Soluble Epoxide Hydrolase Pharmacological Inhibition Decreases Alveolar Bone Loss by Modulating Host Inflammatory Response, RANK-Related Signaling, Endoplasmic Reticulum Stress, and Apoptosis

Abstract

Epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid derived from the cytochrome P450 enzymes, are mainly metabolized by soluble epoxide hydrolase (sEH) to their corresponding diols. EETs but not their diols, have anti-inflammatory properties, and inhibition of sEH might provide protective effects against inflammatory bone loss. Thus, in the present study, we tested the selective sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), in a mouse model of periodontitis induced by infection with Oral treatment of wild-type mice with TPPU and sEH knockout (KO) animals showed reduced bone loss induced by This was associated with decreased expression of key osteoclastogenic molecules, receptor activator of nuclear factor-κB/RANK ligand/osteoprotegerin, and the chemokine monocyte chemotactic protein 1 in the gingival tissue without affecting bacterial counts. In addition, downstream kinases p38 and c-Jun N-terminal kinase known to be activated in response to inflammatory signals were abrogated after TPPU treatment or in sEH KO mice. Moreover, endoplasmic reticulum stress was elevated in periodontal disease but was abrogated after TPPU treatment and in sEH knockout mice. Together, these results demonstrated that sEH pharmacological inhibition may be of therapeutic value in periodontitis.

Soluble epoxide hydrolase as a therapeutic target for pain, inflammatory and neurodegenerative diseases

“…In these animals, the chief osteoclastogenic molecules RANK/RANKL/OPG and the chemokine MCP-1 were downregulated and downstream inflammatory JNK and p38 kinase signaling was abated. In addition, this study demonstrated that ER Stress was upregulated with periodontal disease but was blocked by both sEHI administration and in the sEH knockout mice (Trindade da Silva, et al, 2017). Thus, given the role of sEHI and EpFA action against inflammation combined with the effects on other bone loss conditions, sEH inhibition may be a useful strategy to combat periodontitis.…”

Lipid mediators and biomarkers associated with type 1 diabetes development

“…These included lower DHETs but greater decreases in EETs, higher LTC 4 (activates NOX4 and induces ROS production) ( 40 ) with a corresponding decrease in its precursor LTE 4 (inflammatory through GPR99) ( 41 ), and detection of LTB 4 (potent chemoattractant and induces ROS) in the NOD-WT, relative to NOD-HET. The EETs are generated via CYP-catalyzed metabolism of arachidonic acid and have antiinflammatory properties ( 42 ). However, they can be converted by soluble epoxide hydrolase (sEH1) to DHETs, which are proinflammatory, and the present findings suggest that sEH1 is induced in the NOD, causing a decrease in the EET/DHET ratio.…”

Modulation of mitochondrial dysfunction and endoplasmic reticulum stress are key mechanisms for the wide-ranging actions of epoxy fatty acids and soluble epoxide hydrolase inhibitors

“…As these inflammatory pathologies were examined unexpected and usually beneficial effects were observed. For example, sEHI not only reduce periodontal inflammation but also enhanced the regrowth of bone through alteration of the RANK - RANKL system [38]. The reduction of inflammation was observed in multiple models of intestinal, renal, pancreatic, brain and even cardiac inflammation, so it was not a surprise that they reduced atrial fibrillation and fibrosis that lead to cardiac hypertrophy [39].…”