Targeting MAPKs, NF‐κB, and PI3K/AKT pathways by methyl palmitate ameliorates ethanol‐induced gastric mucosal injury in rats

Abstract

Excessive drinking of alcohol has been frequently associated with gastric injury; however, its underlying molecular mechanisms have been inadequately investigated. Methyl palmitate (MP) has demonstrated marked hepato‐, cardio‐ and pulmonary protective features; however, its effects on ethanol‐induced gastric injury have not been studied. The aim of the present study was to evaluate the potential gastroprotective activity of MP against ethanol‐evoked gastric mucosal damage in rats and associated molecular mechanisms, for example, mitogen‐activated protein kinases (MAPKs), nuclear factor κB (NF‐κB), and phosphoinositide 3 kinase/protein kinase B (PI3K/AKT) pathways. The rat stomachs were examined in terms of the inflammatory, oxidative, and apoptotic perturbations. Current data demonstrated that pretreatment with MP attenuated the gross gastric damage, scores of ulcer index, area of mucosal lesions and histopathology outcomes; actions which were similar to the reference antiulcer omeprazole. MP inhibited NF‐κB expression, its nuclear translocation, and the expression of its downstream signals, for example, tumor necrosis factor‐α and myeloperoxidase besides restoration of interleukin‐10 levels. Western blot analysis revealed that MP counteracted the disruption of MAPKs signaling via lowering p‐c‐Jun N‐terminal kinase 1/2 (p‐JNK1/2) expression and restoring the phospho‐extracellular signal‐regulated kinase 1/2 (p‐ERK1/2) levels without affecting p‐p38MAPK levels. Additionally, MP improved the antioxidant milieu via diminishing lipid peroxides and enhancing glutathione, glutathione peroxidase, total antioxidant capacity and mucosal nitric oxide. In the context of apoptosis, MP inhibited the cleavage of caspase‐3 and poly(ADP‐ribose)polymerase (PARP) and Bax protein expression with upregulating B cell lymphoma‐2 expression (Bcl‐2), thus, promoting gastric cellular survival. This was confirmed by MP activation of the PI3K/AKT pathway manifested by enhanced expression of PI3K p110α and p‐AKT. Together, the present findings report the gastroprotective actions of MP mediated via its anti‐inflammatory, antioxidant, and antiapoptotic actions. The underlying molecular mechanisms involve, at least partly, the modulation of MAPKs, NF‐κB and PI3K/AKT transduction.