CN111658740A - 具有改善年龄相关性黄斑变性的药食两用组合物及其制备方法与应用 - Google Patents
具有改善年龄相关性黄斑变性的药食两用组合物及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开了一种改善年龄相关性黄斑变性的药食两用组合物及其制备方法和应用，它由下列重量份数的原料制成：枸杞子1~5份，山楂4‑8份，黄芪4~8份，益智仁1~5份，铁皮石斛1~5份，牡蛎5~10份，菊花1~5份，葡萄籽原花青素0.01~0.1份，叶黄素0.01~0.1份，牛磺酸0.01~0.1份。本发明提供的药食两用组合物，可改善年龄性黄斑变性，安全性好，可用于制备改善年龄相关性黄斑变性的普通食品或保健品或药品。
Description
技术领域
本发明涉及一种药食两用组合物，特别是涉及一种具有改善年龄相关性黄斑变性的药食两用组合物及其制备方法与应用。
背景技术
各方面资料显示，中国已进入老龄化社会并呈加速态势发展。中国现有老龄人口已超过1.6亿，且每年以近800万的速度增加。预计到2050年，中国老龄人口将达到总人口的三分之一。老年人口的快速增加，特别是80岁以上的高龄老人和失能老人年均100万的增长速度，对老年人的生活照料、康复护理、医疗保健、精神文化等需求日益凸显，养老问题日趋严峻。
在老龄化疾病中，对视力影响最大的疾病是年龄相关性黄斑变性(age-relatedmacular degeneration，AMD)。这是一种影响视网膜黄斑区域，导致视力进行性丢失的疾病。早期AMD的临床症状包括，视网膜出现玻璃疣，视网膜色素异常。晚期AMD有两种临床表现：萎缩性(干性)以视网膜色素上皮细胞(Retinal pigment epithelial,RPE)、感光细胞进行性丢失为特征，占临床病例的85％-90％。渗出性(湿性)，患者眼底视网膜出现以未成熟的脉络膜新生血管发育，并伴有视网膜水肿或视网膜下出血，占临床病例的10％-15％的患者。疾病的晚期，病人可发生严重和永久性视力障碍或失明。AMD主要影响60岁以上的老人，是全球范围内老年人视力不可逆转障碍的主要原因。
目前，在45-85岁范围内，AMD的全球患病率约为8.7％，其中早期患病率约8％，晚期患病率约0.4％。随着人口老龄化加剧，全球范围内，受AMD影响的人数预计将在2040年增加到2.88亿。一项流行病学研究发现，在中国发达城市50岁以上人群中早期AMD患病率为9.5％，晚期AMD患病率为1.0％。
AMD是一种复杂的多因素疾病。目前认为，AMD可能与年龄、种族、家族史、吸烟、体重指数(BMI)、饮食习惯(低维生素C、维生素E、类胡萝卜素、ω-3不饱和脂肪酸摄入和高饱和脂肪酸、高胆固醇摄入)等因素有关。对于湿性AMD，临床上，美国眼科协会(AAO)2019年AMD的临床指南中建议使用抗血管内皮生长因子(VEGF)药物(Ranibizumab、Aflibercept、Brolucizumab)进行玻璃体内注射作为处理的一线治疗方案；对于干性AMD的治疗，国际上尚无批准的临床的药物。随着老龄化社会的推进，考虑到AMD重大的医疗、个人、社会经济成本，AMD迫切需要新的预防和治疗方案。
发明内容
发明目的：本发明的目的在于提供一种安全性好，具有改善年龄相关性黄斑变性作用的药食两用组合物。本发明的另一目的是提供上述组合物的制备方法和应用。
技术方案：为了实现以上目的，本发明采取的技术方案为：
一种具有改善年龄相关性黄斑变性的药食两用组合物，其特征在于，它包括下列重量份数的原料：枸杞子1～5份，山楂4-8份，黄芪4～8份，益智仁1～5份，铁皮石斛1～5份，牡蛎5～10份，菊花1～5份，葡萄籽原花青素0.01～0.1份，叶黄素0.01～0.1份，牛磺酸0.01～0.1份。
在此基础上形成的其较优配方为，它包括下列重量份数的原料：枸杞子2～4份，山楂5-7份，黄芪5～7份，益智仁2～4份，牡蛎6～9份，铁皮石斛2～4份，菊花2～4份，葡萄籽原花青素0.03～0.08份，叶黄素0.03～0.08份，牛磺酸0.03～0.08份。
进一步优化后得到的其最优配方为，它包括下列重量份数的原料：枸杞子3份，山楂6份，黄芪6份，益智仁3份，铁皮石斛3份，牡蛎8份，菊花3份，葡萄籽原花青素0.05份，叶黄素0.05份，牛磺酸0.05份。
本发明所述的具有改善年龄相关性黄斑变性与视疲劳的药食两用组合物的制备方法，包括以下步骤：
(1)按重量份数取枸杞子、山楂、黄芪、益智仁、铁皮石斛、牡蛎、菊花，加入提取溶剂，回流提取，过滤；收集滤液。
(2)取步骤(1)中的药渣，加入提取溶剂，回流提取，过滤；收集滤液。
(3)取步骤(1)与(2)滤液，合并减压浓缩，加入葡萄籽原花青素、叶黄素、牛磺酸，制得组合物。
作为优选方案，步骤(1)所述的回流提取条件为：首先加入药材重量10倍体积量的提取溶剂水，100℃回流提取120min。步骤(2)回流条件为：加入药材重量10倍体积量的提取溶剂水，100℃回流提取120min。
发明优势：本发明是在AMD，尤其是干性AMD缺乏有效药物的情况下。基于中医药理论与AMD的病理机制，优选得到的改善AMD的有效组合物。
中医学将AMD归属于“视直为曲”、“视瞻昏渺”、“暴盲”的范畴。《灵枢·大惑论》曰：“五脏六腑之精气皆上注于目而为之精”；明确了眼睛与脏腑之间的关系，也说明AMD的发生发展与脏腑衰老密切相关。中医认为，AMD的主要病机为：年老体弱，肝肾不足日益加重，阴液亏虚，不能荣养目睛，产生眼底退变。同时，随着年龄增长，脾胃虚损，运化乏力，水谷不归正化，变生水湿，湿聚为痰，痰湿内阻，积聚眼底，变生玻璃膜疣、渗出；脾胃虚损，气血生化乏源，目睛失养，眼底黄斑萎缩；脾气亏虚，统摄乏力，津血溢于脉外，形成眼底出血、渗出，停留眼底，形成瘀血痰湿。因此，基于AMD，治疗应以补益肝肾、健脾利湿、补养气血为主、辅以凉血化瘀、活血明目、软坚散结化痰。
本药食两用组合物中，枸杞子滋肝补肾，益精明目。山楂活血化瘀，健运脾胃。两者相伍，使精血畅通无虞，目睛得养。黄芪补脾益气、益智温脾暖肾，两者相伍，联合山楂，可健脾运，助水谷化生精微，摄血不致妄行。铁皮石斛滋补肝肾阴，牡蛎平肝潜阳，菊花平肝明目，三者相伍，可防阴虚阳亢，虚火上炎而致目睛灼伤。牡蛎又可以其软坚散结之性，消痰湿郁结、使眼底瘀积得散。
从方中药物的现代药理研究来看，枸杞子中玉米黄素可防止老年人黄斑色素减退和玻璃疣的积聚；多糖和类胡萝卜素成分有效保护视网膜色素上皮细胞氧化与炎性损伤；甜菜碱可抑制糖尿病患者视网膜新生血管形成。山楂具有显著的降压、降脂、抗动脉粥样硬化的功效，在改善老年人脂质代谢的同时，又可降低脂质代谢物过氧化作用，保护视网膜微血管。黄芪甲苷与黄芪多糖不仅对视网膜缺血再灌注损伤具有显著保护作用，还可清除氧自由基、减轻视网膜神经节细胞膜的脂质过氧化状态、维持细胞膜的完整性，抑制凋亡。益智仁水提液具有较高的清除过氧化氢、氧自由基功能，并有抗衰老作用。铁皮石斛中的多糖成分具有降低视网膜及整体炎症因子的水平，抑制视网膜血管内皮因子(VEGF)表达，抑制新生血管生长。牡蛎富含锌、镁等微量元素，可降低氧自由基水平。菊花所含的芹菜素、木樨草素等黄酮类成分可保护视网膜色素上皮细胞免于氧化、炎症损伤，减少上述损伤引起的细胞凋亡，保护视网膜上皮色素细胞。
此外，添加的葡萄籽原花青素、叶黄素与牛磺酸均对年龄相关性黄斑变性多有裨益。葡萄籽原花青素，可抑制晶状体氧自由基生成和脂质过氧化，减小毛细血管壁脆性，保护毛细血管物质转运能力，同时防止紫外线诱导的DNA氧化损伤。叶黄素可通过滤过可见光中引起光损伤的短波长光保护视网膜免受损伤，并且可以加强视锥细胞外节膜抗氧化损伤的功能，还可保护视网膜神经节细胞免受缺氧和氧化损伤。牛磺酸可通过改善膜通透性、抗脂质过氧化、提高抗氧化酶活性、抑制细胞凋亡等途径，保护视网膜抵御光损伤，发挥保护作用。
本发明提供的药食两用组合物，动物模型实验结果表明：本发明提供的药食两用组合物可有效降低高氧化应激水平这一导致年龄相关性黄斑变性的最主要病理环节，从而保护动物视网膜免收损伤。细胞模型实验结果表明，本发明提供的药食两用组合物可提高视网膜色素上皮细胞抵御氧化损伤能力，增加视网膜米勒细胞内神经营养因子的表达，从而达到保护视网膜损伤的效果。
本发明所述的具有改善年龄相关性黄斑变性的药食两用组合物在年龄相关性黄斑变性中的应用，将此药食两用组合物制备成食品或保健品或药品可接受的载体制成片剂、丸剂、散剂、汤剂、颗粒剂、煎膏剂或浸膏剂剂型的食品或保健品或药品，临床服用方便。尤其重要的是，该药食两用组合物所有组成药味与成分均为药食两用品种，安全性好，适合长期使用，可以起到预防和改善AMD的效果。
附图说明
图1为药食两用组合物对小鼠血清中ROS影响的柱状图。
图2为药食两用组合物对小鼠血清中MDA影响的柱状图。
图3为药食两用组合物对小鼠血清中SOD活性影响的柱状图。
图4为药食两用组合物对小鼠血清中GSH-Px活性影响的柱状图。
图5为药食两用组合物对小鼠血清中CAT活性影响的柱状图。
图6为药食两用组合物对小鼠视网膜中Nrf2 mRNA表达水平影响的柱状图。
图7为药食两用组合物对小鼠视网膜中HO-1 mRNA表达水平影响的柱状图。
图8为药食两用组合物对小鼠视网膜中NQO-1 mRNA表达水平影响的柱状图。
图9为药食两用组合物对小鼠视网膜中GCL mRNA表达水平影响的柱状图。
图10为药食两用组合物对小鼠视网膜中VEGF表达影响的柱状图。
图11为药食两用组合物对氧化损伤APRE-19细胞存活率影响的柱状图。
图12为药食两用组合物对Müller细胞中BBDNF表达影响的柱状图。
具体实施方式
下面结合具体实施例进一步阐明本发明，应理解这些实施例仅用于说明本发明而不用于限制本发明的范围，在阅读了本发明之后，本领域技术人员对本发明的各种等价形式的修改均落于本申请所附权利要求所限定的范围。
实施例1一种具有改善年龄相关性黄斑变性的药食两用组合物的制备方法，包括如下步骤：
(1)取枸杞子1份，山楂2份，黄芪2份，益智仁1份，铁皮石斛2份，牡蛎2份，菊花1份，混合。加入药材重量8倍量的水回流提取120min，过滤，收集滤液和滤渣。
(2)取步骤(1)中的药渣，加入药材重量10倍体积量的水回流提取120min，过滤，收集滤液。
(3)合并步骤(1)与步骤(2)中所得滤液，减压浓缩得浸膏，加入葡萄籽原花青素0.01份，叶黄素0.01份，牛磺酸0.01份，低温减压制得提取物。
实施例2一种具有改善年龄相关性黄斑变性的药食两用组合物的制备方法，包括如下步骤：
(1)取枸杞子4份，山楂7份，黄芪7份，益智仁4份，铁皮石斛4份，牡蛎9份，菊花4份，混合。加入药材重量8倍量的水回流提取120min，过滤，收集滤液和滤渣。
(2)取步骤(1)中的药渣，加入药材重量10倍体积量的水回流提取120min，过滤，收集滤液。
(3)合并步骤(1)与步骤(2)中所得滤液，减压浓缩得浸膏，加入葡萄籽原花青素0.08份，叶黄素0.08份，牛磺酸0.08份，低温减压制得提取物。
实施例3一种具有改善年龄相关性黄斑变性的药食两用组合物的制备方法，包括如下步骤：
(1)取枸杞子3份，山楂6份，黄芪6份，益智仁3份，铁皮石斛3份，牡蛎8份，菊花3份，混合。加入药材重量8倍量的水回流提取120min，过滤，收集滤液和滤渣。
(2)取步骤(1)中的药渣，加入药材重量10倍体积量的水回流提取120min，过滤，收集滤液。
(3)合并步骤(1)与步骤(2)中所得滤液，减压浓缩得浸膏，加入葡萄籽原花青素0.05份，叶黄素0.05份，牛磺酸0.05份，低温减压制得提取物。
实施例4药食两用组合物改善年龄相关性黄斑变性动物实验研究
一、实验材料与药物
1.实验动物
SPF级雌性昆明种小鼠，体重18～22g，购自南京中医药大学实验动物中心，合格证号SCXK(苏)2015-0002。实验小鼠放置于南京中医药大学实验动物中心喂养，实验动物设施使用许可证SYXK(苏)2012-0047。
2.药物和试剂
苯代谢物氢醌(浓度为0.8％，Alfa Aesar公司)；高脂饲料(Research Diets公司)；过氧化氢酶(CAT)试剂盒、谷胱甘肽过氧化物酶(GSH-PX)试剂盒、活性氧(ROS)测试盒、超氧化物歧化酶(SOD)试剂盒、丙二醛(MDA)试剂盒(货号:A003-1)均购自南京建成生物工程研究所。TRIzol RNA提取试剂盒(15596-026，Invitrogen)。RT-PCR反转录试剂盒(PrimeScriptTMRT reagent Kit with gDNA Eraser,RR047A，TAKARA)；SYBR荧光定量PCR试剂(FastStart Universal SYBR Green Master(ROX),04913914001，Roche)。Bradford试剂盒(T9310A，TAKARA)。
3.实验仪器
酶标仪(美国Perkin-Elmer公司)；BT125型电子天平(赛多利斯科学仪器有限公司)；KQ-250E型超声波清洗器(昆山禾创超声仪器有限公司)；AnkeGL-16GII型离心机(上海安亭科学仪器厂)。
二、实验方法
1.小鼠视网膜黄斑变性疾病模型的建立与药食两用组合物给药
健康小鼠适应性喂养5d后，随机分组：正常对照组(正常饮食)、模型对照组(高脂饮食十氢醌)、给药组(高脂饮食+氢醌+药物)。干预药物分别为每组8只动物，灌胃给药。正常对照组：正常饮食，正常饮水。模型对照组：饮水中加入0.8％氧化物氢醌，结合高脂饮食，喂养3个月。给药组：实施例1、2、3，各分高剂量(8g/kg)、低剂量(4g/kg)两组。给予高脂饮食，并在饮水中加0.8％氢醌喂养3个月后，予实施例1、2、3治疗3个月。灌胃给药，每天下午2点开始灌胃，每周记录一次小鼠体重，每天早晚观察小鼠状态，及摄食和饮水情况。
2.小鼠血清中SOD、GSH-Px、CAT活性和ROS、MDA含量测定
观察期满，处死动物，摘取眼球，眼周围静脉取血，3000rpm，4℃离心10min，分离血清，-20度保存备用。分别按照SOD、GSH-Px、CAT、ROS、MDA试剂盒说明书测定血清中SOD、GSH-Px、CAT活性和ROS、MDA含量。
3.小鼠视网膜中氧化应激通路关键因子mRNA表达水平测定
取出处理好的眼球组织，研磨均匀，加入裂解液，使其均匀分布于组织表面，室温放置2min，将trizol转移至无RNA酶的EP管中。加入氯仿200ul，用力振摇15s，室温静置15min，离心(4℃，12,000rpm，15min)，离心后取上层液体加入一个EP管中。再加入等量体积的异丙醇，上下颠倒混匀，室温静置5min，离心(4℃，12,000rpm，15min)。去上清，沉淀加入75％乙醇1ml，轻微振荡15s，在温度4℃，转速为7500rpm条件下离心5min。去上清液，使沉淀尽量干燥后，加入50uLDEPC水。
cDNA的制备：用Nanodrop测试RNA的浓度和纯度，根据TaKaRa逆转录试剂盒的说明，总计取用1μg的RNA来进行逆转录的操作。
依照SYBR荧光实时定量试剂盒操作步骤，利用荧光实时定量PCR仪测定小鼠视网膜中氧化应激通路关键因子的基因转录水平表达。所用引物序列如下表1：Nrf2、HO-1、NQO-1、GCL
表1引物序列
4.小鼠视网膜中血管生长因子(VEGF)表达水平测定
取出各组小鼠眼球，加入HBSS缓冲液匀浆，离心取上清，利用小鼠VEGFELISA试剂盒测定各组小鼠眼球中VEGF表达。
5.统计学处理
所有实验数据均采用SPSS18.0统计处理软件进行统计学处理，结果以
表示，组间差异采用t检验，P<0.05为差异有统计学意义。
三、实验结果
1.药食两用组合物显著降低小鼠血清中氧化应激水平
如图1-2所示，与正常对照组相比，模型对照组(高脂饮食十氢醌)小鼠血清中总活性氧(ROS)水平明显提高(P<0.01)，表明模型小鼠体内存在高水平的氧化应激；同时模型组中的脂质过氧化物丙二醛(MDA)含量也显著升高(P<0.01)，表明高脂饮食+氢醌喂养的小鼠眼球后静脉血中存在高水平的氧化应激(P<0.01)。
经实施例1～3三种不同配比的药食两用组合物灌胃治疗后，与模型对照组相比，低、高剂量组小鼠血清中总ROS水平均明显降低，血清中MDA含量亦显著降低(P<0.01)，说明药食两用组合物可以降低血清中总ROS和MDA的含量，可以改善模型小鼠视网膜的氧化应激状态，减少活性氧及各种氧自由基对小鼠视网膜的损伤。且经过对比，实施例1～3三种不同配比的药食两用组合物中，以实施例3的最优配比降低氧化应激水平最好。
2.药食两用组合物显著提升小鼠体内抗氧化应激酶水平
如图3-图5所示，与正常对照组比较，高脂饮食+氢醌喂养的模型小鼠血清中，超氧化物歧化酶(SOD)活性明显降低(P<0.01)，同时血清中谷胱甘肽过氧化物酶(GSH-PX)活性也显著降低(P<0.01)，提示模型小鼠体内由于存在较高水平的氧化损伤，导致抗氧化应激因子水平下降。同时模型组小鼠血清中过氧化氢酶(CAT)活性显著下降(P<0.01)，由于CAT为氢氧自由基(OH-)的水解酶，CAT活性下降，会导致氧自由基水平相对升高，提示模型小鼠体内存在氧化应激状态。对小鼠视网膜组织造成较强氧化损伤。
与模型对照组比较，实施例1～3药食两用组合物均可以明显提高氧化损伤小鼠血清中SOD、GSH-Px、CAT的活性，各组合物的高剂量组均优于低剂量组。且经过比较，其中以实施例3最优配比的效果最显著(P<0.01)，提示药食两用组合物可以提高氧化损伤小鼠视网膜血清中抗氧化酶的活性，并具有剂量依赖性，发挥抗氧化作用，从而改善视网膜的氧化应激状态，抵御视网膜氧化损伤
3.药食两用组合物显著抑制小鼠体内氧化应激通路的激活
在上述实验的基础上，我们对小鼠体内氧化应激通路的关键激酶的表达水平进行了检测。如图6-9所示，与正常对照组相比，模型组小苏体内氧化应激通路的关键激酶Nrf2、HO-1、NQO-1、GCL的mRNA表达水平明显升高(P<0.01)，说明高脂饮食+氢醌造模使小鼠机体处于氧化应激状态，从而激活Nrf2通路，激发自身释放II相酶发挥抗氧化作用。经实施例1～3药食两用组合物治疗与模型对照组相比，给药组的Nrf2、HO-1、NQO-1、GCLmRNA表达水平均有所下降，提示药食两用组合物可以降低机体氧化应激状态，使细胞恢复平衡稳定状态，从而保护视网膜细胞免受氧化损伤。且三种药食两用组合物中，也以实施例3的效果最好(P<0.01)。
4.药食两用组合物显著抑制小鼠眼球内VEGF的表达
检测小鼠眼球内VEGF的表达，如图10所示，与正常对照组相比，模型组小鼠眼球内VEGF的表达水平明显升高(P<0.01)，说明高脂饮食+氢醌造模使小鼠眼球内出现血管增生趋势。经药食两用组合物治疗与模型对照组相比，给药组的VEGF表达水平均有所下降，提示药食两用组合物可以抑制因动物体内高氧化应激状态导致的血管增生，避免眼底出血，抑制湿性AMD的发生。实施例1～3三种药食两用组合物中，也以实施例3的效果最好(P<0.01)。
实施例5药食两用组合物抗视网膜色素上皮细胞(ARPE-19)氧化损伤
一、实验材料与药物
1.细胞
人视网膜上皮色素细胞(ARPE-19)购自ATCC，存于江苏省中药资源产业化过程协同创新中心。
2.实验仪器
二氧化碳培养箱(Forma series Ⅱ water jacket CO2 incubator，Thermo公司)，1300series A2超净工作台(Thermo公司)，AutoVertA1倒置荧光显微镜(ZEISS公司)，Nanodrop(DS11spectrophotometer，DeNovix公司)，ABI7500荧光实时定量PCR仪(Invitrogen公司)，高速离心机(Allegra X-12R Centrifuge和Microfuge 22RCentrifuge，Backman公司)，恒温水浴锅(Bluepard公司)，恒温振荡器(IS-RDV1 incubatorshaker，CRYSTAL公司)，细胞培养器皿(CORNING公司)。
3.试剂
无水乙醇(分析纯)、H2O2溶液(分析纯)均购自国药上海公司。DMEM/F12培养基、10％胎牛血清(FBS)、1％双抗(青霉素和链霉素，P/S)购自Biological Industries公司。细胞培养所用的耗材均购自Corning公司。TNF-α购自Novel Protein公司。其他未特别注明的试剂，均购自Sigma-Aldrich公司。
二、实验方法
1.细胞培养与给药
ARPE-19细胞为人视网膜色素上皮细胞，培养基为DMEM/F12，并在其中加入10％FBS和1％P/S。将冻存于液氮罐中的ARPE-19细胞在37℃水浴复苏，置于60mm培养皿中培养。每48h换液1次，观察细胞密度，当达到85％时，吹打传代，使每个60mm培养皿中细胞数为1X105。当细胞传代三次后，生长稳定，将细胞按浓度5×103个/孔，接种于96孔板中，每孔的培养体积为100μL，给药3小时前更换新的培养基。实施例1～3药食两用组合物分为高(10μg/mL)、低(3μg/mL)两个剂量进行给药，给药48h。
过氧化氢用培养基稀释成相应的稀释倍数，与药物共同作用或预先给药后再损伤。
2.MTT检测
将ARPE-19细胞加以药食两用组合物培养48h后，加入MTT(5mg/mL)10μL。在培养箱内培养3小时，用移液枪吸去培养液，每孔加入150μL二甲基亚砜，置摇床上室温低速震荡30min，使结晶物充分溶解，并在酶联免疫检测仪OD570nm处测量各孔的吸光值(A570)。计算每组细胞存活率，存活率(％)＝A(实验组)/A(对照组)×100％。每个实验平行操作三次。
3.统计学处理
所有实验数据均采用SPSS18.0统计处理软件进行统计学处理，结果以
表示，组间差异采用t检验，P<0.05为差异有统计学意义。
三、实验结果
将体外培养的ARPE-19细胞，利用过氧化氢构建氧化损伤模型，加以不同比例的药食两用组合物24h后，利用MTT法检测细胞存活率。如图11所示，实施例各药食两用组合物可以显著保护ARPE-19细胞免受过氧化氢损伤，其中实施例3保护效果最为显著。
实施例6药食两用组合物促进视网膜米勒细胞神经营养因子表达
一、实验材料与药物
1.细胞
米勒细胞(Müller)购自ATCC，存于江苏省中药资源产业化过程协同创新中心。
2.实验仪器
二氧化碳培养箱(Forma series Ⅱ water jacket CO2 incubator，Thermo公司)，1300 series A2超净工作台(Thermo公司)，Auto Vert A1倒置荧光显微镜(ZEISS公司)，Nanodrop(DS11 spectrophotometer，DeNovix公司)，ABI7500荧光实时定量PCR仪(Invitrogen公司)，高速离心机(Allegra X-12R Centrifuge和Microfuge 22RCentrifuge，Backman公司)，恒温水浴锅(Bluepard公司)，恒温振荡器(IS-RDV1 incubatorshaker，CRYSTAL公司)，细胞培养器皿(CORNING公司)。
3.试剂
TRIzol RNA提取试剂盒(15596-026，Invitrogen)。RT-PCR反转录试剂盒(PrimeScriptTM RT reagent Kit with gDNA Eraser,RR047A，TAKARA)；SYBR荧光定量PCR试剂(FastStart Universal SYBR Green Master(ROX),04913914001，Roche)。Bradford试剂盒(T9310A，TAKARA)。
二、实验方法
1.细胞培养与给药
Müller细胞为人视网膜米勒细胞，培养基为DMEM，并在其中加入10％FBS和1％P/S。将冻存于液氮罐中的Müller细胞在37℃水浴复苏，置于60mm培养皿中培养。每48h换液1次，观察细胞密度，当达到85％时，吹打传代，使每个60mm培养皿中细胞数为，以1×106/皿的细胞密度接种于直径为60mm的培养皿中。
待培养皿中的细胞长至汇合度为90％时，给以实施例1-3药食两用组合物高(10μg/mL)、低(3μg/mL)两个剂量，阳性药cAMP(50μM)，培养24h。
2.实时定量荧光PCR仪测定神经营养因子转录水平表达
RNA提取：吸去细胞培养液，加入2mL的PBS冲洗，每盘细胞中加入500μL的TRIzol，按TRIzolRNA提取试剂盒所列步骤进行操作。所提取RNA于-80℃保存。
cDNA的制备：用Nanodrop测试RNA的浓度和纯度，根据TaKaRa逆转录试剂盒的说明，总计取用1μg的RNA来进行逆转录的操作。
依照SYBR荧光实时定量试剂盒操作步骤，利用荧光实时定量PCR仪测定神经营养因子的基因转录水平表达。所用引物序列如下：
表2引物序列
3.统计学处理
所有实验数据均采用SPSS18.0统计处理软件进行统计学处理，结果以
表示，组间差异采用t检验，P<0.05为差异有统计学意义。
三、实验结果
视网膜米勒细胞可提供神经营养因子，维持视网膜神经节细胞的正常生长。将体外培养的人视网膜米勒细胞，加以不同比例的药食两用组合物24h后，利用qPCR技术检测细胞内神经营养因子BDNF的表达。如图12所示，不同浓度的药食两用组合物均可以显著促进人视网膜米勒细胞内BDNF的表达，表现出较好的神经营养活性，并且呈现浓度依赖性。
本发明提供的药食两用组合物，动物模型实验结果表明：本发明提供的药食两用组合物可有效降低高氧化应激水平这一导致年龄相关性黄斑变性的最主要病理环节，从而保护动物视网膜免收损伤。细胞模型实验结果表明，本发明提供的药食两用组合物可提高视网膜色素上皮细胞抵御氧化损伤能力，增加视网膜米勒细胞内神经营养因子的表达，从而达到保护视网膜损伤的效果。
以上实验结果表明，本发明提供的药食两用组合物具有显著的对抗氧化应激所致的视网膜损伤功能，表明本发明提供的药食两用组合物具有很好的改善高氧化应激导致的年龄相关性黄斑变性作用。该组合物不仅能提高视网膜色素上皮细胞抵御氧化损伤能力，还能增加视网膜米勒细胞内神经营养因子的表达作用，从而达到保护视网膜损伤的效果，具有多靶点的作用特点。尤其重要的是，该药食两用组合物所有组成药味与成分均为药食两用品种，安全性好，适合长期使用，可以起到预防和改善AMD的效果。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (6)
1.一种具有改善年龄相关性黄斑变性的药食两用组合物，其特征在于，它包括下列重量份数的原料：枸杞子1~5份，山楂4-8份，黄芪4~8份，牡蛎5~10份，铁皮石斛1~5份，菊花1~5份，益智仁1~5份，葡萄籽原花青素0.01~0.1份，叶黄素0.01~0.1份，牛磺酸0.01~0.1份。
2.根据权利要求1所述的一种具有改善年龄相关性黄斑变性的药食两用组合物，其特征在于，它包括下列重量份数的原料：枸杞子2~4份，山楂5-7份，黄芪5~7份，牡蛎6~9份，铁皮石斛2~4份，菊花2~4份，益智仁2~4份，葡萄籽原花青素0.03~0.08份，叶黄素0.03~0.08份，牛磺酸0.03~0.08份。
3.根据权利要求1所述的具有改善年龄相关性黄斑变性的药食两用组合物，其特征在于，它包括下列重量份数的原料：枸杞子3份，山楂6份，黄芪6份，牡蛎8份，铁皮石斛3份，菊花3份，益智仁3份，葡萄籽原花青素0.05份，叶黄素0.05份，牛磺酸0.05份。
4.权利要求1至3任一项所述的具有改善视疲劳与年龄相关性黄斑变性的药食两用组合物的制备方法，其特征在于，它包括以下步骤：
（1）按重量份数取枸杞子、山楂、黄芪、牡蛎、铁皮石斛、菊花、益智仁，加入5~15倍量的水，回流提取1~2h，过滤；收集滤液；
（2）取步骤（1）中的药渣，加入5~15倍量的水，回流提取1~2h，过滤；收集滤液；
（3）取步骤（1）与（2）滤液，合并减压浓缩，加入葡萄籽原花青素、叶黄素、牛磺酸，制得组合物。
5.权利要求1至3任一项所述的具有改善年龄相关性黄斑变性的药食两用组合物在制备改善年龄相关性黄斑变性的食品或保健品或药品中的应用。
6.根据权利要求5所述的应用，其特征在于，将组合物的提取物和食品及药学上可接受的载体制成口服液、软糖、片剂、汤剂、颗粒剂、煎膏剂或浸膏剂的药物。
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