Verification of resveratrol ameliorating vascular endothelial damage in sepsis-associated encephalopathy through HIF-1α pathway based on network pharmacology and experiment.
10.19540/j.cnki.cjcmm.20241012.301
- Author:
Rong LI
1
;
Yue WU
2
;
Wen-Xuan ZHU
3
;
Meng QIN
1
;
Si-Yu SUN
4
;
Li-Ya WANG
1
;
Mei-Hui TIAN
2
;
Ying YU
1
Author Information
1. Department of Physiology, Bengbu Medical University Bengbu 233000, China Key Laboratory of Basic and Clinical Cardiovascular Diseases, Bengbu Medical University Bengbu 233000, China.
2. Key Laboratory of Basic and Clinical Cardiovascular Diseases, Bengbu Medical University Bengbu 233000, China Department of Epidemiology and Health Statistics, Bengbu Medical University Bengbu 233000, China.
3. Key Laboratory of Basic and Clinical Cardiovascular Diseases, Bengbu Medical University Bengbu 233000, China.
4. Department of Physiology, Bengbu Medical University Bengbu 233000, China Department of Epidemiology and Health Statistics, Bengbu Medical University Bengbu 233000, China.
- Publication Type:Journal Article
- Keywords:
HIF-1α;
mitochondrial dynamics;
resveratrol;
sepsis-associated encephalopathy;
vascular endothelial damage
- MeSH:
Animals;
Mice;
Network Pharmacology;
Resveratrol/administration & dosage*;
Male;
Sepsis-Associated Encephalopathy/genetics*;
Signal Transduction/drug effects*;
Hypoxia-Inducible Factor 1, alpha Subunit/genetics*;
Endothelium, Vascular/metabolism*;
Molecular Docking Simulation;
Protein Interaction Maps/drug effects*;
Humans;
Sepsis/complications*;
Oxidative Stress/drug effects*
- From:
China Journal of Chinese Materia Medica
2025;50(4):1087-1097
- CountryChina
- Language:Chinese
-
Abstract:
This study aims to investigate the mechanism by which resveratrol(RES) alleviates cerebral vascular endothelial damage in sepsis-associated encephalopathy(SAE) through network pharmacology and animal experiments. By using network pharmacology, the study identified common targets and genes associated with RES and SAE and constructed a protein-protein interaction( PPI) network. Gene Ontology(GO) analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis were performed to pinpoint key signaling pathways, followed by molecular docking validation. In the animal experiments, a cecum ligation and puncture(CLP) method was employed to induce SAE in mice. The mice were randomly assigned to the sham group, CLP group, and medium-dose and high-dose groups of RES. The sham group underwent open surgery without CLP, and the CLP group received an intraperitoneal injection of 0. 9% sodium chloride solution after surgery. The medium-dose and high-dose groups of RES were injected intraperitoneally with 40 mg·kg-1 and 60 mg·kg~(-1) of RES after modeling, respectively, and samples were collected 12 hours later. Neurological function scores were assessed, and the wet-dry weight ratio of brain tissue was detected. Serum superoxide dismutase(SOD), catalase( CAT) activity, and malondialdehyde( MDA) content were measured by oxidative stress kit. Histopathological changes in brain tissue were examined using hematoxylin-eosin(HE) staining. Transmission electron microscopy was employed to evaluate tight cell junctions and mitochondrial ultrastructure changes in cerebral vascular endothelium. Western blot analysis was performed to detect the expression of zonula occludens1( ZO-1), occludin, claudins-5, optic atrophy 1( OPA1), mitofusin 2(Mfn2), dynamin-related protein 1(Drp1), fission 1(Fis1), and hypoxia-inducible factor-1α(HIF-1α). Network pharmacology identified 76 intersecting targets for RES and SAE, with the top five core targets being EGFR, PTGS2, ESR1, HIF-1α, and APP. GO enrichment analysis showed that RES participated in the SAE mechanism through oxidative stress reaction. KEGG enrichment analysis indicated that RES participated in SAE therapy through HIF-1α, Rap1, and other signaling pathways. Molecular docking results showed favorable docking activity between RES and key targets such as HIF-1α. Animal experiment results demonstrated that compared to the sham group, the CLP group exhibited reduced nervous reflexes, decreased water content in brain tissue, as well as serum SOD and CAT activity, and increased MDA content. In addition, the CLP group exhibited disrupted tight junctions in cerebral vascular endothelium and abnormal mitochondrial morphology. The protein expression levels of Drp1, Fis1, and HIF-1α in brain tissue were increased, while those of ZO-1, occludin, claudin-5, Mfn2, and OPA1 were decreased. In contrast, the medium-dose and high-dose groups of RES showed improved neurological function, increased water content in brain tissue and SOD and CAT activity, and decreased MDA content. Cell morphology in brain tissue, tight junctions between endothelial cells, and mitochondrial structure were improved. The protein expressions of Drp1, Fis1, and HIF-1α were decreased, while those of ZO-1, occludin, claudin-5, Mfn2, and OPA1 were increased. This study suggested that RES could ameliorate cerebrovascular endothelial barrier function and maintain mitochondrial homeostasis by inhibiting oxidative stress after SAE damage, potentially through modulation of the HIF-1α signaling pathway.
