基于“肝/肾-肠轴”的铁皮石斛叶黄酮碳苷抗高尿酸血症伴高血压的机制研究

At present, the incidence of hyperuricemia is increasing year by year(>10%).There is no ideal treatment drugs, which have serious liver and kidney damage. It is believed that liver/kidney-gut axis plays a crucial role in the formation of hyperuricemia. Previous researches show that the stems and leaves of Dendrobium officinaie shared the similar chemical composition(flavone C-glycosides), which could reduce blood pressure and serum uric acid, improve the liver and kidney damage. According to the Dendrobium officinaie is helpful for stomach and can producing fluid, nourishing yin and clearing heat, which can make the source of generation and transformation of the spleen and stomach, and make the congenital foundation sufficient. As the saying goes: improper diet, overeating greasy, excessive drinking, irregular work and rest will lead to dysfunction of the spleen in transport, lost transport department, even to dampness endogenous. So we can infer that leaves of Dendrobium officinaie may reduce the generation of liver and intestinal UA and promote excretion of kidney intestine UA by regulating the intestinal function, protecting the intestinal mucosa barrier, thereby reducing the generation of liver-intestine UA, and promoting excretion of kidney-intestine UA, finally lowering blood pressure and uric acid. In order to get close to a human way of hyperuricemia in animal models, this project selects of three stimulation methods (high sugar, high fat diet, excessive drinking, sleep disorders) to simulate the unhealthy lifestyle’s effects on uric acid and blood pressure. As stated above, methods such as RT-PCR, Western blot and Flow cytometry will be used to make clear the mechanism of flavone C-glycosides from Dendrobium officinaie leaves of prevention and treatment on the hyperuricemia with hypertension caused by unhealthy-life styles and the protectional function of liver and kidney. What’s more, we will illuminate that leaves of flavone C-glycosides from Dendrobium officinaie may reduce the generation of liver and intestinal UA and promote excretion of kidney intestine UA by regulating the intestinal function, protecting the intestinal mucosa barrier, as well as blocking inflammatory cascade reaction mediated by TLR4, thereby reducing the generation of liver-intestine UA, and promoting excretion of kidney-intestine UA, then lowering blood pressure and uric acid. Finally, to lay the foundation for the development of anti hyperuricemia drugs and make full use of Dendrobium officinaie, and provide a new way of thinking for the advantages and mechanism research of lowering uric acid in Chinese traditional medicine.

高尿酸血症（HUA）发病率高达10%，尚无治疗药，现有治痛风降尿酸药对肝肾有损害。HUA与“肝-肠轴”和“肾-肠轴”的尿酸生成与排泄密切相关。前期研究发现铁皮石斛叶与茎含有类似的黄酮碳苷成分，且能降尿酸、降血压。中医认为“过食肥甘、醇酒厚味、情志失调、起居无常，易运化失司”是HUA的主要病因。模拟人类不良生活方式，采用高脂高糖等饮食制备高尿酸血症伴高血压模型动物。用RT-PCR、Western blot、流式细胞等，从整体、细胞、分子等层面，研究铁皮石斛叶黄酮碳苷对TLR4信号通路多个环节的影响，进一步观察“肝-肠轴”XDH/XOD系统和“肾-肠轴”尿酸转运系统、RAAS的影响，从而减少尿酸生成或促进排泄，并观察其调肠胃和护肝肾功能，系统阐述铁皮石斛叶黄酮碳苷的降尿酸机制及保肝肾等特点，为开发抗高尿酸血症中药新药和铁皮石斛叶充分利用奠定基础；为降尿酸中药的优势与机制研究提供依据。

高尿酸血症（HUA）常伴随高血压病，尚无治疗药，现有治痛风降尿酸药对肝肾有损害。本项目在前期研究基础上，按计划系统阐述铁皮石斛叶黄酮碳苷（MRE）的降尿酸机制及保肝肾等优势特色。创新性采用拟人“情志所伤，起居无常，饮食不节，多食肥甘，嗜酒厚味”不良生活方式，建立并完善了三种高尿酸血症伴高血压（HUP）大鼠模型。采用响应面、大孔吸附树脂ADS-17纯化、LC-MS/MS等技术手段，确定了MRE的提取工艺和质量检测特征性成分。采用拟人“情志所伤+饮食不节”、“过食膏粱”和“过食甘甜”三种高尿酸血症伴高血压大鼠模型，系统地阐述了MRE的降尿酸、降血压作用及保肝肾优势特色，发现MRE降低模型大鼠尿酸和血压的同时，具有明显的“肝/肾-肠轴”及血管保护，还可改善糖脂代谢、“痰湿气虚”症候，与别嘌醇抗高尿酸血症具有增效减毒作用等优势特色。并进一步采用拟人“过食膏粱”和“过食甘甜”两种HUP模型大鼠，以TLR4炎症信号通路为中心，从“肝-肠轴”、“肾-肠轴”的XDH/XOD系统、尿酸转运系统、肝肾肠功能出发，多层次多环节系统揭示了MRE防治高尿酸血症伴高血压的作用机制，发现了MRE可抑制XOD/ADA活性抑制尿酸生成，调节尿酸转运蛋白（ABCG2、URAT1、GLUT9）抑制肾脏尿酸重吸收、促进尿酸排泄的多途径系统降尿酸作用；抑制肾脏RAAS系统，激活血管内皮eNOS/NO系统的降血压作用；并阐明抑制“肝-肾/肠轴”LPS/TLR4/NF-κB信号通路是MRE改善肝、肾炎症损伤，发挥抗高尿酸血症伴高血压的主要分子机制。.完成了项目的全部研究内容及任务指标，并达到了项目的研究目标。发表学术论文12篇，其中SCI论文8篇（JCR 1区3篇）；申请国家发明专利3项；制定了铁皮石斛叶标准1项。为开发抗高尿酸血症中药新药和铁皮石斛叶充分利用奠定了基础，为降尿酸中药的优势与机制研究提供了依据。

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