Chongqing Hospital of Traditional Chinese Medicine, No.6, Panxi 7th Road, Jiangbei District, Chongqing, 400021, China.
Cardiovasc Toxicol. 2024 Nov;24(11):1139-1150. doi: 10.1007/s12012-024-09917-7. Epub 2024 Sep 6.
Doxorubicin (Dox) has been limited in clinical application due to its cardiac toxicity that varies with the dose. This study aimed to explore how Rhein modulates Dox-induced myocardial toxicity. The general condition and echocardiographic changes of mice were observed to evaluate cardiac function and structure, with myocardial cell injury and apoptosis checked by TUNEL and HE staining. The ELISA assessed markers of myocardial damage and inflammation. The TCMSP and SwissTargetPrediction databases were used to retrieve Rhein's targets while GeneCards was used to find genes related to Dox-induced myocardial injury. Intersection genes were analyzed by Protein-Protein Interaction Networks. The core network genes underwent GO and KEGG enrichment analysis using R software. Western blot was used to detect protein expression. Compared to the Dox group, there was no remarkable difference in heart mass /body mass ratio in the Rhein+Dox group. However, heart mass/tibia length increased. Mice in the Rhein+Dox group had significantly increased LVEF, LVPWs, and LVFS compared to those in the Dox group. Myocardial cell damage, inflammation, and apoptosis significantly reduced in the Rhein+Dox group compared to the model group. Eleven core network genes were selected. Further, Rhein+Dox group showed significantly downregulated expression of p38/p-p38, HSP90AA1, c-Jun/p-c-Jun, c-Fos/p-c-Fos, Bax, and cleaved-caspase-3/caspase-3 while Bcl-2 expression significantly upregulated compared to the Dox group. The study suggests that Rhein mediates cardioprotection against Dox-induced myocardial injury, at least partly, by influencing multiple core genes in the MAPK signaling pathway to inhibit myocardial cell apoptosis.
多柔比星（Dox）由于其剂量相关的心脏毒性而在临床应用中受到限制。本研究旨在探讨瑞滨如何调节多柔比星诱导的心肌毒性。观察小鼠的一般情况和超声心动图变化，评估心脏功能和结构，通过 TUNEL 和 HE 染色检查心肌细胞损伤和凋亡。ELISA 评估心肌损伤和炎症的标志物。使用 TCMSP 和 SwissTargetPrediction 数据库检索瑞滨的靶点，使用 GeneCards 查找与多柔比星诱导的心肌损伤相关的基因。通过蛋白质-蛋白质相互作用网络分析交集基因。使用 R 软件对核心网络基因进行 GO 和 KEGG 富集分析。Western blot 用于检测蛋白表达。与 Dox 组相比，瑞滨+Dox 组的心脏质量/体重比无显著差异。然而，心脏质量/胫骨长度增加。与 Dox 组相比，瑞滨+Dox 组的 LVEF、LVPWs 和 LVFS 显著增加。与模型组相比，瑞滨+Dox 组的心肌细胞损伤、炎症和凋亡明显减少。选择了 11 个核心网络基因。进一步的，瑞滨+Dox 组与 Dox 组相比，p38/p-p38、HSP90AA1、c-Jun/p-c-Jun、c-Fos/p-c-Fos、Bax 和 cleaved-caspase-3/caspase-3 的表达明显下调，而 Bcl-2 的表达明显上调。研究表明，瑞滨通过影响 MAPK 信号通路中的多个核心基因来抑制心肌细胞凋亡，介导对多柔比星诱导的心肌损伤的心脏保护作用。
