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Soluble epoxide hydrolase inhibitor, TPPU, increases regulatory T cells pathway in an arthritis model.

ABSTRACT: Epoxyeicosatrienoic acids (EET) and related epoxy fatty acids (EpFA) are endogenous anti-inflammatory compounds, which are converted by the soluble epoxide hydrolase (sEH) to dihydroxylethersatrienoic acids (DHETs) with lessened biological effects. Inhibition of sEH is used as a strategy to increase EET levels leading to lower inflammation. Rheumatoid arthritis is a chronic autoimmune disease that leads to destruction of joint tissues. This pathogenesis involves a complex interplay between the immune system, and environmental factors. Here, we investigate the effects of inhibiting sEH with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) on a collagen-induced arthritis model. The treatment with TPPU ameliorates hyperalgesia, edema, and decreases the expression of important pro-inflammatory cytokines of Th1 and Th17 profiles, while increasing Treg cells. Considering the challenges to control RA, this study provides robust data supporting that inhibition of the sEH is a promising target to treat arthritis.

SUBMITTER: Trindade-da-Silva CA

PROVIDER: S-EPMC7383812 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Soluble epoxide hydrolase inhibitor, TPPU, increases regulatory T cells pathway in an arthritis model.

Trindade-da-Silva Carlos A CA Clemente-Napimoga Juliana T JT Abdalla Henrique B HB Rosa Sergio Marcolino SM Ueira-Vieira Carlos C Morisseau Christophe C Verri Waldiceu A WA Montalli Victor Angelo Martins VAM Hammock Bruce D BD Napimoga Marcelo H MH

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20200513 7

Epoxyeicosatrienoic acids (EET) and related epoxy fatty acids (EpFA) are endogenous anti-inflammatory compounds, which are converted by the soluble epoxide hydrolase (sEH) to dihydroxylethersatrienoic acids (DHETs) with lessened biological effects. Inhibition of sEH is used as a strategy to increase EET levels leading to lower inflammation. Rheumatoid arthritis is a chronic autoimmune disease that leads to destruction of joint tissues. This pathogenesis involves a complex interplay between the i ...[more]

PMID: 32400048

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Project description:Objective Paclitaxel-induced peripheral neuropathy (PIPN) is a debilitating and difficult-to-treat side effect of paclitaxel. Soluble epoxide hydrolase (sEH) can rapidly metabolize the endogenous anti-inflammatory mediators' epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids. This study aimed to assess whether the sEH inhibitor N-(1-(1-oxopropy)-4-piperidinyl]-N′-(trifluoromethoxy) phenyl)-urea (TPPU) plays a critical role in PIPN of rats and provides a new target for treatment. Methods A Sprague–Dawley male rat model of PIPN induced by nab-paclitaxel was established. Rats were randomly divided into a control group, nab-paclitaxel group, and nab-paclitaxel + TPPU (sEH inhibitor) group, with 36 rats in each group. The effects of the sEH inhibitor TPPU on behavioural assays, apoptosis, glial activation, axonal injury, microstructure, and permeability of the blood-spinal cord barrier were detected, and the underlying mechanisms were explored by examining the expression of NF-κB signalling pathways, inflammatory cytokines, and oxidative stress. Results The results showed that the mechanical and thermal pain thresholds of rats were decreased after nab-paclitaxel treatment, accompanied by an increased expression of axonal injury-related proteins, enhanced cell apoptosis, aggravated destruction of vascular permeability, intense glial responses, and elevated inflammatory cytokines and oxidative stress in the L4-L6 spinal cord. TPPU restored the mechanical and thermal thresholds, decreased cell apoptosis, alleviated axonal injury and glial responses, and protected vascular permeability by increasing the expression of tight junction proteins. TPPU relieved PIPN by inhibiting the activation of the sEH and NF-κB signalling pathways by decreasing the levels of inflammatory cytokines and oxidative stress. Conclusion These findings support a role for sEH in PIPN and suggest that the inhibition of sEH represents a potential new therapeutic target for PIPN.

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Soluble epoxide hydrolase inhibitor, TPPU, increases regulatory T cells pathway in an arthritis model.

Publications

Soluble epoxide hydrolase inhibitor, TPPU, increases regulatory T cells pathway in an arthritis model.

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