Direct interaction of garcinol and related polyisoprenylated benzophenones of Garcinia cambogia fruits with the transcription factor STAT-1 as a likely mechanism of their inhibitory effect on cytokine signaling pathways

J Nat Prod. 2014 Mar 28;77(3):543-9. doi: 10.1021/np400804y. Epub 2014 Jan 13.

Abstract

Garcinol (1), a polyisoprenylated benzophenone occurring in Garcinia species, has been reported to exert anti-inflammatory activity in LPS-stimulated macrophages, through inhibition of NF-κB and/or JAK/STAT-1 activation. In order to provide deeper insight into its effects on the cytokine signaling pathway and to clarify the underlying molecular mechanisms, 1 was isolated from the fruits of Garcinia cambogia along with two other polyisoprenylated benzophenones, guttiferones K (2) and guttiferone M (3), differing from each other in their isoprenyl moieties and their positions on the benzophenone core. The affinities of 1-3 for the STAT-1 protein have been evaluated by surface plasmon resonance and molecular docking studies and resulted in KD values in the micromolar range. Consistent with the observed high affinity toward the STAT-1 protein, garcinol and guttiferones K and M were able to modulate cytokine signaling in different cultured cell lines, mainly by inhibiting STAT-1 nuclear transfer and DNA binding, as assessed by an electrophorectic mobility shift assay.

MeSH terms

  • Benzophenones / chemistry
  • Benzophenones / isolation & purification*
  • Benzophenones / pharmacology*
  • Blotting, Northern
  • Female
  • Fruit / chemistry
  • Garcinia cambogia / chemistry*
  • Humans
  • Lipopolysaccharides / pharmacology
  • Macrophages / drug effects*
  • Methicillin-Resistant Staphylococcus aureus / drug effects
  • Molecular Conformation
  • Molecular Structure
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / drug effects
  • STAT1 Transcription Factor / drug effects*
  • Signal Transduction / drug effects
  • Sri Lanka
  • Terpenes / chemistry*
  • Terpenes / isolation & purification
  • Terpenes / pharmacology*

Substances

  • Benzophenones
  • Lipopolysaccharides
  • NF-kappa B
  • STAT1 Transcription Factor
  • Terpenes
  • guttiferone I
  • guttiferone K
  • garcinol