CXCL8 and JAK2, modulated by apigenin, are two regulators in the pathogenesis of diabetic foot ulcer

Background : Diabetic foot ulcer (DFU) is one of the major chronic complications of diabetes mellitus and a leading cause of disability and death. The aim of this study was to identify immune-related therapeutic targets and drugs for DFU. Methods : Two Gene Expression Omnibus datasets (GSE68183 and GSE80178) were merged, and differentially expressed genes (DEGs) were identified. Immune-related genes (IRGs) were extracted from the Immport database. Then the differentially expressed IRGs (DE-IRGs) were screened. Based on the DE-IRGs, protein-protein interaction network was constructed and hub genes were identified via Cytoscape software. An external dataset GSE134431 was used to verify the expression and diagnostic value of the hub genes. Potential compounds targeting key hub proteins, including C-X-C motif chemokine ligand 8 (CXCL8) and Janus kinase 2 (JAK2), were explored using the HIT2.0 platform and HERB database, and the binding activity between them was verified using molecular docking. Human immortalized keratinocytes (HaCaT cells) induced by high glucose (HG) were used to construct the DFU model in vitro , and cell proliferation, apoptosis and migration were detected by CCK-8, flow cytometry and Transwell assay after apigenin (API) treatment. Reverse transcriptional quantitative polymerase chain reaction and Western blot were used to detect the expression of key hub genes. Results : CXCL8, and JAK2 were identified as hub genes in the pathogenesis of DFU. API, curcumin, quercetin, resveratrol and simvastatin had good binding activity with CXCL8 and JAK2 proteins. Treatment with Apigenin could reverse HG-induced inhibition of HaCaT cell viability and migration, and reduce cell apoptosis. After HaCaT cells were induced by HG, CXCL8 mRNA was significantly up-regulated in DFU, while JAK2 mRNA was significantly down-regulated. API treatment inhibited the expression of CXCL8 and increased the expression of JAK2, p-PI3K, p-AKT and p-mTOR in HG-induced HaCaT cells. Conclusion : CXCL8 and JAK2 may be potential therapeutic targets for DFU. API can reduce HG-induced HaCaT cell injury and is expected to be a potential compound for DFU treatment.