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[Infinite1]

I just happened to run across an article in which a fairly novel approach to reducing inflammation by targeting Soluble epoxide hydrolase (sEH). Given this is my first exposure to this I'm far from very knowledgeable on the topic, however I'm still surprised there was any talk of this in this forum given the myriad of diseases characterized by inflammation, essentially all have some footing within. 

 

Ok, so this will be mostly copy and paste to start this off. 

 

Courtesy of wikipedia..

 

Clinical significance
Through metabolism of EETs and other lipid mediators, sEH plays a role in several diseases, including hypertension, cardiac hypertrophy, arteriosclerosis, brain and heart ischemia/reperfusion injury, cancer and pain.[8] Because of its possible role in cardiovascular and other diseases, sEH is being pursued as a pharmacological target, and potent small molecule inhibitors are available.[11]

Because of the implications to human health, sEH has been pursued as a pharmaceutical target and several sEH inhibitors have been developed in the private and public sectors.[11] One such inhibitor, UC1153 (AR9281), was taken to a phase IIA clinal trial for treatment of hypertension by Arête Therapeutics.[17] However, UC1153 failed the clinical trial, due in large part because of its poor pharmacokinetic properties.[11] Since this trial, a different sEH inhibitor, GSK2256294, developed for chronic obstructive pulmonary disease by GlaxoSmithKline has entered the pre-recruiting phase of a phase I clinical trial for obese male smokers.[18] Thus, interest continues in sEH as a therapeutic target.

One indication of the possible therapeutic value of sEH inhibition comes from studies examining physiologically relevant single nucleotide polymorphisms (SNPs) of sEH in human populations.[19] The Coronary Artery Risk Development in Young Adults (CARDIA) and the Atherosclerosis Risk in Communities (ARIC) studies both associated SNPs in the sEH coding region with coronary heart disease.[20][21] In these studies, two nonsynonymous SNPs were identified, R287Q and K55R. R287Q changes the arginine in position 287 in the most frequent allele to glutamine, while K55R changes the lysine in position 55 to an arginine. R287Q was associated with coronary artery calcification in African American population participating in the CARDIA study.[20][22]

 

 

 

 

Oral treatment of rodents with soluble epoxide hydrolase inhibitor 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU): Resulting drug levels and modulation of oxylipin pattern.
Ostermann AI1, Herbers J1, Willenberg I1, Chen R2, Hwang SH3, Greite R2, Morisseau C3, Gueler F2, Hammock BD3, Schebb NH4.

 

Author information
Abstract
Epoxides from polyunsaturated fatty acids (PUFAs) are potent lipid mediators. In vivo stabilization of these epoxides by blockade of the soluble epoxide hydrolase (sEH) leads to anti-inflammatory, analgesic and normotensive effects. Therefore, sEH inhibitors (sEHi) are a promising new class of drugs. Herein, we characterized pharmacokinetic (PK) and pharmacodynamic properties of a commercially available potent sEHi 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU). Cell culture studies suggest its high absorption and metabolic stability. Following administration in drinking water to rats (0.2, 1, and 5mg TPPU/L with 0.2% PEG400), TPPU's blood concentration increased dose dependently within the treatment period to reach an almost steady state after 8 days. TPPU was found in all the tissues tested. The linoleic epoxide/diol ratios in most tissues were dose dependently increased, indicating significant sEH inhibition. Overall, administration of TPPU with the drinking water led to systemic distribution as well as high drug levels and thus makes chronic sEH inhibition studies possible.

 

Abstract: http://www.ncbi.nlm....pubmed/26117215

 

 

 

 

Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress

 

Abstract

Depression is a severe and chronic psychiatric disease, affecting 350 million subjects worldwide. Although multiple antidepressants have been used in the treatment of depressive symptoms, their beneficial effects are limited. The soluble epoxide hydrolase (sEH) plays a key role in the inflammation that is involved in depression. Thus, we examined here the role of sEH in depression. In both inflammation and social defeat stress models of depression, a potent sEH inhibitor, TPPU, displayed rapid antidepressant effects. Expression of sEH protein in the brain from chronically stressed (susceptible) mice was higher than of control mice. Furthermore, expression of sEH protein in postmortem brain samples of patients with psychiatric diseases, including depression, bipolar disorder, and schizophrenia, was higher than controls. This finding suggests that increased sEH levels might be involved in the pathogenesis of certain psychiatric diseases. In support of this hypothesis, pretreatment with TPPU prevented the onset of depression-like behaviors after inflammation or repeated social defeat stress. Moreover, sEH KO mice did not show depression-like behavior after repeated social defeat stress, suggesting stress resilience. The sEH KO mice showed increased brain-derived neurotrophic factor  and phosphorylation of its receptor TrkB in the prefrontal cortex, hippocampus, but not nucleus accumbens, suggesting that increased BDNF-TrkB signaling in the prefrontal cortex and hippocampus confer stress resilience. All of these findings suggest that sEH plays a key role in the pathophysiology of depression, and that epoxy fatty acids, their mimics, as well as sEH inhibitors could be potential therapeutic or prophylactic drugs for depression.ary heart disease in Caucasians participating in the ARIC study, where it was also associated with a higher risk of hypertension and ischemic stroke in male homozygotes.[21]

 

Full Text: BDhttp://www.pnas.org/...01532113.fullNF

 

 

 

 

 

 

 

[Infinite1]

There appears to be a natural source in the case that RC's makes one squeamish. Not sure where it can be sourced however...

 

Potent Natural Soluble Epoxide Hydrolase Inhibitors from Pentadiplandra brazzeana Baillon: Synthesis, Quantification, and Measurement of Biological Activities In Vitro and In Vivo

 

We describe here three urea-based soluble epoxide hydrolase (sEH) inhibitors from the root of the plant Pentadiplandra brazzeana. The concentration of these ureas in the root was quantified by LC-MS/MS, showing that 1, 3-bis (4-methoxybenzyl) urea (MMU) is the most abundant (42.3 μg/g dry root weight). All of the ureas were chemically synthesized, and their inhibitory activity toward recombinant human and recombinant rat sEH was measured. The most potent compound, MMU, showed an IC50 of 92 nM via fluorescent assay and a Ki of 54 nM via radioactivity-based assay on human sEH. MMU effectively reduced inflammatory pain in a rat nociceptive pain assay. These compounds are among the most potent sEH inhibitors derived from natural sources. Moreover, inhibition of sEH by these compounds may mechanistically explain some of the therapeutic effects of P. brazzeana.

 

full text: http://www.ncbi.nlm....les/PMC4319826/