Omega-3 epoxides ameliorate murine inflammatory arthritis

Background Epoxy fatty acids (EpFA), cytochrome P450(CYP)-mediated metabolites of polyunsaturated fatty acids (PUFA), have anti-inflammatory effects [1] . However, EpFA is quickly converted to an inactive form by the soluble epoxide hydrolase(sEH). In recent years, the efficacy of sEH inhibitors (sEHi) has been reported in a variety of diseases [2-4] . However, compared to ω-6 epoxides, such as epoxyeicosatirienioic acids (EET) derived from arachidonic acid (AA), there are few reports on ω-3 epoxides, epoxyeicosapentaenoic acid (EEQ) from eicosapentaenoic acid (EPA) and epoxydocosapentaenoic acids (EDP) from docosapentaenoic acid (DHA)5), and their effects on arthritis are not well understood. Objectives To investigate and compare the effects of ω-6 and ω-3 epoxides on inflammatory arthritis. Methods Collagen induced arthritis (CIA) were treated with three different diets (ω-6 PUFA rich, ω-3 PUFA rich, and Control) and two types of drinking solution, one containing sEHi and the other containing only polyethylene glycol as solvent control (total 6 groups, 8 mice each). Arthritis and pathological scores were evaluated, and feces were collected before the onset of arthritis (day 25) for intergroup comparative analysis of bacterial flora. Results In all the dietary groups, there was a tendency for arthritis scores to decrease with sEHi administration, but the incidence of arthritis, arthritis scores, and pathological scores decreased dramatically in the group fed with the ω-3 rich diet and sEHi combination. The groups fed the ω-6 rich diet and Control diet showed almost similar results. In the ω-3 rich diet and sEHi combination group, showed an increase in a certain specific bacterial strain. Conclusion ω-3 epoxides were found to be more effective in reducing arthritis, and changes in intestinal bacteria may have influenced this pathological change. References [1]Shi, Z. et al. CYP450 Epoxygenase Metabolites, Epoxyeicosatrienoic Acids, as Novel Anti-Inflammatory Mediators. Molecules 2022,27,3873 [2]Sandra, C. et al. Discovery and In Vivo Proof of Concept of a Highly Potent Dual Inhibitor of Soluble Epoxide Hydrolase and Acetylcholinesterase for the Treatment of Alzheimer’s Disease. J.Med.Chem,2022,65,4909-4925 [3]Merce, P.et al. Soluble Epoxide Hydrolase Inhibition to Face Neuroinflammation in Parkinson’s Disease: A New Therapeutic Strategy.Biomolecules 2020, 10, 703; doi:10.3390/biom10050703 [4]Rebecca, L.et al. Protection from hypertension in mice by the Mediterranean diet is mediated by nitro fatty acid inhibition of soluble epoxide hydrolase. PNAS,2014,22,111,8167-8172 [5]Yang, Y. et al. Differential Effects of 17,18-EEQ and 19,20-EDP Combined with Soluble Epoxide Hydrolase Inhibitor t-TUCB on Diet-Induced Obesity in Mice. Int. J. Mol. Sci. 2021,22,8267 g. Characters from table content including title and footnotes. Figure 1. Acknowledgements: NIL. Disclosure of Interests None Declared.