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This study evaluated the protective effects of inhibiting caspase-1 activity or gastric acid secretion on acute gastric injury in mice. AC-YVAD-CMK, omeprazole, or vehicle were administered to mice before cold-restraint stress- or ethanol-induced gastric injury. Survival rates and histological evidence of gastric injury of mice pretreated with AC-YVAD-CMK or omeprazole, and exposed to cold-restraint stress, improved significantly relative to the vehicle group. The increased levels of tumour necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-18 following cold-stress injury were decreased by AC-YVAD-CMK, but not omeprazole, pretreatment. The increased expression of CD68 in gastric tissues was inhibited significantly by AC-YVAD-CMK pretreatment. Inhibiting caspase-1 activity in the NLRP3 inflammasome decreased gastric cell apoptosis, and the expression of Bax and cleaved caspase-3. AC-YVAD-CMK pretreatment significantly inhibited cold-restraint stress-induced increases in the expression of phosphorylated IκB-alpha and P38. General anatomy and histological results showed the protective effect of AC-YVAD-CMK on ethanol-induced acute gastric injury. Overall, our results showed that the caspase-1 inhibitor AC-YVAD-CMK protected against acute gastric injury in mice by affecting the NLRP3 inflammasome and attenuating inflammatory processes and apoptosis. This was similar to the mechanism associated with NF-κB and P38 mitogen-activated protein kinase signalling pathways.

Titel:	The caspase-1 inhibitor AC-YVAD-CMK attenuates acute gastric injury in mice: involvement of silencing NLRP3 inflammasome activities.
Autor/in / Beteiligte Person:	Zhang, F ; Wang, L ; Wang, JJ ; Luo, PF ; Wang, XT ; Xia, ZF
Link:	Volltext (PDF)
Zeitschrift:	Scientific reports, Jg. 6 (2016-04-07), S. 24166
Veröffentlichung:	London : Nature Publishing Group, copyright 2011-, 2016
Medientyp:	academicJournal
ISSN:	2045-2322 (electronic)
DOI:	10.1038/srep24166
Schlagwort:	Acute Disease Animals Apoptosis drug effects Blotting, Western Central Nervous System Depressants administration & dosage Central Nervous System Depressants toxicity Cold Temperature adverse effects Cysteine Proteinase Inhibitors pharmacology Cytokines metabolism Ethanol administration & dosage Ethanol toxicity Gastric Mucosa metabolism Gene Expression Regulation drug effects Inflammasomes genetics Inflammasomes metabolism Male Mice, Inbred C57BL NF-kappa B metabolism NLR Family, Pyrin Domain-Containing 3 Protein genetics Restraint, Physical adverse effects Reverse Transcriptase Polymerase Chain Reaction Signal Transduction drug effects Stomach drug effects Stomach pathology Stomach Diseases etiology Stomach Diseases genetics p38 Mitogen-Activated Protein Kinases metabolism Amino Acid Chloromethyl Ketones pharmacology Caspase 1 metabolism Inflammasomes drug effects NLR Family, Pyrin Domain-Containing 3 Protein metabolism Stomach Diseases prevention & control
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Sci Rep] 2016 Apr 07; Vol. 6, pp. 24166. <i>Date of Electronic Publication: </i>2016 Apr 07. MeSH Terms: Amino Acid Chloromethyl Ketones / pharmacology ; Caspase 1 / metabolism ; Inflammasomes / drug effects ; NLR Family, Pyrin Domain-Containing 3 Protein / metabolism ; Stomach Diseases / *prevention & control ; Acute Disease ; Animals ; Apoptosis / drug effects ; Blotting, Western ; Central Nervous System Depressants / administration & dosage ; Central Nervous System Depressants / toxicity ; Cold Temperature / adverse effects ; Cysteine Proteinase Inhibitors / pharmacology ; Cytokines / metabolism ; Ethanol / administration & dosage ; Ethanol / toxicity ; Gastric Mucosa / metabolism ; Gene Expression Regulation / drug effects ; Inflammasomes / genetics ; Inflammasomes / metabolism ; Male ; Mice, Inbred C57BL ; NF-kappa B / metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein / genetics ; Restraint, Physical / adverse effects ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction / drug effects ; Stomach / drug effects ; Stomach / pathology ; Stomach Diseases / etiology ; Stomach Diseases / genetics ; p38 Mitogen-Activated Protein Kinases / metabolism References: Mucosal Immunol. 2016 May;9(3):659-68. (PMID: 26349656) ; Biol Pharm Bull. 2001 Jan;24(1):1-9. (PMID: 11201234) ; J Pharmacol Exp Ther. 2013 Sep;346(3):465-72. (PMID: 23833276) ; Genome Biol Evol. 2015 Jan;7(1):218-27. (PMID: 25527836) ; J Immunol. 2014 Oct 1;193(7):3566-76. (PMID: 25172489) ; Chem Biol Interact. 2010 Jan 5;183(1):249-54. (PMID: 19788892) ; Molecules. 2015;20(12):22553-64. (PMID: 26694339) ; PLoS One. 2014;9(1):e86686. (PMID: 24466200) ; World J Gastroenterol. 2008 Aug 14;14(30):4784-90. (PMID: 18720540) ; Circ Res. 2008 Apr 11;102(7):804-12. (PMID: 18276918) ; Alcohol. 2013 Sep;47(6):481-93. (PMID: 23830200) ; Chem Biol Interact. 2012 Apr 15;197(1):31-9. (PMID: 22465177) ; Biochem Biophys Res Commun. 2013 May 10;434(3):547-51. (PMID: 23583384) ; Am J Kidney Dis. 2005 Jan;45(1):54-65. (PMID: 15696444) ; Immunology. 2013 Oct;140(2):250-8. (PMID: 23777345) ; Int Immunopharmacol. 2013 Jun;16(2):248-53. (PMID: 23499678) ; Pflugers Arch. 2013 Nov;465(11):1613-20. (PMID: 23756852) ; J Immunol. 2012 Apr 15;188(8):3594-602. (PMID: 22403439) ; Chem Biol Interact. 2014 Feb 5;208:18-27. (PMID: 24300194) ; Dig Dis Sci. 2014 Dec;59(12):2927-34. (PMID: 25283375) ; World J Gastroenterol. 2014 Dec 7;20(45):17020-8. (PMID: 25493014) ; Am J Reprod Immunol. 2015 Apr;73(4):301-12. (PMID: 25041469) ; Clin Biochem. 2007 Jun;40(9-10):615-22. (PMID: 17466292) ; Nat Rev Drug Discov. 2012 Aug;11(8):633-52. (PMID: 22850787) ; Toxicol Appl Pharmacol. 2013 Oct 1;272(1):21-9. (PMID: 23769714) ; Mol Cell Biol. 2015 Feb;35(3):582-97. (PMID: 25452302) ; World J Gastroenterol. 2013 Sep 7;19(33):5473-84. (PMID: 24023490) ; PLoS Pathog. 2014 Nov;10(11):e1004462. (PMID: 25375146) ; Eur J Gastroenterol Hepatol. 2012 Jun;24(6):675-82. (PMID: 22441511) ; Am J Physiol Cell Physiol. 2013 Jul 15;305(2):C182-9. (PMID: 23636457) ; Exp Ther Med. 2013 May;5(5):1456-1460. (PMID: 23737898) ; Front Physiol. 2014 Sep 29;5:352. (PMID: 25324778) Substance Nomenclature: 0 (Amino Acid Chloromethyl Ketones) ; 0 (Central Nervous System Depressants) ; 0 (Cysteine Proteinase Inhibitors) ; 0 (Cytokines) ; 0 (Inflammasomes) ; 0 (N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone) ; 0 (NF-kappa B) ; 0 (NLR Family, Pyrin Domain-Containing 3 Protein) ; 0 (Nlrp3 protein, mouse) ; 3K9958V90M (Ethanol) ; EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) ; EC 3.4.22.36 (Caspase 1) Entry Date(s): Date Created: 20160408 Date Completed: 20170310 Latest Revision: 20190424 Update Code: 20231215 PubMed Central ID: PMC4823746

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The caspase-1 inhibitor AC-YVAD-CMK attenuates acute gastric injury in mice: involvement of silencing NLRP3 inflammasome activities.