Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Nov 15, 2023; 14(11): 1672-1692
Published online Nov 15, 2023. doi: 10.4239/wjd.v14.i11.1672
Exploring the targets and molecular mechanism of glycyrrhetinic acid against diabetic nephropathy based on network pharmacology and molecular docking
Fan-Di Meng, Ling Yuan, Duo-Jie Xu, Meng-Ying Che, Shao-Zhang Hou, Dou-Dou Lu, Wen-Jing Liu, Yi Nan
Fan-Di Meng, Duo-Jie Xu, Meng-Ying Che, Dou-Dou Lu, Yi Nan, Traditional Chinese Medicine College, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
Fan-Di Meng, Wen-Jing Liu, Yi Nan, Key Laboratory of Ningxia Ethnomedicine 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
Shao-Zhang Hou, Ningxia Key Laboratory of Craniocerebral Diseases, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
Author contributions: Meng FD, Yuan L, Xu DJ, Che MY, Hou SZ, and Lu DD designed the study; Meng FD, Yuan L, Lu DD, and Yi Nan conducted the study; Che MY and Hou SZ contributed new reagents and analytical tools; Meng FD, Yuan L, and Xu DJ analyzed the data and wrote the manuscript; and all authors have read and approved the final manuscript.
Supported by Ningxia Natural Science Foundation, No. 2022AAC02039; National Natural Science Foundation of China, No. 81860894, 82260879, and 81674096; Ningxia Innovation Team of the Foundation and Clinical Researches of Diabetes and its Complications, No. NXKJT2019010.
Institutional review board statement: The study was reviewed and approved by the Medical Ethics Review Committee of Ningxia Medical University (No. 2018-144).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at 20080011@nxmu.edu.cn. Participants gave informed consent for data sharing.
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, PhD, Professor, Traditional Chinese Medicine College, Ningxia Medical University, No. 1160 Shengli Street, Yinchuan 750004, Ningxia Hui Autonomous Region, China. 20080011@nxmu.edu.cn
Received: August 23, 2023
Peer-review started: August 23, 2023
First decision: September 14, 2023
Revised: September 25, 2023
Accepted: October 23, 2023
Article in press: October 23, 2023
Published online: November 15, 2023
Processing time: 78 Days and 17.2 Hours
ARTICLE HIGHLIGHTS
Research background

The prognosis of diabetes nephropathy is poor. Its pathological changes are chronic progressive damage. The clinical symptoms appear late. Once there is persistent proteinuria, its renal function will inevitably decline and develop into end-stage renal failure, causing a huge health burden.

Research motivation

We executed experimental validations to furnish a novel reference method for the treatment of DN.

Research objectives

This study employed network pharmacology and molecular docking methods to predict the mechanism by which glycyrrhetinic acid (GA) treats DN, subsequently validating these predictions through experimental means.

Research methods

Utilizing comprehensive databases such as PharmMapper, TCMSP, GeneCards, OMIM, and TTD, we meticulously searched for targets associated with both the drug GA and the disease DN. Subsequently, we identified common targets by taking their intersections. The pivotal target-pathway relationships were elucidated through a protein-protein interaction network analysis. Furthermore, we conducted Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses to gain deeper insights. Molecular docking studies were performed employing GA constituents to provide a comprehensive understanding of potential interactions.

Research results

In summary, GA appears to modulate the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, resulting in the inhibition of HK-2 cell proliferation and a reduction in HK-2 cell apoptosis. It also induces a G2/M phase cell cycle arrest while upregulating glycogen synthase kinase-3 and p-AKT expression, and downregulating AKT, PI3K, and p-PI3K proteins. These actions potentially involve the reactivation or restoration of the impaired PI3K/AKT pathway in the presence of hyperglycemia, thereby affording protection to renal parenchymal cells.

Research conclusions

This study found 186 therapeutic targets for DN with GA, and GA may act on DN through the PI3K/AKT signaling pathway. The results of in vitro cell experiments indicate that GA inhibits the proliferation of HK2 cells, blocks the cell cycle in the G2/M phase, and reduces the apoptosis of HK2 cells. GA can activate or restore the activity of the PI3K/AKT pathway damaged under high glucose conditions, thereby protecting inherent kidney cells.

Research perspectives

We plan to conduct genetic testing using high-throughput validation techniques. Gene silencing or overexpression experiments targeting the core genes will be employed to verify whether the predicted targets serve as viable drug targets. Additionally, we will perform pathway validation by employing transcriptional and translational inhibitors targeting upstream and downstream signaling proteins. Furthermore, experimental techniques including the assessment of transcription factors and DNA binding through dual luciferase assays and chromatin immunoprecipitation will be utilized to delve deeper into the therapeutic mechanism of GA in the context of DN.