文献类型：期刊文献

英文题名：Britanin Ameliorates Cerebral Ischemia-Reperfusion Injury by Inducing the Nrf2 Protective Pathway

作者：Wu, Guozhen[1];Zhu, Lili[2];Yuan, Xing[1];Chen, Hao[1,3];Xiong, Rui[2];Zhang, Shoude[2];Cheng, Hao;Shen, Yunheng[1];An, Huazhang[4];Li, Tiejun[3];Li, Honglin[2];Zhang, Weidong[1]

机构：[1]Second Mil Med Univ, Sch Pharm, Dept Phytochem, 325 Guohe Rd, Shanghai 200433, Peoples R China;[2]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, State Key Lab Bioreactor Engn, 130 Meilong Rd, Shanghai 200237, Peoples R China;[3]Second Mil Med Univ, Sch Pharm, Dept Pharmacol, Shanghai, Peoples R China;[4]Second Mil Med Univ, Canc Inst, Inst Translat Med, Shanghai, Peoples R China

年份：2017

卷号：27

期号：11

起止页码：754

外文期刊名：ANTIOXIDANTS & REDOX SIGNALING

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000409224400004)】；

基金：The authors thank Professor Yongjun Dang (Fudan University) for providing Flag-Nrf2 and Ub plasmids and Professor Guoquan Yan (Fudan University) for LC-MS-MS analysis. They thank the staff of the Shanghai Synchrotron Radiation Facility for kind assistance and use of facilities. This work was supported by Professor of Chang Jiang Scholars Program, National Natural Science Foundation of China (81230090, 81520108030, 81573318, 81373301, 1302658, 81302651), Shanghai Engineering Research Center for the Preparation of Bioactive Natural Products (10DZ2251300), the Scientific Foundation of Shanghai China (12401900801, 13401900103, 13401900101, 16401901300), National Major Project of China (2011ZX09307-002-03), and the National Key Technology R&D Program of China (2012BAI29B06).

语种：英文

外文关键词：Nrf2; stroke; Britanin; keap1; ROS

摘要：Aims: Oxidative stress is considered the major cause of tissue injury after cerebral ischemia. The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is one of the most important defensive mechanisms against oxidative stresses and has been confirmed as a target for stroke treatment. Thus, we desired to find new Nrf2 activators and test their neuronal protective activity both in vivo and in vitro. Results: The herb-derived compound, Britanin, is a potent inducer of the Nrf2 system. Britanin can induce the expression of protective enzymes and reverse oxygen-glucose deprivation, followed by reperfusion (OGD-R)induced neuronal injury in primary cortical neurons in vitro. Furthermore, the administration of Britanin significantly ameliorated middle cerebral artery occlusion-reperfusion (MCAO-R) insult in vivo. We report here the crystal structure of the complex of Britanin and the BTB domain of Keap1. Britanin selectively binds to a conserved cysteine residue, cysteine 151, of Keap1 and inhibits Keap1-mediated ubiquitination of Nrf2, leading to induction of the Nrf2 pathway. Innovation: Britanin is a potent inducer of Nrf2. The complex crystal structure of Britanin and the BTB domain of Keap1 help clarify the mechanism of Nrf2 induction. Britanin was proven to protect primary cortical neurons against OGD-R-induced injury in an Nrf2-dependant way. Additionally, Britanin had excellent cerebroprotective effect in an MCAO-R model. Conclusion: Our results demonstrate that the natural product Britanin with potent Nrf2-activating and neural protective activities both in vitro and in vivo could be developed into a cerebroprotective therapeutic agent.