Dietary Flavones and flavonoles are inhibitors of Poly(ADP-ribose)polymerase-1 in pulmonary epithelial Cells
Dietary Flavones and flavonoles are inhibitors of Poly(ADP-ribose)polymerase-1 in pulmonary epithelial Cells
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DOI：
10.1093/jn/137.10.2190
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发表时间：
2007-10-01
影响因子：
4.2
通讯作者：
Hageman, Geja J.
中科院分区：
文献类型：
--
作者：
Geraets, Liesbeth;Moonen, Harald J. J.;Hageman, Geja J.
核酶聚（ADP-核糖）聚合酶-1（PARP-1），最初被认为是由氧化应激诱导的DNA链断裂高度激活，已被证明参与急性和慢性炎症性疾病的病理生理学。小鼠中的PARP-1缺陷导致发现其在核因子-κ B介导的基因表达中的共激活功能，此外，PARP-1的药物抑制显示出减少炎症介质的产生。在这项研究中，研究了各种黄酮类化合物的体外PARP-1抑制作用。黄酮类化合物杨梅素，三萜，棉黄酮，飞燕草素，槲皮素，和非瑟酮被确定为纯化的酶的显着抑制剂。在N-甲基-N '-硝基-N-亚硝基胍处理的人肺上皮细胞中对这些化合物的进一步评价表明，槲皮素、非瑟酮和三羟甲基丙烷减少了聚（ADP-核糖）聚合物的形成以及NAD（+）水平的降低。最后，这些黄酮类化合物可以显着降低LPS刺激的人肺上皮细胞产生IL-8。这项研究的结果表明，特定的黄酮类化合物具有PARP-1抑制活性，除了前面描述的抗氧化作用。PARP-1抑制和细胞NAD（+）和能量产生的保护可能在这些特定黄酮类化合物的抗氧化活性中发挥作用。此外，这些结果表明，黄酮类化合物可以发挥抗肿瘤活性的其他机制。此外，这些结果表明可能使用食物来源的黄酮类化合物治疗慢性炎症性疾病。
The nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1), which was initially known to be highly activated by oxidative stress-induced DNA strand breaks, has been shown to be involved in the pathophysiology of acute and chronic inflammatory diseases. PARP-1 deficiency in mice led to the discovery of its coactivating function in the nuclear factor-kappa B-mediated gene expression and in addition, pharmaceutical inhibition of PARP-1 was shown to reduce the production of inflammatory mediators. In this study, the in vitro PARP-1-inhibiting effect of various flavonoids was investigated. The flavonoids myricetin, tricetin, gossypetin, delphinidin, quercetin, and fisetin were identified as significant inhibitors of the purified enzyme. Further evaluation of these compounds in N-methyl-N'-nitro-N-nitrosoguanidine-treated human pulmonary epithelial cells showed that the formation of the poly(ADP-ribose) polymers, as well as the decreased NAD(+) levels, was reduced by quercetin, fisetin, and tricetin. Finally, IL-8 production of LPS-stimulated human pulmonary epithelial cells could be significantly reduced by these flavonoids. The results of this study indicate that specific flavonoids have PARP-1-inhibiting activity in addition to the earlier described antioxidant effects. PARP-1 inhibition and preservation of cellular NAD(+) and energy production could play a role in the antiinflammatory activity of these specific flavonoids. In addition, these results indicate additional mechanisms by which flavonoids can exert antiinflammatory activity. Furthermore, these results indicate possibilities to use food-derived flavonoids in the treatment of chronic inflammatory diseases.