飞燕草素通过Nrf2信号通路在癌症化学预防中的作用机制的研究

Delphinidin is a well-known food polyphenol compound, which widely exist in fruits, vegetables and other plants. It is demonstrated that this food polyphenol compound possesses anti-cancer, anti-inflammation, anti-angiocardiopathy biological properties and enhance immune systems. Prvious studies showed that polyphenol compound's protection cell potency activated the Nrf2 signaling pathways, upregulated the transcription activity of Nrf2, induced phase II metabolism enzyme gene expression, in the cell protection process Two intracelluar signal pathways, Nrf2 and NF-κB and even their crosstalk were involved. However, the molecular mechanisms of delphinidin are still unclear. In this program, we will study delphinidin's chemoprevention mechanism in the initial stage of of cancerization, in vivo and in vitro. which covers several aspects: 1. We will use the rat and cell model to study the expression of phase II metabolizing enzyme were inducted by Delphinidin. 2. To clarify Delphinidin on Nrf2 pathway regulated mechanism, molecular biology technology were used. 3.To clarify Delphinidin on Nrf2/NF-?B crosstalk regulated mechanism, siRNA technology were used. The current research will also contribute to the fully understanding of the mechanism of delphinidin and to the exploring of the new drug research, provide theoretial foundation for the development of cancer prevention.

飞燕草素是一种广泛存在于水果、蔬菜等植物中的食品多酚化合物，具有抗炎、防癌、预防心血管疾病等作用。研究表明多酚类化合物可以激活Nrf2信号通路、调高Nrf2的转录活性、诱导下游II相代谢酶基因的表达来保护细胞；在这个过程中Nrf2和NF-κB之间又能通过crosstalk相互影响，发挥化学预防的作用，但飞燕草在这些机制中的作用尚不明确。本研究拟通过体内和体外实验，研究飞燕草素在癌变启动阶段中的化学预防机制。研究方案包括：1.利用大鼠和细胞模型研究飞燕草素对II相代谢酶表达的诱导作用；2.利用分子生物学技术研究飞燕草素对Nrf2通路的调剂机制；3.利用siRNA技术研究飞燕草素在Nrf2/NF-κB之间的crosstalk中的调节机制。通过以上研究为飞燕草素在今后药物方向上的研发奠定理论基础，为癌症预防的发展提供新的理论依据。

随着社会经济发展，许多急、慢性传染病在一定程度上得到有效控制，疾病模式和死因谱发生了由以传染病为主转向以心脑血管病、肿瘤等慢性非传染性疾病为主的重大变化。体内氧化与抗氧化失衡导致的ROS聚集与超过200种临床疾病的早期发生相关，这其中就包括常见的慢性病如心血管疾病、癌症、慢性呼吸系统疾病和糖尿病。飞燕草素和非瑟酮是广泛存在于水果、蔬菜等植物中的食品多酚类化合物，具有抗炎、防癌、预防心血管疾病等多种生理活性作用。还有研究显示，激活Nrf2信号通路可以诱导下游II相代谢酶的表达来清除ROS，发挥保护正常细胞的作用。因此本课题采用H2O2构建氧化损伤细胞模型，研究植物化学物（非瑟酮、飞燕草素）通过激活Nrf2-ARE通路来诱导Ⅱ相酶的表达，从而实现清除HepG2细胞内活性氧（ROS）的作用。我们的研究结果显示，非瑟酮在10uM、20uM、30uM、飞燕草素在10uM、20uM、40uM浓度时能够诱导Ⅱ相酶表达，从而清除H2O2诱导的HepG2细胞内的ROS；在HepG2细胞中，非瑟酮通过增加Nrf2的蛋白稳定性，促进Nrf2向核内转移，增强Nrf2转录调控活性。本课题的结果为阐明这2种植物化学物对慢性病预防的分子机理和今后的应用提供了科学依据，对慢病防治工作的开展提供了可供参考的建议。