CN101951934A - 用于防治心血管疾病的含有三桠乌药提取物的组合物 - Google Patents
用于防治心血管疾病的含有三桠乌药提取物的组合物 Download PDFInfo
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- CN101951934A CN101951934A CN2008801250717A CN200880125071A CN101951934A CN 101951934 A CN101951934 A CN 101951934A CN 2008801250717 A CN2008801250717 A CN 2008801250717A CN 200880125071 A CN200880125071 A CN 200880125071A CN 101951934 A CN101951934 A CN 101951934A
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- lindera obtusiloba
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Abstract
本发明涉及用于防治心血管疾病的组合物,所述组合物含有三桠乌药(lindera obtusiloba)的提取物。更具体地,所述三桠乌药提取物能强烈抑制作为血管病主要诱因的NAD(P)H氧化酶,并同时调节血管平滑肌的收缩和舒张,表现出强力的舒张血管效应,从而能改善血压调节以及血管内皮功能障碍。因此,含有三桠乌药提取物作为活性成分的组合物可有效地用于防治心血管疾病。
Description
技术领域
本发明涉及一种用于防治心血管病的含有三桠乌药(Lindera obtusiloba)的提取物的组合物,以及功能保健食品。更具体地,本发明的特点是含有三桠乌药的提取物作为活性成分,所述提取物通过直接抑制NAD(P)H氧化酶抑制氧化应激,同时激活内皮型一氧化氮合酶,从而调节血管平滑肌细胞的收缩和舒张,具有防治心血管疾病的作用。
背景技术
根据世界卫生卫生组织的统计信息(WHO)的报告,1999年,世界范围内心血管疾病的死亡率为30%或更高,到2010年,在发达国家心血管疾病将成为致死率排名第一的疾病,而在亚洲国家包括日本、韩国等,心血管疾病的增长率尤其高。人们推测这是由于冠状动脉疾病的危险因素增加所致,是正在到来的老龄化社会、饮食习惯的改变等因素导致的结果。
内皮功能障碍是诱导范围广泛的心血管疾病,包括高血压、动脉硬化、高血脂、糖尿病、肥胖等的主要机制(Brunner H.等,J.Hypertens.,2005,23:233-246),在1990年,人们就已经发现高血压患者的血管异常舒张(Panza JA等,New England Journal of Medicine,323:22-27,1990)。内皮细胞为沿着血管和淋巴管腔排列的上皮细胞,其主要功能为生成血管舒张物质和血管舒张介质以调节血管张力和结构。
心血管疾病开始时表现为内皮功能障碍并最终导致心脏和血管系统异常。心血管疾病是心脏和血管中的一组异常的泛称,包括但不限于,动脉硬化、高血压、高脂血症、冠状动脉疾病(心脏病)、脑血管疾病(中风、老年痴呆症),周围性血管疾病、心律失常、心力衰竭、充血性心脏病、心肌疾病,等等。
对于导致心血管疾病的主要因素,已知的多种因素为例如遗传因素、生活方式、以及糖尿病并发症。从现代医学的角度看,已知还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)氧化酶活性增加导致活性氧(ROS)和血管的氧化应激增加,以及内皮型一氧化氮合酶(eNOS)减少导致一氧化氮减少为主要因素。由内皮型一氧化氮合酶生成的一氧化氮是一种强力血管舒张因子,通过抑制血小板聚集、血管平滑肌细胞增殖、单核细胞的血管粘附,以及动脉粥样硬化相关蛋白的表达而在心血管系统的整体稳态调节中起到决定性作用(Forstermann等,Circulation,113:1708-1714,2006)。然而,多种因子导致的负责生成血管中活性氧的NADPH氧化酶的增加导致一氧化氮生成的减少[Gryglewski等.,Nature,320:454-456,1986;Paravicini等,Circulation Research,91:54-61,2002;Dusting等,Clinical and Experimental Pharmacology and Physiology,25:S34-41,1998],而且因此生成的活性氧调节粘附分子的表达[Lo等,Am.J.Physiol.,264:L406-412,1993],刺激血管平滑肌细胞(VSMC)的增殖和迁移[Griendling and Ushio-Fukai,J.Lab.Clin.Med.,132:9-15,1998],调节具有氧化能力的脂蛋白等等,从而导致心血管疾病[Lynch and Frei,J.Lipid Res.,34:1745-1753,1993]。此外,NAD(P)H氧化酶引起的血管中活性氧生成增加,与具有动脉粥样硬化和冠状动脉疾病的临床风险因素的患者的内皮一氧化氮(NO)的功能削弱有关。基本上,活性氧的产生导致血管收缩[Guzik等,Cir.Res.,86:E85-90,2000]。
一般来说,通过直接抑制AD(P)H氧化酶造成的活性氧减少、下游活性氧的产生的抑制,以及内皮型一氧化氮合酶的活性诱导被认为是心血管防治中非常重要的靶标[Forstermann等,Circulation,113:1708-1714,2006;Doggrell SA,Drug News Perspect.,17(9)615-632,2004;Inoguchi T.,Curr.Drug Targets,6(4):495-501,2005;Muzaffar S.等,Trends Cardiovasc Med.,15(8):278-282]。
迄今为止,已知二亚苯基碘鎓(DPI)和4-羟基-3-甲氧基苯乙酮(夹竹桃麻素)为抑制NAD(P)H氧化酶的物质[Holland J,等,US5902831]。然而,因为毒性和专一性问题,这些物质尚未投入商用或临床应用。此外,作为一氧化氮调节剂,可用的有硝普钠和硝酸甘油。然而,因为临床应用中出现的抵抗和毒性问题,这些物质也仅在紧急情况下,例如心脏病发作时使用。
同时,三桠乌药为樟科落叶灌木。它长到2-3m高,花期从3月至4月,而结实的季节是9月。压榨果实得到的油已被妇女们用作发油。这种植物被称为姜树,因为当把叶子或树枝扯下来后,它闻起来有姜味,其还被称为傻瓜山茶花(Fool′s Camellia)或矮脚枫(Japanese spicebush)。已知三桠乌药能有效地活化血液、肌肉的慢抽搐以及抗脓肿等,并能治疗血液外渗造成的瘀伤、肿胀和疼痛。它主要用来抵抗胃疼,也用作解热或咳嗽药。私下里,三桠乌药的叶子和芽象茶一样被用来冲泡并拿来用作解热或咳嗽药[Illustrated book of Korean Plants,by Chang-Bok Lee,1980;Illustrated book of Korean Folk Medicine,by Jong-Hee Park,2005,Encyclopedia of Local Medicines].
在对三桠乌药成分的研究方面,Park,Jong-Chul,等(J.Korean Soc.Food Nutr.1996.25(1),p.76-79)从叶子中分离出槲皮素,从树枝中分离出金丝桃苷,而Kwon,Hak-Cheol,等(Archives of Pharmacal Research,22,p.417-422,1999)分离出抗叶酸(actifolin)、pluviatiolol,5,6-二羟基罗汉松树脂酚、(+)-丁香树脂酚,9-O-反式-阿魏酰基-5,5-二甲氧基落叶松树脂醇等等。据报道,分离的各成分的功效包括抗癌作用、消炎作用等等(Planta Medica,69,610-616,2003;Archives of Pharmacal Research,22,p.417-422,1999)。
然而,上述文献未曾披露或教导三桠乌药提取物通过抑制NADPH氧化酶而具有抑制血管氧化应激、舒张血管以及调节血压的作用。
发明内容
技术问题
因此,本发明人使用了大量植物提取物对抑制NAD(P)H氧化酶的活性和舒张作用进行研究,并最终确证了强烈抑制NAD(P)H氧化酶活性、减少血管的氧化应激、直接增强内皮型一氧化氮合酶的活性、舒张血管和调节血压的效果,从而完成了本发明。
本发明的设计是为了解决例如上述的问题,本发明的目的是提供一种防治心血管疾病的组合物,其包括三桠乌药提取物作为活性成分。
本发明的另一个目的是提供一种防治心血管疾病的功能保健食品,其包括三桠乌药提取物作为活性成分。
技术方案
为了实现上述目的,用于防治心血管疾病的组合物具有下述特点:含有三桠乌药的提取物作为活性成分。
所述三桠乌药的提取物优选取自树枝、树叶及其混合物。
所述三桠乌药的提取物优选由选自水、C1-C5低级醇及其混合物的溶剂提取得到。
所述三桠乌药的提取物优选由30-95wt%的乙醇水溶液提取得到。
优选所述三桠乌药的提取物由选自水、C1-C3低级醇及其混合物的溶剂提取,并用丁醇再提取得到。
所述三桠乌药的提取物的特点是具有NAD(P)H氧化酶抑制活性。
所述三桠乌药的提取物的特点是具有血管舒张效用。
所述三桠乌药的提取物的特点是具有增强内皮型一氧化氮合酶活性的效用。
所述三桠乌药的提取物的特点是具有降低血压和减少血管氧化应激的作用。
所述心血管疾病可选自下组:充血性心脏病、冠状动脉疾病(心脏病)、缺血性心脏疾病(心肌缺血)、高脂血症、动脉硬化、高血压、低血压、心律失常、心力衰竭、血管再狭窄、脑血管疾病(中风、老年痴呆症)、周围性血管疾病和代谢性疾病。
同时,防治心血管疾病的功能保健食品的特点是含有三桠乌药提取物作为活性成分。
有益效果
如上所述,本发明的三桠乌药提取物能强烈抑制作为血管病主要病因的NAD(P)H氧化酶,同时显示出强效的舒张血管效应,因此可用于防治心血管疾病的药物组合物或功能性保健食品。
附图说明
图1示出了三桠乌药提取物对猪冠状动脉的血管舒张作用的测定图谱;
图2示出了三桠乌药提取物对白色大鼠主动脉的血管舒张作用的测定图谱;
图3示出了在三桠乌药提取物作用下,内皮型一氧化氮合酶(eNOS)和Akt蛋白的活性水平的测定图谱;
图4示出了三桠乌药提取物对心率的影响水平的测定图谱;
图5示出了在三桠乌药提取物作用下,血管氧化应激减少水平的测定图谱;
图6示出了三桠乌药提取物的细胞毒水平的测定图谱。
具体实施方式
以下将具体描述本发明的优选实施方案。下面对各种特征术语例如具体的组成要素进行了详细说明,但这些只是为了更全面的理解本发明,本领域技术人员容易知道没有这些特征术语也可以实施本发明。此外,在本发明的描述中,如果任何相关的已知功能或组成的具体解释被认为是不必要地使本发明不清楚,则这个具体的解释应予以删除。
本发明的三桠乌药提取物可由如下方式获得。
可使用三桠乌药的地上部分,更具体地,是叶子和树枝,来源形式不限,可以是从自然界收集的植物、培育的植物、市售获得的植物等等。提取用的溶剂选自水、C1-C5低级醇及其混合物。本发明的发明人对三桠乌药的叶子和树枝进行了清洗以去除杂质和盐并对其进行干燥。随后,用极性溶剂例如水或C1-C5低级醇例如甲醇、乙醇或丁醇或其混合物进行提取,混合溶剂的混合比例为约1∶0.1-1∶10,优选使用30-95wt%的乙醇水溶液,溶剂的体积约为三桠乌药样品的5-50倍,优选10-30倍,在50-95℃下提取1小时-7天。重复上述的提取步骤2-5次,优选3次,然后将所得产物减压浓缩和/或冻干,得到三桠乌药粗提物。
在本发明的提取物中,通过下述步骤可获得非极性溶剂可溶的提取物:将前述粗提物悬浮于蒸馏水中,随后加入相当于悬浮液体积0.1-100倍,优选1-5倍的非极性溶剂例如己烷、乙酸乙酯或氯仿,提取分离1-10次,优选2-5次。此外,可再进行常规的分馏步骤(Harborne,J.B.,Phytochemical methods:A guide to modern techniques of plant analysis,3rd Ed.,pp.6-7,1998)。
更优选地,将前述步骤获得的三桠乌药粗提物,优选地,三桠乌药的乙醇水溶液提取物用有机溶剂,例如正丁醇、己烷和乙酸乙酯进行顺序溶剂分提,溶剂的使用顺序为溶剂极性由低至高,优选的顺序为己烷、乙酸乙酯和正丁醇,然后减压浓缩,从而获得己烷、乙酸乙酯和正丁醇馏分。
本发明提供防治心血管疾病的组合物,其含有由上述方法获得的三桠乌药粗提物或非极性溶剂可溶的提取物作为活性成分。
本发明的防治心血管疾病的组合物按重量计含有0.1-99%上述提取物,基于该组合物的总重量。
含有本发明三桠乌药提取物的组合物还可含有组合物制备中常用的合适的载体、赋形剂和稀释剂。
本发明的提取物的药物剂型可以药用盐的形式使用,也可单独使用,或与其它药物活性化合物适当组配以复合物的形式使用。
含有本发明提取物的药物组合物可根据常规方法分别制备成口服制剂例如粉末、颗粒剂、片剂、胶囊剂、悬浮液、乳液、糖浆和气雾剂,也可制成局部制剂、栓剂和无菌注射液后使用。
至于可包含于含提取物的组合物的载体、赋形剂和稀释剂,可提及的有乳糖、右旋糖、蔗糖、山梨醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯胶、海藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、非结晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石粉、硬脂酸镁,及矿物油。
就制剂的配制而言,可使用常规使用的稀释剂或赋形剂,例如填充剂、膨胀剂、粘合剂、润湿剂、崩解剂和表面活性剂。
口服固体制剂的示例包括片剂、丸剂、粉剂、颗粒剂、胶囊等,这些固体制剂通过混合至少一种赋形剂例如,淀粉、碳酸钙、蔗糖、乳糖、明胶等前述提取物中制得。此外,除了简单的赋形剂之外,也可使用乳化剂例如硬脂酸镁和滑石粉。
口服液体制剂的示例包括悬浮液、内用液体、乳液、糖浆等。这些液体制剂可包括各种赋形剂,例如,润湿剂、甜味剂、香精、防腐剂等,此外,水和液体石蜡是常规使用的简单稀释剂。
胃肠外给药的制剂的示例包括菌水溶液、非水溶液、悬浮液、乳液、冻干制剂和栓剂。作为非水溶剂或悬浮剂,可使用丙二醇、聚乙二醇、植物油如橄榄油、注射酯如油酸乙酯等。作为栓剂的底料,半合成脂肪酸酯(witepsol)、聚乙二醇、吐温、可可黄油、月桂精脂肪(laurin fat)、甘油明胶等均可使用。
本发明提取物优选的给药剂量可根据患者体重、疾病的严重程度、药物剂型、给药途经和周期变化有所不同,但可由本领域技术人员对此进行适当的选择。然而,为了得到更好的效果,施予本发明提取物的理想的剂量为每天0.0001-100mg/kg,优选0.001-100mg/kg。可一天给药一次或一天给药七次。给药剂量绝不限于本发明的范围。
本发明提供一种功能保健食品,其含有具有预防心血管疾病作用的前述提取物,和可食用的食品添加剂。
对于可添加三桠乌药提取物的功能保健食品。例如,可提及各种普通食品、饮料、口香糖、茶叶、维生素复合物等。
为了获得预防心血管疾病的效果,也可将三桠乌药提取物添加到食品或饮料中。在这种情况下,食品或饮料中的提取物含量基于食品的总重量为0.01-15%。保健饮料中的提取物含量相对于饮料的总重量100g可为0.02-5g,优选0.3-1g。
本发明的功能保健饮料组合物除了含有指定比例的提取物作为必需成分外,对含有的其它组分并不特别限定,其可含有其它成分,例如传统饮料常用的各种芳香剂或天然碳水化合物。上述天然碳水化合物的示例包括常见的糖,例如单糖,例如葡萄糖,果糖等,双糖,例如麦芽糖,蔗糖等,以及多糖,如糊精,环糊精等,和糖醇例如木糖醇、山梨醇和赤藓糖醇。除了前述的试剂之外,可作为芳香剂善加使用的还有奇异果甜蛋白、甜叶菊提取物,例如莱鲍迪甙A(levaudioside A)、甘草酸等;以及合成的芳香剂,如,糖精、阿斯巴甜等。碳水化合物的比例通常为每100克本发明的组合物,约1至20克,优选约5至12克。
除了这些,本发明的提取物可含有各种营养素、维生素、矿物质(电解质)、合成和天然芳香剂、着色剂和加重剂(奶酪、巧克力等)、果胶酸及其盐、藻朊酸及其盐、有机酸,保护性胶体增稠剂、pH值调节剂、稳定剂、防腐剂、甘油、醇,用于碳酸饮料的碳酸化剂等等。除了这些之外,本发明的提取物可含有天然果汁、以及制备果汁饮料和蔬菜饮料用的果肉。这些成分可以单独或组合使用。在这种情况下,添加剂的比例并不重要,但通常选择每100重量份本发明的提取物,含0.01至约20份添加剂。
以下,将参照下述实施例和实验例对本发明作更具体地描述。实施例1:三桠乌药粗提物的制备
将从江原道(Kangwon-do)省采集的三桠乌药的树枝和叶子用水冲洗去除杂质和盐。然后干燥粉碎。在提取容器中,加入每份25g粉碎的三桠乌药的树枝或粉碎的树叶,和总量500mi 70wt%的乙醇水溶液,在回流冷却下于70℃进行热提取,重复三次,每次三小时。所得产物用滤纸过滤,并将滤液在40℃水浴中减压浓缩并冻干。结果,得到了6.4g三桠乌药树枝粗提物和7.0g三桠乌药树叶粗提物。
实施例2:三桠乌药粗提物的馏分的制备
将实施例1获得的三桠乌药的叶和枝的粗提物,每份5g,分别悬浮于50ml纯净水中,按己烷、乙酸乙酯和正丁醇的顺序,每种溶剂50ml,对所得产物分别进行顺序溶剂分提,提取三次,分别得到各溶剂的馏分,将这些馏分减压浓缩。结果得到了三桠乌药的己烷馏分、乙酸乙酯馏分和正丁醇馏分。
实验例1:三桠乌药粗提物对NAD(P)H氧化酶活性的抑制效果的测定
对上述实施例1和实施例2得到的三桠乌药粗提物和馏分抑制NAD(P)H氧化酶活性的效果进行测定,NAD(P)H 氧 化 酶为心血管疾病发展的指标酶。为此目的,采用大白鼠的动脉平滑肌细胞(大鼠动脉平滑肌细胞 ;RASMC)和牛血管内皮细胞(牛主动脉内皮细胞 ;BAECs)比较NAD(P)H氧化酶活性的变化。结果参见表1。首先,将动脉平滑肌细胞和血管内皮细胞分别与MEM(最基本培养基)、DMEM ( Dulbecco’s最基本培养基) 和10%FBS (胎牛血清)溶液混合,并将这些细胞在5%CO2/37℃条件下分别置于96孔板中培养24小时。然后在不含FBS的培养液中再培养24小时。稳定细胞后,将其用HBSS(Hank′s平衡盐溶液)冲洗。将这些细胞与实施例1获得的三桠乌药的树叶提取物或树枝提取物一起振荡,然后使所得混合物反应15分钟,再用HBSS冲洗。随后,向反应液中加入100mMNAD(P)H和5μM 光泽精(Lucigenin),使用荧光读数器(Victor Light,PerkinElmer)测量NAD(P)H氧化酶的活性1小时。本实验重复3次,而每次操作重复2-7次。随后比较对照组 和样品处理组的活性,计算IC50值。IC50值为实验材料的浓度,以μg/ml表示,在此浓度下,50%NAD(P)H氧化酶活性受到抑制。
【表1】
三桠乌药提取物对NAD(P)H氧化酶活性的抑制效果(单位:μg/ml)
IC50(BAECs) | IC50(RASMC) | |
三桠乌药的树枝粗提物 | 2.1 | 2.0 |
三桠乌药树枝的丁醇馏分 | 0.9 | 1.5 |
三桠乌药树枝的乙酸乙酯馏分 | 1.0 | 2.5 |
三桠乌药树枝的己烷馏分 | 10.5 | >30 |
如表1所示,可以看出本发明的三桠乌药粗提物在抑制血管细胞的NAD(P)H氧化酶活性方面具有极好的效果。此外,在这些馏分中,可以看到正丁醇提取物显示出极好的效果。
实验例2:三桠乌药提取物的血管舒张作用的测定(冠状动脉和主动
脉)
对实施例1和实施例2制备的三桠乌药粗提物和馏分的血管舒张作用进行确证。为实现此目的,对猪心脏的冠状动脉和大鼠主动脉的舒张作用进行了比较,结果示于表1、图2、表2(冠状动脉)和表3(主动脉)。冠状动脉取自屠宰场宰杀后即刻购买得到的猪心脏。主动脉取自雄性SD(Sprague-Dawley)大白鼠,将其浸在含有18mMNaCl,4.7mM KCl,1.1mM MgSO4,1.2mM KH2PO4,1.5mM CaCl2,25mM NaHCO3和10mM葡萄糖的Krebs溶液中(pH 7.4)
以去除结缔组织和脂肪,然后切成长度约为3mm的样品。
将制备的冠状动脉和主动脉样品固定于37℃的Krebs溶液中,该溶液已用95%O2和5%CO2气体充饱和。用装配有压力移动传感器(Hugo Sachs,Germany)的Grass生理记录仪(Grass physiograph)(Hugo Sachs,Germany)测量样品的等长张力。对于冠状动脉,首先使用U46619(1-60nM),一种血栓素衍生物,将动脉收缩至最大血管收缩的80%。这之后10分钟,用10μM乙酰胆碱舒张主动脉,测定血管内皮细胞的安全性。然后用Krebs溶液冲洗主动脉三次以进行试验。通过下述步骤测量血管舒张作用的变化:首先用药物U46619收缩动脉,然后以浓度依赖性的方式测定三桠乌药提取物诱导的舒张反应。
对于大白鼠的主动脉,用苯肾上腺素将主动脉收缩至最大血管收缩的80%。这之后15分钟,用300nM缓激肽(Bradykinin)舒张动脉,测定血管内皮细胞的安全性。然后用Krebs溶液冲洗动脉三次以进行试验。通过下述步骤测量血管舒张作用的变化:首先用药物苯肾上腺素收缩主动脉,然后以浓度依赖性的方式测定三桠乌药粗提物和馏分提取物诱导的舒张反应。采用取自5-10个不同个体的的血管重复进行实验。ED50值是指样品的浓度(μg/ml),在此浓度下,用样品处理的结果为收缩的血管显示出50%的血管舒张作用。
【表2】
三桠乌药提取物对猪冠状动脉的舒张作用(单位:μg/ml)
ED50 | |
三桠乌药的树叶粗提物 | 59.4 |
三桠乌药的树枝粗提物 | 12.9 |
三桠乌药树叶的丁醇馏分 | 18.6 |
三桠乌药树叶的乙酸乙酯馏分 | >100 |
三桠乌药树叶的己烷馏分 | >100 |
三桠乌药树枝的丁醇馏分 | 6.4 |
三桠乌药树枝的乙酸乙酯馏分 | 71.1 |
【表3】
三桠乌药提取物对白大鼠主动脉的舒张作用(单位:μg/ml)
ED50 | |
三桠乌药树叶粗提物 | 14.8 |
三桠乌药树枝粗提物 | 5.0 |
三桠乌药树叶的丁醇馏分 | 5.4 |
三桠乌药树叶的乙酸乙酯馏分 | 48.3 |
三桠乌药树叶的己烷馏分 | 79.6 |
三桠乌药树枝的丁醇馏分 | 1.7 |
三桠乌药树枝的乙酸乙酯馏分 | 15.0 |
三桠乌药树枝的己烷馏分 | 95.0 |
实验结果示于图1和图2,本发明的三桠乌药提取物在浓度为1-10μg/ml时开始表现显著舒张作用,在浓度为30μg/ml时达到94±2%舒张效果。如表1和表2所示,可以看到三桠乌药提取物具有极好的舒张冠状动脉和主动脉血管的作用。在这些馏分中,可以看到正丁醇提取物表现出极好的效果。
实验例3:三桠乌药提取物对内皮型一氧化氮合酶活性作用的试验
观察实施例1和实施例2制备的三桠乌药粗提物对增强内皮型一氧化氮合酶活性的作用。基于内皮型一氧化氮合酶(eNOS)的丝氨酸残基和牛主动脉内皮细胞的Akt的丝氨酸残基473的磷酸化作用,对前述作用进行比较。结果示于图3。
首先,将动脉平滑肌细胞和血管内皮细胞与DMEM(Dulbecco’s最基本培养基)和10%FBS(胎牛血清)溶液混合并培养,然后在不含FBS的培养液中再培养24小时。稳定细胞后,用各自浓度下的样品处理细胞,然后反应30分钟。接着,提取蛋白冰离心,收集上清液以去除细碎片。提取的蛋白在SDS-聚丙烯酰胺凝胶上进行电泳,然后将凝胶中的蛋白用硝酸纤维膜进行印迹。用3%BSA封闭1小时后,将磷酸化-内皮型一氧化氮合酶(phospho-eNOS)和磷酸化-Akt(phospho-Akt)(Cell Signaling,the USA)以1∶1,000的比例在4℃下培养过夜。随后,对以1∶2000比例稀释的二级抗体进行处理并在环境温度下培养1小时,然后,通过化学荧光使二级抗体显像。
结果如图3所示,看以看到三桠乌药提取物表现出很强的增强能生成一氧化氮的内皮型一氧化氮合酶(phospho-eNOS)活化的作用,所述内皮型一氧化氮合酶能生成一氧化氮,并能增强上游调控因子Akt(phospho-Akt)的活化。
实验例4:心血管疾病动物模型中的三桠乌药提取物的作用检测
对由实施例2获得的三桠乌药提取物所引起的对患病动物的低血作用、改善血管氧化应激的作用以及改善内皮功能障碍的作用进行确证。为实现此目的,对由血管紧张素2诱导的患病动物模型的作用的程度进行比较,结果示于图4、图5、图6和表4。
雄性SD(Sprague-Dawley,6周龄)白色大鼠购自Orientbio,Inc.,并使这些大鼠适应环境一周,同时在可调节为明暗各12小时周期的小型动物饲喂室中随时向其供应固体饲料和水。然后将大鼠任意分为对照组和血管紧张素2处理组,每组包括6只动物。用血管紧张素2处理前的三天里,将实施例2获得的三桠乌药提取物以100mg/kg的浓度分别悬浮于0.5%CMC(羧甲基纤维素)中,经口给予该悬浮液,每天2次。对照组仅服用0.5%CMC。将血管紧张素2以65ng/min/kg的浓度溶于生理盐水,并将所得溶液置于微型渗透泵中(Alzet Model 2002)。麻醉白色大鼠,通过切开皮肤,并将微型泵插入到肩胛区进行血管紧张素2处理。在开始口服给药的同时测量血压,两天测定一次,测定两周,在早晨口服给药后一小时进行。样品预先在45-50℃下加热约10分钟,然后以非侵入方式通过尾套体积描记法采用自动血压记录系统测量最高压(心脏收缩压)。同时测量心率。
按实验例2相同的方式取主动脉,以DHE ( 二 氢 乙 锭 )引起的染色程度和乙酰胆碱诱导的舒张程度为特征测量血管氧化应激和血管内皮功能障碍的程度。将检测结果与对照组的结果进行比较。
【表4】
三桠乌药提取物的低压作用(单位:mmHg)
第1天 | 第7天 | 第14天 | |
对照 | 107.6 | 107.4 | 112.6 |
血管紧张素2 | 110.3 | 169.6 | 158.3 |
三桠乌药的树枝提取物 | 113.9 | 129.7 | 127.4 |
三桠乌药的树叶提取物 | 112.5 | 144.2 | 145.4 |
如实验结果所示,由表4可以看出血管紧张素2诱导的测试动物的血压升高通过服用三桠乌药提取物受到显著抑制。
测定到心率升高,结果示于图4,证实三桠乌药提取物对心脏没有副作用,例如心跳过速。
如图5所示,可以看到血管紧张素2诱导血管氧化应激的增加通过服用三桠乌药提取物受到显著抑制(图5为照片黑白变化的产物,红色表示目标,黑色表示背景,变化时,使背景变白以更清楚地与目标区分开来)。
将用血管紧张素2处理的动物中由0.01μM乙酰胆碱诱导的舒张与对照组的进行比较。发现在舒张不能顺利发生的地方发生血管内皮功能障碍(对照组-27%,乙酰胆碱组-8%)。可以看出,通过服用三桠乌药的树枝提取物(20%)和树叶提取物(19%),内皮功能障碍得到改善。
实验例5:三桠乌药提取物的细胞毒检测
对实施例1和实施例2制备的三桠乌药粗提物的细胞毒程度进行比较,结果示于图6。
首先,将动脉平滑肌细胞和血管内皮细胞与MEM(最基本培养基)和10%FBS(胎牛血清)溶液混合,将这些细胞在5%CO2/37℃的条件下培养24小时。稳定细胞后,用实施例2获得的三桠乌药提取物处理细胞,振荡,并反应24小时。此后,在MTS溶液(CellTiter 96 Aqueous One Solution,Promega)存在下培养细胞1小时,然后测量490nm处的吸光度。
如图6所示,可以看到,未发现本发明的三桠乌药提取物对细胞的存活有影响,它是一种非常安全的药物。
实验例6:数据处理
对实验结果进行t-检验和单向方差分析确定实验结果的显著性,p为0.05或更小时,具有显著性差异。
下面将对含有本发明提取物的药物组合物和功能保健食品的制备例进行描述,但本发明并不限于这些制备例,只是对它们进行具体描述。
制备例1:粉剂的制备
三桠乌药提取物粉末20mg
乳糖100mg
滑石10mg
将这些成分混合并填充到密封包中,从而制得粉剂。
制备例2:片剂的制备
三桠乌药提取物粉末10mg
玉米淀粉100mg
乳糖100mg
硬脂酸镁2mg
将这些成分混合,然后按照常规的片剂制备方法制片,从而制得片剂。
制备例3:胶囊剂的制备
三桠乌药提取物粉末10mg
结晶纤维素3mg
乳糖14.8mg
硬脂酸镁2mg
根据常规的胶囊剂的制备方法,将这些成分混合并填充入胶囊,从而制得胶囊剂。
制备例4:注射制剂的制备
三桠乌药提取物粉末10mg
甘露醇180mg
注射用无菌蒸馏水2794mg
Na2HPO412H2O 26mg
根据常规的注射制剂的制备方法,按前述组分配比制得注射制剂,每安瓿2ml。
制备例5:液体制剂的制备
三桠乌药提取物粉末10mg
高果糖玉米糖浆10g
甘露醇5g
纯净水 适量
根据常规的液体制剂的制备方法,添加各成分并溶于纯净水中,向其中加入适量的柠檬芳香剂,混合各成分。加纯净水将总量调至100ml。所得溶液填充到棕色瓶中,灭菌,从而制得液体制剂。
制备例6:保储饮料的制备
三桠乌药提取物粉末10mg
维生素C 15g
维生素E(粉)100g
乳酸铁19.75g
氧化锌3.5g
烟酰胺3.5g
维生素A 0.2g
维生素B10.25g
维生素B20.3g
水适量
根据常规的健康饮料制备方法,混合各成分,搅拌下将所得混合物在85℃加热约一个小时,过滤。将滤液置于2升容器中,密封、灭菌并冷藏,这被用于制备本发明的保健饮料。在上述配比中,将相对适于制备风味饮料的的成分混合并配成优选实施例。然而,该混合比例可根据地域和种族的偏爱,例如消费阶层或消费者的国别,用途等,任意改变。
Claims (10)
1.一种用于防治心血管疾病的组合物,其含有三桠乌药(Lindera obtusiloba)的提取物作为活性成分。
2.根据权利要求1所述的防治心血管疾病的组合物,其中所述三桠乌药选自树枝、树叶及其混合物。
3.根据权利要求1所述的防治心血管疾病的组合物,其中,所述三桠乌药的提取物由选自水、C1-C5低级醇及其混合物的溶剂提取得到。
4.根据权利要求3所述的防治心血管疾病的组合物,其中,所述三桠乌药的提取物由30-95wt%的乙醇水溶液提取得到。
5.根据权利要求3所述的防治心血管疾病的组合物,其中,所述三桠乌药的提取物由选自水、C1-C3低级醇及其混合物的溶剂提取,并用丁醇再提取得到。
6.根据权利要求1所述的防治心血管疾病的组合物,其中,所述三桠乌药的提取物具有NAD(P)H氧化酶抑制活性。
7.根据权利要求1所述的防治心血管疾病的组合物,其中,所述三桠乌药的提取物具有血管舒张作用。
8.根据权利要求1所述的防治心血管疾病的组合物,其中,所述三桠乌药的提取物具有增强内皮型一氧化氮合酶活性的作用。
9.根据权利要求1-8任一项所述的防治心血管疾病的组合物,其中,所述心血管疾病选自下组:充血性心脏病、冠状动脉疾病(心脏病)、缺血性心脏疾病(心肌缺血)、高脂血症、动脉硬化、高血压、低血压、心律失常、心力衰竭、血管再狭窄、脑血管疾病(中风、老年痴呆症)、周围性血管疾病和代谢性疾病。
10.一种用于预防心血管疾病的功能保健食品,其含有活性成分三桠乌药提取物。
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PCT/KR2008/007484 WO2009091120A2 (en) | 2008-01-18 | 2008-12-17 | Composition comprising the extracts of lindera obtusiloba for prevention and treatment of cardiovascular diseases |
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KR101283810B1 (ko) * | 2011-04-13 | 2013-07-08 | 고려대학교 산학협력단 | 생강나무로부터 쿼세틴-3-0-알파-람노사이드 및 캠페롤-3-0-알파-람노사이드의 분리 방법 및 그것의 항산화 또는 간 보호 용도 |
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KR102016078B1 (ko) | 2012-11-30 | 2019-08-30 | (주)아모레퍼시픽 | 심장 질환 예방 또는 치료용 조성물 |
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KR102232330B1 (ko) * | 2018-02-21 | 2021-03-26 | 경북대학교 산학협력단 | 생강나무 잎 추출물을 유효성분으로 포함하는 비만 또는 비만 관련 합병증의 예방, 치료, 또는 개선용 조성물 |
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