Huang Y C, Guh J H, Cheng Z J, Chang Y L, Hwang T L, Liao C H, Tzeng C C, Teng C M
Pharmacological Institute, College of Medicine, National Taiwan University, No.1, Jen-Ai Road, Sec. 1, Taipei, Taiwan.
Eur J Pharmacol. 2001 Apr 20;418(1-2):133-9. doi: 10.1016/s0014-2999(01)00922-0.
Nitric oxide is an important biological mediator associated with multiple pathophysiological phenomena, such as platelet aggregation, vasodilation, septic shock, and autoimmune diseases. Prostaglandins, derived from cyclooxygenases, play prominent roles in homeostasis and inflammation. In this study, we characterized the effects of 7HQ derivatives (7-[(4-methylene-5-oxo-2-R-2-tetrahydrofuranyl) methoxy]-3,4-dihydrocarbostyril, where R is methyl, phenyl, p-fluorophenyl and p-phenylphenyl; 7HQ-1,-2,-3 and-4, respectively) in murine RAW 264.7 cells, a macrophage-like cell line. Lipopolysaccharide, the active component of endotoxin, significantly induced the expression of inducible nitric oxide synthase and cyclooxygenase-2, leading to the accumulation of nitrite and prostaglandin E(2), respectively. These actions of lipopolysaccharide were inhibited by 7HQ derivatives; additionally, the inhibition of the expression, rather than the activity, of inducible nitric oxide synthase correlated well with that of nitric oxide formation. Western blotting and electrophoretic mobility shift assay results demonstrated that the 7HQ derivatives could effectively inhibit IkappaB-alpha degradation and nuclear factor kappaB (NF-kappaB) translocation. At higher concentrations, 7HQ derivatives also inhibited cyclooxygenase-2 enzyme activity. These results suggest that 7HQ derivatives exhibit inhibitory effects on lipopolysaccharide-induced nitric oxide production and expression of inducible nitric oxide synthase and cyclooxygenase-2 through inhibition of IkappaB-alpha degradation and NF-kappaB activation.
一氧化氮是一种重要的生物介质，与多种病理生理现象相关，如血小板聚集、血管舒张、脓毒症休克和自身免疫性疾病。源自环氧化酶的前列腺素在体内平衡和炎症中发挥着重要作用。在本研究中，我们对7HQ衍生物（7-[(4-亚甲基-5-氧代-2-R-2-四氢呋喃基)甲氧基]-3,4-二氢咔啉，其中R为甲基、苯基、对氟苯基和对苯基苯基；分别为7HQ-1、-2、-3和-4）在小鼠RAW 264.7细胞（一种巨噬细胞样细胞系）中的作用进行了表征。脂多糖是内毒素的活性成分，可显著诱导诱导型一氧化氮合酶和环氧化酶-2的表达，分别导致亚硝酸盐和前列腺素E2的积累。脂多糖的这些作用被7HQ衍生物抑制；此外，诱导型一氧化氮合酶表达的抑制而非活性的抑制与一氧化氮生成的抑制密切相关。蛋白质印迹和电泳迁移率变动分析结果表明，7HQ衍生物可有效抑制IkappaB-α降解和核因子kappaB（NF-kappaB）易位。在较高浓度下，7HQ衍生物也抑制环氧化酶-2的酶活性。这些结果表明，7HQ衍生物通过抑制IkappaB-α降解和NF-kappaB激活，对脂多糖诱导的一氧化氮产生以及诱导型一氧化氮合酶和环氧化酶-2的表达具有抑制作用。
