期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 87, 期 -, 页码 15-25出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2015.05.045
关键词
Ionizing radiation; Oxidative stress; Hematopoietic stem cells; Radioprotection; Metformin; Free radicals
资金
- National Program on Key Basic Research Project (973 Program) [2011CB964800-G]
- National Natural Science Foundation of China [81129020, 81372928]
- Natural Science Foundation of Tianjin [15JCZDJC35200]
- U.S. National Institutes of Health [CA122023]
Exposure to ionizing radiation (IR) increases the production of reactive oxygen species (ROS) not only by the radiolysis of water but also through IR-induced perturbation of the cellular metabolism and disturbance of the balance of reduction/oxidation reactions. Our recent studies showed that the increased production of intracellular ROS induced by IR contributes to IR-induced late effects, particularly in the hematopoietic system, because inhibition of ROS production with an antioxidant after IR exposure can mitigate IR-induced long-term bone marrow (BM) injury. Metformin is a widely used drug for the treatment of type 2 diabetes. Metformin also has the ability to regulate cellular metabolism and ROS production by activating AMP-activated protein kinase. Therefore, we examined whether metformin can ameliorate IR-induced long-term BM injury in a total-body irradiation (TBI) mouse model. Our results showed that the administration of metformin significantly attenuated TBI-induced increases in ROS production and DNA damage and upregulation of NADPH oxidase 4 expression in BM hematopoietic stem cells (HSCs). These changes were associated with a significant increase in BM HSC frequency, a considerable improvement in in vitro and in vivo HSC function, and complete inhibition of upregulation of p16(Ink4a) in HSCs after TEL These findings demonstrate that metformin can attenuate TBI-induced long-term BM injury at least in part by inhibiting the induction of chronic oxidative stress in HSCs and HSC senescence. Therefore, metformin has the potential to be used as a novel radioprotectant to ameliorate TBI-induced long-term BM injury. (C) 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommuns.org/licenses/byond/4.0/).
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