Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Jul 15, 2023; 14(7): 1057-1076
Published online Jul 15, 2023. doi: 10.4239/wjd.v14.i7.1057
Network-pharmacology-based research on protective effects and underlying mechanism of Shuxin decoction against myocardial ischemia/reperfusion injury with diabetes
Ling Yang, Yang Jian, Zai-Yuan Zhang, Bao-Wen Qi, Yu-Bo Li, Pan Long, Yao Yang, Xue Wang, Shuo Huang, Jing Huang, Long-Fu Zhou, Jie Ma, Chang-Qing Jiang, Yong-He Hu, Wen-Jing Xiao
Ling Yang, Yu-Bo Li, Xue Wang, Shuo Huang, Yong-He Hu, School of Clinical Medicine, Chengdu University of TCM, Chengdu 610072, Sichuan Province, China
Yang Jian, Department of Clinical Pharmacy, The General Hospital of Western Theater Command, Chengdu 610083, Sichuan Province, China
Zai-Yuan Zhang, Jing Huang, Yong-He Hu, College of Medicine, Southwest Jiaotong University, Chengdu 610031, Sichuan Province, China
Bao-Wen Qi, South China Hospital of Shenzhen University, Shenzhen 518116, Guangdong Province, China
Pan Long, Department of Ophthalmology, The General Hospital of Western Theater Command, Chengdu 610083, Sichuan Province, China
Yao Yang, Jie Ma, Chang-Qing Jiang, Wen-Jing Xiao, Department of Pharmacy, The General Hospital of Western Theater Command, Chengdu 610083, Sichuan Province, China
Long-Fu Zhou, Department of Biomedical Engineering, The General Hospital of Western Theater Command, Chengdu 610083, Sichuan Province, China
Author contributions: Yang L designed the study, performed the network pharmacological analysis, and wrote the manuscript; Jian Y, Zhang ZY, Qi BW, Jiang CQ, and Yang Y performed the production and identification of SXT; Li YB, Huang S, Huang J, and Ma J performed the animal experiments; Long P performed the statistical analysis; Wang X, Zhou LF, and Hu YH designed the study; Xiao WJ revised the manuscript and approved the final proof as the corresponding author; all authors approved the final version of the article.
Supported by Natural Science Foundation of Sichuan Province, No. 2022NSFSC0738; Basic Research Funds for Central Universities, No. 2682022ZTPY038; and Tibet Autonomous Region Science and Technology Planning Project, No. XZ2022RH001.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of The General Hospital of Western Theater Command (No. 2022ky028-1).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE Guidelines, and the manuscript was prepared and revised according to the ARRIVE Guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Wen-Jing Xiao, PhD, Doctor, Department of Pharmacy, The General Hospital of Western Theater Command, No. 270 Tianhui Road, Chengdu 610083, Sichuan Province, China. xwj-4321@163.com
Received: January 20, 2023
Peer-review started: January 20, 2023
First decision: April 11, 2023
Revised: April 14, 2023
Accepted: May 5, 2023
Article in press: May 5, 2023
Published online: July 15, 2023
Processing time: 173 Days and 20.8 Hours
Abstract
BACKGROUND

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.

AIM

To further determine the mechanism of SXT in attenuating MI/RI associated with diabetes.

METHODS

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.

RESULTS

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.

CONCLUSION

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.

Keywords: Chinese herbal drugs; Network-pharmacology; Diabetes; Myocardial reperfusion injury; Shuxin decoction

Core Tip: Patients with diabetes are susceptible to myocardial ischemia/reperfusion injury (MI/RI). The efficacy of implementing strict glycemic control to reduce cardiovascular mortality in patients with diabetes has not been established to yield significant benefits. Here, we evaluated a recipe [Shuxin decoction (SXT)], which was modified from the classic herbal formula "Wu-tou-chi-shi-zhi-wan" in traditional Chinese medicine. Animal experiments based on findings from network pharmacology indicated that SXT could regulate lipid metabolism, alleviate cardiomyocyte apoptosis, and attenuate MI/RI in diabetes through the advanced glycation end products (AGE)-receptor for AGE signaling pathway. These findings could potentially facilitate developing a novel complementary or alternative form of medicine for effectively managing MI/RI with diabetes.