CN110292596A - 黑树莓花色苷在制备抗肝损伤药物或保健食品中的应用 - Google Patents
黑树莓花色苷在制备抗肝损伤药物或保健食品中的应用 Download PDFInfo
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- CN110292596A CN110292596A CN201910737858.9A CN201910737858A CN110292596A CN 110292596 A CN110292596 A CN 110292596A CN 201910737858 A CN201910737858 A CN 201910737858A CN 110292596 A CN110292596 A CN 110292596A
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- black raspberry
- anthocyanin
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Abstract
本发明属于医药技术领域,公开了黑树莓花色苷在制备抗肝损伤药物中的应用。黑树莓花色苷为黑树莓提取物中富含花色苷的成分,具有治疗肝损伤的作用,其有效剂量为25‑100mg/kg/d。小鼠体内研究表明,黑树莓花色苷能够降低化学性肝损伤的危害,显著降低小鼠血清中AST、ALT、CHOL、LDL、TBIL的水平,同时小鼠肝脏病理切片显示黑树莓花色苷能够显著逆转肝损伤的趋势。因此,黑树莓花色苷可以很好地应用于抗肝损伤的药物及保健食品中。
Description
技术领域
本发明主要属于天然产物化学领域,主要涉及黑树莓花色苷在制备抗肝损伤药物或保健食品中的应用,具体涉及黑树莓(包括黑树莓果实,黑树莓叶)中富含花色苷的部分在制备抗肝损伤药物和保健食品中的应用。
背景技术
肝脏是身体内以代谢功能为主的一个器官,并在身体里起着去氧化、储存肝糖、分泌性蛋白质的合成等作用。肝脏是人体最大的器官,也是人体消化系统中最大的消化腺。
根据发病原因,肝损伤主要分为病毒性、化学性以及酒精性三类。肝病直接影响着人们的生活和身体健康,严重的还会威胁人的生命。肝脏疾病主要包括甲肝、乙肝、丙肝、肝硬化、脂肪肝、肝癌、酒精肝等。常见的肝脏疾病临床表现多种多样,主要有黄疸、胆汁淤积、肝肿大、门静脉高压、肝腹水、肝性疾病以及肝衰竭。
随着人民的生活水平不断提高,酒精消费人群在我国逐年升高,酒精滥用和酒精依赖已经成为当今世界日益严重的公共卫生问题。长时间的酒精摄入会导致消化系统、循环系统、泌尿系统、血液系统受损。据世界卫生组织2009年的统计,酒精引发的疾病在世界居于领先地位。2010年全世界患有慢性酒精性肝损伤的人数高达49.3万人次,占全世界死亡人数的0.9%。2011年中国酿酒行业总产量为7103千万升,同比增长13.42%,我国酒精性肝损伤的发病也呈现逐年攀升趋势,酒精性肝损伤也成为继肝炎后的又一大肝脏疾病。我国酒精性肝损伤呈发病率逐年增高、肝脏损害程度加重、受损功能器官增多等态势,己对我国人群健康造成系统性危害。现在很多肝脏疾病患者,都是因为长期过量饮酒而引发的,如果不及时进行控制和治疗,可能会发展成为脂肪肝、肝硬化、肝癌等疾病。
肝硬化是由多种原因引起的慢性进行性肝病,其中毒性肝炎是我国导致肝硬化的首要病因,约60-80%来自慢性乙型肝炎、慢性丙型肝炎或慢性丁型肝炎病毒感染。大量肝细胞坏死和肝纤维化的极性或亚急性肝炎都可以直接发展成为肝硬化。
肝硬化腹水俗称肝腹水。正常人腹腔内有少量的游离腹水,一般为50毫升左右,起着维持脏器间润滑作用,当腹腔内出现过多游离液体时,称为腹水。肝硬化腹水是一种慢性肝病。由大块型、结节型、弥漫型的肝细胞性变,坏死、再生;再生、坏死,促使组织纤维增生和瘢痕的收缩,致使肝质变硬,形成肝硬化。肝硬化肝功能减退引起门静脉高压,导致脾肿大,对蛋白质和维生素的不吸收而渗漏出的蛋白液,形成了腹水症。腹水最常见的病因是肝硬化,特别是酒精肝硬化。
肝纤维化是一个病理生理过程,是指由各种致病因子所致肝内结缔组织异常增生。任何肝脏损伤在肝脏修复愈合的过程中都有肝纤维化的过程,如果损伤因素长期不能去除,纤维化的过程长期持续就会发展成肝硬化。
肝炎是肝脏炎症的统称。通常是指多种致病因素,如病毒、细菌、寄生虫、化学毒物、酒精、自身免疫因素等使肝脏细胞受到破坏,肝脏功能受到损害,引起身体一系列不适症状,以及肝功能指标的异常。
酒精性肝损伤的发病原因非常复杂,多种因素可能参与酒精性肝损伤的发生发展。涉及酒精性肝损伤的发生与发展,还与营养遗传因素密切相关。长期过量饮酒是酒精性肝损伤发生的必备条件,酒精性肝损伤与乙醇的消耗量及饮酒时间有关。乙醇的摄入会引起一系列的肝功能紊乱,如脂肪肝,酒精性肝炎,肝纤维化,肝硬化以及增加肝癌的发病率。这些都严重危害着人类的健康,目前发病率呈年轻化趋势发展,已引起了全球广泛的关注,也成为了亟待解决的健康因素。
黑树莓(Rubus occidentalis L.)为蔷薇科悬钩子属,别名黑马林,紫树莓,是国内外近年兴起的第三代水果之王。黑树莓含有丰富的生物活性物质,花色苷尤为丰富,主要是矢车菊素、矢车菊素-3-桑布双糖苷、矢车菊素3-芸香糖苷、矢车菊素-3-木糖芸香糖苷,矢车菊素-3-丙二酰葡萄糖苷,矢车菊素-3-草酸苷酰葡萄糖苷,花葵素-3-芸香糖苷,芍药素-3-芸香糖苷,花葵素-3-葡萄糖苷。同时含有大量的黄酮、酚酸及挥发性类物质。挥发性物质主要是萜烯,内酯,羰基化合物,酯类以及醇。酚酸类物质主要为水杨酸衍生物,表儿茶素,原儿茶酸,槲皮素-3-葡萄糖苷,槲皮素-3-芸香糖苷,p-香豆酸,鞣花酸甲酯衍生物,柠檬酸衍生物。
黑树莓还含有大量有益于人体健康的氨基酸和有机酸。如异亮氨酸、亮氨酸、缬氨酸、丙氨酸、瓜氨酸、精氨酸、谷氨酸、氨基戊二酸、脯氨酸、谷氨酸盐、天冬酰胺、天冬氨酸、组氨酸、甘氨酸、苯丙氨酸、甘氨酸、酪氨酸。有机酸主要是乳酸、乙酸、3-羟丁酸、丙酮酸、琥珀酸、柠檬酸、抗坏血酸、马来酸、富马酸。
此外,维生素A、C、E和叶酸,以及钙、硒、锌等矿物质在黑树莓中含量也很高。
大量研究证明其具有抗肿瘤、抗癌、抗氧化、抗炎、抗血管生成、修复DNA损伤、降血脂、降血糖、调节免疫、肝保护等广泛的生物活性,有重要的研究价值。
现有技术中,并未有黑树莓或其提取物或富含花色苷的部分在治疗肝硬化、肝腹水、肝炎、酒精性肝损伤等方面的相关的报道。
发明内容
本发明的目的是提供黑树莓花色苷在制备抗肝损伤药物或保健食品中的应用。
进一步地,
本发明提供了黑树莓花色苷在制备抗酒精性肝损伤药物或保健食品中的应用。
所述的黑树莓花色苷通过如下方法制备:采用70-75%乙醇对黑树莓冻干粉进行提取得到黑树莓乙醇提取物,接着采用聚酰胺柱色谱对黑树莓提取物进行纯化,采用10%乙醇除杂以及30%乙醇进行洗脱,并收集30%乙醇浓度洗脱馏分。
本发明提供的抗酒精性肝损伤的药物制剂或保健食品,以黑树莓花色苷是主要有效成分,其总有效剂量为25-100mg/kg/d。
本发明所提供的黑树莓花色苷的部分主要为聚酰胺柱层析30%乙醇洗脱部分。
本发明所提供的黑树莓花色苷可以与药学上可接受的载体制备临床上可接受的药物制剂,所述的药物剂型可为颗粒剂、片剂、胶囊剂、口服液或散剂。
本发明所提供的黑树莓富含花色苷部分可以与国家许可添加的食用级可接受的辅料制备成保健食品。
本发明的主要功效是:黑树莓花色苷能够降低肝损伤的危害,同模型组相比较,黑树莓花色苷提取物治疗组能够显著降低小鼠血清中AST、ALT、CHOL、LDL、TBIL的水平,同时小鼠肝脏病理切片显示黑树莓提取物能够显著逆转肝细胞损伤的趋势。
附图说明
图1慢性酒精性肝损伤实验对小鼠体重的影响。
图2慢性酒精性肝损伤实验对小鼠血清指标的影响。
图3慢性酒精性肝损伤病理切片组织观察。
图4CCl4对肝损伤的病理切片组织观察。
具体实施方式
实施案例1:黑树莓提取物的制备方法
精密称量黑树莓冻干粉50g,用10倍体积的75%乙醇进行超声提取3次,每次1h,提取液用布氏漏斗过滤,合并提取液,用旋转蒸发仪进行溶剂回收,得到黑树莓75%乙醇提取部位浸膏。
实施案例2:黑树莓富含花色苷部分的制备方法
将黑树莓75%乙醇提取部位浸膏用10%乙醇进行复溶,复溶后采用聚酰胺进行柱层析,采用10%乙醇除杂,并用30%乙醇进行洗脱,收集30%乙醇洗脱馏分,用旋转蒸发仪进行溶剂回收,得到黑树莓富含花色苷的有效部位,其中含有的主要花色苷为矢车菊素-3-O-葡萄糖苷(2.63mg/g),矢车菊素-3-O-芸香糖苷(16.91mg/g)。
实施案例3:黑树莓花色苷抗肝纤维化活性实验研究
黑树莓富含花色苷部分抗肝纤维化活性实验采用MTT法测试,黑树莓富含花色苷有效部位(100、75、50、25、12.5μg/mL)对人肝星状细胞HSC的抑制活性结果表明,黑树莓提取物在25、50、75、100μmol/L均有很好的抑制癌细胞生长的作用,且优于阳性药四链霉素C,抑制效果呈现剂量依赖性。测试结果如表1所示:
表1黑树莓提取物对HSC细胞抑制活性
实施案例4:黑树莓花色苷对慢性酒精性肝损伤的小鼠实验研究
1.材料与方法
1.1样品:黑树莓富含花色苷的有效部分。
1.2实验动物:昆明种小鼠,雄性,18-22克,每组10只。
1.3实验方法:
1.3.1剂量和分组
设置黑树莓富含花色苷的有效剂量为高(100mg/kg/d)、中(50mg/kg/d)、低(25mg/kg/d)三个剂量组,同时设阴性对照组和模型对照组。
1.3.2受试样品的给予
称取受试样品适量,研磨,溶于0.5%羧甲基纤维素钠溶液中,混合均匀,经口灌胃给予受试样品,并记录每只动物的饲料摄入量或饮水量。连续给予30天。
1.3.3实验步骤
1.3.3.1造模方法
每日经口灌胃给予受试样品,阴性对照组和模型对照组给予纯净水。将动物每周称重两次,以调整受试样品剂量。模型组和样品组于实验结束前14天每天经口灌胃给予30%的乙醇,小鼠灌胃量10mL/kg BW(乙醇密度0.8g/mL,折合乙醇的剂量为2400mg/kgBW)。样品灌胃后间隔4小时以上再给予乙醇。实验结束前禁食4h,经腹腔注射60mg/kg BW的戊巴比妥钠溶液麻醉后,腹主动脉采血,检测血清中胆固醇(CHOL)、血清中低密度脂蛋白胆固醇(LDL)、血清中胆红素(TBIL),并取小鼠肝脏左叶用10%福尔马林固定,从肝左叶中部做横切面取材,常规制片,HE染色,进行各项指标的检测及病理组织学检查。
1.4实验结果
实验结束后,对小鼠体重进行称量,得到模型组小鼠体重较阴性对照组和样品组少(*p<0.05),样品组小鼠体重与对照组相比没有明显的变化。模型对照组与阴性对照组比较,血清CHOL、LDL和TBIL含量明显升高(***p<0.001),且具有统计学意义,造模成功。受试样品组血清CHOL、LDL和TBIL含量与模型对照组比较均有所降低,差异有显著性(#P<0.05),且高剂量组中血清指标接近于阴性对照组,效果优于低剂量组和中剂量组。即本发明抗酒精性肝损伤药物或保健食品对酒精性肝损伤的有一定的辅助保护功能。见表2,表3,图1和图2。
表2慢性酒精性肝损伤对小鼠体重的影响
注:同阴性对照组相比:*p<0.05。
表3慢性酒精性肝损伤对小鼠血清指标的影响
注:同阴性对照组相比:***p<0.001.,同模型组相比:#p<0.05;##,p<0.01;,p<0.001。
1.5镜检
用5倍物镜连续观察整张组织切片,主要观察肝细胞变性、肝细胞坏死和炎症改变等,并同时给予记录。结果见表4.
1.6病理结果
从以上表中可以观察到:模型对照组与阴性对照组比较,肝细胞坏死严重,中央静脉处出现大量的炎症,大面积细胞出现空泡变性,水样变性,且细胞呈堆砌状排列。肝细胞病变程度与阴性对照组比较明显加重,病变增加且有统计学意义(***P<0.001),模型成立。在模型成立的前提下,灌胃给予黑树莓提取物有效部位样品高、中、低任何一个剂量组与模型对照组之间,肝细胞病变程度明显减轻,呈现剂量依赖性,且有统计学意义(*P<0.05),且高剂量组组表现出接近于阴性对照组的效果,表现出最好的保肝活性,即本发明抗酒精性肝损伤药物或保健食品对酒精造成的慢性化学性肝损伤具有辅助保护功能。结果如图3所示。
实施案例5:黑树莓富含花色苷部分抗CCl4肝损伤实验研究
黑树莓富含花色苷部分对小鼠肝纤维化的保护作用:将30只雄性昆明种小鼠随机分为5组:对照组、模型组以及黑树莓富含花色苷部分高、中、低剂量组。模型组和黑树莓富含花色苷部分各剂量组动物腹腔注射CCl4混悬液8mg/kg(2mL/kg),对照组组腹腔注射同容量生理盐水,每周三次,给药三周。黑树莓富含花色苷部分样品各剂量组灌胃给予CMC-Na悬浮液25、50、100mg/kg,对照组和模型组灌胃给予同容量生理盐水,造模同时同给于黑树莓富含花色苷部分样品,每天一次,连续灌胃给药6周。最后一次灌胃给药结束后禁食24h,门静脉取血,取肝脏。静脉血液静置后离心取血清,测定各组血清中AST和ALT水平。肝脏病理标本固定于10%福尔马林溶液中,之后进行HE染色。
实验结果得到:与对照组相比,模型组动物血清中的ALT、ALT含量明显上升(P<0.01)。与模型组相比,黑树莓富含花色苷部分各剂量组动物血清中的AST、ALT含量均有所下降(P<0.05),表明黑树莓花色苷具有改善CCl4引起的肝脏损伤的作用。
病理切片观察结果显示:对照组肝细胞排列整齐、有序,汇管区结构以及肝小叶结构正常。模型组肝细胞排列紊乱,有气球性样变,能够观察到明显的肝损伤。给予黑树莓富含花色苷部分的小鼠组肝细胞结构较模型组正常,有极少量的气球性样变,高剂量组接近于对照组肝细胞,逆转了肝细胞的损伤。结果见图4。
表4 CCl4对小鼠血清中AST、ALT结果的影响
实施案例6:
将黑树莓富含花色苷有效部位干燥后,过筛,进一步根据制剂学常规技术制备成片剂。
实施案例7:
将黑树莓富含花色苷有效部位干燥后,过筛,进一步根据制剂学常规技术制备成丸剂。
实施案例8:
将黑树莓富含花色苷有效部位干燥后,过筛,进一步根据制剂学常规技术制备成胶囊剂。
实施案例9:
将黑树莓富含花色苷有效部位干燥后,过筛,进一步根据制剂学常规技术制备成颗粒剂。
实施案例10:
将黑树莓富含花色苷有效部位干燥后,过筛,进一步根据制剂学常规技术制备成口服液制剂。
实施案例11:
将黑树莓富含花色苷有效部位干燥后,过筛,进一步根据制剂学常规技术制备成膏剂。
实施实例12:
将黑树莓富含花色苷有效部位干燥后,制成单独含有黑树莓花色苷的保健食品或包括国家许可添加的食用级可接受的辅料的保健食品。
Claims (7)
1.黑树莓花色苷在制备抗肝损伤药物或保健食品中的应用。
2.如权利要求1所述的应用,其特征在于,所述的肝损伤为化学性肝损伤、肝纤维化、肝硬化、肝腹水或肝炎。
3.如权利要求1或2所述的应用,其特征在于,所述的黑树莓花色苷为黑树莓冻干粉的乙醇提取物中富含花色苷的部分。
4.如权利要求3所述的应用,其特征在于,所述的黑树莓富含花色苷的部分通过如下方法制备:采用70-75%乙醇对黑树莓冻干粉进行提取得到黑树莓乙醇提取物,接着采用聚酰胺柱色谱对黑树莓提取物进行纯化,采用10%乙醇除杂以及30%乙醇进行洗脱,并收集30%乙醇浓度洗脱馏分。
5.如权利要求1-4任何一项所述的应用,其特征在于,所述的黑树莓花色苷的总有效剂量为25-100mg/kg/d。
6.如权利要求1-5任何一项所述的应用,其特征在于,所述的黑树莓花色苷部分可以与药学上可接受的载体制备成临床上可接受的颗粒剂、片剂、胶囊剂、口服液或散剂。
7.如权利要求1-5任何一项所述的应用,其特征在于,所述的黑树莓富含花色苷部分可以与国家许可添加的食用级可接受的辅料制备成保健食品。
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