Background

Jolkinolide B (JB), an ent‑abietane-type diterpenoid in Euphorbia plants, has various pharmacological activities, including anticancer, anti-inflammatory, and anti-tuberculosis activities. However, no previous studies have proven whether JB can be regarded as a targeted drug for the treatment of rheumatoid arthritis (RA).

Purpose

This study aimed to evaluate the anti-RA effects of JB and explore the potential mechanisms.

Methods

Components and targets of JB and RA were identified in different databases, and potential targets and pathways were predicted by protein-protein interaction (PPI) network analysis and pathway enrichment analysis. Then, molecular docking and surface-plasmon resonance (SPR) were used to confirm the predict. The anti-arthritic effects of JB were studied in vivo with collagen-induced arthritis (CIA) rat model and in vitro with lipopolysaccharide (LPS) and interleukin-6 (IL-6)-induced RAW264.7 macrophage. Potential mechanisms were further verified by in vivo and in vitro experiments.

Results

The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that Th17 cell differentiation, prolactin signaling pathway, and JAK/STAT signaling pathway might be associated with anti-RA effects of JB. Molecular docking and SPR results showed that JB bound effectively to JAK2. JB significantly decreased body weight loss, arthritis index, paw thickness, and synovial thickness in CIA rats. Histomorphological results suggested the protective effects of JB on CIA rats with ankle joint injury. Molecular biology analysis indicated that JB suppressed the mRNA expression of inflammatory factors in ankle joints for CIA rats and reduced the concentration of these factors in LPS- induced RAW264.7 macrophage. The protein expression level of the JAK2/STAT3 pathway was also significantly decreased by JB.

Conclusion

JB had a novel inhibitory effect on inflammation and bone destruction in CIA rats, and the mechanism might be related to the JAK2/STAT3 signaling pathway.

中文翻译：

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Jolkinolide B 通过调节 JAK2/STAT3 信号通路改善类风湿性关节炎

背景

Jolkinolide B (JB) 是大戟属植物中的一种ent ‑abietane 型二萜类化合物，具有多种药理活性，包括抗癌、抗炎和抗结核活性。然而，此前还没有研究证明JB是否可以作为治疗类风湿性关节炎（RA）的靶向药物。

目的

本研究旨在评估 JB 的抗 RA 作用并探讨其潜在机制。

方法

在不同的数据库中鉴定了JB和RA的成分和靶点，并通过蛋白质-蛋白质相互作用（PPI）网络分析和通路富集分析预测了潜在的靶点和通路。然后，分子对接和表面等离子共振（SPR）被用来证实预测。JB 的抗关节炎作用通过胶原诱导关节炎 (CIA) 大鼠模型进行体内研究，并通过脂多糖 (LPS) 和白细胞介素 6 (IL-6) 诱导的 RAW264.7 巨噬细胞进行体外研究。通过体内和体外实验进一步验证了潜在的机制。

结果

京都基因与基因组百科全书（KEGG）分析表明，Th17细胞分化、催乳素信号通路和JAK/STAT信号通路可能与JB的抗RA作用有关。分子对接和SPR结果表明JB与JAK2有效结合。JB 显着降低 CIA 大鼠的体重减轻、关节炎指数、爪子厚度和滑膜厚度。组织形态学结果提示JB对CIA大鼠踝关节损伤具有保护作用。分子生物学分析表明，JB 抑制 CIA 大鼠踝关节炎症因子 mRNA 表达，并降低 LPS 诱导的 RAW264.7 巨噬细胞中这些因子的浓度。JB 也显着降低了 JAK2/STAT3 通路的蛋白表达水平。

结论

JB对CIA大鼠炎症和骨破坏具有新颖的抑制作用，其机制可能与JAK2/STAT3信号通路有关。