Yang Ling, Jian Yang, Zhang Zai-Yuan, Qi Bao-Wen, Li Yu-Bo, Long Pan, Yang Yao, Wang Xue, Huang Shuo, Huang Jing, Zhou Long-Fu, Ma Jie, Jiang Chang-Qing, Hu Yong-He, Xiao Wen-Jing
School of Clinical Medicine, Chengdu University of TCM, Chengdu 610072, Sichuan Province, China.
Department of Clinical Pharmacy, The General Hospital of Western Theater Command, Chengdu 610083, Sichuan Province, China.
World J Diabetes. 2023 Jul 15;14(7):1057-1076. doi: 10.4239/wjd.v14.i7.1057.
Patients with diabetes mellitus are at higher risk of myocardial ischemia/ reperfusion injury (MI/RI). Shuxin decoction (SXT) is a proven recipe modi-fication from the classic herbal formula "Wu-tou-chi-shi-zhi-wan" according to the traditional Chinese medicine theory. It has been successfully used to alleviate secondary MI/RI in patients with diabetes mellitus in the clinical setting. However, the underlying mechanism is still unclear.
To further determine the mechanism of SXT in attenuating MI/RI associated with diabetes.
This paper presents an ensemble model combining network pharmacology and biology. The Traditional Chinese Medicine System Pharmacology Database was accessed to select key components and potential targets of the SXT. In parallel, therapeutic targets associated with MI/RI in patients with diabetes were screened from various databases including Gene Expression Omnibus, DisGeNet, Genecards, Drugbank, OMIM, and PharmGKB. The potential targets of SXT and the therapeutic targets related to MI/RI in patients with diabetes were intersected and subjected to bioinformatics analysis using the Database for Annotation, Visualization and Integrated Discovery. The major results of bioinformatics analysis were subsequently validated by animal experiments.
According to the hypothesis derived from bioinformatics analysis, SXT could possibly ameliorate lipid metabolism disorders and exert anti-apoptotic effects in MI/RI associated with diabetes by reducing oxidized low density lipoprotein (LDL) and inhibiting the advanced glycation end products (AGE)-receptor for AGE (RAGE) signaling pathway. Subsequent animal experiments confirmed the hypothesis. The treatment with a dose of SXT (2.8 g/kg/d) resulted in a reduction in oxidized LDL, AGEs, and RAGE, and regulated the level of blood lipids. Besides, the expression of apoptosis-related proteins such as Bax and cleaved caspase 3 was down-regulated, whereas Bcl-2 expression was up-regulated. The findings indicated that SXT could inhibit myocardial apoptosis and improve cardiac function in MI/RI in diabetic rats.
This study indicated the active components and underlying molecular therapeutic mechanisms of SXT in MI/RI with diabetes. Moreover, animal experiments verified that SXT could regulate the level of blood lipids, alleviate cardiomyocyte apoptosis, and improve cardiac function through the AGE-RAGE signaling pathway.
糖尿病患者发生心肌缺血/再灌注损伤（MI/RI）的风险更高。舒心汤（SXT）是根据中医理论对经典中药方剂“乌头赤石脂丸”进行改良而来的验方。在临床中，它已成功用于减轻糖尿病患者的继发性MI/RI。然而，其潜在机制仍不清楚。
进一步确定舒心汤减轻糖尿病相关MI/RI的机制。
本文提出了一种结合网络药理学和生物学的整合模型。通过访问中药系统药理学数据库来选择舒心汤的关键成分和潜在靶点。同时，从包括基因表达综合数据库（Gene Expression Omnibus）、疾病基因数据库（DisGeNet）、基因卡片数据库（Genecards）、药物银行数据库（Drugbank）、在线人类孟德尔遗传数据库（OMIM）和药物基因组知识库（PharmGKB）在内的多个数据库中筛选糖尿病患者中与MI/RI相关的治疗靶点。将舒心汤的潜在靶点与糖尿病患者中与MI/RI相关的治疗靶点进行交集分析，并使用注释、可视化和综合发现数据库（Database for Annotation, Visualization and Integrated Discovery）进行生物信息学分析。随后通过动物实验验证生物信息学分析的主要结果。
根据生物信息学分析得出的假设，舒心汤可能通过降低氧化型低密度脂蛋白（LDL）和抑制晚期糖基化终产物（AGE）与其受体（RAGE）的信号通路，改善脂质代谢紊乱，并在糖尿病相关的MI/RI中发挥抗凋亡作用。随后的动物实验证实了这一假设。给予剂量为2.8 g/kg/d的舒心汤治疗可降低氧化型LDL、AGEs和RAGE水平，并调节血脂水平。此外，凋亡相关蛋白如Bax和裂解的半胱天冬酶3的表达下调，而Bcl-2表达上调。这些结果表明舒心汤可抑制糖尿病大鼠MI/RI中的心肌细胞凋亡并改善心脏功能。
本研究表明了舒心汤在糖尿病相关MI/RI中的活性成分和潜在分子治疗机制。此外，动物实验证实舒心汤可通过AGE-RAGE信号通路调节血脂水平、减轻心肌细胞凋亡并改善心脏功能。
