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

Jang Hoon Kim; Ji Hyeon Park; Sung Cheol Koo; Yun-Chan Huh; Mok Hur; Woo Tae Park; Youn-Ho Moon; Tae Il Kim; Byoung Ok Cho

doi:10.3390/plants12203656

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

Plants (Basel). 2023 Oct 23;12(20):3656. doi: 10.3390/plants12203656.

Authors

Jang Hoon Kim¹, Ji Hyeon Park², Sung Cheol Koo¹, Yun-Chan Huh¹, Mok Hur¹, Woo Tae Park¹, Youn-Ho Moon¹, Tae Il Kim¹, Byoung Ok Cho²

Affiliations

¹ Department of Herbal Crop Research, National Institute of Horticultural and Herbal Science, RDA, Eumseong 27709, Chungcheongbuk-do, Republic of Korea.
² Institute of Health Science, Jeonju University, 303 Cheonjam-ro, Wansan-gu, Jeonju-si 55069, Jeollabuk-do, Republic of Korea.

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 k_i 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: anti-inflammation; cis-khellactone; competitive inhibitor; molecular simulation; soluble epoxide hydrolase.

Grants and funding

The research presented in this paper was supported by a “Cooperative Research Program for Agriculture Science & Technology Development” (Project No. RS-2022-RD010239) funded by the Rural Development Administration of the Republic of Korea.