糖尿病视网膜病变的脂肪酸营养

发布时间：2018-07-05 04:45

本文选题：糖尿病视网膜病变 + 多不饱和脂肪酸　；参考：《浙江大学》2015年博士论文

【摘要】：糖尿病视网膜病变(Diabetic retinopathy, DR)是糖尿病最常见的并发症之一,具有较高发病率,病程长、终可致盲。目前尚无方法可对其进行根治,现有的药物治疗方法也大都存在副作用。长链多不饱和脂肪酸,尤其是n-3系的二十二碳六烯酸(Docosahexaenoic acid, DHA),不仅是视网膜的重要组成成分,而且其代谢产物也影响着视网膜的正常功能。临床和动物实验也证明多不饱和脂肪酸可以改善胰岛素抵抗,对糖尿病有一定的缓解作用。故本研究以多不饱和脂肪酸为研究对象,探究其对DR的影响与调节作用,并通过体外和体内实验,分别对炎性反应、氧化损伤、脂肪酸代谢等方面加以考察。体外部分以人视网膜色素上皮细胞(Human retinal pigment epithelium, ARPE-19)细胞系作为研究对象,成功构建了高糖损伤糖尿病视网膜病变细胞模型,细胞线粒体功能被破坏,同时促炎因子大量分泌。ARPE-19细胞株对不同脂肪酸耐受量存在差异,100 μM是本实验用到的五种脂肪酸亚油酸(Linoleic acid,LA)、亚麻酸(Alpha-linolenic acid, ALA)、花生四烯酸(Arachidonic acid, AA)、二十碳五烯酸(Eicosapentaenoic acid, EPA)、DHA都能耐受的最高安全浓度。以此浓度进一步对糖损伤细胞进行修复和预防处理,发现存在如下效果：(1)不同脂肪酸在调节炎性因子分泌方面的效应。LA、ALA、 EPA、DHA同步或之后处理,LA、ALA和DHA预处理均能抑制高糖对肿瘤坏死因子α(Tumor necrosis factor-a,TNF-α)分泌的刺激；而AA因本身脂代谢能够生成其他炎性因子,故无效果。不同脂肪酸在同步添加处理时均能减弱高糖对白细胞介素-6(Interleukin-6,IL-6)分泌的刺激,但之后添加处理中仅ALA有效,之前预处理LA、ALA和DHA有效。所有脂肪酸无论预处理还是同步或之后处理都能抑制高糖对白细胞介素-4(Interleukin-4,IL-4)分泌的刺激。(2)不同脂肪酸在调节氧化-还原方面的效应。LA、ALA、AA、EPA、DHA同步或之后处理,LA、AA、EPA、DHA预处理能使细胞活性氧自由簇(Reactive oxygen species, ROS)恢复常态。DHA之后处理,LA、ALA、AA预处理能够显著提升超氧化物歧化酶(Superoxide dismutase, SOD)活性。LA、ALA、AA、DHA之后处理,AA、EPA、DHA预处理能提升过氧化氢酶(Catalase,CAT)活(3)脂肪酸的添加能够明显调节细胞脂肪酸组成,尤其是n-6/n-3比；而且对下游代谢产物如人脂氧素A4 (Lipoxin A4, LXA4)生成也有所影响。体内研究以SD大鼠为研究对象,脂肪酸处理选用ALA,采用修复和预处理两种方式作用于糖尿病视网膜病变大鼠。两种处理均能有效降低病变所造成的血管生成因子和炎性因子的含量,使其恢复到正常水平。同时能够提升脑源性神经营养因子的分泌。在氧化还原调节方面,ALA添加组谷胱甘肽过氧化物酶(Glutathione peroxidase, GSH-Px)活力显著提升。综上,多不饱和脂肪酸对高糖损伤的视网膜细胞存在着一定的保护作用,主要体现在抑制炎症反应发生；对大鼠糖尿病视网膜病变也有着一定的预防和修复功效。
[Abstract]:Diabetic retinopathy (Dr) is one of the most common complications of diabetes mellitus. At present, there are no methods to cure it, and most of the existing drug therapy methods have side effects. Long chain polyunsaturated fatty acids, especially the 22 carbohexaenoic acid (DHA) of n-3 series, are not only important components of the retina, but also affect the normal function of the retina. Clinical and animal experiments have also shown that polyunsaturated fatty acids can improve insulin resistance and alleviate diabetes. Therefore, the effect and regulation of polyunsaturated fatty acids on Dr were investigated in vitro and in vivo, including inflammatory reaction, oxidative damage, fatty acid metabolism and so on. In vitro, the human retinal pigment epithelium, ARPE-19 cell line was used as the research object, and the cell model of diabetic retinopathy with high glucose injury was successfully constructed. The mitochondrial function of the cells was destroyed. At the same time, ARPE-19 cells secreted a lot of proinflammatory factors have different tolerance to different fatty acids. 100 渭 M is the five fatty acid linoleic acid (Linoleic acid), linolenic acid (Ala) and (Arachidonic acid, AA), eicosapentaenoic acidic acid (EPA). The highest safety concentration that can be tolerated. At this concentration, the cells damaged by sugar were repaired and prevented. The results were as follows: (1) the effects of different fatty acids on the regulation of inflammatory factor secretion. ALAA, EPA-DHA, and DHA pretreatment could inhibit the stimulation of Tumor necrosis factor-a TNF- 伪 by high glucose. AA can produce other inflammatory factors because of its lipid metabolism, so it has no effect. Different fatty acids could attenuate the stimulation of high glucose on the secretion of interleukin-6 (IL 6), but only Ala was effective in the later treatment, and pretreatment with LAA and DHA was effective. All fatty acids could inhibit the stimulation of high glucose on the secretion of interleukin-4 (IL-4). (2) the effects of different fatty acids on the regulation of oxidation-reduction. The pretreatment of reactive oxygen specieses (Ros) returned to normal. After pretreatment with LAALAALAA AA, the activity of superoxide dismutase (sod), and the pretreatment of APA DHA after treatment could increase the activity of catalase cat (3) fatty acids. Enough to regulate cell fatty acid composition, In particular, the ratio of n-6/n-3 and the production of downstream metabolites such as human lipoxin A4 (LXA4) were also affected. In vivo, SD rats were studied. The fatty acids were treated with ALA.The diabetic retinopathy rats were treated by repair and preconditioning. Both treatments can effectively reduce the contents of angiogenic factors and inflammatory factors and restore them to normal levels. It can also enhance the secretion of brain-derived neurotrophic factor. The activity of glutathione peroxidase (GSH-Px) was significantly increased in the redox regulation group. In conclusion, polyunsaturated fatty acids have a certain protective effect on retinal cells damaged by high glucose, mainly reflected in the inhibition of inflammatory reaction; diabetic retinopathy in rats also has a certain preventive and repair effect.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R587.2;R774.1

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