Abstract
Alkannin-based pharmaceutical formulations for improving wound healing have been on the market for several years. However, detailed molecular mechanisms of their action have yet to be elucidated. Here, we investigated the potential roles of AAN-II in improving the healing of pressure-induced venous ulcers using a rabbit model generated by combining deep vein thrombosis with a local skin defect/local skin defect. The extent of healing was evaluated using hematoxylin and eosin (HE) or vimentin staining. Rabbit skin fibroblasts were cultured for AAN-II treatment or TGFB1-sgRNA lentivirus transfection. ELISA was used to evaluate the levels of various cytokines, including IL-1β, IL-4, IL-6, TNF-α, VEGF, bFGF, TGF-β and PDGF. The protein levels of TGF-β sensors, including TGF-β, Smad7 and phosphor-Smad3, and total Smad3, were assayed via western blotting after TGF-β knockout or AAN-II treatment. The results show that, for this model, AAN-II facilitates ulcer healing by suppressing the development of inflammation and promoting fibroblast proliferation and secretion of proangiogenic factors. AAN-II enhances the activation of the TGF-β1-Smad3 signaling pathway during skin ulcer healing. In addition, the results demonstrate that AAN-II and TGF-β have synergistic effects on ulcer healing. Our findings indicate that AAN-II can promote healing of pressure-induced venous skin ulcers via activation of TGF-β-Smad3 signaling in fibroblast cells and provide evidence that could be used in the development of more effective treatments.
Highlights
Venous leg ulcers (VLUs) are a common vascular condition that can cause a high socioeconomic burden
AAN‐II facilitates ulcer healing by suppressing the development of inflammation in this model To determine whether AAN-II promotes ulcer healing in the pressure-induced venous ulcers in this rabbit model, we performed a histological analysis of ulcer wound morphology in the two ulcer groups
To investigate possible changes in chemokines during wound healing with AAN-II treatment, we analyzed the overall features of cytokines, including IL-1β, IL-6, Tumor necrosis factor-α (TNF-α) and IL-4, in all three groups on days 7 and 14 (Fig. 1D–G)
Summary
Venous leg ulcers (VLUs) are a common vascular condition that can cause a high socioeconomic burden. They are an advanced clinical manifestation of venous insufficiency. Their incidence is increasing along with the increased incidence of obesity and diabetes. VLUs are generally secondary to venous hypertension. They are known to arise due to a series of complex cellular humeral events and potentially some genetic factors [3]
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