红参总皂苷对佐剂性关节炎大鼠及类风湿关节炎成纤维样滑膜细胞的抗类风湿关节炎作用。
Anti-rheumatoid arthritis effects of total saponins from Rhizoma Panacis Majoris on adjuvant-induced arthritis in rats and rheumatoid arthritis fibroblast-like synoviocytes.
机构信息
Co-Construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi and Education Ministry, State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xianyang 712083, PR China.
Co-Construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi and Education Ministry, State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xianyang 712083, PR China.
出版信息
Phytomedicine. 2023 Oct;119:155021. doi: 10.1016/j.phymed.2023.155021. Epub 2023 Aug 14.
BACKGROUND
Total saponins from Rhizoma Panacis Majoris (RPMTG) showed significant antitumour activity in our previous studies. Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) with tumour-like characteristics have received attention as a therapeutic target for RA. However, the potential effect and mechanism of action of RPMTG against RA-FLS remain unclear.
OBJECTIVE
The study investigated the therapeutic effect of RPMTG on adjuvant-induced arthritis (AIA) in rats, and the regulation effect and underlying mechanism on apoptosis, autophagy of RA-FLS.
METHODS
The therapeutic effect of RPMTG was determined by the symptoms and signs of AIA rats. The production of inflammatory cytokines was detected by ELISA. Histopathological change of the ankle and synovial tissues were detected by HE staining. Flow cytometry, Hoechst 33342/PI staining, MDC staining, and TEM were used to determine the effects of RPMTG on apoptosis and autophagy. Western blotting was applied to detect the expression levels of proteins.
RESULTS
In AIA rats, RPMTG treatment ameliorated paw swelling, and arthritis score, restored synovial histopathological changes, inhibited the expression of IL-6 and IL-1β, exhibiting its potent anti-arthritis effect. In vitro, RPMTG depressed the proliferation of RA-FLS, arrested cell cycle in G0/G1 phase, and induced mitochondria-mediated apoptosis. Moreover, RPMTG significantly inhibited the autophagy in vivo and in vitro, proved by decreasing the expression of autophagy-related indicators (LC3II/LC3I, Beclin-1). Mechanistically, the study demonstrated that the activation of p38 MAPK and PI3K/Akt/mTOR pathways was mainly involved in the therapeutic effects of RPMTG. Interestingly, the effect of RPMTG on apoptosis was reversed after Rapamycin treatment, which preliminarily demonstrated that the inhibitory effect of RPMTG on autophagy was beneficial to the effect on inducing apoptosis. The regulation effect of RPMTG concurrently on apoptosis and autophagy revealed its unique advantages in RA treatment.
CONCLUSION
RPMTG showed potent therapeutic effects on AIA rats and induced apoptosis, inhibited autophagy mainly through activating the p38 MAPK and PI3K/Akt/mTOR pathways in RA-FLS.
背景
在我们之前的研究中，人参总皂苷（RPMTG）表现出显著的抗肿瘤活性。具有肿瘤样特征的类风湿关节炎成纤维样滑膜细胞（RA-FLS）作为类风湿关节炎的治疗靶点受到了关注。然而，RPMTG 对 RA-FLS 的潜在作用和作用机制尚不清楚。
目的
本研究探讨了 RPMTG 对佐剂诱导关节炎（AIA）大鼠的治疗作用，以及对 RA-FLS 凋亡、自噬的调节作用及其机制。
方法
通过 AIA 大鼠的症状和体征来确定 RPMTG 的治疗效果。通过 ELISA 检测炎症细胞因子的产生。用 HE 染色检测踝关节和滑膜组织的组织学变化。流式细胞术、Hoechst 33342/PI 染色、MDC 染色和 TEM 用于确定 RPMTG 对凋亡和自噬的影响。Western blot 用于检测蛋白表达水平。
结果
在 AIA 大鼠中，RPMTG 治疗改善了爪肿胀和关节炎评分，恢复了滑膜组织学变化，抑制了 IL-6 和 IL-1β的表达，表现出其强大的抗关节炎作用。在体外，RPMTG 抑制 RA-FLS 的增殖，将细胞周期阻滞在 G0/G1 期，并诱导线粒体介导的细胞凋亡。此外，RPMTG 显著抑制体内和体外的自噬，这一点通过降低自噬相关指标（LC3II/LC3I、Beclin-1）的表达得到证实。机制上，研究表明 p38 MAPK 和 PI3K/Akt/mTOR 通路的激活主要参与了 RPMTG 的治疗作用。有趣的是，在雷帕霉素处理后，RPMTG 对细胞凋亡的作用被逆转，这初步表明 RPMTG 对自噬的抑制作用有利于诱导细胞凋亡的作用。RPMTG 对凋亡和自噬的同时调节作用揭示了其在 RA 治疗中的独特优势。
结论
RPMTG 对 AIA 大鼠表现出强大的治疗作用，并通过激活 RA-FLS 中的 p38 MAPK 和 PI3K/Akt/mTOR 通路诱导细胞凋亡，抑制自噬。
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