Inhibitory effects of sesquiterpenes from bay leaf on nitric oxide production in lipopolysaccharide-activated macrophages: Structure requirement and role of heat shock protein induction
Inhibitory effects of sesquiterpenes from bay leaf on nitric oxide production in lipopolysaccharide-activated macrophages: Structure requirement and role of heat shock protein induction
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DOI：
10.1016/s0024-3205(00)00542-7
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发表时间：
2000-04-21
期刊：
影响因子：
6.1
通讯作者：
Yoshikawa, M
中科院分区：
文献类型：
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作者：
Matsuda, H;Kagerura, T;Yoshikawa, M
月桂(Laurus Nobilis)叶的甲醇提取物能抑制脂多糖(LPS)激活的小鼠腹腔巨噬细胞产生一氧化氮(NO)。通过生物测定引导分离，从活性部位中分离出14个已知的倍半萜类化合物，并对其抑制NO产生的能力进行了检测。7种倍半萜内酯(木香内酯、脱氢木香内酯、马钱子碱、扎鲁扎宁C、厚朴内酯、檀香碱和螺旋体)对脂多糖诱导的NO产生有明显的抑制作用(IC50-1.2，与3.8mM相似)。其他倍半萜类化合物也表现出抑制活性(IC50大于或等于21µM)，但其抑制活性低于倍半萜内酯类化合物。α-亚甲基-γ-丁内酯也有抑制活性(IC_(50)-9.6 mU/M)，而Mokko内酯和Watsonol A等，用NaBH_4或Dibal还原的α-亚甲基-γ-丁内酯部分和脱氢肋骨内酯的2-巯基乙醇加合物的活性很小(IC_(50)大于或等于18 mU/M)。这些结果表明，α-亚甲基-伽马-丁内酯部分对活性是重要的。此外，木香内酯和脱氢木香内酯抑制诱导型一氧化氮合酶(INOS)的诱导，与热休克蛋白72(HSP72)的诱导一致。这些结果提示，倍半萜内酯诱导HSP72的作用机制之一是阻止核因子-kappaB的活化，进而抑制iNOS的诱导。
The methanolic extract from the leaves of Laurus nobilis (bay leaf, laurel) was found to inhibit nitric oxide (NO) production in lipopolysaccharide (LPS)-activated mouse peritoneal macrophages. Through bioassay-guided separation, fourteen known sesquiterpenes were isolated from the active fraction and were examined for ability to inhibit the NO production. Seven sesquiterpene lactones (costunolide, dehydrocostus lactone, eremanthine, zaluzanin C, magnolialide, santamarine and spirafolide) potently inhibited LPS-induced NO production (IC50 - 1.2 similar to 3.8 mu M). Other sesquiterpene constituents also showed the inhibitory activity (IC50 greater than or equal to 21 mu M), but their inhibitory activities were less than those of sesquiterpene lactones. alpha-Methylene-gamma-butyrolactone also showed inhibitory activity (IC50 - 9.6 mu M), while mokko lactone and watsonol A etc., reductants of the alpha-methylene-gamma-butyrolactone moiety by NaBH4 or DIBAL, and a 2-mercaptoethanol adduct of dehydrocostus lactone showed little activity (IC50 greater than or equal to 18 mu M). These results indicated that the alpha-methylene-gamma-butyrolactone moiety is important for the activity. Furthermore, costunolide and dehydrocostus lactone inhibited inducible nitric oxide synthase (iNOS) induction in accordance with induction of heat shock protein 72 (HSP 72). These results suggested that, as one of their mechanisms of action, sesquiterpene lactones induce HSP 72 thereby preventing nuclear factor-kappa B activation followed by iNOS induction.