Wang Shuhui, Huang Zheng, Lei Yu, Han Xu, Tian Dean, Gong Jin, Liu Mei
Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Front Pharmacol. 2022 Mar 10;13:816350. doi: 10.3389/fphar.2022.816350. eCollection 2022.
This work aims to explore the potential targets and underlying therapeutic mechanisms of celastrol in autoimmune hepatitis (AIH) through network pharmacology and experiments on Laboratory Animals. A drug-target interaction network was constructed to predict the possible targets of celastrol and their potential relationship with the drug; docking studies were also performed for validation. This study used both acute and chronic rodent models of autoimmune hepatitis. Gross appearance of liver and spleen were obtained from murine models, hematoxylin-eosin staining and Sirius red staining were performed to examine hepatic inflammation and fibrosis respectively. By combining molecular docking and enrichment analysis results, the most prominent signaling pathway was selected and further confirmed by Western blot in AIH models administered with celastrol. In total, 82 common targets of celastrol and AIH were obtained from databases, identified by network pharmacology, and adequately enriched. Among them, PIK3R1, SRC, MAPK1, AKT1, and HRAS were selected as the top 5 closely related targets to celastrol. They all performed effectively in molecular docking, with AKT1 and PIK3R1 exhibiting more-prominent binding energy. Subsequently, celastrol administration significantly ameliorated hepatitis and liver fibrosis by reducing AKT1 and PI3K phosphorylation in both acute liver injury and chronic models of autoimmune hepatitis. In summary, celastrol significantly attenuates autoimmune hepatitis by suppressing the PI3K/AKT signaling pathway, confirmed by validated animal models. These findings may help identify the mechanism involved in the anti-inflammatory action of celastrol in autoimmune hepatitis and provide ideas for future comprehensive studies.
本研究旨在通过网络药理学和实验动物实验，探索雷公藤红素在自身免疫性肝炎（AIH）中的潜在靶点和潜在治疗机制。构建药物-靶点相互作用网络，以预测雷公藤红素的可能靶点及其与药物的潜在关系；还进行了对接研究以进行验证。本研究使用了自身免疫性肝炎的急性和慢性啮齿动物模型。从鼠模型获取肝脏和脾脏的大体外观，分别进行苏木精-伊红染色和天狼星红染色以检查肝脏炎症和纤维化。通过结合分子对接和富集分析结果，选择最突出的信号通路，并在给予雷公藤红素的AIH模型中通过蛋白质免疫印迹进一步证实。通过网络药理学从数据库中总共获得了82个雷公藤红素和AIH的共同靶点，进行了鉴定并充分富集。其中，PIK3R1、SRC、MAPK1、AKT1和HRAS被选为与雷公藤红素关系最密切的前5个靶点。它们在分子对接中均表现有效，AKT1和PIK3R1表现出更显著的结合能。随后，在急性肝损伤和自身免疫性肝炎慢性模型中，雷公藤红素给药均通过降低AKT1和PI3K磷酸化显著改善肝炎和肝纤维化。总之，经验证的动物模型证实，雷公藤红素通过抑制PI3K/AKT信号通路显著减轻自身免疫性肝炎。这些发现可能有助于确定雷公藤红素在自身免疫性肝炎中抗炎作用的机制，并为未来的综合研究提供思路。
