文献类型：期刊文献

英文题名：Deciphering the active constituents of Dabushen decoction of ameliorating osteoarthritis via PPARγ preservation by targeting DNMT1

作者：Qiu, Lu[1,2];Zhang, Min[1,3];Li, Chenghao[1,2];Hou, Yehu[1,2];Liu, Hao[1,3];Lin, Jia[1,3];Yao, Juan[1,3];Duan, Dong Zhu[4,5];Zhang, Yi Xi[1,3];Li, Mi[1,3];Li, Ya Ling[1,2];Wang, Peng[1];Li, Jin Tian[2];Jin, Xiao Jie[1,2,3];Liu, Yong Qi[1,2]

第一作者：Qiu, Lu

通信作者：Jin, XJ[1];Liu, YQ[1];Jin, XJ[2];Liu, YQ[2];Jin, XJ[3]

机构：[1]Gansu Univ Chinese Med, Gansu Univ Key Lab Mol Med & Chinese Med Prevent &, Lanzhou, Peoples R China;[2]Gansu Univ Chinese Med, Key Lab Dunhuang Med, Minist Educ, Lanzhou, Peoples R China;[3]Gansu Univ Chinese Med, Coll Pharm, Lanzhou, Peoples R China;[4]Baoji Univ Arts & Sci, Shaanxi Key Lab Phytochemistry, Baoji, Peoples R China;[5]Baoji Univ Arts & Sci, Coll Chem & Chem Engn, Baoji, Peoples R China

第一机构：甘肃中医药大学

通信机构：[1]corresponding author), Gansu Univ Chinese Med, Gansu Univ Key Lab Mol Med & Chinese Med Prevent &, Lanzhou, Peoples R China;[2]corresponding author), Gansu Univ Chinese Med, Key Lab Dunhuang Med, Minist Educ, Lanzhou, Peoples R China;[3]corresponding author), Gansu Univ Chinese Med, Coll Pharm, Lanzhou, Peoples R China.|[1073501e14fb35863569f]甘肃中医药大学药学院（西北中藏药协同创新中心办公室）;[10735]甘肃中医药大学;

年份：2022

卷号：13

外文期刊名：FRONTIERS IN PHARMACOLOGY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000894975100001)】；

基金：Funding This study was supported by the National Natural Science Foundation of China (No. 81960823) and Provincial University Industry Support Project in Gansu (2020C-15).

语种：英文

外文关键词：traditional Chinese medicine; Dabushen decoction; osteoarthritis; epigenetics; Dnmt1; PPAR gamma

摘要：Osteoarthritis (OA) is a multifactorial and chronic degenerative joint disease. Due to the adverse effects of currently used drugs, a safer and more effective therapy for treating OA is needed. Peroxisome proliferator-activated receptor-gamma (PPAR gamma) is a key protein protecting cartilage. DNMT1-mediated hypermethylation of PPAR gamma promoter leads to its suppression. Therefore, DNMT1 might be an effective target for exerting cartilage protective effects by regulating the epigenetic expression of PPAR gamma. Dabushen decoction (DD) is a representative prescription of Dunhuang ancient medical prescription, which has a potential therapeutic effect on OA. So far, the research of the efficacy and material basis of DD in the treatment of OA remains unclear. In this study, Micro-CT, HE staining, S-O staining, and immunohistochemistry analysis were used to demonstrate that DD increased the expression of PPAR gamma and collagen synthesis in an OA rat model. Next, the structure of DNMT1 was used to screen the active constituents of DD by molecular docking method for treatment OA. Seven potential active constituents, including isoliquiritigenin, emodin, taxifolin, catalpol, alisol A, zingerone, and schisandrin C were hited. The protective effect of the potential active constituents to chondrocytes were evaluated by protein capillary electrophoresis, immunofluorescence assays, and ex vivo culture of rat knee cartilage. The five constituents, such as alisol A, emodin, taxifolin, isoliquiritigenin, and schisandrin C could promote the expression of PPAR gamma and ameliorate IL-1 beta-induced downregulation of collagen II and the production of MMP-13. Alisol A and Emodin could effectively mitigate cartilage damage. At last, molecular dynamics simulations with MM-GBSA method was applied to investigate the interaction pattern of the active constituents and DNMT1 complexes. The five constituents, such as alisol A, emodin, taxifolin, isoliquiritigenin, and schisandrin C achieved a stable binding pattern with DNMT1, in which alisol A has a relatively high binding free energy. In conclusion, this study elucidates that the active constituents of DD (alisol A, emodin, taxifolin, isoliquiritigenin, and schisandrin C) could ameliorate osteoarthritis via PPAR gamma preservation by targeting DNMT1. These findings facilitated clinical use of DD and provided a valuable strategy for developing natural epigenetic modulators from Chinese herbal formula.