Quercitrin functions as an antioxidant and protects UV-induced carcinogenesis

描述（由申请人提供）：活性氧（ROS）和相关的氧化应激与多种疾病有关，包括心血管疾病、癌症、慢性肺部疾病和糖尿病。有利于清除活性氧以减轻氧化应激的干预措施可能预防氧化应激相关疾病。最近的研究表明，各种水果和蔬菜含有高浓度的抗氧化剂。槲皮素是类黄酮化合物的糖基化形式，广泛存在于自然界，普遍存在于植物、水果、种子和蔬菜中。我们的初步研究表明，在相同的浓度范围内，该化合物比抗坏血酸表现出更强的抗氧化活性。阻断tpa诱导的jb6p +细胞的肿瘤转化。槲皮苷预处理JB6细胞可下调UVB或TPA诱导的AP-1、NF-:B的活化。在AP-1荧光素酶转基因小鼠皮肤中，槲皮素局部处理可明显阻断tpa诱导的AP-1激活。进一步的研究表明，这些抑制作用似乎是通过抑制MAPKs磷酸化介导的，包括ERKs、p38激酶和JNKs。此外，槲皮素还能刺激nf - e2相关因子（Nrf2）的激活和GST ARE-荧光素酶的活性。彗星实验表明，槲皮素可以阻断UVB引起的DNA损伤。这些初步研究表明，槲皮素可能具有潜在的化学预防和化学治疗作用。这项应用的总体假设是，槲皮素作为一种抗氧化剂起作用，并保护紫外线诱导的致癌作用。这个提议的目的是检验这个假设。目的1将研究槲皮素在非细胞和细胞中的抗氧化性能。我们将研究槲皮苷是清除自由基还是抑制自由基的产生，并确定槲皮苷与氧自由基反应的反应速率常数。此外，我们将利用体内电子自旋共振（ESR）自旋捕获技术检测紫外线照射活体动物皮肤产生的自由基，并鉴定产生的自由基。目的2将研究槲皮素对紫外线诱导的脂质、蛋白质和DNA氧化损伤的抑制作用，以及紫外线诱导的SKH-1无毛小鼠肿瘤发生和细胞增殖的抑制作用。本研究首次检测到紫外线照射活体动物皮肤产生的自由基，为评价抗氧化剂对活体动物产生的自由基的抗氧化性能开辟了新的途径。该研究的另一个重要意义是确定了槲皮素可以预防紫外线引起的皮肤癌。

DESCRIPTION (provided by applicant): Reactive oxygen species (ROS) and related oxidative stress are linked with various diseases including cardiovascular disease, cancer, chronic lung diseases, and diabetes mellitus. Interventions favoring the scavenging of ROS to attenuate the oxidative stress may prevent oxidant stress associated diseases. Recent studies suggest that various fruits and vegetables contain high concentrations of antioxidants. Quercitrin is a glycosylated form of flavonoid compounds, widely distributed in nature, and is ubiquitous in plants, fruits, seeds, and vegetables. Our preliminary studies show that this compound displayed a stronger antioxidant activity than that of ascorbic acid over the same concentration range. It blocked TPA-induced neoplastic transformation in JB6 P+ cells. Pretreatment of JB6 cells with quercitrin down-regulated activation of AP-1, NF- :B induced by UVB or TPA. In the skin of AP-1-luciferase transgenic mice, topical treatment of mouse with quercitrin markedly blocked the TPA-induced AP-1 activation. Further studies indicated that these inhibitory actions appear to be mediated through the inhibition of MAPKs phosphorylation, including ERKs, p38 kinase, and JNKs. In addition, quercitrin stimulated the activation of NF-E2-related factor (Nrf2) and GST ARE- luciferase activity. Comet assays showed that quercitrin could block DNA damage induced by UVB. These preliminary studies indicate that quercitrin may function as a potential chemopreventive and chemotherapeutic agent. The overall hypothesis of this application is that quercitrin functions as an antioxidant and protects UV- induced carcinogenesis. The goal of this proposal is to test this hypothesis. Aim 1 will investigate the antioxidant properties of quercitrin in both non-cellular and cellular. We will study whether quercitrin scavenges free radicals or inhibits their generation and determine reaction rate constants of the reactions between quercitrin and oxygen radicals. Moreover, we will detect the UV-induced free radical generation from UV- irradiated skin of living animal using in vivo electron spin resonance (ESR) spin trapping and identify the radicals generated. Aim 2 will investigate the inhibitory effects of quercitrin against the UV-induced oxidative damage to lipid, protein, and DNA, and UV-induced tumorigenesis and cell proliferation in SKH-1 hairless mice. This study represents first detection of free radicals generated by UV-irradiated skin of living animals and may potentially open a new avenue to evaluate the properties of antioxidant against free radicals generated in living animals. Another significance of the study is the identification of qucertrin as a preventive agent against UV-induced skin cancers. PUBLIC HEALTH RELEVANCE: Reactive oxygen species (ROS) and related oxidative stress are linked with various diseases including cardiovascular disease, cancer, chronic lung diseases, and diabetes mellitus. Interventions favoring the scavenging of ROS to attenuate the oxidative stress may prevent oxidative stress associated diseases. This proposal will test the hypothesis that quercitrin, a compound found in blackberries and other foods, functions as an antioxidant and protects UV-induced carcinogenesis.