Yang Fang, Luo Gang, Liu Meng-Nan, Liu Ping, Wu Dan, Chen Hao-Ling, Li Shan, Yang Si-Jin, Dong Li
National Traditional Chinese Medicine Clinical Research Base and Cardiology department of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China.
Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China.
PLoS One. 2025 May 15;20(5):e0323745. doi: 10.1371/journal.pone.0323745. eCollection 2025.
Diabetes cardiomyopathy (DCM) is a prevalent complication of diabetes, characterized by a multifaceted pathogenesis. Zhilong Huoxue Tongyu Capsule (ZL), a traditional Chinese medicine, is extensively employed for the treatment of cardiovascular diseases. Thus, this study aimed to comprehensively explore the mechanism of action of ZL on DCM.
Network pharmacology approaches were applied to predict the potential pathways and targets of ZL on DCM. Then, a DCM model mouse was constructed and divided into a control group, DCM group, DCM + ZL group, SB203580 group, and DCM + R group. The DCM + ZL group was administered 6.24g/kg/d ZL via gavage, the SB203580 group was given 1 mg/kg/d SB203580 (p38MAPK inhibitor) via intraperitoneal injection, the DCM + R group received 4 mg/kg/d rosiglitazone via gavage, and the control group and DCM group were given equal volume of physiological saline by gavage. The intervention period lasted for 6 weeks to verify these key targets.
Network pharmacology analyses identified 45 active ingredients in ZL linked to 719 potential targets, forming an herbal compound-target network. Screening of databases revealed 1032 DCM-related targets, with MAPK14, TNF, FOS, AKT1, and IL-10 emerging as key hub genes from PPI network analysis. Additionally, enrichment analysis indicated that the candidate targets were enriched in response to the MAPK signaling pathway. Finally, in vivo studies in DCM mice demonstrated that ZL significantly mitigated myocardial fibrosis and down-regulated the expression of p-P38MAPK, TNF-α, α-SMA, and Collagen-I proteins in myocardial tissue.
Our results collectively indicated that ZL can effectively ameliorate diabetes cardiomyopathy, possibly by modulating the P38MAPK signaling pathway.
糖尿病性心肌病（DCM）是糖尿病常见的并发症，其发病机制具有多方面特点。中药制剂芪龙活血通瘀胶囊（ZL）广泛用于治疗心血管疾病。因此，本研究旨在全面探究ZL对DCM的作用机制。
采用网络药理学方法预测ZL对DCM的潜在作用途径和靶点。然后，构建DCM模型小鼠并分为对照组、DCM组、DCM+ZL组、SB203580组和DCM+R组。DCM+ZL组通过灌胃给予6.24g/kg/d的ZL，SB203580组通过腹腔注射给予1mg/kg/d的SB203580（p38丝裂原活化蛋白激酶抑制剂），DCM+R组通过灌胃给予4mg/kg/d的罗格列酮，对照组和DCM组通过灌胃给予等量生理盐水。干预期持续6周以验证这些关键靶点。
网络药理学分析确定ZL中的45种活性成分与719个潜在靶点相关，形成了一个草药-化合物-靶点网络。数据库筛选显示1032个与DCM相关的靶点，通过蛋白质-蛋白质相互作用网络分析，发现丝裂原活化蛋白激酶14（MAPK14）、肿瘤坏死因子（TNF）、原癌基因FOS（FOS）、蛋白激酶B1（AKT1）和白细胞介素10（IL-10）为关键枢纽基因。此外，富集分析表明候选靶点在对丝裂原活化蛋白激酶信号通路的反应中富集。最后，在DCM小鼠中的体内研究表明，ZL显著减轻心肌纤维化，并下调心肌组织中磷酸化p38丝裂原活化蛋白激酶（p-P38MAPK）、肿瘤坏死因子-α（TNF-α）、α-平滑肌肌动蛋白（α-SMA）和I型胶原蛋白（Collagen-I）蛋白的表达。
我们的研究结果共同表明，ZL可能通过调节P38丝裂原活化蛋白激酶信号通路有效改善糖尿病性心肌病。
