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Soluble epoxide hydrolase inhibition confers neuroprotective and anti-inflammatory effect in a tauopathy mouse model

ABSTRACT: Inhibition of soluble epoxide hydrolase (sEH) has been shown to suppress neuroinflammation through stabilizing epoxy fatty acids. Here we examined the role of sEH inhibitor TPPU in PS19 tauopathy mouse model by treating the 6-month-old wild-type and PS19 mice with vehicle or TPPU via drinking water continuously for 12 weeks, followed by performing single nucleus RNA-sequencing of the hippocampal tissues of the treated mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE272373 | GEO | 2025/04/30

REPOSITORIES: GEO

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A regulatory loop involving the cytochrome P450-soluble epoxide hydrolase axis and TGF-b signaling

Project description:Fatty acid metabolites generated by the sequential actions of cytochrome P450 enzymes and the soluble epoxide hydrolase (sEH) regulate inflammation. Here we report that the TGF--induced polarization of macrophages to a pro-resolving phenotype requires the activation of Alk5 and Smad2 to increase sEH expression and activity. Macrophages lacking sEH failed to fully repolarize, were less efficient at phagocytosis, and retained a pro-inflammatory gene expression profile. 11,12-Epoxyeicosatrienoic acid (EET) was one of the fatty acid metabolites altered in sEH-/- macrophages and was able to reproduce the effect of sEH deletion on gene expression. Importantly, 11,12-EET also attenuated the expression of Alk5 to inhibit the TGF--induced phosphorylation of Smad2 by eliciting the cytosolic translocation of the E3 ligase Smurf2. These results indicate that the expression of sEH is not only controlled by TGF- but that the activity of the enzyme, which keeps 11,12-EET levels low, actually promotes TGF- signaling by preventing the proteolytic degradation of Alk5. Thus, an autocrine loop between the sEH/11,12-EET and TGF-1 determines macrophage function.

2024-08-15 | GSE273900 | GEO

An epoxide hydrolase inhibitor reduces neuroinflammation in a mouse model of Alzheimer’s disease

Project description:Neuroinflammation has been increasingly recognized to play a critical role in Alzheimer’s disease (AD). The epoxy fatty acids (EpFAs) are derivatives of the arachidonic acid metabolism pathway and have anti-inflammatory activities. However, their efficacy is limited due to their rapid hydrolysis by the soluble epoxide hydrolase (sEH). We report that sEH is predominantly expressed in astrocytes and its concentrations are elevated in postmortem brain tissue from AD patients and in the 5xFAD -amyloid mouse model of AD. The amount of sEH expressed in AD mouse brains correlated with a reduction in brain EpFA concentrations. Using a specific small molecule sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), we report that TPPU treatment protected AD mice against LPS-induced inflammation in vivo. Long-term administration of TPPU to the 5xFAD mouse model via drinking water reversed microglia and astrocyte reactivity and immune pathway dysregulation. This was associated with reduced β-amyloid pathology and improved synaptic integrity and cognitive function on two behavioral tests. Importantly, TPPU treatment correlated with an increase in EpFA concentrations in the brains of 5xFAD mice, demonstrating brain penetration and target engagement. These findings support further investigation of TPPU as a potential therapeutic agent for the treatment of AD.

2020-11-20 | GSE161848 | GEO

Soluble epoxide hydrolase inhibition confers neuroprotective and anti-inflammatory effect in a tauopathy mouse model

Project description:Soluble epoxide hydrolase inhibition confers neuroprotective and anti-inflammatory effect in a tauopathy mouse model

| PRJNA1136532 | ENA

Inhibition of Soluble Epoxide Hydrolase is Protective Against the Multiomic Effects of a High Glycemic Diet on Brain Microvascular Inflammation and Cognitive Dysfunction

Project description:Diet is a modifiable risk factor for cardiovascular disease (CVD) and dementia, yet relatively little is known about the effect of a high glycemic diet (HGD) on the brain microvasculature. The objective of our study was to determine the molecular effects of a HGD on hippocampal microvessels and cognitive function, and to determine if a soluble epoxide hydrolase (sEH) inhibitor (sEHI), known to be vasculoprotective and anti-inflammatory, modulates these effects. Global hippocampal microvascular gene expression was fundamentally different for mice fed the HGD vs the LGD. The HGD response was characterized by differential expression of 608 genes involved in cell signaling, neurodegeneration, metabolism, and cell adhesion/inflammation/oxidation effects reversible by t-AUCB and hence sEH inhibitor correlated with protection against Alzheimer’s dementia.

2021-12-07 | GSE185057 | GEO

TFEB-vacuolar ATPase signaling regulates lysosomal activity and immune response in tauopathy

Project description:Transcription factor EB (TFEB) mediates gene expression through binding to the Coordinated Lysosome Expression And Regulation (CLEAR) sequence. We created a knock-in mouse line in which the CLEAR sequence of ATP6V1H was mutated. Crossing the CLEAR mutant with PS19 mice led to higher tau pathology but dampened glial cell activation. snRNA-seq revealed that the CLEAR mutant failed to be activated in tauopathy conditions.

2023-06-02 | GSE218728 | GEO

Differential Multigenomic Effect of Soluble Epoxide Hydrolase Inhibition on the Hippocampal Brain Microvasculature of FeFemale Mice on Low and High Glycemic Diets.

Project description:Microvascular dysfunction is central to the development of dementia. The effect of high glycemic diet (HGD), independent from dietary fat, on brain microvasculature is crucial, yet an understudied research topic, especially in feFemales. Our study aimed to determine the transcriptomic changes in feFemale brain hippocampal microvasculature induced by a HGD and characterize the response to soluble epoxide hydrolase inhibitor (sEHI). We demonstrated for the first time in feFemales that the HGD had an opposite gene expression profile compared to the LGD and differentially expressed 506 genes, primarily downregulated, with functions related to cell signaling, cell adhesion, cellular metabolism, and neurodegenerative diseases. Surprisingly, the sEHI modified the transcriptome of feFemale mice consuming the LGD more than the HGD, by modulating genes involved in metabolic pathways that synthesize neuroprotective epoxyeicosatrienoic acids (EETs) and associated with a higher EETs/ dihydroxyeicosatrienoic acids (DHETs) ratio.

2022-11-16 | GSE195975 | GEO

Soluble epoxide hydrolase dimerization is required for hydrolase activity.

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

Consequences of sEH deletion in the polyoma middle T (PyMT) breast cancer tumor proteome

Project description:The aim of this investigation was to study the consequences of interfering with soluble epoxide hydrolase (sEH) expression on tumor growth and metastasis in genetically modified animals that spontaneously generate tumors without the exogenous application of high concentrations of epoxide mediators or inhibitors. Therefore, breast cancer development was studied in mice expressing the polyoma middle T oncogene (PyMT) under the control of the mouse mammary tumor virus promoter, to induce spontaneous mammary tumors. To facilitate the study of endogenous sEH activity in tumor growth, PyMT mice were then crossed with sEH-/- mice to generate sEH-deficient mice that spontaneously generate breast tumors (so called PyMTsEH mice). For these analyses, primary tumors were removed from 20 week old mice.

2021-09-14 | PXD026214 | Pride

Orally bioavailable potent soluble epoxide hydrolase inhibitors.

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

Adamantyl thioureas as soluble epoxide hydrolase inhibitors.

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

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