基于肠-肾轴LPS-TLR4/Nrf2信号通路研究铁皮石斛六妙方改善高尿酸伴高脂血症的尿酸排泄机制

The incidence of high uric acid and hyperlipidemia increased year by year with the improvement of living standard, the change of diet structure. TCM believes that "overeatingfeigan, wine Atsumi, easy loss of transportation" is a major cause of hyperuricemia with hyperlipidemia, meanwhile dys-splenism, kidney deficien resulted in dampness block, fat and grease inflexibility, excretion disadvantageous is the main pathogenesis. Dendrobium officinale Six Miao prescription (DOFLMF) has the effect on tonifying stomach and spleen, tonifying kidney and removing dampness through diuresis. Pharmacological experiments showed that DOFLMF had effect on reducing uric acid, blood lipid, improve liver function and intestinal renal disease in spleen and kidney deficiency type high uric acid with hyperlipidemia, but the mechanism has not been elucidated. This research adopts the fat emulsion / high fat hyperpurine diet to establish the high uric acid and hyperlipidemia model, using methods of RT-PCR, WB, immunohistochemistry and Elisa to study intestinal function through"LPS-TLR4/Nrf2" pathway to regulate the "intestinal-kidney" uric acid transport and its correlation analysis; from the whole, cell、 protein / gene levels to know effects of DOFLMF on multilinks of the intestinal tract the function, formulate the mechanism of descending uric acid and characteristics of protecting liver and kidney based on intestinal function, laying the foundation for the development of new medicine for anti hyperuricemia.

随着生活水平改善，饮食结构的变化，高尿酸伴高脂血症发病率逐年升高。中医认为“过食肥甘、醇酒厚味，易运化失司”是高尿酸伴高脂血症的主要病因，脾失健运、肾亏虚致湿浊阻滞，膏脂内生、排泄不利是主要病机。课题组自主研制的以铁皮石斛为君药的铁皮石斛六妙方具“益胃健脾、补肾利湿”功效。前期药理实验表明铁皮石斛六妙方对模型动物具有降尿酸、调血脂、改善肠肾病变，但其作用机制尚未阐明。本课题进一步采用脂肪乳剂/高脂高嘌呤等拟“过食膏粱肥甘”建立高尿酸伴高脂血症模型，用RT-PCR、WB、免疫组化、Elisa等方法，研究基于肠-肾轴LPS-TLR4/Nrf2信号通路调节尿酸转运及其之间相关性分析。从整体、细胞、蛋白/基因等层面，研究铁皮石斛六妙方对肠道功能多环节影响，阐述其“益胃健脾、补肾利湿”的科学内涵，探讨基于肠-肾轴功能的降尿酸调血脂机制，为铁皮石斛复方中药新药开发奠定药理学基础。

随着生活水平改善，饮食结构的变化，高尿酸伴高脂血症发病率逐年升高。中医认为“过食膏粱肥甘，易运化失司”是高尿酸伴高脂血症的主要病因，脾失健运、肾亏虚致湿阻滞，膏脂内生、排泄不利是主要病机。以铁皮石斛为君药的铁皮石斛六妙方具“益胃健脾、补肾利湿”功效，其防治高尿酸伴高脂血症的药效和优势特色有待明确，且其作用机制尚未阐明。.本研究进一步采用脂肪乳剂、高脂高嘌呤等拟“过食膏粱肥甘”建立高尿酸伴高脂血症大鼠模型，阐明了肠道功能紊乱引起LPS生成增多，进而诱导TLR4级联炎症反应和Keap1-Nrf2抗氧化抑制，使“肠-肾轴”尿酸转运系统失调是高尿酸血症发生重要机制。3种大鼠模型反复验证明确了铁皮石斛六妙方的降尿酸、降血脂药效，同时还具有改善模型大鼠体征、抗肝肾损伤和改善肠功能等优势特色。并重点基于“肠-肾轴”LPS-TLR4/Nrf2信号通路，揭示了铁皮石斛六妙方改善尿酸排泄障碍的降尿酸作用机制。该研究阐述了铁皮石斛六妙方“益胃健脾、补肾利湿”的科学内涵，为铁皮石斛复方中药新药开发奠定基础。发表学术论文9篇，其中SCI论文8篇（JCR 1区3篇）；授权国家发明专利1项、申请2项；制定了铁皮石斛团体标准。完成了项目的全部研究内容及任务指标。