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Rutaecarpine inhibits KEAP1-NRF2 interaction to activate NRF2 and ameliorate dextran sulfate sodium-induced colitis.
Free Radical Biology and Medicine ( IF 7.1 ) Pub Date : 2019-12-21 , DOI: 10.1016/j.freeradbiomed.2019.12.012 Youbo Zhang 1 , Tingting Yan 2 , Dongxue Sun 3 , Cen Xie 2 , Tianxia Wang 4 , Xiaoyan Liu 5 , Jing Wang 5 , Qiong Wang 2 , Yuhong Luo 2 , Ping Wang 2 , Tomoki Yagai 2 , Kristopher W Krausz 2 , Xiuwei Yang 5 , Frank J Gonzalez 2
Free Radical Biology and Medicine ( IF 7.1 ) Pub Date : 2019-12-21 , DOI: 10.1016/j.freeradbiomed.2019.12.012 Youbo Zhang 1 , Tingting Yan 2 , Dongxue Sun 3 , Cen Xie 2 , Tianxia Wang 4 , Xiaoyan Liu 5 , Jing Wang 5 , Qiong Wang 2 , Yuhong Luo 2 , Ping Wang 2 , Tomoki Yagai 2 , Kristopher W Krausz 2 , Xiuwei Yang 5 , Frank J Gonzalez 2
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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 Kd of 19.6 μM. 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.
中文翻译：
Rutaecarpine抑制KEAP1-NRF2相互作用以激活NRF2并改善硫酸葡聚糖钠引起的结肠炎。
炎症性肠病（IBD）代表一组慢性复发性肠道疾病。据报道，从吴茱E的中药（TCM）中分离得到的芸香果碱（RUT）可抑制IBD。但是，RUT改善硫酸葡聚糖硫酸钠（DSS）诱导的IBD的机制尚不清楚。通过使用核因子-类胡萝卜素2相关因子2（NRF2）敲除小鼠，基于细胞的研究，表面等离振子共振（SPR），蛋白质印迹分析和分子对接研究，RUT影响DSS诱导的结肠炎的机制是探索。在DSS治疗的野生型小鼠中，但在Nrf2无效的小鼠中却没有，RUT可以显着改善结肠炎，这可以通过减轻体重，改善组织学和炎症以及诱导NRF2靶基因在结肠和回肠中的表达来揭示。基于细胞的研究表明，RUT显着增加了过氧化氢（H2O2）诱导的细胞损伤，激活NRF2核易位的LD50，并抑制了H2O2处理的HCT116细胞中活性氧的产生，并激活了HCT116细胞中的NRF2荧光素酶报告基因活性。和HepG2细胞，并诱导NRF2靶基因在原代肠上皮细胞中的表达。在计算机和SPR中进行的分子对接分析表明RUT与海藻样ECH相关蛋白1（KEAP1）相互作用，并且细胞外温育研究表明RUT结合到KEAP1海藻结构域，计算出的平衡解离常数Kd为19.6μM。总之，这些结果表明，RUT可以缓解DSS所致的结肠炎（取决于NRF2），并且可能是IBD患者的潜在治疗选择。
更新日期：2019-12-23
中文翻译：
Rutaecarpine抑制KEAP1-NRF2相互作用以激活NRF2并改善硫酸葡聚糖钠引起的结肠炎。
炎症性肠病（IBD）代表一组慢性复发性肠道疾病。据报道，从吴茱E的中药（TCM）中分离得到的芸香果碱（RUT）可抑制IBD。但是，RUT改善硫酸葡聚糖硫酸钠（DSS）诱导的IBD的机制尚不清楚。通过使用核因子-类胡萝卜素2相关因子2（NRF2）敲除小鼠，基于细胞的研究，表面等离振子共振（SPR），蛋白质印迹分析和分子对接研究，RUT影响DSS诱导的结肠炎的机制是探索。在DSS治疗的野生型小鼠中，但在Nrf2无效的小鼠中却没有，RUT可以显着改善结肠炎，这可以通过减轻体重，改善组织学和炎症以及诱导NRF2靶基因在结肠和回肠中的表达来揭示。基于细胞的研究表明，RUT显着增加了过氧化氢（H2O2）诱导的细胞损伤，激活NRF2核易位的LD50，并抑制了H2O2处理的HCT116细胞中活性氧的产生，并激活了HCT116细胞中的NRF2荧光素酶报告基因活性。和HepG2细胞，并诱导NRF2靶基因在原代肠上皮细胞中的表达。在计算机和SPR中进行的分子对接分析表明RUT与海藻样ECH相关蛋白1（KEAP1）相互作用，并且细胞外温育研究表明RUT结合到KEAP1海藻结构域，计算出的平衡解离常数Kd为19.6μM。总之，这些结果表明，RUT可以缓解DSS所致的结肠炎（取决于NRF2），并且可能是IBD患者的潜在治疗选择。
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