富勒烯—蛋氨酸衍生物的合成及其对PC12细胞氧化损伤的保护作用
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摘要
生命过程中的自由基反应处于动态平衡之中,过多的自由基引起的氧化损伤将会导致细胞损伤、病变和非正常死亡,是多种疾病的发病根源。研究证实:有超过100种疾病与自由基产生过量或人体自身清除自由基能力下降有关,因此自由基被现代医学称为致病中介因子。相对于其它组织而言,神经组织由于含有丰富的多不饱和脂肪酸以及缺乏足够的抗氧化酶而对氧化应激损伤特别敏感,加之其不可再生性,使得研究有效的自由基清除剂具有重要的意义。
富勒烯(fullerene)的出现为我们研究自由基清除剂开辟了新的思路。富勒烯是碳的第三种同素异形体,其中的突出代表为C60。富勒烯衍生物特殊的化学结构使得一分子富勒烯能与多分子的活性氧反应,因此富勒烯被誉为“吸收自由基的海绵”。许多研究表明,C60衍生物在吸收自由基,保护缺血再灌注对机体组织的损伤,保护紫外线对人角化细胞损伤具有良好的应用前景。事实上,由于富勒烯水溶性很低,阻碍了其在生物学上的应用,因此,富勒烯水溶性问题是当今富勒烯研究领域的热点。目前,解决富勒烯水溶性的方案以往主要有以下三种措施:①制备富勒烯水溶性包合物;②制备富勒烯水溶胶;③在富勒烯碳笼上添加水溶性基团,合成制备富勒烯的水溶性衍生物。三种方法中以制备水溶性富勒烯衍生物(soluble fullerene derivate,SFD)最具有前景。
鉴于此,本研究利用有机合成的方法制备出一种C60-氨基酸衍生物(C60-Amino acid derivate, FAAD)——C60-蛋氨酸(C60 Methionine derivative,FMD),并对它们进行了结构表征;同时还研究其对羟自由基和超氧阴离子的清除能力及规律,以及其对经过氧化氢(H2O2)诱导后引起PC12大鼠肾上腺嗜铬细胞瘤细胞氧化损伤的保护作用,为该类化合物在医学领域的应用提供理论和实验依据。
第一部分富勒烯-蛋氨酸衍生物的合成与表征
目的:合成水溶性的富勒烯氨基酸衍生物。方法:利用亲核加成机理将蛋氨酸引入C60球上,并用FT-IR、1H-NMR、RF、UV及粒度分析元素分析等手段对这些物质进行表征。结果:产物在常温下易溶于水,并能稳定存在;FT-IR、1H-NMR、RF、UV都直接或间接地证实蛋氨酸以共价键的方式接到了C60上,粒度分析显示1 mg/ml的C60-蛋氨酸衍生物在水溶液中的平均粒径分别为11.1 nm。结论:成功地合成了C60-蛋氨酸衍生物,该物质具有良好的水溶性。
第二部分富勒烯-蛋氨酸衍生物对PC12细胞氧化损伤的保护作用
目的:研究FMD对活性氧的清除能力和对H2O2诱导的PC12细胞氧化损伤的保护作用及作用机制。方法:将不同浓度的FMD加入邻苯三酚-鲁米诺(PA-L)自氧化发光体系和邻菲罗啉发光体系,观察FMD对发光强度的抑制作用,以此分别评价对超氧阴离子(O2·-)和羟自由基(·OH)的清除能力;体外培养PC12细胞株,在培养液中预先加入不同浓度的FMD后,以500μMH2O2诱导PC12损伤,通过MTT比色法观察不同浓度FMD保护作用下PC12的存活情况,用流式细胞仪检测细胞凋亡情况,采用单细胞凝胶电泳法测定DNA单链损伤,化学比色法检测胞内外MDA含量和SOD活性,荧光法检测进入胞内FMD的量。结果:随着FMD浓度的增加,活性氧抑制率逐渐升高;经H2O2诱导后细胞出现明显损伤形态,细胞存活率明显下降,胞内DNA链损伤明显增加,胞内外MDA含量明显增加,SOD活力明显下降;而预先加入FMD可改善上述结果,细胞凋亡率明显降低,细胞内DNA链损伤明显减少,显著降低MDA含量,提高SOD活性,其作用呈剂量依赖关系;另外,大概有20%的FMD进入细胞。结论:FMD由很好的清除自由基的能力;对H2O2诱导PCl2细胞损伤具有保护作用,其作用机制可能与提高PC12细胞的抗氧化能力有关。
Radical reaction in body must be in dynamic balance. Oxidative injury induced by excess free radicals is etiology of several diseases. It has been confirmed that more than 100 diseases are related to the excess free radicals or the inferior scavenging ability to it, so it is considered to be the modern pathopoiesis media. Compared the other tissues, never tissues are particularly sensitive to oxidative injury because of their abundant content of polyunsaturated fatty acid, the lack of antioxidase. In addition to this, neuron is hard to reproduce itself, so it is important to develop effective scavenging agent to free radicals.
Fullerene, one of allotrope of carbon, has excellent potential of opposing ROS, and C60 , with a structure of icosahedral cage , is the represent of it. Fullerene derivatives have often been used as effective scavengers for reactive oxygen species (ROS). These compounds, thanks to their peculiar structure, are capable of“adding”multiple radicals per molecular, leading Krusic et al. to characterize fullerenes since 1991 as“radical sponge”and to hypothesize their potential activity as free-radical scavengers. Previous studies have pointed out that fullerene derivatives could protect against oxidative stress in organisms and prevent keratinocyte from injury induced by UV. As a matter of fact, fullerene is not able to dissolve in H2O but able to dissolve in some polar solvents such as toluene, which results in the limitation of the fullerene application in biological field. Now there are three ways of making fullerene soluble: one is to prepare soluble fullerene clathrate, the other to produce soluble fullerene collosol, another to add soluble group to the cage, and the third method is the best.
In view of this background, we prepared a novel C60-Amino acid derivate (FAAD)-C60 Methionine derivative (FMD) through the organic synthesis method and described its structural characterization. Meanwhile, we investigated its scavenging capacity and regularity on superoxide and hydroxyl radical as well as its protective effects on hydrogen peroxide induced oxidative damage in rat pheochromocytoma (PC12) cells, aim to provide theoretical and experimental bases for its applications in medical field.
PartⅠThe Synthesis and Exosyndrome of Fullerene-Methionine Derivate
Object: To synthesis soluble fullerene derivate. Methods: C60 methionine derivate was synthesized by nucleophilic addition and characterized by FT-IR,1H-NMR,RF ,UV and Size Analyzer. Results: The product was very solvable in water and stable in air, and all the equipments demonstrated that several methionines were added to fullerenes directly or indirectly. The average aquation diameter of the derivate was 11.1 nm. Conclusion: C60 methionine derivate was synthesis successfully and lyotropic in water.
PartⅡProtective effect of fullerene-Methionine derivate on PC12 cell oxidative stress injury
Object: To investigate the scavenging ability of FMD to ROS and the antioxidant effect on PC12 oxidative stress injury induced by hydrogen peroxide. Methods: FMD of different concentration was added into pyrogallic acid-luminol and Phenanthroline oxyluminescence system to observe the scavenging effect to ROS. FMD’s potential protective effect on hydrogen peroxide-induced oxidative stress and apoptotic death was investigated in PC12 cells. Cells treated with hydrogen peroxide underwent cytotoxicity and apoptotic death determined by MTT assay, flow cytometry analysis, PI/Hoechst 33342 staining. The level of MDA and the activity of SOD were measured by spectroscopy and the level of FMD into cells by fluorometric method. Results: The inhibition to ROS can be enhanced gradually as the concentration of FMD increased. After been exposed to hydrogen peroxide for 24 hours, typical morphological characteristics of injury were observed, with the proliferation activity decreased sharply and the rate of apoptosis increased obviously. Moreover, the level of MDA was increased significantly and the activity of SOD decreased in H2O2 induced group compared with control, while FMD altered the above results, restrained the reduction of PC12 caused by hydrogen peroxide, and diminished the apoptosis. In addition that, approximately 20% of total addition of FMD could enter into cells. Conclusion: FMD has good scavenging effect to ROS, and can protect PC12 cells from oxidative stress injury induced by hydrogen peroxide, which may be related to increasing the activity of anti-oxidation of PC12.
富勒烯(fullerene)的出现为我们研究自由基清除剂开辟了新的思路。富勒烯是碳的第三种同素异形体,其中的突出代表为C60。富勒烯衍生物特殊的化学结构使得一分子富勒烯能与多分子的活性氧反应,因此富勒烯被誉为“吸收自由基的海绵”。许多研究表明,C60衍生物在吸收自由基,保护缺血再灌注对机体组织的损伤,保护紫外线对人角化细胞损伤具有良好的应用前景。事实上,由于富勒烯水溶性很低,阻碍了其在生物学上的应用,因此,富勒烯水溶性问题是当今富勒烯研究领域的热点。目前,解决富勒烯水溶性的方案以往主要有以下三种措施:①制备富勒烯水溶性包合物;②制备富勒烯水溶胶;③在富勒烯碳笼上添加水溶性基团,合成制备富勒烯的水溶性衍生物。三种方法中以制备水溶性富勒烯衍生物(soluble fullerene derivate,SFD)最具有前景。
鉴于此,本研究利用有机合成的方法制备出一种C60-氨基酸衍生物(C60-Amino acid derivate, FAAD)——C60-蛋氨酸(C60 Methionine derivative,FMD),并对它们进行了结构表征;同时还研究其对羟自由基和超氧阴离子的清除能力及规律,以及其对经过氧化氢(H2O2)诱导后引起PC12大鼠肾上腺嗜铬细胞瘤细胞氧化损伤的保护作用,为该类化合物在医学领域的应用提供理论和实验依据。
第一部分富勒烯-蛋氨酸衍生物的合成与表征
目的:合成水溶性的富勒烯氨基酸衍生物。方法:利用亲核加成机理将蛋氨酸引入C60球上,并用FT-IR、1H-NMR、RF、UV及粒度分析元素分析等手段对这些物质进行表征。结果:产物在常温下易溶于水,并能稳定存在;FT-IR、1H-NMR、RF、UV都直接或间接地证实蛋氨酸以共价键的方式接到了C60上,粒度分析显示1 mg/ml的C60-蛋氨酸衍生物在水溶液中的平均粒径分别为11.1 nm。结论:成功地合成了C60-蛋氨酸衍生物,该物质具有良好的水溶性。
第二部分富勒烯-蛋氨酸衍生物对PC12细胞氧化损伤的保护作用
目的:研究FMD对活性氧的清除能力和对H2O2诱导的PC12细胞氧化损伤的保护作用及作用机制。方法:将不同浓度的FMD加入邻苯三酚-鲁米诺(PA-L)自氧化发光体系和邻菲罗啉发光体系,观察FMD对发光强度的抑制作用,以此分别评价对超氧阴离子(O2·-)和羟自由基(·OH)的清除能力;体外培养PC12细胞株,在培养液中预先加入不同浓度的FMD后,以500μMH2O2诱导PC12损伤,通过MTT比色法观察不同浓度FMD保护作用下PC12的存活情况,用流式细胞仪检测细胞凋亡情况,采用单细胞凝胶电泳法测定DNA单链损伤,化学比色法检测胞内外MDA含量和SOD活性,荧光法检测进入胞内FMD的量。结果:随着FMD浓度的增加,活性氧抑制率逐渐升高;经H2O2诱导后细胞出现明显损伤形态,细胞存活率明显下降,胞内DNA链损伤明显增加,胞内外MDA含量明显增加,SOD活力明显下降;而预先加入FMD可改善上述结果,细胞凋亡率明显降低,细胞内DNA链损伤明显减少,显著降低MDA含量,提高SOD活性,其作用呈剂量依赖关系;另外,大概有20%的FMD进入细胞。结论:FMD由很好的清除自由基的能力;对H2O2诱导PCl2细胞损伤具有保护作用,其作用机制可能与提高PC12细胞的抗氧化能力有关。
Radical reaction in body must be in dynamic balance. Oxidative injury induced by excess free radicals is etiology of several diseases. It has been confirmed that more than 100 diseases are related to the excess free radicals or the inferior scavenging ability to it, so it is considered to be the modern pathopoiesis media. Compared the other tissues, never tissues are particularly sensitive to oxidative injury because of their abundant content of polyunsaturated fatty acid, the lack of antioxidase. In addition to this, neuron is hard to reproduce itself, so it is important to develop effective scavenging agent to free radicals.
Fullerene, one of allotrope of carbon, has excellent potential of opposing ROS, and C60 , with a structure of icosahedral cage , is the represent of it. Fullerene derivatives have often been used as effective scavengers for reactive oxygen species (ROS). These compounds, thanks to their peculiar structure, are capable of“adding”multiple radicals per molecular, leading Krusic et al. to characterize fullerenes since 1991 as“radical sponge”and to hypothesize their potential activity as free-radical scavengers. Previous studies have pointed out that fullerene derivatives could protect against oxidative stress in organisms and prevent keratinocyte from injury induced by UV. As a matter of fact, fullerene is not able to dissolve in H2O but able to dissolve in some polar solvents such as toluene, which results in the limitation of the fullerene application in biological field. Now there are three ways of making fullerene soluble: one is to prepare soluble fullerene clathrate, the other to produce soluble fullerene collosol, another to add soluble group to the cage, and the third method is the best.
In view of this background, we prepared a novel C60-Amino acid derivate (FAAD)-C60 Methionine derivative (FMD) through the organic synthesis method and described its structural characterization. Meanwhile, we investigated its scavenging capacity and regularity on superoxide and hydroxyl radical as well as its protective effects on hydrogen peroxide induced oxidative damage in rat pheochromocytoma (PC12) cells, aim to provide theoretical and experimental bases for its applications in medical field.
PartⅠThe Synthesis and Exosyndrome of Fullerene-Methionine Derivate
Object: To synthesis soluble fullerene derivate. Methods: C60 methionine derivate was synthesized by nucleophilic addition and characterized by FT-IR,1H-NMR,RF ,UV and Size Analyzer. Results: The product was very solvable in water and stable in air, and all the equipments demonstrated that several methionines were added to fullerenes directly or indirectly. The average aquation diameter of the derivate was 11.1 nm. Conclusion: C60 methionine derivate was synthesis successfully and lyotropic in water.
PartⅡProtective effect of fullerene-Methionine derivate on PC12 cell oxidative stress injury
Object: To investigate the scavenging ability of FMD to ROS and the antioxidant effect on PC12 oxidative stress injury induced by hydrogen peroxide. Methods: FMD of different concentration was added into pyrogallic acid-luminol and Phenanthroline oxyluminescence system to observe the scavenging effect to ROS. FMD’s potential protective effect on hydrogen peroxide-induced oxidative stress and apoptotic death was investigated in PC12 cells. Cells treated with hydrogen peroxide underwent cytotoxicity and apoptotic death determined by MTT assay, flow cytometry analysis, PI/Hoechst 33342 staining. The level of MDA and the activity of SOD were measured by spectroscopy and the level of FMD into cells by fluorometric method. Results: The inhibition to ROS can be enhanced gradually as the concentration of FMD increased. After been exposed to hydrogen peroxide for 24 hours, typical morphological characteristics of injury were observed, with the proliferation activity decreased sharply and the rate of apoptosis increased obviously. Moreover, the level of MDA was increased significantly and the activity of SOD decreased in H2O2 induced group compared with control, while FMD altered the above results, restrained the reduction of PC12 caused by hydrogen peroxide, and diminished the apoptosis. In addition that, approximately 20% of total addition of FMD could enter into cells. Conclusion: FMD has good scavenging effect to ROS, and can protect PC12 cells from oxidative stress injury induced by hydrogen peroxide, which may be related to increasing the activity of anti-oxidation of PC12.
引文
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