Journal
JOURNAL OF NATURAL MEDICINES
Volume 75, Issue 2, Pages 381-392Publisher
SPRINGER JAPAN KK
DOI: 10.1007/s11418-020-01479-6
Keywords
Cynaropicrin; RAW264.7; iNOS; NF-kappa B; STAT1; ANT2
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Funding
- JSPS KAKENHI [20K07109]
- Grants-in-Aid for Scientific Research [20K07109] Funding Source: KAKEN
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The methanolic extract of artichoke leaves was found to inhibit nitric oxide production, with specific sesquiterpene lactones playing a key role in this inhibitory activity. These lactones were shown to inhibit inducible nitric oxide synthase expression through multiple pathways.
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, 11 beta,13-dihydrocynaropicrin, 3 beta-hydroxy-8 alpha-[(S)-3-hydroxy-2-methylpropionyloxy]guaia-4(15),10(14),11(13)-trien-1 alpha,5 alpha,6 beta H-12,6-olide, 3 beta-hydroxy-8 alpha-[2-methoxymethyl-2-propenoyloxy]guaia-4(15),10(14),11(13)-trien-1 alpha,5 alpha,6 beta H-12,6-olide, and deacylcynaropicrin) inhibited NO production and/or inducible nitric oxide synthase (iNOS) induction. The acyl group having an alpha,beta-unsaturated carbonyl group at the 8-position and the alpha-methylene-gamma-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 kappa NF-kappa B 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.
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