Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.
Chem Biol Interact. 2023 Sep 1;382:110649. doi: 10.1016/j.cbi.2023.110649. Epub 2023 Jul 25.
Gastric ulcer is a serious disease that affects millions of individuals worldwide. Alcohol consumption is a major contributor to the disease pathogenesis and ethanol-induced ulcer in rats closely recapitulates the clinical pathology of ulcer. In this study, rats were pretreated with carvacrol (CAR,50 and 100 mg/kg, orally) 1 h before absolute ethanol administration to induce gastric ulcer. CAR prevented ethanol-induced increases in gastric volume and acidity while restored mucin content. The gastro-protective activity of CAR, particularly the higher dose (100 mg/kg), was further supported by histopathological examination, as manifested by reduced gastric lesions. Interestingly, oxidative stress is linked to early stages of ulcer development and progression. In this study, ethanol administration upregulated the levels of ROS-producing enzymes, NADPH oxidase homologs 1 and 4 (Nox1 and Nox4) and lipid peroxides while depleting the antioxidant defense mechanisms, including GSH, Glutathione Peroxidase (GPX) and catalase. Interestingly, these alterations were significantly ameliorated by CAR pretreatment. Additionally, CAR possesses anti-inflammatory and anti-apoptotic activities. Pretreatment with CAR blunted ethanol-induced increases in inflammatory cytokines (NF-κB and TNF-α) and rectified the apoptosis regulator (Bax/Bcl2 ratio) in gastric tissue. Moreover, the docking simulation of CAR illustrated good fitting and interactions with GPX, Nox1 and TNF-α through the formation of hydrogen and hydrophobic (pi-H) bonds with conservative amino acids, thus, further supporting the anti-inflammatory and antioxidant effects underlying the gastroprotective effects of CAR. In conclusion, this study elucidates, using in silico and in vivo models, that the gastroprotective activity of CAR is attributed, at least in part, to its mucin-secretagogue, antioxidative, anti-inflammatory, and anti-apoptotic mechanisms.
胃溃疡是一种严重的疾病，影响着全球数百万人。饮酒是导致疾病发生的主要因素，乙醇诱导的大鼠胃溃疡与溃疡的临床病理学非常相似。在这项研究中，大鼠在给予无水乙醇前 1 小时用香芹酚（CAR，50 和 100mg/kg，口服）预处理，以诱导胃溃疡。CAR 可防止乙醇引起的胃容积和酸度增加，同时恢复粘蛋白含量。CAR 的胃保护活性，特别是高剂量（100mg/kg），通过组织病理学检查得到进一步支持，表现为胃损伤减少。有趣的是，氧化应激与溃疡发展和进展的早期阶段有关。在这项研究中，乙醇给药上调了 ROS 产生酶、NADPH 氧化酶同源物 1 和 4（Nox1 和 Nox4）和脂质过氧化物的水平，同时耗尽了抗氧化防御机制，包括 GSH、谷胱甘肽过氧化物酶（GPX）和过氧化氢酶。有趣的是，这些变化通过 CAR 预处理得到了显著改善。此外，CAR 具有抗炎和抗凋亡作用。CAR 预处理可减轻乙醇诱导的炎症细胞因子（NF-κB 和 TNF-α）增加，并纠正胃组织中凋亡调节剂（Bax/Bcl2 比值）。此外，CAR 的对接模拟表明，通过与保守氨基酸形成氢键和疏水（pi-H）键，CAR 与 GPX、Nox1 和 TNF-α 具有良好的拟合和相互作用，从而进一步支持了 CAR 发挥胃保护作用的抗炎和抗氧化作用。总之，本研究通过体内和体外模型阐明，CAR 的胃保护活性至少部分归因于其粘蛋白分泌、抗氧化、抗炎和抗凋亡机制。
