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

Abstract

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 µM and ki value of 3.5 µM. 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-1β, and IL-4. These findings affirm that cis-khellactone could serve as a natural therapeutic candidate for the treatment of inflammation.

Keywords

• <i>cis</i>-khellactone
• soluble epoxide hydrolase
• competitive inhibitor
• molecular simulation
• anti-inflammation