Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Sep 15, 2024; 15(9): 1942-1961
Published online Sep 15, 2024. doi: 10.4239/wjd.v15.i9.1942
Molecular mechanisms of Buqing granule for the treatment of diabetic retinopathy: Network pharmacology analysis and experimental validation
Yi-Fan Yang, Ling Yuan, Xiang-Yang Li, Qian Liu, Wen-Jie Jiang, Tai-Qiang Jiao, Jia-Qing Li, Meng-Yi Ye, Yang Niu, Yi Nan
Yi-Fan Yang, Wen-Jie Jiang, Jia-Qing Li, Yang Niu, Yi Nan, Key Laboratory of Ningxia Minority Medicine Modernization Ministry of Education, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
Ling Yuan, College of Pharmacy, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
Xiang-Yang Li, Tai-Qiang Jiao, Meng-Yi Ye, Yang Niu, Traditional Chinese Medicine College, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
Qian Liu, School of Clinical Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
Co-corresponding authors: Yang Niu and Yi Nan.
Author contributions: Yang YF conducted most of the experiments, analyzed the data, completed the figure production, and wrote the manuscript; Li XY and Jiang WJ carried out a portion of the experiments and participated in the production of the figures; Jiao TQ carried out part of the experiments and participated in the statistical analysis of the data; Li JQ and Ye MY performed the network pharmacology prediction; Yuan L and Liu Q Critically reviewed and edited the manuscript. Niu Y and Nan Y have played essential and indispensable roles in the experimental design, data interpretation, and manuscript preparation as the co-corresponding authors - Niu Y Secured resources for the study, including animals, equipment, and funding; Nan Y designed and planned the entire research program. As co-corresponding authors, they played a guiding role in the study, helped team members solve problems encountered during the research process, provided professional advice, and promoted the study's progress. All authors approved the final version of the article.
Supported by National Natural Science Foundation of China, No. 81960836; Ningxia Natural Science Foundation, No. 2020AAC03126; and Ningxia Higher Education Scientific Research Project, No. NGY2020045.
Institutional animal care and use committee statement: All animal experiments were approved by the Laboratory Animal Welfare Ethics Committee of the Ningxia Medical University Laboratory Animal Center (No. IACUC-NYLAC-2022-113).
Conflict-of-interest statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Data sharing statement: Dataset available from the corresponding author at 20080011@nxmu.edu.cn.
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: Yi Nan, MD, Professor, Key Laboratory of Ningxia Minority Medicine Modernization Ministry of Education, Ningxia Medical University, No. 1160 Shengli Street, Yinchuan 750004, Ningxia Hui Autonomous Region, China. 20080011@nxmu.edu.cn
Received: April 12, 2024
Revised: July 5, 2024
Accepted: July 31, 2024
Published online: September 15, 2024
Processing time: 137 Days and 8.6 Hours
Abstract
BACKGROUND

Diabetic retinopathy (DR) is a common microvascular complication of diabetes mellitus. Its blindness rate is high; therefore, finding a reasonable and safe treatment plan to prevent and control DR is crucial. Currently, there are abundant and diverse research results on the treatment of DR by Chinese medicine Traditional Chinese medicine compounds are potentially advantageous for DR prevention and treatment because of its safe and effective therapeutic effects.

AIM

To investigate the effects of Buqing granule (BQKL) on DR and its mechanism from a systemic perspective and at the molecular level by combining network pharmacology and in vivo experiments.

METHODS

This study collected information on the drug targets of BQKL and the therapeutic targets of DR for intersecting target gene analysis and protein-protein interactions (PPI), identified various biological pathways related to DR treatment by BQKL through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses, and preliminarily validated the screened core targets by molecular docking. Furthermore, we constructed a diabetic rat model with a high-fat and high-sugar diet and intraperitoneal streptozotocin injection, and administered the appropriate drugs for 12 weeks after the model was successfully induced. Body mass and fasting blood glucose and lipid levels were measured, and pathological changes in retinal tissue were detected by hematoxylin and eosin staining. ELISA was used to detect the oxidative stress index expression in serum and retinal tissue, and immunohistochemistry, real-time quantitative reverse transcription PCR, and western blotting were used to verify the changes in the expression of core targets.

RESULTS

Six potential therapeutic targets of BQKL for DR treatment, including Caspase-3, c-Jun, TP53, AKT1, MAPK1, and MAPK3, were screened using PPI. Enrichment analysis indicated that the MAPK signaling pathway might be the core target pathway of BQKL in DR treatment. Molecular docking prediction indicated that BQKL stably bound to these core targets. In vivo experiments have shown that compared with those in the Control group, rats in the Model group had statistically significant (P < 0.05) severe retinal histopathological damage; elevated blood glucose, lipid, and malondialdehyde (MDA) levels; increased Caspase-3, c-Jun, and TP53 protein expression; and reduced superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels, ganglion cell number, AKT1, MAPK1, and MAPK3 protein expression. Compared with the Model group, BQKL group had reduced histopathological retinal damage and the expression of blood glucose and lipids, MDA level, Caspase-3, c-Jun and TP53 proteins were reduced, while the expression of SOD, GSH-Px level, the number of ganglion cells, AKT1, MAPK1, and MAPK3 proteins were elevated. These differences were statistically significant (P < 0.05).

CONCLUSION

BQKL can delay DR onset and progression by attenuating oxidative stress and inflammatory responses and regulating Caspase-3, c-Jun, TP53, AKT1, MAPK1, and MAPK3 proteins in the MAPK signaling pathway mediates these alterations.

Keywords: Diabetic retinopathy; Network pharmacology; Animal models; Oxidative stress; Inflammatory

Core Tip: In this study, we constructed a diabetic retinopathy (DR) model in Sprague-Dawley rats and combined network pharmacology and in vivo experiments to thoroughly investigate the therapeutic efficacy of Buqing granule in DR and their mechanism of action. The experimental data showed that Buqing granule could significantly reduce oxidative stress and inflammatory damage, thus delaying DR. This finding not only deepens our understanding of DR pathogenesis, but also provides new ideas and potential therapeutic targets for future innovation in DR treatment.