| Suppression of growth arrest and DNA damage-inducible 45alpha expression confers resistance to sulindac and indomethacin-induced gastric mucosal injury. | |
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MedLine Citation:
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PMID: 20498252 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Nonsteroidal anti-inflammatory drugs (NSAIDs) such as sulindac and indomethacin are a major cause of gastric erosions and ulcers. Induction of apoptosis by NSAIDs is an important mechanism involved. Understanding how NSAIDs affect genes that regulate apoptosis is useful for designing therapeutic or preventive strategies and for evaluating the efficacy of safer drugs being developed. We investigated whether growth arrest and DNA damage-inducible 45alpha (GADD45alpha), a stress signal response gene involved in regulation of DNA repair and induction of apoptosis, plays a part in NSAID-induced gastric mucosal injury and apoptosis in vivo in mice and in vitro in cultured human AGS and rat RGM-1 gastric epithelial cells. Intraperitoneal administration of sulindac and indomethacin both resulted in up-regulation of GADD45alpha expression and induction of significant injury and apoptosis in gastric mucosa of wild-type mice. GADD45alpha(-/-) mice were markedly more resistant to both sulindac- and indomethacin-induced gastric mucosal injury and apoptosis than wild-type mice. Sulindac sulfide and indomethacin treatments also concentration-dependently increased GADD45alpha expression and apoptosis in AGS and RGM-1 cells. Antisense suppression of GADD45alpha expression significantly reduced sulindac and indomethacin-induced activation of caspase-9 and apoptosis in AGS cells. Pretreatments with exogenous prostaglandins and small interfering RNA suppression of cyclooxygenase (COX)-1 and -2 did not affect up-regulation of GADD45alpha by sulindac sulfide and indomethacin in AGS cells. These findings indicate that GADD45alpha up-regulation is a COX-independent mechanism that is required for induction of severe gastric mucosal apoptosis and injury by NSAIDs, probably via a capase-9-dependent pathway of programmed cell death. |
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Authors:
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Shiun-Kwei Chiou; Amy Hodges; Neil Hoa |
Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, Non-P.H.S. Date: 2010-05-24 |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 334 ISSN: 1521-0103 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2010 Sep |
Date Detail:
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Created Date: 2010-08-20 Completed Date: 2010-09-23 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
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Languages: eng Pagination: 693-702 Citation Subset: IM |
Affiliation:
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Department of Veterans Affairs Medical Center, 5901 E. 7th St, Long Beach, CA 90822-5201, USA. skchiou@yahoo.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anti-Inflammatory Agents, Non-Steroidal / toxicity* Antisense Elements (Genetics) / pharmacology Apoptosis / drug effects Caspase 9 / antagonists & inhibitors, metabolism Cell Cycle Proteins / antagonists & inhibitors*, biosynthesis Cell Proliferation / drug effects Cyclooxygenase 1 / metabolism Cyclooxygenase 2 Inhibitors / pharmacology Cyclooxygenase Inhibitors / pharmacology DNA Damage Dinoprostone / pharmacology Endothelial Cells / drug effects, enzymology Enzyme Activation / drug effects Gastric Mucosa / pathology* Humans Indomethacin / toxicity* Mice Mice, Inbred C57BL Mice, Knockout Nuclear Proteins / antagonists & inhibitors*, biosynthesis RNA, Small Interfering / pharmacology Rats Reverse Transcriptase Polymerase Chain Reaction Stomach Ulcer / chemically induced, pathology*, prevention & control* Sulindac / toxicity* Up-Regulation |
| Chemical | |
Reg. No./Substance:
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0/Anti-Inflammatory Agents, Non-Steroidal; 0/Antisense Elements (Genetics); 0/Cell Cycle Proteins; 0/Cyclooxygenase 2 Inhibitors; 0/Cyclooxygenase Inhibitors; 0/Gadd45a protein, rat; 0/Nuclear Proteins; 0/RNA, Small Interfering; 363-24-6/Dinoprostone; 38194-50-2/Sulindac; 53-86-1/Indomethacin; EC 1.14.99.1/Cyclooxygenase 1; EC 3.4.22.-/Caspase 9 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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