| Summary: | 博士 === 國立中興大學 === 生物醫學研究所 === 104 === Natural products drug discovery becomes mainstream strategy due to its safety, efficacy, cost and unique. In this study, we utilize bone marrow dendritic cell as drug screening platform to evaluate the immunomodulatory effect of citrus flavonoid and cembranolide diterpene from Sinularia flexibilis. First, naringenin、sinulariolide、11-dehydrosinulariolide、sinularin and dihydrosinularin inhibit inflammatory cytokine production by LPS-stimulated DC. Furthermore, naringenin and sinularin suppress CD40、CD80 or CD86 expression in LPS-stimulate DCs were analyzed by flow cytometry. We choose naringenin as priority candidate with considering the pharmacokinetic profile and the stability of supply. And we further investigate the immunomodulatory effect of naringenin by affecting DCs function and the underlying mechanism. Naringenin inhibit the ability of LPS-stimulate DCs to activate OVA-specific T cell and also suppress MAPK and NF-κB activation in LPS-stimulated DC. Finally, we demonstrate that naringenin significantly inhibit splenic DCs maturation of LPS-inoculated mice. In structure activity relationship, O-glycosylation may be a critical role of flavonoid for its immunomodulatory ability. Sizes and position of lactone and epoxy ring are important function group in cembranolide diterpene for its anti-inflammatory effect. In vivo, we utilize the collagen-induced arthritis model to evaluate the therapeutic potential of naringenin in rheumatoid arthritis. Oral administration of 200 mg/kg naringenin significantly ameliorated the severity of arthritis, decrease the anti-collagen type Ⅱ IgG expression, T cell proliferation and reduce Th1 and Th17 population in the spleen after restimulation with CⅡ. In conclusion, we present the first report on immunomodulatory effect of naringenin by modulating DCs maturation and function. And naringenin also has therapeutical potential for treating rheumatoid arthritismmune disorders.
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