本文選題：糖尿病視網(wǎng)膜病變 + 多不飽和脂肪酸　； 參考：《浙江大學》2015年博士論文

【摘要】：糖尿病視網(wǎng)膜病變(Diabetic retinopathy, DR)是糖尿病最常見的并發(fā)癥之一,具有較高發(fā)病率,病程長、終可致盲。目前尚無方法可對其進行根治,現(xiàn)有的藥物治療方法也大都存在副作用。長鏈多不飽和脂肪酸,尤其是n-3系的二十二碳六烯酸(Docosahexaenoic acid, DHA),不僅是視網(wǎng)膜的重要組成成分,而且其代謝產(chǎn)物也影響著視網(wǎng)膜的正常功能。臨床和動物實驗也證明多不飽和脂肪酸可以改善胰島素抵抗,對糖尿病有一定的緩解作用。故本研究以多不飽和脂肪酸為研究對象,探究其對DR的影響與調(diào)節(jié)作用,并通過體外和體內(nèi)實驗,分別對炎性反應、氧化損傷、脂肪酸代謝等方面加以考察。體外部分以人視網(wǎng)膜色素上皮細胞(Human retinal pigment epithelium, ARPE-19)細胞系作為研究對象,成功構(gòu)建了高糖損傷糖尿病視網(wǎng)膜病變細胞模型,細胞線粒體功能被破壞,同時促炎因子大量分泌。ARPE-19細胞株對不同脂肪酸耐受量存在差異,100 μM是本實驗用到的五種脂肪酸亞油酸(Linoleic acid,LA)、亞麻酸(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濃度。以此濃度進一步對糖損傷細胞進行修復和預防處理,發(fā)現(xiàn)存在如下效果：(1)不同脂肪酸在調(diào)節(jié)炎性因子分泌方面的效應。LA、ALA、 EPA、DHA同步或之后處理,LA、ALA和DHA預處理均能抑制高糖對腫瘤壞死因子α(Tumor necrosis factor-a,TNF-α)分泌的刺激；而AA因本身脂代謝能夠生成其他炎性因子,故無效果。不同脂肪酸在同步添加處理時均能減弱高糖對白細胞介素-6(Interleukin-6,IL-6)分泌的刺激,但之后添加處理中僅ALA有效,之前預處理LA、ALA和DHA有效。所有脂肪酸無論預處理還是同步或之后處理都能抑制高糖對白細胞介素-4(Interleukin-4,IL-4)分泌的刺激。(2)不同脂肪酸在調(diào)節(jié)氧化-還原方面的效應。LA、ALA、AA、EPA、DHA同步或之后處理,LA、AA、EPA、DHA預處理能使細胞活性氧自由簇(Reactive oxygen species, ROS)恢復常態(tài)。DHA之后處理,LA、ALA、AA預處理能夠顯著提升超氧化物歧化酶(Superoxide dismutase, SOD)活性。LA、ALA、AA、DHA之后處理,AA、EPA、DHA預處理能提升過氧化氫酶(Catalase,CAT)活(3)脂肪酸的添加能夠明顯調(diào)節(jié)細胞脂肪酸組成,尤其是n-6/n-3比；而且對下游代謝產(chǎn)物如人脂氧素A4 (Lipoxin A4, LXA4)生成也有所影響。體內(nèi)研究以SD大鼠為研究對象,脂肪酸處理選用ALA,采用修復和預處理兩種方式作用于糖尿病視網(wǎng)膜病變大鼠。兩種處理均能有效降低病變所造成的血管生成因子和炎性因子的含量,使其恢復到正常水平。同時能夠提升腦源性神經(jīng)營養(yǎng)因子的分泌。在氧化還原調(diào)節(jié)方面,ALA添加組谷胱甘肽過氧化物酶(Glutathione peroxidase, GSH-Px)活力顯著提升。綜上,多不飽和脂肪酸對高糖損傷的視網(wǎng)膜細胞存在著一定的保護作用,主要體現(xiàn)在抑制炎癥反應發(fā)生；對大鼠糖尿病視網(wǎng)膜病變也有著一定的預防和修復功效。
[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- 偽 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.
【學位授予單位】：浙江大學
【學位級別】：博士
【學位授予年份】：2015
【分類號】：R587.2;R774.1

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