B L Slomiany1, J Piotrowski, A Slomiany. 1. Research Center, University of Medicine and Dentistry of New Jersey, 07103-2400, Newark, NJ, USA.
Abstract
AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Authors: J G Ferraz; K A Sharkey; B K Reuter; S Asfaha; A W Tigley; M L Brown; W McKnight; J L Wallace Journal: Gastroenterology Date: 1997-07 Impact factor: 22.682
Authors: A Parenti; L Morbidelli; X L Cui; J G Douglas; J D Hood; H J Granger; F Ledda; M Ziche Journal: J Biol Chem Date: 1998-02-13 Impact factor: 5.157