A novel PPARβ/FFA1 dual agonist Y8 promotes diabetic wound healing

Background: Diabetes ulcer is one of the leading causes of disability and death in diabetics. Y8 [(2-(2-fluoro-4-((4-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)methoxy) phenoxy)acetic acid)], a dual agonist of peroxisome proliferation activated receptor beta (PPAR beta) and free fatty acid receptor 1 (FFA1/FFAR1/GPR40), a new compound molecule with the potential for diabetes ulcer treatment.Objective: To research the effect of the dual target agonist Y8 and its mechanism of action in the treatment of diabetic ulcers.Methods: We have established a wound model in diabetic mice. After treatment with Y8, wound healing was evaluated by tissue pathology, reactive oxygen species (ROS) levels, and gene expression testing. Under high sugar conditions, the mechanism of Y8 affecting fibroblasts' proliferation and keratinocytes' migration is further studied.Results: We found that Y8 accelerated wound healing and shortened healing time in diabetic mice. Granulation tissue generation and extracellular matrix (ECM) deposition were significantly increased in Y8-treated mice. Mechanistically, Y8 promotes keratinocyte proliferation by activating PPAR beta and migration of keratinocytes by triggering FFA1 in vitro. In addition, Y8 also decreased ROS levels in fibroblasts in vitro and in vivo by activating PPAR beta, reducing their release of superoxide anions.Conclusion: Our results suggest that PPAR beta/FFA1 dual agonist Y8 has the effect of promoting the healing of diabetic ulcer wounds in vivo and in vitro, and its therapeutic effect is better than that of single-target agonists.

Automated summary

PPARβ/FFA1 dual agonist Y8 promotes the healing of diabetic ulcer wounds in vivo and in vitro. It accelerates wound healing and reduces healing time in diabetic mice. Mechanistically, Y8 activates PPARβ to promote keratinocyte proliferation and activates FFA1 to enhance keratinocyte migration. Y8 also decreases ROS levels in fibroblasts by activating PPARβ.