CN109200045A - 花色苷提取物在制备防治蒽环类药物心肌细胞毒性的药物组合物中的应用及药物组合物 - Google Patents
花色苷提取物在制备防治蒽环类药物心肌细胞毒性的药物组合物中的应用及药物组合物 Download PDFInfo
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- anthocyanin
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- A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH
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Abstract
本发明公开了一种花色苷提取物在制备防治蒽环类药物心肌细胞毒性的药物组合物中的应用及药物组合物。其中,该药物组合物包括有效剂量的花色苷提取物,花色苷提取物是指从蒺藜科白刺属植物的成熟果实中获得的总花色苷含量大于700mg CGE/g、总抗氧化能力大于200mg TE/g的提取物。细胞生物学和分子生物学研究证明,花色苷提取物对蒽环类药物心肌细胞毒性损伤有显著的保护效果,可以用于预防和减轻蒽环类抗肿瘤药物心脏毒性,从而扩大其临床应用,并减轻了蒽环类抗肿瘤药物给患者带来的毒副作用和化疗患者的痛苦。另外,花色苷提取物所用的原材料来源广泛,成本低,而且使用安全。
Description
技术领域
本发明涉及生物医药技术领域,具体而言,涉及一种花色苷提取物在制备防治蒽环类药物心肌细胞毒性的药物组合物中的应用及药物组合物。
背景技术
蒽环类药物(Anthracyclines)是一类来源于波赛链霉菌青灰变种(Streptomycespeucetius var.caesius)的化疗药物。蒽环类抗生素的化学结构中,均具有蒽及一个六元环为基础带侧链和一个氨基糖的化合物。1950年初由Brockmann等从浅绛红链霉菌(S.purpurascen)的培养液中发现了第一个蒽环类抗生素——紫红霉素(rhodomycin),随后越来越多的蒽环类抗生素相继被发现。蒽环类抗生素抗肿瘤谱广、作用强大,在治疗白血病、乳腺癌、肺癌、胃癌、淋巴瘤等多种恶性实体瘤及血液系统恶性肿瘤有着很好的疗效,对乏氧细胞同样有效等显著特点,其疗效确切,不可或缺,以蒽环类药物为基础的联合治疗是一线治疗的标准方案。目前临床上常用的蒽环类抗肿瘤药物包括阿霉素(doxorubicin,DOX)、柔红霉素(dannoxnbicin,DNR)、表柔比星(epirubicin)、吡柔比星(pirarubicin),阿克拉霉素B(Aclacinomycin B)、伊达比星(idarubicin)、戊柔比星(valrubicin))以及米托蒽醌(mitoxantrone)等,其中阿霉素是最常用的抗肿瘤药物之一。但蒽环类药物具有剂量依赖性和累积性心脏毒性,在接受DOX治疗的患者中,近10%的患者在停止化疗近10年后还会出现心脏并发症,这限制了它在临床上的应用,其心脏毒性甚至可能威胁生命。
尽管临床应用多年,关于蒽环类药物引起心脏毒性的机制目前仍未完全阐明。当前普遍认为,活性氧自由基(Reactive oxygen species,ROS)和脂质过氧化引起的氧化应激增加、钙超载、能量代谢障碍、线粒体损伤、细胞凋亡等在DOX心脏毒性产生中起着重要作用。目前主要的机制或假说有:氧化应激、铁机制、钙失调、线粒体损伤、细胞凋亡等。为了解决蒽环类药物临床应用的局限性,研究人员开展了大量的蒽环类药物引起心脏毒性的防治辅助治疗药物研究,主要包括自由基清除剂、抗氧化剂、铁离子螯合剂、钙拮抗剂、线粒体保护剂、细胞凋亡抑制剂等。
随着社会的发展,人们越来越关注化学药品给人类自身健康及生活环境带来的负面影响,回归自然、保护环境已成为一种处理人类和环境关系的潮流思想。由于天然药物来自大自然、毒副作用小,且在治疗疑难杂症上具有独特优势而倍受重视。近年来,已发现的蒽环类药物心脏毒性保护天然药物,包括20(S)-人参皂苷RH2(ZL200610069844.7)、甘草提取物(ZL200810099467.0)、生物类黄酮化合物(ZL201010201577.0)、23-羟基白桦酸(ZL201010514113.5)、新女贞子苷(ZL201410134883.5)、小檗碱衍生物(ZL201410361037.7)及中药组合提取物(ZL200810041276.9)等。
花色苷(anthocyanin)是花青素(anthocyanidin)与糖以糖苷键结合而成的一类类黄酮化合物,广泛存在于植物的花、果实、茎、叶和根器官的细胞液中。由于其独特的功能性,而被应用于清除体内自由基、增殖叶黄素、抗肿瘤、抗癌、抗炎、抑制脂质过氧化和血小板凝集、预防糖尿病、减肥、保护视力等。花色苷作为一种天然色素,安全、无毒,且对人体具有许多保健功能,已被应用于食品、保健品、化妆品、医药等行业。但是,至今还未见针对蒽环类抗生素心脏毒性的复合花色苷类辅助天然药物的报道。
发明内容
本发明旨在提供一种花色苷提取物在制备防治蒽环类药物心肌细胞毒性的药物组合物中的应用及药物组合物,为蒽环类药物提供一类安全、无毒的辅助性治疗药物。
为了实现上述目的,根据本发明的一个方面,提供了一种用于防治蒽环类药物心肌细胞毒性的药物组合物。该药物组合物包括有效剂量的花色苷提取物,花色苷提取物是指从蒺藜科白刺属植物的成熟果实中获得的总花色苷含量大于700mg CGE/g、总抗氧化能力大于200mg TE/g的提取物。
进一步地,花色苷提取物的来源花青素包括矢车菊素、飞燕草素、锦葵色素、天竺葵素、芍药花素和矮牵牛素。
进一步地,花色苷提取物包括选自由矢车菊素-3-O-二葡糖苷、矢车菊素-3-O-桑布双糖苷、矢车菊素-3-O-(顺式-6”-O-香豆酰基)-二葡糖苷、矢车菊素-3-O-(反式-6”-O-香豆酰基)-二葡糖苷、矢车菊素-3-O-(6”-O-香豆酰基)-葡糖苷、飞燕草素-3-O-(6”-O-香豆酰基)-葡糖苷,5-O-葡糖苷、飞燕草素-3-O-(6”-O-香豆酰基)-葡糖苷、锦葵色素-3-O-葡糖苷、锦葵色素-3-O-(6”-O-乙酰基)-葡糖苷、锦葵色素-3-O-(6”-O-香豆酰基)-葡糖苷,5-O-葡糖苷、锦葵色素-3-O-(顺式-6”-O-香豆酰基)-葡糖苷、锦葵色素-3-O-(反式-6”-O-香豆酰基)-葡糖苷、天竺葵色素-3-O-(6”-O-香豆酰基)-二葡糖苷、芍药色素-3-O-(6”-O-香豆酰基)-葡糖苷、芍药色素-3-O-(6”-O-香豆酰基)-葡糖苷,5-O-葡糖苷和牵牛花色素-3-O-(6”-O-香豆酰基)-葡糖苷组成的组中的六种或六种以上,且花色苷提取物的来源花青素包括矢车菊素、飞燕草素、锦葵色素、天竺葵素、芍药花素和矮牵牛素。
进一步地,花色苷提取物通过以下方法制备得到:白刺果实或白刺果实榨汁后所产生的果渣,按照1:15-1:30g/mL的料液比加入60~90%乙醇,在55-65℃条件下提取30-90分钟;提取液减压浓缩至无醇后,经弱极性大孔吸附树脂分离,以三倍柱体积的水冲洗,然后以60~90%乙醇冲洗,收集流出物,浓缩干燥,即花色苷提取物。
进一步地,蒽环类药物为阿霉素、柔红霉素、阿克拉霉素、表柔比星、吡柔比星、伊达比星、戊柔比星或米托蒽醌中的一种或多种。
进一步地,药物组合物的剂型为胶囊、片剂、口服液、颗粒剂、滴丸中的任意一种。
根据本发明的另一个方面,提供一种花色苷提取物在制备防治蒽环类药物心肌细胞毒性的药物组合物中的应用。其中,花色苷提取物是指从蒺藜科白刺属植物的成熟果实中获得的总花色苷含量大于700mg CGE/g、总抗氧化能力大于200mg TE/g的提取物。
进一步地,花色苷提取物的来源花青素包括矢车菊素、飞燕草素、锦葵色素、天竺葵素、芍药花素和矮牵牛素。
进一步地,花色苷提取物包括选自由矢车菊素-3-O-二葡糖苷、矢车菊素-3-O-桑布双糖苷、矢车菊素-3-O-(顺式-6”-O-香豆酰基)-二葡糖苷、矢车菊素-3-O-(反式-6”-O-香豆酰基)-二葡糖苷、矢车菊素-3-O-(6”-O-香豆酰基)-葡糖苷、飞燕草素-3-O-(6”-O-香豆酰基)-葡糖苷,5-O-葡糖苷、飞燕草素-3-O-(6”-O-香豆酰基)-葡糖苷、锦葵色素-3-O-葡糖苷、锦葵色素-3-O-(6”-O-乙酰基)-葡糖苷、锦葵色素-3-O-(6”-O-香豆酰基)-葡糖苷,5-O-葡糖苷、锦葵色素-3-O-(顺式-6”-O-香豆酰基)-葡糖苷、锦葵色素-3-O-(反式-6”-O-香豆酰基)-葡糖苷、天竺葵色素-3-O-(6”-O-香豆酰基)-二葡糖苷、芍药色素-3-O-(6”-O-香豆酰基)-葡糖苷、芍药色素-3-O-(6”-O-香豆酰基)-葡糖苷,5-O-葡糖苷和牵牛花色素-3-O-(6”-O-香豆酰基)-葡糖苷组成的组中的六种或六种以上,且花色苷提取物的来源花青素包括矢车菊素、飞燕草素、锦葵色素、天竺葵素、芍药花素和矮牵牛素。
进一步地,花色苷提取物通过以下方法制备得到:白刺果实或白刺果实榨汁后所产生的果渣,按照1:15-1:30g/mL的料液比加入60~90%乙醇,在55-65℃条件下提取30-90分钟;提取液减压浓缩至无醇后,经弱极性大孔吸附树脂分离,以三倍柱体积的水冲洗,然后以60~90%乙醇冲洗,收集流出物,浓缩干燥,即花色苷提取物。
细胞生物学和分子生物学研究证明,花色苷提取物对蒽环类药物心肌细胞毒性损伤有显著的保护效果,可以用于预防和减轻蒽环类抗肿瘤药物心脏毒性,从而扩大其临床应用,并减轻了蒽环类抗肿瘤药物给患者带来的毒副作用和化疗患者的痛苦。另外,花色苷提取物所用的原材料来源广泛,成本低,而且使用安全。
附图说明
构成本申请的一部分的说明书附图用来提供对本发明的进一步理解,本发明的示意性实施例及其说明用于解释本发明,并不构成对本发明的不当限定。在附图中:
图1示出了根据本发明一实施方式的白刺花色苷提取物HPLC色谱图;
图2-1示出了根据本发明一实施方式的白刺花色苷提取物中各色谱峰的质谱图;
图2-2示出了根据本发明一实施方式的白刺花色苷提取物中各色谱峰的质谱图(续);
图3示出了实施例1的心肌细胞H9c2细胞活力测定结果图;
图4示出了实施例2的心肌细胞H9c2细胞外液LDH和CK水平测定结果图;
图5示出了实施例3的心肌细胞H9c2细胞及细胞核形态图,其中A1-E1为倒置相差显微镜观察心肌细胞H9c2的细胞形态图,A2-E2为心肌细胞H9c2细胞核荧光染色后荧光显微镜观察结果图;比例尺为25μm;A-1和A-2:空白对照组;B-1和B-2:阿霉素处理细胞损伤模型组;C-1和C-2:白刺花色苷提取物处理低剂量组(5μg/mL);D-1和D-2:白刺花色苷提取物处理中剂量组(50μg/mL);E-1和E-2:白刺花色苷提取物处理高剂量组(500μg/mL);
图6示出了实施例4的心肌细胞H9c2细胞凋亡程度测定结果图,其中A-E为流式细胞术测定结果图(A:空白对照组,B:阿霉素处理细胞损伤模型组,C:5μg/mL白刺花色苷提取物处理组,D:50μg/mL白刺花色苷提取物处理组,E:500μg/mL白刺花色苷提取物处理组),F为所有实验组数据汇总结果图;
图7示出了实施例5的心肌细胞H9c2细胞凋亡关键基因蛋白表达量及Caspase级联反应程度测定结果图,A:免疫印迹试验结果,B:Bax-αand Bcl-2蛋白表达分析结果图,C:Caspase-3蛋白表达分析结果图,D:Caspase-9蛋白表达分析结果图,#p<0.05和###p<0.001表示与空白对照组相比的显著性差异,**p<0.01和***p<0.001表示与模型组相比的显著性差异;
图8示出了实施例6的心肌细胞H9c2细胞内活性氧(ROS)积聚程度测定结果图,其中A-E为流式细胞术测定结果图(A:空白对照组,B:阿霉素处理细胞损伤模型组,C:5μg/mL白刺花色苷提取物处理组,D:50μg/mL白刺花色苷提取物处理组,E:500μg/mL白刺花色苷提取物处理组),F为所有实验组数据汇总结果图;
图9示出了实施例7的心肌细胞H9c2细胞内关键抗氧化酶水平及谷胱甘肽氧化还原循环程度测定结果图;
图10示出了实施例7的心肌细胞H9c2细胞内谷胱甘肽氧化还原循环程度测定结果图;以及
图11示出了实施例8的无细胞体外实验方法对白刺花色苷提取物的还原力、二价铁离子螯合能力和关键自由基及其中间物质清除能力的测定结果图,其中A:还原力,B:二价铁离子螯合能力,C:超氧阴离子自由基清除率,D:羟基自由基清除率,E:DPPH自由基清除率,F:H2O2清除率。
具体实施方式
需要说明的是,在不冲突的情况下,本申请中的实施例及实施例中的特征可以相互组合。下面将参考附图并结合实施例来详细说明本发明。
本发明的发明人发现,花色苷提取物可以用于防治蒽环类药物心肌细胞毒性。因此,开发自然界中大量存在的花色苷类天然药物,不仅可以为蒽环类药物提供一类安全、无毒的辅助性治疗药物,而且可以避免类似于右丙亚胺(Dexrazoxane,ICRF-187)等高成本辅助药物带来的患者治疗费用急剧增加,对于新型蒽环类药物心脏保护剂开发具有现实指导意义。
根据本发明一种典型的实施方式,提供一种用于防治蒽环类药物心肌细胞毒性的药物组合物。该药物组合物包括有效剂量的花色苷提取物,花色苷提取物是指从蒺藜科白刺属植物的成熟果实(如白刺(Nitraria tangutorum Bobr.)、小果白刺(Nitrariasibirica Pall.)、大白刺(Nitraria roborowskii Kom.)、毛瓣白刺(Nitraria praevisaBobr.)等)中获得的总花色苷含量大于700mg CGE/g、总抗氧化能力大于200mg TE/g的提取物。
优选的,花色苷提取物的来源花青素包括矢车菊素、飞燕草素、锦葵色素、天竺葵素、芍药花素和矮牵牛素。
优选的,花色苷提取物包括选自由矢车菊素-3-O-二葡糖苷、矢车菊素-3-O-桑布双糖苷、矢车菊素-3-O-(顺式-6”-O-香豆酰基)-二葡糖苷、矢车菊素-3-O-(反式-6”-O-香豆酰基)-二葡糖苷、矢车菊素-3-O-(6”-O-香豆酰基)-葡糖苷、飞燕草素-3-O-(6”-O-香豆酰基)-葡糖苷,5-O-葡糖苷、飞燕草素-3-O-(6”-O-香豆酰基)-葡糖苷、锦葵色素-3-O-葡糖苷、锦葵色素-3-O-(6”-O-乙酰基)-葡糖苷、锦葵色素-3-O-(6”-O-香豆酰基)-葡糖苷,5-O-葡糖苷、锦葵色素-3-O-(顺式-6”-O-香豆酰基)-葡糖苷、锦葵色素-3-O-(反式-6”-O-香豆酰基)-葡糖苷、天竺葵色素-3-O-(6”-O-香豆酰基)-二葡糖苷、芍药色素-3-O-(6”-O-香豆酰基)-葡糖苷、芍药色素-3-O-(6”-O-香豆酰基)-葡糖苷,5-O-葡糖苷和牵牛花色素-3-O-(6”-O-香豆酰基)-葡糖苷组成的组中的六种或六种以上,且所述花色苷提取物的来源花青素包括矢车菊素、飞燕草素、锦葵色素、天竺葵素、芍药花素和矮牵牛素。。。
优选的,花色苷提取物通过以下方法制备得到:白刺果实或白刺果实榨汁后所产生的果渣,按照1:15-1:30g/mL的料液比加入60~90%乙醇(优选为70%乙醇),在55-65℃条件下提取30-90分钟;提取液减压浓缩至无醇后,经弱极性大孔吸附树脂分离,以三倍柱体积的水冲洗,然后以70%乙醇冲洗,收集流出物,浓缩干燥,即花色苷提取物。该提取物的花色苷的组成成分如表1、图1和图2-1、图2-2所示,其中,表1示出了白刺花色苷提取物中16种花色苷组成成分表;图1示出了白刺花色苷提取物HPLC色谱图;图2-1和图2-2示出了白刺花色苷提取物中各色谱峰的质谱图。
表1白刺花色苷提取物中16种花色苷组成成分表
根据本发明一种典型的实施方式,蒽环类药物为阿霉素、柔红霉素、阿克拉霉素、表柔比星、吡柔比星、伊达比星、戊柔比星或米托蒽醌中的一种或多种。
根据本发明一种典型的实施方式,药物组合物的剂型为胶囊、片剂、口服液、颗粒剂、滴丸中的任意一种。
根据本发明一种典型的实施方式,提供一种花色苷提取物在制备防治蒽环类药物心肌细胞毒性的药物组合物中的应用,其中,花色苷提取物是指从蒺藜科白刺属植物的成熟果实中获得的总花色苷含量大于700mg CGE/g、总抗氧化能力大于200mg TE/g的提取物。
优选的,花色苷提取物的来源花青素包括矢车菊素、飞燕草素、锦葵色素、天竺葵素、芍药花素和矮牵牛素。
优选的,花色苷提取物包括选自由矢车菊素-3-O-二葡糖苷、矢车菊素-3-O-桑布双糖苷、矢车菊素-3-O-(顺式-6”-O-香豆酰基)-二葡糖苷、矢车菊素-3-O-(反式-6”-O-香豆酰基)-二葡糖苷、矢车菊素-3-O-(6”-O-香豆酰基)-葡糖苷、飞燕草素-3-O-(6”-O-香豆酰基)-葡糖苷,5-O-葡糖苷、飞燕草素-3-O-(6”-O-香豆酰基)-葡糖苷、锦葵色素-3-O-葡糖苷、锦葵色素-3-O-(6”-O-乙酰基)-葡糖苷、锦葵色素-3-O-(6”-O-香豆酰基)-葡糖苷,5-O-葡糖苷、锦葵色素-3-O-(顺式-6”-O-香豆酰基)-葡糖苷、锦葵色素-3-O-(反式-6”-O-香豆酰基)-葡糖苷、天竺葵色素-3-O-(6”-O-香豆酰基)-二葡糖苷、芍药色素-3-O-(6”-O-香豆酰基)-葡糖苷、芍药色素-3-O-(6”-O-香豆酰基)-葡糖苷,5-O-葡糖苷和牵牛花色素-3-O-(6”-O-香豆酰基)-葡糖苷组成的组中的六种或六种以上,且所述花色苷提取物的来源花青素包括矢车菊素、飞燕草素、锦葵色素、天竺葵素、芍药花素和矮牵牛素。。
优选的,花色苷提取物通过以下方法制备得到:白刺果实或白刺果实榨汁后所产生的果渣,按照1:15-1:30g/mL的料液比加入60~90%乙醇,在55-65℃条件下提取30-90分钟;提取液减压浓缩至无醇后,经弱极性大孔吸附树脂分离,以三倍柱体积的水冲洗,然后以60~90%乙醇冲洗,收集流出物,浓缩干燥,即花色苷提取物。
根据本发明一种典型的实施方式,蒽环类药物为阿霉素、柔红霉素、阿克拉霉素、表柔比星、吡柔比星、伊达比星、戊柔比星或米托蒽醌中的一种或多种。
根据本发明一种典型的实施方式,药物为药物组合物的剂型为胶囊、片剂、口服液、颗粒剂、滴丸中的任意一种。
根据本发明一种典型的实施方式,提供一种花色苷提取物在防治蒽环类药物心肌细胞毒性中的应用,其中花色苷提取物是指从蒺藜科白刺属植物的成熟果实中获得的总花色苷含量大于700mg CGE/g、总抗氧化能力大于200mg TE/g的提取物。
优选的,所述花色苷提取物的来源花青素包括矢车菊素、飞燕草素、锦葵色素、天竺葵素、芍药花素和矮牵牛素。
优选的,花色苷提取物包括选自由矢车菊素-3-O-二葡糖苷、矢车菊素-3-O-桑布双糖苷、矢车菊素-3-O-(顺式-6”-O-香豆酰基)-二葡糖苷、矢车菊素-3-O-(反式-6”-O-香豆酰基)-二葡糖苷、矢车菊素-3-O-(6”-O-香豆酰基)-葡糖苷、飞燕草素-3-O-(6”-O-香豆酰基)-葡糖苷,5-O-葡糖苷、飞燕草素-3-O-(6”-O-香豆酰基)-葡糖苷、锦葵色素-3-O-葡糖苷、锦葵色素-3-O-(6”-O-乙酰基)-葡糖苷、锦葵色素-3-O-(6”-O-香豆酰基)-葡糖苷,5-O-葡糖苷、锦葵色素-3-O-(顺式-6”-O-香豆酰基)-葡糖苷、锦葵色素-3-O-(反式-6”-O-香豆酰基)-葡糖苷、天竺葵色素-3-O-(6”-O-香豆酰基)-二葡糖苷、芍药色素-3-O-(6”-O-香豆酰基)-葡糖苷、芍药色素-3-O-(6”-O-香豆酰基)-葡糖苷,5-O-葡糖苷和牵牛花色素-3-O-(6”-O-香豆酰基)-葡糖苷组成的组中的六种或六种以上,且所述花色苷提取物的来源花青素包括矢车菊素、飞燕草素、锦葵色素、天竺葵素、芍药花素和矮牵牛素。
优选的,花色苷提取物通过以下方法制备得到:白刺果实或白刺果实榨汁后所产生的果渣,按照1:15-1:30g/mL的料液比加入60~90%乙醇,在55-65℃条件下提取30-90分钟;提取液减压浓缩至无醇后,经弱极性大孔吸附树脂分离,以三倍柱体积的水冲洗,然后以60~90%乙醇冲洗,收集流出物,浓缩干燥,即所述花色苷提取物。
根据本发明一种典型的实施方式,蒽环类药物为阿霉素、柔红霉素、阿克拉霉素、表柔比星、吡柔比星、伊达比星、戊柔比星或米托蒽醌中的一种或多种。
根据本发明一种典型的实施方式,提供一种防治蒽环类药物心肌细胞毒性的方法。该方法包括使用药物组合物对心脏进行保护,该药物组合物包括有效剂量的花色苷提取物,花色苷提取物是指从蒺藜科白刺属植物的成熟果实(如白刺(Nitraria tangutorumBobr.)、小果白刺(Nitraria sibirica Pall.)、大白刺(Nitraria roborowskii Kom.)、毛瓣白刺(Nitraria praevisa Bobr.)等)中获得的总花色苷含量大于700mg CGE/g、总抗氧化能力大于200mg TE/g的提取物。
下面将结合实施例进一步说明本发明的有益效果。
实施例1
大鼠心肌细胞系H9c2,采用DMEM培养基(含10%新生牛血清、2mM谷氨酸盐、1%链霉素/青霉素)培养,培养条件为温度37℃、5%CO2的无菌环境。培养基每2~3天更换一次,细胞培养24h并达到80%聚集程度时,转入96孔板,细胞密度为1×105个/孔,继续培养24h后,进行药物处理。分别设对照组、模型组(含20μM阿霉素)、白刺花色苷提取物实验组(含20μM阿霉素和5~500μg/mL白刺花色苷提取物),处理24h后,MTT法检测细胞活力。实验结果显示如图3所示,20μM阿霉素处理24h,H9c2细胞活力显著降低为正常细胞的62.12%(P<0.001);而白刺花色苷提取物可以显著抑制阿霉素引起的心肌细胞活力损伤(P<0.001),阿霉素与5~500μg/mL白刺花色苷提取物共处理24h,细胞活力为正常心肌细胞的69.02%~95.61%。说明,白刺花色苷提取物对阿霉素造成的心肌细胞活力损伤具有显著的保护作用。
实施例2
大鼠心肌细胞系H9c2,采用DMEM培养基(含10%新生牛血清、2mM谷氨酸盐、1%链霉素/青霉素)培养,培养条件为温度37℃、5%CO2的无菌环境。培养基每2~3天更换一次,细胞培养24h并达到80%聚集程度时,进行药物处理。分别设对照组、模型组(含20μM阿霉素)、白刺花色苷提取物实验组(含20μM阿霉素和5~500μg/mL白刺花色苷提取物),处理24h后,收集细胞外液,应用乳酸脱氢酶(LDH)试剂盒和肌酸激酶(CK)测定试剂盒检测细胞外液中LDH和CK水平。实验结果显示如图4所示,20μM阿霉素处理24h,H9c2细胞外液中LDH和CK水平分别增高到正常细胞的2.65倍和2.87倍(P<0.001);而白刺花色苷提取物可以显著抑制阿霉素引起心肌细胞外液中LDH和CK水平升高(P<0.001),阿霉素与5~500μg/mL白刺花色苷提取物共处理24h,心肌细胞外液中LDH和CK水平分别为正常细胞的1.51~2.42倍和1.30~1.98倍。说明,白刺花色苷提取物对阿霉素造成的心肌细胞膜结构损伤具有显著的保护作用。
实施例3
大鼠心肌细胞系H9c2,采用DMEM培养基(含10%新生牛血清、2mM谷氨酸盐、1%链霉素/青霉素)培养,培养条件为温度37℃、5%CO2的无菌环境。培养基每2~3天更换一次,细胞培养24h并达到80%聚集程度时,进行药物处理。分别设对照组、模型组(含20μM阿霉素)、白刺花色苷提取物实验组(含20μM阿霉素和5~500μg/mL白刺花色苷提取物),处理24h后,应用相差显微镜观察细胞形态变化。随后,细胞核应用Hoechst 33258染料染色30min后,应用荧光倒置显微镜观察细胞核结构变化。实验结果显示如图5所示,5~500μg/mL白刺花色苷提取物可以显著保护由阿霉素导致的从边缘开始的细胞收缩、细胞膜起泡、异质体增强及染色质凝聚。说明,白刺花色苷提取物对阿霉素造成的心肌细胞结构损伤具有显著的保护作用。
实施例4
大鼠心肌细胞系H9c2,采用DMEM培养基(含10%新生牛血清、2mM谷氨酸盐、1%链霉素/青霉素)培养,培养条件为温度37℃、5%CO2的无菌环境。培养基每2~3天更换一次,细胞培养24h并达到80%聚集程度时,进行药物处理。分别设对照组、模型组(含20μM阿霉素)、白刺花色苷提取物实验组(含20μM阿霉素和5~500μg/mL白刺花色苷提取物),处理24h后,应用FITC-Annexin V/propidium iodide(PI)荧光双染法,按照试剂盒操作说明,使用流式细胞仪检测心肌细胞凋亡程度变化。实验结果显示如图6所示,20μM阿霉素处理24h,FITC-Annexin V阳性细胞数量从0.02%增加到1.49%;而阿霉素与5~500μg/mL白刺花色苷提取物共同处理24h,FITC-Annexin V阳性细胞数量仅增加到0.40~0.46%。说明,白刺花色苷提取物对阿霉素导致的心肌细胞凋亡具有显著的保护作用。
实施例5
大鼠心肌细胞系H9c2,采用DMEM培养基(含10%新生牛血清、2mM谷氨酸盐、1%链霉素/青霉素)培养,培养条件为温度37℃、5%CO2的无菌环境。培养基每2~3天更换一次,细胞培养24h并达到80%聚集程度时,进行药物处理。分别设对照组、模型组(含20μM阿霉素)、白刺花色苷提取物实验组(含20μM阿霉素和5~500μg/mL白刺花色苷提取物),处理24h后,刮取、离心收集细胞,经磷酸盐缓冲液清洗后,细胞重悬于裂解缓冲液中。离心除去细胞碎片后,收集上清液使用BCA蛋白浓度测定试剂盒测定可溶性蛋白浓度。蛋白质溶解物经12%SDS-PAGE电泳分离后,转移至PVDF膜,随后用bcl-2、bax、caspase-3和caspase-9抗体进行标记。条带的光密度值应用Quantity One软件进行测定(v4.62,美国Bio-Rad公司)。β-微管蛋白(β-tubulin)作为蛋白质上样内参物。实验结果表明(如图7所示),20μM阿霉素处理24h,bax蛋白表达量显著增加,bcl-2蛋白表达量显著降低,Bax/Bcl-2蛋白表达比例增加至正常细胞的2倍。与此同时,切割活化的caspase-3和caspase-9蛋白表达量显著增加。而阿霉素与5~500μg/mL白刺花色苷提取物共同处理24h,bax蛋白表达量的增加与bcl-2蛋白表达量的降低被显著抑制。与模型组相比,Bax/Bcl-2蛋白表达比例增加量减少1.32~2.42倍。同时,阿霉素导致的切割活化caspase-3和caspase-9蛋白表达量的增加也得到显著抑制(P<0.001)。说明,白刺花色苷提取物能够通过调节凋亡诱导基因(bax)和凋亡抑制基因(bcl-2)的表达,抑制Caspase蛋白家族级联活化,从而保护心肌细胞减轻阿霉素导致细胞凋亡损伤。
实施例6
大鼠心肌细胞系H9c2,采用DMEM培养基(含10%新生牛血清、2mM谷氨酸盐、1%链霉素/青霉素)培养,培养条件为温度37℃、5%CO2的无菌环境。培养基每2~3天更换一次,细胞培养24h并达到80%聚集程度时,进行药物处理。分别设对照组、模型组(含20μM阿霉素)、白刺花色苷提取物实验组(含20μM阿霉素和5~500μg/mL白刺花色苷提取物),处理24h后,加入2′,7′-Dichlorodihydro-fluorescein diacetate(DCFH-DA,20μM)37℃孵育20min,应用流式细胞仪检测心肌细胞活性氧(ROS)积聚水平。实验结果表明(如图8所示),20μM阿霉素处理24h,心肌细胞ROS积聚水平增加至正常细胞的3.5倍;阿霉素与5~500μg/mL白刺花色苷提取物共同处理24h,心肌细胞ROS积聚水平仅为正常细胞的2.16~3.29倍。说明,白刺花色苷提取物能够通过减少细胞内ROS水平而保护阿霉素导致的心肌细胞损伤。
实施例7
大鼠心肌细胞系H9c2,采用DMEM培养基(含10%新生牛血清、2mM谷氨酸盐、1%链霉素/青霉素)培养,培养条件为温度37℃、5%CO2的无菌环境。培养基每2~3天更换一次,细胞培养24h并达到80%聚集程度时,进行药物处理。分别设对照组、模型组(含20μM阿霉素)、白刺花色苷提取物实验组(含20μM阿霉素和5~500μg/mL白刺花色苷提取物),处理24h后,离心收集细胞,然后重悬于细胞裂解缓冲液中。离心收集上清液,按照试剂盒操作说明,检测超氧化物歧化酶(SOD)、过氧化氢酶(CAT)、谷胱甘肽过氧化物酶(GSH-Px)和谷胱甘肽S-转移酶(GST)水平,以及还原型谷胱甘肽(GSH)和氧化型谷胱甘肽GSSG含量。实验结果表明(如图9、图10所示),20μM阿霉素处理24h,心肌细胞中关键抗氧化酶水平显著降低,GSH含量显著降低,GSSG含量显著升高。与正常细胞相比,模型组心肌细胞中SOD、CAT、GSH-Px和GST水平分别降低35.93%、16.62%、20.42%和23.79%,GSH/GSSG比例降低74.10%。而阿霉素与5~500μg/mL白刺花色苷提取物共同处理24h,SOD等关键抗氧化酶水平及GSH/GSSG比例的降低程度和得到显著缓解,500μg/mL剂量下均达到或接近正常细胞水平。说明,白刺花色苷提取物能够显著提高心肌细胞内生抗氧化能力,促进细胞内谷胱甘肽氧化还原循环,从而保护阿霉素导致的心肌细胞损伤。
实施例8
应用无细胞体外实验方法,对白刺花色苷提取物的还原力(reducing power)、二价铁离子螯合能力(chelating Fe2+ability)、超氧阴离子自由基(superoxide radical)、羟自由基(hydroxyl radical)、1,1-二苯基-2-三硝基苯肼自由基(DPPH radical)和过氧化氢(H2O2)清除能力进行测定。抗坏血酸(ascorbic acid,ACS级,含量≥99%,上海阿拉丁生化科技股份有限公司)和葡萄籽提取物(GSE,多酚含量99.04%,批号002-1401001-02天津市尖峰天然产物研究开发有限公司)作为阳性对照药物。
实验结果表明,白刺花色苷提取物具有显著的还原力、良好的Fe2+螯合能力,以及优异的超氧阴离子自由基、羟自由基、DPPH自由基和H2O2清除能力,特别是其还原力、Fe2+螯合能力、超氧阴离子自由基、羟自由基和H2O2清除效率(EC50)均优于阳性对照药物GSE(参见图11)。说明,白刺花色苷提取物能够有效阻止阿霉素获得电子或Fe2+转化成对心肌细胞线粒体造成极大危害的半醌形式或形成阿霉素-Fe2+自由基复合物,有效清除阿霉素诱导心肌细胞氧化应激产生的两种主要自由基(羟自由基和超氧阴离子自由基)和形成自由基的主要媒介物质(H2O2),从而保护阿霉素引起的心肌细胞损伤。
实施例1至8中实验具体操作分别如下列文献所述:①Müller,L.,Theile,K.andV.,In vitro antioxidant activity of tocopherols and tocotrienols andcomparison of vitamin E concentration and lipophilic antioxidant capacity inhuman plasma.Mol.Nutr.Food Res.2010,54,731-742;②Dinis,T.C.P.,Madeira,V.M.C.and Almeida,L.M.,Action of phenolic derivatives(acetaminophen,salicylate,and 5-aminosalicylate)as inhibitors of membrane lipid peroxidationand as peroxyl radical scavengers.Arch.Biochem.Biophys.1994,315,161-169;③i,H.,Gao,T.,Li,Z.,Ji,L.et al.,Structural elucidation and antioxidant activityof a water-soluble polysaccharide from the fruit bodies of Bulgaria inquinans(Fries).Food Chem.2013,138,1470-1475;④Halliwell,B.,Gutteridge,J.M.C.andAruoma,O.I.,The deoxyribose method:A simple‘test-tube’assay for determinationof rate constants for reactions of hydroxyl radicals.Anal.Biochem.1987,165,215–219;⑤Kansci,G.,Dongo,E.and Genot,C.,2,2-Diphenyl-1-picrylhydrazyl(DPPH*)test demonstrates antiradical activity of Dorstenia psilurus and Dorsteniaciliata plant extracts.Mol.Nutr.Food Res.2003,47,434-437;⑥Pick,E.,and Mizel,D.,Rapid microassays for the measurement of superoxide and hydrogen peroxideproduction by macrophages in culture using an automatic enzyme immunoassayreader.J.Immunol.Methods 1981,46(2),211–226。
实施例9
以下实施例9-12中所提到的花色苷提取物是指通过以下步骤制备得到的提取物:白刺果实或白刺果实榨汁后所产生的果渣,按照1:15-1:30g/mL的料液比加入70%乙醇,在55-65℃条件下提取30-90分钟;提取液减压浓缩至无醇后,经弱极性大孔吸附树脂分离,以三倍柱体积的水冲洗,然后以70%乙醇冲洗,收集流出物,浓缩干燥,即所述花色苷提取物。总花色苷含量大于700mg CGE/g、总抗氧化能力大于200mg TE/g的提取物
花色苷提取物以30%的添加量与总添加量为70%的赋形剂(甘油、大豆油、玉米油、蜂蜡等)制备成可防治蒽环类药物心肌细胞毒性的软胶囊。该制剂的具体制法为:白刺花色苷提取物过100~200目筛,再与大豆油、蜂蜡混合,经胶体磨研匀,使药物以极细腻的质点形式均匀的悬浮于赋形剂中,采用滴制法或压制法,制成软胶囊。
实施例10
花色苷提取物以10%的添加量与总添加量为90%的辅料(蔗糖、乳糖、微晶纤维素、改性淀粉、二氧化硅、硬脂酸镁等)制备成可防治蒽环类药物心肌细胞毒性的硬胶囊。该制剂的具体制法为:白刺花色苷提取物过200~300目筛,再与微晶纤维素、改性淀粉、二氧化硅混合,经粉体混合机混匀,灌装制成硬胶囊。
实施例11
花色苷提取物以20%的添加量与总添加量为80%的辅料(木糖醇、蜂蜜、柠檬酸、食盐等)制备成可防治蒽环类药物心肌细胞毒性的口服液。该制剂的具体制法为:白刺花色苷提取物溶于适量乙醇溶液,离心除去残渣后,与含有适量木糖醇、蜂蜜、柠檬酸、食盐等辅料的溶液一同加入至调配罐中搅拌混合均匀,混合料液杀菌、均质后,无菌灌装制成口服液。
实施例12
花色苷提取物以40%的添加量与总添加量为60%的基质(聚乙二醇等)制备成可防治蒽环类药物心肌细胞毒性的口服滴丸。该制剂的具体制法为:白刺花色苷提取物与聚乙二醇6000混合,加热搅拌充分溶散后,滴入二甲基硅烷冷凝液中,收集滴丸,除去滴丸表面的二甲基硅烷,制成口服滴丸。
以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (12)
1.一种用于防治蒽环类药物心肌细胞毒性的药物组合物,其特征在于,所述药物组合物包括有效剂量的花色苷提取物,所述花色苷提取物是指从蒺藜科白刺属植物的成熟果实中获得的总花色苷含量大于700mg CGE/g、总抗氧化能力大于200mg TE/g的提取物。
2.根据权利要求1所述的药物组合物,其特征在于,所述花色苷提取物的来源花青素包括矢车菊素、飞燕草素、锦葵色素、天竺葵素、芍药花素和矮牵牛素。
3.根据权利要求2所述的药物组合物,其特征在于,所述花色苷提取物包括选自由矢车菊素-3-O-二葡糖苷、矢车菊素-3-O-桑布双糖苷、矢车菊素-3-O-(顺式-6”-O-香豆酰基)-二葡糖苷、矢车菊素-3-O-(反式-6”-O-香豆酰基)-二葡糖苷、矢车菊素-3-O-(6”-O-香豆酰基)-葡糖苷、飞燕草素-3-O-(6”-O-香豆酰基)-葡糖苷,5-O-葡糖苷、飞燕草素-3-O-(6”-O-香豆酰基)-葡糖苷、锦葵色素-3-O-葡糖苷、锦葵色素-3-O-(6”-O-乙酰基)-葡糖苷、锦葵色素-3-O-(6”-O-香豆酰基)-葡糖苷,5-O-葡糖苷、锦葵色素-3-O-(顺式-6”-O-香豆酰基)-葡糖苷、锦葵色素-3-O-(反式-6”-O-香豆酰基)-葡糖苷、天竺葵色素-3-O-(6”-O-香豆酰基)-二葡糖苷、芍药色素-3-O-(6”-O-香豆酰基)-葡糖苷、芍药色素-3-O-(6”-O-香豆酰基)-葡糖苷,5-O-葡糖苷和牵牛花色素-3-O-(6”-O-香豆酰基)-葡糖苷组成的组中的六种或六种以上,且所述花色苷提取物的来源花青素包括矢车菊素、飞燕草素、锦葵色素、天竺葵素、芍药花素和矮牵牛素。
4.根据权利要求1所述的药物组合物,其特征在于,所述花色苷提取物通过以下方法制备得到:白刺果实或白刺果实榨汁后所产生的果渣,按照1:15-1:30g/mL的料液比加入60~90%乙醇,在55-65℃条件下提取30-90分钟;提取液减压浓缩至无醇后,经弱极性大孔吸附树脂分离,以三倍柱体积的水冲洗,然后以60~90%乙醇冲洗,收集流出物,浓缩干燥,即所述花色苷提取物。
5.根据权利要求1所述的药物组合物,其特征在于,所述蒽环类药物为阿霉素、柔红霉素、阿克拉霉素、表柔比星、吡柔比星、伊达比星、戊柔比星或米托蒽醌中的一种或多种。
6.根据权利要求1所述的药物组合物,其特征在于,药物组合物的剂型为胶囊、片剂、口服液、颗粒剂、滴丸中的任意一种。
7.一种花色苷提取物在制备防治蒽环类药物心肌细胞毒性的药物组合物中的应用,其特征在于,所述花色苷提取物是指从蒺藜科白刺属植物的成熟果实中获得的总花色苷含量大于700mg CGE/g、总抗氧化能力大于200mg TE/g的提取物。
8.根据权利要求7所述的应用,其特征在于,所述花色苷提取物的来源花青素包括矢车菊素、飞燕草素、锦葵色素、天竺葵素、芍药花素和矮牵牛素。
9.根据权利要求7所述的应用,其特征在于,所述花色苷提取物包括选自由矢车菊素-3-O-二葡糖苷、矢车菊素-3-O-桑布双糖苷、矢车菊素-3-O-(顺式-6”-O-香豆酰基)-二葡糖苷、矢车菊素-3-O-(反式-6”-O-香豆酰基)-二葡糖苷、矢车菊素-3-O-(6”-O-香豆酰基)-葡糖苷、飞燕草素-3-O-(6”-O-香豆酰基)-葡糖苷,5-O-葡糖苷、飞燕草素-3-O-(6”-O-香豆酰基)-葡糖苷、锦葵色素-3-O-葡糖苷、锦葵色素-3-O-(6”-O-乙酰基)-葡糖苷、锦葵色素-3-O-(6”-O-香豆酰基)-葡糖苷,5-O-葡糖苷、锦葵色素-3-O-(顺式-6”-O-香豆酰基)-葡糖苷、锦葵色素-3-O-(反式-6”-O-香豆酰基)-葡糖苷、天竺葵色素-3-O-(6”-O-香豆酰基)-二葡糖苷、芍药色素-3-O-(6”-O-香豆酰基)-葡糖苷、芍药色素-3-O-(6”-O-香豆酰基)-葡糖苷,5-O-葡糖苷和牵牛花色素-3-O-(6”-O-香豆酰基)-葡糖苷组成的组中的六种或六种以上,且所述花色苷提取物的来源花青素包括矢车菊素、飞燕草素、锦葵色素、天竺葵素、芍药花素和矮牵牛素。
10.根据权利要求7所述的应用,其特征在于,所述花色苷提取物通过以下方法制备得到:白刺果实或白刺果实榨汁后所产生的果渣,按照1:15-1:30g/mL的料液比加入60~90%乙醇,在55-65℃条件下提取30-90分钟;提取液减压浓缩至无醇后,经弱极性大孔吸附树脂分离,以三倍柱体积的水冲洗,然后以60~90%乙醇冲洗,收集流出物,浓缩干燥,即所述花色苷提取物。
11.根据权利要求7所述的应用,其特征在于,所述蒽环类药物为阿霉素、柔红霉素、阿克拉霉素、表柔比星、吡柔比星、伊达比星、戊柔比星或米托蒽醌中的一种或多种。
12.根据权利要求7所述的应用,其特征在于,所述药物为药物组合物的剂型为胶囊、片剂、口服液、颗粒剂、滴丸中的任意一种。
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