Inhibitory Activity of Natural cis-Khellactone on Soluble Epoxide Hydrolase and Proinflammatory Cytokine Production in Lipopolysaccharides-Stimulated RAW264.7 Cells

The pursuit of anti-inflammatory agents has led to intensive research on the inhibition of soluble epoxide hydrolase (sEH) and cytokine production using medicinal plants. In this study, we evaluated the efficacy of cis-khellactone, a compound isolated for the first time from the roots of Peucedanum japonicum. The compound was found to be a competitive inhibitor of sEH, exhibiting an IC50 value of 3.1 +/- 2.5 mu M and k(i) value of 3.5 mu M. Molecular docking and dynamics simulations illustrated the binding pose of (-)cis-khellactone within the active site of sEH. The results suggest that binding of the inhibitor to the enzyme is largely dependent on the Trp336-Gln384 loop within the active site. Further, cis-khellactone was found to inhibit pro-inflammatory cytokines, including NO, iNOS, IL-1 beta, and IL-4. These findings affirm that cis-khellactone could serve as a natural therapeutic candidate for the treatment of inflammation.