基于HUVECM和色谱质谱联用的药物筛选模型的建立及其应用
摘要
传统中药有效成分的筛选往往是先将中药混合物的各组分分离、提纯然后再确定各组分的化学特性,最后才是确定其活性与毒性等,只有理想的化合物才能进入下一轮的动物实验及耐受性评估。分离、提纯中药中的单个化合物固然重要,但是这种活性成分的筛选模式往往和中药及其复方配伍理论相悖,中药的疗效往往是不同组分协同作用的结果,在可能的情况下我们最好把它看成一个整体,一个多组分同时作用于多靶点的协同过程,一个基于药物化学成分的中药经验规律的研究。本论文基于活性人脐静脉血管内皮细胞细胞膜(HUVECM, Human umbilical vein endothelial cell membrane)上受体的生物特异性结合及GCMS. LCMS技术建立了几种旨在筛选肿瘤生长抑制剂(TAI)的药物筛选模型,并将其应用于川芎挥发油、川芎醇提物、金牛七和铁牛七醇提物水溶液的筛选、分析和鉴定,为中药成分筛选方法研究提供思路。
本论文的主要研究内容有
一、肿瘤生长抑制剂(TAI)筛选的靶标(HUVECM)上的受体活性变化规律的行为研究。
利用建立的HUVEC细胞膜ATP酶活性测定方法间接考察细胞膜受体的活性变化规律,研究结果显示：保存在PBS缓冲液中的HUVECM的ATP酶的生物活性随着离体时间的增加逐渐降低,但能持续很长一段时间(至少12h)保持活性,这在很大程度上反应了细胞膜受体生物活性的变化规律；提示我们HUVECM在离体的一段时间内可用于药物筛选。
二、活性HUVECM结合GCMS筛选模型的建立及其应用
将研究的中药混合物分别与不同活性的HUVECM—起温浴反应,然后分离细胞膜并借助GCMS技术对温浴前后中药提取液中的各组分进行分离和鉴定,通过对比组分种类和含量的变化来分析、筛选潜在的活性成分。
1.活性HUVECM结合GCMS筛选模型对中药川芎挥发油的分析
研究结果表明：川芎挥发油中至少有28种小分子可能与活性HUVECM上的受体发生特异性结合,他们是：萜品醇、萜品烯、α-柠檬醛、罗汉柏烯、二表雪松烯、γ-衣兰油烯、花柏烯、广藿香烯、花侧柏烯、δ-荜澄茄烯、α-香柑油烯、α-衣兰油烯、α-白菖考烯、细辛醚、角鲨烯,水杨酸甲酯、桧萜、柠檬烯、丁香酚、雪松烯、丁香烯、α-律草烯、α-姜黄烯、丁烯基苯酞、新蛇床内酯、藁本内酯、邻苯二甲酸丁酯等。虽然这些结论还需要进一步的实验来最终确认,但相关文献表明大多数筛选出来的潜在活性物质的确具有很强的药理活性。
2.活性HUVECM结合GCMS筛选模型对中金牛七和铁牛七醇提物的分析
研究结果表明：金牛七和铁牛七醇提物中能够与活性HUVECM受体特异性作用的组分很少,前者有二十九烷和一个未鉴定物质,后者有二十三烷、二十四烷、乙酸十八烷基酯等；还发现了混合物与活性HUVECM作用后某些组分增加的现象,前者有十四烷和十八烷；后者有十四烷和十六烷酸(棕榈酸)。
三、基于HUVEC-CMCSP的LC结合GCMS的筛选模型的建立及其应用
基于LC结合GCMS的筛选模型对川芎醇提物水溶性成分的分析：制备基于HUVEC-CMCSP (Cell membrane chromatographic stationary phase)的微型色谱柱,并结合C18色谱柱建立起一种色谱筛选体系,收集潜在的活性组分借助GCMS进行分离和鉴定,最后利用该筛选系统对各己鉴定组分之间可能发生的协同作用及其与细胞膜上受体的作用作出了初步的推断。
川芎醇提物水溶液中至少有四种物质可能作用于活性HUVECM上的受体,分别是香兰素、川芎嗪和阿魏酸和某未鉴定物质。川芎嗪和阿魏酸都很有可能单向对香兰素有协同作用,川芎嗪和阿魏酸对香兰素的协同作用不具有加合性；川芎醇提物中可能还有其他的组分协同香兰素发挥作用。川芎嗪发挥作用时独立于其他组分,不受川芎醇提物中的其他物质的协同。川芎嗪对阿魏酸有可能有协同作用,川芎醇提物中可能还有其他组分协同阿魏酸发挥作用。
四、基于HUVEC-CMCSP的LC-MS2药物筛选模型的建立及其应用
1.中药金牛七和铁牛七醇提物中高级脂肪酸的气质分析
借助GCMS分别对中药金牛七和铁牛七醇提物中的主要高级脂肪酸进行鉴定,建立定量测定所鉴定的游离脂肪酸的GCMS方法并对中药金牛七和铁牛七醇提物进行分析。研究结果表明金牛七和铁牛七醇提物中主要含有6种主要脂肪酸；其中金牛七醇提物富含亚油酸(13.89±0.36mg/g)、棕榈酸(12.47±0.32mg/g)和α[-亚麻酸(5.34±0.12mg/g),铁牛七醇提物一样富含亚油酸(8.49±0.22mg/g)、棕榈酸(7.16±0.18mg/g)和α-亚麻酸(6.19±0.16mg/g),提取物中游离不饱和脂肪酸含量占总游离脂肪酸70%以上。
2.基于HUVEC-CMCSP的LC-MS2药物筛选模型对金牛七和铁牛七醇提物的应用。
基于特殊和具有高效分离功能的HUVEC-CMCSP色谱微柱建立了LC-MS2药物筛选模型,并对中药金牛七和铁牛七醇提物中水溶性成分进行了分析,研究结果显示：金牛七和铁牛七醇提物水溶液组成可能比较类似,而且其水溶液与细胞膜色谱固定相作用的行为也很类似。发现了一些的确可能与活性细胞膜受体特异性结合的组分,包括克氏千里光碱、2S-[2a(8R*,10R*),4p,6p]]-10-[(4-氨基四氢-6-甲基-2H-吡喃-2-基)氧代]-7,8,9,10-四氢-6,8,11-三羟基-8-(羟基乙酰基)-l-甲氧基-5,12-萘并萘二酮或(8S-cis)-8-乙酰基-10-[(3-氨基-2,3,6-三去氧-a-L-来苏己吡喃基)-氧]-7,8,9,10-四氢-6,8,11-三羟基-1-甲氧基-5,12-并四苯二酮、3-乙酰基-10-羟基中乌头碱、8-O-油酰苯甲酰去氧乌头原碱或8-O-亚油酰苯甲酰中乌头原碱,相关文献表明所筛选鉴定的物质确实具有非常重要的药理研究价值。同时还发现基于HUVEC-CMCSP的色谱柱具有一些完全不同于传统色谱柱的现象,有待进一步研究。
It is a common practice to separate and purify compounds from the traditional Chinese medicine (TCM) before their chemical characteristics, biological activity and toxicity are studied. Only those available will be given further consideration for animal test and enduringness evaluation. It is beyond argument that this kind of screening for natural compounds from medicinal plants is very important, yet it does not often comply with the philosophy for the administration and study on TCMs. The therapeutic performance of TCM and its compound formulas is supposed to be a result of multiple compounds upon multiple targets under synergistic action, so we are well advised to deem the compounds in TCM and its compound formulas as a whole rather than many individuals, i.e. it is more of a study on the rule for TCM administration experience than a mere compounds concern. At the advantage of GCMS, LCMS techniques and special affinity for active receptors on HUVECM (Human Umbilical Vein Endothelial Cell Membrane), we establish several screening models for active compounds in TCM, with an aim to screen potential TAI (Tumor angiogenesis inhibitor). The applications of the established screening models, as part of the contribution to the sreening methods for TCM, are carried out in the essential oil and alcohol extract of Chinese herb Ligusticum chuanxiong Hort., alcohol extract of Chinese herb Aconitum taipeicum Hand.-Mazz.and alcohol extract of Tie Bang Chui, respectively.
The main contents of this dissertation are as follows:
Part1:Development of an online method for determining ATPase bioactivity and its application to the study on activity of acceptors on HUVECM.
Experiment results reveals that the bioactivity of ATPase decreases with increasing duration time in vitro in buffer solution, while the ATPase on HUVECM remains bioactive over a certain time (at least12h). It indicates the rule about variation of the acceptor activity. Thus HUVECM is eligible for pertinent medicine discovery.
Part2:The establishment and application.of the screening model at the advantage of combination of active acceptors on HUVECM with GCMS techniques.
HUVECM at different activity levels is incubated with multiple-compound extract of TCM, the content of individual volatile compound in the extract is determined before and after the incubation. With probing the variation of the their content, those potentially active are preliminarily screened.
1. The application to the preliminary screening for potentially active compounds in the essential oil of Chinese herb Ligusticum chuanxiong Hort.
According to the experimental results, there are at least28compounds which show specific affinity for active acceptors on HUVECM, they are:terpineol, terpinen, citral, thujopsene, di-epi-.alpha.-cedrene, gamma.-muurolene, chamigrene, patchoulene, cuparene, delta.-cadinene, alpha.-bergamotene, alpha.-muurolene, alpha.-calacorene, asarone, squalene, salicylic acid methyl ester, sabinene, alpha.-limonene, eugenol, alpha.-cedrene, caryophyllene, humulene, alpha.-curcumen, butylidenephthalide, neocnidilide, ligustilide, dibutylphthalate. Many of the compounds screened out have been reported to have special pharmacological activities, though our conclusion needs further confirmation with more facts.
2. The applicaton to the preliminary screening for potentially active compounds in alcohol extract of Chinese herb Aconitum taipeicum Hand.-Mazz.and alcohol extract of Tie Bang Chui, respectively.
Experimental results reveal that there are only a few volatile compounds in the alcohol extracts that show specific affinity, with nonacosane and one unidentified compound for Aconitum taipeicum Hand.-Mazz, and tricosane, tetracosane and acetic acid-octadecyl ester for Tie Bang Chui.
Part3:The establishment of HUVEC-CMCSP based LC-GCMS screening model and its application to the alcohol extract of Chinese herb Ligusticum chuanxiong Hort.
A mini-chromatographic column based on HUVEC-CMCSP (Cell membrane chromatographic stationary phase) is prepared for a special chromatographic column, with which an online LC system combined with GCMS is established for screening pontentially active compounds in alcohol extract of Chinese herb Ligusticum chuanxiong Hort. There are at least4compounds that show specific affinity for active acceptors on HUVECM, they are vanillin, ligustrazine, tetramethylpyrazine and one unidentified compound, repectively. Both ligustrazine and tetramethylpyrazine show unilateral synergistic action on vanillin, and no apparent additivity is observed between the two actions. Ligustrazine is found to show unilateral synergistic action on both vanillin and tetramethylpyrazine, it is likely that there are still some other unknown compounds in the extract that show synergistic action on both vanillin and tetramethylpyrazine. Nothing was found showing unilateral synergistic action on ligustrazine.
Part4:The establishment and application of HUVEC-CMCSP-based LC-MS2screening system for potentially active compounds.
1. Free fatty acids profile analysis of alcohol extracts of Aconitum taipeicum Hand.-Mazz. and of Tie Bang Chui with GCMS
The main free fatty acids in the extracts of Aconitum taipeicum Hand.-Mazz. and of Tie Bang Chui are identified and quantified, respectively, with a GCMS method. Experimental results show both Chinese herbs are all abundant in6kinds of free fatty acids, linoleic acid (13.89±0.36mg/g), palmitic acid (12.47±0.32mg/g) and linolenic acid (5.34±0.12mg/g) top the content list of alcohol extracts of Aconitum taipeicum Hand.-Mazz., while for the same top three of Tie Bang Chui, their contents are8.49±0.22mg/g,7.16±0.18mg/g,6.19±0.16mg/g, respectively. The unsaturated free fatty acids account for70%of the total content of free fatty acids.
2. The application of HUVEC-CMCSP-based LC-MS2screening system to alcohol extracts of Aconitum taipeicum Hand.-Mazz. and of Tie Bang Chui.
LC-MS2screening system for potentially active compounds is established based on the special and high performance of the chromatographic column that is filled with HUVEC-CMCSP, and its application to water-soluble compounds in both alcohol extracts of Aconitum taipeicum Hand.-Mazz. and of Tie Bang Chui. are carried out. Experimental results show that there seems to be a similarity of both components and binding behaviors on acceptors between the two Chinese herbs. Some compounds with specific affinity for active acceptors on HUVECM are found and identified, they include senkirkine,3-Acetylbeiwutine, daunorubicin, esorubicin,8-O-ole-benzoyldeoxyaconine and/or8-O-lino-benzoylmesaconine, etc. Some compounds screened out is reported to have special pharmacological activities or severe toxicity, this screening system has showed its difference from the traditional ones, though it still requires further improvement and perfection.
本论文的主要研究内容有
一、肿瘤生长抑制剂(TAI)筛选的靶标(HUVECM)上的受体活性变化规律的行为研究。
利用建立的HUVEC细胞膜ATP酶活性测定方法间接考察细胞膜受体的活性变化规律,研究结果显示：保存在PBS缓冲液中的HUVECM的ATP酶的生物活性随着离体时间的增加逐渐降低,但能持续很长一段时间(至少12h)保持活性,这在很大程度上反应了细胞膜受体生物活性的变化规律；提示我们HUVECM在离体的一段时间内可用于药物筛选。
二、活性HUVECM结合GCMS筛选模型的建立及其应用
将研究的中药混合物分别与不同活性的HUVECM—起温浴反应,然后分离细胞膜并借助GCMS技术对温浴前后中药提取液中的各组分进行分离和鉴定,通过对比组分种类和含量的变化来分析、筛选潜在的活性成分。
1.活性HUVECM结合GCMS筛选模型对中药川芎挥发油的分析
研究结果表明：川芎挥发油中至少有28种小分子可能与活性HUVECM上的受体发生特异性结合,他们是：萜品醇、萜品烯、α-柠檬醛、罗汉柏烯、二表雪松烯、γ-衣兰油烯、花柏烯、广藿香烯、花侧柏烯、δ-荜澄茄烯、α-香柑油烯、α-衣兰油烯、α-白菖考烯、细辛醚、角鲨烯,水杨酸甲酯、桧萜、柠檬烯、丁香酚、雪松烯、丁香烯、α-律草烯、α-姜黄烯、丁烯基苯酞、新蛇床内酯、藁本内酯、邻苯二甲酸丁酯等。虽然这些结论还需要进一步的实验来最终确认,但相关文献表明大多数筛选出来的潜在活性物质的确具有很强的药理活性。
2.活性HUVECM结合GCMS筛选模型对中金牛七和铁牛七醇提物的分析
研究结果表明：金牛七和铁牛七醇提物中能够与活性HUVECM受体特异性作用的组分很少,前者有二十九烷和一个未鉴定物质,后者有二十三烷、二十四烷、乙酸十八烷基酯等；还发现了混合物与活性HUVECM作用后某些组分增加的现象,前者有十四烷和十八烷；后者有十四烷和十六烷酸(棕榈酸)。
三、基于HUVEC-CMCSP的LC结合GCMS的筛选模型的建立及其应用
基于LC结合GCMS的筛选模型对川芎醇提物水溶性成分的分析：制备基于HUVEC-CMCSP (Cell membrane chromatographic stationary phase)的微型色谱柱,并结合C18色谱柱建立起一种色谱筛选体系,收集潜在的活性组分借助GCMS进行分离和鉴定,最后利用该筛选系统对各己鉴定组分之间可能发生的协同作用及其与细胞膜上受体的作用作出了初步的推断。
川芎醇提物水溶液中至少有四种物质可能作用于活性HUVECM上的受体,分别是香兰素、川芎嗪和阿魏酸和某未鉴定物质。川芎嗪和阿魏酸都很有可能单向对香兰素有协同作用,川芎嗪和阿魏酸对香兰素的协同作用不具有加合性；川芎醇提物中可能还有其他的组分协同香兰素发挥作用。川芎嗪发挥作用时独立于其他组分,不受川芎醇提物中的其他物质的协同。川芎嗪对阿魏酸有可能有协同作用,川芎醇提物中可能还有其他组分协同阿魏酸发挥作用。
四、基于HUVEC-CMCSP的LC-MS2药物筛选模型的建立及其应用
1.中药金牛七和铁牛七醇提物中高级脂肪酸的气质分析
借助GCMS分别对中药金牛七和铁牛七醇提物中的主要高级脂肪酸进行鉴定,建立定量测定所鉴定的游离脂肪酸的GCMS方法并对中药金牛七和铁牛七醇提物进行分析。研究结果表明金牛七和铁牛七醇提物中主要含有6种主要脂肪酸；其中金牛七醇提物富含亚油酸(13.89±0.36mg/g)、棕榈酸(12.47±0.32mg/g)和α[-亚麻酸(5.34±0.12mg/g),铁牛七醇提物一样富含亚油酸(8.49±0.22mg/g)、棕榈酸(7.16±0.18mg/g)和α-亚麻酸(6.19±0.16mg/g),提取物中游离不饱和脂肪酸含量占总游离脂肪酸70%以上。
2.基于HUVEC-CMCSP的LC-MS2药物筛选模型对金牛七和铁牛七醇提物的应用。
基于特殊和具有高效分离功能的HUVEC-CMCSP色谱微柱建立了LC-MS2药物筛选模型,并对中药金牛七和铁牛七醇提物中水溶性成分进行了分析,研究结果显示：金牛七和铁牛七醇提物水溶液组成可能比较类似,而且其水溶液与细胞膜色谱固定相作用的行为也很类似。发现了一些的确可能与活性细胞膜受体特异性结合的组分,包括克氏千里光碱、2S-[2a(8R*,10R*),4p,6p]]-10-[(4-氨基四氢-6-甲基-2H-吡喃-2-基)氧代]-7,8,9,10-四氢-6,8,11-三羟基-8-(羟基乙酰基)-l-甲氧基-5,12-萘并萘二酮或(8S-cis)-8-乙酰基-10-[(3-氨基-2,3,6-三去氧-a-L-来苏己吡喃基)-氧]-7,8,9,10-四氢-6,8,11-三羟基-1-甲氧基-5,12-并四苯二酮、3-乙酰基-10-羟基中乌头碱、8-O-油酰苯甲酰去氧乌头原碱或8-O-亚油酰苯甲酰中乌头原碱,相关文献表明所筛选鉴定的物质确实具有非常重要的药理研究价值。同时还发现基于HUVEC-CMCSP的色谱柱具有一些完全不同于传统色谱柱的现象,有待进一步研究。
It is a common practice to separate and purify compounds from the traditional Chinese medicine (TCM) before their chemical characteristics, biological activity and toxicity are studied. Only those available will be given further consideration for animal test and enduringness evaluation. It is beyond argument that this kind of screening for natural compounds from medicinal plants is very important, yet it does not often comply with the philosophy for the administration and study on TCMs. The therapeutic performance of TCM and its compound formulas is supposed to be a result of multiple compounds upon multiple targets under synergistic action, so we are well advised to deem the compounds in TCM and its compound formulas as a whole rather than many individuals, i.e. it is more of a study on the rule for TCM administration experience than a mere compounds concern. At the advantage of GCMS, LCMS techniques and special affinity for active receptors on HUVECM (Human Umbilical Vein Endothelial Cell Membrane), we establish several screening models for active compounds in TCM, with an aim to screen potential TAI (Tumor angiogenesis inhibitor). The applications of the established screening models, as part of the contribution to the sreening methods for TCM, are carried out in the essential oil and alcohol extract of Chinese herb Ligusticum chuanxiong Hort., alcohol extract of Chinese herb Aconitum taipeicum Hand.-Mazz.and alcohol extract of Tie Bang Chui, respectively.
The main contents of this dissertation are as follows:
Part1:Development of an online method for determining ATPase bioactivity and its application to the study on activity of acceptors on HUVECM.
Experiment results reveals that the bioactivity of ATPase decreases with increasing duration time in vitro in buffer solution, while the ATPase on HUVECM remains bioactive over a certain time (at least12h). It indicates the rule about variation of the acceptor activity. Thus HUVECM is eligible for pertinent medicine discovery.
Part2:The establishment and application.of the screening model at the advantage of combination of active acceptors on HUVECM with GCMS techniques.
HUVECM at different activity levels is incubated with multiple-compound extract of TCM, the content of individual volatile compound in the extract is determined before and after the incubation. With probing the variation of the their content, those potentially active are preliminarily screened.
1. The application to the preliminary screening for potentially active compounds in the essential oil of Chinese herb Ligusticum chuanxiong Hort.
According to the experimental results, there are at least28compounds which show specific affinity for active acceptors on HUVECM, they are:terpineol, terpinen, citral, thujopsene, di-epi-.alpha.-cedrene, gamma.-muurolene, chamigrene, patchoulene, cuparene, delta.-cadinene, alpha.-bergamotene, alpha.-muurolene, alpha.-calacorene, asarone, squalene, salicylic acid methyl ester, sabinene, alpha.-limonene, eugenol, alpha.-cedrene, caryophyllene, humulene, alpha.-curcumen, butylidenephthalide, neocnidilide, ligustilide, dibutylphthalate. Many of the compounds screened out have been reported to have special pharmacological activities, though our conclusion needs further confirmation with more facts.
2. The applicaton to the preliminary screening for potentially active compounds in alcohol extract of Chinese herb Aconitum taipeicum Hand.-Mazz.and alcohol extract of Tie Bang Chui, respectively.
Experimental results reveal that there are only a few volatile compounds in the alcohol extracts that show specific affinity, with nonacosane and one unidentified compound for Aconitum taipeicum Hand.-Mazz, and tricosane, tetracosane and acetic acid-octadecyl ester for Tie Bang Chui.
Part3:The establishment of HUVEC-CMCSP based LC-GCMS screening model and its application to the alcohol extract of Chinese herb Ligusticum chuanxiong Hort.
A mini-chromatographic column based on HUVEC-CMCSP (Cell membrane chromatographic stationary phase) is prepared for a special chromatographic column, with which an online LC system combined with GCMS is established for screening pontentially active compounds in alcohol extract of Chinese herb Ligusticum chuanxiong Hort. There are at least4compounds that show specific affinity for active acceptors on HUVECM, they are vanillin, ligustrazine, tetramethylpyrazine and one unidentified compound, repectively. Both ligustrazine and tetramethylpyrazine show unilateral synergistic action on vanillin, and no apparent additivity is observed between the two actions. Ligustrazine is found to show unilateral synergistic action on both vanillin and tetramethylpyrazine, it is likely that there are still some other unknown compounds in the extract that show synergistic action on both vanillin and tetramethylpyrazine. Nothing was found showing unilateral synergistic action on ligustrazine.
Part4:The establishment and application of HUVEC-CMCSP-based LC-MS2screening system for potentially active compounds.
1. Free fatty acids profile analysis of alcohol extracts of Aconitum taipeicum Hand.-Mazz. and of Tie Bang Chui with GCMS
The main free fatty acids in the extracts of Aconitum taipeicum Hand.-Mazz. and of Tie Bang Chui are identified and quantified, respectively, with a GCMS method. Experimental results show both Chinese herbs are all abundant in6kinds of free fatty acids, linoleic acid (13.89±0.36mg/g), palmitic acid (12.47±0.32mg/g) and linolenic acid (5.34±0.12mg/g) top the content list of alcohol extracts of Aconitum taipeicum Hand.-Mazz., while for the same top three of Tie Bang Chui, their contents are8.49±0.22mg/g,7.16±0.18mg/g,6.19±0.16mg/g, respectively. The unsaturated free fatty acids account for70%of the total content of free fatty acids.
2. The application of HUVEC-CMCSP-based LC-MS2screening system to alcohol extracts of Aconitum taipeicum Hand.-Mazz. and of Tie Bang Chui.
LC-MS2screening system for potentially active compounds is established based on the special and high performance of the chromatographic column that is filled with HUVEC-CMCSP, and its application to water-soluble compounds in both alcohol extracts of Aconitum taipeicum Hand.-Mazz. and of Tie Bang Chui. are carried out. Experimental results show that there seems to be a similarity of both components and binding behaviors on acceptors between the two Chinese herbs. Some compounds with specific affinity for active acceptors on HUVECM are found and identified, they include senkirkine,3-Acetylbeiwutine, daunorubicin, esorubicin,8-O-ole-benzoyldeoxyaconine and/or8-O-lino-benzoylmesaconine, etc. Some compounds screened out is reported to have special pharmacological activities or severe toxicity, this screening system has showed its difference from the traditional ones, though it still requires further improvement and perfection.
引文
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