党参多糖基于不同链结构、分子量对大鼠溃疡性结肠炎的调控及机制研究

With the rapid development of glycomics and glycobiology, more and more polysaccharides from traditional Chinese medicine have been proved to have many biological functions. It was reported that the chemical structure, chain conformation and molecular weight of polysaccharides significantly affected their bioactivity. Therefore, it has become an important scientific issue in the field of life sciences to explore the basic scientific issues of sugar chains, diseases and drugs. However, due to its complex structure and difficult characterization, the progress of structure-activity relationship of polysaccharides from traditional Chinese medicine has come to a standstill. Recently, our studies have found that polysaccharides extracted from Codonopsis pilosula (COP) have good preventive and therapeutic effects on ulcerative colitis (UC). However, some scientific problems, such as the structure-activity relationship between the therapeutic effect and the structure of COP, the regulation mechanism of the inflammation, remain unsolved. This project intends to screen the best structure of COP for UC treatment based on structural changes, such as the chemical structure, chain conformation and molecular weight, and further clarify the anti-inflammatory mechanism. This project not only provides a theoretical basis for the modification and synthesis of COP, as well as the construction of polysaccharide-based materials, but also provides a new idea for the pharmacological study of other traditional Chinese medicine polysaccharides.

随着糖组学、糖生物学的飞速发展，已有越来越多的传统中药多糖被证实具有多种生物功能。结构决定性能，研究表明，多糖化学结构、链构象以及分子量等因素显著影响其生物活性。探索糖链、疾病与药物三者相互联系的基础科学问题已成为生命科学领域的重大科学问题。然而，中药多糖由于结构复杂，表征困难，其构效关系研究进展缓慢。近来，项目组研究发现党参多糖对于溃疡性结肠炎（UC）呈现出良好的预防和治疗作用。但是，影响党参多糖治疗效果的构效关系研究以及党参多糖如何调控炎症等科学问题尚未解决。本项目拟对党参多糖逐级分离纯化，精准表征其化学结构、链构象以及分子量等理化性质，基于结构变化筛选其治疗UC效果最佳的结构形态，建立党参多糖抗炎活性的构效关系，并在此基础上进一步阐明其抗炎作用机制。该项目不仅为后期党参多糖的改性、合成以及多糖基复合材料构筑和性能研究提供理论基础，也为其它中药多糖的药理研究提供新的思路。

结构决定性能，多糖的化学结构、链构象以及分子量等因素显著影响其生物活性。前期研究发现，党参多糖对于溃疡性结肠炎（UC）呈现出良好的预防和治疗作用。然而，影响党参多糖治疗效果的构效关系及机制尚未阐明。本项目拟通过中药党参多糖的分离纯化、结构表征，基于结构变化筛选其治疗UC效果最佳的结构形态，建立党参多糖抗炎活性的构效关系，并在此基础上进一步阐明其抗炎作用机制。.本项目首先基于网络药理学，初步探究了中药党参抗胃溃疡的活性成分，预测了党参治疗胃溃疡修复胃肠黏膜的作用机制，可能与IL-17信号通路有关；通过传统提取方法和优化后的提取方法比对，成功从湖北恩施的道地药材---板党，提取得高纯度、高产率的均一性党参多糖，并确定其结构为2→1-β-D-果糖键接、具有柔性链构象的菊粉型果聚糖；基于DSS诱导的小鼠UC炎症模型，证实党参多糖的抗炎效果优于阳性药物，并进一步通过LPS诱导的细胞炎症模型，阐明了党参多糖的抗炎机制可能与抑制TLR4/NF-κB通路的活化，从而抑制如TNF-α、IL-6等炎症因子的生成与释放有关；利用党参多糖不同组分的结构差异，基于细胞实验探究了党参多糖分子量、单糖组成、链构象以及其他理化性质对其抗炎活性和免疫调节活性的影响，发现链构象对活性影响巨大，其次是单糖组成和分子量，建立了党参多糖抗炎和免疫调节活性的构效关系。此外，本项目进一步拓展将党参多糖用于稳定和分散纳米硒，所得复合物对肝癌细胞有较好的抑制活性，并证实其机制和促进细胞凋亡、细胞周期阻滞有关。同时，基于类似多糖，如黑木耳多糖、茯苓多糖以及透明质酸等，开展了相关的研究，取得一定的进展。