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Deciphering the active constituents of Dabushen decoction of ameliorating osteoarthritis via PPARγ preservation by
Lu Qiu1,2, Min Zhang1,3, Chenghao Li1,2
1Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, China.
Abstract:
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.
Insights
Dabushen decoction (DD) ameliorates osteoarthritis by preserving cartilage protective protein PPARγ. Active compounds in DD target DNMT1, offering a natural epigenetic strategy for OA treatment.
Area of Science:
- Epigenetics and Molecular Biology
- Pharmacology and Traditional Chinese Medicine
- Biochemistry and Structural Biology
Background:
- Osteoarthritis (OA) is a degenerative joint disease with limited safe and effective treatments.
- Current OA therapies have adverse effects, necessitating novel approaches.
- Peroxisome proliferator-activated receptor-γ (PPARγ) is crucial for cartilage protection, but its expression is suppressed by DNMT1-mediated hypermethylation.
Purpose of the Study:
- To investigate the therapeutic potential of Dabushen decoction (DD) for osteoarthritis.
- To identify the active constituents of DD and elucidate their mechanism of action.
- To explore DD's role in regulating epigenetic expression of PPARγ via DNMT1.
Main Methods:
- Osteoarthritis rat model creation and assessment using Micro-CT, HE, S-O staining, and immunohistochemistry.
- Molecular docking to screen active constituents of DD targeting DNMT1.
- In vitro evaluation of chondrocyte protection using protein capillary electrophoresis, immunofluorescence, and ex vivo cartilage culture.
- Molecular dynamics simulations to analyze binding interactions between active constituents and DNMT1.
Main Results:
- DD treatment increased PPARγ expression and collagen synthesis in OA rats.
- Five active constituents (alisol A, emodin, taxifolin, isoliquiritigenin, schisandrin C) were identified with chondroprotective effects.
- These constituents promoted PPARγ expression, counteracted IL-1β-induced downregulation of collagen II and MMP-13 production.
- Alisol A and Emodin demonstrated significant mitigation of cartilage damage.
- The five constituents exhibited stable binding with DNMT1, with alisol A showing high binding free energy.
Conclusions:
- Active constituents of DD, particularly alisol A and emodin, ameliorate osteoarthritis by preserving PPARγ through DNMT1 inhibition.
- This study provides a scientific basis for the clinical use of DD in OA treatment.
- The findings highlight a promising strategy for developing natural epigenetic modulators from traditional Chinese medicine for OA.
