Omega-6 oxylipins generated by soluble epoxide hydrolase are associated with knee osteoarthritis.
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SUBMITTER: Valdes AM
PROVIDER: S-EPMC6121933 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveChronic pain due to osteoarthritis (OA) is a major clinical problem, and existing analgesics often have limited beneficial effects and/or adverse effects, necessitating the development of novel therapies. Epoxyeicosatrienoic acids (EETs) are endogenous antiinflammatory mediators, rapidly metabolized by soluble epoxide hydrolase (EH) to dihydroxyeicosatrienoic acids (DHETs). We undertook this study to assess whether soluble EH-driven metabolism of EETs to DHETs plays a critical role in chronic joint pain associated with OA and provides a new target for treatment.MethodsPotential associations of chronic knee pain with single-nucleotide polymorphisms (SNPs) in the gene-encoding soluble EH and with circulating levels of EETs and DHETs were investigated in human subjects. A surgically induced murine model of OA was used to determine the effects of both acute and chronic selective inhibition of soluble EH by N-[1-(1-oxopropy)-4-piperidinyl]-N'-(trifluoromethoxy)phenyl]-urea (TPPU) on weight-bearing asymmetry, hind paw withdrawal thresholds, joint histology, and circulating concentrations of EETs and DHETs.ResultsIn human subjects with chronic knee pain, 3 pain measures were associated with SNPs of the soluble EH gene EPHX2, and in 2 separate cohorts of subjects, circulating levels of EETs and DHETs were also associated with 3 pain measures. In the murine OA model, systemic administration of TPPU both acutely and chronically reversed established pain behaviors and decreased circulating levels of 8,9-DHET and 14,15-DHET. EET levels were unchanged by TPPU administration.ConclusionOur novel findings support a role of soluble EH in OA pain and suggest that inhibition of soluble EH and protection of endogenous EETs from catabolism represents a potential new therapeutic target for OA pain.
| S-EPMC8957539 | biostudies-literature
Project description:Polyunsaturated fatty acids (PUFAs) including epoxide-modified ?-3 and ?-6 fatty acids are made via oxidation to create highly polarized carbon-oxygen bonds crucial to their function as signaling molecules. A critical PUFA, arachidonic acid (ARA), is metabolized to a diverse set of lipids signaling molecules through cyclooxygenase (COX), lipoxygenase (LOX), cytochrome P450 epoxygenase, or cytochrome P450 hydroxylase; however, the majority of ARA is metabolized into anti-inflammatory epoxides via cytochrome P450 enzymes. These short-lived epoxide lipids are rapidly metabolized or inactivated by the soluble epoxide hydrolase (sEH) into diol-containing products. sEH inhibition or knockout has been a practical approach to study the biology of the epoxide lipids, and has been shown to effectively treat inflammatory conditions in the preclinical models including gastrointestinal ulcers and colitis by shifting oxylipins to epoxide profiles, inhibiting inflammatory cell infiltration and activation, and enhancing epithelial cell defense via increased mucin production, thus providing further evidence for the role of sEH as a pro-inflammatory protein. Non-steroidal anti-inflammatory drugs (NSAIDs) with COX-inhibitor activity are among the most commonly used analgesics and have demonstrated applications in the management of cardiovascular disease and intriguingly cancer. Major side effects of NSAIDs however are gastrointestinal ulcers which frequently precludes their long-term application. In this review, we hope to bridge the gap between NSAID toxicity and sEH-mediated metabolic pathways to focus on the role of epoxy fatty acid metabolic pathway of PUFAs in NSAIDS-ulcer formation and healing as well as inflammation-related carcinogenesis. Specifically we address the potential application of sEH inhibition to enhance ulcer healing at the site of inflammation via their activity on altered lipid signaling, mitochondrial function, and diminished reactive oxygen species, and further discuss the significance of dual COX and sEH inhibitor in anti-inflammation and carcinogenesis.
| S-EPMC6603234 | biostudies-literature
Project description:Many cytochrome p450-derived lipids promote resolution of inflammation, in contrast to their soluble epoxide hydrolase(sEH)-derived oxylipin breakdown products. Here we compare plasma oxylipins and precursor fatty acids between seasons in participants with major depressive disorder with seasonal pattern (MDD-s). Euthymic participants with a history of MDD-s recruited in summer-fall were followed-up in winter. At both visits, a structured clinical interview (DSM-5 criteria) and the Beck Depression Inventory II (BDI-II) were administered. Unesterified and total oxylipin pools were assayed by liquid chromatography tandem mass-spectrometry (LC-MS/MS). Precursor fatty acids were measured by gas chromatography. In nine unmedicated participants euthymic at baseline who met depression criteria in winter, BDI-II scores increased from 4.9±4.4 to 19.9±7.7. Four sEH-derived oxylipins increased in winter compared to summer-fall with moderate to large effect sizes. An auto-oxidation product (unesterified epoxyketooctadecadienoic acid) and lipoxygenase-derived 13-hydroxyoctadecadienoic acid also increased in winter. The cytochrome p450-derived 20-COOH-leukotriene B4 (unesterified) and total 14(15)-epoxyeicosatetraenoic acid, and the sEH-derived 14,15-dihydroxyeicostrienoic acid (unesterified), decreased in winter. We conclude that winter depression was associated with changes in cytochrome p450- and sEH-derived oxylipins, suggesting that seasonal shifts in omega-6 and omega-3 fatty acid metabolism mediated by sEH may underlie inflammatory states in symptomatic MDD-s.
| S-EPMC5611448 | biostudies-literature
Project description:Background Cerebral small vessel disease is associated with higher ratios of soluble-epoxide hydrolase derived linoleic acid diols (12,13-dihydroxyoctadecenoic acid [DiHOME] and 9,10-DiHOME) to their parent epoxides (12(13)-epoxyoctadecenoic acid [EpOME] and 9(10)-EpOME); however, the relationship has not yet been examined in stroke. Methods and Results Participants with mild to moderate small vessel stroke or large vessel stroke were selected based on clinical and imaging criteria. Metabolites were quantified by ultra-high-performance liquid chromatography-mass spectrometry. Volumes of stroke, lacunes, white matter hyperintensities, magnetic resonance imaging visible perivascular spaces, and free water diffusion were quantified from structural and diffusion magnetic resonance imaging (3 Tesla). Adjusted linear regression models were used for analysis. Compared with participants with large vessel stroke (n=30), participants with small vessel stroke (n=50) had a higher 12,13-DiHOME/12(13)-EpOME ratio (β=0.251, P=0.023). The 12,13-DiHOME/12(13)-EpOME ratio was associated with more lacunes (β=0.266, P=0.028) but not with large vessel stroke volumes. Ratios of 12,13-DiHOME/12(13)-EpOME and 9,10-DiHOME/9(10)-EpOME were associated with greater volumes of white matter hyperintensities (β=0.364, P<0.001; β=0.362, P<0.001) and white matter MRI-visible perivascular spaces (β=0.302, P=0.011; β=0.314, P=0.006). In small vessel stroke, the 12,13-DiHOME/12(13)-EpOME ratio was associated with higher white matter free water diffusion (β=0.439, P=0.016), which was specific to the temporal lobe in exploratory regional analyses. The 9,10-DiHOME/9(10)-EpOME ratio was associated with temporal lobe atrophy (β=-0.277, P=0.031). Conclusions Linoleic acid markers of cytochrome P450/soluble-epoxide hydrolase activity were associated with small versus large vessel stroke, with small vessel disease markers consistent with blood brain barrier and neurovascular-glial disruption, and temporal lobe atrophy. The findings may indicate a novel modifiable risk factor for small vessel disease and related neurodegeneration.
| S-EPMC9973594 | biostudies-literature
Project description:Osteoarthritis (OA) is a degenerative joint disease that causes pain and bone deterioration driven by an increase in prostaglandins (PGs) and inflammatory cytokines. Current treatments focus on inhibiting prostaglandin production, a pro-inflammatory lipid metabolite, with NSAID drugs; however, other lipid signaling targets could provide safer and more effective treatment strategies. Epoxides of polyunsaturated fatty acids (PUFAs) are anti-inflammatory lipid mediators that are rapidly metabolized by the soluble epoxide hydrolase (sEH) into corresponding vicinal diols. Interestingly, diol levels are increased in the synovial fluid of humans with OA, warranting further research on the biological role of this lipid pathway in the progression of OA. sEH inhibitors (sEHI) stabilize these biologically active, anti-inflammatory lipid epoxides, resulting in analgesia in both neuropathic, and inflammatory pain conditions. Most experimental studies testing the analgesic effects of sEH inhibitors have used experimental rodent models, which do not completely represent the complex etiology of painful diseases. Here, we tested the efficacy of sEHI in aged dogs with natural arthritis to provide a better representation of the clinical manifestations of pain. Two sEHI were administered orally, once daily for 5 days to dogs with naturally occurring arthritis to assess efficacy and pharmacokinetics. Blinded technicians recorded the behavior of the arthritic dogs based on pre-determined criteria to assess pain and function. After 5 days, EC1728 significantly reduced pain at a dose of 5 mg/kg compared to vehicle controls. Pharmacokinetic evaluation showed concentrations exceeding the enzyme potency in both plasma and synovial fluid. In vitro data showed that epoxyeicosatrienoic acid (EETs), epoxide metabolites of arachidonic acid, decreased inflammatory cytokines, IL-6 and TNF-?, and reduced cytotoxicity in canine chondrocytes challenged with IL1? to simulate an arthritic environment. These results provide the first example of altering lipid epoxides as a therapeutic target for OA potentially acting by protecting chondrocytes from inflammatory induced cytotoxicity. Considering the challenges and high variability of naturally occurring disease in aged dogs, these data provide initial proof of concept justification that inhibiting the sEH is a non-NSAID, non-opioid, disease altering strategy for treating OA, and warrants further investigation.
| S-EPMC6554663 | biostudies-literature
Project description:Background & aimsAlcohol-associated liver disease (ALD) is a significant cause of liver-related morbidity and mortality worldwide and with limited therapies. Soluble epoxide hydrolase (sEH; Ephx2) is a largely cytosolic enzyme that is highly expressed in the liver and is implicated in hepatic function, but its role in ALD is mostly unexplored.MethodsTo decipher the role of hepatic sEH in ALD, we generated mice with liver-specific sEH disruption (Alb-Cre; Ephx2fl/fl). Alb-Cre; Ephx2fl/fl and control (Ephx2fl/fl) mice were subjected to an ethanol challenge using the chronic plus binge model of ALD and hepatic injury, inflammation, and steatosis were evaluated under pair-fed and ethanol-fed states. In addition, we investigated the capacity of pharmacologic inhibition of sEH in the chronic plus binge mouse model.ResultsWe observed an increase of hepatic sEH in mice upon ethanol consumption, suggesting that dysregulated hepatic sEH expression might be involved in ALD. Alb-Cre; Ephx2fl/fl mice presented efficient deletion of hepatic sEH with corresponding attenuation in sEH activity and alteration in the lipid epoxide/diol ratio. Consistently, hepatic sEH deficiency ameliorated ethanol-induced hepatic injury, inflammation, and steatosis. In addition, targeted metabolomics identified lipid mediators that were impacted significantly by hepatic sEH deficiency. Moreover, hepatic sEH deficiency was associated with a significant attenuation of ethanol-induced hepatic endoplasmic reticulum and oxidative stress. Notably, pharmacologic inhibition of sEH recapitulated the effects of hepatic sEH deficiency and abrogated injury, inflammation, and steatosis caused by ethanol feeding.ConclusionsThese findings elucidated a role for sEH in ALD and validated a pharmacologic inhibitor of this enzyme in a preclinical mouse model as a potential therapeutic approach.
| S-EPMC7851189 | biostudies-literature
Project description:Soluble epoxide hydrolase (sEH) plays a key role in the metabolic conversion of the protective eicosanoid 14,15-epoxyeicosatrienoic acid to 14,15-dihydroxyeicosatrienoic acid. Accordingly, inhibition of sEH hydrolase activity has been shown to be beneficial in multiple models of cardiovascular diseases, thus identifying sEH as a valuable therapeutic target. Recently, a common human polymorphism (R287Q) was identified that reduces sEH hydrolase activity and is localized to the dimerization interface of the protein, suggesting a relationship between sEH dimerization and activity. To directly test the hypothesis that dimerization is essential for the proper function of sEH, we generated mutations within the sEH protein that would either disrupt or stabilize dimerization. We quantified the dimerization state of each mutant using a split firefly luciferase protein fragment-assisted complementation system. The hydrolase activity of each mutant was determined using a fluorescence-based substrate conversion assay. We found that mutations that disrupted dimerization also eliminated hydrolase enzymatic activity. In contrast, a mutation that stabilized dimerization restored hydrolase activity. Finally, we investigated the kinetics of sEH dimerization and found that the human R287Q polymorphism was metastable and capable of swapping dimer partners faster than the WT enzyme. These results indicate that dimerization is required for sEH hydrolase activity. Disrupting sEH dimerization may therefore serve as a novel therapeutic strategy for reducing sEH hydrolase activity.
| S-EPMC3597810 | biostudies-literature
Project description:A series of N,N'-disubstituted ureas having a conformationally restricted cis- or trans-1,4-cyclohexane alpha to the urea were prepared and tested as soluble epoxide hydrolase (sEH) inhibitors. This series of compounds showed low nanomolar to picomolar activities against recombinant human sEH. Both isomers showed similar potencies, but the trans isomers were more metabolically stable in human hepatic microsomes. Furthermore, these new potent inhibitors show a greater metabolic stability in vivo than previously described sEH inhibitors. We demonstrated that trans-4-[4-(3-adamantan-1-ylureido)cyclohexyloxy]benzoic acid 13g (t-AUCB, IC50 = 1.3 +/- 0.05 nM) had excellent oral bioavailability (98%, n = 2) and blood area under the curve in dogs and was effective in vivo to treat hypotension in lipopolysaccharide challenged murine models.
| S-EPMC2596069 | biostudies-literature
Project description:A series of inhibitors of the soluble epoxide hydrolase (sEH) containing one or two thiourea groups has been developed. Inhibition potency of the described compounds ranges from 50 μM to 7.2 nM. 1,7-(Heptamethylene)bis[(adamant-1-yl)thiourea] (6f) was found to be the most potent sEH inhibitor, among the thioureas tested. The inhibitory activity of the thioureas against the human sEH is closer to the value of activity against rat sEH rather than murine sEH. While being less active, thioureas are up to 7-fold more soluble than ureas, which makes them more bioavailable and thus promising as sEH inhibitors.
| S-EPMC6442743 | biostudies-literature
Project description:Hepoxilins are lipid signaling molecules derived from arachidonic acid through the 12-lipoxygenase pathway. These trans-epoxy hydroxy eicosanoids play a role in a variety of physiological processes, including inflammation, neurotransmission, and formation of skin barrier function. Mammalian hepoxilin hydrolase, partly purified from rat liver, has earlier been reported to degrade hepoxilins to trioxilins. Here, we report that hepoxilin hydrolysis in liver is mainly catalyzed by soluble epoxide hydrolase (sEH): i) purified mammalian sEH hydrolyses hepoxilin A? and B? with a V(max) of 0.4-2.5 ?mol/mg/min; ii) the highly selective sEH inhibitors N-adamantyl-N'-cyclohexyl urea and 12-(3-adamantan-1-yl-ureido) dodecanoic acid greatly reduced hepoxilin hydrolysis in mouse liver preparations; iii) hepoxilin hydrolase activity was abolished in liver preparations from sEH(-/-) mice; and iv) liver homogenates of sEH(-/-) mice show elevated basal levels of hepoxilins but lowered levels of trioxilins compared with wild-type animals. We conclude that sEH is identical to previously reported hepoxilin hydrolase. This is of particular physiological relevance because sEH is emerging as a novel drug target due to its major role in the hydrolysis of important lipid signaling molecules such as epoxyeicosatrienoic acids. sEH inhibitors might have undesired side effects on hepoxilin signaling.
| S-EPMC3284163 | biostudies-literature