葡萄籽原花青素聚合度与功效关系的研究
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摘要
我国葡萄的种植历史悠久,种植面积及产量都很大,且近年来葡萄年产量呈逐年上升趋势。作为葡萄酒及葡萄汁厂的下脚料,葡萄籽中富含天然抗氧化剂原花青素,但由于葡萄籽皮厚而硬,大多数葡萄酒(汁)厂都将其作为废物丢弃,或作为粗饲料使用,造成资源的严重浪费。因此,深入研究葡萄籽原花青素的组成、活性及提取工艺,对于合理利用葡萄籽资源、提高产品附加值具有重要意义。
葡萄籽原花青素是(+)-儿茶素、(-)-表儿茶素及 (-)-表儿茶素没食子酸酯通过C4→ C8 或C4→C6连接而成的不同聚合度的混合物。由于原花青素强大的自由基清除能力、广泛的生理活性及出色的安全性,在营养及医学领域引起了越来越多的关注。原花青素的活性受其结构特别是聚合度的影响,但由于葡萄籽原花青素结构复杂,对原花青素检测方法的研究仍然存在一些不足,特别是对构效关系的研究还很缺乏,限制了原花青素的应用范围。本文提出了适宜的葡萄籽原花青素定性定量检测方法,按聚合度区段对原花青素进行分级分离,系统地研究了聚合度对原花青素抗氧化、自由基清除能力及体外抗肿瘤作用的影响,并在此基础上研究其提取分离工艺。主要研究结果如下:
用RP-HPLC-ESI-MS分析葡萄籽粗提物中的原花青素,可以在没有对照品的情况下根据准分子离子及碎片信息简便地分析其中低聚原花青素的基本组成,并能够比较不同来源原花青素低聚体的相对含量。通过反相液相色谱分离、电喷雾质谱定性,从葡萄籽粗提液中检测出了三个单体、七个二聚体、七个三聚体及一个四聚体。由于各聚合体的异构体数目繁多,其ESI质谱行为也很相近,除单体外,还未能对各异构体的具体结构作出准确的鉴定。另外,RP-HPLC-ESI-MS分析葡萄籽原花青素时只能分离聚合度≤3的单体和聚合体,更高聚合度的原花青素,异构体数目更多,极性分布更复杂,在反相色谱上无法分开。
对酸化香草醛法作了改进,用于测定葡萄籽中原花青素含量。以H2SO4作为反应的酸性介质,找出了合适的比色反应条件:反应体系0.5mL提取物水溶液+2.5mL 3%香草醛+2.5mL 30%硫酸,30℃反应15min后测定A500nm。方法评价结果表明本方法重现性好、回收率高,与其它方法相比,本体系检测灵敏度高、稳定性好,可以准确测定、比较不同来源的葡萄籽中原花青素的含量。应用本方法对国内几种不同产地及发酵/未发酵的葡萄籽原花青素含量进行测定,结果表明葡萄籽原花青素含量受葡萄的品种、地域及葡萄酒酿造方法的影响,原花青素的提取应选择未发酵的葡萄籽作为原料。除葡萄籽外,本方法还可用于测定不含二氢查耳酮及VC含量相对较低的植物原料中的原花青素。
基于葡萄籽原花青素结构的复杂性,难以分离,提出按聚合度区段分离并以此来研究葡萄籽原花青素的构效关系。以硫解法、正相HPLC及凝胶渗透色谱、质谱等作为检测手段测定平均聚合度及聚合度、分子量的分布情况,采用氯仿-甲醇两相溶剂逐步沉淀及柱层析结合的方法。将原花青素分为二聚体、聚合度>2的低聚体、及平均聚合度分别为3.4、6.4、9.1、11.9、14.3的几个组分;原花青素的硫解实验测定结果表明,葡
萄籽原花青素主要是由表儿茶素组成的,儿茶素及表儿茶素没食子酸酯在原花青素构成单元中的比例相对较低。儿茶素主要存在于原花青素的末端基团,表儿茶素主要构成原花青素的延伸段基团。
用聚酰胺、HW-40凝胶色谱等分离手段对葡萄籽原花青素进行分离纯化,并用核磁共振技术进行化合物的结构鉴定。从原花青素提取物中分离出两种单体:(+)-儿茶素和(-)-表儿茶素;一种原花青素二聚体B4;两种其它酚类物质:对羟基苯甲酸及没食子酸乙酯。表明原花青素提取物中除主要成分原花青素外,还存在其它酚类活性成分,这些物质也对原花青素提取物的抗氧化功能作出贡献。
采用亚油酸体系、脂质体体系、DPPH·自由基及化学发光法,研究分级得到的不同聚合度原花青素组分的抗氧化活性。结果表明,在亚油酸及脂质体体系中,原花青素的抗氧化作用高于VC和VE。原花青素对DPPH·自由基的清除能力优于VC、VE及BHT,半抑制浓度分别为:原花青素1.8μg/mL、VC 2.5μg/mL、VE 6.3μg/mL、BHT 3.5μg/mL。对O2ˉ·的清除能力优于VE而与VC相近。以质量浓度表示时,原花青素对DPPH·自由基的清除作用与聚合度无关,对亚油酸及脂质体体系的抗氧化活性及对HO·、O2ˉ·的清除能力随着聚合度的升高而下降。但以摩尔浓度(μM)表示时,原花青素的自由基清除能力基本上随着聚合度的增加而提高。说明原花青素的抗氧化和自由基清除能力与所处的溶剂环境有关,水相体系中原花青素分子中单位酚羟基的活性随着聚合度的增加而下降。可能与水溶液中酚羟基参与形成原花青素分子内或分子间氢键,从而降低酚羟基活性有关。
人肝癌细胞Bel-7402及正常细胞3T3体外培养实验证明,原花青素能够选择性地抑制癌细胞而对正常细胞影响较小。所研究的20-200 μg/mL浓度范围内原花青素对人肝癌细胞Bel-7402具有生长抑制作用,且存在剂量效应关系。以质量浓度表示时,随着聚合度的增加,原花青素对Bel-7402的抑制作用降低。
通过体外抗氧化、消除自由基及体外抗肿瘤实验,表明原花青素的聚合度是影响其活性的重要因素,以质量单位表示时,随着聚合度的增加,水相体系中原花青素的
Grape, which has a long history in china, is widely cultivated with an increasing production in recent years. As the by-product of grape juice and wine making, grape seeds are a rich source of procyanidins (a kind of natural antioxidants), but due to the hard hull, they are usually discarded as unwanted or used as crude feed, which is a waste of resources. For better use of the grape seeds, it is of great importance to analysis the procyanidins in grape seeds and study its biological activities and extraction.
Grape seed procyanidins are oligomers and polymers of (+)-catechin, (-)-epicatechin, and (-)-epicatechin-O-gallate linked by C4→C8 or C4→C6 B-type bonds. They have attracted great attention in the fields of nutriology and pharmacology because of their potent radical-scavenging activity, broad biological and pharmacological effects and excellent security. The pharmacological properties of procyanidins largely depend on their structure and especially on their degree of polymerization (DP). But due to the diversity of procyanidin structures, the studies on the analysis methods as well as the relationship between the structure and activity are not thorough, which limits the utilization of procyanidins. In this work, feasible qualitative and quantitative methods were established, and the procyanidins were fractionated according to their degree of polymerization. And then the effects of DP on the antioxidant and anti-tumor activity in vitro were investigated systematically. Furthermore, studies on the extraction and isolation of procyanidins were also carried out for commercial preparation. The main results of this dissertation were described as following:
The qualitative analysis of oligomeric procyanidins in crude grape seed extracts can be performed by reversed-phase high-performance liquid chromatography coupled with electrospray ionization mass spectrometry (RP-HPLC-ESI-MS). Pseudomolecular ion and fragment information of ESI-MS made it possible to analyze the composition of oligmeric procyanidins directly without standards. By RP-HPLC-ESI-MS, three monomers, seven dimers, seven trimers and one tetramer were tentatively identified in crude grape seed extract, but due to the large number of isomers and their similar ESI-MS characters, the isomers are not identified precisely except monomers. In fact, only oligomers with DP below 4 can be well detected by RP-HPLC-MS, the higher polymers, with more isomers and more diverse polarity, can neither be separated nor be analyzed by RP-HPLC.
Acid-catalyzed vanillin assay was improved for quantitation of procyanidins in grape seed. By the use of H2SO4 as acid medium, proper reaction conditions were obtained as following: after 0.5mL aqueous solution of grape seed extract was mixed with 2.5mL 3% vanillin in methanol and 2.5mL 30% H2SO4 in methanol, the reaction was carried out at 30℃ for 15 minutes and the absorbance at 500nm was measured. Evaluation of the method proved that it has good repeatability and high recovery, and is also more sensitive and stable compared with previous methods. Procyanidins of different grape seeds can be quantified and compared by this method. The assay was then used to determine the procyanidin content of
several kinds of grape seeds from different district and different fermentation process. Results showed that the procyanidin content of grape seed was affected by the variety, clime and wine-making methods. Procyanidins should be extracted from unfermented grape seeds. Besides grape seeds, this assay can also be used to quantify the procyanidin of other plant in which vitamin C and dihydrochalcone are absent or scarce.
Because of the complexity of procyanidin structure, the proyanidins were separated according to their degree of polymerization (DP) for further study of the relationship between structure and activity. By use of thiolysis for determining the mean degree of polymerization (mDP) and normal-phase HPLC, gel permeation chromatography (GPC) and mass spectrometry (MS) for analysis of molecule profile of procyan
葡萄籽原花青素是(+)-儿茶素、(-)-表儿茶素及 (-)-表儿茶素没食子酸酯通过C4→ C8 或C4→C6连接而成的不同聚合度的混合物。由于原花青素强大的自由基清除能力、广泛的生理活性及出色的安全性,在营养及医学领域引起了越来越多的关注。原花青素的活性受其结构特别是聚合度的影响,但由于葡萄籽原花青素结构复杂,对原花青素检测方法的研究仍然存在一些不足,特别是对构效关系的研究还很缺乏,限制了原花青素的应用范围。本文提出了适宜的葡萄籽原花青素定性定量检测方法,按聚合度区段对原花青素进行分级分离,系统地研究了聚合度对原花青素抗氧化、自由基清除能力及体外抗肿瘤作用的影响,并在此基础上研究其提取分离工艺。主要研究结果如下:
用RP-HPLC-ESI-MS分析葡萄籽粗提物中的原花青素,可以在没有对照品的情况下根据准分子离子及碎片信息简便地分析其中低聚原花青素的基本组成,并能够比较不同来源原花青素低聚体的相对含量。通过反相液相色谱分离、电喷雾质谱定性,从葡萄籽粗提液中检测出了三个单体、七个二聚体、七个三聚体及一个四聚体。由于各聚合体的异构体数目繁多,其ESI质谱行为也很相近,除单体外,还未能对各异构体的具体结构作出准确的鉴定。另外,RP-HPLC-ESI-MS分析葡萄籽原花青素时只能分离聚合度≤3的单体和聚合体,更高聚合度的原花青素,异构体数目更多,极性分布更复杂,在反相色谱上无法分开。
对酸化香草醛法作了改进,用于测定葡萄籽中原花青素含量。以H2SO4作为反应的酸性介质,找出了合适的比色反应条件:反应体系0.5mL提取物水溶液+2.5mL 3%香草醛+2.5mL 30%硫酸,30℃反应15min后测定A500nm。方法评价结果表明本方法重现性好、回收率高,与其它方法相比,本体系检测灵敏度高、稳定性好,可以准确测定、比较不同来源的葡萄籽中原花青素的含量。应用本方法对国内几种不同产地及发酵/未发酵的葡萄籽原花青素含量进行测定,结果表明葡萄籽原花青素含量受葡萄的品种、地域及葡萄酒酿造方法的影响,原花青素的提取应选择未发酵的葡萄籽作为原料。除葡萄籽外,本方法还可用于测定不含二氢查耳酮及VC含量相对较低的植物原料中的原花青素。
基于葡萄籽原花青素结构的复杂性,难以分离,提出按聚合度区段分离并以此来研究葡萄籽原花青素的构效关系。以硫解法、正相HPLC及凝胶渗透色谱、质谱等作为检测手段测定平均聚合度及聚合度、分子量的分布情况,采用氯仿-甲醇两相溶剂逐步沉淀及柱层析结合的方法。将原花青素分为二聚体、聚合度>2的低聚体、及平均聚合度分别为3.4、6.4、9.1、11.9、14.3的几个组分;原花青素的硫解实验测定结果表明,葡
萄籽原花青素主要是由表儿茶素组成的,儿茶素及表儿茶素没食子酸酯在原花青素构成单元中的比例相对较低。儿茶素主要存在于原花青素的末端基团,表儿茶素主要构成原花青素的延伸段基团。
用聚酰胺、HW-40凝胶色谱等分离手段对葡萄籽原花青素进行分离纯化,并用核磁共振技术进行化合物的结构鉴定。从原花青素提取物中分离出两种单体:(+)-儿茶素和(-)-表儿茶素;一种原花青素二聚体B4;两种其它酚类物质:对羟基苯甲酸及没食子酸乙酯。表明原花青素提取物中除主要成分原花青素外,还存在其它酚类活性成分,这些物质也对原花青素提取物的抗氧化功能作出贡献。
采用亚油酸体系、脂质体体系、DPPH·自由基及化学发光法,研究分级得到的不同聚合度原花青素组分的抗氧化活性。结果表明,在亚油酸及脂质体体系中,原花青素的抗氧化作用高于VC和VE。原花青素对DPPH·自由基的清除能力优于VC、VE及BHT,半抑制浓度分别为:原花青素1.8μg/mL、VC 2.5μg/mL、VE 6.3μg/mL、BHT 3.5μg/mL。对O2ˉ·的清除能力优于VE而与VC相近。以质量浓度表示时,原花青素对DPPH·自由基的清除作用与聚合度无关,对亚油酸及脂质体体系的抗氧化活性及对HO·、O2ˉ·的清除能力随着聚合度的升高而下降。但以摩尔浓度(μM)表示时,原花青素的自由基清除能力基本上随着聚合度的增加而提高。说明原花青素的抗氧化和自由基清除能力与所处的溶剂环境有关,水相体系中原花青素分子中单位酚羟基的活性随着聚合度的增加而下降。可能与水溶液中酚羟基参与形成原花青素分子内或分子间氢键,从而降低酚羟基活性有关。
人肝癌细胞Bel-7402及正常细胞3T3体外培养实验证明,原花青素能够选择性地抑制癌细胞而对正常细胞影响较小。所研究的20-200 μg/mL浓度范围内原花青素对人肝癌细胞Bel-7402具有生长抑制作用,且存在剂量效应关系。以质量浓度表示时,随着聚合度的增加,原花青素对Bel-7402的抑制作用降低。
通过体外抗氧化、消除自由基及体外抗肿瘤实验,表明原花青素的聚合度是影响其活性的重要因素,以质量单位表示时,随着聚合度的增加,水相体系中原花青素的
Grape, which has a long history in china, is widely cultivated with an increasing production in recent years. As the by-product of grape juice and wine making, grape seeds are a rich source of procyanidins (a kind of natural antioxidants), but due to the hard hull, they are usually discarded as unwanted or used as crude feed, which is a waste of resources. For better use of the grape seeds, it is of great importance to analysis the procyanidins in grape seeds and study its biological activities and extraction.
Grape seed procyanidins are oligomers and polymers of (+)-catechin, (-)-epicatechin, and (-)-epicatechin-O-gallate linked by C4→C8 or C4→C6 B-type bonds. They have attracted great attention in the fields of nutriology and pharmacology because of their potent radical-scavenging activity, broad biological and pharmacological effects and excellent security. The pharmacological properties of procyanidins largely depend on their structure and especially on their degree of polymerization (DP). But due to the diversity of procyanidin structures, the studies on the analysis methods as well as the relationship between the structure and activity are not thorough, which limits the utilization of procyanidins. In this work, feasible qualitative and quantitative methods were established, and the procyanidins were fractionated according to their degree of polymerization. And then the effects of DP on the antioxidant and anti-tumor activity in vitro were investigated systematically. Furthermore, studies on the extraction and isolation of procyanidins were also carried out for commercial preparation. The main results of this dissertation were described as following:
The qualitative analysis of oligomeric procyanidins in crude grape seed extracts can be performed by reversed-phase high-performance liquid chromatography coupled with electrospray ionization mass spectrometry (RP-HPLC-ESI-MS). Pseudomolecular ion and fragment information of ESI-MS made it possible to analyze the composition of oligmeric procyanidins directly without standards. By RP-HPLC-ESI-MS, three monomers, seven dimers, seven trimers and one tetramer were tentatively identified in crude grape seed extract, but due to the large number of isomers and their similar ESI-MS characters, the isomers are not identified precisely except monomers. In fact, only oligomers with DP below 4 can be well detected by RP-HPLC-MS, the higher polymers, with more isomers and more diverse polarity, can neither be separated nor be analyzed by RP-HPLC.
Acid-catalyzed vanillin assay was improved for quantitation of procyanidins in grape seed. By the use of H2SO4 as acid medium, proper reaction conditions were obtained as following: after 0.5mL aqueous solution of grape seed extract was mixed with 2.5mL 3% vanillin in methanol and 2.5mL 30% H2SO4 in methanol, the reaction was carried out at 30℃ for 15 minutes and the absorbance at 500nm was measured. Evaluation of the method proved that it has good repeatability and high recovery, and is also more sensitive and stable compared with previous methods. Procyanidins of different grape seeds can be quantified and compared by this method. The assay was then used to determine the procyanidin content of
several kinds of grape seeds from different district and different fermentation process. Results showed that the procyanidin content of grape seed was affected by the variety, clime and wine-making methods. Procyanidins should be extracted from unfermented grape seeds. Besides grape seeds, this assay can also be used to quantify the procyanidin of other plant in which vitamin C and dihydrochalcone are absent or scarce.
Because of the complexity of procyanidin structure, the proyanidins were separated according to their degree of polymerization (DP) for further study of the relationship between structure and activity. By use of thiolysis for determining the mean degree of polymerization (mDP) and normal-phase HPLC, gel permeation chromatography (GPC) and mass spectrometry (MS) for analysis of molecule profile of procyan
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