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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Inhibiting Protein Arginine Deiminases Has Antioxidant Consequences

Erin E. Witalison, Xiangli Cui, Anne B. Hofseth, Venkataraman Subramanian, Corey P. Causey, Paul R. Thompson and Lorne J. Hofseth
Journal of Pharmacology and Experimental Therapeutics April 2015, 353 (1) 64-70; DOI: https://doi.org/10.1124/jpet.115.222745
Erin E. Witalison
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.)
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Xiangli Cui
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.)
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Anne B. Hofseth
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.)
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Venkataraman Subramanian
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.)
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Corey P. Causey
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.)
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Paul R. Thompson
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.)
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Lorne J. Hofseth
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.)
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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.

Footnotes

    • Received January 7, 2015.
    • Accepted January 28, 2015.
  • This work was supported by the National Institutes of Health National Cancer Institute [Grant 5R01-CA151304].

  • dx.doi.org/10.1124/jpet.115.222745.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 353 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 353, Issue 1
1 Apr 2015
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Antioxidant/Anti-DNA Damage Consequences of PAD Inhibition

Erin E. Witalison, Xiangli Cui, Anne B. Hofseth, Venkataraman Subramanian, Corey P. Causey, Paul R. Thompson and Lorne J. Hofseth
Journal of Pharmacology and Experimental Therapeutics April 1, 2015, 353 (1) 64-70; DOI: https://doi.org/10.1124/jpet.115.222745

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Antioxidant/Anti-DNA Damage Consequences of PAD Inhibition

Erin E. Witalison, Xiangli Cui, Anne B. Hofseth, Venkataraman Subramanian, Corey P. Causey, Paul R. Thompson and Lorne J. Hofseth
Journal of Pharmacology and Experimental Therapeutics April 1, 2015, 353 (1) 64-70; DOI: https://doi.org/10.1124/jpet.115.222745
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