Protective effects of quercetin, the key component of Zuo Gui Wan, against Alzheimer's disease via the PI3K/AKT pathway: insights from network pharmacology, molecular docking, and cell experiments.
10.3724/zdxbyxb-2025-0661
- Author:
Guangya LI
1
,
2
;
Peize LI
3
;
Liuling HUANG
3
;
Jingwen ZHU
3
;
Xiude QIN
4
;
Yunwei LU
5
Author Information
1. Depart-ment of Neurology and Psychology, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518000, China. 13999704253@
2. com.
3. Depart-ment of Neurology and Psychology, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518000, China.
4. Depart-ment of Neurology and Psychology, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518000, China. qinxiude@foxmail.com.
5. Depart-ment of Neurology and Psychology, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518000, China. 417213243@qq.com.
- Publication Type:Journal Article
- Keywords:
Alzheimer’s disease;
Apoptosis;
Bioinformatics;
Experimental study;
Quercetin;
Zuo Gui Wan;
in vitro
- From:
Journal of Zhejiang University. Medical sciences
2025;():1-12
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVES:To investigate the protective mechanism of quercetin, the core component of Zuo Gui Wan, against Alzheimer's disease through the PI3K/AKT signaling pathway, based on network pharmacology, molecular docking, and cell experi-ments.
METHODS:The active components of Zuo Gui Wan were identified by searching TCMSP, PubChem, Swiss Target Prediction, and BATMAN-TCM databases, and their potential targets were predicted. The target information was standardized using Uniprot, and Alzheimer's disease-related target genes were obtained from Drugbank, GeneCards, and OMIM. The intersection of these datasets was used to identify the potential targets of Zuo Gui Wan for treating Alzheimer's disease. Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. The protein-protein interaction (PPI) network of potential targets was visualized using Cytoscape 3.10.1 software and the STRING database. The key active compounds and core potential targets for treating Alzheimer's disease with Zuo Gui Wan were identified through calculation. Based on the enrichment analysis results and literature, quercetin and the PI3K/AKT pathway were selected for verification. Molecular docking and binding ability prediction between quercetin and the core target AKT were performed using CB-Dock2, and visualization was conducted with AutoDock and PyMOL software. Finally, Aβ1-42-induced HT-22 mouse hippocampal neuronal cells were used to construct an Alzheimer's disease cell model. Quercetin, the PI3K inhibitor LY294002, and the activator EGF were used as interventions. The groups were divided as follows: Control, Aβ1-42, Aβ1-42+Quercetin 2.5 μM, Aβ1-42+Quercetin 5 μM, Aβ1-42+Quercetin 10 μM, Aβ1-42+EGF, and the PI3K/AKT modulation group: Control, LY294002, LY294002+Quercetin 10 μM, LY294002+EGF. CCK-8 assays were performed to detect cell viability, while JC-1, Calcein AM-PI, and Hoechst staining were used to assess cell apoptosis. Western blotting was employed to detect the expression of relevant target proteins.
RESULTS:Network pharmacology and cell experiments collectively demonstrate that the key active ingredient of Zuo Gui Wan, quercetin, targets core proteins such as AKT1 and GSK3β through a network-based approach, significantly enriching the PI3K/AKT pathway. Molecular docking results indicate that quercetin has a strong binding affinity with AKT. Experimental validation in the Aβ1-42 oligomer-induced HT-22 model reveals that quercetin significantly activates the PI3K/AKT signaling pathway, which is inhibited by Aβ1-42 oligomers, as well as Bcl-2 protein expression. It also suppresses the expression of Cleaved Caspase 3/Caspase 3, BAX, and Cytochrome C proteins. JC-1, Hoechst 33342, and Calcein AM-PI staining results further show that quercetin can significantly alleviate apoptosis induced by Aβ1-42 oligomers in HT-22 cells. Treatment with the PI3K inhibitor LY294002 in HT-22 cells leads to reduced cell viability and decreased expression of p-AKT/AKT and Bcl-2 proteins, while increasing the expression of Cleaved Caspase 3/Caspase 3, BAX, and Cytochrome C proteins. Additionally, apoptosis levels increase as observed in JC-1, Hoechst 33342, and Calcein AM-PI staining, all of which can be reversed by quercetin and the PI3K agonist EGF.
CONCLUSIONS:Quercetin, the key active ingredient of Zuo Gui Wan, exerts its protective effects against Alzheimer's disease by regulating the PI3K/AKT signaling pathway, inhibiting neuronal cell damage and apoptosis.
