title: Inhibiting protein arginine deiminases has antioxidant consequences.
abstract: Ulcerative colitis is a dynamic, idiopathic, chronic inflammatory condition that carries a high colon cancer risk. We previously showed that Cl-amidine, a small-molecule inhibitor of the protein arginine deiminases, suppresses colitis in mice. Because colitis is defined as inflammation of the colon associated with infiltration of white blood cells that release free radicals and citrullination is an inflammation-dependent process, we asked whether Cl-amidine has antioxidant properties. Here we show that colitis induced with azoxymethane via intraperitoneal injection + 2% dextran sulfate sodium in the drinking water is suppressed by Cl-amidine (also given in the drinking water). Inducible nitric oxide synthase, an inflammatory marker, was also downregulated in macrophages by Cl-amidine. Because epithelial cell DNA damage associated with colitis is at least in part a result of an oxidative burst from overactive leukocytes, we tested the hypothesis that Cl-amidine can inhibit leukocyte activation, as well as subsequent target epithelial cell DNA damage in vitro and in vivo. Results are consistent with this hypothesis, and because DNA damage is a procancerous mechanism, our data predict that Cl-amidine will not only suppress colitis, but we hypothesize that it may prevent colon cancer associated with colitis.
authors: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina (E.E.W., X.C., A.B.H., L.J.H.); Shanxi Medical University, Taiyuan, Shanxi, China (X.C.); Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, Florida (V.S.); Department of Chemistry, University of North Florida, Jacksonville, Florida (C.P.C.); and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts (P.R.T.).
authors: Erin E
authors: EE
authors: Witalison
authors: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina (E.E.W., X.C., A.B.H., L.J.H.); Shanxi Medical University, Taiyuan, Shanxi, China (X.C.); Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, Florida (V.S.); Department of Chemistry, University of North Florida, Jacksonville, Florida (C.P.C.); and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts (P.R.T.).
authors: Xiangli
authors: X
authors: Cui
authors: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina (E.E.W., X.C., A.B.H., L.J.H.); Shanxi Medical University, Taiyuan, Shanxi, China (X.C.); Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, Florida (V.S.); Department of Chemistry, University of North Florida, Jacksonville, Florida (C.P.C.); and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts (P.R.T.).
authors: Anne B
authors: AB
authors: Hofseth
authors: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina (E.E.W., X.C., A.B.H., L.J.H.); Shanxi Medical University, Taiyuan, Shanxi, China (X.C.); Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, Florida (V.S.); Department of Chemistry, University of North Florida, Jacksonville, Florida (C.P.C.); and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts (P.R.T.).
authors: Venkataraman
authors: V
authors: Subramanian
authors: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina (E.E.W., X.C., A.B.H., L.J.H.); Shanxi Medical University, Taiyuan, Shanxi, China (X.C.); Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, Florida (V.S.); Department of Chemistry, University of North Florida, Jacksonville, Florida (C.P.C.); and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts (P.R.T.).
authors: Corey P
authors: CP
authors: Causey
authors: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina (E.E.W., X.C., A.B.H., L.J.H.); Shanxi Medical University, Taiyuan, Shanxi, China (X.C.); Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, Florida (V.S.); Department of Chemistry, University of North Florida, Jacksonville, Florida (C.P.C.); and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts (P.R.T.).
authors: Paul R
authors: PR
authors: Thompson
authors: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina (E.E.W., X.C., A.B.H., L.J.H.); Shanxi Medical University, Taiyuan, Shanxi, China (X.C.); Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, Florida (V.S.); Department of Chemistry, University of North Florida, Jacksonville, Florida (C.P.C.); and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts (P.R.T.) hofseth@cop.sc.edu.
authors: Lorne J
authors: LJ
authors: Hofseth
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D004249:DNA Damage; D016264:Dextran Sulfate; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008810:Mice, Inbred C57BL; D009952:Ornithine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000076342:Protein-Arginine Deiminases
chemical_list: D000975:Antioxidants; C558727:N-alpha-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide; D016264:Dextran Sulfate; D009952:Ornithine; D006867:Hydrolases; D000076342:Protein-Arginine Deiminases
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