本文選題：硫氧還蛋白 + 高糖�。� 參考：《大連醫(yī)科大學(xué)》2017年博士論文

【摘要】：目的:糖尿病是一種由多種因素所引起的糖、脂肪、蛋白質(zhì)代謝紊亂綜合癥,持續(xù)性高血糖是其主要表現(xiàn)之一,并且長期處于高血糖環(huán)境可以引起視網(wǎng)膜、心臟、腎臟、腦等諸多組織器官的損傷。長期高血糖狀態(tài),可以引起大量糖基化終末產(chǎn)(AGEs)的積累,有研究表明AGEs在糖尿病所引起的各種組織損傷中發(fā)揮著重要生物學(xué)作用。糖尿病視網(wǎng)膜病變(Diabetic retinopathy,DR)是糖尿病一種常見并發(fā)癥,早期研究認(rèn)為該疾病是一種微血管并發(fā)癥;而隨著研究的深入越來越多的學(xué)者認(rèn)為DR是一種神經(jīng)損傷早于血管病變的退行性疾病,但相關(guān)作用機(jī)制不明,因此糖尿病所引起的視網(wǎng)膜神經(jīng)組織損傷越來越受到人們的關(guān)注,尋找相關(guān)作用靶點及探討相關(guān)作用機(jī)制就顯得極其重要。硫氧還蛋白(Thioredoxin,Trx),是體內(nèi)一種重要的小分子蛋白,在抗氧化、抗凋亡、增殖、調(diào)節(jié)轉(zhuǎn)錄等過程中發(fā)揮重要的生物學(xué)功能。蘿卜硫素(Sulforphane,SF)是一種十字花科植物中的有效提取物,在我們前期的研究中發(fā)現(xiàn)可有效上調(diào)硫氧還蛋白的表達(dá)從而延遲視網(wǎng)膜感光細(xì)胞退行性病變。本論文通過建立糖尿病小鼠模型,同時采用高糖培養(yǎng)神經(jīng)細(xì)胞,通過不同方法上調(diào)或下調(diào)Trx表達(dá),研究Trx在糖尿病視網(wǎng)膜神經(jīng)細(xì)胞損傷中的作用及機(jī)制,旨在為臨床治療糖尿病視網(wǎng)膜病變提供關(guān)鍵靶點和新的理論依據(jù)。方法:體內(nèi)研究:Balb/c小鼠,雄性,4~6周,隨機(jī)分為正常對照組(non-diabetes)、糖尿病模型組(diabetes)、糖尿病-蘿卜硫素處理組(diabetes+SF)、糖尿病-蘿卜硫素-PX12聯(lián)合處理組(diabetes+SF+PX12)。采用HE染色觀察視網(wǎng)膜組織形態(tài)學(xué)及視網(wǎng)膜感光細(xì)胞核層計數(shù)分析,視網(wǎng)膜凝集素標(biāo)記血管形態(tài);視網(wǎng)膜電圖(ERG)進(jìn)行視網(wǎng)膜功能檢測;免疫熒光對Opsin、Rhodposin、Trx等相關(guān)蛋白進(jìn)行定位、定性分析;Western blot和Real time PCR對相關(guān)信號通路蛋白表達(dá)進(jìn)行檢測。體外研究:選用小鼠視網(wǎng)膜衍生感光細(xì)胞661w、Neuro2a細(xì)胞、HUVEC細(xì)胞、RF/6A細(xì)胞、h RPC細(xì)胞,將實驗組分為正常葡萄糖對照組(NG)、高糖處理組(HG)、甘露醇對照處理組(Mannitol)、高糖-蘿卜硫素處理組(HG+SF)、高糖-蘿卜硫素-PX12聯(lián)合作用組(HG+SF+PX12)。采用CCK8法篩選作用于不同細(xì)胞的葡萄糖濃度;流式細(xì)胞術(shù)以及TUNEL染色、DNA-Ladder等方法檢測高糖環(huán)境下細(xì)胞凋亡情況;轉(zhuǎn)基因以及RNA干擾等方法上調(diào)或下調(diào)Trx表達(dá),探討Trx在高糖所引起的視網(wǎng)膜神經(jīng)細(xì)胞凋亡過程中的作用;Western blot和Real-time PCR法檢測相關(guān)信號通路蛋白的表達(dá)。結(jié)果:第一部分糖尿病性視網(wǎng)膜感光細(xì)胞退行性病變及相關(guān)機(jī)制初探體內(nèi)研究結(jié)果顯示:從HE染色視網(wǎng)膜感光細(xì)胞形態(tài)學(xué)分析結(jié)果看出,糖尿病組小鼠在發(fā)病后,視網(wǎng)膜感光細(xì)胞數(shù)與非糖尿病組比較已經(jīng)開始丟失,并隨時間延長不斷減少;而此時的凝集素血管鋪片結(jié)果顯示,糖尿病小鼠視網(wǎng)膜血管與正常組相比形態(tài)無差異。ERG結(jié)果顯示:在糖尿病小鼠中視桿細(xì)胞a波振幅大小在發(fā)病后第10天與對照組比較明顯降低,并隨時間延長不斷減小(p0.05);b波振幅大小在發(fā)病后第10天與對照組比較明顯降低并隨時間延長不斷減小(p0.05)。而在糖尿病小鼠中,視錐細(xì)胞a、b波振幅大小與對照組比較未見明顯變化。另外視桿細(xì)胞功能相關(guān)蛋白Rhodopsin表達(dá)與對照組比較發(fā)生明顯改變,對照組Rhodopsin在內(nèi)外節(jié)表達(dá)分布均勻,而在糖尿病小鼠中,整體表達(dá)分布不均,視網(wǎng)膜各層均有表達(dá)。而視錐細(xì)胞相關(guān)功能蛋白Opsin的表達(dá)強(qiáng)度明顯降低,但是陽性細(xì)胞數(shù)量未見統(tǒng)計學(xué)差異。體外研究結(jié)果顯示:經(jīng)不同濃度高糖處理后,細(xì)胞凋亡百分比明顯升高,并與高糖濃度呈正相關(guān);線粒體生物合成相關(guān)基因PGC1a、Nrf1、Tfam表達(dá)以及線粒體膜電位隨著高糖濃度的升高逐漸降低。與對照組比較均有顯著差異(p0.05)。在體內(nèi)及體外水平結(jié)果顯示:隨著糖尿病發(fā)病時間的延長、高糖濃度的升高,與對照組比較Trx表達(dá)逐漸降低(p0.05)。第二部分硫氧還蛋白對糖尿病性神經(jīng)血管損傷的影響經(jīng)不同濃度葡萄糖處理Neuro2a、HUVEC、RF/6A、h RPC四種細(xì)胞后,隨著葡萄糖濃度的升高,Neuro2a、h RPC兩種細(xì)胞與對照組比較細(xì)胞存活率明顯降低(p0.05),而HUVEC、RF/6A兩種細(xì)胞與對照組比較細(xì)胞存活率未見明顯變化。Real time PCR檢測Trx表達(dá)結(jié)果顯示:經(jīng)不同濃度葡萄糖處理后Neuro2a、h RPC兩種細(xì)胞與對照組比較明顯下調(diào)(p0.05),而HUVEC、RF/6A兩種細(xì)胞未見明顯變化。高表達(dá)Trx的Neuro2a-Trx細(xì)胞經(jīng)高糖處理后與Neuro2a細(xì)胞比較凋亡百分比明顯降低(p0.05);在HUVEC細(xì)胞中,下調(diào)Trx表達(dá)后,經(jīng)高糖處理后凋亡百分與正常HUVEC細(xì)胞比較明顯升高(p0.05)。第三部分蘿卜硫素對糖尿病視網(wǎng)膜神經(jīng)細(xì)胞損傷的作用及相關(guān)機(jī)制研究HE染色分析結(jié)果顯示,糖尿病小鼠與正常小鼠比較視網(wǎng)膜感光細(xì)胞明顯丟失(p0.05),而給予SF處理后可以有效抑制視網(wǎng)膜感光細(xì)胞的丟失(p0.05),經(jīng)SF和PX12同時處理后,視網(wǎng)膜感光細(xì)胞的丟失更為明顯(p0.05)。ERG結(jié)果顯示:糖尿病小鼠a波、b波與正常小鼠比較振幅大小明顯降低(p0.05);而給予SF處理后可以有效抑制a波、b波振幅大小的降低(p0.05),經(jīng)SF和PX12同時處理a波、b波振幅大小降低更為明顯(p0.05)。采用流式細(xì)胞術(shù)對Neuro2a細(xì)胞進(jìn)行凋亡分析結(jié)果顯示:Neuro2a細(xì)胞經(jīng)高糖處理后,與對照組比較凋亡百分比較明顯上升(p0.05);而經(jīng)SF處理后,可以有效抑制其凋亡百分比升高;經(jīng)SF和PX12共同處理后與SF單獨處理時相比較,凋亡百分比明顯升高(p0.05)。采用real time PCR、Western blot技術(shù),在Neuro2a細(xì)胞中對相關(guān)通路蛋白在m RNA及蛋白水平表達(dá)檢測結(jié)果發(fā)現(xiàn):經(jīng)高糖處理后其ASK1、Txnip與對照組比較明顯升高,而Trx表達(dá)明顯降低(p0.05);經(jīng)SF處理后ASK1、Txnip表達(dá)與高糖組比較明顯降低,而Trx表達(dá)明顯升高(p0.05);經(jīng)SF和PX12聯(lián)合處理后與SF單獨處理組比較ASK1、Txnip表達(dá)明顯升高,Trx表達(dá)明顯降低(p0.05)。第四部分硫氧還蛋白抑制糖基化終末產(chǎn)物誘導(dǎo)神經(jīng)細(xì)胞凋亡的體外研究糖尿病小鼠與正常對照組比較視網(wǎng)膜AGE表達(dá)明顯升高,通過PX12或RNAi方法下調(diào)Trx表達(dá)后,再以AGE處理的Neuro2a細(xì)胞凋亡百分比明顯升高、細(xì)胞存活率明顯降低、線粒體膜電位明顯降低、DNA斷裂現(xiàn)象更明顯,與AGE單獨處理組比較均有顯著差異(p0.05)。經(jīng)SF上調(diào)Trx表達(dá)后,再以AGE處理的Neuro2a細(xì)胞凋亡百分比明顯降低、細(xì)胞存活率明顯升高,與AGE單獨處理組比較均有顯著差異(p0.05)。結(jié)論:第一部分糖尿病性視網(wǎng)膜感光細(xì)胞退行性病變及相關(guān)機(jī)制初探1.糖尿病性視網(wǎng)膜神經(jīng)細(xì)胞退行性病變早于血管損傷的發(fā)生。2.糖尿病性視網(wǎng)膜感光細(xì)胞退行性病變最先發(fā)生在視桿細(xì)胞。3.高糖誘導(dǎo)視網(wǎng)膜感光細(xì)胞凋亡的主要機(jī)制與線粒體的生物合成抑制或功能障礙有關(guān)4.高糖誘導(dǎo)視網(wǎng)膜感光細(xì)胞退行性病變的發(fā)生與Trx表達(dá)具有相關(guān)性。第二部分硫氧還蛋白對糖尿病性神經(jīng)血管損傷的影響1.高糖環(huán)境下神經(jīng)細(xì)胞的損傷早于血管內(nèi)皮細(xì)胞的損傷,主要原因與二者Trx表達(dá)水平的差異相關(guān)。2.在神經(jīng)細(xì)胞過表達(dá)Trx可以抑制高糖所誘導(dǎo)的細(xì)胞凋亡。3.在血管內(nèi)皮細(xì)胞下調(diào)Trx表達(dá)可以促進(jìn)高糖所誘導(dǎo)的細(xì)胞凋亡。第三部分蘿卜硫素對糖尿病性視網(wǎng)膜神經(jīng)細(xì)胞損傷的作用及相關(guān)機(jī)制研究1.蘿卜硫素上調(diào)Trx表達(dá)的主要作用機(jī)制與ERK信號通路相關(guān)。2.Trx在抑制高糖所致神經(jīng)細(xì)胞損傷的過程中發(fā)揮重要作用,其作用機(jī)制與Trx/ASK1/Txnip信號通路相關(guān)。第四部分硫氧還蛋白抑制糖基化終末產(chǎn)物誘導(dǎo)神經(jīng)細(xì)胞凋亡的體外研究1.糖尿病引起神經(jīng)細(xì)胞損傷的主要因素是由于AGE大量積累所致。2.Trx在AGE誘導(dǎo)的神經(jīng)細(xì)胞損傷過程中起到關(guān)鍵作用。3.SF介導(dǎo)Trx表達(dá)上調(diào)可以抑制AGE所引起的神經(jīng)細(xì)胞損傷。
[Abstract]:Objective: diabetes is a kind of sugar, fat, protein metabolism disorder syndrome caused by a variety of factors, persistent hyperglycemia is one of its main manifestations, and long-term hyperglycemic environment can cause damage to many tissues and organs of the retina, heart, kidney, brain and so on. Long term hyperglycemia can cause a large number of glycosylation end production ( AGEs) accumulation, studies have shown that AGEs plays an important biological role in various tissue injuries caused by diabetes. Diabetic retinopathy (Diabetic retinopathy, DR) is a common complication of diabetes. Early studies suggest that the disease is a microvascular and hair disorder; and as more and more scholars believe that the disease is more and more popular. DR is a kind of neurodegenerative disease which is earlier than vascular lesion, but the mechanism of the related action is unknown. Therefore, the retinal nerve tissue damage caused by diabetes is getting more and more attention. It is very important to find the related target and explore the related mechanism. Thioredoxin (Trx) is a kind of weight in the body. Small molecular proteins are important biological functions in the process of antioxidation, anti apoptosis, proliferation and regulation of transcription. Sulforphane (SF) is an effective extract from cruciferous plants. In our previous study, it was found that the expression of thioredoxin could be effectively raised to delay the degeneration of retinal photoreceptor cells. The purpose of this paper is to study the role and mechanism of Trx in diabetic retinal nerve cell injury by setting up a diabetic mouse model and using high glucose to raise or down the expression of Trx. The aim of this study is to provide key targets and new theoretical basis for the clinical treatment of diabetic retinopathy. Study: Balb/c mice, male, 4~6 weeks, randomly divided into normal control group (non-diabetes), diabetes model group (diabetes), diabetes - sulforaphin treatment group (diabetes+SF), diabetes - sulforaphin -PX12 combined treatment group (diabetes+SF+PX12). The retinal histomorphology and retinal photoreceptor cell nuclear layer count analysis were observed by HE staining. Retinal agglutinin (retinal agglutinin) marked vascular morphology; electroretinogram (ERG) for retinal function detection; immunofluorescence on Opsin, Rhodposin, Trx and other related proteins to locate, qualitative analysis; Western blot and Real time PCR to detect the expression of related signaling pathway protein. Cells, HUVEC cells, RF/6A cells, and H RPC cells were divided into normal glucose control group (NG), high glucose treatment group (HG), mannitol control treatment group (Mannitol), high sugar sulforaphane treatment group (HG+SF), high sugar sulforaphane -PX12 joint action group (HG+SF+PX12). The concentration of glucose in different cells was screened by CCK8 method; flow formula was selected. Cell apoptosis, TUNEL staining, DNA-Ladder and other methods were used to detect the apoptosis in high glucose environment, and the expression of Trx was up or down by transgene and RNA interference. The role of Trx in the apoptosis of retinal nerve cells caused by high glucose was investigated. The expression of related signaling pathway proteins was detected by Western blot and Real-time PCR method. The first part of the study of diabetic retina photoreceptor degeneration and related mechanisms in vivo showed that: from the morphological analysis of HE stained retinal photoreceptor cells, the number of retinal photoreceptor cells in the diabetic group had been lost after the onset of diabetes, and decreased with time. The results showed that the retinal vessels of diabetic mice had no difference in morphology compared with the normal group.ERG results showed that the amplitude of a wave amplitude in the optic rod cells in diabetic mice decreased significantly at tenth days after the onset and decreased with time (P0.05), and the amplitude of B wave was tenth days after the onset of onset. Compared with the control group, the amplitude of the A and B waves in the cones was not significantly changed in the diabetic mice, and the Rhodopsin expression of the rod cell function related protein was significantly different from the control group, and the expression of Rhodopsin in the control group was evenly distributed in the control group, and in the control group, the expression of Rhodopsin in the control group was evenly distributed, and the expression of Rhodopsin in the control group was evenly distributed in the control group. In the diabetic mice, the overall expression distribution was uneven, and the retina was expressed in all layers. The expression intensity of the conical cell related functional protein Opsin was significantly reduced, but the number of positive cells was not statistically significant. The results of in vitro study showed that the percentage of apoptotic cells increased significantly after the treatment of different concentrations of high sugar, and the concentration of high glucose was significantly higher than that of high glucose. The mitochondrial biosynthesis related genes PGC1a, Nrf1, Tfam expression and mitochondrial membrane potential decreased gradually with high glucose concentration. There was significant difference compared with the control group (P0.05). In vivo and in vitro results showed that with the prolongation of the onset of diabetes, high glucose concentration increased, and the Trx expression was compared with the control group. Gradually decreasing (P0.05). The effect of second part of thioredoxin on diabetic neurovascular injury after different concentrations of glucose treatment Neuro2a, HUVEC, RF/6A, H RPC four cells, with the increase of glucose concentration, Neuro2a, H RPC two cells compared with the control group, compared with the control group, the survival rate of fine cell decreased significantly (P0.05), HUVEC, RF/6A two cells and Compared with the control group, the cell survival rate was not significantly changed by.Real time PCR detection Trx expression results showed that after the treatment of Neuro2a, H RPC two cells were significantly lower than the control group after different concentrations of glucose treatment (P0.05), but HUVEC, RF/6A two kinds of cells were not obviously changed. The percentage of apoptosis was significantly lower (P0.05); in HUVEC cells, after the downregulation of Trx, the apoptotic percentage was significantly higher than that of normal HUVEC cells after high glucose treatment (P0.05). The effect of third part of sulforaphane on diabetic retinal nerve cell injury and its mechanism The retinal photoreceptor cells were significantly lost in mice (P0.05), and the loss of retinal photoreceptor cells (P0.05) was effectively suppressed by SF treatment. After SF and PX12 treatment, the loss of retinal photoreceptor cells was more obvious (P0.05).ERG results showed that the amplitude of B wave in mice was significantly lower than normal mice (P0.05). When treated with SF, the a wave could be suppressed effectively and the amplitude of B wave was reduced (P0.05). The amplitude of B wave was reduced by SF and PX12 at the same time, and the amplitude of B wave decreased more obviously (P0.05). The apoptosis analysis of Neuro2a cells by flow cytometry showed that the apoptotic percentage of Neuro2a cells was significantly higher than that of the control group after high glucose treatment (P0) was significantly higher than that of the control group (P0). .05); and after SF treatment, the percentage of apoptosis could be inhibited effectively; the percentage of apoptosis increased significantly after the CO treatment of SF and PX12 and SF alone (P0.05). Real time PCR, Western blot technique was used to detect the expression of related pathway proteins in the Neuro2a cells. After treatment, the ASK1, Txnip and the control group were significantly higher, but the expression of Trx decreased significantly (P0.05). After SF treatment, the expression of Txnip was significantly lower than that in the high sugar group, but the expression of Trx increased significantly (P0.05), and the expression of Trx was significantly increased after the joint treatment of SF and PX12, and the expression was significantly reduced. The fourth part of the expression was significantly reduced. In vitro study of thioredoxin inhibition of glycosylation end products induced neuronal apoptosis in vitro, the AGE expression in the retina was significantly increased in diabetic mice compared with the normal control group. The percentage of apoptosis in Neuro2a cells treated with AGE increased significantly, the cell survival rate decreased significantly, and the mitochondrial membrane potential was significantly reduced by the PX12 or RNAi method. Obviously decreased, DNA fracture was more obvious, compared with AGE alone (P0.05). After SF up regulation of Trx, the percentage of apoptosis in Neuro2a cells treated with AGE decreased obviously and the cell survival rate increased significantly (P0.05) compared with that of AGE alone (P0.05). Conclusion: the first part of the diabetic retina is: the first part of diabetic retina A preliminary study of photoreceptor degeneration and related mechanisms 1. the degenerative disease of diabetic retina is earlier than that of vascular injury..2. diabetic retinal photoreceptor degeneration first occurs in the main mechanism of.3. high glucose induced retinal photoreceptor cell apoptosis and the inhibition or function of mitochondrial biosynthesis. The relationship between the occurrence of 4. high glucose induced retinal photoreceptor degeneration and the expression of Trx. Second the effect of partial thioredoxin on diabetic neurovascular injury. The damage of nerve cells in the 1. high glucose environment is earlier than that of vascular endothelial cells, the main cause of which is related to the difference of the level of Trx expression in.2.. Overexpression of Trx can inhibit the apoptosis induced by high glucose.3. in vascular endothelial cells down regulation of Trx expression can promote the apoptosis induced by high glucose. Third the effect of sulforaphane on diabetic retinal nerve cell injury and its mechanism study 1. the main mechanism of the action of sulforaphane on the up regulation of Trx expression and ER K signaling pathway related.2.Trx plays an important role in inhibiting the injury of nervous cells caused by high glucose. Its mechanism is related to the Trx/ASK1/Txnip signaling pathway. Part fourth thioredoxin inhibits the apoptosis of neural cells induced by glycosylation end products. 1. the main factor for the injury of nerve cells induced by diabetes is due to A The accumulation of GE caused by the accumulation of.2.Trx plays a key role in the process of AGE induced nerve cell damage. The up regulation of Trx expression mediated by.3.SF can inhibit the injury of nerve cells caused by AGE.
【學(xué)位授予單位】：大連醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R587.2;R774.1

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