CN115581702A - 芍药素-3-o-阿拉伯糖苷在制备药物或保健食品的应用 - Google Patents
芍药素-3-o-阿拉伯糖苷在制备药物或保健食品的应用 Download PDFInfo
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Abstract
本申请提供了芍药素‑3‑O‑阿拉伯糖苷在制备药物或保健食品的应用,该药物或保健食品为用于抑制AGEs的药物或保健食品、治疗AGEs相关损伤、疾病或症状的药物或保健食品、或缓解AGEs相关损伤、疾病或症状的药物或保健食品。本申请通过试验验证了芍药素‑3‑O‑阿拉伯糖苷能够抑制AGEs、可以治疗AGEs相关损伤、疾病或症状、或缓解AGEs相关损伤、疾病或症状,且相对于常用AGEs抑制剂氨基胍具有更高的活性,从而为抑制AGEs、治疗AGEs相关损伤、疾病或症状、或缓解AGEs相关损伤、疾病或症状的发生和发展提供了新思路。
Description
技术领域
本申请涉及药物制剂领域,具体涉及芍药素-3-O-阿拉伯糖苷在制备药物或保健食品的应用。
背景技术
晚期糖基化终末产物( advanced glycationend products AGEs) 是指蛋白质、脂质或核酸等大分子在没有酶参与的条件下,自发的与葡萄糖或其他还原单糖反应所生成的稳定的共价加成物。它是非酶糖基化反应(Maillard反应)的终末产物,是过量的糖和蛋白质结合的产物。已鉴定的AGEs已有数十种,如羧甲基赖氨酸(CML)、羧乙基赖氨酸(CEL)、吡咯素等。
AGEs在体内有两个来源,一是过量的糖和蛋白质在体内合成AGEs,二是通过进食将食物中存在的AGEs摄入体内。AGEs能够和身体的组织细胞相组合并破坏它们。正常情况下,体内的AGEs可以依靠肾脏清除。然而,随着年龄的增加,或在某些病理条件下AGEs在体内发生蓄积,这对机体可以产生明显的损伤等不利影响,干预正常的体内生理生化过程,影响机体的正常代谢,导致疾病的发生和发展。在病理情况下,相应病变组织中均可有AGEs存在。
目前的研究证明,AGEs会加速人体的衰老和导致很多慢性退化型疾病的发生,比如心脑血管疾病、神经退行性疾病、骨关节疾病、肾脏疾病等疾病。研究表明,AGEs水平升高是糖尿病及并发症发生的风险因素。AGEs是导致胰岛素抵抗的独立危险因素,通过多元回归分析结果表明,AGEs水平与健康受试者的胰岛素抵抗独立相关。在另一项研究中,对300多名非糖尿病患者进行了检查,证实血清AGEs水平与HOMA-IR独立相关。研究人员,对138名患有代谢综合征的肥胖受试者进行了为期1年的临床实验,结果表明,与高AGEs饮食组相比,在无需大幅减少体重的前提下,低AGEs饮食可改善受试人群的胰岛素抵抗,并可能降低2型糖尿病的风险。另外,糖尿病患者的高血糖又可以进一步促进糖基化反应过程,促进AGEs水平的升高进而导致相关并发症的发生。通过染色观察到糖尿病人肝细胞、肾小管中AGEs含量明显增高。在肾小球和肾小管中发现β生长因子的过度表达及血管内皮生长因子浓度增加。AGEs与特异受体相结合导致细胞因子的过度表达可能在糖尿病血管并发症,如糖尿病视网膜病变(DR)、糖尿病肾病(DN)、动脉粥样硬化中起着重要作用。
AGEs水平升高与老年人的认知能力下降密切相关。研究表明,在阿尔茨海默病等神经退行性疾病患者的大脑和中枢神经系统中,AGEs的含量显著增加,而且AGEs的含量增加主要集中在具有明显病理特征的组织区域(例如阿尔茨海默氏症的海马区)中。而且研究发现,膳食AGEs或其前体可能导致血脑屏障选择性渗透性的丧失。阿尔茨海默病小鼠实验结果显示,外源性摄入的AGE可以降低 SIRT1表达,从而通过解聚素和金属蛋白酶途径增加β-淀粉样蛋白和斑块的产生。一项针对老年人的横断面研究显示,高水平的AGEs饮食与记忆力下降更快相关。
AGEs水平升高与骨关节疾病的发生密切相关。糖基化途径被认为是导致骨质疏松症的重要因素之一。在骨质疏松症患者中发现血清AGEs水平升高,如戊糖苷和CML。研究表明,非酶糖基化是影响骨重塑的新因素。骨基质中积累的AGEs通过与其受体结合来影响成骨细胞分化和增殖。在这些细胞中,AGEs与RAGE的结合激活了NF-κB,导致细胞因子、生长因子和细胞粘附分子的表达增加。这会引发炎症过程并引发氧化应激,导致成骨细胞功能异常和骨重建障碍。关节软骨中与年龄相关的主要变化之一是AGEs水平的增加。从20岁开始,AGEs会在关节软骨的胶原蛋白和蛋白聚糖中积累。关节软骨中的AGEs的积累也导致了骨关节炎的患病率随着年龄的增长而增加。最近的研究发现,AGEs水平升高可以通过增加关节软骨的硬度、提高软骨细胞介导的蛋白多糖降解、减少蛋白多糖合成和诱导软骨细胞外基质 (ECM) 的降解来对关节软骨产生负面作用。
除此之外,大量实证研究表明AGEs的水平升高与各种疾病之间存在关联,例如皮肤衰老,多囊卵巢综合征,伤口愈合,牙周炎,勃起功能障碍,老年妇女贫血,老年人行走速度缓慢,周围神经病变,周围动脉疾病,阻塞性睡眠呼吸暂停,癌症,精神分裂症,阿尔茨海默病,更高的全因死亡率、冠状动脉粥样硬化的严重程度、心血管疾病死亡率以及成人和儿童代谢综合征等。
AGEs在多种疾病的发生或进展中起重要作用,降低其水平对健康有益是肯定的。减少循环中AGEs的方法包括抑制AGEs形成、加速现有AGEs的分解代谢或抑制AGEs交联以及阻断AGEs的生物学反应。AGEs形成的抑制可能存在几种机制,包括醛糖还原酶、抗氧化活性、反应性二羰基捕获、糖自氧化抑制和氨基结合。花色苷是花色素与糖以糖苷键结合而成的一类化合物,广泛存在于植物的花、果实、茎、叶和根器官的细胞液中,使其呈现由红、紫红到兰等不同颜色,是一种色彩艳丽的水溶性色素。花色苷属黄酮类化合物,其骨架结构为2-苯基苯并吡喃阳离子。目前已知花色素有 20 多种,最常见的有 6 种,分别为矢车菊色素(Cy)、天竺葵色素(Pg)、飞燕草色素(Dp)、矮牵牛花色素(Pt)、芍药色素(Pn)和锦葵色素(Mv),上述各花色素的区别主要在于基团R1和R2的变化。
据初步统计,已经发现27个科、73个属的数万种植物中含有花色苷。目前有超过500种的花色苷从植物中被分离得到。各种各样的花色苷随它们形成共振结构的能力、C6-C3-C6核上的取代基及环境因素的不同,可表现出黄、红、紫、黑等不同的色泽。
游离的花色素很不稳定,在自然界中一般以糖苷结合物的形式存在。其糖苷形式比糖苷配基稳定,因此在植物中主要以糖苷(配糖体),即花色苷的形式存在。通常这些糖苷包括单葡萄糖苷、双葡萄糖苷和酰基衍生物。在已知的花色苷或花色素中,绝大部分以糖苷化的形式存在,成苷的糖主要有葡萄糖、半乳糖、鼠李糖、阿拉伯糖、木糖和由这些单糖构成的二糖和三糖,常见的二糖苷有槐糖、芸香糖和接骨木二糖等。糖与花色苷均以O-键连接,主要在3-,5-和 7-碳位,也有小部分连接在3'-碳位,几乎所有的花色苷在3-位都会糖苷化。
此外,植物体内的花色苷还会与有机酸通过酯键结合形成酰化的花色苷,即酰化花色苷而存在,参与糖基酰化的最常见酸为阿魏酸、咖啡酸、芥子酸等各种羟基肉桂酸衍生物或苹果酸、乙酸、琥珀酸、丙二酸、草酸等脂肪酸及对羟基苯甲酸等。花色苷分子中的羟基数目、羟基的甲基化程度,连接到花色苷分子上糖的种类、数量和位置,连接到糖分子上的脂肪酸或芳香酸的种类和数目及花色苷分子与其他物质的不同作用等,造成了自然界中多种多样花色苷的存在。
针对花色苷单体抑制AGEs亦有相关研究。比如研究证实了矢车菊素-3-O-半乳糖苷、飞燕草素-3-O-葡萄糖苷、芍药素-3-O-葡萄糖苷对AGEs的抑制作用。
硕士论文《花色苷单体中压快速分离制备及其抑制荧光糖基化终产物构效关系及机理研究》对七种花色苷在抑制荧光糖基化终产物的活性进行了实验,且研究表明分子量大具有糖基数目多的花色苷具有较多的羟基,可与蛋白质形成较多的氢键及其他分子间作用力,且分子量大的花色苷具有较大的空间位阻可有效的阻碍羰基类化合物对 β-Lg 的糖基化修饰,进而其抑制糖基化的效果好。在原花青素抗氧化性及构效关系研究中发现,B 环具有邻苯三酚结构的原花青素的抗氧化性大于 B 环具有邻苯二酚的原花青素,且邻苯三酚结构对原花青素的抗氧化能力影响最大。糖基化反应伴随着氧化变化,因此推测由于母核具有邻苯三酚结构的花色苷具有比母核具有邻二酚羟基结构的花色苷较强的抗氧化性,所以表现出较优的抑制荧光 AGEs 的效果。因此,为了提高抑制AGEs的效果,本领域的技术人员通常会筛选分子量大、且羟基数量多的花色苷。例如,在花色苷的提取、纯化过程中,通过分子筛、柱层析、膜过滤的方式富集分子量大、羟基数量多的花色苷,或者对具体的花色苷进行糖基化修饰、增加B环羟基取代的获得分子量大、羟基数量多的花色苷,以此来提升花色苷AGEs的抑制率。
发明内容
本申请提供了芍药素-3-O-阿拉伯糖苷在制备药物或保健食品的应用,以提高对AGEs的抑制效果。
本申请的第一方面提供了芍药素-3-O-阿拉伯糖苷在制备药物或保健食品中的应用,药物或保健食品为用于抑制AGEs的药物或保健食品、治疗AGEs相关损伤、疾病或症状的药物或保健食品、或缓解AGEs相关损伤、疾病或症状的药物或保健食品。
进一步地,上述药物还包括药学上可接受的辅料,保健食品还包括食品学上可接受的辅料。
进一步地,上述药物或保健食品的剂型为口服制剂或注射制剂。
进一步地,上述口服制剂为片剂、粉剂、胶囊剂、颗粒剂、丸剂、散剂、膏剂、固体饮料或口服液。
进一步地,上述口服制剂中芍药素-3-O-阿拉伯糖苷的质量含量≥0.0122%。
进一步地,上述注射制剂为注射液或注射用粉针剂。
进一步地,上述注射制剂中芍药素-3-O-阿拉伯糖苷的质量含量≥0.0122%。
进一步地,上述抑制AGEs为抑制AGEs生成、或促进AGEs分解。
进一步地,上述AGEs相关损伤为AGEs介导的细胞凋亡升高、活性氧含量升高、炎症因子TNF-α的过度表达、炎症因子ICAM-1的过度表达、炎症因子VCAM-1的过度表达和/或线粒体ATP含量的降低。
进一步地,上述AGEs相关疾病为心脑血管疾病、神经退行性疾病、骨关节疾病中的任意一种或多种。
进一步地,上述心脑血管疾病选自糖尿病及其并发症、动脉粥样硬化。
进一步地,上述神经退行性疾病选自阿尔茨海默症、帕金森症、肌肉萎缩侧索硬化症。
进一步地,上述骨关节疾病为骨质疏松、骨关节炎。
进一步地,上述AGEs相关症状为衰老。
本申请通过试验验证了芍药素-3-O-阿拉伯糖苷能够抑制AGEs、可以治疗AGEs相关损伤、疾病或症状、或缓解AGEs相关损伤、疾病或症状,且相对于常用AGEs抑制剂氨基胍具有更高的活性,从而为抑制AGEs、治疗AGEs相关损伤、疾病或症状、或缓解AGEs相关损伤、疾病或症状的发生和发展提供了新思路。
附图说明
为了更清楚地说明本申请实施例的技术方案,下面将对本申请实施例中所需要使用的附图作简单地介绍,显而易见地,下面所描述的附图仅仅是本申请的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据附图获得其他的附图。
图1示出了试验例2中酶联免疫法检测各试验组HUVEC细胞的AGEs的含量结果,其中,#表示与对照组比P<0.05;*表示与模型组比P<0.05;^表示与其他组花色苷比P<0.05。
图2示出了试验例2 中CCK8法检测各试验组的细胞存活率结果,其中,#表示与对照组比P<0.05;*表示与模型组比P<0.05;^表示与其他组花色苷比P<0.05。
图3示出了试验例2中酶标仪检测各试验组的活性氧ROS的生成结果,其中,#表示与对照组比P<0.05;*表示与模型组比P<0.05;^表示与其他组花色苷比P<0.05。
图4示出了试验例3中碘化丙啶(PI)染色法检测各试验组的细胞凋亡率,其中,#表示与对照组比P<0.05;*表示与模型组比P<0.05;^表示与其他组花色苷比P<0.05。
图5示出了试验例3中qPCR检测各试验组的炎症因子TNF-α表达结果,其中,#表示与对照组比P<0.05;*表示与模型组比P<0.05;^表示与其他组花色苷比P<0.05。
图6示出了试验例3中qPCR检测各试验组的炎症因子ICAM-1表达结果,其中,#表示与对照组比P<0.05;*表示与模型组比P<0.05;^表示与其他组花色苷比P<0.05。
图7示出了试验例3中qPCR检测各试验组的炎症因子VCAM-1表达结果,其中,#表示与对照组比P<0.05;*表示与模型组比P<0.05;^表示与其他组花色苷比P<0.05。
图8示出了试验例3中各试验组的线粒体相关ATP指标的测试结果,其中,#表示与对照组比P<0.05;*表示与模型组比P<0.05;^表示与其他组花色苷比P<0.05。
具体实施方式
下面结合附图和实施例对本申请的实施方式作进一步详细描述。以下实施例的详细描述和附图用于示例性地说明本申请的原理,但不能用来限制本申请的范围,即本申请不限于所描述的实施例。
如本申请背景技术所记载的,为了提高花色苷对AGEs的抑制效果,本领域技术人员通常会筛选分子量大、且羟基数量多的花色苷。例如,在花色苷的提取、纯化过程中,通过分子筛、柱层析、膜过滤的方式富集分子量大、羟基数量多的花色苷,或者对具体的花色苷进行糖基化修饰、增加B环羟基取代的获得分子量大、羟基数量多的花色苷,以此来提升花色苷AGEs的抑制率。但是这种尝试导致研究成本、工业化成本以及实际应用成本增加。在实验中,本申请发明人偶然发现,同样都是芍药素花色苷,芍药素-3-O-阿拉伯糖苷对AGEs具有较好的抑制作用,且其对AGEs的抑制效果明显高于芍药素-3-O-葡萄糖苷、芍药素-3-O-半乳糖苷、芍药素-3-O-芸香糖苷、芍药素-3,5-O-二葡萄糖苷对AGEs的抑制效果。基于上述发现,本申请提供了芍药素-3-O-阿拉伯糖苷在制备药物或保健食品的应用,药物或保健食品为用于抑制AGEs的药物或保健食品、治疗AGEs相关损伤、疾病或症状的药物或保健食品、或缓解AGEs相关损伤、疾病或症状的药物或保健食品。
本申请通过试验验证了芍药素-3-O-阿拉伯糖苷能够抑制AGEs、可以治疗AGEs相关损伤、疾病或症状、或缓解AGEs相关损伤、疾病或症状,且相对于常用AGEs抑制剂氨基胍具有更高的活性,从而为抑制AGEs、治疗AGEs相关损伤、疾病或症状、或缓解AGEs相关损伤、疾病或症状的发生和发展提供了新思路。
结合前述的6种花色素结构的分析可知,芍药素-3-O-阿拉伯糖苷不仅B环上的R1和R2基团不为羟基;而且为分子量较小的单糖类糖苷,但是其表现出了与现有技术的推测完全不同的AGEs的抑制效果。虽然目前无法解释芍药素-3-O-阿拉伯糖苷的构效关系,但是试验证明了其具有优异的AGEs抑制效果。
在一些实施方案中,上述药物还包括药学上可接受的辅料,保健食品还包括食品学上可接受的辅料。
无论是药学上可接受的辅料还是食品学上可接受的辅料,均可从常用的相应辅料中进行选择,而且可以根据药物或保健食品的具体剂型进行选择。
在一些实施方案中,上述药物或保健食品的剂型为口服制剂或注射制剂。优选地,口服制剂为片剂、粉剂、胶囊剂、颗粒剂、丸剂、散剂、膏剂、固体饮料或口服液。或者优选地,注射制剂为注射液或注射用粉针剂。
为了便于患者或者使用者服用,在一些实施方案中,上述口服制剂中芍药素-3-O-阿拉伯糖苷的质量含量≥0.0122%。
在一些实施方案中,上述注射制剂中芍药素-3-O-阿拉伯糖苷的质量含量≥0.0122%。
本申请研究证明了芍药素-3-O-阿拉伯糖苷具有突出的抑制AGEs的效果,该抑制AGEs可以为抑制AGEs生成、或促进AGEs分解。
经过申请人的进一步试验研究发现,在一些实施方式中,上述AGEs相关损伤为AGEs介导的细胞凋亡升高、活性氧含量升高、炎症因子TNF-α的过度表达、炎症因子ICAM-1的过度表达、炎症因子VCAM-1的过度表达和/或线粒体ATP含量的降低。
基于AGEs与多种疾病的关联性,在一些实施方式中,上述AGEs相关疾病为心脑血管疾病、神经退行性疾病、骨关节疾病中的任意一种或多种;优选心脑血管疾病选自糖尿病及其并发症、动脉粥样硬化;优选神经退行性疾病选自阿尔茨海默症、帕金森症、肌肉萎缩侧索硬化症;优选骨关节疾病为骨质疏松、骨关节炎。或者在一些实施方式中,上述AGEs相关症状为衰老。
以下将结合试验,进一步说明本申请的有益效果。
下表列出了以下试验所用花色苷的来源。
表1试验所用花色苷的来源表
试验例1、 抑制AGEs生成功效检测方法:
实验原理:
牛血清清蛋白(Bovine serum albumin, BSA)与甲基乙二醛(Methylglyoxal,MGO)相互作用可产生AGEs,将待测化合物与BSA及MGO共同孵育,通过检测体系内荧光值变化,判断AGEs生成量高低,从而评价化合物对AGEs的生成是否具有抑制作用。阳性对照组使用氨基胍(AG)。空白对照组为不使用任何花色苷或氨基胍。
研究采用无菌黑色非透明96孔板进行试验检测,反应体系如下表所示,每孔加入90 μL 10 mg/mL BSA 溶液及加入 10 μL1.25 M MGO 溶液,随后,各试验孔根据设计加入受试物溶液10 μL 或生理盐水(空白对照) 10 μL,阳性对照组加入阳性药溶液。反应液充分混匀后,用 M5 酶标仪分别检测实验开始时荧光值(激发波长Ex=370 nm,发射波长Em=440 nm)。检测结束后,无菌封板膜封板,黑色非透明96孔板置于 37 °C 避光反应 24 h后相同条件下再次检测荧光值。每个受试物组及对照组均进行6-8个复孔检测,计算每组各孔的荧光值增加量,换算各组 AGEs 生成抑制率。
表2:初筛试验96孔板反应体系
在相同的反应体系和条件下,受试物进行不同梯度浓度(50、10、1、0.1、0.03、0.01mg/mL)检测,每个受试物各浓度组及对照组均进行5个复孔检测,检测结果使用Graphpad进行拟合处理,求得受试物 IC50 值。
主要的实验结果:
表3. 不同种类花色苷对AGEs生成的抑制作用
备注:P<0.05 * 1 :与锦葵素-3-O-阿拉伯糖苷、飞燕草素-3-O-阿拉伯糖苷、芍药素-3-O-葡萄糖苷、芍药素-3-O-半乳糖苷、芍药素-3-O-芸香糖苷、芍药素-3,5-O-二葡萄糖苷、矮牵牛素-3-O-芸香糖苷(对香豆酰)-5-O-葡萄糖苷、越橘混合花色苷相比,具有显著性差异。
P<0.05 * 2 :与飞燕草素-3-O-葡萄糖苷、芍药素-3-O-葡萄糖苷、锦葵素-3-O-半乳糖苷、锦葵素-3-O-阿拉伯糖苷、锦葵素-3,5-O-二葡萄糖苷、矮牵牛素-3-O-芸香糖苷(对香豆酰)-5-O-葡萄糖苷、越橘混合花色苷相比,具有显著性差异。
备注:P<0.05 * 3 :与锦葵素-3-O-半乳糖苷、芍药素-3-O-半乳糖苷、飞燕草素-3-O-葡萄糖苷、飞燕草素-3-O-阿拉伯糖苷、飞燕草素-3-O-芸香糖苷、飞燕草素-3,5-O-二葡萄糖苷、矮牵牛素-3-O-芸香糖苷(对香豆酰)-5-O-葡萄糖苷、越橘混合花色苷相比,具有显著性差异。
表4. 不同种类花色苷对AGEs生成的抑制的IC50值
根据上述表3和表4数据可以看出,芍药素-3-O-阿拉伯糖苷相对于所试验的其他花色苷对AGEs生成具有更好的抑制作用。B环上R1和R2取代基团均不为羟基的芍药素-3-O-阿拉伯糖苷与与骨架结构的B环上具有两个羟基的飞燕草素-3-O-阿拉伯糖苷相比时,具有更为明显的优势;同时芍药素连接糖链为阿拉伯糖(五碳糖,相对分子质量150)时,与连接糖链为葡萄糖(六碳糖,相对分子质量160)、半乳糖(六碳糖,相对分子质量160)、芸香糖(十二碳糖,相对分子质量326)、二葡萄糖(双六碳糖,相对分子质量320)时相较,同样具有更明显的优势。此外,芍药素-3-O-阿拉伯糖苷相对于阳性对照组也具有明显的优势,而其他试验组中除了越橘混合花色苷、锦葵素-3-O-葡萄糖苷和飞燕草素-3-O-半乳糖苷相对于阳性对照组具有优势外,均不如阳性对照组的抑制AGEs生成的效果。
而且,根据表3和表4的数据可以看出,芍药素花色苷中芍药素-3-O-阿拉伯糖苷对AGEs生成的抑制作用最为突出、锦葵素花色苷中锦葵素-3-O-葡萄糖苷对AGEs生成的抑制作用最为突出、飞燕草素花色苷中飞燕草素-3-O-半乳糖苷对AGEs生成的抑制作用最为突出,即本申请所试验的单糖类花色苷或二糖类花色苷等上述小分子花色苷对AGEs生成的抑制作用未发现一致性规律,本申请在试验中上述芍药素-3-O-阿拉伯糖苷、锦葵素-3-O-葡萄糖苷和飞燕草素-3-O-半乳糖苷实现了对AGEs生成起到了预料不到的技术效果。
试验例2、抑制高糖诱导的AGEs生成及对脐静脉内皮细胞的保护作用
实验原理:将体外培养的HUVEC细胞随机分为对照组(不进行任何诱导和干预)、模型组( 40mmol/L葡萄糖) 、芍药素-3-O-葡萄糖苷组、芍药素-3-O-半乳糖苷组、芍药素-3-O-阿拉伯糖苷组、芍药素-3-O-芸香糖苷组、矮牵牛素-3-芸香糖苷(对香豆酰)-5-葡萄糖苷组、越橘混合花色苷组,40mmol/L高糖诱导、并用100μmol/L的不同花色苷干预内皮细胞24h。
2.1 HVUECs的原代、传代培养 采用改良的Jaffe等法,进行HVUECs原代和传代培养,取3- 6代生长良好的HVUECs进行实验。
2.2 实验分组和条件培养 取生长良好的3- 6代HVUECs制成细胞悬液,按4.0×105 cells/well的细胞密度接种于24孔板,加含10%胎牛血清的DMEM培养基,置于37℃、5%CO2孵箱中进行培养,待HUVECs生长呈亚融合状态换无血清培养液,继续培养12- 24 h。然后按实验要求加入浓度为100μmol/L样品预处理8h,再然后加入40mmol/L浓度的葡萄糖作用24h。分组:①空白对照组:加与药物等量的DMEM培养液;②模型组:加入葡萄糖 (40mmol/L);③高糖+样品1~6组,设3个以上复孔,继续培养24h,离心收集细胞及培养液。
测试:
1)、酶联免疫法检测AGEs含量变化,结果见图1。
2)、采用检测试剂盒(CCK-8细胞增殖及细胞毒性检测试剂盒,日本同仁公司)按照操作说明书,使用CCK8法检测细胞存活率,结果见图2;
3)、采用活性氧检测试剂盒(碧云天,产品编号: S0033S),按照操作说明书,使用酶标仪检测活性氧ROS的生成,结果见图3。
从图1至图3可以看出,芍药素-3-O-阿拉伯糖苷作用后AGEs的含量最少、细胞存活率最高、活性氧ROS含量最少,最接近对照组。
试验例3、抑制AGEs对脐静脉内皮细胞损伤的保护作用
实验原理:将体外培养的HUVEC细胞随机分为对照组、模型组(200μg/mL AGEs) 、芍药素-3-O-葡萄糖苷组、芍药素-3-O-半乳糖苷组、芍药素-3-O-阿拉伯糖苷组、芍药素-3-O-芸香糖苷组、矮牵牛素-3-O-芸香糖苷(对香豆酰)-5-O-葡萄糖苷组、越橘混合花色苷组。用100μmol/L 的各组花色苷预处理8h,然后再加入200μg/mL AGEs作用内皮细胞24h。
测试:
1)、碘化丙啶(PI)染色法检测细胞凋亡情况,碘化丙啶(propidium iodide,PI)是一种可对DNA染色的细胞核染色试剂,可嵌入双链DNA后释放红色荧光。PI不能通过活细胞膜,只能穿过破损的细胞膜而对核染色。因此,PI经常被用来与DAPI等核荧光探针一起使用,能同时对活细胞和死细胞染色。当PI与DAPI等核染料共染时,DAPI可被活细胞摄取,与DNA结合在紫外光下呈蓝色荧光;而PI使死细胞着染而产生红色荧光。测试结果见图4。
2)、采用检测试剂盒(碧云天,BeyoFast™ SYBR Green One-Step qRT-PCR Kit),按照说明书,使用qPCR检测炎症因子表达水平,测试结果见图5至7。
3)、采用ATP检测试剂盒(ATP Assay Kit)(碧云天,产品编号S0026)按照操作说明书,进行线粒体相关ATP指标检测,测试结果见图8。
4)、采用检测试剂盒,按照说明书检测内皮细胞功能NO(碧云天,产品编号S0021)及eNOs(eNOs酶联免疫吸附测定试剂盒,南京建成生物工程研究所)酶活性数据,测试结果见表5。
表5内皮细胞功能
备注:#与对照组比P<0.05;*与模型组比P<0.05;*^与其他组花色苷比P<0.05。
从图4可以看出,芍药素-3-O-阿拉伯糖苷作用后细胞凋亡率最少最接近对照组;从图5至7可以看出,芍药素-3-O-阿拉伯糖苷作用后各炎症因子表达最少,最接近对照组;从图8可以看出,芍药素-3-O-阿拉伯糖苷作用后线粒体含量最多,最接近对照组。
试验例4、动物实验(芍药素-3-O-阿拉伯糖苷急毒实验)
实验标准:按照GB 15193.3-2014《食品安全国家标准 急性经口毒性试验》规定的方法进行实验。
动物分组:将20只SPF级的SD大鼠,雌雄各半,同性别体重个体值均在均数±20%范围内。
实验方法:称取适量样品,加入适量去离子水充分混匀,配制浓度为0.25 g/mL的受试物溶液。试验前,动物整夜禁食(约16 h),自由饮水。正式试验时,试验组动物按20 mL/kg体重灌胃给予受试物溶液,24 h内灌胃给予受试物溶液2次,两次灌胃时间间隔约4 h,期间给予少量饲料,首次给予受试物后继续禁食约3 h。给予受试物后,观察并记录中毒作用体征出现和消失时间和死亡时间,观察期为14 天。观察期内中毒死亡动物应进行大体解剖,肉眼观察,如发现组织或脏器出现异常,进一步作组织病理学检查。分别在第0、1、3、7、14天称重。
实验结果:动物在给予样品期间及14 d观察期内均未见异常症状,体重正常增长,未见动物死亡,LD50>10 g/kg体重。试验结束所有动物大体解剖,肉眼观察未见异常。
实验结论:样品按GB 15193.3-2014《食品安全国家标准 急性经口毒性试验》检测,对SD大鼠的急性经口毒性LD50>10 g/kg体重,实际无毒。
试验例5、动物实验(芍药素-3-O-阿拉伯糖苷与血液AGEs水平)
实验方法:
动物分组:将2月龄小鼠按照体重进行分组,随机分为1个模型组、芍药素-3-O-葡萄糖苷组、芍药素-3-O-阿拉伯糖苷组、芍药素-3-O-半乳糖苷组、芍药素-3-O-芸香糖苷组、矮牵牛素-3-O-芸香糖苷(对香豆酰)-5-O-葡萄糖苷组、越橘混合花色苷组和1个空白对照组。
饲料制备:普通饲料:SPF级维持饲料;高AGEs饲料:将60Co辐照灭菌的SPF级维持饲料在160℃烘烤40分钟,制备高晚期糖基化终末产物饲料(高AGEs饲料),测定其中的羧甲基赖氨酸及羧乙基赖氨酸,高AGEs饲料中羧甲基赖氨酸及羧乙基赖氨酸浓度应为对照组饲料的2倍以上。
实验方法:将样品溶于纯化水中制备1mg/mL的储备液,按照0.9-3mg/kg的剂量灌胃给药。其中模型组及样品组给予高AGEs饲料,空白对照组给予普通饲料,持续1个月。同时样品组灌胃给予受试样品,模型组及空白对照组给予同体积溶剂。干预开始前取尾尖血0.4mL作为基线样本,实验结束时处死动物取血样0.4mL,采用UPLC-MS的方法检测血压样本中结合型羧甲基赖氨酸(CML)及结合型羧乙基赖氨酸(CEL)含量。
实验结果:与空白对照组相比,模型组小鼠血液中的CML与CEL显著上升(P<0.05);与模型组相比,芍药素-3-O-阿拉伯糖苷、越橘混合花色苷可以显著降低血液中CML与CEL含量(P<0.05),且芍药素-3-O-阿拉伯糖苷效果显著优于越橘混合花色苷(P<0.05);矮牵牛素-3-O-芸香糖苷(对香豆酰)-5-O-葡萄糖苷可以显著降低血液中的CML的含量,但CEL的含量变化不明显。芍药素-3-O-葡萄糖苷、芍药素-3-O-半乳糖苷、芍药素-3-O-芸香糖苷对于小鼠血液中的AGEs无显著变化(P>0.05)。
实验结论:芍药素-3-O-阿拉伯糖苷可以显著降低小鼠血液中的AGEs,且显著优于其他样品组。
试验例6、动物实验(芍药素-3-O-阿拉伯糖苷与Ⅱ型糖尿病)
基于AGEs水平升高是糖尿病及并发症发生的风险因素,AGEs是导致胰岛素抵抗的独立危险因素,本申请进一步研究芍药素-3-O-阿拉伯糖苷与Ⅱ型糖尿病之间的关系。
实验动物模型及分组:按60mg/kgBW在大鼠左下腹腔一次性注射链脲佐菌素(STZ,Sigma产品,溶于pH4.5浓度为0.1 mmol/L的柠檬酸盐缓冲液中,现配现用)。正常对照组注射等体积的柠檬酸盐缓冲液。72小时后取大鼠尾血测血糖,取血糖浓度大于16.7mmol/L的作为糖尿病大鼠。将糖尿病大鼠随机分为1个模型组、芍药素-3-O-阿拉伯糖苷组,另设1个空白对照组。
给药方法:将样品溶于纯化水中制备1mg/mL的储备液,按照0.9-3mg/kg的剂量灌胃给药。样品组灌胃给予受试样品,模型组及空白对照组给予同体积溶剂。
检测指标:主要测定指标有体重,糖耐量,空腹血糖(Fastingblood-glucose,FBG),血清胰岛素(Insulin,INS)含量等。
实验结果:芍药素-3-O-阿拉伯糖苷能够显著降低Ⅱ型糖尿病大鼠FBG水平和血清INS含量,改善Ⅱ型糖尿病大鼠体重减轻和胰岛素抵抗症状。
试验例7、动物实验(芍药素-3-O-阿拉伯糖苷与阿尔兹海默症)
基于AGEs水平升高与老年人的认知能力下降密切相关,本申请进一步研究芍药素-3-O-阿拉伯糖苷与阿尔茨海默症之间的关系。
实验动物模型及分组:3x Tg-AD小鼠(C57BL6背景的Psen1tm1Mpm Tg(APPSwe,tauP301L)三转AD小鼠),将4月龄的AD小鼠随机分为1个模型组、芍药素-3-O-阿拉伯糖苷组,另设1个空白对照组。
给药方法:将样品按照0.9-3mg/kg的剂量混入小鼠饲料中,采用自由取食的方式给药,周期为3个月。样品组给予添加受试样品的饲料,模型组及空白对照组给予添加安慰剂的维持饲料。
检测指标:采用Morris水迷宫、跳台、避暗等行为学实验检测各组小鼠学习记忆水平;检测小鼠脑内Aβ、Tau相关病理指标。
实验结果: 芍药素-3-O-阿拉伯糖苷能够显著改善AD小鼠的学习记忆能力,并降低脑内Aβ、Tau相关病理蛋白的表达水平,改善阿尔兹海默症。
试验例8、动物实验(芍药素-3-O-阿拉伯糖苷与动脉粥样硬化)
基于AGEs水平升高以及内皮细胞损伤与动脉粥样硬化之间密切相关,本申请进一步研究芍药素-3-O-阿拉伯糖苷与动脉粥样硬化之间的关系。
实验动物模型及分组:将4周龄雄性的C57BL/6J小鼠,高脂饲料喂养12周以建立动脉粥样硬化模型。将动脉粥样硬化模型小鼠随机分为1个模型组、芍药素-3-O-阿拉伯糖苷组,另设1个空白对照组。
给药方法:将样品溶于纯化水中制备1mg/mL的储备液,按照0.9-3mg/kg的剂量灌胃给药。样品组灌胃给予受试样品,模型组及空白对照组给予同体积溶剂。从高脂饲料喂养开始后的第6周开始预防给药,持续6周。
检测指标:检测小鼠血脂水平,炎症及活性氧指标(ROS、TNFα、ICAM、VCAM)等。
实验结果:芍药素-3-O-阿拉伯糖苷能够显著改善动脉粥样硬化小鼠的血脂代谢,包括TC、LDL-C水平下降;通过降低ROS及炎症因子(TNFα、ICAM、VCAM)的水平,改善小鼠内皮功能,从而减缓动脉粥样硬化的发生发展。
因此,根据上述各试验的结果可以看出,芍药素-3-O-阿拉伯糖苷在抑制AGES、治疗AGEs相关损伤、疾病或症状、或缓解AGEs相关损伤、疾病或症状方面具有相对于其他各受试组更优的效果;而且其为单组份物质相对于越橘混合花色苷具有更稳定、可控的抑制AGES生成的效果。
需要说明的是,本申请不限定于上述实施方式。上述实施方式仅为示例,在本申请的技术方案范围内具有与技术思想实质相同的构成、发挥相同作用效果的实施方式均包含在本申请的技术范围内。此外,在不脱离本申请主旨的范围内,对实施方式施加本领域技术人员能够想到的各种变形、将实施方式中的一部分构成要素加以组合而构筑的其它方式也包含在本申请的范围内。
Claims (12)
1.芍药素-3-O-阿拉伯糖苷在制备药物或保健食品中的应用,所述药物或保健食品为用于抑制AGEs的药物或保健食品、治疗AGEs相关损伤、疾病或症状的药物或保健食品、或缓解AGEs相关损伤、疾病或症状的药物或保健食品。
2.根据权利要求1所述的应用,其特征在于,所述药物还包括药学上可接受的辅料,所述保健食品还包括食品学上可接受的辅料。
3.根据权利要求1所述的应用,其特征在于,所述药物或保健食品的剂型为口服制剂或注射制剂。
4.根据权利要求3所述的应用,其特征在于,所述口服制剂为片剂、粉剂、胶囊剂、颗粒剂、丸剂、散剂、膏剂、固体饮料或口服液。
5.根据权利要求3所述的应用,其特征在于,所述口服制剂中所述芍药素-3-O-阿拉伯糖苷的质量含量≥0.0122%。
6.根据权利要求3所述的应用,其特征在于,所述注射制剂为注射液或注射用粉针剂。
7.根据权利要求3所述的应用,其特征在于,所述注射制剂中所述芍药素-3-O-阿拉伯糖苷的质量含量≥0.0122%。
8.根据权利要求1至7中任一项所述的应用,其特征在于,所述抑制AGEs为抑制AGEs生成、或促进AGEs分解。
9.根据权利要求1至7中任一项所述的应用,其特征在于,所述AGEs相关损伤为AGEs介导的细胞凋亡升高、活性氧含量升高、炎症因子TNF-α的过度表达、炎症因子ICAM-1的过度表达、炎症因子VCAM-1的过度表达和/或线粒体ATP含量的降低。
10.根据权利要求1至7中任一项所述的应用,其特征在于,所述AGEs相关疾病为心脑血管疾病、神经退行性疾病、骨关节疾病中的任意一种或多种。
11.根据权利要求10所述的应用,其特征在于,所述心脑血管疾病选自糖尿病及其并发症、动脉粥样硬化;和/或所述神经退行性疾病选自阿尔茨海默症、帕金森症、肌肉萎缩侧索硬化症;和/或所述骨关节疾病为骨质疏松、骨关节炎。
12.根据权利要求1至7中任一项所述的应用,其特征在于,所述AGEs相关症状为衰老。
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