当归多糖防治溃疡性结肠炎癌变的组分-效应关系及分子机制

Ulcerative colitis (UC) was easy to relapse and tumorigenesis, and the incidence rate was continue increasing. Due to the mechenism was still unclear, few treatment could be applied in clinic. It was urgent to discover new target and new drugs in prevention UC and associated tumorigenesis. It was reproted recently that the Heparanase (Hpa) play a key role in crosstalk between epicelium cells and immune cells during UC and associated tumorigenesis, maintaining chronic inflammation and powering colitis associated tumorigenesis. Our research found that Angelica sinensis polysaccharide (ASP) could alleviate colitis, decrease incidence of tumorigenesis and reduce the expression of Hpa in colonic epithelium. Based on this findings, we made the hypothesis that ASP could prevent UC tumorigenesis through downregulation of Hpa expression. However, it was still unclear the constituent-activity relationship of ASP and the molecular machenism. Therefore,in this project our research includes the two parts of study. One is to explore the constituent-activity relationship of ASP in prevention of UC associated tumorigenesis employing Hpa as target. The other is to explore the machenism of active ASP consituent in prevention UC and associated tumorigenesis. This study will further confirm Hpa as a target for treatment of UC and associated tumorigenesis and reveal the structure characteristic of active ASP constituent. It will also provide more evidence for constituent-activity relationship of polysaccharide and a new strategy in the reseach of relationship between stucture information and activity of macromolecular like polysaccharide.

溃疡性结肠炎(UC)易复发，易癌变，且发病率持续升高。由于发病机制不清，治疗措施有限，迫切需要寻找防治UC及其癌变的新靶点、新药物。文献报道，乙酰肝素酶（Heparanase，Hpa）在联系上皮细胞与免疫细胞间的crosstalk、维持结肠慢性炎症、促进癌变发生发展中起关键作用，是防治UC癌变潜在的新靶点。我们的研究发现，当归多糖可以改善结肠炎症、抑制癌变发生，抑制结肠粘膜Hpa的表达。据此推测，当归多糖可能通过抑制Hpa，发挥防治UC癌变的作用，但其组分-效应关系和分子机制尚不清楚。因此，本课题拟以Hpa为靶点，通过当归多糖防治UC癌变的组分-效应关系研究，发现当归多糖的活性组分，揭示活性组分的结构特征并深入研究其分子机制。阐明上述问题，有助于进一步确认Hpa是防治UC癌变的新靶点，为多糖"组分-效应"关系研究提供新的实验依据，为多糖类大分子结构信息与生物活性之间的关系研究提供新策略。

溃疡性结肠炎(ulcerative colitis, UC)发病率在欧美较高，近年在我国也呈明显上升趋势，UC易复发、易癌变，已成为严重威胁人类健康的全球性公共卫生问题。UC发病原因及发病机制尚不清楚，治疗措施有限。预防性结肠切除手术虽可预防癌变的发生，但对患者的生存质量影响很大。目前临床上应用的激素及非甾体抗炎药虽然可以缓解症状，但长期用药会产生严重的副作用。因此，寻找治疗UC及预防癌变的新靶点、新药物成为迫切需要解决的问题。. 本课题制备了3种不同分子量的当归多糖组分，体外研究比较了这3种当归多糖组分对乙酰肝素酶（Hpa）表达的组分-效应关系，发现低分子量的组分AP-3（重均分子量5万）抑制Hpa的表达作用最强。此外，AP-3还具有抑制TNF-α诱导的正常肠上皮细胞Hpa的表达的作用，同时在炎症相关结肠癌小鼠模型中，也证实了AP-3能够缓解结肠炎症、降低癌变率，抑制结肠炎癌变小鼠肠上皮细胞Hpa的表达。进一步研究发现，AP-3能够抑制LPS诱导的炎症因子IL-6、TNF-α的表达、抑制LPS引起的NF-κB炎症信号通路的激活，还可以通过抑制CatL的表达从而抑制Hpa的活化。综合本课题体内外研究结果，证实当归多糖不仅可以通过抑制NF-κB炎症信号通路的激活降低炎症因子的产生、进而抑制Hpa的表达，还可以通过抑制CatL的表达而抑制Hpa的活化，发挥缓解UC的结肠炎症、降低癌变的作用。课题完成了预期计划，证实了课题所提出的设想，有助于进一步确认Hpa是防治UC癌变的新靶点，同时为当归多糖用于UC及其癌变的防治、为阐明中药当归作用的物质基础提供新的实验依据。