@article {ZHANG5261, author = {WANYING ZHANG and HAONAN LI and HUA DONG and JIE LIAO and BRUCE D. HAMMOCK and GUANG-YU YANG}, title = {Soluble Epoxide Hydrolase Deficiency Inhibits Dextran Sulfate Sodium-induced Colitis and Carcinogenesis in Mice}, volume = {33}, number = {12}, pages = {5261--5271}, year = {2013}, publisher = {International Institute of Anticancer Research}, abstract = {Soluble epoxide hydrolase (sEH) hydrolyses/inactivates anti-inflammatory epoxyeicosatrienoic acids (EETs) to their corresponding diols, and targeting sEH leads to strong anti-inflammatory effects. In the present study, using a tissue microarray and immunohistochemical approach, a significant increase of sEH expression was identified in ulcerative colitis (UC)-associated dysplasia and adenocarcinoma. The effects of deficiency in the sEH gene were determined on dextran sulfate sodium (DSS) colitis-induced carcinogenesis. The effects of EETs on lipopolysaccharide (LPS)-activated macrophages were analyzed in vitro. With extensive histopathological and immunohistochemical analyses, compared to wild-type mice, sEH-/- mice exhibited a significant decrease in tumor incidence (13/20 vs. 6/19, p\<0.05) and a markedly reduced average tumor size (59.62{\textpm}20.91 mm3 vs. 22.42{\textpm}11.22 mm3), and a significant number of pre-cancerous dysplasia (3{\textpm}1.18 vs. 2{\textpm}0.83, p\<0.01). The inflammatory activity, as measured by the extent/proportion of erosion/ulceration/dense lymphoplasmacytosis (called active colitis index) in the colon, was significantly lower in sEH-/- mice (44.7\%{\textpm}24.9\% vs. 20.2\%{\textpm}16.2\%, p\<0.01). The quantitative polymerase chain reaction (qPCR) assays demonstrated significantly low levels of cytokines/chemokines including monocyte chemoattractant protein (MCP-1), inducible nitric oxide synthase (iNOS), vasopressin-activated calcium-mobilizing (VCAM-1), interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α). In vitro, LPS-activated macrophages treated with 14,15-EET showed a significant reduction of LPS-triggered IL-1β and TNF-α expression. Eicosanoic acid metabolic profiling revealed a significant increase of the ratios of EETs/ dihydroeicosatrienoic acids (DHETs) and epoxyoctadecennoic acid/dihydroxyoctadecenoic acid (EpOMEs/DiHOMEs). These results indicate that sEH plays an important role in the development of colitis and in inducing carcinogenesis.}, issn = {0250-7005}, URL = {https://ar.iiarjournals.org/content/33/12/5261}, eprint = {https://ar.iiarjournals.org/content/33/12/5261.full.pdf}, journal = {Anticancer Research} }