Potential mechanism of sea cucumber gut peptides in protecting ethanol-induced gastric mucosal injury

Alcoholic gastric injury is a prevalent condition that can result in gastric ulcers. This research delves into the protective effects of sea cucumber gut peptides, Val-Thr-Pro-Tyr (VTPY) and Val-Leu-Leu-Tyr (VLLY), on ethanol-induced gastric injury. These peptides significantly alleviate the pathological symptoms of gastric tissue affected by ethanol, reducing ulcer area and index, epithelial cell loss, submucosal edema, and inflammatory infiltration. High doses of VTPY and VLLY resulted in a significant decrease in ulcer index, with reductions from 5.38 to 2.63 and 1.13, respectively (P < 0.05). Moreover, the levels of P–NF-κB/p65 expression decreased by 33.47% and 54.27%, while myeloperoxidase (MPO) activity decreased by 42.98% and 55.33%, respectively. These treatments also effectively suppressed inflammatory cytokine expression and inhibited macrophage infiltration, ultimately alleviating the inflammatory response in gastric mucosal tissue. They also enhance mitochondrial function by regulating factors associated with mitochondrial dynamics and increasing succinate dehydrogenase (SDH) activity. Furthermore, they alleviate endoplasmic reticulum stress by reducing the immunoglobulin heavy chain-binding protein (Bip), phosphorylated eukaryotic translation initiation factor 2 alpha (P-eIF2α), and activating transcription factor 4 (ATF4) expression levels. Ultimately, high doses of VTPY and VLLY increased the B-cell lymphoma-extra large to B-cell lymphoma-2 associated death promoter ratio (Bcl-XL/Bad ratio) by 138.68% and 247.99%, respectively, while the expression level of cleaved-caspase 3 decreased by 35.26% and 48.22%, thereby preventing the activation of the apoptotic pathway. Sea cucumber gut peptides VTPY and VLLY exhibit effective anti-inflammatory and anti-apoptotic properties, along with anti-endoplasmic reticulum stress effects, by inhibiting the ATF4/Bcl-2 signaling pathway, thus effectively shielding against ethanol-induced gastric damage. VLLY appears to be more potent in this aspect.