南方医科大学学报

南方医科大学学报 ›› 2024, Vol. 44 ›› Issue (11): 2209-2219.doi: 10.12122/j.issn.1673-4254.2024.11.18

• • 上一篇    

白花丹素通过抑制JAK2/STAT3通路减弱焦亡对抗脓毒症心肌损伤

杜若丽1,2(), 云琦2,3, 王奕人1,2, 窦欣雨4, 叶红伟1,2, 王佳慧2, 高琴1,2()   

  1. 1.蚌埠医科大学，生理学教研室，安徽 蚌埠 233030
    2.蚌埠医科大学，心脑血管疾病基础与临床重点实验室，安徽 蚌埠 233030
    3.蚌埠医科大学，生命科学学院，安徽 蚌埠 233030
    4.蚌埠医科大学，卫生管理学院，安徽 蚌埠 233030
  • 收稿日期:2024-08-10 出版日期:2024-11-20 发布日期:2024-11-29
  • 通讯作者: 高琴 E-mail:hello1112drl@126.com;bbmcgq@126.com
  • 作者简介:杜若丽，在读硕士研究生，E-mail: hello1112drl@126.com
  • 基金资助:
    安徽省教育厅研究生创新项目(2023xscx126);安徽省大学生创新创业项目(S202310367114)

Plumbagin protect against sepsis-induced myocardial injury in mice by inhibiting the JAK2/STAT3 signaling pathway to reduce cardiomyocyte pyroptosis

Ruoli DU1,2(), Qi YUN2,3, Yiren WANG1,2, Xinyu DOU4, Hongwei YE1,2, Jiahui WANG2, Qin GAO1,2()   

  1. 1.Department of Physiology, Bengbu Medical University, Bengbu 233030, China
    2.Key Laboratory of Preclinical and Clinical Research of Cardiovascular Diseases, Bengbu Medical University, Bengbu 233030, China
    3.School of Life Sciences, Bengbu Medical University, Bengbu 233030, China
    4.School of Health Management, Bengbu Medical University, Bengbu 233030, China
  • Received:2024-08-10 Online:2024-11-20 Published:2024-11-29
  • Contact: Qin GAO E-mail:hello1112drl@126.com;bbmcgq@126.com

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摘要：

目的 基于网络药理学探讨白花丹素是否通过减轻焦亡来抑制脓毒症心肌损伤的机制。 方法 通过网络药理学方法获得白花丹素与疾病的关键靶点，进行GO、KEGG分析，通过分子对接验证结合能。将小鼠随机分为4组，8只/组：Sham组、盲肠结扎组（CLP）、白花丹素（PLB，2 mg/kg）+CLP组和PLB（4 mg/kg）+CLP组。采用CLP诱导脓毒症小鼠心脏损伤。超声心动图和HE染色检测心肌功能和形态的变化；检测小鼠血清CK-MB、LDH、MDA和心肌ROS水平，ELISA检测小鼠血清IL-1β和IL-18水平。Western blotting测定心肌STAT3、GSDMD、Caspase-11、JAK2、P-STAT3、P-JAK2、GSDMD-N和HMGB1的蛋白水平。 结果 从交集的10个基因中筛选出5个核心靶点，分子对接显示，白花丹素与STAT3、p-STAT3和JAK2结合较好。与Sham组相比，CLP组的CO、LVEF、LVFS和SV水平下降（P<0.01）。血清 CK-MB、LDH、MDA、心肌炎症因子和ROS水平升高（P<0.01），HE染色结果显示心脏损伤；相关蛋白水平升高（P<0.05）。与CLP组相比，白花丹素处理组的心超功能指标水平升高（P<0.05）；血清 CK-MB、LDH、MDA、炎症因子和心肌ROS水平降低（P<0.01）；相关蛋白水平降低（P<0.05）。 结论 白花丹素减轻小鼠脓毒症心肌损伤作用，其机制可能与抑制STAT3减轻焦亡有关。

关键词: 白花丹素, 脓毒症心肌损伤, 焦亡, 网络药理学

Abstract:

Objective To explore the mechanism of plumbagin for protecting against sepsis-induced myocardial injury in mice. Methods Network pharmacology analysis was used to obtain the key targets of plumbagin and diseases, which were subjected to GO and KEGG analysis, and the binding energy was verified using molecular docking. In a mouse model of cecal ligation and puncture (CLP), the protective effect of plumbagin treatment prior to CLP against sepsis-induced myocardial injury was evaluated by examination of myocardial function and pathology using echocardiography and HE staining. Serum levels of CK-MB, LDH, MDA, IL-1β and IL-18 and myocardial ROS level in the mice were detected, and Western blotting was used to determine the protein expression levels of STAT3, GSDMD, caspase-11, JAK2, P-STAT3, P-JAK2, GSDMD-N and HMGB1 in the myocardial tissues. Results Five core targets were screened from the 10 intersecting genes. Molecular docking showed strong binding affinity of plumbagin to STAT3, p-STAT3, and JAK2. Compared with the sham-operated mice, the mouse models of CLP-induced sepsis had significantly decreased CO, LVEF, LVFS and SV and increased serum levels of CK-MB, LDH, MDA and myocardial inflammatory factors and ROS. HE staining and Western blotting showed obvious myocardial injury in the septic mice with increased expressions of JAK2/STAT3 signaling pathway and pyroptosis-related proteins (P<0.05). Pretreatment with plumbagin significantly improved cardiac functions of CLP mice, lowered serum levels of CK-MB, LDH, MDA, inflammatory factors and myocardial ROS, and decreased the expression levels of JAK2/STAT3 signaling pathway and pyroptosis-related proteins. Conclusion Plumbagin pretreatment alleviates myocardial injury in septic mice possibly by inhibiting the STAT3 signaling pathway to reduce cardiomyocyte pyroptosis.

Key words: plumbagin, sepsis induced myocardial injury, pyroptosis, network pharmacology