title: Anti-Ulcer Efficacy of Soluble Epoxide Hydrolase Inhibitor TPPU on Diclofenac-Induced Intestinal Ulcers.
abstract: Proton pump inhibitors such as omeprazole (OME) reduce the severity of gastrointestinal (GI) ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs) but can also increase the chance of dysbiosis. The aim of this study was to test the hypothesis that preventive use of a soluble epoxide hydrolase inhibitor (sEHI) such as TPPU can decrease NSAID-induced ulcers by increasing anti-inflammatory epoxyeicosatrienoic acids (EETs). Dose- [10, 30, and 100 mg/kg, by mouth (PO)] and time-dependent (6 and 18 hours) ulcerative effects of diclofenac sodium (DCF, an NSAID) were studied in the small intestine of Swiss Webster mice. Dose-dependent effects of TPPU (0.001-0.1 mg/kg per day for 7 days, in drinking water) were evaluated in DCF-induced intestinal toxicity and compared with OME (20 mg/kg, PO). In addition, the effect of treatment was studied on levels of Hb in blood, EETs in plasma, inflammatory markers such as myeloperoxidase (MPO) in intestinal tissue homogenates, and tissue necrosis factor-α (TNF-α) in serum. DCF dose dependently induced ulcers that were associated with both a significant (P < 0.05) loss of Hb and an increase in the level of MPO and TNF-α, with severity of ulceration highest at 18 hours. Pretreatment with TPPU dose dependently prevented ulcer formation by DCF, increased the levels of epoxy fatty acids, including EETs, and TPPU's efficacy was comparable to OME. TPPU significantly (P < 0.05) reversed the effect of DCF on the level of Hb, MPO, and TNF-α Thus sEHI might be useful in the management of NSAID-induced ulcers.
authors.affiliation: Department of Entomology and Nematology, and Comprehensive Cancer Center (S.K.G., D.W., J.Y., C.A.T.S., C.M., S.D.K., B.I., B.D.H.), University of California-Davis, Davis, California; Department of Genetics and Biochemistry (C.A.T.S.), Federal University of Uberlandia, Uberlandia, Minas Gerais, Brazil; Department of Pathology (G.-Y.Y.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Sumanta Kumar
authors.initials: SK
authors.lastname: Goswami
authors.affiliation: Department of Entomology and Nematology, and Comprehensive Cancer Center (S.K.G., D.W., J.Y., C.A.T.S., C.M., S.D.K., B.I., B.D.H.), University of California-Davis, Davis, California; Department of Genetics and Biochemistry (C.A.T.S.), Federal University of Uberlandia, Uberlandia, Minas Gerais, Brazil; Department of Pathology (G.-Y.Y.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Debin
authors.initials: D
authors.lastname: Wan
authors.affiliation: Department of Entomology and Nematology, and Comprehensive Cancer Center (S.K.G., D.W., J.Y., C.A.T.S., C.M., S.D.K., B.I., B.D.H.), University of California-Davis, Davis, California; Department of Genetics and Biochemistry (C.A.T.S.), Federal University of Uberlandia, Uberlandia, Minas Gerais, Brazil; Department of Pathology (G.-Y.Y.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Entomology and Nematology, and Comprehensive Cancer Center (S.K.G., D.W., J.Y., C.A.T.S., C.M., S.D.K., B.I., B.D.H.), University of California-Davis, Davis, California; Department of Genetics and Biochemistry (C.A.T.S.), Federal University of Uberlandia, Uberlandia, Minas Gerais, Brazil; Department of Pathology (G.-Y.Y.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Trindade da Silva
authors.affiliation: Department of Entomology and Nematology, and Comprehensive Cancer Center (S.K.G., D.W., J.Y., C.A.T.S., C.M., S.D.K., B.I., B.D.H.), University of California-Davis, Davis, California; Department of Genetics and Biochemistry (C.A.T.S.), Federal University of Uberlandia, Uberlandia, Minas Gerais, Brazil; Department of Pathology (G.-Y.Y.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.affiliation: Department of Entomology and Nematology, and Comprehensive Cancer Center (S.K.G., D.W., J.Y., C.A.T.S., C.M., S.D.K., B.I., B.D.H.), University of California-Davis, Davis, California; Department of Genetics and Biochemistry (C.A.T.S.), Federal University of Uberlandia, Uberlandia, Minas Gerais, Brazil; Department of Pathology (G.-Y.Y.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Sean D
authors.initials: SD
authors.lastname: Kodani
authors.affiliation: Department of Entomology and Nematology, and Comprehensive Cancer Center (S.K.G., D.W., J.Y., C.A.T.S., C.M., S.D.K., B.I., B.D.H.), University of California-Davis, Davis, California; Department of Genetics and Biochemistry (C.A.T.S.), Federal University of Uberlandia, Uberlandia, Minas Gerais, Brazil; Department of Pathology (G.-Y.Y.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Guang-Yu
authors.initials: GY
authors.lastname: Yang
authors.affiliation: Department of Entomology and Nematology, and Comprehensive Cancer Center (S.K.G., D.W., J.Y., C.A.T.S., C.M., S.D.K., B.I., B.D.H.), University of California-Davis, Davis, California; Department of Genetics and Biochemistry (C.A.T.S.), Federal University of Uberlandia, Uberlandia, Minas Gerais, Brazil; Department of Pathology (G.-Y.Y.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Bora
authors.initials: B
authors.lastname: Inceoglu
authors.affiliation: Department of Entomology and Nematology, and Comprehensive Cancer Center (S.K.G., D.W., J.Y., C.A.T.S., C.M., S.D.K., B.I., B.D.H.), University of California-Davis, Davis, California; Department of Genetics and Biochemistry (C.A.T.S.), Federal University of Uberlandia, Uberlandia, Minas Gerais, Brazil; Department of Pathology (G.-Y.Y.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois bdhammock@ucdavis.edu.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects; D019610:Cytoprotection / Q000187:drug effects; D004008:Diclofenac / Q000009:adverse effects*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D055786:Gene Knockout Techniques; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D009195:Peroxidase / Q000378:metabolism; D010671:Phenylurea Compounds / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014456:Ulcer / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: C581572:1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D010671:Phenylurea Compounds; D010880:Piperidines; D014409:Tumor Necrosis Factor-alpha; D004008:Diclofenac; D009195:Peroxidase; D004851:Epoxide Hydrolases