title: Soluble Epoxide Hydrolase Pharmacological Inhibition Decreases Alveolar Bone Loss by Modulating Host Inflammatory Response, RANK-Related Signaling, Endoplasmic Reticulum Stress, and Apoptosis.
abstract: Epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid derived from the cytochrome P450 enzymes, are mainly metabolized by soluble epoxide hydrolase (sEH) to their corresponding diols. EETs but not their diols, have anti-inflammatory properties, and inhibition of sEH might provide protective effects against inflammatory bone loss. Thus, in the present study, we tested the selective sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), in a mouse model of periodontitis induced by infection withAggregatibacter actinomycetemcomitansOral treatment of wild-type mice with TPPU and sEH knockout (KO) animals showed reduced bone loss induced byA. actinomycetemcomitansThis was associated with decreased expression of key osteoclastogenic molecules, receptor activator of nuclear factor-κB/RANK ligand/osteoprotegerin, and the chemokine monocyte chemotactic protein 1 in the gingival tissue without affecting bacterial counts. In addition, downstream kinases p38 and c-Jun N-terminal kinase known to be activated in response to inflammatory signals were abrogated after TPPU treatment or in sEH KO mice. Moreover, endoplasmic reticulum stress was elevated in periodontal disease but was abrogated after TPPU treatment and in sEH knockout mice. Together, these results demonstrated that sEH pharmacological inhibition may be of therapeutic value in periodontitis.
authors.affiliation: Department of Entomology and Nematology and University of California, Davis Comprehensive Cancer Center (C.A.T.-S., K.S.S.L., B.I., S.K.G., B.D.H.), Nutrition Department (F.G.H.), and Department of Molecular Biosciences, School of Veterinary Medicine (D.B.), University of California, Davis, California; Institute of Genetics and Biochemistry, Federal University of Uberlândia, Uberlândia, Brazil (C.A.T.-d.-S., C.U.-V.); Laboratory of Immunology and Molecular Biology, São Leopoldo Mandic Institute and Research Center, Campinas, Brazil (M.H.N.); and Department of Nutrition, University of Tennessee-Knoxville, Knoxville, Tennessee (A.B.).
authors.forename: Carlos Antonio
authors.initials: CA
authors.lastname: Trindade-da-Silva
authors.affiliation: Department of Entomology and Nematology and University of California, Davis Comprehensive Cancer Center (C.A.T.-S., K.S.S.L., B.I., S.K.G., B.D.H.), Nutrition Department (F.G.H.), and Department of Molecular Biosciences, School of Veterinary Medicine (D.B.), University of California, Davis, California; Institute of Genetics and Biochemistry, Federal University of Uberlândia, Uberlândia, Brazil (C.A.T.-d.-S., C.U.-V.); Laboratory of Immunology and Molecular Biology, São Leopoldo Mandic Institute and Research Center, Campinas, Brazil (M.H.N.); and Department of Nutrition, University of Tennessee-Knoxville, Knoxville, Tennessee (A.B.).
authors.forename: Ahmed
authors.initials: A
authors.lastname: Bettaieb
authors.affiliation: Department of Entomology and Nematology and University of California, Davis Comprehensive Cancer Center (C.A.T.-S., K.S.S.L., B.I., S.K.G., B.D.H.), Nutrition Department (F.G.H.), and Department of Molecular Biosciences, School of Veterinary Medicine (D.B.), University of California, Davis, California; Institute of Genetics and Biochemistry, Federal University of Uberlândia, Uberlândia, Brazil (C.A.T.-d.-S., C.U.-V.); Laboratory of Immunology and Molecular Biology, São Leopoldo Mandic Institute and Research Center, Campinas, Brazil (M.H.N.); and Department of Nutrition, University of Tennessee-Knoxville, Knoxville, Tennessee (A.B.).
authors.forename: Marcelo Henrique
authors.initials: MH
authors.lastname: Napimoga
authors.affiliation: Department of Entomology and Nematology and University of California, Davis Comprehensive Cancer Center (C.A.T.-S., K.S.S.L., B.I., S.K.G., B.D.H.), Nutrition Department (F.G.H.), and Department of Molecular Biosciences, School of Veterinary Medicine (D.B.), University of California, Davis, California; Institute of Genetics and Biochemistry, Federal University of Uberlândia, Uberlândia, Brazil (C.A.T.-d.-S., C.U.-V.); Laboratory of Immunology and Molecular Biology, São Leopoldo Mandic Institute and Research Center, Campinas, Brazil (M.H.N.); and Department of Nutrition, University of Tennessee-Knoxville, Knoxville, Tennessee (A.B.).
authors.forename: Kin Sing Stephen
authors.initials: KSS
authors.lastname: Lee
authors.affiliation: Department of Entomology and Nematology and University of California, Davis Comprehensive Cancer Center (C.A.T.-S., K.S.S.L., B.I., S.K.G., B.D.H.), Nutrition Department (F.G.H.), and Department of Molecular Biosciences, School of Veterinary Medicine (D.B.), University of California, Davis, California; Institute of Genetics and Biochemistry, Federal University of Uberlândia, Uberlândia, Brazil (C.A.T.-d.-S., C.U.-V.); Laboratory of Immunology and Molecular Biology, São Leopoldo Mandic Institute and Research Center, Campinas, Brazil (M.H.N.); and Department of Nutrition, University of Tennessee-Knoxville, Knoxville, Tennessee (A.B.).
authors.forename: Bora
authors.initials: B
authors.lastname: Inceoglu
authors.affiliation: Department of Entomology and Nematology and University of California, Davis Comprehensive Cancer Center (C.A.T.-S., K.S.S.L., B.I., S.K.G., B.D.H.), Nutrition Department (F.G.H.), and Department of Molecular Biosciences, School of Veterinary Medicine (D.B.), University of California, Davis, California; Institute of Genetics and Biochemistry, Federal University of Uberlândia, Uberlândia, Brazil (C.A.T.-d.-S., C.U.-V.); Laboratory of Immunology and Molecular Biology, São Leopoldo Mandic Institute and Research Center, Campinas, Brazil (M.H.N.); and Department of Nutrition, University of Tennessee-Knoxville, Knoxville, Tennessee (A.B.).
authors.forename: Carlos
authors.initials: C
authors.lastname: Ueira-Vieira
authors.affiliation: Department of Entomology and Nematology and University of California, Davis Comprehensive Cancer Center (C.A.T.-S., K.S.S.L., B.I., S.K.G., B.D.H.), Nutrition Department (F.G.H.), and Department of Molecular Biosciences, School of Veterinary Medicine (D.B.), University of California, Davis, California; Institute of Genetics and Biochemistry, Federal University of Uberlândia, Uberlândia, Brazil (C.A.T.-d.-S., C.U.-V.); Laboratory of Immunology and Molecular Biology, São Leopoldo Mandic Institute and Research Center, Campinas, Brazil (M.H.N.); and Department of Nutrition, University of Tennessee-Knoxville, Knoxville, Tennessee (A.B.).
authors.forename: Donald
authors.initials: D
authors.lastname: Bruun
authors.affiliation: Department of Entomology and Nematology and University of California, Davis Comprehensive Cancer Center (C.A.T.-S., K.S.S.L., B.I., S.K.G., B.D.H.), Nutrition Department (F.G.H.), and Department of Molecular Biosciences, School of Veterinary Medicine (D.B.), University of California, Davis, California; Institute of Genetics and Biochemistry, Federal University of Uberlândia, Uberlândia, Brazil (C.A.T.-d.-S., C.U.-V.); Laboratory of Immunology and Molecular Biology, São Leopoldo Mandic Institute and Research Center, Campinas, Brazil (M.H.N.); and Department of Nutrition, University of Tennessee-Knoxville, Knoxville, Tennessee (A.B.).
authors.forename: Sumanta Kumar
authors.initials: SK
authors.lastname: Goswami
authors.affiliation: Department of Entomology and Nematology and University of California, Davis Comprehensive Cancer Center (C.A.T.-S., K.S.S.L., B.I., S.K.G., B.D.H.), Nutrition Department (F.G.H.), and Department of Molecular Biosciences, School of Veterinary Medicine (D.B.), University of California, Davis, California; Institute of Genetics and Biochemistry, Federal University of Uberlândia, Uberlândia, Brazil (C.A.T.-d.-S., C.U.-V.); Laboratory of Immunology and Molecular Biology, São Leopoldo Mandic Institute and Research Center, Campinas, Brazil (M.H.N.); and Department of Nutrition, University of Tennessee-Knoxville, Knoxville, Tennessee (A.B.).
authors.forename: Fawaz G
authors.initials: FG
authors.lastname: Haj
authors.affiliation: Department of Entomology and Nematology and University of California, Davis Comprehensive Cancer Center (C.A.T.-S., K.S.S.L., B.I., S.K.G., B.D.H.), Nutrition Department (F.G.H.), and Department of Molecular Biosciences, School of Veterinary Medicine (D.B.), University of California, Davis, California; Institute of Genetics and Biochemistry, Federal University of Uberlândia, Uberlândia, Brazil (C.A.T.-d.-S., C.U.-V.); Laboratory of Immunology and Molecular Biology, São Leopoldo Mandic Institute and Research Center, Campinas, Brazil (M.H.N.); and Department of Nutrition, University of Tennessee-Knoxville, Knoxville, Tennessee (A.B.) bdhammock@ucdavis.edu.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
mesh_terms: D016301:Alveolar Bone Loss / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D007249:Inflammation / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010518:Periodontitis / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: C581572:1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea; D018836:Inflammation Mediators; D010671:Phenylurea Compounds; D010880:Piperidines; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; D004851:Epoxide Hydrolases