生姜中II相酶诱导子的发现及其对Nrf2/ARE通路的诱导机理研究

诱导II相解毒酶，可以有效保护机体免受外源性致癌物及活性氧的损害，这已被证实是许多植物化学成分发挥癌症预防作用的关键。生姜具有防癌抗癌等生物学活性，申请人前期研究表明生姜中某些成分具有很强的II相酶诱导活性，生姜可能是十分有前途的II相酶诱导子的来源。本项目拟采用高通量的II相酶诱导子体外细胞筛选模型，从生姜中筛选II相酶诱导子，并结合UV、NMR和ESI-MS等波谱手段解析其化学结构。在此基础上，结合细胞模型及动物实验，从酶活、蛋白表达和基因转录等不同水平研究生姜中II相酶诱导子对II相酶的诱导作用，分析其对Nrf2/ARE信号通路、MAPKs、PKC、PI3K等调控因子的影响以期阐明其作用靶点和诱导机制，为深入理解生姜的防癌抗癌作用和开发设计潜在有效的癌症化学预防剂提供理论依据。

It is well-documented that induction of phase II detoxifying enzymes can provide cellular protection against xenobiotics and reactive oxygen species in human bodies. The evaluation of phase II enzyems has been proposed as a major mechanim underlying chemopreventive actions of numerous phytochemicals. Ginger exhibits chemopreventive activity against multiple cancers; Our previous study has shown that some ginger components possess potent capacity to induce phase II enzyme, suggesting that ginger is a promisng source for phase II enzyme inducer. The objective of the present project is to screen phase II enzyme inducers from ginger rhizome using murine hepatoma Hepa1c1c7 cell, and identify them on the basis of modern spectroscopic methods. The effects of these compounds on phase II enzymes activity, protein expression and gene transcription will be investigated in cells and animal experiments. Furthermore, their effects on Nrf2/ARE signal pathway, MAPKs、PKC、PI3K proteins will be analyzed to elucidate their action targets and inducing mechanism. These findings will contribute a theoretical basis for better understanding chemopreventive activity of ginger,and for developping the potential chempreventive agents against various cancers.