Pogostone suppresses proinflammatory mediator production and protects against endotoxic shock in mice
Pogostone suppresses proinflammatory mediator production and protects against endotoxic shock in mice
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Pogostone 抑制小鼠促炎介质的产生并防止内毒素休克
DOI：
10.1016/j.jep.2014.09.023
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发表时间：
2014-11-18
影响因子：
5.4
通讯作者：
Lai, Xiao-Ping
中科院分区：
文献类型：
--
作者：
Li, Yu-Cui;Xian, Yan-Fang;Lai, Xiao-Ping
民族药理学相关性：广藿香（Pogostemon cablin（布兰科）Benth）是一种众所周知的草药，通常在许多亚洲国家用于炎性疾病。广藿香酮（Pogostone，PO）是从广藿香（Pogostemon cablin）中分离得到的天然产物，具有多种药理活性。本研究旨在探讨PO的抗炎特性，阐明其作用机制，并评估其潜在的急性毒性。材料和方法：采用脂多糖（LPS）刺激的RAW 264.7巨噬细胞体外抗炎活性进行了评估。采用ELISA法和RT-PCR法分别检测促炎介质的蛋白和mRNA水平。Western blot检测NF-κ B B和MAPK家族蛋白表达，探讨其分子机制。采用LPS诱导的内毒素休克小鼠模型，检测PO的体内抗炎活性。结果：PO在体外可显著抑制TNF-α、IL-6、IL-1 β、NO和PGE等促炎介质的蛋白和mRNA表达（2）。PO的抗炎作用机制部分依赖于抑制NF-κ B的激活以及JNK和p38 MAPK的磷酸化。在体内，PO能够显著降低LPS诱导的小鼠死亡率。PO还能明显抑制血清中促炎介质的产生，减轻肝、肺损伤。PO在内毒素休克中的作用机制可能是通过抑制NF-κ B B的活化和p38 MAPK的磷酸化，下调多器官炎症介质的mRNA表达。PO静脉给药对小鼠的LD 50约为163 mg/kg，是动物实验剂量的8倍。我们的研究结果有关的抗炎症作用的PO和潜在的分子机制，有助于证明使用广藿香在中药治疗炎症性疾病。更重要的是，这些结果也使PO成为一种有前途的抗炎剂，值得进一步开发为治疗感染性休克的药物。(C)2014爱思唯尔爱尔兰有限公司版权所有。
Ethnopharmacological relevance: Pogostemon cablin (Blanco) Benth is a well-known medicinal herb commonly used in many Asian countries for inflammatory diseases. Pogostone (PO), a natural product isolated from Pogostemon cablin, is known to exert various pharmacological activities. This study aimed to investigate the anti-inflammatory property of PO, to elucidate its mechanism of action, and to evaluate its potential acute toxicity.Materials and methods: The in vitro anti-inflammatory activity of PO was assessed using lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. The protein and mRNA levels of proinflammatory mediators were measured with ELISA and RT-PCR, respectively. Proteins of the NF-kappa B and MAPK family were determined by Western blot to investigate the underlying molecular mechanisms. The in vivo anti-inflammatory activity of PO was tested using LPS-induced endotoxic shock in mice. In addition, the median lethal dose (LD50) of PO in mice was tested in an acute toxicity test.Results: In vitro, PO significantly inhibited the protein and mRNA expression of proinflammatory mediators including TNF-alpha, IL-6, IL-1 beta, NO, and PGE(2). The action mechanism of the anti-inflammatory activity of PO was partly dependent on inhibition of the activation of NF-kappa B and the phosphotylation of JNK and p38 MAPK. In vivo, PO was able to significantly reduce the mortality induced by LPS in mice. Furthermore, PO could markedly suppress the production of the proinflammatory mediators in serum, and attenuate liver and lung injury. The action mechanisms of PO during endotoxic shock may be attributed to down-regulation of the mRNA expression of inflammatory mediators in multiple organs via inhibition of the activation of NF-kappa B and the phosphorylation of p38 MAPK Moreover, the LD50 of PO in mice was about 163 mg/kg with intravenous administration, which was about 8-fold higher than the dose used in the animal experiment.Conclusions: Our findings regarding the anti-inflammatory effect of PO and the underlying molecular mechanisms help justify the use of Pogostemon cablin in Chinese medicine for the treatment of inflammatory diseases. More importantly, the results also render PO a promising anti-inflammatory agent worthy of further development into a pharmaceutical drug for the treatment of septic shock. (C) 2014 Elsevier Ireland Ltd. All rights reserved.