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Objective: Evodiamine (EVO), an important alkaloidal component extracted from the fruit of Evodiae fructus, has been known to possess anti-tumor, anti-inflammatory, anti-oxidative and other therapeutic capabilities.In the present study, the effects of EVO on zymosan-induced inflammation and its underlying mechanism were investigated in both in vitro and in vivo.Design: Randomized and controlled ex vivo and in vivo study.Settings: Hospital-base research laboratories.Subjects: RAW264.7 cells, peritoneal macrophages, and adult C57 BL/6J mice.Interventions: In vitro, RAW264.7 cells and primary peritoneal macrophages were treated with different dose of EVO (25, 50 or 100μM) for lh prior to incubation with zymosan (100μg/ml).In vivo, mice received intraperitoneally zymosan (500mg/kg) to induce non-septic shock, the effects of EVO (10mg/kg) on systemic inflammatory response were evaluated.The effect of EVO on a lethal zymosan challenge (1800mg/kg) was also assessed.Measurements and Main Results: EVO effectively suppressed the expression of interleukin-1 β (IL-1β), interleukin-6 (IL-6) as well as rumor necrosis facotror-α (TNF-α) in both protein and mRNA level in vitro.Zymosan-induced DNA-binding activity of nuclear factor-kappa B (NF-κB) was attenuated by EVO, which was achieved through the inhibitory effects on the phosphorylation of inhibitory κB α (Iκ B α) and p65 nuclear translocation, but was little association with mitogen-activated protein kinases (MAPKs) activation.In vivo, treatment with EVO markedly decreased the level of TNF-α and IL-6 in plasma.EVO also repressed the inflammatory cytokines expression and ameliorated abnormal state in both lung and intestine tissues by inactivation of NF-κB.In addition, EVO significantly reduced the mortality caused by zymosan.Conclusion: EVO blocks zymosan-induced NF-κB activation by suppressing the phosphorylation of IκBα and protects against the zymosan-induced generalized inflammation.