Suppression of colitis in mice by Cl-amidine: a novel peptidylarginine deiminase inhibitor.
Authors
Chumanevich, Alexander A.Causey, Corey P.
Knuckley, Bryan
Jones, Justin E.
Poudyal, Deepak
Davis, Tia
Chumanevich, Alena P.
Matesic, Lydia E.
Thompson, Paul R
Hofseth, Lorne J.
UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyDocument Type
Journal ArticlePublication Date
2011-06-01Keywords
Administration, OralAnimals
Anti-Inflammatory Agents
Apoptosis
Arginine
Citrulline
Colitis
Colon
Dextran Sulfate
Disease Models, Animal
Dose-Response Relationship, Drug
Enzyme Inhibitors
Gastrointestinal Agents
HT29 Cells
Humans
Hydrolases
Mice
Mice, Inbred C57BL
Ornithine
Protein Processing, Post-Translational
Up-Regulation
Biochemistry
Enzymes and Coenzymes
Medicinal-Pharmaceutical Chemistry
Therapeutics
Metadata
Show full item recordAbstract
Inflammatory bowel diseases (IBDs), mainly Crohn's disease and ulcerative colitis, are dynamic, chronic inflammatory conditions that are associated with an increased colon cancer risk. Inflammatory cell apoptosis is a key mechanism for regulating IBD. Peptidylarginine deiminases (PADs) catalyze the posttranslational conversion of peptidylarginine to peptidylcitrulline in a calcium-dependent, irreversible reaction and mediate the effects of proinflammatory cytokines. Because PAD levels are elevated in mouse and human colitis, we hypothesized that a novel small-molecule inhibitor of the PADs, i.e., chloramidine (Cl-amidine), could suppress colitis in a dextran sulfate sodium mouse model. Results are consistent with this hypothesis, as demonstrated by the finding that Cl-amidine treatment, both prophylactic and after the onset of disease, reduced the clinical signs and symptoms of colitis, without any indication of toxic side effects. Interestingly, Cl-amidine drives apoptosis of inflammatory cells in vitro and in vivo, providing a mechanism by which Cl-amidine suppresses colitis. In total, these data help validate the PADs as therapeutic targets for the treatment of IBD and further suggest Cl-amidine as a candidate therapy for this disease.Source
Am J Physiol Gastrointest Liver Physiol. 2011 Jun;300(6):G929-38. doi: 10.1152/ajpgi.00435.2010. Epub 2011 Mar 17. Link to article on publisher's siteDOI
10.1152/ajpgi.00435.2010Permanent Link to this Item
http://hdl.handle.net/20.500.14038/50038Notes
At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.
Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1152/ajpgi.00435.2010