Sea cucumber gut tetrapeptide ameliorates alcoholic gastric damage via restoring mitochondrial dynamics

This paper aimed to explore the mechanism of tetrapeptide Val-Thr-Pro-Tyr (VTPY) in improving alcoholic gastric injury. VTPY has the potential to enhance the growth and movement of normal human gastric epithelial cells (GES-1). Following ethanol-induced impairment, VTPY effectively improved migration of GES-1 and human umbilical vein endothelial cells (HUVEC) cells, enhanced angiogenesis, eliminated cellular and mitochondrial reactive oxygen species (ROS), inhibited excessive mitochondrial division, enhanced F-actin polymerization and mitochondrial respiratory capacity. To counteract excessive mitochondrial fission, VTPY primarily restores the mitochondria dynamics by reducing the expression of Drp1 and Fis1, while increasing Mfn2. Further studies utilizing inhibitors clarifies that the inhibition of excessive mitochondrial fission can markedly reduce F-actin depolymerization, consequently enhancing cell migration. Additionally, VTPY can inhibit the apoptosis pathway by maintaining potential of mitochondrial membrane, preventing the release of mitochondrial cytochrome c, bolstering the levels of Bcl-XL, while reducing the levels of Bax and cleaved-caspase-3. Further investigations using inhibitors demonstrates that excessive mitochondrial fission could activate apoptotic pathway. However, VTPY counteracts this effect and enhance cells viability. Further evidence suggests that VTPY effectively improves ulcer index and pathologic changes, relieves inflammation, enhances the balance of oxidation and anti-oxidation, promotes angiogenesis, improves the expression of mitochondrial dynamics factors, blocks apoptotic pathway, and subsequently ameliorates gastric damage in mice through Fis-1/Bcl-2 pathway.