Teaching and Research Department of Chinese Materia Medica Resources, College of Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China.
School of Pharmaceutical Sciences, Hubei University of Medicine, Shiyan, 442000, People's Republic of China; Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Shiyan, 442000, People's Republic of China.
J Ethnopharmacol. 2023 Oct 5;314:116574. doi: 10.1016/j.jep.2023.116574. Epub 2023 May 7.
Darutigenol (DL) is a natural active product derived from the Chinese herbal medicine Sigesbeckia glabrescens (Makino) Makino. It is administered as a traditional Chinese medicine (TCM) to dispel rheumatism, benefit the joints, and detoxify. However, its potential mechanism in the treatment of rheumatoid arthritis (RA) remains unknown.
The objectives of this research were to determine the effects and elucidate the modes of action of DL on RA-related joint inflammation.
Network pharmacology and molecular docking were used to screen and validate candidate DL targets for RA treatment, respectively. A DBA/1 mouse rheumatoid arthritis model was induced with bovine type II collagen. Intragastric DL administration was followed by the calculation of the clinical arthritis index. A section of the ankle joint was excised and stained and the pathological changes in it were observed. Enzyme-linked immunosorbent assays (ELISA) and western blotting (WB) were used to clarify the mechanisms of DL in RA treatment.
DL effectively attenuated the inflammation, mitigated the articular cartilage degradation, and bone erosion, and alleviated the inflammatory joints associated with RA. Network pharmacology screened six key targets of DL while molecular docking revealed that it docked well with its protein targets. The DL treatment group presented with significantly less ankle joint redness and swelling, a lower arthritis index scores and serum and bone marrow supernatant IL-6 levels, more complete ankle joint surfaces, and less synovial inflammation, cartilage degradation, and bone erosion than the collagen-induced arthritis (CIA) group. The DL treatment also substantially downregulated the Janus kinase (JAK)1, JAK3, matrix metalloproteinase (MMP)2, MMP9, and phospho-signal transducer and activator of transcription (p-STAT)3 proteins in the joints.
To the best of our knowledge, the present work was the first to demonstrate that DL has significant anti-inflammatory efficacy and reduces cartilage degradation and bone erosion. It also demonstrated that the anti-RA effect of DL may be explained by its ability to inhibit joint inflammation and reduce articular cartilage degradation through the interleukin (IL)-6/JAK1,3/STAT3 axis and downregulate MMP2 and MMP9. Hence, DL might play a therapeutic role in a mouse RA model.
独活酚（DL）是一种从中药豨莶草（Makino）中提取的天然活性产物。它被用作一种传统中药（TCM）来祛风、益关节和解毒。然而，其在治疗类风湿关节炎（RA）方面的潜在机制尚不清楚。
本研究旨在确定 DL 对 RA 相关关节炎症的作用，并阐明其作用机制。
分别采用网络药理学和分子对接技术筛选和验证 DL 治疗 RA 的候选靶点。用牛Ⅱ型胶原诱导 DBA/1 小鼠类风湿关节炎模型。灌胃 DL 后，计算临床关节炎指数。切除踝关节并染色，观察其病理变化。采用酶联免疫吸附试验（ELISA）和蛋白质印迹法（WB）阐明 DL 治疗 RA 的机制。
DL 有效减轻了炎症，缓解了软骨降解和骨侵蚀，减轻了与 RA 相关的炎症关节。网络药理学筛选出 DL 的 6 个关键靶点，分子对接显示其与蛋白靶点结合良好。DL 治疗组的踝关节红肿、关节炎指数评分、血清和骨髓上清液 IL-6 水平均明显降低，踝关节表面更完整，滑膜炎症、软骨降解和骨侵蚀程度均低于胶原诱导关节炎（CIA）组。DL 治疗还显著下调了关节中的 Janus 激酶（JAK）1、JAK3、基质金属蛋白酶（MMP）2、MMP9 和磷酸信号转导和转录激活因子（p-STAT）3 蛋白。
据我们所知，本研究首次证明 DL 具有显著的抗炎作用，可减少软骨降解和骨侵蚀。它还表明，DL 通过白细胞介素（IL）-6/JAK1、3/STAT3 轴抑制关节炎症和减少软骨降解，下调 MMP2 和 MMP9，从而降低关节炎的严重程度，发挥其在 RA 中的治疗作用。因此，DL 可能在小鼠 RA 模型中发挥治疗作用。
