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Deciphering the active constituents of Dabushen decoction of ameliorating osteoarthritis via PPARγ preservation by targeting DNMT1

Affiliation
Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine ,Lanzhou ,China
Qiu, Lu;
Affiliation
Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine ,Lanzhou ,China
Zhang, Min;
Affiliation
Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine ,Lanzhou ,China
Li, Chenghao;
Affiliation
Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine ,Lanzhou ,China
Hou, Yehu;
Affiliation
Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine ,Lanzhou ,China
Liu, Hao;
Affiliation
Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine ,Lanzhou ,China
Lin, Jia;
Affiliation
Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine ,Lanzhou ,China
Yao, Juan;
Affiliation
Shaanxi Key Laboratory of Phytochemistry and College of Chemistry and Chemical Engineering, Baoji University of Arts and Sciences ,Baoji ,China
Duan, Dong Zhu;
Affiliation
Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine ,Lanzhou ,China
Zhang, Yi Xi;
Affiliation
Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine ,Lanzhou ,China
Li, Mi;
Affiliation
Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine ,Lanzhou ,China
Li, Ya Ling;
Affiliation
Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine ,Lanzhou ,China
Wang, Peng;
Affiliation
Key Laboratory of Dunhuang Medicine, Ministry of Education, Gansu University of Chinese Medicine ,Lanzhou ,China
Li, Jin Tian;
Affiliation
Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine ,Lanzhou ,China
Jin, Xiao Jie;
Affiliation
Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine ,Lanzhou ,China
Liu, Yong Qi

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-γ (PPARγ) is a key protein protecting cartilage. DNMT1-mediated hypermethylation of PPARγ promoter leads to its suppression. Therefore, DNMT1 might be an effective target for exerting cartilage protective effects by regulating the epigenetic expression of PPARγ. 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 PPARγ 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 PPARγ and ameliorate IL-1β-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 PPARγ 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.

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License Holder: Copyright © 2022 Qiu, Zhang, Li, Hou, Liu, Lin, Yao, Duan, Zhang, Li, Li, Wang, Li, Jin and Liu.

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