVIER IRELAND LTD, Pages: S88-S89, ISSN: 0378-4274
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- Citations: 1
Papaioannou MD, Koufaris C, Gooderham NJ, 2014, The cooked meat-derived mammary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) elicits estrogenic-like microRNA responses in breast cancer cells, TOXICOLOGY LETTERS, Vol: 229, Pages: 9-16, ISSN: 0378-4274
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- Citations: 17
Gooderham NJ, Koufaris C, 2014, Using microRNA profiles to predict and evaluate hepatic carcinogenic potential, TOXICOLOGY LETTERS, Vol: 228, Pages: 127-132, ISSN: 0378-4274
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- Citations: 13
Chilloux J, Fearnside J, Rothwell A, et al., 2014, Gut Microbial Metabolite Trimethylamine Inhibits the Toll-Like Receptor (TLR) Inflammation Pathway, Diabetes, Vol: 63
Chilloux J, Fearnside JF, Rothwell AR, et al., 2014, Gut Microbial Metabolite Trimethylamine Inhibits the Toll-Like Receptor (TLR) Inflammation Pathway, Publisher: AMER DIABETES ASSOC, Pages: A451-A451, ISSN: 0012-1797
Rietjens IMCM, Cohen SM, Fukushima S, et al., 2014, Impact of Structural and Metabolic Variations on the Toxicity and Carcinogenicity of Hydroxy- and Alkoxy-Substituted Allyl- and Propenylbenzenes, Chemical Research in Toxicology, Vol: 27, Pages: 1092-1103, ISSN: 1520-5010
The metabolic fate of a compound isdetermined by numerous factors including its chemicalstructure. Although the metabolic options for a variety offunctional groups are well understood and can often provide arationale for the comparison of toxicity based on structuralanalogy, at times quite minor structural variations may havemajor consequences for metabolic outcomes and toxicity. In this perspective, the effects of structural variations on metabolicoutcomes is detailed for a group of related hydroxy- and alkoxy-substituted allyl- and propenylbenzenes. These classes ofcompounds are naturally occurring constituents of a variety of botanical-based food items. The classes vary from one another bythe presence or absence of alkylation of their para-hydroxyl substituents and/or the position of the double bond in the alkyl sidechain. We provide an overview of how these subtle structural variations alter the metabolism of these important food-bornecompounds, ultimately influencing their toxicity, particularly their DNA reactivity and carcinogenic potential. The data reveal thatdetailed knowledge of the consequences of subtle structural variations for metabolism is essential for adequate comparison ofstructurally related chemicals. Taken together, it is concluded that predictions in toxicological risk assessment should not beperformed on the basis of structural analogy only but should include an analogy of metabolic pathways across compounds and
Marnett LJ, Cohen SMRE, Fukushima S, et al., 2014, GRASr2 Evaluation of Aliphatic Acyclic and Alicyclic Terpenoid Tertiary Alcohols and Structurally Related Substances Used as Flavoring Ingredients, Journal of Food Science, Vol: 79, Pages: R428-R441, ISSN: 1750-3841
This publication is the 1st in a series of publications by the Expert Panel of the Flavor and Extract Manufacturers Assoc. summarizing the Panel's 3rd re-evaluation of Generally Recognized as Safe (GRAS) status referred to as the GRASr2 program. In 2011, the Panel initiated a comprehensive program to re-evaluate the safety of more than 2700 flavor ingredients that have previously met the criteria for GRAS status under conditions of intended use as flavor ingredients. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, pharmacokinetics, and toxicology. Flavor ingredients are evaluated individually and in the context of the available scientific information on the group of structurally related substances. Scientific data relevant to the safety evaluation of the use of aliphatic acyclic and alicyclic terpenoid tertiary alcohols and structurally related substances as flavoring ingredients are evaluated. The group of aliphatic acyclic and alicyclic terpenoid tertiary alcohols and structurally related substances was reaffirmed as GRAS (GRASr2) based, in part, on their rapid absorption, metabolic detoxication, and excretion in humans and other animals; their low level of flavor use; the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels determined from subchronic studies and the lack of significant genotoxic and mutagenic potential. © 2014 Institute of Food Technologists®.
Irfan A, Cauchi M, Edmands W, et al., 2014, Assessment of temporal dose-toxicity relationship of fumed silica nanoparticle in human lung A549 cells by conventional cytotoxicity and ¹H-NMR-based extracellular metabonomic assays., Toxicol Sci, Vol: 138, Pages: 354-364
As nanoparticles could form aggregates in biological systems, the dynamics of their dispersity drives the temporal effect of nanoparticles in vitro. To test this hypothesis, the fumed silica nanoparticles (SiNPs) that have primary sizes of 7-14 nm and form aggregates in culture medium were selected for toxicity study in human lung A549 cells. The dispersity of SiNPs was analyzed by dynamic light scattering and transmission of electron microscopy. Cytotoxicity assays including mitochondrial activity, intracellular level of reactive oxygen species (ROS), and membrane damage together with the ¹H-NMR-based extracellular metabonomic assay were conducted to determine the temporal dose-effect relationship of SiNPs. In cell culture medium, SiNPs dispersed well initially at 25-100 μg/ml; however, they sedimented rapidly in a concentration-dependent manner. SiNPs caused a dose-dependent increase of intracellular ROS and cell membrane damage at 4 h and a loss of cell viability after 48 h. SiNPs also induced an elevation of extracellular glucose, lactate, phenylalanine, histidine, and tyrosine levels in a time- and concentration-dependent manner. The dose-effect patterns at 4 h were different from that at 12 and 24 h as assessed by both cytotoxicity and metabonomic assays. Both fitted better with polynomial regression than linear regression, implying multimode action of SiNPs at different concentrations. The early NP-cell interaction and the late sedimentation could be attributable to the temporal effects of SiNPs. The extracellular ¹H-NMR-based metabonomics demonstrated a potential as a robust nondestructive tool for monitoring the temporal effect of NPs that tend to aggregate in nature.
Boyce A, David RM, Gooderham NJ, 2014, The mutagenic effects of 2-amino-1-methyl-6-phenylimidazo[4,5-<i>b</i>] pyridine in Muta™Mouse colon is attenuated by resveratrol, TOXICOLOGY RESEARCH, Vol: 3, Pages: 197-204, ISSN: 2045-452X
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- Citations: 5
Koufaris C, Wright J, Osborne M, et al., 2013, Time and dose-dependent effects of phenobarbital on the rat liver miRNAome, TOXICOLOGY, Vol: 314, Pages: 247-253, ISSN: 0300-483X
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- Citations: 23
Dietrich DR, von Aulock S, Marquardt H, et al., 2013, Scientifically unfounded precaution drives European Commission's recommendations on EDC regulation, while defying common sense, well-established science and risk assessment principles., Toxicon, Vol: 76, Pages: A1-A2
Glover A, 2013, Scientifically unfounded precaution drives European Commission's recommendations on EDC regulation, while defying common sense, well-established science and risk assessment principles, FOOD AND CHEMICAL TOXICOLOGY, Vol: 62, Pages: A1-A4, ISSN: 0278-6915
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- Citations: 3
Dietrich DR, von Aulock S, Marquardt H, et al., 2013, Untitled, REGULATORY TOXICOLOGY AND PHARMACOLOGY, Vol: 67, Pages: 317-318, ISSN: 0273-2300
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- Citations: 7
Dietrich DR, von Aulock S, Marquardt H, et al., 2013, Scientifically unfounded precaution drives European Commission's recommendations on EDC regulation, while defying common sense, well-established science and risk assessment principles, TOXICOLOGY IN VITRO, Vol: 27, Pages: 2110-2114, ISSN: 0887-2333
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- Citations: 12
Dietrich DR, von Aulock S, Marquardt H, et al., 2013, Scientifically unfounded precaution drives European Commission's recommendations on EDC regulation, while defying common sense, well-established science and risk assessment principles, CHEMICO-BIOLOGICAL INTERACTIONS, Vol: 205, Pages: A1-A2, ISSN: 0009-2797
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- Citations: 25
Dietrich DR, Aulock SV, Marquardt H, et al., 2013, Scientifically unfounded precaution drives European Commission's recommendations on EDC regulation, while defying common sense, well-established science and risk assessment principles
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- Citations: 17
Dietrich D, von Aulock S, Marquardt HWJ, et al., 2013, Open letter to the European commission: scientifically unfounded precaution drives European commission's recommendations on EDC regulation, while defying common sense, well-established science, and risk assessment principles, ARCHIVES OF TOXICOLOGY, Vol: 87, Pages: 1739-1741, ISSN: 0340-5761
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- Citations: 19
Marnett LJ, Cohen SM, Fukushima S, et al., 2013, GRAS FLAVORING SUBSTANCES 26, FOOD TECHNOLOGY, Vol: 67, Pages: 38-56, ISSN: 0015-6639
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- Citations: 26
Koufaris C, Gooderham NJ, 2013, Are differences in microRNA regulation implicated in species-dependent response to toxicological exposures?, Toxicological Sciences, Vol: 131, Pages: 337-342, ISSN: 1096-6080
Equivalent exposures can result in qualitatively or quantitatively dissimilar toxic effects across species, with the underlying molecular mechanisms being often not well defined. In many cases, differences in metabolic handling of the chemical (metabolism and disposition) provide an explanation of these differences, but in other cases the explanation is less obvious. This variability in the outcome of toxicant exposures complicates the interspecies extrapolation of human hazard from animal testing data. MicroRNAs (miRNAs) are a family of noncoding RNAs that posttranscriptionally regulate the expression of their target genes that have fundamental roles in physiology, disease, and toxicological responses. Importantly, these noncoding genes are characterized by a high evolutionary flux, in terms of miRNA repertoire and functioning, even among closely related species. Furthermore, evidence is emerging that the enzymes of drug metabolism are also under miRNA regulation and thus offer a new twist to an old para digm, whereby manipulation of the expression of these enzymes affects toxic outcomes. In this review, we discuss how miRNA may contribute to the interspecies variability observed in the response to toxicant exposures. Although few studies have so far specifically examined the contribution of differences in miRNA regulation to species-dependent responses to toxicological exposures, we believe that this will be an area of intense research in the coming years. © The Author 2012. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.
Dietrich DR, von Aulock S, Marquardt H, et al., 2013, Scientifically unfounded precaution drives European Commission's recommendations on EDC regulation, while defying common sense, well-established science and risk assessment principles., Toxicon : official journal of the International Society on Toxinology, Vol: 76
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- Citations: 2
, 2013, Scientifically unfounded precaution drives European Commission's recommendations on EDC regulation, while defying common sense, well-established science and risk assessment principles, TOXICOLOGY RESEARCH, Vol: 2, Pages: 297-298, ISSN: 2045-452X
Gooderham N, Kelly R, 2013, Happy new year from <i>Toxicology Research</i>, TOXICOLOGY RESEARCH, Vol: 2, Pages: 10-10, ISSN: 2045-452X
Edmands WMB, Gooderham NJ, Holmes E, et al., 2013, <i>S</i>-Methyl-L-cysteine sulphoxide: the Cinderella phytochemical?, TOXICOLOGY RESEARCH, Vol: 2, Pages: 11-22, ISSN: 2045-452X
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- Citations: 28
Dietrich DR, von Aulock S, Marquardt H, et al., 2013, Scientifically unfounded precaution drives European Commission's recommendations on EDC regulation, while defying common sense, well-established science and risk assessment principles, ALTEX-ALTERNATIVES TO ANIMAL EXPERIMENTATION, Vol: 30, Pages: 381-382, ISSN: 1868-596X
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- Citations: 11
Reshat R, Priestley CC, Gooderham NJ, 2012, Mutagenesis by an Antisense Oligonucleotide and Its Degradation Product, TOXICOLOGICAL SCIENCES, Vol: 130, Pages: 319-327, ISSN: 1096-6080
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- Citations: 4
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