CN108743915A - 海马多肽sp1在制备预防和治疗酒精性肝损伤的药物、保健品或饮食补充剂中的用途 - Google Patents
海马多肽sp1在制备预防和治疗酒精性肝损伤的药物、保健品或饮食补充剂中的用途 Download PDFInfo
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明涉及一种海马多肽SP1在制备预防和治疗酒精性肝损伤的药物、保健品或饮食补充剂中的用途,所述海马多肽SP1的氨基酸序列为Glu‑Asn‑Ala‑Asn‑Gly‑Pro。所述来源于海马的多肽SP1能够清除DPPH自由基,对HepG2细胞无毒性,抑制酒精诱导的HepG2细胞损伤,能够抑制DNA在氧化反应中的断裂,并且能够降低细胞内ROS含量。
Description
技术领域
本发明涉及多肽领域,尤其涉及海马多肽SP1在制备预防和治疗酒精性肝损伤的药物、保健品或饮食补充剂中的用途。
背景技术
海马隶属于海龙科、海马属,是小型海洋硬骨鱼类,广泛分布于热带或亚热带的浅海海域。作为一种名贵的传统中药材,海马中的甾体类化学物质有壮阳补肾的功效;脂肪酸、蛋白质和氨基酸为强身健体提供了必要条件;矿物质和磷脂类有增强人体免疫和抗衰老等功效。Ryu等人报告了从海马提取的多肽及其在抑制TPA诱导的MMP、iNOS和COX-2表达方面的用途,所述多肽的氨基酸序列为LEDPFDKDDWDNWK(Ryu B,Qian ZJ,KimSK.Purification of a peptide from seahorse,that inhibits TPA-induced MMP,iNOSand COX-2expression through MAPK and NF-kappa B activation,and induces humanosteoblastic and chondrocytic differentiation[J].Chemico-biologicalinteractions,2010,184(3):413-422)。
长期饮酒容易导致酒精性肝损伤。氧化应激和膜磷脂过氧化作用对酒精性肝损伤的发生和发展起关键作用。目前认为自由基增多即是其中的一个重要原因,酒精在肝细胞内通过细胞色素并在铁离子参与下的氧化作用,会产生过多的氧化应激产物,如-OH、O2 -、H2O2等自由基,这些自由基可激活磷脂酶及脂质过氧化反应,降低膜磷脂,改变其通透性和流动性,从而改变与膜结合的酶、受体和离子通透的微环境,影响其功能。此外,脂质过氧化还影响和蛋白质的结构和功能,肝细胞膜是氧化应激最活跃的部位,因此是酒精性肝损伤的好发部位。近年来,氧化应激在酒精性肝损伤中作用逐渐受到重视。
具有保肝功能的活性物质主要有多糖、多肽、萜类化合物、不饱和脂肪酸类、脑苷类、核苷类、牛磺酸、维生素类。海洋生物中存在许多天然活性多肽,一些海洋多肽对肝损伤具有明显的修复作用(王佳佳,陈锐,杨最素,等.海洋活性物质对肝损伤修复作用的研究进展[J].浙江海洋学院学报(自然科学版),2016(1):76-80)。例如,6kD多肽通过抑制TGFβ-1、TIMP1的表达及HYP、PCIII的合成来减轻肝纤维化的程度;鲨肝活性肽(sHSS)对乙酰氨基酚(AAP)诱导小鼠急性肝损伤起到保护作用并有抑制肝细胞凋亡的作用(吕正兵,李谦,叶波平,等,鲨肝活性肽对对乙酰氨基酚致小鼠急性肝损伤的保护作用,[J].药学学报,2004,39(1):17-21)。
肝癌细胞株(HepG2)是研究酒精性肝损伤的良好模型,其生命力强,容易培养繁殖,并广泛应用于肝细胞毒性和代谢类研究。目前尚无利用海马多肽对酒精诱导肝细胞氧化应激损伤的保护作用及其机制的研究。
发明内容
为了解决上述现有技术中的问题,本发明提供了以下技术方案:
在一个方面,本发明提供一种海马多肽SP1在制备预防和治疗酒精性肝损伤的药物、保健品或饮食补充剂中的用途,其中所述海马多肽SP1的氨基酸序列为Glu-Asn-Ala-Asn-Gly-Pro。
进一步地,所述海马多肽SP1能够清除DPPH自由基。
进一步地,所述海马多肽SP1对HepG2细胞无毒性。
进一步地,所述海马多肽SP1能够抑制酒精诱导的HepG2细胞损伤。
进一步地,所述海马多肽SP1的浓度大于等于10μM,优选为20-100μM。
进一步地,所述海马多肽SP1能够抑制DNA在氧化反应中的断裂。
进一步地,所述海马多肽SP1能够降低细胞内ROS含量。
在本发明中,来源于海马的多肽SP1具有调节机体生理功能和为机体提供营养的双重功效。本文利用DPPH法评估了SP1的抗氧化能力。以HepG2细胞为模型,并在评价细胞毒性的基础上,加酒精诱导其发生氧化应激损伤。利用MTT方法评价了SP1对酒精诱导HepG2细胞损伤的保护作用;用琼脂糖凝胶电泳检测了SP1对DNA的保护作用;用DCFH-DA法检测了SP1对HepG2损伤后细胞内的活性氧水平。MTT结果表明,SP1对HepG2细胞没有毒性;1M酒精可以导致50%HepG2细胞死亡;20-100μM SP1可有效抑制酒精诱导HepG2细胞的损伤。电泳结果表明,与对照组相比,实验组DNA完整性明显增强。DCFH-DA方法结果表明,对照组荧光最强,而加多肽组荧光明显减弱,并随样品浓度增加而减弱。因此证明SP1对酒精诱导HepG2氧化应激和细胞凋亡有着明显的保护作用,可用于制备预防和治疗酒精性肝损伤的药物、保健品或饮食补充剂。
在本发明中,术语“基本”或“基本上”并不排除“完全”的意思。如一个成分“基本上不含”Y,也可以是完全不含有Y。在限定具体数值的情况下,是指该具体数值具有以该具体数值为基础的上下浮动的范围,浮动范围可以是该具体数值的+/-5%,+/-4%,+/-3%,+/-2%,+/-1%,+/-0.5%,+/-0.2%,+/-0.1%,+/-0.05%,+/-0.01%等。如果需要,“基本”或“基本上”可以以上浮动范围代替或从本发明定义中删除。
“含有”既包括提到的因素,也允许包括附加的、不确定的因素。
“大约”、“约”、“左右”在限定具体数值的情况下,是指该具体数值具有以该具体数值为基础的上下浮动的范围,浮动范围可以是该具体数值的+/-5%,+/-4%,+/-3%,+/-2%,+/-1%,+/-0.5%,+/-0.2%,+/-0.1%,+/-0.05%,+/-0.01%等。
“和/或”表示由其连接的多个术语可以各自单独地使用,也可以相互任意地组合。
本发明中,为简明起见而使用的数值范围不仅包括其端点值,也包括其所有的子范围和此范围内所有的单独的数值。例如,数值范围1-6不仅包括子范围,例如1-3、1-4、1-5、2-4、2-6、3-6等,也包括此范围内单独的数值,例如1、2、3、4、5、6。
附图说明
图1是不同浓度的SP1作用于细胞24h后的细胞相对活力;
图2是在10×40倒置显微镜下观察不同浓度酒精对HepG2细胞的影响;
图3是MTT法测定不同浓度酒精对HepG2细胞的影响;
图4是SP1对酒精诱导HepG2细胞损伤的影响;
图5是SP1对样品DNA的影响;
图6是DCFH-DA法测定细胞内ROS含量。
具体实施方式
在下面描述和图解本发明的示例性实施方案。为了清楚和准确,下面讨论的所述示例性实施方案可以包括优选的步骤、方法和特征,本领域普通技术人员将可以认识到,这些优选的步骤、方法和特征不是落在本发明范围内的必要条件。
在下述实施例中所使用的实验方法如无特殊说明,均为常规方法。在下述实施例中所用的材料、试剂等如无特殊说明,均可从商业途径得到。
本文中的海马多肽SP1由杭州丹港生物科技公司提供,其中通过链霉蛋白酶E进行海马蛋白水解,然后对水解产物进行分离和提纯而得,氨基酸序列的测定结果表明:SP1的分子量为600.59,氨基酸序列为Glu-Asn-Ala-Asn-Gly-Pro。
本文中,HepG2细胞复苏、培养、传代与冻存的方法如下:
a.细胞复苏与培养
先从液氮罐中取出HepG2细胞(复旦IBS细胞资源中心FDCC),迅速投入37℃水浴并不断摇晃,使管中的液体快速融化。同时,配制DMEM培养基(50mL血清+5mL双抗+500mL新鲜培养基)。然后取10mL DMEM培养基于培养瓶中,等细胞完全解冻后将其全部吸入培养瓶中,并放入37℃、5%CO2培养箱中培养,定期观察细胞生长状况。待细胞长满后进行传代,从CO2培养箱中取出培养瓶,倒弃培养基(在无菌工作台中操作),用PBS洗2次,用胰蛋白酶消化后再加入培养基培养。
b.细胞传代
HepG2细胞的传代:通过电子显微镜观察选择生长状况好且长满培养瓶的细胞进行传代,取出培养瓶,倒弃培养基,PBS洗涤2次,用0.25%的胰蛋白酶消化后加入DMEM培养基3mL,用移液枪充分吹打培养瓶壁,当细胞完全脱离培养瓶壁且充分混匀后以一传三的方式分别加到三个培养瓶中,最后再在每个培养瓶中加入4mL DMEM培养基于37°℃、5%CO2培养箱中培养,以同样方式传10瓶细胞待用。
c.细胞冻存
预先配制冻存液(50%培养基+40%血清+10%DMSO),取对数期生长期细胞,经胰蛋白酶消化,离心弃上清液后加入适量冻存液,并吹打成细胞悬液(1-5×106细胞/mL)。然后加入1mL细胞于冻存管中,密封后标记细胞名称,姓名,日期。
实施例1:DPPH法测定SP1清除自由基的能力
DPPH(1,1-二苯基-2-三硝基苯肼)在有机溶剂中是一种稳定的自由基,其醇溶液呈紫色,且需低温避光储藏。它具有单一电子,故能接受一个电子或氢离子。在波长为517nm下具有最大吸收。有自由基清除剂存在时,DPPH的单电子被捕捉而使其颜色变浅。在最大光吸收波长处的吸光值下降,且下降程度呈线性关系,吸光值得降低表明抗氧化性的增加。从而以评价样品的抗氧化能力。
用95%的乙醇溶解DPPH(北京索莱宝科技有限公司)配制0.1mM的DPPH溶液。先将粉末状SP1用超纯水溶解并配制成100mM的溶液,于-20℃冰箱中冻存备用,稀释100mM SP1为不同浓度(10、20、50、100μM),后取50μL加到96孔板,同时加入50μL的DPPH溶液,在摇床震荡混匀后避光反应30min,在517nm波长处测定吸光度(A1)。并设置空白组和对照组,空白组为50μL 95%乙醇溶液代替DPPH溶液加入50μL超纯水,测吸光值(A2);对照组为50μL DPPH溶液加上50μL超纯水代替样品,测定吸光值(A3)。最后按以下公式计算DPPH自由基清除率:
DPPH自由基清除率=[A3-(A1-A2)]/A3×100%
DPPH自由基溶液呈紫色,在517nm波长出最高峰,当SP1产生的自由电子与DPPH孤电子对结合而消除自由基。用酶标仪测得空白组和对照组的吸光值分别为0.045、0.052,测得各实验组的吸光值,并根据公式计算DPPH自由基清除率,结果如表1所示。SP1对DPPH自由基的清除率达到80%以上,并随着底物浓度的增加而增加。
表1:SP1对DPPH自由基的清除力
实施例2:MTT法测定SP1对HepG2细胞的影响
活细胞线粒体中的琥珀酸脱氢酶能将MTT(四甲基偶氮唑盐)还原成不溶于水的蓝紫色结晶产物甲瓒,并沉淀在细胞中,而死细胞无此功能。二甲基亚砜(DMSO)能溶解沉积的甲瓒,溶液颜色深浅与其含量成正比,可用酶标仪测定吸光值。
将HepG2细胞接种于96孔细胞培养板中并于37℃、5%CO2培养箱中培养,定期观察细胞生长状况,等细胞繁殖铺满板后配制不同浓度的SP1(10、20、50、100μM)处理细胞24h,用MTT法检测细胞活性来确定SP1对HepG2细胞的毒性。
SP1对HepG2细胞的毒性检测
测定结果如图1所示,图为不同浓度的SP1(0-100μM)作用于细胞24h后的细胞相对活力,各不同多肽浓度组细胞活性与空白组相比都无明显变化。说明SP1对细胞没有毒性。
实施例3:MTT法测定酒精对HepG2细胞的影响
采用如实施例2同样的方法,以不同浓度的酒精(0、0.25、0.5、0.75、1.0、1.25、1.5M)处理细胞24h后,用MTT法检测细胞活性来观察酒精对HepG2细胞的毒性。
结果如图2和图3所示,不同浓度酒精(0-1.5M)作用于HepG2细胞24h后对细胞的毒性,各不同酒精浓度组与对照组相比,在浓度区间0-1.25M下细胞相对活力均随酒精浓度增加而依次下降;而1.25M和1.5M浓度相比,细胞相对活力无明显变化。
可见酒精对细胞的毒性作用非常明显,0.25-1.5M酒精处理组细胞活性均有所下降,最高酒精浓度组细胞几乎无活性。为便于后续实验中SP1效果的观察,采用了细胞活性接近50%的1M实验组作为后续实验的酒精处理浓度。
实施例4:MTT法测定SP1对酒精诱导HepG2细胞损伤的影响
将HepG2细胞接种于96孔板中并于37℃、5%CO2培养箱中培养并定期观察细胞生长状况,等细胞铺满板后以不同浓度的SP1(0、10、20、50、100μM)预先处理HepG2细胞24h后,加入浓度为1M的酒精诱导24h,之后吸去培养基并在每孔中加入20μL MTT,孵育4h后吸去培养基,加入100μL DMSO,用锡纸包裹于摇床上孵育10min,待紫色结晶完全溶解后,经酶标仪490nm下测定吸光值。
SP1对抗酒精毒性的细胞相对活力检测如图4所示。结果表明,与对照组相比,10、20、50和100μM SP1实验组对细胞均有明显的保护作用,且50μM组比20μM这一组效果好一些,但50μM和100μM两组几乎无明显差异。此结果为今后实际应用中药用剂量的选择提供了有力的参考数据及理论依据。
实施例5:琼脂糖凝胶电泳法测定SP1对DNA的影响
1)HepG2细胞DNA提取
配制0.2M乙酸钠350μL,10%SDS 25μL,10mg/mL蛋白酶-K 10μL,10mg/mL RNAase25μL。将预先培养好的HepG2细胞消化后转入30mL离心管中,在离心机1000rpm下离心10min,弃去培养基后用含5mM的PBS洗涤并转入10mL的离心管中,再次离心(1000rpm×10min),后吸掉上清液,依次加入乙酸钠、SDS、蛋白酶K和RNAase。用涡旋振荡器混匀后在54℃金属浴中反应60min。然后配制酚:氯仿:异戊醇(25:24:1)的溶液410μL加入离心管中并震荡30s使其混匀,反应完全后再离心(1200rpm×10min),完成后吸出上清液转入另一支离心管中,并加入100μL在-20℃放置15min的乙醇,后吸去乙醇干燥,得到DNA(冻存备用)。
2)DNA琼脂糖凝胶电泳法
(1)原理
DNA在琼脂糖凝胶中泳动时有电荷效应和分子筛效应。DNA分子在高于等电点的pH溶液中带负电荷,在电场中向正极移动。由于糖-磷酸骨架在结构上的重要性质,相同数量的双链DNA几乎具有等量的净电荷,因此它们能以同样的速率向正极方向移动。
(2)操作流程
预先配制50×TAE(pH=8.0)溶液、130mM EDTA溶液、0.1mM H2O2、300μM FeSO4溶液(用锡纸包裹)。
制胶:将制胶板放置于水平位置,并放好梳子。称取0.6-0.7g琼脂于烧杯中,并加入60-70mL的超纯水,在微波炉中加热溶解,待降温后加入制胶板中。待胶凝固后,小心地拔出梳子并放在电泳槽内。加电泳缓冲液至电泳槽中,加液量要使液面没过胶面1-1.5mm。
样品处理:配制样品时,多肽与DNA以及与后续加入的硫酸亚铁和过氧化氢需要反应10min。实验组以不同浓度SP1与DNA作用,空白组加4μL DNA以及36μL超纯水,对照组加入4μL DNA用4μL H2O代替样品。
加样:用移液枪将已加入上样缓冲液的DNA样品加入加样孔(记录点样顺序及点样量)。
电泳:最佳条件是100V,30-40min。
染色:将电泳凝胶放入核酸染料池中染色2-3h。
检测:在凝胶成像分析系统中观察染色后的电泳凝胶。
3)检测结果
如图5所示,对照组DNA在氧化反应中完全断裂以致没有条带,而实验组条带明显且随SP1浓度的增加而变长,说明SP1对细胞包内蛋白和DNA有抗氧化效果,并有效抑制氧化。结果表明,在FeSO4和H2O2的共同作用下预先加了SP1的实验组与对照组相比,DNA含量明显较多;DNA含量随样品SP1浓度增高而增加,且浓度为100μM时含量最高。这就说明SP1对细胞DNA损伤起到保护性作用。
实施例6:DCFH-DA法测定HepG2细胞内ROS含量
(1)原理:利用化学荧光指示剂即荧光探针:二氯二氢荧光素-乙酰乙酸酯(DCFH-DA),可以穿过细胞膜,被细胞内的酯酶水解生成一种非荧光物质二氯二氢荧光素(DCFH),DCFH继而可以被细胞内的各种ROS所氧化,转变成一种可以产生荧光信号的物质,即二氯荧光素(DCF)。DCF所产生的荧光信号可以被倒置荧光显微镜检测到。细胞内活性氧的量与DCF的荧光信号成比例。
(2)步骤:接种HepG2细胞于24孔板在37℃、5%CO2培养箱中培养24h,等细胞生长繁殖铺满板后加入不同浓度的SP1(10、20、50、100μM),再培养24h,后吸掉DMEM培养基,并用PBS洗涤3次(每次3min最佳),然后在各孔加入200μL 10μM的DCFH-DA(北京索莱宝科技有限公司)后用锡纸包裹放在37℃下反应20min,后吸掉试剂,再用PBS洗涤3次(10-15min),最后在荧光显微镜下观察细胞的生长状况及细胞内ROS的生成。
(3)结果:细胞内ROS含量的测定结果如图6所示,荧光染色剂DCFH-DA并无荧光效果,它是在细胞内的酯酶和活性氧的共同作用下才生成荧光物质,可见对照组仅有少量的绿色荧光效果,在加入不同浓度的SP1刺激后,较空白组荧光效果明显有所降低,并且随着浓度的增加而逐渐减弱,说明SP1对细胞有抗氧化作用。
ROS是一类含氧的有较强氧化性的自由基氧与非自由基氧的总称,包括超氧阴离子,过氧化氢以及一氧化氮等。上述DPPH自由基消除率检测(因为人体细胞内的ROS等同于DPPH自由基)的结果显示10、20、50、100μM SP1对DPPH自由基的消除率随浓度的增大而逐渐增强;上述ROS检测实验的结果表明荧光强度随多肽浓度增加而减弱,因此说明SP1对细胞有保护作用。
可见,SP1可以通过清除ROS、减弱ROS生成酶活性和对DNA片段的修复与保护等不同途径发挥抗氧化作用。
以上所述仅为本发明的较佳实施例,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 (10)
1.一种海马多肽SP1在制备预防和治疗酒精性肝损伤的药物、保健品或饮食补充剂中的用途,其中所述海马多肽SP1的氨基酸序列为Glu-Asn-Ala-Asn-Gly-Pro。
2.根据权利要求1的所述海马多肽SP1在制备预防和治疗酒精性肝损伤的药物、保健品或饮食补充剂中的用途,其中所述海马多肽SP1能够清除DPPH自由基。
3.根据权利要求1的所述海马多肽SP1在制备预防和治疗酒精性肝损伤的药物、保健品或饮食补充剂中的用途,其中所述海马多肽SP1能够抑制酒精诱导的HepG2细胞损伤。
4.根据权利要求4的所述海马多肽SP1在制备预防和治疗酒精性肝损伤的药物、保健品或饮食补充剂中的用途,其中所述海马多肽SP1的浓度大于等于10μM。
5.根据权利要求1的所述海马多肽SP1在制备预防和治疗酒精性肝损伤的药物、保健品或饮食补充剂中的用途,其中所述海马多肽SP1能够抑制DNA在氧化反应中的断裂。
6.根据权利要求1的所述海马多肽SP1在制备预防和治疗酒精性肝损伤的药物、保健品或饮食补充剂中的用途,其中所述海马多肽SP1能够降低细胞内ROS含量。
7.一种海马多肽SP1在体内或体外清除自由基的用途,其中所述海马多肽SP1的氨基酸序列为Glu-Asn-Ala-Asn-Gly-Pro。
8.一种海马多肽SP1在体内或体外抑制酒精诱导的HepG2细胞损伤的用途,其中所述海马多肽SP1的氨基酸序列为Glu-Asn-Ala-Asn-Gly-Pro。
9.一种海马多肽SP1在体内或体外抑制DNA在氧化反应中的断裂的用途,其中所述海马多肽SP1的氨基酸序列为Glu-Asn-Ala-Asn-Gly-Pro。
10.一种海马多肽SP1在体内或体外降低细胞内ROS含量的用途,其中所述海马多肽SP1的氨基酸序列为Glu-Asn-Ala-Asn-Gly-Pro。
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