中文摘要
鄂伦春族特色药材坎库拉民间作为降压药使用。前期研究发现,坎库拉不仅能降低SHR大鼠的血压,还能显著改善小鼠糖耐量,降低STZ诱导的糖尿病鼠血糖水平,初步研究表明其是通过改善胰岛素抵抗发挥作用,但药效物质基础和分子机制不清。在本研究中,拟在3T3-L1细胞、糖耐量、ACE抑制和离体血管环“双模式四通道”的活性指导下,采用各种色谱技术追踪分离坎库拉中的活性成分并鉴定其结构,基于糖尿病和高血压的共同病理基础—胰岛素抵抗,阐明活性成分是通过PI3K/AKT、AMPK、PPAR-γ还是IKK/NF-κB及JNK/AP-1信号通路而改善胰岛素抵抗,并利用高盐饮食诱导高血压的糖尿病GK大鼠验证其体内活性和作用模式,同时阐明活性成分是否通过依赖内皮的NO-cGMP通路及依赖Ca2+等途径舒张血管。本研究为坎库拉的成药性奠定坚实的研究基础,为研发同时具有抗糖尿病和抗高血压作用的中药新药提供新思路。
英文摘要
Heracleum dissectum, a typical ethnic herb of Oroqen nationality, is eaten by local people as a naturally antihypertensive drug and delicious vegetable. The previous study revealed that H. dissectum significantly decreased the blood pressure in SHR rats mainly by inhibiting ACE activity and partly by dilating vessels. Meanwhile, it could potently inhibit the elevation of blood glucose in STZ-induced diabetic mice and greatly improve the glucose tolerance in mice. However, the antihypertensive and antidiabetic constituents and their mechanisms are unclear. In the present study, with the guide of TG accumulation assay in 3T3-L1 cells, OGTT in mice, ACE inhibition screening and vasorelaxant activity assay, the antihypertensive and antidiabetic principles of H. dissectum will be tracked down and purified by the various modern chromatographic techniques, and in vivo activities of the active constituents will be validated in high salt diet-induced GK rats. Most importantly, focusing on the common pathophysiological basis of diabetes and hypertension--insulin resistance, we will elucidate the detailed mechanisms underlying the insulin resistance improvement by investigating PI3K/AKT, AMPK, PPAR-γ, IKK/NF-κB and JNK/AP-1 signalling cascades in vitro and in vivo using the various cellular and molecular biological techniques. Furthermore, the mechanisms of relaxing the artery by the obtained vasodilators will be clarified by investigating the role of NO-cGMP in endothelium and K+ channel and the effects of calcium. This study will establish the solid research foundation for the development of H. dissectum potentially as a new drug and provide the new ideas for the discovery of the natural medicine both with the antihypertensive and antidiabetic activities.
