Hydroxytyrosol from Olive Oil Mitigates Endothelial Dysfunction in Diabetic Foot Ulcers via Redox, Inflammatory, and Survival Pathways

Abstract

Background: Diabetic foot ulcers (DFUs) remain a devastating complication of diabetes mellitus, with endothelial dysfunction playing a central role in their pathophysiology. Despite advances in wound care, current therapies often fail to address the complex molecular underpinnings of impaired healing.

Objectives: Diabetic foot ulcers (DFUs) remain a devastating complication of diabetes mellitus, with endothelial dysfunction playing a central role in their pathophysiology. Despite advances in wound care, current therapies often fail to address the complex molecular underpinnings of impaired healing.

Methods: Using network pharmacology, molecular docking, in-vitro experiments, we identified 170 potential targets of Hy in DFU treatment.

Results: We found nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), serine/threonine protein kinase (AKT), and caspase-3 emerging as crucial hub proteins. Molecular docking revealed strong binding affinity (<-6.27 kcal/mol), particularly with Nrf2. In human endothelial cells exposed to a hyperglycemic microenvironment (HGM), Hy (5-10 μM) significantly restored cell viability while promoting Nrf2 nuclear translocation. This activation enhanced downstream antioxidant enzymes heme oxygenase-1, NAD(P)H quinone oxidoreductase 1, Catalase and suppressed oxidative stress markers p22phox, thioredoxin interacting protein. Hy inhibited NF-κB signaling and proinflammatory cytokines interleukin (IL)-6, IL-18 under hyperglycemic conditions. The compound also reversed HGM-induced suppression of angiogenic factors, vascular endothelial growth factor A, hypoxia-inducible factor 1-alpha, improving tube formation and migration in functional assays. Mechanistically, Hy restored AKT phosphorylation and modulated the Bcl-2 asscoiated X protein/B-cell lymphoma-2 (BAX/BCL2) ratio, protecting endothelial cells from apoptosis.

Conclusion: Our findings highlight Hy's multifaceted action across redox, inflammatory, and survival pathways as a significant advantage over current single-target therapies. Although in vitro results are promising, animal models are needed to validate Hy's efficacy in the complex DFU microenvironment. Nevertheless, Hy's favorable absorption-distribution-metabolism-excretion profile and pleiotropic effects position it as an intriguing candidate for DFU management, potentially bridging preventive and regenerative approaches in diabetic wound healing.

Keywords: Nrf2; antioxidant; diabetic foot ulcer; hydroxytyrosol; molecular docking; network pharmacology; wound healing.