Chemopreventive effects of a curcumin-like diarylpentanoid [2,6-bis(2,5-dimethoxybenzylidene)cyclohexanone] in cellular targets of rheumatoid arthritis in vitro.
OBJECTIVE
Synovial fibroblast has emerged as a potential cellular target in progressive joint destruction in rheumatoid arthritis development. In this study, BDMC33 (2,6-bis[2,5-dimethoxybenzylidene]cyclohexanone), a curcumin analogue with enhanced anti-inflammatory activity has been synthesized and the potency of BDMC33 on molecular and cellular basis of synovial fibroblasts (SF) were evaluated in vitro.


METHODS
Synovial fibroblast cells (HIG-82) were cultured in vitro and induced by phorbol-12-myristate acetate (PMA) to stimulate the expression of matrix metalloproteinase (MMPs) and pro-inflammatory cytokines. The protective effects of BDMC33 were evaluated toward MMP activities, pro-inflammatory cytokine expression and nuclear factor kappa-B (NF-κB) activation by using various bioassay methods, including zymography, Western blotting, reverse transcription polymerase chain reaction, immunofluorescense microscopy and electrophoretic mobility shift assay.


RESULTS
The results showed that BDMC33 significantly inhibited the pro-gelatinase B (pro-MMP-9) and collagenase activities via suppression of MMP-1 in activated SF. In addition, BDMC33 strongly suppressed MMP-3 gene expression as well as inhibited COX-2 and IL-6 pro-inflammatory gene expression. We also demonstrated that BDMC33 abolished the p65 NF-κB nuclear translocation and NF-κB DNA binding activity in PMA-stimulated SF.


CONCLUSIONS
BDMC33 represents an effective chemopreventive agent and could be used as a promising lead compound for further development of rheumatoid arthritis therapeutic intervention.
Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Kuala Lumpur, Selangor, Malaysia.
Ka-Heng
KH
Lee
Institute of Bioscience, Universiti Putra Malaysia, Kuala Lumpur, Selangor, Malaysia.|Faculty of Food Science and Technology, Universiti Putra Malaysia, Kuala Lumpur, Selangor, Malaysia.
Faridah
F
Abas
Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Kuala Lumpur, Selangor, Malaysia.
Noorjahan Banu
NB
Mohamed Alitheen
Institute of Bioscience, Universiti Putra Malaysia, Kuala Lumpur, Selangor, Malaysia.|Faculty of Science, Universiti Putra Malaysia, Kuala Lumpur, Selangor, Malaysia.
Khozirah
K
Shaari
Institute of Bioscience, Universiti Putra Malaysia, Kuala Lumpur, Selangor, Malaysia.|Faculty of Science, Universiti Putra Malaysia, Kuala Lumpur, Selangor, Malaysia.
Nordin Haji
NH
Lajis
Institute of Bioscience, Universiti Putra Malaysia, Kuala Lumpur, Selangor, Malaysia.|Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Kuala Lumpur, Selangor, Malaysia.
Daud Ahmad
DA
Israf
Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Kuala Lumpur, Selangor, Malaysia.|Institute of Bioscience, Universiti Putra Malaysia, Kuala Lumpur, Selangor, Malaysia.
Ahmad
A
Syahida
D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001597:Benzylidene Compounds / Q000494:pharmacology*; D002460:Cell Line; D003512:Cyclohexanones / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects; D013583:Synovial Membrane / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
C570840:2,6-bis(2,5-dimethoxybenzylidene)cyclohexanone; D018501:Antirheumatic Agents; D001597:Benzylidene Compounds; D003512:Cyclohexanones; D016207:Cytokines; D018836:Inflammation Mediators; D020782:Matrix Metalloproteinases; D013755:Tetradecanoylphorbol Acetate
BDMC33; HIG-82; NF-κB; curcumin; matrix metalloproteinase; synovial fibroblast