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Pi J.,Hamner Institutes for Health Sciences | Collins S.,Sanford Burnham Institute for Medical Research
Diabetes, Obesity and Metabolism | Year: 2010

Growing evidence indicates that reactive oxygen species (ROS) are not just deleterious by-products of respiratory metabolism in mitochondria, but can be essential elements for many biological responses, including in pancreatic β-cells. ROS can be a 'second-messenger signal' in response to hormone/receptor activation that serves as part of the 'code' to trigger the ultimate biological response, or it can be a 'protective signal' to increase the levels of antioxidant enzymes and small molecules to scavenge ROS, thus restoring cellular redox homeostasis. In pancreatic β-cells evidence is emerging that acute and transient glucose-dependent ROS contributes to normal glucose-stimulated insulin secretion (GSIS). However, chronic and persistent elevation of ROS, resulting from inflammation or excessive metabolic fuels such as glucose and fatty acids, may elevate antioxidant enzymes such that they blunt ROS and redox signalling, thus impairing β-cell function. An interesting mitochondrial protein whose main function appears to be the control of ROS is uncoupling protein 2 (UCP2). Despite continuing investigation of the exact mechanism by which UCP2 is 'activated', it is clear that UCP2 levels and/or activity impact the efficacy of GSIS in pancreatic islets. This review will focus on the paradoxical roles of ROS in pancreatic β-cell function and the regulatory role of UCP2 in ROS signalling and GSIS. © 2010 Blackwell Publishing Ltd. Source

Campbell Jr. J.L.,Hamner Institutes for Health Sciences
Methods in molecular biology (Clifton, N.J.) | Year: 2012

Physiologically based pharmacokinetic (PBPK) models differ from conventional compartmental pharmacokinetic models in that they are based to a large extent on the actual physiology of the organism. The application of pharmacokinetics to toxicology or risk assessment requires that the toxic effects in a particular tissue are related in some way to the concentration time course of an active form of the substance in that tissue. The motivation for applying pharmacokinetics is the expectation that the observed effects of a chemical will be more simply and directly related to a measure of target tissue exposure than to a measure of administered dose. The goal of this work is to provide the reader with an understanding of PBPK modeling and its utility as well as the procedures used in the development and implementation of a model to chemical safety assessment using the styrene PBPK model as an example. Source

Krewski D.,University of Ottawa | Westphal M.,University of Ottawa | Al-Zoughool M.,University of Ottawa | Croteau M.C.,University of Ottawa | Andersen M.E.,Hamner Institutes for Health Sciences
Annual Review of Public Health | Year: 2011

In 2007, the U.S. National Research Council (NRC) published a groundbreaking report entitled Toxicity Testing in the 21st Century: A Vision and a Strategy. The purpose of this report was to develop a long-range strategic plan to update and advance the way environmental agents are tested for toxicity. The vision focused on the identification of critical perturbations of toxicity pathways that lead to adverse human health outcomes using modern scientific tools and technologies. This review describes how emerging scientific methods will move the NRC vision forward and improve the manner in which the potential health risks associated with exposure to environmental agents are assessed. The new paradigm for toxicity testing is compatible with the widely used four-stage risk assessment framework originally proposed by the NRC in 1983 in the so-called Red Book. The Nrf2 antioxidant pathway provides a detailed example of how relevant pathway perturbations will be identified within the context of the new NRC vision for the future of toxicity testing. The implications of the NRC vision for toxicity testing for regulatory risk assessment are also discussed. © 2011 by Annual Reviews. rights reserved. Source

Yagishita Y.,Tohoku University | Fukutomi T.,Tohoku University | Sugawara A.,Tohoku University | Kawamura H.,Tohoku University | And 4 more authors.
Diabetes | Year: 2014

Mice Transcription factor Nrf2 (NF-E2-related factor 2) regulates wide-ranging cytoprotective genes in response to environmental stress. Keap1 (Kelch-like ECH-associated protein 1) is an adaptor protein for Cullin3-based ubiquitin E3 ligase and negatively regulates Nrf2. The Keap1-Nrf2 system plays important roles in the oxidative stress response and metabolism. However, the roles Nrf2 plays in prevention of pancreatic β-Cells damage remain elusive. To demonstrate the roles of Nrf2 in pancreatic β-Cellss, we used four genetically engineered mouse models: 1) β-Cells-specific Keap1- conditional knockout mice, 2) β-Cells-specific Nos2 transgenic mice, 3) conventional Nrf2-heterozygous knockout mice, and 4) β-Cells-specific Nrf2- conditional knockout mice. We found that Nrf2 induction suppressed the oxidative DNA-adduct formation in pancreatic islets of iNOS-Tg mice and strongly restored insulin secretion from pancreatic β-Cellss in the context of reactive species (RS) damage. Consistently, Nrf2 suppressed accumulation of intracellular RS in isolated islets and pancreatic β-Cells lines and also decreased nitrotyrosine levels. Nrf2 induced glutathione-related genes and reduced pancreatic β-Cells apoptosis mediated by nitric oxide. In contrast, Nrf2 depletion in Nrf2-heterozygous knockout and β-Cells-specific Nrf2-conditional knockout mice strongly aggravated pancreatic β-Cells damage. These results demonstrate that Nrf2 induction prevents RS damage in pancreatic β-Cellss and that the Keap1-Nrf2 system is the crucial defense pathway for the physiological and pathological protection of pancreatic β-Cellss. © 2014 by the American Diabetes Association. Source

Wetmore B.A.,Hamner Institutes for Health Sciences
Toxicology | Year: 2015

High-throughput in vitro toxicity screening provides an efficient way to identify potential biological targets for environmental and industrial chemicals while conserving limited testing resources. However, reliance on the nominal chemical concentrations in these in vitro assays as an indicator of bioactivity may misrepresent potential in vivo effects of these chemicals due to differences in clearance, protein binding, bioavailability, and other pharmacokinetic factors. Development of high-throughput in vitro hepatic clearance and protein binding assays and refinement of quantitative in vitro-to-. in vivo extrapolation (QIVIVE) methods have provided key tools to predict xenobiotic steady state pharmacokinetics. Using a process known as reverse dosimetry, knowledge of the chemical steady state behavior can be incorporated with HTS data to determine the external in vivo oral exposure needed to achieve internal blood concentrations equivalent to those eliciting bioactivity in the assays. These daily oral doses, known as oral equivalents, can be compared to chronic human exposure estimates to assess whether in vitro bioactivity would be expected at the dose-equivalent level of human exposure. This review will describe the use of QIVIVE methods in a high-throughput environment and the promise they hold in shaping chemical testing priorities and, potentially, high-throughput risk assessment strategies. © 2014 Elsevier Ireland Ltd. Source

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