A Paradigm Shift in the Understanding of Oxidative Stress and its Implications to Exposure of Low-level Ionizing Radiation
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概要
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For many years, research on oxidative stress focused primarily on determining how reactive oxygen species (ROS) damage cells by indiscriminate reactions with its macromolecular machinery, particularly lipids, proteins and DNA. However, many chronic diseases affiliated with oxidative stress are not always a consequence of tissue necrosis, DNA, or protein damage but rather to altered gene expression. Gene expression is highly regulated by the coordination of extra-, intra- and inter-cellular communication systems that typically maintain tissue homeostasis by sustaining a balance between proliferation, differentiation and apoptosis. Therefore, much research has shifted to the understanding of how ROS reversibly controls gene expression at noncytotoxic doses through cell signaling mechanisms. Cell proliferation typically involves a transient inhibition of gap junctional intercellular communication (GJIC) and the activation of mitogen activated protein kinase pathways (MAPK). We demonstrate that epidermal growth factor (EGF) inhibited GJIC in normal rat liver epithelial cells in addition to activating extracellular signal regulatory kinase, a MAPK. Inhibition of NADPH oxidase, which reduces oxygen to H<SUB>2</SUB>O<SUB>2</SUB> with the very selective inhibitor diphenyleneiodonium, prevented EGF from inhibiting GJIC, suggesting that the generation of H<SUB>2</SUB>O<SUB>2</SUB> is an essential component of the intracellular pathway controlling GJIC. We previously demonstrated that reduced-glutathione (GSH) was also a necessary cofactor of H<SUB>2</SUB>O<SUB>2</SUB>-induced inhibition of GJIC. These results demonstrate that ROS and GSH play essential roles in controlling EGF-dependent control of GJIC. Therefore, the overly simplistic approach of either preventing the generation of ROS or accelerate the removal by antioxidants could deleteriously alter normal signaling functions.
- 長崎大学医学部の論文
長崎大学医学部 | 論文
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