發(fā)布時間：2018-03-18 23:21

  本文選題：氧化應(yīng)激　切入點(diǎn)：神經(jīng)退行性疾病　出處：《蘭州大學(xué)》2017年博士論文　論文類型：學(xué)位論文

【摘要】：大腦是人體神經(jīng)系統(tǒng)的高級中樞區(qū)域,它控制著人的感覺、記憶、情緒、運(yùn)動以及邏輯思維等,儼然已經(jīng)是人體的“中央處理器”。然而隨著人類年齡不斷地增長以及周遭環(huán)境日益的變化,與大腦有關(guān)的疾病也不斷地侵襲而來,比如阿爾茲海默癥、帕金森癥、肌肉萎縮癥、抑郁癥以及精神分裂癥等,這些疾病嚴(yán)重影響著病患的生活質(zhì)量乃至威脅到生命,而隨著人類平均年齡的增長,患此類疾病的概率也隨之增加。因此,研究這些疾病的發(fā)病機(jī)制,并且尋找有效地治療方案是極其重要的。當(dāng)細(xì)胞內(nèi)氧化還原平衡被打破,即產(chǎn)生活性氧的能力超越消除活性氧的能力時,細(xì)胞內(nèi)很容易發(fā)生氧化應(yīng)激,而氧化應(yīng)激會引發(fā)很多疾病,所以機(jī)體都會盡量維持細(xì)胞內(nèi)氧化還原平衡。由于大腦內(nèi)含有大量不飽和脂肪酸,所以很容易受到活性氧的攻擊。當(dāng)大腦部位的活性氧過多,而內(nèi)源性抗氧化系統(tǒng)過度疲勞時,會引發(fā)多種神經(jīng)退行性疾病。因此,維持大腦內(nèi)部的氧化還原平衡對于預(yù)防神經(jīng)退行性疾病是尤為重要的。轉(zhuǎn)錄因子Nrf2是細(xì)胞內(nèi)源性抗氧化系統(tǒng)非常重要的組成部分,當(dāng)細(xì)胞內(nèi)出現(xiàn)氧化應(yīng)激或被親電試劑進(jìn)攻時,Nrf2能夠逃脫它的抑制劑Keap1介導(dǎo)的泛素化-降解的過程,并轉(zhuǎn)位到細(xì)胞核。在細(xì)胞核中,Nrf2作為轉(zhuǎn)錄因子,它會結(jié)合Maf蛋白,進(jìn)而增加抗氧化應(yīng)答元件(ARE)的轉(zhuǎn)錄,最終激活一系列細(xì)胞保護(hù)分子,比如血紅素加氧酶-1(HO-1),NAD(P)H:醌氧化還原酶1(NQO1),硫氧還蛋白還原酶(TrxR),硫氧還蛋白(Trx)和谷胱甘肽(GSH)等,所有的這些分子都能夠調(diào)節(jié)細(xì)胞內(nèi)氧化還原平衡。因此,發(fā)展Nrf2的激活劑是非常重要的,并且可以形成靶向治療神經(jīng)退行性疾病的新療法。一般含有酚羥基和或邁克爾加成受體的天然小化合物可能會具有抗氧化和保護(hù)細(xì)胞的性質(zhì)。在本文中,我們的目標(biāo)是篩選或合成一些具有類似基團(tuán)的化合物,檢測其神經(jīng)保護(hù)作用,并探索作用機(jī)制,為發(fā)展基于體內(nèi)氧化還原調(diào)節(jié)體系為靶點(diǎn)的神經(jīng)保護(hù)藥物提供實(shí)驗和理論數(shù)據(jù)。本論文的內(nèi)容總結(jié)歸納如下:1.對Keap1-Nrf2-ARE信號通路進(jìn)行了概述,也對Keap1-Nrf2-ARE和神經(jīng)退行性疾病之間的關(guān)系做了簡介,同時,我也對此通路的調(diào)節(jié)方式進(jìn)行了總結(jié)。2.從日常飲食和中草藥中篩選并發(fā)現(xiàn)五種化合物,包括羥基酪醇(HT)、姜烯酚(6-S)、小豆蔻明(CD)、芒果苷(Mg)和木香烴內(nèi)酯(COS),實(shí)驗表明這五種化合物均對過氧化氫(H2O2)或6-羥基多巴胺(6-OHDA)誘導(dǎo)的PC12細(xì)胞損傷有很好的抵御作用。機(jī)理研究表明這五種化合物可以激活PC12細(xì)胞內(nèi)的Nrf2,使Nrf2發(fā)生核轉(zhuǎn)位,進(jìn)而促進(jìn)一系列Nrf2驅(qū)動的抗氧化分子,如HO-1,NQO1,GSH,Trx和TrxR。此外,通過shRNA轉(zhuǎn)染沉默PC12細(xì)胞中Nrf2的表達(dá),可以消除或削弱這些化合物的保護(hù)作用,說明激活Nrf2是這五個化合物在PC12細(xì)胞中保護(hù)作用的主要分子機(jī)制。3.設(shè)計、合成Hispolon以及其五個類似物,并評價了它們對PC12細(xì)胞的神經(jīng)保護(hù)作用。通過一系列生物實(shí)驗,我們篩選了兩種化合物(H1和H6)用于后續(xù)研究。該課題表明,這兩種化合物均有神經(jīng)保護(hù)作用,而且可以激活PC12細(xì)胞中轉(zhuǎn)錄因子Nrf2,這為發(fā)展神經(jīng)保護(hù)藥物提供了很好的途徑。
[Abstract]:The brain is a senior central region of human nervous system, which controls people's feeling, memory, emotion, movement and logical thinking, has become the body's "central processor". However, with the change of human age increasing and the environment increasingly, associated with brain diseases are constantly invasion, for example, Alzheimer's disease, Parkinson's disease, muscular dystrophy, depression and schizophrenia, these diseases seriously affect the patient's quality of life and even threaten life, with the average age of human growth, the probability of disease is also increased. Therefore, the pathogenesis of these diseases, and to find effective treatment plan is extremely important. When the intracellular redox balance is broken, the production of reactive oxygen species beyond the ability to eliminate ROS, intracellular oxidative stress occurs easily However, oxidative stress may induce many diseases, so the body will try to maintain the intracellular redox balance. Because the brain contains large amounts of unsaturated fatty acids, so it is vulnerable to ROS attack. When ROS brain excessive, excessive fatigue and endogenous antioxidant system, will lead to a variety of neural diseases degeneration. Therefore, to maintain the oxidation reduction equilibrium inside the brain is particularly important for the prevention of neurodegenerative diseases. The transcription factor Nrf2 is a very important part of the endogenous antioxidant system, when intracellular oxidative stress or by electrophilic attack, Nrf2 inhibitors can escape its Keap1 mediated ubiquitination - degradation, and translocate to the nucleus. In the nucleus, Nrf2 as a transcription factor, it will bind to the Maf protein, thus increasing the antioxidant response element (ARE) transcription, the final activation of a series of Column cell protective molecules, such as heme oxygenase -1 (HO-1), NAD (P) H: quinone oxidoreductase 1 (NQO1), thioredoxin reductase (TrxR), thioredoxin (Trx) and glutathione (GSH) and so on, all of these molecules can regulate the intracellular redox balance. Therefore, the development of Nrf2 activator is very important, and can form a new targeted therapy for the treatment of neurodegenerative diseases. Generally contain natural compounds or small phenolic hydroxyl and Michael addition receptors may have antioxidant and protective properties. In this paper, our goal is to screening or synthetic compounds have some similar groups, detect its neuroprotective effect, and to explore the mechanism, for the development of in vivo redox regulation system to provide theoretical and experimental data for the neuroprotective drugs target. Based on the contents of total nodes are summarized as follows: 1. to Keap1-Nrf2-AR The E signaling pathway are reviewed, also on the relationship between Keap1-Nrf2-ARE and neurodegenerative diseases were briefly introduced, at the same time, I also have access regulation are summarized from the.2. diet and Chinese herbal medicine screening and found five compounds, including hydroxytyrosol (HT), Jiang Xifen (6-S), cardamom Ming (CD), mangiferin (Mg) and costunolide (COS), the experiment shows that the five compounds are on hydrogen peroxide (H2O2) or 6- 6-hydroxydopamine (6-OHDA) induced PC12 cell injury has good effect against. Mechanism research showed that these five compounds can activate PC12 cells within the Nrf2. The Nrf2 nuclear translocation, and promote a series of antioxidant molecules, Nrf2 driver such as HO-1, NQO1, GSH, Trx and TrxR. in Nrf2 expression by transfection of shRNA silencing in PC12 cells, which can eliminate or weaken the protective effect of these compounds, suggest that the activation of Nrf2 is five The main molecular mechanism of protective effect of compounds in PC12 cells in.3. design, synthesis of Hispolon and its analogues, and evaluate their neuroprotective effects on PC12 cells. Through a series of biological experiments, we screened two compounds (H1 and H6) for the following research. The project shows that the two the compound have neuroprotective effect, but also can activate the transcription factor Nrf2 in PC12 cells, which provides a good way for the development of neuroprotective drugs.

【學(xué)位授予單位】：蘭州大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R91

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相關(guān)期刊論文 前2條

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本文編號：1631791