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Title: [Tujia medicine Toddalia asiatica improves synovial pannus in rats with collagen-induced arthritis through the PI3K/Akt signaling pathway].
Author: Xiang S, Zhang Z, Jiang L, Liu D, Li W, Bao Z, Tian R, Cheng D, Yuan L.
Journal: Nan Fang Yi Ke Da Xue Xue Bao; 2024 Aug 20; 44(8):1582-1588. PubMed ID: 39276054.
Abstract:
OBJECTIVE: To investigate the therapeutic mechanism of Tujia medicine Toddalia asiatica alcohol extract (TAAE) for synovial pannus formation in rats with college-induced arthritis (CIA). METHODS: Sixty male SD rats were randomized into normal control group, CIA model group, TGT group, 3 TAAE treatment groups at low, medium and high doses (n=10). Except for those in the normal control group, all the rats were subjected to CIA modeling using a secondary immunization method and treatment with saline, TGT or TAAE by gavage once daily for 35 days. The severity of arthritis was assessed using arthritis index (AI) score, and knee joint synovium pathologies were examined with HE staining. Serum levels of TNF-α, IL-6, and IL-1β were detected with ELISA; the protein expressions of PI3K, Akt, p-PI3K, p-Akt, VEGF, endostatin, HIF-1α, MMP1, MMP3, and MMP9 in knee joint synovial tissues were determined using Western blotting, and the mRNA expressions of TNF‑α, IL-6, IL-1β, VEGF, HIF-1α, PI3K, and Akt were detected with RT-PCR. RESULTS: Treatment of CIA rat models with TAAE and TGT significantly alleviated paw swelling, lowered AI scores, and reduced knee joint pathology, neoangiogenesis, and serum levels of inflammatory factors. TAAE treatment obviously increased endostatin protein expression, downregulated p-PI3K, p-Akt, MMP1, MMP3, MMP9, VEGF, and HIF-1α proteins, and reduced TNF‑α, IL-6, IL-1β, PI3K, Akt, VEGF, and HIF-1α mRNA levels in the synovial tissues, and these changes were comparable between high-dose TAAE group and TGT group. CONCLUSION: TAAE can improve joint symptoms and inhibit synovial pannus formation in CIA rats by regulating the expressions of HIF-1α, VEGF, endostatin, MMP1, MMP3, and MMP9 via the PI3K/Akt signalling pathway. 目的: 探讨三百棒醇提物（TAAE）通过PI3K/Akt信号通路改善胶原诱导性（CIA）大鼠血管翳的治疗作用及其机制。方法: 将60只雄性SD大鼠随机分为正常组、模型组、雷公藤多苷片组（TGT）、三百棒醇提物低剂量组（TAAE-L）、三百棒醇提物中剂量组（TAAE-M）、三百棒醇提物高剂量组（TAAE-H），10只/组。除正常组外，对其余大鼠采用二次免疫法建立CIA大鼠模型。二次免疫结束后，三百棒醇提物组和雷公藤多苷组按相应剂量灌胃给药，1次/d，连续35 d。采用关节炎指数（AI）评分评估大鼠关节炎症程度；HE染色法观察膝关节滑膜病理变化；ELISA检测细胞因子（TNF-α、IL-6、IL-1β）的水平；Western blotting法检测各组大鼠滑膜组织中 PI3K、Akt、p-PI3K、p-Akt、血管内皮生长因子（VEGF）、血管内皮抑制因子内皮抑素（ES）、缺氧诱导因子1-α（HIF-1α）、基质金属蛋白酶（MMP1、MMP3、MMP9）蛋白含量的变化；RT-PCR检测各组大鼠滑膜组织中TNF-α、IL-6、IL-1β、VEGF、HIF-1α、PI3K、Akt mRNA水平。结果: 与模型组相比较，TAAE和TGT组大鼠的足肿胀度和AI评分降低（P<0.05），膝关节病理变化明显改善，新生血管生成减少，血清中炎症因子（TNF-α、IL-6、IL-1β）水平降低（P<0.01）。Western blotting实验结果显示，与模型组相比较，TAAE的干预上调ES蛋白水平，下调p-PI3K、p-Akt、MMP1、MMP3、MMP9、VEGF、HIF-1α蛋白水平，差异有统计学意义（P<0.05，P<0.01）。TAAE还降低了TNF-α、IL-6、IL-1β、PI3K、Akt、VEGF、HIF-1α mRNA水平，差异有统计学意义（P<0.05，P<0.01）。TAAE-H组与TGT组相比较，差异无统计学意义（P>0.05）。结论: TAAE可通过PI3K/Akt信号通路调控HIF-1α、VEGF、ES、MMP1、MMP3、MMP9等蛋白的表达，改善CIA大鼠关节症状，抑制RA血管翳形成。

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