Phellopterin Cream Exerts an Anti-Inflammatory Effect That Facilitates Diabetes-Associated Cutaneous Wound Healing Via SIRT1.

Background: Diabetic ulcers, which are characterized by chronic nonhealing wounds with a long-lasting in-flammatory state, are a typical symptom in individuals with diabetes, and there is still no effective treatment for these lesions. Angelica dahurica plays a critical role in inflammatory diseases. Among numerous monomeric compounds, phellopterin has been shown to have anti-inflammatory properties. Purpose: To research the bioactive constituents in Angelica dahurica and their mechanism of action in treating diabetic ulcers. Study design: Chemical research of Angelica dahurica led to the identification of a new coumarin, dahuricoumarin A (1), along with seven known compounds (2 -8). All compounds were tested for anti-inflammatory activity, and phellopterin, compound (3), significantly decreased the expression of intercellular cell adhesion molecule-1 (ICAM-1), a representative indicator of inflammation. Phellopterin can also increase SIRT1 protein, a key target for inflammation. In our research, we confirmed the anti-inflammatory effects of phellopterin on diabetic ulcers and explored the underlying mechanism of action. Methods: The expression of IFN-gamma, SIRT1, and ICAM-1 in human diabetic ulcer tissues was studied using immunohistochemistry. Streptozotocin was used to induce a diabetic model in C57BL/6J mice, and ulcers were surgically introduced. After phellopterin treatment, the skin lesions of diabetic mice were observed over a period of time. The protein and mRNA expression levels of SIRT1 and ICAM-1 were measured using H&E, qRT-PCR and immunohistochemical staining. A HaCaT cell inflammatory model was induced by IFN-gamma. Using a lentiviral packaging technique, MTT assay, and Western blotting, the effect of phellopterin on the proliferation of HaCaT cells and the expression of ICAM-1 was evaluated under normal and SIRT1 knockdown conditions. Results: High levels of ICAM-1 and IFN-gamma were identified, but low levels of SIRT1 were found in human diabetic ulcer tissues, and phellopterin showed therapeutic benefits in the healing process by attenuating chronic inflammation and promoting re-epithelialization, along with SIRT1 upregulation and ICAM-1 downregulation. However, inhibiting SIRT1 reversed its proliferative and anti-inflammatory effects. Conclusion: In vitro and in vivo, phellopterin exerts anti-inflammatory and proliferative effects that promote diabetic wound healing, and the potential mechanism depends on SIRT1.