Abstract
Our preliminary screening had shown that the curcumin derivative [2,6-bis(2,5-dimethoxybenzylidene)cyclohexanone] or BDMC33 exhibited improved anti-inflammatory activity by inhibiting nitric oxide synthesis in activated macrophage cells. In this study, we further investigated the anti-inflammatory properties of BDMC33 on PGE2 synthesis and cyclooxygenase (COX) expression in IFN-γ/LPS-stimulated macrophages. We found that BDMC33 significantly inhibited PGE2 synthesis in a concentration-dependent manner albeit at a low inhibition level with an IC50 value of 47.33 ± 1.00 µM. Interestingly, the PGE2 inhibitory activity of BDMC33 is not attributed to inhibition of the COX enzyme activities, but rather BDMC33 selectively down-regulated the expression of COX-2. In addition, BDMC33 modulates the COX expression by sustaining the constitutively COX-1 expression in IFN-γ/LPS-treated macrophage cells. Collectively, the experimental data suggest an immunodulatory action of BDMC33 on PGE2 synthesis and COX expression, making it a possible treatment for inflammatory disorders with minimal gastrointestinal-related side effects.
Highlights
Prostaglandins (PG) are potent bioactive lipid molecules derived from arachidonic acid (AA) and produced by most cells within the body
COX-1 in gastro-protection, the non-selective inhibitory action of non-steroidal anti-inflammatory drugs (NSAID) on both COX-1 and COX-2 enzyme results in high degree of gastrointestinal toxicity and ulceration. This phenomenon prompted an investigation aimed at discovering alternative and selective drug targeting on COX-2 with minimal gastrointestinal-related side effects [7,8]
We further demonstrate the immunomodulatory action of BDMC33 on inhibition of PGE2 synthesis via suppression of COX-2 in IFN- /LPS-challenged macrophage cells
Summary
Prostaglandins (PG) are potent bioactive lipid molecules derived from arachidonic acid (AA) and produced by most cells within the body. COX-1 in gastro-protection, the non-selective inhibitory action of NSAID on both COX-1 and COX-2 enzyme results in high degree of gastrointestinal toxicity and ulceration. This phenomenon prompted an investigation aimed at discovering alternative and selective drug targeting on COX-2 with minimal gastrointestinal-related side effects [7,8]. BDMC33 [2,6-bis(2,5-dimethoxybenzylidene) cyclohexanone] exhibited improved anti-inflammatory activities by inhibiting NO production in IFN- /LPS challenged macrophage cells [13]. We further demonstrate the immunomodulatory action of BDMC33 on inhibition of PGE2 synthesis via suppression of COX-2 in IFN- /LPS-challenged macrophage cells
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