Peptide RL-QN15 derived from skin secretions of Rana limnocharis has a pronounced pro-healing effect on acute and chronic wounds, but its precise mechanism is remains to be elucidated. Epidermal stem cells are of utmost importance in wound healing and thus constitute a primary focus of wound repair research. Here, we explored the mechanism of RL-QN15 promoting wound healing by regulating epidermal stem cells. Our results showed that RL-QN15 activated the Wnt/β-catenin signaling pathway by binding to the FZD8. This interaction resulted in the up-regulation of target genes MYC and CCND1, thereby facilitating the proliferation of epidermal stem cells. MMP3 can degrade E-cadherin and activate Wnt/β-catenin pathway further. This enhanced pathway activity induced epithelial-to-mesenchymal transition and N-cadherin expression, further encouraging cell proliferation and migration. RL-QN15 can also effect the stemness of epidermal stem cells. In summary, as an excellent candidate for novel pro-healing agent, RL-QN15 can promote the activation of Wnt/β-catenin pathway through binding with membrane receptor FZD8, thus regulating epidermal stem cell functions and promoting wound healing. This study elucidated a novel mechanism by which amphibian-derived peptides promote skin wound healing, focusing on the regulatory role of epidermal stem cells and providing a new target for skin regeneration research.

Background and Purpose: Ischemia reperfusion (I/R) is the main cause of acute ischemic stroke injury. However, existing treatments for I/R injury are relatively poor, and relevant drugs need to be further explored. Experimental Approach: In this study, the neuroprotective function and related mechanism of OL-FS13 were studied through rat I/R model and PC12 cell model of oxygen glucose deprivation/reoxygenation model (OGD/R), combined with cell viability experiment, tissue H&E and Nissl staining experiment and Western blot experiment. Key Results: In this study, we identified a novel neuroprotective peptide (OL-FS13, amino acid sequence: FSLLLTWWRRRVC) from the odorous frog species Odorrana livida using a constructed cDNA library. OL-FS13 significantly alleviated brain injury from cerebral I/R in rats by reducing infarct volume in the brain, improving behavioral and histological abnormalities, and rescuing PC12 cell from damage caused by oxygen glucose deprivation/reoxygenation (OGD/R). Mechanistically, OL-FS13 increased the level of antioxidative enzymes to resist oxidative stress induced by I/R and OGD/R by activating the Nrf2/HO-1 pathway and alleviated endoplasmic reticulum (ER) stress induced by OGD/R by inhibiting the IRE1α/TRAF2/JNK pathway. Conclusion and Implications: Collectively, the novel peptide exerted significant anti-stroke activities by alleviating oxidative and ER stress via activation of Nrf2 signaling and suppression of the IRE1α/TRAF2/JNK pathway. Thus, this research provides a potential drug candidate for the clinical treatment of cerebral I/R.