CN113940939A - 甘露葡萄糖醛酸寡糖和多糖及衍生物在制备治疗和/或预防衰老药物中的应用 - Google Patents
甘露葡萄糖醛酸寡糖和多糖及衍生物在制备治疗和/或预防衰老药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种甘露葡萄糖醛酸寡糖和多糖及衍生物在制备治疗和/或预防衰老药物中的应用,用于解决现有抗衰老药物副作用大,效果一般的问题。本发明具有显著抗衰老的作用,毒副作用小,安全有效,可以用于制备抗衰老药物。本发明制备流程简单,成品率高,来源安全。
Description
技术领域
本发明涉及药学领域,具体涉及甘露葡萄糖醛酸寡糖和多糖及衍生物在制备治疗和/或预防衰老药物中的应用。
背景技术
进入21世纪后,人类面临人口老龄化的严峻挑战,许多国家(包括我国)已经进入人口老龄化社会,≥60岁的老年人占总人口的10%以上。目前,我国老年人(包括一部分中年人)受到衰老的严重困扰,直接影响他们的健康状况和生活质量。如何完整地阐明衰老的发病机理,如何提高老年人的健康状况和生活质量,是当前研究者们需要着重解决的问题。近年来,随着科技的发展,研究手段的不断提高,现代人们研究的焦点是这些中草药的西医抗衰老机制及药用潜力,正展现出巨大的诱人前景。
在衰老过程中,p16基因在人类和小鼠胰腺β细胞中的活性增加,并限制了它们分裂的潜能。这种活性被认为是有负面影响的,希伯来大学的博士后Ronny Helman,在IttaiBen-Porath博士以及Yuval Dor教授等人发现,在正常的衰老过程中,p16和细胞衰老实际上可改善β细胞的主要功能:葡萄糖刺激之后的胰岛素分泌。β细胞衰老主要诱因为过氧化氢,其进入人体后可加速人体的衰老进程,过氧化氢与老年痴呆,尤其是早老性痴呆的发生或发展关系密切,过氧化氢与老年帕金森氏病、脑中风、动脉硬化及糖尿病性肾病和糖尿病性神经性病变的发展密切相关。
细胞衰老发生于受损细胞,并防止其在生物体增殖。细胞损伤本身并不直接导致明显的衰老迹象,而是当损伤累积和达到一定的限度,细胞停止增殖,导致肉眼可见的组织衰弱和生理上的衰老表型。一些衰老诱导因素(包括DNA损伤、致癌突变、活性代谢产物、高促分裂原和营养信号增加mTOR 活动、蛋白毒性压力)可以单独或协同作用于细胞,通过p16INK4a/Rb、 p53/p21通路或其他路径导致细胞衰老。这些可能导致普遍的基因表达变化和染色质重塑(异染色质的形成),这些是SASP、衰老相关生长停滞以及形态学变化的基础。
糖类是生物体内除蛋白质和核酸外又一类重要的生物分子,在细胞的分裂分化,生长代谢等方面发挥着重要的作用。多糖(polysaccharide)是由多个单糖分子缩合、失水而成,是一类分子结构复杂的糖类物质。多糖可以通过增大巨噬细胞体积来提高机体免疫力。多糖也可以通过调节巨噬细胞细胞因子的分泌量来调节巨噬细胞功能。多糖还可以通过调节巨噬细胞内酶的活性进而影响巨噬细胞的功能。此外,多糖对淋巴细胞的调节作用主要体现在对其增殖能力、亚群结构、细胞因子分泌等的影响。多糖也具有良好的降血糖和抗糖尿病效应,其主要经由促肝糖元合成,促糖酵解或抑制α-糖苷酶的活性等途径影响糖代谢,也可直接作用胰岛β细胞,促进胰岛素分泌,增加胰岛素敏感性以及增强抗氧化应激而发挥降血糖功能。因此,多糖降血糖作用机制呈多效应、多靶点、多途径等特点。寡糖也同时具有多种作用,如影响机体肠道生态和生理的作用,抗凝血,抗炎,提高机体免疫,抗老年痴呆等活性。
甘露葡萄糖醛酸寡糖和多糖作为一类新型的糖类物质,前期研究发现甘露葡萄糖醛酸寡糖和多糖具有预防帕金森病和/或老年痴呆(专利 201410092395.2),预防2型糖尿病(专利201910380776.3)和抗氧化(专利 201810546910.8)等方面的作用。
发明内容
为了解决现有抗衰老药物副作用大,效果一般的问题,我们提出了一种甘露葡萄糖醛酸寡糖和多糖及衍生物在制备治疗和/或预防衰老药物中的应用。
本发明是通过以下技术方案实现的:
为实现上述目的,本发明提供一种甘露葡萄糖醛酸寡糖和多糖及衍生物在制备治疗和/或预防衰老药物中的应用,其中甘露葡萄糖醛酸寡糖结构式如下:
其中,n1为0-4之间的整数;R1为H或NH4 +;
在一次甘露葡萄糖醛酸寡糖的制备过程中,样品提取仅会出现4种寡糖(G1-G4),G1-G4分别为甘露葡萄糖醛酸八糖(GM8),六糖(GM6),四糖(GM4)和二糖(GM2),均符合上述结构式,其中:
G4为甘露葡萄糖醛酸八糖(GM8),式中n1=3;
G3为甘露葡萄糖醛酸六糖(GM6),式中n1=2;
G2为甘露葡萄糖醛酸四糖(GM4),式中n1=1;
G1为甘露葡萄糖醛酸二糖(GM2),式中n1=0。
另外,甘露葡萄糖醛酸多糖结构式如下:
其中,n2为5-40之间的整数;R2为H,K或者Na中的一种或二种以上。
在甘露葡萄糖醛酸多糖的制备过程中,得到n2≈20,并命名为GMn。
优选的,上述甘露葡萄糖醛酸寡糖结构式中的n1为0或1或2或3;R1为H或NH4 +。
优选的,上述甘露葡萄糖醛酸多糖结构式中的n2为18或19或20或21 或22;R2为H,K或者Na中的一种或二种以上。
优选的,上述甘露葡萄糖醛酸多糖结构式中的n2为20;R2为H,K或者Na中的一种或二种以上。
优选的,上述衍生物为一种甘露葡萄糖醛酸寡糖或甘露葡萄糖醛酸多糖的硫酸化衍生物。
优选的,上述药物为药学上可接受载体或剂型,包括药学可接受的载体和/或赋形剂的药物组合物。载体包括海藻酸纳微球、脂质体等。赋形剂包括甘露醇、硬脂酸镜、淀粉、环糊精等。药物类型包括以下几种:
(1)内服药:有溶液、合剂、片剂、酊剂、粉剂、胶囊、丸散及纸型等;
(2)注射药:有溶液、油剂、混悬剂、结晶、粉剂;
(3)外用药有软膏、溶液、酊剂、粉剂、搽剂、洗剂、滴剂、栓剂、涂膜剂等;
(4)新剂型有粘贴敷片、植入慢溶药片、胰岛素泵等。
本发明同时提供一种治疗和/或预防衰老的方法,施用有效量的甘露葡萄糖醛酸寡糖或甘露葡萄糖醛酸多糖或其衍生物。
优选的,上述衍生物为甘露葡萄糖醛酸寡糖或甘露葡萄糖醛酸多糖的硫酸化衍生物。
与现有技术相比,本发明的有益效果在于:
(1)本发明具有显著抗衰老的作用,毒副作用小,安全有效,可以用于制备抗衰老药物。
(2)本发明制备流程简单,成品率高,来源安全。
附图说明
图1为寡糖制备过程中酒精洗脱液的凝胶色谱图;
图2为甘露葡萄糖醛酸寡糖G1-G4的ESI-MS图和HPLC图;其中a为 GM2;b为GM4;c为GM6;d为GM8;
图3为GMn的氢谱;
图4为GMn的碳谱;
图5为GMn的二维HMBC谱图;
图6为GMn的二维HSQC谱图;
图7为GMn的二维HHCOSY谱图;
图8为GMn的GPC-HPLC谱图;
图9为本发明对细胞活力促进图;
其中A为:本发明对MIN6细胞处理图;
B为:本发明对干预H2O2预处理的胰岛β细胞处理图;
图10为:SA-β-gal染色显示图;(1:CTR,2:H2O2,3:H2O2+GM2, 4:H2O2+GM4,5:H2O2+GM6,6:H2O2+GM8,7:H2O2+GMn)
具体实施方式
下面结合实施例,更具体地说明本发明的内容。应当理解,本发明的实施并不局限于下面的实施例,对本发明所做的任何形式上的变通或改变都落入本发明保护范围;且下述实施例中的方法,如无特别说明,均为本领域的常规方法。
实施例1:甘露葡萄糖醛酸寡糖的制备
将干海带等褐藻采用30倍质量的蒸馏水100℃下提取3小时,除褐藻胶胶,提取液经过过滤,透析,浓缩后,加乙醇至终浓度为75%沉淀,静置12 小时后收集沉淀,沉到经真空干燥得到褐藻多糖硫酸酯。将褐藻多糖硫酸酯样品溶于质量浓度为4%的硫酸溶液中(料液比为60mg/mL)加热回流5小时,用氢氧化钡中和至PH=6-7,离心,上清液浓缩至原始体积的五分之一,浓缩液上活性炭柱层析,首先用蒸馏水平衡,然后用50%-90%乙醇梯度洗脱,将50%-90%乙醇洗脱液浓缩至原始体积的五分之一,蒸去乙醇,直接上Bio-gel P4柱层析(柱体积:2.6cm×100cm;流动相:0.5mol/L碳酸氢铵),分离得到六个组分,如图1所示。对上面收集得到的样品进行ESI-MS 和HPLC分析,如图2所示。结果进一步确认寡糖的结构。结果显示,G1-G4 分别为甘露葡萄糖醛酸八糖(GM8),六糖(GM6),四糖(GM4)和二糖 (GM2)。其结构均符合如下所示的结构式:
其中G1为甘露葡萄糖醛酸八糖(GM8),式中n1=3,R1为H或者NH4 +;
G2为甘露葡萄糖醛酸六糖(GM6),式中n1=2,R1为H或者NH4 +;
G3为甘露葡萄糖醛酸四糖(GM4),式中n1=1,R1为H或者NH4 +;
G4为甘露葡萄糖醛酸二糖(GM2),式中n1=0,R1为H或者NH4 +;
实施例2:甘露葡萄糖醛酸多糖的制备
将实施例1中的得到褐藻多糖硫酸酯溶于质量浓度为4%的硫酸溶液中 (料液比为60mg/mL)加热回流4小时,用氢氧化钡中和至PH=6-7,离心,上清液浓缩至小体积,浓缩液上DEAE Sepharose Fast Flow(DEAE琼脂糖凝胶,分别采用水洗,0.2M氯化钠和2M氯化钠洗脱,2M洗脱液通过500Da 透析袋透析制备得到甘露葡萄糖醛酸多糖GMn(7.0kDa),对样品进行1H-NMR,13C-NMR,二维NMR和GPC-HPLC等。如图3和图4所示,1H-NMR,13C-NMR分别为氢核磁共振谱和碳13核磁共振谱。如图5所示,二维HMBC(1H detected heteronuclearmultiple bond correlation)为1H的异核多碳相关谱,将1H核和远程耦合的13C核关联起来,通常2~3个键的质子与碳的耦合信息较多;HMBC给出的是远程偶合的碳氢关系,采用较小的2JcH或3JcH偶合常数进行调节,则可得相隔2个或3个键的碳氢相关谱。如图6所示,二维HSQC(heteronuclear singular quantum correlation)为异核单量子关系,隶属于NMR(核磁共振)C-H COSY谱图中的一种,HSQC 给出的信息是直接相连的碳氢关系,给出一键CH连接问题。如图7所示,二维HHCOSY,二维相关谱(COSY)对角线上的峰是一来维谱峰,对角线以外的峰为交叉峰,交叉峰相对于对角线为轴对称,从一个交叉峰出发分别作垂直线与水平线与对角线相交,相交处的两峰所对应的核之间有J耦合。因此交叉自峰将标量耦合的质子相关联。如图8所示,凝胶渗透色谱法GPC和高效液相谱HPLC,用于检测蛋白、多糖和水溶性聚合物的分子量,同样可以用于化合物和含量检测。综合图3-图8的信息,可知甘露葡萄糖醛酸多糖的结构如下,结果进一步确认甘露葡萄糖醛酸多糖的结构。其结构均符合如下所示的结构式:
其中GMn为甘露葡萄糖醛酸多糖,式中n1≈20,R1为H,K或者Na。
实施例3:甘露葡萄糖醛酸多(寡)糖能缓解过氧化氢引起的β细胞活力下降
用100μg/ml浓度的本发明甘露葡萄糖醛酸多(寡)糖处理MIN6细胞,细胞活力不受影响,说明该浓度没有细胞毒作用(图9A);继而甘露葡萄糖醛酸多(寡)糖用干预H2O2预处理后的胰岛β细胞24h,甘露葡萄糖醛酸多(寡)糖对细胞活力有明显的增强作用(图9B),如图9所示。
实施例4:甘露葡萄糖醛酸多(寡)糖能缓解过氧化氢引起的β细胞衰老
SA-β-gal染色显示甘露葡萄糖醛酸多(寡)糖干预后,染色阳性的细胞越来越少(图10)。说明甘露葡萄糖醛酸多(寡)糖能够延缓胰岛β细胞衰老。
Claims (8)
2.如权利要求1所述的应用,其特征在于,所述甘露葡萄糖醛酸寡糖结构式中的n1为0或1或2或3;R1为H或NH4 +。
3.如权利要求1所述的应用,其特征在于,所述甘露葡萄糖醛酸多糖结构式中的n2为18或19或20或21或22;R2为H,K或者Na中的一种或二种以上。
4.如权利要求3所述的应用,其特征在于,所述甘露葡萄糖醛酸多糖结构式中的n2为20;R2为H,K或者Na中的一种或二种以上。
5.如权利要求1所述的应用,其特征在于,所述衍生物为一种甘露葡萄糖醛酸寡糖或甘露葡萄糖醛酸多糖的硫酸化衍生物。
6.如权利要求1所述的应用,其特征在于,所述药物为药学上可接受载体或剂型。
7.一种治疗和/或预防衰老的方法,其特征在于,施用有效量的甘露葡萄糖醛酸寡糖或甘露葡萄糖醛酸多糖或其衍生物。
8.如权利要求7所述的方法,其特征在于,所述衍生物为一种甘露葡萄糖醛酸寡糖或甘露葡萄糖醛酸多糖的硫酸化衍生物。
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