Paeonol regulates the DDIT4-mTOR signaling pathway in macrophages to promote diabetic wound healing.

Abstract

<p>BACKGROUND: Diabetic foot ulcers are a common complication in people with diabetes, and patients with severe disease are at risk of amputation. Current studies have found that one of the reasons for the difficulty in healing diabetic foot ulcers is the Abnormal polarization of the M1/M2 phenotype of macrophages, which leads to a prolonged inflammatory period of the wound. The aim of this study was to investigate whether paeonol can promote the polarization of macrophages towards the M2 type and whether M2 type macrophages can regulate the DDIT4-mTOR signaling pathway and slow down the inflammatory response of diabetic foot ulcers. METHODS: C57BL/6 mice were used to establish an animal model of diabetic foot ulcers and the effect of paeonol on wound healing was investigated. The effects of paeonol on wound healing of foot ulcer in diabetic mice were evaluated using histological staining and immunohistochemistry. The molecular mechanism of refractory healing of foot ulcers was speculated through network pharmacology. The effects of Paeonol on phenotypic polarization of macrophages and the mechanism of inhibiting inflammation were studied by q-PCR, ELISA, immunofluorescence and Western. RESULTS: Paeonol can effectively promote wound healing in diabetic mice. HE staining showed that paeonol could improve the inflammatory infiltration in the ulcer wound of diabetic mice; Masson trichromatic staining showed that paeonol could increase the increase of muscle fibers and collagen in the wound tissue of diabetic mice; immunofluorescence results showed that paeonol could increase the angiogenesis in the wound tissue of diabetic mice. Network pharmacological analysis showed that the molecular mechanism of paeonol in treating diabetic wound healing may be through DDIT4-mTOR signaling pathway. q-PCR, ELISA, immunofluorescence and Western blot showed that paeonol could reduce the expression of the signature protein CD86 and inflammatory factors in M1 macrophages, and promote the phenotypic polarization of M2 macrophages, which is the mechanism of inhibiting inflammation by activating DDIT4-mTOR signaling pathway. CONCLUSION: Paeonol can promote the polarization of macrophages towards M2 type, reduce inflammatory response and accelerate wound surface healing through DDIT4-mTOR signaling pathway, providing a new therapeutic strategy for the treatment of diabetic foot ulcers.</p>