環(huán)糊精延緩動(dòng)脈粥樣硬化形成的作用及其機(jī)制研究
發(fā)布時(shí)間：2018-11-26 17:29
【摘要】：環(huán)糊精作為藥物載體在藥物學(xué)方面被廣泛應(yīng)用,最近幾年作為藥物用于治療C型尼曼匹克氏等特殊疾病。由于環(huán)糊精“腔內(nèi)疏水,腔外親水”獨(dú)特立體結(jié)構(gòu),環(huán)糊精具備剔除脂蛋白復(fù)合分子中或活細(xì)胞表面脂質(zhì)分子的能力,尤其是膽固醇。多種血漿脂蛋白和細(xì)胞被證實(shí)參與動(dòng)脈粥樣硬化的形成與發(fā)展,其中低密度脂蛋白膽固醇水平與氧化型低密度脂蛋白濃度是誘發(fā)該疾病的關(guān)鍵因素。鑒于環(huán)糊精特性與動(dòng)脈粥樣硬化誘因之間的關(guān)聯(lián),我們推測(cè)環(huán)糊精可以剔除血漿脂蛋白與動(dòng)脈粥樣硬化形成相關(guān)細(xì)胞表面的膽固醇等脂質(zhì)分子,改變其結(jié)構(gòu)、性質(zhì)或功能,最終影響動(dòng)脈粥樣硬化的形成與發(fā)展。本課題旨在驗(yàn)證此推測(cè),揭示環(huán)糊精抗動(dòng)脈粥樣硬化的作用及其潛在機(jī)制。為揭示環(huán)糊精抗動(dòng)脈粥樣硬化的作用,選擇ApoE-/-小鼠為模型小鼠,以2-羥丙基-β-環(huán)糊精為代表,進(jìn)行動(dòng)物實(shí)驗(yàn),結(jié)果表明:環(huán)糊精能顯著降低血清甘油三酯含量、降低ox-LDL水平、減少血管脂質(zhì)斑塊量等,最終有效緩解動(dòng)脈粥樣硬化的病發(fā)進(jìn)程。為探討環(huán)糊精延緩動(dòng)脈粥樣硬化的可能機(jī)制,檢測(cè)不同種類不同濃度環(huán)糊精對(duì)血液主要脂蛋白LDL與HDL的結(jié)構(gòu)與體外氧化影響及原因,結(jié)果顯示環(huán)糊精能剔除這兩者的部分脂類成分,能抑制這兩類脂蛋白的氧化,抑制效果呈濃度依賴性,揭示環(huán)糊精延緩AS的可能機(jī)制1:環(huán)糊精影響LDL結(jié)構(gòu)成分并抑制其氧化;可能機(jī)制2:環(huán)糊精影響HDL的成分并抑制其氧化。為進(jìn)一步探討作用機(jī)制,設(shè)計(jì)細(xì)胞與分子實(shí)驗(yàn),檢測(cè)環(huán)糊精對(duì)單核細(xì)胞與血管內(nèi)皮細(xì)胞之間粘附作用的影響及機(jī)制,結(jié)果表明環(huán)糊精通過(guò)影響?zhàn)じ椒肿覫CAM-1、VCAM、E-Selectin的分泌、細(xì)胞骨架及其相關(guān)分子,顯著抑制單核細(xì)胞THP-1與內(nèi)皮細(xì)胞HUVEC的黏附,后者是動(dòng)脈粥樣硬化形成的關(guān)鍵步驟,這揭示了環(huán)糊精延緩AS的可能機(jī)制3:環(huán)糊精能減少內(nèi)皮細(xì)胞黏附分子的分泌等,抑制單核細(xì)胞與內(nèi)皮細(xì)胞的黏附�？偠灾�,本論文明確了環(huán)糊精抗動(dòng)脈粥樣硬化的作用。由于動(dòng)脈粥樣硬化的誘發(fā)因素復(fù)雜多樣,故環(huán)糊精抗動(dòng)脈粥樣硬化的幾種機(jī)制可能會(huì)相互干擾或影響,或許會(huì)如同文中所描述那樣錯(cuò)綜復(fù)雜。本研究不僅為動(dòng)脈粥樣硬化的預(yù)防或治療提供了一種可能的新藥或新方向,而且讓具備促溶、低毒、安全等優(yōu)點(diǎn)的環(huán)糊精在生物醫(yī)藥領(lǐng)域中的應(yīng)用被拓展升華。
[Abstract]:Cyclodextrins have been widely used in pharmacology as drug carriers and in recent years as drugs for the treatment of specific diseases such as type C Neimanpik's. Due to the unique three-dimensional structure of cyclodextrin, especially cholesterol, cyclodextrin has the ability to remove lipids from lipoprotein complex molecules or living cell surface. A variety of plasma lipoproteins and cells have been proved to be involved in the formation and development of atherosclerosis, among which the level of low density lipoprotein cholesterol and the concentration of oxidized low density lipoprotein are the key factors to induce the disease. In view of the correlation between cyclodextrin properties and the causes of atherosclerosis, we speculate that cyclodextrin can remove lipid molecules such as cholesterol on the surface of cells associated with atherosclerosis and alter their structure, properties or functions. Ultimately affect the formation and development of atherosclerosis. The aim of this study was to verify this hypothesis and to reveal the anti-atherosclerotic effect of cyclodextrin and its underlying mechanism. In order to reveal the anti-atherosclerosis effect of cyclodextrin, ApoE-/- mice were selected as model mice and 2-hydroxypropyl- 尾 -cyclodextrin was used as the representative in animal experiments. The results showed that cyclodextrin could significantly reduce serum triglyceride content. Reduce the level of ox-LDL, reduce the amount of vascular lipid plaque, and ultimately alleviate the progression of atherosclerosis. In order to explore the possible mechanism of cyclodextrin delaying atherosclerosis, the effects of different kinds of cyclodextrins on the structure and in vitro oxidation of main lipoprotein LDL and HDL were detected. The results showed that cyclodextrin could remove some of the lipids and inhibit the oxidation of these two lipoproteins in a concentration-dependent manner. The possible mechanism of cyclodextrin delaying AS was 1: cyclodextrin affected the structural components of LDL and inhibited its oxidation. Mechanism 2: cyclodextrin affects the composition of HDL and inhibits its oxidation. In order to further explore the mechanism, cell and molecular experiments were designed to detect the effect and mechanism of cyclodextrin on adhesion between monocytes and vascular endothelial cells. The results showed that cyclodextrin affected the adhesion molecule ICAM-1,VCAM, by the effect of cyclodextrin on the adhesion between monocytes and vascular endothelial cells. The secretion of E-Selectin, cytoskeleton and its associated molecules significantly inhibit the adhesion of monocyte THP-1 to endothelial cell HUVEC, which is a key step in the formation of atherosclerosis. This reveals the possible mechanism of cyclodextrin delaying AS 3: cyclodextrin can reduce the secretion of endothelial cell adhesion molecules and inhibit the adhesion of monocytes to endothelial cells. All in all, the effect of cyclodextrin on atherosclerosis is clarified. Several mechanisms of cyclodextrin anti-atherosclerosis may interfere or affect each other because of the complexity of the inducing factors of atherosclerosis, and may be as complicated as described in this paper. This study not only provides a possible new drug or new direction for the prevention or treatment of atherosclerosis, but also expands the application of cyclodextrin in biomedical field with the advantages of promoting dissolution, low toxicity and safety.
【學(xué)位授予單位】：南昌大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R96
[Abstract]:Cyclodextrins have been widely used in pharmacology as drug carriers and in recent years as drugs for the treatment of specific diseases such as type C Neimanpik's. Due to the unique three-dimensional structure of cyclodextrin, especially cholesterol, cyclodextrin has the ability to remove lipids from lipoprotein complex molecules or living cell surface. A variety of plasma lipoproteins and cells have been proved to be involved in the formation and development of atherosclerosis, among which the level of low density lipoprotein cholesterol and the concentration of oxidized low density lipoprotein are the key factors to induce the disease. In view of the correlation between cyclodextrin properties and the causes of atherosclerosis, we speculate that cyclodextrin can remove lipid molecules such as cholesterol on the surface of cells associated with atherosclerosis and alter their structure, properties or functions. Ultimately affect the formation and development of atherosclerosis. The aim of this study was to verify this hypothesis and to reveal the anti-atherosclerotic effect of cyclodextrin and its underlying mechanism. In order to reveal the anti-atherosclerosis effect of cyclodextrin, ApoE-/- mice were selected as model mice and 2-hydroxypropyl- 尾 -cyclodextrin was used as the representative in animal experiments. The results showed that cyclodextrin could significantly reduce serum triglyceride content. Reduce the level of ox-LDL, reduce the amount of vascular lipid plaque, and ultimately alleviate the progression of atherosclerosis. In order to explore the possible mechanism of cyclodextrin delaying atherosclerosis, the effects of different kinds of cyclodextrins on the structure and in vitro oxidation of main lipoprotein LDL and HDL were detected. The results showed that cyclodextrin could remove some of the lipids and inhibit the oxidation of these two lipoproteins in a concentration-dependent manner. The possible mechanism of cyclodextrin delaying AS was 1: cyclodextrin affected the structural components of LDL and inhibited its oxidation. Mechanism 2: cyclodextrin affects the composition of HDL and inhibits its oxidation. In order to further explore the mechanism, cell and molecular experiments were designed to detect the effect and mechanism of cyclodextrin on adhesion between monocytes and vascular endothelial cells. The results showed that cyclodextrin affected the adhesion molecule ICAM-1,VCAM, by the effect of cyclodextrin on the adhesion between monocytes and vascular endothelial cells. The secretion of E-Selectin, cytoskeleton and its associated molecules significantly inhibit the adhesion of monocyte THP-1 to endothelial cell HUVEC, which is a key step in the formation of atherosclerosis. This reveals the possible mechanism of cyclodextrin delaying AS 3: cyclodextrin can reduce the secretion of endothelial cell adhesion molecules and inhibit the adhesion of monocytes to endothelial cells. All in all, the effect of cyclodextrin on atherosclerosis is clarified. Several mechanisms of cyclodextrin anti-atherosclerosis may interfere or affect each other because of the complexity of the inducing factors of atherosclerosis, and may be as complicated as described in this paper. This study not only provides a possible new drug or new direction for the prevention or treatment of atherosclerosis, but also expands the application of cyclodextrin in biomedical field with the advantages of promoting dissolution, low toxicity and safety.
【學(xué)位授予單位】：南昌大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R96
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本文編號(hào)：2359180
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