Rutaecarpine inhibits KEAP1-NRF2 interaction to activate NRF2 and ameliorate dextran sulfate sodium-induced colitis

doi:10.1016/j.freeradbiomed.2019.12.012

CORC > 兰州理工大学 > 兰州理工大学

	Rutaecarpine inhibits KEAP1-NRF2 interaction to activate NRF2 and ameliorate dextran sulfate sodium-induced colitis
	Zhang, Youbo 1,2,3; Yan, Tingting 3; Sun, Dongxue 3,4; Xie, Cen 3; Wang, Tianxia 1,2,5; Liu, Xiaoyan 1,2; Wang, Jing 1,2; Wang, Qiong 3; Luo, Yuhong 3; Wang, Ping 3
刊名	FREE RADICAL BIOLOGY AND MEDICINE
	2020-02-20
卷号	148 页码:33-41
关键词	Dextran sulfate sodium Inflammatory bowel disease Kelch-like ECH-Associated protein 1 Nuclear factor-erythroid 2-related factor 2 Rutaecarpine
ISSN号	0891-5849
DOI	10.1016/j.freeradbiomed.2019.12.012
英文摘要	Inflammatory bowel disease (IBD) represents a group of chronic relapsing intestinal disorders. Rutaecarpine (RUT), isolated from the Traditional Chinese Medicine (TCM) of Evodia rutaecarpa, was reported to suppress IBD. However, the mechanism by which RUT ameliorates dextran sulfate sodium (DSS)-induced IBD is largely unknown. By use of nuclear factor-erythroid 2-related factor 2 (NRF2) knockout mice, cell-based studies, surface plasmon resonance (SPR), western blotting analysis, and molecular docking studies, the mechanism by which RUT affects DSS-induced colitis was explored. In DSS-treated wild-type mice but not in Nrf2-null mice, RUT significantly improved colitis as revealed by rescued body weight loss, improved histology and inflammation, and induced expression of NRF2 target genes in colon and ileum. Cell-based studies showed that RUT significantly increased the LD50 for hydrogen peroxide (H2O2)-induced cell damage, activated NRF2 nuclear translocation, and suppressed the production of reactive oxygen species in H2O2-treated HCT116 cells, activated NRF2 luciferase reporter activities in HCT116 cells and HepG2 cells, and induced expression of NRF2 target genes in primary intestinal epithelial cells. Molecular docking in silico and SPR assays indicated that RUT interacted with kelch-like ECH-associated protein 1 (KEAP1), and extracellular incubation studies revealed that RUT bound to the KEAP1 kelch domain with a calculated equilibrium dissociation constant K-d of 19.6 mu M. In conclusion, these results demonstrate that RUT ameliorates DSS-induced colitis, dependent on NRF2, and could be a potential therapeutic option for IBD patients. Mechanistically, RUT potentiates NRF2 nuclear translocation to upregulate NRF2-mediated antioxidant response by directly inhibiting KEAP1-NRF2 interaction.
WOS研究方向	Biochemistry & Molecular Biology ; Endocrinology & Metabolism
语种	英语
出版者	ELSEVIER SCIENCE INC
WOS记录号	WOS:000512981100004
内容类型	期刊论文
源URL	[http://ir.lut.edu.cn/handle/2XXMBERH/155233]
专题	兰州理工大学
作者单位	1.Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China; 2.Peking Univ, Dept Nat Med, Sch Pharmaceut Sci, Beijing 100191, Peoples R China; 3.NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA; 4.Shenyang Pharmaceut Univ, Coll Tradit Chinese Med, Shenyang 110016, Liaoning, Peoples R China; 5.Lanzhou Univ Technol, Sch Life Sci & Engn, Lanzhou 730050, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Youbo,Yan, Tingting,Sun, Dongxue,et al. Rutaecarpine inhibits KEAP1-NRF2 interaction to activate NRF2 and ameliorate dextran sulfate sodium-induced colitis[J]. FREE RADICAL BIOLOGY AND MEDICINE,2020,148:33-41.
APA	Zhang, Youbo.,Yan, Tingting.,Sun, Dongxue.,Xie, Cen.,Wang, Tianxia.,...&Gonzalez, Frank J..(2020).Rutaecarpine inhibits KEAP1-NRF2 interaction to activate NRF2 and ameliorate dextran sulfate sodium-induced colitis.FREE RADICAL BIOLOGY AND MEDICINE,148,33-41.
MLA	Zhang, Youbo,et al."Rutaecarpine inhibits KEAP1-NRF2 interaction to activate NRF2 and ameliorate dextran sulfate sodium-induced colitis".FREE RADICAL BIOLOGY AND MEDICINE 148(2020):33-41.