CN114129589B - 榴莲种子发酵多糖及其在预防治疗阿尔茨海默症中的应用 - Google Patents
榴莲种子发酵多糖及其在预防治疗阿尔茨海默症中的应用 Download PDFInfo
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Abstract
本发明提供一种榴莲种子发酵多糖及其在预防或治疗阿尔茨海默症中的应用,是使用榴莲种子多糖抑制β‑淀粉样蛋白聚集;所述的榴莲种子多糖,其制备方法,是将榴莲种子粉末用水进行提取,水提取液用贝莱斯芽孢杆菌进行了发酵制备的;所使用的贝莱斯芽孢杆菌的保藏编号为CGMCC No:18065。本发明使用在普洱茶中分离得到的贝莱斯芽孢杆菌与榴莲种子共发酵制备榴莲种子多糖,借助微生物的发酵,有效降解了榴莲种子中的蛋白质、淀粉和纤维素等大分子杂质,有利于榴莲种子多糖的提取,并且提高了有益多糖的含量,改善了生物活性,经过提取获得的多糖FDSP具有更好的抗AD活性。
Description
技术领域
本发明属于活性物质制备技术领域,具体涉及一种榴莲种子发酵多糖及其在预防治疗阿尔茨海默症中的应用。
技术背景
阿尔茨海默症(Alzheimer disease,AD)是一种以进行性认知障碍和记忆力损害为主的中枢神经***退行性疾病,是目前老年医学领域中危害最严重的疾病之一。现阶段国内外临床治疗AD主要依赖于胆碱酯酶抑制剂和N-甲基-D-天冬氨酸受体拮抗剂两类药物。但上述两种药物价格昂贵,副作用明显,且只能延缓疾病进程,不能逆转病情。淀粉样蛋白级联假说认为β-淀粉样蛋白(amyloidβ-protein,Aβ)在脑内沉积是AD病理改变的中心环节,研究也证明有效抑制和清除Aβ蛋白聚集和沉积是预防和治疗AD的重要手段。
榴莲又名韶子,麝香猫果,是木棉科榴莲属植物,营养价值丰富。据统计,2020年中国从泰国进口的新鲜榴莲数量已经超过57万吨。榴莲种子中不仅含有丰富的氨基酸和多糖,还富含黄酮和多酚等多种活性物质,具有很好的潜在利用价值,但目前对于榴莲种子中富含的多糖组分还没有进行深层次的开发利用。
发明内容
本发明的目的是提供一种榴莲种子发酵多糖及其在预防或治疗阿尔茨海默症中的应用,从而弥补现有技术的不足。
本发明首先提供榴莲种子多糖在制备用于抑制β-淀粉样蛋白聚集的制品中的应用,
所述的榴莲种子多糖,其制备方法,是将榴莲种子粉末用水进行提取,水提取液进行酶解,酶解后用乙醇进行沉淀;沉淀离心干燥获得的榴莲种子多糖;
所述的乙醇进行沉淀,其中乙醇溶液的添加终浓度为70%;
更进一步的,所述的榴莲种子多糖,其制备方法中,对榴莲种子粉末的水提取液用贝莱斯芽孢杆菌进行了发酵;
所述的贝莱斯芽孢杆菌,作为实施例的一种具体记载,其保藏编号为CGMCC No:18065。
所述的发酵,其一种具体的方法,是将浓度达到8×107cfu/mL的贝莱斯芽孢杆菌种子液按照榴莲种子粉末质量的1%-5%进行接种;
所述的发酵,作为实施例的具体记载,其最优的发酵条件如下:pH值为7;发酵温度为30℃;发酵时间为36h。
本发明再一个方面提供一种用于预防或治疗阿尔茨海默症的制品,所述的制品中包含有药理有效浓度的榴莲种子多糖。
本发明使用在普洱茶中分离得到的贝莱斯芽胞杆菌与榴莲种子共发酵制备榴莲种子多糖,借助微生物的发酵,有效降解了榴莲种子中的蛋白质、淀粉和纤维素等大分子杂质,有利于榴莲种子多糖的提取,并且提高了有益多糖的含量,改善了生物活性,经过提取获得的多糖FDSP具有更好的抗AD活性。
附图说明
图1:DSP多糖对Aβ1-42聚集的影响图;
图2:不同接种量制备的FDSP对Aβ1-42聚集的影响图;
图3:不同pH条件下制备的FDSP对Aβ1-42聚集的影响图;
图4:不同发酵温度下制备的FDSP对Aβ1-42聚集的影响图;
图5:不同发酵时间制备的FDSP对Aβ1-42聚集的影响图;
图6:FDSP对Aβ1-42聚集的影响图;
图7:两种榴莲种子多糖清除DPPH·的活性比较图;
图8:两种榴莲种子多糖清除·OH的活性比较图;
图9:两种榴莲种子多糖清除O2-·的活性比较图;
图10:榴莲种子多糖分子量分布图;
图11:榴莲种子发酵多糖分子量分布图;
图12:FDSP对AD秀丽隐杆线虫生理生化指标的影响图;
图13:FDSP对线虫寿命的影响图;
图14:FDSP对线虫生殖能力的影响图;
图15:FDSP对线虫瘫痪速率的影响图;
图16:FDSP对线虫运动能力的影响图;
图17线虫体内Aβ沉积情况图。
具体实施方式
下面结合实施例和附图对本发明进行详细的描述。
实施例1:榴莲种子多糖及发酵产物抑制Aβ1-42聚集能力
1、榴莲种子多糖(DSP)的制备及对Aβ1-42聚集的影响
(1)榴莲种子多糖(DSP)的制备
金枕榴莲种子购自青岛城阳果品集散中心,将清理干净的榴莲种子切为薄片后进行冷冻干燥,再经高速粉碎机粉碎并过100目筛后得到干燥的榴莲种子粉末。
取干燥的榴莲种子粉末50g装入1000mL烧杯中,按照1:10的料液比加入去离子水,依次添加α-淀粉酶(酶活50000U/g,添加量200U/g)、中性蛋白酶(酶活50000U/g,添加量270U/g)和纤维素酶(酶活130000U/g,添加量400U/g),三种酶均在pH值6~7的范围内进行酶解1h,酶解完成后用保鲜膜封口置于80℃水浴锅中水浴30min,进行灭酶灭菌处理,冷却至室温后,经抽滤和高速离心的方式去除大量不溶性杂质,保留的上清液使用旋转蒸发仪浓缩至70mL,再加入95%可食用乙醇沉降多糖,使乙醇终浓度达到70%,4℃静置过夜后离心分离保留沉淀,用少量95%可食用乙醇清洗沉淀2-3次,-80℃超低温冰箱冷冻后进行冷冻干燥,得到榴莲种子多糖命名为DSP。
(2)榴莲种子多糖(DSP)对Aβ1-42聚集的影响
将1mg Aβ1-42冻干粉溶于适量六氟异丙醇中,涡旋混匀后等量分装成4组,置于通风橱中过夜,在室温条件下挥发掉六氟异丙醇,得到无色透明肽膜,保存在-80℃超低温冰箱中,以不同浓度的DSP溶液溶解Αβ1-42肽膜,使蛋白终浓度达到10μM,置于37℃恒温培养箱孵育,同时以超纯水溶解Αβ1-42肽膜作为空白对照,每间隔8小时取样一次,Αβ1-42在聚集过程中,构象会由α-螺旋向β-片层转变。ThT嵌入β-片层结构后,受到激发会发射荧光,荧光强度随β-片层的增多而升高,从而Αβ1-42聚集越明显,同时ThT溶解在pH 7.4的磷酸盐缓冲液中时,在440nm处激发下产生的荧光强度低,与β-片层结合后,在480nm处产生荧光强度的高,因此向10μL样液中加入PBS稀释至3μM的ThT溶液990μL,利用硫黄素T染色后分析荧光强度的变化,探究DSP对Αβ1-42聚集是否有抑制效果。
由图1可知,随着孵育时间的延长,Aβ1-42的荧光强度增加,表明Aβ1-42单体不断聚集为寡聚体。添加200μg/mL的DSP和600μg/mL的DSP均抑制了Aβ1-42的聚集,并具有浓度依赖性,但抑制效果并不显著,随时间的延长,尤其是200μg/mL DSP对Aβ1-42的抑制效果并不明显。
2、三种菌发酵对榴莲种子多糖抑制Aβ1-42聚集能力的影响
1)菌种来源:
保藏编号为CGMCC No.18065的贝莱斯芽孢杆菌Bacillus velezensis,分离自普洱茶;于2019年07月03日保藏在中国微生物菌种保藏管理委员会普通微生物中心(CGMCC);地址:北京市朝阳区北辰西路1号院3号,中国科学院微生物研究所。
保藏编号为JC33075的酿酒酵母Saccharomyces cerevisiae和保藏编号为JCI6045的德氏乳杆菌保加利亚亚种Lactobacillus delbrueckii subsp.Bulgaricus;上述三株菌都来源于青岛农业大学发酵功能食品研究与开发研究室。
2)菌种活化及种子液制备:
用接种环分别挑取甘油保藏管中贝莱斯芽孢杆菌、酵母菌和乳酸菌各一环,分别在LB培养基、PDA培养基和MRS培养基上进行平板划线活化,30℃倒置培养24h后用接种环挑取长势良好的单菌落接种至相应斜面培养基,30℃静置培养24h。挑取斜面上的菌株接种于液体培养基中,30℃条件下以180r/min的转速震荡培养24~48h,使浓度达到8×107cfu/mL左右,从而得到贝莱斯芽孢杆菌、酵母菌和乳酸菌的种子液。
3)三种菌发酵多糖的制备:
取3份50g干燥的榴莲种子粉末装入不同的1000mL烧杯中,以1:10的料液比加入去离子水,保鲜膜封口后置于80℃水浴锅中灭菌30min,室温冷却后分别以榴莲种子粉末质量的3%的添加量加入贝莱斯芽孢杆菌、酵母菌和乳酸菌的种子液,于摇床中30℃,180rpm/min发酵36h,过滤除菌除杂,通过旋转蒸发仪浓缩发酵液,利用95%可食用乙醇进行醇沉,使乙醇终浓度达到70%,4℃静置过夜,沉降粗多糖,沉降充分后用离心机分离得到三组醇沉多糖,冷冻干燥后得到贝莱斯芽孢杆菌发酵榴莲种子多糖FDSP、酵母菌发酵榴莲种子多糖SDSP和乳酸菌发酵榴莲种子多糖LDSP。
4)三种发酵多糖抑制Aβ1-42聚集能力的测定
为验证三组发酵多糖对Aβ1-42聚集的抑制作用,将等量Aβ1-42冻干粉分别溶解于100μg/mL的三组发酵多糖溶液和醇提多糖DSP溶液中,同时以等体积的PBS溶液溶解Aβ1-42作为空白对照,使每组Aβ1-42的终浓度达到10μM,混匀器充分混匀后,将三组溶液置于37℃恒温箱中孵育24h,促使Aβ1-42聚集,为了测定其荧光强度的变化,使用PBS溶液将ThT粉末稀释为3μM,并取990μL稀释后的ThT溶液与10μL孵化24h的样品溶液混匀,通过与PBS孵育的Aβ1-42相比较,计算出各组多糖的抑制率。
表1不同处理榴莲种子多糖对Aβ1-42聚集的抑制作用
表1数据表明,四组多糖对Aβ1-42的聚集均具有抑制作用,其中由淀粉酶、中性蛋白酶和纤维素酶解后醇沉获得的榴莲种子多糖DSP呈现出最低的抑制率,由酿酒酵母和德氏乳杆菌保加利亚亚种发酵而成的SDSP和LDSP多糖对Aβ1-42的抑制效果均高于榴莲种子多糖DSP,而经过贝莱斯芽孢杆菌发酵获得榴莲种子多糖FDSP对Aβ1-42的聚集的抑制能力提升至32.48%,具有最明显的抑制效果。
实施例2:贝莱斯芽孢杆菌发酵条件的优化及发酵多糖的分析
1.贝莱斯芽孢杆菌发酵榴莲种子多糖提取条件的优化
取LB斜面上的贝莱斯芽孢杆菌菌株接种于MRS液体培养基(pH值6.2-6.4)中,30℃条件下以180r/min的转速震荡培养24~48h,制备出贝莱斯芽孢杆菌种子液。
1)最佳种子液接种量的确定
为了验证接种量对抑制能力的影响,试验以榴莲种子粉末质量的1%-5%接种贝莱斯芽孢杆菌种子液,从而制备出五组贝莱斯芽孢杆菌发酵榴莲种子多糖(1%-5%),采用ThT荧光染色方法,计算在200μg/mL浓度下的五组发酵多糖与等量Aβ1-42共同孵育24h后的抑制能力,同时孵育一组Aβ1-42作为对照来计算样品组的相对荧光强度,结果显示随接种量的增加,对Aβ1-42聚集作用先升高再下降,当接种量在3%时,制备出的FDSP拥有最好的抑制Aβ1-42聚集效果。
2)最佳发酵pH值的确定
以食品级盐酸和氢氧化钠调节发酵液的酸碱度,使发酵过程中的pH值分别在5-9的条件下制备出五组发酵多糖,采用ThT荧光染色方法,计算在200μg/mL浓度下的五组发酵多糖与等量Aβ1-42共同孵育24h后的抑制能力,同时孵育一组Aβ1-42作为对照来计算样品组的相对荧光强度。随着酸碱环境的改变,FDSP对Aβ1-42聚集的抑制作用先升高再下降,当pH在7或8时,制备出的FDSP均拥有较好的抑制Aβ1-42聚集效果,选取pH 7为最佳条件。
3)最佳发酵温度的确定
以恒温恒箱保持发酵过程中的温度,使贝莱斯芽孢杆菌在25℃-45℃环境下发酵榴莲种子,从而制备出五组发酵多糖,采用ThT荧光染色方法,计算在200μg/mL浓度下的五组发酵多糖与等量Aβ1-42共同孵育24h后的抑制能力,同时孵育一组Aβ1-42作为对照来计算样品组的相对荧光强度。实验结果证明,随接温度的改变,所制备的FDSP对Aβ1-42聚集的抑制作用先升高再下降,当温度在30℃时,FDSP拥有最佳的抑制Aβ1-42聚集效果。
4)最佳发酵时间的确定
利用接种贝莱斯芽孢杆菌种子液发酵榴莲种子粉末12-60小时,从而制备出五组发酵多糖,采用ThT荧光染色方法,计算在200μg/mL浓度下的五组发酵多糖与等量Aβ1-42共同孵育24h后的抑制能力,同时孵育一组Aβ1-42作为对照来计算样品组的相对荧光强度。结果如图所示,随发酵时间的增加,制备所得的FDSP对Aβ1-42聚集的抑制作用逐渐增强,但发酵48h后的相对荧光强度高于36h组,说明抑制能力下降,所以发酵36h时,FDSP拥有最佳的Aβ1-42聚集抑制效果。
2.发酵前后多糖DSP和FDSP活性的比较
(1)对Aβ1-42聚集的影响
将Aβ1-42(10μM)分别与200μg/mL的榴莲种子发酵多糖FDSP和200μg/mL的榴莲种子多糖DSP于37℃共同孵育,24h后取样检测,同时以单独孵育的Aβ1-42作为对照,利用ThT荧光染色检测相对荧光强度的变化。图6表明,相同测试条件下,榴莲种子发酵多糖FDSP的荧光强度高于榴莲种子多糖DSP,说明经过贝莱斯芽孢杆菌发酵,使得种子多糖的结构发生了部分改变,从而更有效的抑制了Aβ1-42的聚集。
(2)抗氧化活性的比较
DPPH自由基清除能力
以0.025mg/mL维生素C溶液作为阳性对照,分别以0.25mg/mL浓度测定两种多糖溶液的清除DPPH活性;由图7所示,榴莲种子多糖的清除率达到66.19%,而榴莲种子发酵多糖的清除率达到73.88%,DPPH自由基清除能力明显升高。
OH自由基清除能力
以0.75mg/mL维生素C溶液作为阳性对照,分别以0.25mg/mL浓度测定两种多糖溶液的清除·OH活性;由图8所示榴莲种子发酵的清除率达到44.52%,而榴莲种子发酵多糖的清除率达到52.53%,·OH自由基清除能力有所升高。
O2 -自由基清除能力
以0.4mg/mL维生素C溶液作为阳性对照,分别以0.25mg/mL浓度测定两种多糖溶液的清除·OH活性,由图9所示榴莲种子多糖的清除率达到11.69%,而榴莲种子发酵的清除率达到21.34%,·OH自由基清除能力有所提高。
3.发酵多糖分子量的测定
采用多角度激光光散射与凝胶色谱联用***测定榴莲种子多糖和榴莲种子发酵多糖分子量,将两组多糖稀释至适当浓度,经过0.22μm水系滤膜过滤,置于***进样器托盘中取样检测,以观察贝莱斯芽孢杆菌共发酵过程中榴莲种子多糖分子量的改变;由图10和图11可以看出榴莲种子多糖和发酵多糖的组分和含量发生了明显改变,图10中DSP的平均分子量为1.775×106Da,图11中发酵多糖FDSP的平均分子量降为1.526×105Da;表明采用贝莱斯芽孢杆菌共发酵的方式制备榴莲种子发酵多糖FDSP,分子量明显降低。
实施例3:榴莲种子发酵多糖对热诱导秀丽隐杆线虫AD模型的影响
1.榴莲种子发酵多糖FDSP对热诱导秀丽隐杆线虫AD模型的影响
(1)选取活力旺盛的秀丽隐杆线虫进行实验,线虫于16℃环境下正常生长,挑选10-20条成熟带卵线虫,置于食物充足的新培养基上产卵100只,16℃培养获得同期化线虫,通过23℃恒温诱导,建立AD模型,并通过饲喂FDSP,达到给药的目的;通过CAT、SOD、MDA和AChE试剂盒,测定线虫体内部分指标变化;通过线虫寿命、生殖、瘫痪、运动四项生理指标,测定FDSP对AD线虫的影响,结果如图12-17所示。
图12显示,多糖样品组与空白组的线虫相比,样品组线虫的体内保护酶CAT和SOD活力高于空白组,表明样品组线虫的抗氧化能力提高,MAD含量和AChE活性降低,表示FDSP具有较好的体内抗氧化和抗阿尔茨海默症作用;
寿命、生殖、瘫痪和运动四项生理指标数据显示,样品组线虫的生存曲线(图13)右移,说明FDSP延缓了线虫的衰老并延长了线虫的寿命;热诱导会损伤线虫的生殖腺,降低生殖能力,图14数据显示,线虫的生殖期约在4天,空白组线虫总产卵数目约在167个,样品组线虫的总产卵数均高于空白组,尤其是饲喂3mg/mL FDSP的线虫,产卵数达到了212左右,说明FDSP有效缓解了热诱导产生的生殖腺损伤,提高了秀丽隐杆线虫的后代数目;随热诱导时间的增加,活跃状态的线虫会慢慢瘫痪,身体和尾部不再完全摆动,仅头部可以摆动进食,如图15数据所示,样品组的线虫瘫痪率均低于空白组,并且随时间增加而显著,说明FDSP有效减缓了线虫的瘫痪;随着热诱导时间的增长,各组秀丽隐杆线虫的整体运动能力(图16)均呈下降趋势,样品组线虫的运动能力均高于空白组,且随着时间延长样品效果趋于显著,即FDSP在一定程度上能够延缓衰老、提高运动能力;图17的荧光实验表明,FDSP能够减少线虫体内Aβ沉积,缓解氧化损伤。
Claims (5)
1.榴莲种子多糖在制备用于预防或治疗阿尔茨海默症的药品中的应用, 所述的榴莲种子多糖是将榴莲种子粉末用水进行提取,水提取液用保藏编号为CGMCC No:18065的贝莱斯芽孢杆菌进行发酵酶解,酶解液用乙醇进行沉淀;沉淀离心干燥获得的。
2.如权利要求1所述的应用,其特征在于,所述的乙醇溶液的添加终浓度为70%。
3.如权利要求1所述的应用,其特征在于,所述的莱斯芽孢杆菌进行发酵,是将浓度为8×107cfu/ mL的贝莱斯芽孢杆菌种子液按照榴莲种子粉末质量的1%-5%进行接种。
4.如权利要求3所述的应用,其特征在于,所述的莱斯芽孢杆菌进行发酵,其发酵条件如下:pH 值为7.0;发酵温度为30℃;发酵时间为36 h。
5.一种用于预防或治疗阿尔茨海默症的药物,其特征在于,所述的药物中包含有药理有效浓度的榴莲种子多糖;所述的榴莲种子多糖的制备方法,是将榴莲种子粉末用水进行提取,水提取液用保藏编号为CGMCC No:18065的贝莱斯芽孢杆菌进行发酵酶解,酶解液用乙醇进行沉淀;沉淀离心干燥获得的。
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