Inhibitory effects of cynaropicrin and related sesquiterpene lactones from leaves of artichoke (Cynara scolymus L.) on induction of iNOS in RAW264.7 cells and its high-affinity proteins

J Nat Med. 2021 Mar;75(2):381-392. doi: 10.1007/s11418-020-01479-6. Epub 2021 Jan 23.


The methanolic extract of the leaves of artichoke (Cynara scolymus L.) was found to inhibit nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Among the constituents of the extract, six sesquiterpene lactones (cynaropicrin, grosheimin, 11β,13-dihydrocynaropicrin, 3β-hydroxy-8α-[(S)-3-hydroxy-2-methylpropionyloxy]guaia-4(15),10(14),11(13)-trien-1α,5α,6βH-12,6-olide, 3β-hydroxy-8α-[2-methoxymethyl-2-propenoyloxy]guaia-4(15),10(14),11(13)-trien-1α,5α,6βH-12,6-olide, and deacylcynaropicrin) inhibited NO production and/or inducible nitric oxide synthase (iNOS) induction. The acyl group having an α,β-unsaturated carbonyl group at the 8-position and the α-methylene-γ-butyrolactone moiety were important for the strong inhibitory activity. Our results suggested that these sesquiterpene lactones inhibited the LPS-induced iNOS expression via the suppression of the JAK-STAT signaling pathway in addition to the κNF-κB signaling pathway. With regard to the target molecules of the sesquiterpene lactones, high-affinity proteins of cynaropicrin were purified from the cell extract. ATP/ADP translocase 2 and tubulin were identified and suggested to be involved in the cytotoxic effects of cynaropicrin, although the target molecules for the inhibition of iNOS expression were not clarified.

Keywords: ANT2; Cynaropicrin; NF-κB; RAW264.7; STAT1; iNOS.

MeSH terms

  • Animals
  • Cynara scolymus / chemistry*
  • Lactones / chemistry*
  • Lactones / pharmacology
  • Lactones / therapeutic use
  • Mice
  • Nitric Oxide Synthase Type II / metabolism*
  • Plant Leaves / chemistry*
  • RAW 264.7 Cells / metabolism*
  • Sesquiterpenes / pharmacology
  • Sesquiterpenes / therapeutic use*


  • Lactones
  • Sesquiterpenes
  • Nitric Oxide Synthase Type II
  • cynaropicrin