(5-Hydroxy-4-oxo-4H-pyran-2-yl)methyl 6-hydroxynaphthalene-2-carboxylate, a kojic acid derivative, inhibits inflammatory mediator production via the suppression of Syk/Src and NF-κB activation

To Thi Mai Dung, Seung Cheol Kim, Byong Chul Yoo, Gi Ho Sung, Woo Seok Yang, Han Gyung Kim, Jae Gwang Park, Man Hee Rhee, Kye Won Park, Keejung Yoon, Yunmi Lee, Sungyoul Hong, Jong Hoon Kim, Jae Youl Cho

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Numerous derivatives of kojic acid have been synthesised to expand its immunopharmacological uses. Kojic acid is known to have anti-cancer, anti-inflammatory, and anti-melanogenesis effects. We found that (5-hydroxy-4-oxo-4H-pyran-2-yl)methyl 6-hydroxynaphthalene-2-carboxylate (MHNC) strongly suppressed the production of nitric oxide (NO) in an initial screening experiment. In this study, we explored the in vitro and in vivo anti-inflammatory activity of MHNC and its inhibitory mechanisms using lipopolysaccharide (LPS)-treated RAW264.7 cells and HCl/EtOH-treated ICR mice. MHNC dose-dependently diminished the secretion of nitric oxide (NO) and prostaglandin (PG)E2 in LPS-treated RAW264.7 cells. This compound also suppressed the upregulation of mRNA levels for the inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 genes. Additionally, the transcriptional activation of these genes was inhibited by MHNC through the suppression of the nuclear translocation of nuclear factor (NF)-κB subunits (p65 and p50), as determined by a luciferase reporter assay. Interestingly, MHNC treatment was found to suppress a series of upstream signalling cascades consisting of IκBα, AKT, PDK1, Src, and Syk for NF-κB activation. Furthermore, a direct enzyme assay with purified Src and Syk and luciferase assays using Src and Syk overexpression indicated that these enzymes were directly inhibited by MHNC. Finally, MHNC (20 mg/kg) prevented inflammatory symptoms of the stomach in mice treated with HCl/EtOH by reducing phospho-IκBα levels. Taken together, our data suggest that MHNC may negatively modulate in vitro and in vivo inflammatory responses via the direct suppression of Syk/Src and NF-κB.

Original languageEnglish
Pages (from-to)37-45
Number of pages9
JournalInternational Immunopharmacology
Volume20
Issue number1
DOIs
StatePublished - May 2014

Keywords

  • (5-Hydroxy-4-oxo-4H-pyran-2-yl)methyl 6-hydroxynaphthalene-2-carboxylate
  • Anti-inflammatory effect
  • NF-κB
  • Src
  • Syk

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