CN110420216A - 石莼多糖在抑制β-淀粉样蛋白聚集中的用途 - Google Patents
石莼多糖在抑制β-淀粉样蛋白聚集中的用途 Download PDFInfo
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- CN110420216A CN110420216A CN201910734873.8A CN201910734873A CN110420216A CN 110420216 A CN110420216 A CN 110420216A CN 201910734873 A CN201910734873 A CN 201910734873A CN 110420216 A CN110420216 A CN 110420216A
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Abstract
本发明提出石莼多糖在抑制β‑淀粉样蛋白聚集中的用途,属于医药、保健品或食品技术领域。将石莼多糖用于制备药物、保健品或食品中,石莼多糖能够有效抑制β‑淀粉样蛋白聚集,从而防止阿尔茨海默症的发生。在一定浓度范围内,随着石莼多糖浓度增加,抑制效果越好;石莼多糖改变了聚集体的形貌,阻止并减缓了其向纤维状形貌的转化;同时,有效抑制了β‑淀粉样蛋白聚集过程中形成的聚集体所诱导的细胞毒性。
Description
技术领域
本发明属于医药、保健品或食品技术领域,尤其涉及石莼多糖在抑制β-淀粉样蛋白聚集中的用途。
背景技术
阿尔茨海默症(Alzheimer’s Disease,AD)是以进行性认知功能障碍和行为损害为特征的神经退行性疾病,是一种多发生在老年及老年前期的慢性疾病。
AD的病因复杂,其中淀粉样级联假说是目前AD发病机制的主流学说,即β-淀粉样蛋白(Aβ)在脑内的错误折叠和聚集是AD发生发展的关键因素之一。Aβ是由β-分泌酶和γ-分泌酶依次水解淀粉样前体蛋白APP产生的多肽片段,一般含有39-43个氨基酸。其中,Aβ40在脑内的含量最为丰富。研究表明,Aβ40蛋白在AD发病过程中均发挥着重要的作用。例如,Lee等人的研究(Lee et al.,Bioorganic&medicinal chemistry,2012,(16):4921)表明由于Aβ聚集物的积累被广泛认为是神经退行性病理学最初发展的基础,许多治疗AD的方法可通过降低大脑Aβ的浓度来降低神经毒性。因此,以Aβ40为研究对象来筛选Aβ聚集抑制剂就成为开发抗AD药物的研究热点。
石莼(Ulva lacutuca L.)俗名海莴苣、海白菜,为绿藻石莼科植物。石莼以其叶状藻体入药,具有软坚散结、清热解毒、利水降脂等功效。目前对石莼的化学及药理学研究中,多倾向于报道具有降胆固醇、抗肿瘤和抗凝血等作用。如公布号为CN1377897A的专利公开了石莼多糖在调节血脂中的应用。公布号为EP 3142749A的专利申请公开了石莼多糖在治疗关节炎中的应用。
然而以上报道和申请均未涉及石莼多糖对Aβ异构体纤维化的影响。
发明内容
本发明提出石莼多糖在抑制β-淀粉样蛋白聚集中的用途,通过抑制β-淀粉样蛋白聚集,从而预防或阻止AD疾病的发生或发展。
本发明提出石莼多糖在抑制β-淀粉样蛋白聚集中的用途。
进一步地,β-淀粉样蛋白为Aβ40。
进一步地,石莼多糖包括艾杜糖醛酸、葡萄糖醛酸、木糖、鼠李糖和葡萄糖。
进一步地,石莼多糖的糖单位包括式I和式II,具体如下:
进一步地,石莼多糖作为β-淀粉样蛋白聚集抑制剂在制备药物、保健品或食品中的用途。
进一步地,石莼多糖作为β-淀粉样蛋白聚集抑制剂用于制备预防或治疗阿尔兹海默症的药物。
进一步地,石莼多糖以水分散体系存在。
进一步地,石莼多糖在水分散体系中的浓度为250μg/mL-1mg/mL。
本发明的石莼多糖在抑制β-淀粉样蛋白聚集中的用途具有以下优势:
本发明提出了石莼多糖在抑制Aβ40聚集中的用途,可作为β-淀粉样蛋白聚集抑制剂并将其用于制备药物、保健品或食品中,能够有效抑制β-淀粉样蛋白聚集,从而防止AD的发生。在一定浓度范围内,随着石莼多糖浓度增加,抑制效果越好;石莼多糖改变了聚集的形貌,阻止并减缓了其向纤维状形貌的转化;同时,有效抑制了β-淀粉样蛋白聚集过程中形成的聚集体所诱导的细胞毒性。石莼多糖作为一种潜在的新药、保健品或食品分子,是理想的聚集抑制剂。
附图说明
构成本发明的一部分附图用来提供对本发明的进一步理解,本发明的示意性实施例及其说明用于解释本发明,并不构成对本发明的不当限定。在附图中:
图1为实施例1中不同浓度石莼多糖与Aβ40共培养不同时间后培养物的ThT荧光图。
图2为实施例2中1mg/mL石莼多糖与Aβ40共培养后培养物的原子力显微镜(AFM)图。
图3为实施例3中不同浓度石莼多糖与Aβ40共培养后培养物对PC12的细胞毒性图。
图4为实施例4中石莼多糖与Aβ40共培养后培养物的FDA/PI染色图。
具体实施方式
需要说明的是,在不冲突的情况下,本发明中的实施例及实施例中的特征可以相互组合。
本发明实施例提出石莼多糖在抑制β-淀粉样蛋白聚集中的用途。
石莼多糖的主要重复双糖结构式,即石莼多糖的糖单位,具体如式I、式II所示:
石莼多糖(Ulvan)是存在于绿藻(石莼和浒苔)细胞壁中的结构酸多糖,是目前研究较多的绿藻多糖结构。Ulvan为高度磺酸化,从其结构中提取出的水溶性多糖主要组成为艾杜糖醛酸、葡萄糖醛酸、木糖、鼠李糖和葡萄糖。Ulvan的主要连接方式如式I、式II所示,其糖残基绝大多数以α-(1→4)-和β-(1→4)-连接构成主链。分支位于鼠李糖的O-2位置,硫酸化基团位于鼠李糖的C-3位置。葡萄糖通过β-(1→4)-连接,鼠李糖通过α-(1→4)-连接,木糖通过β-(1→4)-连接,艾杜糖醛酸也通过β-(1→4)-连接。
现有技术中,石莼主要作为海菜食用,有清口、解毒、消炎等功效,也可防中暑、消肿、治喉痛、除口臭等。石莼的藻体或多糖具有降胆固醇、抗凝血、抗氧化、抗肿瘤等作用,主要应用于农业,食品和制药等诸多领域,具有潜在的生物学价值。而本申请提供了一种Ulvan在制备β-淀粉样蛋白聚集抑制剂的新用途,为β-淀粉样蛋白聚集抑制剂的研究提供了新思路。
在本发明一实施例中,β-淀粉样蛋白可以为Aβ39,Aβ40,Aβ42或Aβ43中的一种或两种以上。β-淀粉样蛋白是I型跨膜蛋白淀粉样前体蛋白(amyloid precursor protein,APP),是在β-和γ-分泌酶的水解作用下形成的以α-螺旋或无规则卷曲为主的淀粉样多肽。由于γ-分泌酶的水解位点不同从而产生不同类型的Aβ异构体,如Aβ39,Aβ40,Aβ42和Aβ43。优选的,β-淀粉样蛋白为Aβ40。Aβ40是最主要的短肽之一,在AD形成和发展中起至关重要的作用。
在本发明又一实施例中,Ulvan作为β-淀粉样蛋白聚集抑制剂在制备药物、保健品或食品中的用途。本发明充分利用Ulvan药食两用,毒副作用小、来源丰富,且食用方便,患者顺应性良好的特性,将其用于药物、保健品或食品的新开发。
具体而言,Ulvan可以作为Aβ40聚集抑制剂用于制备预防和/或治疗AD的药物。将Ulvan用于制备抑制Aβ聚集的药物中,可通过抑制Aβ40的产生和聚集,从而防止AD的发生。
AD是一种中枢神经系统退行性疾病。正常生理条件下,Aβ40是可溶的,它的产生、降解和清除是一个动态平衡过程。但在AD患者脑内,这种平衡被破坏,Aβ40通过自身聚集形成难溶的沉淀,并生成老年斑,导致AD发生。通过抑制Aβ40的产生和聚集,从而防止AD的发生(Gaudreault,R.et al,Mitigating Alzheimer's Disease by Natural Polyphenols:AReview,Curr Alzheimer Res,2019;Yanru Xin,et al,Conformation-DependentManipulation of Human Islet Amyloid Polypeptide Fibrillation by Shiitake-Derived Lentinan,ACS Appl Mater Interfaces,2018,10/37:31069)。
本发明实施例中所用Ulvan购自上海甄准生物科技有限公司。
制备各种含有各种比例活性成分的药物组合物的方法是已知的,或根据本发明的公开内容对于本领域技术人员是显而易见的。本发明在此不再赘述。
在本发明又一实施例中,药物的剂型可以为针剂、片剂、硬胶囊或软胶囊。具体地,Ulvan可以以粉末混合物的形式存在,可以用于制备用于抑制β-淀粉样蛋白聚集的粉末混合物型药物,如片剂、硬胶囊;或者,可以以Ulvan的分散体系的形式存在,即,Ulvan可以用于制备用于抑制β-淀粉样蛋白聚集的液体型药物,如针剂、注射液、软胶囊。
如上,在本发明一实施例中,Ulvan可以以水分散体系存在,如剂型可以为胶囊、糖浆,液体载体为水作为分散介质。制备药物方法包括掺入适当的药学赋形剂、载体、稀释剂等。因此,当剂型为胶囊时,还可以包括植物油或聚乙二醇。当剂型为糖浆时,还可以蔗糖或果糖作为甜味剂,对羟苯甲酸甲酯或对羟苯甲酸丙酯作为防腐剂,染料和调味剂。当然,用于制备任何单位剂型的任何材料应该是药学上可以接受的且以应用的量为无毒。
具体而言,这些制剂应该包含250μg/mL-1mg/mL的活性成分,即Ulvan在水分散体系中的浓度为250μg/mL-1mg/mL,具体可以为250μg/mL,500μg/mL和1mg/mL等。控制在该浓度范围内,可实现较好的β-淀粉样蛋白聚集的抑制效果。
在本发明又一实施例中,Ulvan也可以作为β-淀粉样蛋白聚集抑制剂用于制备食品和保健品。Ulvan作为β-淀粉样蛋白聚集的抑制剂制备的保健品或食品也可用于预防阿尔茨海默病的发生。保健品和食品对人体的毒副作用相对较小,将其用于预防阿尔茨海默病具有良好效果。可见,本发明实施例提供的用途进一步促进了治疗阿尔茨海默病的研究进展。
具体而言,Ulvan可以以水分散体系存在,如可以制备为口服液、液体饮料的形式,以水作为分散介质。当制备为口服液、液体饮料形式时,还可以包括维生素、微量元素等营养成分。
具体而言,口服液、液体饮料等应该包含250μg/mL-1mg/mL的活性成分,即Ulvan在水分散体系中的浓度为250μg/mL-1mg/mL,具体可以为250μg/mL,500μg/mL和1mg/mL等。
制备各种保健品或食品的方法是已知的,或根据本发明的公开内容对于本领域技术人员是显而易见的。本发明在此不再赘述。
下面参照具体实施例进一步阐述Ulvan在抑制Aβ40聚集中的用途。
实施例1:不同浓度Ulvan与Aβ40共培养不同时间后培养物的硫黄素(ThT)荧光强度变化
首先将Aβ40溶于六氟异丙醇溶液,得到1mg/mL的Aβ40溶液,超声10min,使Aβ40处于单分散状态,冷冻干燥,获得Aβ40干粉,于-20℃保存。
称取4.38mg硫黄素T(Thioflavin,ThT)溶于50mL磷酸盐缓冲液(phosphatebuffer saline,PBS;其中磷酸盐浓度为100mM,NaCl浓度为10mM),得275μM ThT母液。
将冻干的Aβ40粉末溶于20mM NaOH溶液中,使其终浓度为275μM。超声10min使之充分溶解。16000g离心20min去除已经发生聚集的多肽。取上清75%,加入上述ThT母液,按终浓度比为1:1用PBS稀释至25μM,37℃原位培养,得275μM的Aβ40母液。
称取5mgUlvan粉末溶于1mL超纯水中,得5mg/mL的Ulvan母液。
将浓度为275μM的Aβ40母液与上述Ulvan母液按梯度稀释,获Ulvan终浓度分别为250μg/mL,500μg/mL和1mg/mL的Aβ40溶液(其中,溶液中的Aβ40和ThT的浓度均为25μM),37℃进行原位培养。
在不同培养时间下测定其在480nm处发射波长下的荧光强度,激发和发射缝宽均为5nm,扫描速度为100nm/min,扫描结果均为3次平均值。将480nm处的荧光强度对时间作图,结果如图1所示。
由图1可知,Aβ40单独培养时的ThT荧光图为典型的“S”型曲线,分为滞后期(0~70h),快速增长期(70h~96h)和稳定平台期(≥96h)。加入Ulvan后Aβ40的ThT荧光强度明显下降,且ThT荧光下降程度与加入的Ulvan的浓度呈正比,加入Ulvan的浓度越大,荧光抑制效果越强。同时,可以观察到延迟期随着Ulvan浓度的增加,延迟期逐渐增长,当Ulvan浓度为1mg/mL时,延迟期增大到96h,与对照组未添加Ulvan延迟期为70h相比,时间延长了26h。说明Ulvan有效抑制了Aβ40的聚集。
实施例2:1mg/mL Ulvan与Aβ40共培养120h后培养物的形貌变化
按照与实施例1相同的方法处理Aβ40,并配制含有浓度为1mg/mLUlvan的Aβ40溶液,溶液中Aβ40的终浓度为25μM。将上述溶液于37℃,200rpm条件下进行培养。
在不同培养时间下,取100μL Aβ40培养液,超声10min,在干净的培养皿中用双面胶固定好圆形铁片,再在圆形铁片上用双面胶固定好云母片,然后用透明胶带连续将云母片粘三次,去掉云母片的不干净层数。后用20μL的移液枪,取20μL超声好的样品滴在云母片上,待5-10min后,再用移液枪取200μL屈臣氏纯净水慢冲洗5次(总共冲洗用水量为1mL),后自然晾干。然后用原子力显微镜(JEOL Inc.,Tokyo,Japan)进行观察,检测电压为100KV,选取放大尺度为1μm的图像进行观察,结果如图2所示。
由图2可知,加入Ulvan后Aβ40聚集体的形貌发生了变化;培养时间为120h,Aβ40单独培养时出现了致密的成熟纤维,细且长(图2A)纤维高度约为8nm左右,与报道的纤维长度一致。加入Ulvan组并未出现成熟的纤维聚集体(图2B),主要以短而粗的短棒状聚集体存在,纤维高度约为12nm。说明Ulvan的存在改变了Aβ40聚集体的形貌,阻止了纤维化过程。也证明Ulvan对Aβ40的聚集有抑制作用。
实施例3:用MTT方法检测不同浓度Ulvan与Aβ40共培养120h后培养物对PC12的细胞毒性
细胞毒性实验中使用的细胞为鼠嗜铬细胞瘤株(PC12)。RPMI 1640培养基加体积分数为10%胎牛血清和1%青霉素-链霉素,5%CO2,37℃培养细胞。待细胞增长至70%融合时,用含0.1g/L乙二胺二乙酸二钠盐的0.5g/L胰蛋白酶消化,再用含有10%胎牛血清和1%青霉素-链霉素的RPMI 1640培养基以适当浓度稀释细胞,以5×103cell/孔的细胞浓度加入到96孔板,每孔90μL。5%CO2,37℃培养24h。
配制浓度为30μM Aβ40和Ulvan终浓度分别为250μg/mL,500μg/mL和1mg/mL的Aβ40溶液,其中Aβ40的处理方法与实施例1相同,37℃培养120h。
将上述老化好的Aβ40和加入不同浓度Ulvan的Aβ40溶液加入到已经培养24h的含有PC12的96孔板中,10μL/孔。空白对照孔中不加Ulvan和Aβ40溶液,而加入PBS缓冲液10μL/孔。最终使加药孔每孔中Ulvan终浓度为25μg/mL,50μg/mL和100μg/mL,Aβ40的终浓度为3μM。细胞在培养箱中以5%CO2,37℃培养48h后,加入10μL/孔的MTT溶液,使得培养基中的MTT终浓度为0.5mg/mL。5%CO2,37℃条件继续培养4h。
移除96孔板中溶液,每孔加入100μL的DMSO 37℃培养10min,检测570nm处吸光值。将培养基中不含Aβ40和Ulvan孔作为空白对照组,记为细胞活性为100%,然后将其作为对照计算加药组的细胞存活率(图3)。实验中每个Ulvan浓度梯度设置6个复孔。由图3A可知,当Aβ40单独培养时,细胞存活率为55%。而加入不同终浓度Ulvan(25μg/mL,50μg/mL和100μg/mL)后细胞存活率提高到62%、66%和85%,加入Ulvan浓度越大,毒性缓解作用越强,说明Ulvan能够有效缓解Aβ40产生的细胞毒性。由图3B可知虽然高浓度Ulvan本身会对细胞有一定的影响,但不影响其对Aβ40聚集的抑制作用。
实施例4:用FDA/PI混合双染检测Ulvan与Aβ40共培养120h后培养物对PC12的细胞毒性
配制储藏液,称取FDA 5mg,加入15mL离心管。加入1mL的丙酮,振荡,包住锡纸并标记,-4℃度低温保存。称取PI1mg,加入15mL离心管。加入lmL的PBS缓冲液,振荡,包住锡纸并标记,-4℃低温保存。配制工作液,取10mL的PBS到离心管,加入FDA储存液20μL,PI储存液50μL,使FDA终浓度为10μg/mL,PI终浓度为5μg/mL。包住锡纸并标记,-4℃度低温保存。
取与实施例3相同方法分化处理好的PC12细胞,以密度5×104cell/mL稀释细胞,加入到6孔板,每孔2mL。5%CO2,37℃培养24h。
配制浓度分别为0mg/mL,1mg/mL的Ulvan溶液的Aβ40溶液(此时溶液中的Aβ40的浓度为30μM),其中Aβ40的处理方法与实施例1相同,37℃培养120h。
将上述老化好的Aβ40,含有不同浓度Ulvan的Aβ40溶液加入到已经培养24h的含有PC12的6孔板中,200μL/孔。空白对照孔中加入PBS缓冲液200μL/孔。细胞在培养箱中以5%CO2,37℃培养48h后,进行FDA/PI混合双染。
慢速轻轻吸出培养基,用PBS轻洗2次并吸出。慢速贴壁加入染色液避光染色1-2min,PBS轻洗后荧光显微镜进行观察(图4)。与对照组相比,Aβ40可以使能被FDA染色的存活细胞数量减少,使能被PI染色的凋亡细胞数量增加。加入Ulvan后,可以明显观察到荧光信号的减少,表明Ulvan能显著降低Aβ40引起的细胞凋亡。
实施例5:石莼多糖用于保健品的制备
重量份组成为(每份为0.01g):石莼多糖1份、维生素C 10份、维生素H 10份、硫酸亚铁5份、氧化锌1份。
引用时加水1L冲服。
使用该保健品与Aβ40制得的混合溶液进行荧光强度测试,与对照组(未添加石莼多糖的保健品与Aβ40形成的溶液)进行比较,加入石莼多糖后Aβ40的荧光强度明显下降,说明石莼多糖有效抑制了Aβ40的聚集。
实施例6:石莼多糖用于饮料的制备
重量份数为(每份为0.01g):石莼多糖0.01份、柠檬酸50份、葡萄糖25份、水1000份。
通过溶解活性组分,混合,在85℃下搅拌1h,过滤,然后将所有组分填装进瓶中进行灭菌制得健康饮料。
Aβ聚集抑制剂是AD治疗新药开发的主要热点。Aβ聚集抑制剂通过抑制β-淀粉样蛋白(Aβ)的产生和聚集,从而预防或治疗AD。本发明通过多种实验手段证明,Ulvan能有效抑制Aβ40的聚集并改变聚集体的形态,减缓或阻止Aβ40纤维化进程。同时,能有效抑制Aβ40聚集体对细胞产生的毒性。Ulvan作为药食同源的物质,毒副作用小,食用方便,是Aβ40聚集的理想抑制剂,具有广泛的应用前景。
以上仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (8)
1.石莼多糖在抑制β-淀粉样蛋白聚集中的用途。
2.根据权利要求1所述的用途,其特征在于,所述β-淀粉样蛋白为Aβ40。
3.根据权利要求1所述的用途,其特征在于,所述石莼多糖包括艾杜糖醛酸、葡萄糖醛酸、木糖、鼠李糖和葡萄糖。
4.根据权利要求1所述的用途,其特征在于,所述石莼多糖的糖单位包括式I和式II,具体如下:
5.根据权利要求1所述的用途,其特征在于,所述石莼多糖作为β-淀粉样蛋白聚集抑制剂在制备药物、保健品或食品中的用途。
6.根据权利要求1所述的用途,其特征在于,所述石莼多糖作为β-淀粉样蛋白聚集抑制剂用于制备预防或治疗阿尔兹海默症的药物。
7.根据权利要求1所述的用途,其特征在于,所述石莼多糖以水分散体系存在。
8.根据权利要求1所述的用途,其特征在于:所述石莼多糖在水分散体系中的浓度为250μg/mL-1mg/mL。
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