Vicenin-2 reduces inflammation and apoptosis to relieve skin photoaging via suppressing GSK3β

Background: Skin photoaging caused by ultraviolet rays (UVR) not only affects the appearance, but also leads to benign and malignant skin tumors. Vicenin-2, a bioflavonoid, exhibits anti-UVB properties, but its potential in preventing skin photoaging and the underlying mechanisms remain unclear. This study aims to elucidate the molecular mechanisms of Vicenin-2 in treating photoaging through network pharmacology, molecular docking, molecular dynamics simulation, and experimental validation.

Methods: We utilized PubChem, Swiss Target Prediction, and Target Net databases to obtain the action targets of Vicenin-2. The Online Mendelian Inheritance in Man (OMIM), GeneCards, and Therapeutic Target Database (TTD) databases were employed to hunt for photoaging-related targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted via the Metascape database. Molecular docking and dynamics simulation methods were used for analyzing the binding sites and binding energies between Vicenin-2 and photoaging targets. Then, a photoaging mouse model and a Human foreskin fibroblast cells (HFF-1) model were created, the therapeutic effect and molecular mechanism of action of Vicenin-2 were validated by Hematoxylin and eosin (H&E), Masson staining and Elastica-Van Gieson (EVG) Staining, enzyme-linked immunosorbent assay (ELISA), Western blot (WB), Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling (TUNEL) Assay, Antioxidant Enzyme activities and quantitative reverse transcription-polymerase chain reaction (qRT-PCR).

Result: The screening of chemical composition and targets indicated that 249 genetic targets of Vicenin-2 were related to photoaging. Bioinformatics analysis suggested that Matrix Metalloproteinases 9(MMP9), Glycogen Synthase Kinase 3(GSK3β), Heat Shock Protein 90 AA1(HSP90AA1) and Nuclear Factor kappa-B1(NF-κB1) might be potential targets for Vicenin-2 in photoaging therapy. Molecular docking and dynamics simulation further showed that Vicenin-2 had the best binding to GSK3β. Through experimental verification, it has been demonstrated that Vicenin-2 alleviate photoaging, acting on GSK3β to regulate the phosphatidylinositol 3- kinase/serine-threonione kinase (PI3K/Akt) pathways, by reducing inflammation and Apoptosis.

Conclusions: Vicenin-2 has anti-inflammatory and apoptosis-reducing effects through the action of multiple targets to relieve skin photoaging. Among them, GSK3β is the validated therapeutic target of Vicenin-2, which provides new ideas and clues for the development of photoaging therapy.

GSK3β; Molecular docking; Molecular dynamics simulation; Network pharmacology; PI3K/AKT; Skin photoaging; Vicenin-2.