GENISTEIN IN INVESTIGATIVE AND CLINICAL DERMATOLOGY

描述：（申请人的描述）本申请提出测试 大豆异黄酮抑制紫外线辐射假说 （UVR）诱导的嘧啶二聚体和氧化DNA损伤，并调节UVR 激活信号转导级联，从而抑制启动和 促进光致癌作用。该项目的第一个目标是确定 如果染料木黄酮应用前或应用后防止了UVR诱导的皮肤 致癌作用染料木黄酮将局部应用于无毛小鼠， 暴露于UVR。将通过分析 潜伏期、肿瘤发生率和多样性。第二个目标是评估 金雀异黄素对启动、促进和进展的影响 紫外线诱发皮肤癌。染料木黄酮将局部应用于小鼠 皮肤在开始剂量的UVR之前，随后是TPA促进，或应用 在紫外线照射之前，在DMBA中引发小鼠皮肤。紫外-化学复合 模型将被用来剖析的反启动或反促进的影响， 染料木黄酮对紫外线辐射的影响将通过以下方式评价抗进展作用： 将染料木黄酮应用于现有的皮肤肿瘤并记录肿瘤 消退率和恶变率。第三个目的是审查是否 染料木黄酮抑制紫外线诱导的与启动相关的中间终点 和促进，例如DNA光产物，氧化DNA损伤，炎症 反应、鸟氨酸脱羧酶（ODC）诱导和原癌基因表达 in vivo.第四个目的是进一步阐明分子机制 由此染料木黄酮在体外抑制光致癌作用。的影响 染料木黄酮对紫外线诱导的酪氨酸蛋白/丝裂原活化的影响 蛋白激酶，表皮生长因子受体的磷酸化， 以及小鼠和人中AP-1转录因子的激活 检查角质形成细胞。最后，申请人将评估 金雀异黄素对紫外线照射引起皮肤红斑和不适的保护作用 人类的皮肤此外，某些分子端点，如 8-OHdG、嘧啶二聚体、p53和增殖细胞核抗原（PCNA） 将在人皮肤活检组织中检测到表达， 3-三维人体皮肤成功完成拟议的研究将 有助于开发这种大豆根瘤菌作为预防和/或 抗人皮肤癌和光损伤的治疗剂。

DESCRIPTION: (applicant's description) This application proposes to test the hypothesis that genistein, a soybean isoflavone, inhibits ultraviolet radiation {UVR)-induced pyrimidine dimers and oxidative DNA damage, and modulates UVR activated signal transduction cascades, thereby suppressing the initiation and promotion of photocarcinogenesis. The first aim of the project is to determine if pre- or post-application of genistein prevents UVR-induced skin carcinogenesis. Genistein will be topically applied to hairless mice during exposure to UVR. The protective efficacy will be evaluated by analyzing the latency period, tumor incidence and multiplicity. The second aim is to evaluate the effect of genistein on initiation, promotion, and progression of UVR-induced skin carcinogenesis. Genistein will be topically applied to mouse skin before an initiating dose of UVR, followed by TPA promotion, or applied before UV irradiation in DMBA initiated mouse skin. UVR-chemical combination models will be used to dissect the anti-initiation or anti-promotion effects of genistein on the UVR exposure. The anti-progression effect will be evaluated by applying genistein to existing cutaneous tumors and recording the tumor regression and malignant conversion rate. The third aim is to examine if genistein inhibits UVR-induced intermediate endpoints relevant to initiation and promotion, e.g. DNA photoproducts, oxidative DNA damage, inflammatory responses, ornithine decarboxylase (ODC) induction and protooncogene expression in vivo. The fourth aim is to further elucidate the molecular mechanism(s) whereby genistein inhibits photocarcinogenesis in vitro. The effect of genistein on UVR-induced activation of tyrosine protein/mitogen activated protein kinases, phosphorylation of the epidermal growth factor receptor as well as activation of the AP-1 transcription factor in murine and human keratinocytes will be examined. Lastly, the applicant will evaluate the efficacy of genistein in protection of UVR-induced erythema and discomfort in the skins of human subjects. In addition, certain molecular endpoints such as 8-OHdG, pyrimidine dimers, p53 and proliferating cell nuclear antigen (PCNA) expression will be detected in human skin biopsies and the reconstituted 3-dimensional human skin. Successful completion of the proposed studies will contribute to development of this soybean isoflavone as a preventive and/or therapeutic agent against human skin cancer and photodamage.