【摘要】：鋅是一種金屬化學(xué)元素,廣泛存在于自然界中。同時(shí),鋅離子是人體必需的金屬離子之一,能參與體內(nèi)微環(huán)境的穩(wěn)態(tài)調(diào)節(jié)、免疫調(diào)節(jié)、氧化應(yīng)激響應(yīng)、凋亡過(guò)程、老化等等。動(dòng)物實(shí)驗(yàn)證明,鋅能促進(jìn)抗氧化劑金屬硫蛋白(metallothionein, MT)生成增加,互相作用,使機(jī)體的抗氧化能力提高；能與銅離子共同形成銅／鋅超氧岐化酶(Cu/Zn SOD)發(fā)揮其抗氧化作用;能穩(wěn)定核因子E2相關(guān)因子2(nuclear factor erythroid-2related factor2, Nrf2)的結(jié)構(gòu),使其在體內(nèi)蛋白含量增加,功能性增加,從而調(diào)控下游的多種抗氧化基因水平,如醌氧化還原酶1(NQ01),第一型血色素氧化酵素(HO-1),超氧岐化酶1、2(SOD1, SOD2)等等,激活機(jī)體的多種抗氧化機(jī)制。 糖尿病是一種常見(jiàn)病、多發(fā)病,以其高發(fā)病率、高致死率嚴(yán)重影響人們的生活質(zhì)量而被廣泛關(guān)注。隨著病情的發(fā)展,能誘發(fā)多種嚴(yán)重的并發(fā)癥,其并發(fā)癥主要分兩大類(lèi),即糖尿病大血管并發(fā)癥如糖尿病大血管病變、動(dòng)脈粥樣硬化；糖尿病微血管并發(fā)癥如糖尿病心肌病,糖尿病腎臟病,糖尿病視網(wǎng)膜病變等等,很多報(bào)道指出,氧化應(yīng)激損傷對(duì)糖尿病以及其并發(fā)癥的發(fā)生與發(fā)展負(fù)有不可推卸的責(zé)任。眾所周知,糖尿病能引起機(jī)體血糖增高,代謝系統(tǒng)紊亂。這會(huì)導(dǎo)致組織器官炎癥反應(yīng),氧化應(yīng)激水平增高,氧化應(yīng)激產(chǎn)物活性氧自由基(ROS)、活性氮自由基(RNS)產(chǎn)生增多,在組織器官中的累積也相應(yīng)增多。它會(huì)攻擊機(jī)體的組織器官、血管內(nèi)皮細(xì)胞,產(chǎn)生一系列的損傷反應(yīng),例如炎癥、纖維化、凋亡等等。流行病學(xué)報(bào)道指出,糖尿病患者血清鋅離子含量降低。而外源性的補(bǔ)鋅,能使血清中鋅離子含量增高,而產(chǎn)生抗氧化作用�；诖�,我們?cè)O(shè)計(jì)了如下實(shí)驗(yàn),意在探究補(bǔ)鋅對(duì)糖尿病引起的血管并發(fā)癥(以大血管為中心)、微血管并發(fā)癥(以糖尿病視網(wǎng)膜病變?yōu)橹行?的保護(hù)作用,及其可能機(jī)制。 我們首先建立了C57/6小鼠高脂喂養(yǎng)6個(gè)月的動(dòng)物模型,檢測(cè)代謝綜合征時(shí)期,視網(wǎng)膜的病理學(xué)改變。結(jié)果表明,早在代謝綜合征時(shí)期,視網(wǎng)膜就已經(jīng)出現(xiàn)相應(yīng)的炎癥反應(yīng)增高,氧化應(yīng)激水平增高,抗氧化物質(zhì)代償性增高等改變。同時(shí),與我們猜測(cè)一致,部分炎癥反應(yīng)因子、抗氧化物質(zhì)的增高集中體現(xiàn)在血管周?chē)?這暗示血管損傷是糖尿病引起的主要損傷和首發(fā)損傷。所以,我們進(jìn)一步應(yīng)用自發(fā)Ⅰ型糖尿病轉(zhuǎn)基因小鼠OVE26建立了鋅補(bǔ)充6個(gè)月的糖尿病模型。結(jié)果表明,補(bǔ)鋅對(duì)糖尿病引起的血管并發(fā)癥有明顯的保護(hù)和預(yù)防作用。無(wú)論是6個(gè)月時(shí)的糖尿病血管損傷還是補(bǔ)鋅的保護(hù)作用都沒(méi)有性別差異。同時(shí),我們也觀察到,補(bǔ)鋅能使血管管壁中MT以及Nrf2的表達(dá)以及功能增高(其下游抗氧化基因表達(dá)增高),這暗示著補(bǔ)鋅所引起的糖尿病血管損傷的保護(hù)作用可能是由于上調(diào)MT和Nrf2的表達(dá)及功能引起。Nrf2是生物體內(nèi)重要的抗氧化物質(zhì),所以我們進(jìn)一步探討了Nrf2的預(yù)防與治療作用。我們分別應(yīng)用了經(jīng)典的糖尿病模型(STZ模型)與自發(fā)Ⅰ型糖尿病模型(OVE26小鼠)給予不同的Nrf2的激動(dòng)劑——蘿卜硫素(sulforaphane, SFN)和蛋白酶體抑制劑(MG132),探討Nrf2的預(yù)防與治療作用。結(jié)果表明,SFN對(duì)糖尿病血管損傷有預(yù)防作用,這種預(yù)防作用是通過(guò)上調(diào)Nrf2引起的。并且,SFN的作用不僅僅在于給藥過(guò)程中,這種影響在停藥后的三個(gè)月仍呈現(xiàn)出較高水平,而對(duì)糖尿病引起的血管損傷提供持續(xù)的保護(hù)和預(yù)防作用。MG132能抑制Nrf2降解,增強(qiáng)其功能,對(duì)糖尿病引起的血管損傷有明顯的治療作用。即使開(kāi)始用藥時(shí),糖尿病小鼠已經(jīng)出現(xiàn)明顯的蛋白尿,血管也已經(jīng)顯示出明顯的炎癥、氧化應(yīng)激等病理學(xué)損傷,給予MG132三個(gè)月后,這種損傷響應(yīng)基本被完全治愈,并且預(yù)防和延緩了糖尿病血管損傷的發(fā)展。綜合上述兩部分研究說(shuō)明,上調(diào)Nrf2的表達(dá)與功能,對(duì)糖尿病引起的血管損傷有明顯的預(yù)防與治療作用。 本研究通過(guò)建立多種糖尿病并發(fā)癥模型,使用多種物質(zhì)干預(yù),利用免疫組織化學(xué)染色及real-time PCR的方法,在動(dòng)物研究中,證明了糖尿病視網(wǎng)膜病變是以糖尿病引起的血管損傷為首要發(fā)病因素的疾病,補(bǔ)鋅對(duì)糖尿病引起的血管損傷有預(yù)防和保護(hù)作用,可能的原因是外源補(bǔ)充的鋅離子上調(diào)了內(nèi)生的抗氧化系統(tǒng),如MT, Nrf2的表達(dá)和功能。這為治療和預(yù)防糖尿病并發(fā)癥的發(fā)生發(fā)展提供了新的思路；同時(shí)也為補(bǔ)鋅能預(yù)防治療糖尿病視網(wǎng)膜病變的基礎(chǔ)與機(jī)制研究提供了新的依據(jù)。
[Abstract]:Zinc is a kind of metal chemical element, which is widely present in nature. At the same time, the zinc ion is one of the necessary metal ions in the human body, and can participate in the steady state regulation, the immunoregulation, the oxidative stress response, the apoptosis process, the aging and the like of the in vivo microenvironment. The results of animal experiments show that zinc can promote the formation of metallothionein (MT) and increase the anti-oxidation ability of the body. The copper/ zinc superoxide dismutase (Cu/ Zn SOD) can be formed by co-forming the copper/ zinc superoxide dismutase (Cu/ Zn SOD) with the copper ions. the structure of the nuclear factor E2 related factor 2 (Nrf2) can be stabilized, so that the protein content in the body is increased, the function is increased, and a plurality of anti-oxidation gene levels downstream, such as the oxidoreductase 1 (NQ01), the first type blood pigment oxidation enzyme (HO-1) and the superoxide dismutase 1,2 (SOD1, SOD2) and the like, activate various antioxidant mechanisms of the body. Diabetes is a common disease, it is a common disease, with its high morbidity and high mortality, it is widely used to influence the quality of life. Note: With the development of the disease, many serious complications can be induced, and the complications are mainly divided into two categories, namely, diabetic macrovascular complications such as diabetic macroangiopathy, atherosclerosis, diabetic microangiopathy such as diabetic cardiomyopathy, diabetic kidney, Many reports indicate that oxidative stress damage has an unshirkable responsibility for the occurrence and development of diabetes and its complications, according to a number of reports. It is well known that diabetes can cause an increase in blood glucose and a metabolic system in the body. This can lead to the inflammatory reaction of the tissue organ, the level of oxidative stress, the reactive oxygen free radical (ROS) of the oxidative stress product, the increase of the active nitrogen free radical (RNS) and the corresponding increase in the accumulation of the tissue organ. It will attack the body's tissue organs, vascular endothelial cells, and produce a series of damage reactions, such as inflammation, fibrosis, apoptosis, etc. Et al. The epidemiological report indicates that the serum zinc ion content in patients with diabetes is reduced. Low, and exogenous zinc supplement, can increase the content of zinc ion in the serum, and produce anti-oxidation. With this, we have designed the following experiments to explore the protective effect of zinc-supplementing on the vascular complications caused by diabetes (with large blood vessels as the center), microvessel complications (with diabetic retinopathy as the center), and the possible machines Methods: We first established the animal model of 6-month high-fat feeding of C57/6 mice to detect the pathological conditions of the metabolic syndrome and the pathology of the retina. The results showed that, in the period of metabolic syndrome, the corresponding inflammatory reaction of the retina was increased, the level of oxidative stress increased, and the compensatory increase of the anti-oxidation substance was increased. At the same time, with our guesses, some of the inflammatory response factors and the increase in the antioxidant substance are concentrated around the blood vessel, suggesting that the vascular injury is the main lesion and the head caused by diabetes. So, we used the spontaneous type I diabetic transgenic mouse OVE26 to set up zinc for 6 months of glycosuria. The results show that the zinc supplement has obvious protection and pre-treatment for vascular complications caused by diabetes. It has no sexual function, no matter whether the diabetic vascular injury or the protective effect of zinc supplement at 6 months has no sex. At the same time, we have also observed that zinc supplementation can increase the expression and function of MT and Nrf2 in the vessel wall, which suggests that the protective effect of zinc supplementation on diabetic vascular injury may be due to the up-regulation of the expression and work of MT and Nrf2. Nrf2 is an important antioxidant in the organism, so we further explore the prevention and treatment of Nrf2. We applied the classic diabetes model (STZ model) and the spontaneous type I diabetes model (OVE26 mouse) to give different Nrf2 agonist _ radish (SFN) and proteasome inhibitor (MG132) to explore the prevention and treatment of Nrf2. The results show that SFN has a preventive effect on diabetic vascular injury, and the prevention effect is to increase Nrf2 by up-regulation of Nrf2. and the effect of the sfn is not only in the course of administration, but this effect remains high in the three months after the withdrawal, while providing continuous protection and pre-treatment of the vascular damage caused by diabetes Anti-action. MG132 can inhibit Nrf2 degradation, enhance its function, and have obvious treatment for vascular injury caused by diabetes The effect of the treatment is that, even when the medicine is started, the diabetic mice have obvious proteinuria, and the blood vessels have shown obvious inflammation, oxidative stress and other pathological damage, and after the MG132 is given for three months, the damage response is basically completely cured, and the vascular injury of the diabetes is prevented and delayed. The development of the two-part study indicated that up-regulation of the expression and function of Nrf2 and the prevention and treatment of vascular injury caused by diabetes In this study, by establishing a variety of diabetic complication models and using a variety of substance interventions, the method of immunohistochemical staining and real-time PCR was used to prove that diabetic retinopathy was the first type of vascular injury caused by diabetes. The disease of the factor, zinc supplement has the effect of preventing and protecting the blood vessel damage caused by diabetes, and the possible cause is that the externally-supplemented zinc ion upregulates the endogenous anti-oxidation system, such as MT, Nrf2. Expression and function. This provides a new way for the treatment and prevention of the development of diabetic complications, and also provides the basis and mechanism for the prevention and treatment of diabetic retinopathy.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2013
【分類(lèi)號(hào)】：R587.2;R774.1

【共引文獻(xiàn)】

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