中文摘要
针对湿毒蕴结、痰浊内生为大肠癌的基本病机,结合痰浊所致的酸性微环境限制了CD8+T细胞对癌症控制的现代认识。在盐肤木三萜抑制大肠癌细胞酸性产物代谢及其上调CD8+T细胞活性的前期实验基础上,本项目提出“盐肤木三萜抗大肠癌作用机制可能通过调节酸性微环境进而增强CD8+ T细胞活性与抗肿瘤活力”的工作假说。本项目以调节酸性微环境平衡为切入点,观察盐肤木总三萜及其活性部位对大肠癌细胞糖酵解途径的酸性产物生成、CD8+ T细胞活性的影响并分析其信号调控机制;采用流式分析和分子生物学技术,研究盐肤木三萜类物质对CD8+ T细胞活性与抗肿瘤活力的影响及PD-L1/ PD-1、Fas/Fas L信号机制;采用脾脏注射肝转移模型进行宿主免疫机能与抗肿瘤活力关系的研究。本项目以调节酸性微环境与CD8+ T细胞活性为聚焦点,深入研究盐肤木三萜改善CD8+ T细胞的抗肿瘤活力,调动机体自身免疫和肿瘤杀伤功能的作用,进而揭示其改善肿瘤细胞糖酵解、乳酸代谢与增强机体抗肿瘤免疫反应的分子机制。以期阐明化痰解毒中草药抗癌作用机理的科学内涵,进而为中医药防治大肠癌提供更为有效的治疗策略、研究新方法和思路。
英文摘要
Wet poison accumulate and endogenous phlegm is the basic pathogenesis of colorectal cancer (CRC), and tumor acidic microenvironment that induced by phlegm is one of the main factors that restricted CD8 + T cell activity and limited its response to killing the tumor. In our previous studies, we have found that triterpenoids of Rhus chinensis Mill. could inhibit acidic metabolites and increase CD8 + T cell activity in CRC. As a breakthrough point in this project, we put forward the working hypothesis that the mechanism of triterpenoids of Rhus chinensis Mill. inhibiting the CRC maybe by adjusting the acidic environment and enhancing the vitality of CD8 + T cell and antitumor activity. The total triterpenoids and its active sites are separated for detecting the influence on the tumor glycolysis and the lactic acid metabolism, and its effect on the regulation of CD8 + T cell activity in CRC are analyzed. Moreover, we discuss the roles and mechanisms of triterpene components in the intervention of glucose metabolic signaling pathways in CRC cells. In addition, the influence of triterpene components on CD8 + T cell and antitumor activity are analyzed, furthermore, the regulatory mechanism in PD-L1/PD-1, Fas/Fas L pathways are investigated by the flow and the molecular biology technology. The spleen injection of liver metastasis model is used to investigate the relationship between the host immune function and antitumor activity. This project takes the acidic microenvironment and CD8 + T cell activity as the focal point, further to study the role of triterpenoids in Rhus chinensis Mill. in improving antitumor activity of CD8 + T cells, and mobilizing the body's own immune and killing tumor function. Furthermore, we discuss its molecular mechanisms on regulation of lactic acid metabolism, glycolysis in tumor cells and the enhanced antitumor immune response. The aim of this project is to clarify the scientific connotations and mechanisms of herbal medicine with the efficacy of phlegm and detoxification on inhibiting CRC, further to provide more effective therapeutic strategies, new methods and ideas for TCM prevention and treatment of colorectal cancer.
