本文選題：晚期糖基化終末產(chǎn)物 + 羧甲基賴氨酸　； 參考：《江南大學(xué)》2016年博士論文

【摘要】：晚期糖基化終末產(chǎn)物(Advanced glycation end products,AGEs)是還原糖(如葡萄糖)的活性羰基與蛋白質(zhì)、脂肪以及核酸的自由氨基經(jīng)非酶促反應(yīng)形成的一系列結(jié)構(gòu)穩(wěn)定的化合物的總稱。近年來,與體內(nèi)AGEs水平相關(guān)的慢性疾病受到越來越多的關(guān)注。食物在熱加工過程中產(chǎn)生大量AGEs,使得飲食成為體內(nèi)AGEs的重要環(huán)境來源。目前關(guān)于外源性AGEs對生物體健康影響的研究不多且存在爭議。因此本論文以AGEs的代表性生物標(biāo)志物羧甲基賴氨酸(Nε?(Carboxymethyl)lysine,CML)純品為研究材料,以健康成年大鼠和幼年大鼠為研究對象,探究CML對生物體健康的影響,以便明確評價外源性AGEs的生物毒性。首先,本論文系統(tǒng)考察了普通飲食條件下長期攝入游離態(tài)CML(60mg/kg體重/天)對健康成年SD大鼠組織的影響。研究發(fā)現(xiàn)大鼠各組織中結(jié)合態(tài)CML含量有所增加,其中肝臟、腎臟、心臟及肺中結(jié)合態(tài)CML含量增加顯著(P0.05),脾臟和胰腺中結(jié)合態(tài)CML含量變化不明顯;同時血清中尿素氮(blood urea nitrogen,BUN)、肌酸酐(creatinine,CREA)、谷丙轉(zhuǎn)氨酶(alanine aminotransferase,ALT)及谷草轉(zhuǎn)氨酶(aspartate aminotransferase,AST)水平顯著升高(P0.05),證實大鼠肝腎功能受到損傷。不過大鼠的空腹血糖水平(fasting blood glucose,FBG)及能量消耗方面未受到明顯影響。此外利用GC-TOF/MS技術(shù)對這些成年大鼠的血液和尿液進行了代謝組學(xué)分析,發(fā)現(xiàn)內(nèi)源性代謝物3-羥基癸酸和胍基琥珀酸水平上升,進一步表明健康成年大鼠的肝腎功能發(fā)生了損傷;同時這些成年大鼠體內(nèi)的能量代謝、碳水化合物代謝及氨基酸代謝也發(fā)生了紊亂。其次,本論文系統(tǒng)考察了高脂飲食條件下長期攝入游離態(tài)CML(60mg/kg體重/天)對健康成年SD大鼠組織的影響。研究發(fā)現(xiàn)大鼠主要組織(腎臟、心臟、肺、胰腺和肌肉)中結(jié)合態(tài)CML含量均有不同程度地增加,尤其是胰腺(與普通飲食相比);不過脾臟和肝臟中結(jié)合態(tài)CML含量無顯著變化;同時大鼠FBG水平、血清低密度脂蛋白膽固醇(low-density lipoprotein cholesterol,LDL-C)及能量消耗水平均顯著升高(P0.05)。首次提出了外源性游離態(tài)CML與組織中蛋白可能的結(jié)合方式是共價鍵結(jié)合。此外利用GC-TOF/MS技術(shù)對這些成年大鼠的血液和尿液進行了代謝組學(xué)分析,發(fā)現(xiàn)內(nèi)源代謝物胍基琥珀酸水平上升、同時花生四烯酸水平下降,表明這些成年大鼠腎功能受損;甲硫氨酸亞砜水平的上升表明大鼠體內(nèi)氧化應(yīng)激水平升高;同時這些成年大鼠體內(nèi)的氨基酸代謝及脂類代謝也發(fā)生了紊亂。最后,本論文系統(tǒng)考察了攝入添加不同劑量游離態(tài)CML(低劑量1.5g CML/kg飼料,中劑量4.5 g CML/kg飼料,高劑量13.5g CML/kg飼料)的普通飼料對健康幼年SD大鼠組織的影響。研究發(fā)現(xiàn)隨著游離態(tài)CML攝入劑量的增加,大鼠各組織中結(jié)合態(tài)CML含量和尿蛋白含量呈劑量依賴性增加,血清總蛋白(total protein,TP)和白蛋白(albumin,ALB)水平以及肝臟臟器系數(shù)呈劑量依賴性下降,證實幼年大鼠肝腎功能受到影響;同時血液系統(tǒng)發(fā)生紊亂。不過幼年大鼠FBG水平及能量消耗方面未受到明顯影響。此外利用GC-TOF/MS技術(shù)對攝入高劑量游離態(tài)CML的健康幼年大鼠的血液和尿液代謝物進行了代謝組學(xué)分析,發(fā)現(xiàn)高劑量組幼年大鼠的內(nèi)源性代謝物乙酰-5羥色胺酸水平上升,表明這些幼年大鼠體內(nèi)氧化應(yīng)激水平升高;同時這些幼年大鼠體內(nèi)的核苷酸代謝、氨基酸代謝、脂類代謝、輔因子及維生素代謝、碳水化合物代謝、轉(zhuǎn)錄及能量代謝等也發(fā)生了紊亂�；谝陨涎芯拷Y(jié)果,本論文認(rèn)為普通飲食條件下長期攝入大量游離態(tài)CML會對健康大鼠的肝腎功能造成影響,尤其是成年大鼠肝腎功能會發(fā)生損傷;高脂飲食會影響健康成年大鼠的血糖水平,而大量游離態(tài)CML的攝入會加速血糖水平的上升。無論何種飲食,長期攝入大量游離態(tài)CML都會使健康大鼠體內(nèi)的氧化應(yīng)激水平升高,從而可能會對一系列慢性疾病的產(chǎn)生與發(fā)展(包括2型糖尿病)造成潛在風(fēng)險。本論文的研究為人們了解長期攝入富含AGEs食品的潛在風(fēng)險提供了基礎(chǔ)理論參考,這對于人們改善不良的飲食習(xí)慣有積極的指導(dǎo)意義。
[Abstract]:Advanced glycosylation end products (Advanced glycation end products, AGEs) are a series of structural stable compounds formed by the active carbonyl of reducing sugar (such as glucose) and proteins, fat, and free amino groups of nucleic acids by non enzymatic reactions. In recent years, more and more attention has been paid to the chronic diseases associated with the level of AGEs in the body. Food produces a large number of AGEs during hot processing, making diet an important source of AGEs in the body. At present, there are few and controversial studies on the effects of exogenous AGEs on the health of organisms. Therefore, this paper uses AGEs's representative biomarker, carboxymethyl lysine (N? (Carboxymethyl) lysine, CML), as a research material. Healthy adult rats and young rats were studied to investigate the effects of CML on the health of the organisms so as to make a clear evaluation of the biological toxicity of exogenous AGEs. First, the effect of long intake of free CML (60mg/kg weight / day) on the tissues of healthy adult SD rats under normal diet was systematically investigated. The content of the binding state of CML in the liver, kidney, heart and lung increased significantly (P0.05), and the content of binding state CML in the spleen and pancreas was not significantly changed, and the serum urea nitrogen (blood urea nitrogen, BUN), creatinine (creatinine, CREA), alanine aminotransferase (alanine aminotransferase,) and glutamic aminotransferase were also found in the spleen and pancreas. Partate aminotransferase, AST) increased significantly (P0.05) and confirmed that the rat liver and kidney function was damaged. However, the fasting blood glucose level (fasting blood glucose, FBG) and energy consumption in rats were not significantly affected. In addition, the blood and urine of these adult rats were metabolized by GC-TOF/MS technique. The increased levels of 3- hydroxy decanic acid and guanidic succinic acid in the source metabolites further indicate that the liver and kidney function of healthy adult rats have been damaged, and the energy metabolism, carbohydrate metabolism and amino acid metabolism in these adult rats are also disturbed. Secondly, this paper examines the long-term intake of free diet under high fat diet. The effect of state CML (60mg/kg weight / day) on the tissue of healthy adult SD rats. It was found that the binding state CML content in the main tissues of the rats (kidney, heart, lung, pancreas and muscle) increased in varying degrees, especially in the pancreas (compared with the common diet), but there was no significant change in the CML content in the spleen and liver, and the level of FBG in rats. Serum low density lipoprotein cholesterol (low-density lipoprotein cholesterol, LDL-C) and energy consumption level were significantly increased (P0.05). It was first proposed that the combination of exogenous free CML and protein in tissue was covalent bond. In addition, the metabolic group of the blood and urine of these adult rats was carried out by GC-TOF/MS technology. It was found that the level of endogenous metabolite guanidic succinic acid increased and the level of four arachidic acid decreased, indicating that the renal function of these adult rats was impaired; the rise of methionine sulfoxide level indicated that the level of oxidative stress in the rats increased; at the same time, the metabolism of ammonia acid and lipid metabolism in these adult rats was also disturbed. Finally, In this paper, the effects of diet supplemented with different doses of free CML (low dose 1.5g CML/kg feed, medium dose of 4.5 g CML/kg feed and high dose 13.5g CML/kg feed) on the tissue of healthy young SD rats were investigated. The study found that with the increase of free CML intake dose, the binding state CML content and urine protein in the tissues of rats were added. The levels of the serum total protein (total protein, TP) and albumin (albumin, ALB) and the liver organ coefficient decreased in a dose-dependent manner. The liver and kidney function of young rats were affected, and the blood system was disturbed. However, the level of FBG and the energy consumption of young rats were not significantly affected. The metabolomics of blood and urine metabolites of healthy young rats with high dose of free CML was analyzed by GC-TOF/MS technique. The increase of endogenous metabolite acetyl -5 HT in young rats of high dose group showed that the levels of oxidative stress in these young rats increased; and the nucleus of these young rats Glucoside metabolism, amino acid metabolism, lipid metabolism, cofactor and vitamin metabolism, carbohydrate metabolism, transcription and energy metabolism have also been disturbed. Based on the above results, this paper suggests that a long intake of free CML in normal diet can affect the liver and kidney function of healthy rats, especially the liver and kidney of adult rats. A high fat diet may affect the level of blood sugar in healthy adult rats, while a large number of free CML intake will accelerate the rise of blood sugar levels. A diet and a long intake of free CML will increase the level of oxidative stress in healthy rats, which may produce and develop a series of chronic diseases. The research in this paper provides a basic theoretical reference for people to understand the potential risks of long term intake of AGEs foods, which has a positive guiding significance for people to improve their unhealthy dietary habits.

【學(xué)位授予單位】：江南大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R994.4

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