目的 探讨大戟二烯醇（EUP）对类风湿性关节炎（RA）的防治作用及机制。方法 将雄性大鼠随机分为6组，每组8只，分别为对照组、模型组、雷公藤多苷（TG，阳性药，7.5 mg·kg^-1）组和EUP低、中、高剂量（16、32、64 mg·kg^-1）组，除对照组外，其余大鼠右后足趾sc 0.2 mL弗氏完全佐剂（FCA）制备佐剂性关节炎（AA）模型，造模后第2天开始给药，TG组和EUP组按相应剂量ig给药，每天1次，连续ig给药30 d。实验期间测量大鼠体质量和足趾肿胀度并进行关节指数评分；给药结束后，采用苏木精-伊红（HE）染色观察大鼠踝关节组织病理学变化； ELISA法检测大鼠血清中类风湿因子（RF）、C反应蛋白（CRP）、肿瘤坏死因子α（TNF-α）、白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）的含量； Westernblotting法检测大鼠关节组织中磷脂酰肌醇3-激酶（PI3K）、蛋白激酶B（Akt）、磷酸化蛋白激酶B（p-Akt）、哺乳动物雷帕霉素靶蛋白（mTOR）、磷酸化哺乳动物雷帕霉素靶蛋白（p-mTOR）、缺氧诱导因子1α（HIF-1α）、血管内皮生长因子受体2（VEGFR2）、血管生成素2（ANG2）蛋白的表达。结果 与模型组相比，经EUP治疗后，大鼠双侧后肢肿胀程度明显减轻，关节炎评分显著下降（P＜0.001），关节组织病变程度有所改善；大鼠血清中RF、CRP、TNF-α、IL-1β、IL-6水平显著降低（P＜0.05、0.01、0.001），关节组织中PI3K蛋白表达及p-Akt/Akt、p-mTOR/mTOR比值明显下调，HIF-1α、VEGFR2、ANG2蛋白表达明显下调（P＜0.05、0.01）。结论 EUP有较好的抗RA活性，其作用机制可能与PI3K/Akt/mTOR、HIF-1α/VEGFR2/ANG2信号通路有关。

Objective To investigate the preventive and therapeutic effects of euphol (EUP) on rheumatoid arthritis (RA) and its underlying mechanism. Methods Male rats were randomly divided into six groups, with 8 rats in each group, namely the control group, the model group, the tripterygium glycosides (TG, positive drug, 7.5 mg·kg^-1) group, and the low-, medium-, and high-dose EUP (16, 32, and 64 mg·kg^-1) groups. Except for the control group, the right hind toe of the remaining rats was subcutaneously injected with 0.2 mL of complete Freund's adjuvant (FCA) to establish adjuvant arthritis (AA) models. Administration began on the second day after modeling. The TG and EUP groups were administered the corresponding doses ig once a day for 30 consecutive days. During the experiment, the body weight and toe swelling degree of the rats were measured, and the arthritis index was scored. After administration, hematoxylin-eosin (HE) staining was used to observe the histopathological changes of the rat ankle joint. The levels of rheumatoid factor (RF), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-1β (IL^-1β), and interleukin-6 (IL-6) in the rat serum were detected by ELISA. The expressions of phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), phosphorylated protein kinase B (p-Akt), mammalian target of rapamycin (mTOR), phosphorylated mammalian target of rapamycin (p-mTOR), hypoxia-inducible factor 1α (HIF-1α), vascular endothelial growth factor receptor 2 (VEGFR2), and angiopoietin 2 (ANG2) proteins in the rat joint tissues were detected by Western blotting. Results Compared with the model group, after treatment with EUP, the swelling degree of the bilateral hind limbs of the rats was significantly reduced, and the arthritis score was significantly decreased (P<0.001). The degree of joint tissue lesions was improved. The levels of RF, CRP, TNF-α, IL^-1β, and IL-6 in the rat serum were significantly decreased (P<0.05, 0.01, 0.001), PI3K expression and the p-Akt/Akt and pmTOR/mTOR ratios in joint tissues were significantly decreased, while the protein expressions of HIF-1α, VEGFR2, and ANG2 were also downregulated (P<0.05, 0.01). Conclusion EUP exhibits potent anti-RA activity, which may be associated with inhibition of the PI3K/Akt/mTOR and HIF-1α/VEGFR2/ANG2 signaling pathways.

R965

国家自然科学基金资助项目（82360764）