The effects of a synthetic curcuminoid analogue, 2,6-bis-(4-hydroxyl-3- methoxybenzylidine)cyclohexanone on proinflammatory signaling pathways and CLP-induced lethal sepsis in mice

Chau Ling Tham, Kok Wai Lam, Revathee Rajajendram, Yoke Kqueen Cheah, Mohd Roslan Sulaiman, Nordin H. Lajis, Min Kyu Kim, Daud A. Israf

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

We previously showed that 2,6-bis-(4-hydroxyl-3-methoxybenzylidine) cyclohexanone (BHMC), suppressed the synthesis of various proinflammatory mediators. In this study we explain the mechanism of action of BHMC in lipopolysaccharide (LPS)-induced U937 monocytes and further show that BHMC prevents lethality of CLP-induced sepsis. BHMC showed dose-dependent inhibitory effects on p38, JNK and ERK 1/2 activity as determined by inhibition of phosphorylation of downstream transcription factors ATF-2, c-Jun and Elk-1 respectively. Inhibition of these transcription factors subsequently caused total abolishment of AP-1-DNA binding. BHMC inhibited p65 NF-κB nuclear translocation and DNA binding of p65 NF-κB only at the highest concentration used (12.5 μM) but failed to alter phosphorylation of JNK, ERK1/2 and STAT-1. Since the inhibition of p38 activity was more pronounced we evaluated the possibility that BHMC may bind to p38. Molecular docking experiments confirmed that BHMC fits well in the highly conserved hydrophobic pocket of p38 MAP kinase. We also show that BHMC was able to improve survival from lethal sepsis in a murine caecal-ligation and puncture (CLP) model.

Original languageEnglish
Pages (from-to)136-144
Number of pages9
JournalEuropean Journal of Pharmacology
Volume652
Issue number1-3
DOIs
Publication statusPublished - 10 Feb 2011
Externally publishedYes

Fingerprint

Punctures
Hydroxyl Radical
Ligation
Sepsis
Activating Transcription Factors
Phosphorylation
cyclohexanone
DNA
Transcription Factor AP-1
p38 Mitogen-Activated Protein Kinases
Lipopolysaccharides
Monocytes
Transcription Factors

Keywords

  • BHMC
  • Curcumin
  • MAPK
  • Monocyte
  • NF-κB
  • Sepsis

ASJC Scopus subject areas

  • Pharmacology

Cite this

The effects of a synthetic curcuminoid analogue, 2,6-bis-(4-hydroxyl-3- methoxybenzylidine)cyclohexanone on proinflammatory signaling pathways and CLP-induced lethal sepsis in mice. / Tham, Chau Ling; Lam, Kok Wai; Rajajendram, Revathee; Cheah, Yoke Kqueen; Sulaiman, Mohd Roslan; Lajis, Nordin H.; Kim, Min Kyu; Israf, Daud A.

In: European Journal of Pharmacology, Vol. 652, No. 1-3, 10.02.2011, p. 136-144.

Research output: Contribution to journalArticle

Tham, Chau Ling ; Lam, Kok Wai ; Rajajendram, Revathee ; Cheah, Yoke Kqueen ; Sulaiman, Mohd Roslan ; Lajis, Nordin H. ; Kim, Min Kyu ; Israf, Daud A. / The effects of a synthetic curcuminoid analogue, 2,6-bis-(4-hydroxyl-3- methoxybenzylidine)cyclohexanone on proinflammatory signaling pathways and CLP-induced lethal sepsis in mice. In: European Journal of Pharmacology. 2011 ; Vol. 652, No. 1-3. pp. 136-144.
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