Research Center, University of Medicine and Dentistry of New Jersey, 07103-2400, Newark, NJ, USA.
Inflammopharmacology. 1998;6(3):243-53. doi: 10.1007/s10787-998-0023-3.
In this study we investigated the effect of the antiulcer agent, sulglycotide, on the activity of a key pro-apoptotic protease, caspase-3, and the expression of inducible nitric oxide synthase (NOS-2) associated with gastric epithelial cell apoptosis triggered by the enhancement in tumour necrosis factor-alpha (TNF-alpha) during indomethacin-induced gastric mucosal injury.
The experiments were conducted with rats pretreated intragastrically with sulglycotide (200 mg/kg) or vehicle, followed 30 min later by an intragastric dose of indomethacin (60 mg/kg). The animals were killed 2 h later and their mucosal tissue used for macroscopic assessment, assays of epithelial cell apoptosis and TNF-alpha, and the measurement of caspase-3 and NOS-2 activities.
In the absence of sulglycotide, indomethacin caused multiple haemorrhagic lesions accompanied by a 20-fold enhancement in gastric epithelial cell apoptosis and a 47% increase in mucosal expression of TNF-alpha, while NOS-2 showed an 11.9-fold induction and the activity of caspase-3 increased 3.9-fold. Pretreatment with sulglycotide produced a 51.2% reduction in the extent of mucosal damage caused by indomethacin, a 43.9% decrease in the epithelial cell apoptosis and a 39.7% reduction in TNF-alpha, while the activity of caspase-3 decreased by 58.8% and that of NOS-2 showed a 47.3% decline.
Our findings implicate the enhanced expression of caspase-3 and NOS-2 in the process of death signalling cascade associated with indomethacin-induced gastric mucosal injury, and show that sulglycotide is capable of suppressing the pathway of apoptotic events propagated by TNF-alpha, NOS-2 and caspase-3.
本研究旨在探讨抗溃疡剂硫糖酯对肿瘤坏死因子-α（TNF-α）增强诱导的胃上皮细胞凋亡过程中关键促凋亡蛋白酶 caspase-3 活性和诱导型一氧化氮合酶（NOS-2）表达的影响。
采用大鼠模型，大鼠预先给予硫糖酯（200mg/kg）或载体灌胃，30 分钟后给予吲哚美辛（60mg/kg）灌胃。2 小时后处死动物，取胃黏膜组织进行大体评估、上皮细胞凋亡和 TNF-α检测，并测定 caspase-3 和 NOS-2 活性。
在没有硫糖酯的情况下，吲哚美辛导致多个出血性病变，同时胃上皮细胞凋亡增加 20 倍，黏膜 TNF-α表达增加 47%，NOS-2 诱导增加 11.9 倍，caspase-3 活性增加 3.9 倍。硫糖酯预处理使吲哚美辛引起的黏膜损伤程度减少 51.2%，上皮细胞凋亡减少 43.9%，TNF-α减少 39.7%，同时 caspase-3 活性减少 58.8%，NOS-2 活性减少 47.3%。
我们的发现表明，caspase-3 和 NOS-2 的表达增强与吲哚美辛诱导的胃黏膜损伤相关的死亡信号级联反应有关，并且表明硫糖酯能够抑制 TNF-α、NOS-2 和 caspase-3 介导的凋亡事件途径。
