soluble epoxide hydrolase
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2021 ◽  
Vol 12 ◽  
Author(s):  
Karen M. Wagner ◽  
Jun Yang ◽  
Christophe Morisseau ◽  
Bruce D. Hammock

The soluble epoxide hydrolase (sEH) enzyme is a major regulator of bioactive lipids. The enzyme is highly expressed in liver and kidney and modulates levels of endogenous epoxy-fatty acids, which have pleiotropic biological effects including limiting inflammation, neuroinflammation, and hypertension. It has been hypothesized that inhibiting sEH has beneficial effects on limiting obesity and metabolic disease as well. There is a body of literature published on these effects, but typically only male subjects have been included. Here, we investigate the role of sEH in both male and female mice and use a global sEH knockout mouse model to compare the effects of diet and diet-induced obesity. The results demonstrate that sEH activity in the liver is modulated by high-fat diets more in male than in female mice. In addition, we characterized the sEH activity in high fat content tissues and demonstrated the influence of diet on levels of bioactive epoxy-fatty acids. The sEH KO animals had generally increased epoxy-fatty acids compared to wild-type mice but gained less body weight on higher-fat diets. Generally, proinflammatory prostaglandins and triglycerides were also lower in livers of sEH KO mice fed HFD. Thus, sEH activity, prostaglandins, and triglycerides increase in male mice on high-fat diet but are all limited by sEH ablation. Additionally, these changes also occur in female mice though at a different magnitude and are also improved by knockout of the sEH enzyme.


2021 ◽  
Vol 14 (12) ◽  
pp. 1323
Author(s):  
Juan Martín-López ◽  
Sandra Codony ◽  
Clara Bartra ◽  
Christophe Morisseau ◽  
María Isabel Loza ◽  
...  

The pharmacological inhibition of soluble epoxide hydrolase (sEH) has been suggested as a potential therapy for the treatment of pain and inflammatory diseases through the stabilization of endogenous epoxyeicosatrienoic acids. Numerous potent sEH inhibitors (sEHI) have been developed, however many contain highly lipophilic substituents limiting their availability. Recently, a new series of benzohomoadamantane-based ureas endowed with potent inhibitory activity for the human and murine sEH was reported. However, their very low microsomal stability prevented further development. Herein, a new series of benzohomoadamantane-based amides were synthetized, fully characterized, and evaluated as sEHI. Most of these amides were endowed with excellent inhibitory potencies. A selected compound displayed anti-inflammatory effects with higher effectiveness than the reference sEHI, TPPU.


2021 ◽  
Vol 22 (24) ◽  
pp. 13218
Author(s):  
Paul-Emmanuel Vanderriele ◽  
Qing Wang ◽  
Anne-Marie Mérillat ◽  
Frédérique Ino ◽  
Gilles Aeschlimann ◽  
...  

Mutations within the glucocorticoid receptor (GR) gene locus lead to glucocorticoid resistance which is characterized by several clinical symptoms such as adrenal gland hyperplasia and salt-sensitive hypertension, although the underlying mechanisms are still unknown. We studied GR haploinsufficient (GR+/−) Sprague Dawley rats which, on a standard diet, showed significantly increased plasma aldosterone and corticosterone levels and an adrenocortex hyperplasia accompanied by a normal systolic blood pressure. Following a high salt diet, these rats developed salt-sensitive hypertension and maintained elevated enzyme-soluble epoxide hydrolase (sEH) in adrenal glands, while sEH was significantly decreased in wild-type rats. Furthermore, GR+/− rats showed dysregulation of the equilibrated linoleic and arachidonic acid pathways, with a significant increase of less active metabolites such as 8,9-DiHETrE. In Sprague Dawley rats, GR haploinsufficiency induced steroid disturbances, which provoked hypertension only in combination with high salt intake, which was accompanied by disturbances in sEH and fatty acid metabolism. Our results suggest that sEH inhibition could be a potential target to treat hypertension in patients with GR haploinsufficiency.


Author(s):  
Mona Mashayekhi ◽  
Celestine N. Wanjalla ◽  
Christian M. Warren ◽  
Joshua D. Simmons ◽  
Kakali Ghoshal ◽  
...  

2021 ◽  
Vol 17 (S9) ◽  
Author(s):  
Jacopo Di Lucente ◽  
Hercules R Freitas ◽  
Karen M Wagner ◽  
Bruce D. Hammock ◽  
Izumi Maezawa ◽  
...  

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ranran Tu ◽  
Jillian Armstrong ◽  
Kin Sing Stephen Lee ◽  
Bruce D. Hammock ◽  
Adam Sapirstein ◽  
...  

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