scholarly journals In vitro and in vivo Metabolism of a Potent Inhibitor of Soluble Epoxide Hydrolase, 1-(1-Propionylpiperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea

2019 ◽  
Vol 10 ◽  
Author(s):  
Debin Wan ◽  
Jun Yang ◽  
Cindy B. McReynolds ◽  
Bogdan Barnych ◽  
Karen M. Wagner ◽  
...  
Keyword(s):  
Epoxide Hydrolase ◽  
Potent Inhibitor ◽  
Soluble Epoxide Hydrolase ◽  
In Vivo Metabolism

scholarly journals In vitro and in vivo metabolism of N-adamantyl substituted urea-based soluble epoxide hydrolase inhibitors

2015 ◽  
Vol 98 (4) ◽  
pp. 718-731 ◽  
Author(s):  
Jun-Yan Liu ◽  
Hsing-Ju Tsai ◽  
Christophe Morisseau ◽  
Jozsef Lango ◽  
Sung Hee Hwang ◽  
...  
Keyword(s):  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
In Vivo Metabolism ◽  
Soluble Epoxide Hydrolase Inhibitors ◽  
Substituted Urea

scholarly journals Inhibition of soluble epoxide hydrolase preserves cardiomyocytes: role of STAT3 signaling

2010 ◽  
Vol 298 (2) ◽  
pp. H679-H687 ◽  
Author(s):  
Matthias J. Merkel ◽  
Lijuan Liu ◽  
Zhiping Cao ◽  
William Packwood ◽  
Jennifer Young ◽  
...  
Keyword(s):  
Epoxide Hydrolase ◽  
Glucose Deprivation ◽  
Soluble Epoxide Hydrolase ◽  
Nucleotide Polymorphisms ◽  
Gene Encoding ◽  
Mutant Proteins ◽  
Stat3 Signaling ◽  
Stat3 Inhibition

Soluble epoxide hydrolase (sEH) metabolizes epoxyeicosatrienoic acids (EETs), primarily 14,15-EET. EETs are derived from arachidonic acid via P-450 epoxygenases and are cardioprotective. We tested the hypothesis that sEH deficiency and pharmacological inhibition elicit tolerance to ischemia via EET-mediated STAT3 signaling in vitro and in vivo. In addition, the relevance of single nucleotide polymorphisms (SNPs) of EPHX2 (the gene encoding sEH) on tolerance to oxygen and glucose deprivation and reoxygenation and glucose repletion (OGD/RGR) was assessed in male C57BL\6J (WT) or sEH knockout (sEHKO) cardiomyocytes by using transactivator of transcription (TAT)-mediated transduction with sEH mutant proteins. Cell death and hydrolase activity was lower in Arg287Gln EPHX2 mutants vs. nontransduced controls. Excess 14,15-EET and SEH inhibition did not improve cell survival in Arg287Gln mutants. In WT cells, the putative EET receptor antagonist, 14,15-EEZE, abolished the effect of 14,15-EET and sEH inhibition. Cotreatment with 14,15-EET and SEH inhibition did not provide increased protection. In vitro, STAT3 inhibition blocked 14,15-EET cytoprotection, but not the effect of SEH inhibition. However, STAT3 small interfering RNA (siRNA) abolished cytoprotection by 14,15-EET and sEH inhibition, but cells pretreated with JAK2 siRNA remained protected. In vivo, STAT3 inhibition abolished 14,15-EET-mediated infarct size reduction. In summary, the Arg287Gln mutation is associated with improved tolerance against ischemia in vitro, and inhibition of sEH preserves cardiomyocyte viability following OGD/RGR via an EET-dependent mechanism. In vivo and in vitro, 14,15-EET-mediated protection is mediated in part by STAT3.

scholarly journals Inhibition of soluble epoxide hydrolase ameliorates hyperhomocysteinemia-induced hepatic steatosis by enhancing β-oxidation of fatty acid in mice

2019 ◽  
Vol 316 (4) ◽  
pp. G527-G538 ◽  
Author(s):  
Liu Yao ◽  
Boyang Cao ◽  
Qian Cheng ◽  
Wenbin Cai ◽  
Chenji Ye ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Hepatic Steatosis ◽  
Fatty Liver Disease ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nonalcoholic Fatty Liver

Hepatic steatosis is the beginning phase of nonalcoholic fatty liver disease, and hyperhomocysteinemia (HHcy) is a significant risk factor. Soluble epoxide hydrolase (sEH) hydrolyzes epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids, attenuating their cardiovascular protective effects. However, the involvement of sEH in HHcy-induced hepatic steatosis is unknown. The current study aimed to explore the role of sEH in HHcy-induced lipid disorder. We fed 6-wk-old male mice a chow diet or 2% (wt/wt) high-metnionine diet for 8 wk to establish the HHcy model. A high level of homocysteine induced lipid accumulation in vivo and in vitro, which was concomitant with the increased activity and expression of sEH. Treatment with a highly selective specific sEH inhibitor (0.8 mg·kg−1·day−1 for the animal model and 1 μM for cells) prevented HHcy-induced lipid accumulation in vivo and in vitro. Inhibition of sEH activated the peroxisome proliferator-activated receptor-α (PPAR-α), as evidenced by elevated β-oxidation of fatty acids and the expression of PPAR-α target genes in HHcy-induced hepatic steatosis. In primary cultured hepatocytes, the effect of sEH inhibition on PPAR-α activation was further confirmed by a marked increase in PPAR-response element luciferase activity, which was reversed by knock down of PPAR-α. Of note, 11,12-EET ligand dependently activated PPAR-α. Thus increased sEH activity is a key determinant in the pathogenesis of HHcy-induced hepatic steatosis, and sEH inhibition could be an effective treatment for HHcy-induced hepatic steatosis. NEW & NOTEWORTHY In the current study, we demonstrated that upregulation of soluble epoxide hydrolase (sEH) is involved in the hyperhomocysteinemia (HHcy)-caused hepatic steatosis in an HHcy mouse model and in murine primary hepatocytes. Improving hepatic steatosis in HHcy mice by pharmacological inhibition of sEH to activate peroxisome proliferator-activated receptor-α was ligand dependent, and sEH could be a potential therapeutic target for the treatment of nonalcoholic fatty liver disease.

scholarly journals Correction to Optimized Inhibitors of Soluble Epoxide Hydrolase Improve in Vitro Target Residence Time and in Vivo Efficacy

2018 ◽  
Vol 61 (9) ◽  
pp. 4271-4271 ◽  
Author(s):  
Kin Sing Stephen Lee ◽  
Jun-Yan Liu ◽  
Karen M. Wagner ◽  
Svetlana Pakhomova ◽  
Hua Dong ◽  
...  
Keyword(s):  
Residence Time ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
In Vivo Efficacy

scholarly journals Homocysteine Upregulates Soluble Epoxide Hydrolase in Vascular Endothelium In Vitro and In Vivo

2012 ◽  
Vol 110 (6) ◽  
pp. 808-817 ◽  
Author(s):  
Donghong Zhang ◽  
Xina Xie ◽  
Yequn Chen ◽  
Bruce D. Hammock ◽  
Wei Kong ◽  
...  
Keyword(s):  
Vascular Endothelium ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase

scholarly journals Metabolic products of soluble epoxide hydrolase are essential for monocyte chemotaxis to MCP-1 in vitro and in vivo

2012 ◽  
Vol 54 (2) ◽  
pp. 436-447 ◽  
Author(s):  
Suman Kundu ◽  
Talat Roome ◽  
Ashish Bhattacharjee ◽  
Kevin A. Carnevale ◽  
Valentin P. Yakubenko ◽  
...  
Keyword(s):  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Metabolic Products ◽  
Monocyte Chemotaxis
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