CN114134104A - 虾青素在制备缓解卵泡氧化应激损伤的药物中的应用 - Google Patents
虾青素在制备缓解卵泡氧化应激损伤的药物中的应用 Download PDFInfo
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Abstract
本发明属于药物研究技术领域,具体公开了虾青素在制备缓解卵泡氧化应激损伤的药物中的应用。通过实验验证,虾青素可有效促进卵泡发育和卵母细胞成熟,并且通过促进卵泡颗粒细胞对雌激素和孕激素的分泌和颗粒细胞对ERα的表达等达到缓解BPA引起的卵泡氧化应激损伤。
Description
技术领域
本发明属于药物研究技术领域,具体公开了虾青素在制备缓解卵泡氧化应激损伤的药物中的应用。
背景技术
双酚A(Bisphenol A,BPA)作为一种工业原料,被广泛地用来生产聚碳酸酯塑料和环氧树脂。在日常生活中的食品包装、个人护理用品和日用品等都含有BPA,甚至在大气、土壤和水生环境中都检测到BPA。BPA作为一种内分泌和代谢的干扰物,发现其可通过提高氧化反应的介导物和降低抗氧化酶的产生,而显著提高neuroblastoma cell、雄性生殖细胞、intestinal epithelial cells和kidney tubular cells等的脂质过氧化水平和ROS水平,引起细胞内线粒体功能紊乱、改变细胞内的信号通路、诱导细胞凋亡,使得机体免疫系统、神经系统、生殖系统和消化系统等都受到氧化应激损伤。临床研究发现,不孕女性尿液中高浓度的BPA与其原始卵泡数量降低有明确关联。越来越多的实验室数据也表明BPA的长期暴露会损伤生殖细胞,影响生殖功能。
近几年来,许多的抗氧化剂被用来缓解BPA引起的氧化反应、抑制过量ROS的产生,如维生素C、维生素E、N-乙酰半胱氨酸、硫辛酸、生姜提取物和没食子酸等,这些抗氧化剂的添加对精子的活力、运动力和精子形态等都具有一定的保护作用,在不同程度上减少了BPA引起的氧化应激和细胞凋亡。1,25-二羟维生素D3对BPA引起的卵巢颗粒细胞的氧化应激和线粒体损伤也具有明显的缓解作用。但尚不清楚抗氧化剂对接触BPA的卵泡和卵母细胞的作用及作用机制。
虾青素是存在于水产品(鲑鱼、虾和螃蟹等)中的一种类胡萝卜素,具有比维生素C、维生素E和β-胡萝卜素更强的抗氧化性,其抗氧化的能力是α-维生素E的100-500倍,是类胡萝卜素的15倍,其能控制脂质的过氧化、清除过量的ROS。由于虾青素是脂溶性的,其能进入细胞膜,减少DNA损伤。虾青素在牛胚胎体外发育过程中可诱导抗氧化基因的表达和抑制凋亡基因的表达,从而提高热应激损伤胚胎的体外发育率。在热应激损伤的猪卵母细胞体外培养液中添加虾青素,其能促进卵母细胞成熟和受精。在牛的腔前卵泡的培养液中添加虾青素,显著减少了卵母细胞中ROS的含量和cathepin B基因的表达,通过其抗氧化作用促进了卵母细胞成熟。我们在小鼠腔前卵泡的培养液中添加虾青素,发现2.5nmol/L虾青素也显著促进了卵泡发育和卵母细胞成熟。虾青素能缓解热应激对卵母细胞和胚胎的氧化损伤,但其是否能缓解BPA对卵泡产生的氧化应激损伤尚未见报道。
发明内容
针对以上问题,本发明提供了以下技术方案:
本发明提供了虾青素在制备缓解卵泡氧化应激损伤的药物中的应用,所述所述卵泡氧化应激损伤是由双酚A引起。
优选地,所述虾青素能够促进卵泡发育和卵母细胞成熟。
优选地,所述虾青素能够促进颗粒细胞PCNA的表达及颗粒细胞的增殖。
优选地,所述虾青素能够促进卵泡颗粒细胞对雌激素和孕激素的分泌,并促进颗粒细胞对ERα的表达。
优选地,所述虾青素能够降低卵泡中MDA及卵母细胞中ROS的产生。
优选地,所述虾青素用于制备卵母细胞的凋亡抑制剂。
优选地,所述虾青素能够促进抗氧化基因CAT、SOD1、SOD2及抗凋亡基因Bcl-2的表达,并抑制caspase 3、cathepsin B的表达。
优选地,所述虾青素能够提高卵母细胞线粒体的膜电位。
本发明还提供一种用于缓解BPA引起的卵泡氧化应激损伤的药物,其包括所述虾青素及药学上可接受的辅料或载体。
对比现有技术,本发明的有益效果为:
本发明提供的虾青素能够用于制备缓解BPA引起的卵泡氧化应激损伤的药物。药效学实验证明,虾青素能够促进卵泡发育和卵母细胞成熟,其还能促进颗粒细胞PCNA的表达及颗粒细胞增殖、促进卵泡颗粒细胞对雌激素和孕激素的分泌和颗粒细胞对ERα的表达、降低卵泡中MDA及卵母细胞中ROS的产生、抑制卵母细胞的凋亡,促进CAT、SOD1、SOD2和Bcl-2基因的表达、抑制caspase 3和cathepsin B基因的表达。
附图说明
图1是不同时间卵泡的发育状态;
图2是各组卵泡在不同时期的贴壁面积;
图3是D8和D10颗粒细胞PCNA的蛋白印迹分析图;
图4是各组D8和D10颗粒细胞PCNA的表达水平;*与正常组比较,p<0.05;#与BPA组比较,p<0.05;
图5是各组D10卵泡分泌的雌激素水平;*与正常组比较,p<0.05;#与BPA组比较,p<0.05;
图6是各组D10卵泡分泌的孕激素水平;*与正常组比较,p<0.05;#与BPA组比较,p<0.05;
图7是D10颗粒细胞的雌激素受体α的蛋白印迹分析图;
图8是各组D10颗粒细胞对ERα的表达水平;*与正常组比较,p<0.05;#与BPA组比较,p<0.05;
图9是各组D10卵泡培养液中MDA的水平;*与正常组比较,p<0.05;#与BPA组比较,p<0.05;
图10是D11卵母细胞的ROS染色检测图;
图11是各组卵母细胞中ROS的平均荧光强度;*与正常组比较,p<0.05;#与BPA组比较,p<0.05;
图12是卵母细胞的线粒体膜电位检测图;
图13是JC-1染色后各组卵母细胞红色荧光和绿色荧光的比值;*与正常组比较,p<0.05;#与BPA组比较,p<0.05;
图14是各组卵母细胞中抗氧化基因CAT、SOD1及SOD2的表达水平;*与正常组比较,p<0.05;#与BPA组比较,p<0.05;
图15是各组卵母细胞中caspase 3、cathepsin B及Bcl-2的表达水平;*与正常组比较,p<0.05;#与BPA组比较,p<0.05。
具体实施方式
下面通过具体的实施例对本发明做进一步说明,但是并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
需要说明的是,实验例中所用试剂或材料后的括号内,前者表示英文缩写,中间表示型号或批号,后者表示生产厂家或购买来源。
本发明提供了虾青素在制备缓解BPA引起的卵泡氧化应激损伤的药物中的应用。具体地,所述虾青素能够促进卵泡发育和卵母细胞成熟,其通过促进颗粒细胞PCNA的表达及颗粒细胞增殖、促进卵泡颗粒细胞对雌激素和孕激素的分泌和颗粒细胞对ERα的表达、降低卵泡中MDA及卵母细胞中ROS的产生、抑制卵母细胞的凋亡、促进CAT、SOD1、SOD2和Bcl-2基因的表达、抑制caspase 3和cathepsin B基因的表达来达到缓解BPA引起的卵泡氧化应激损伤。
实验例
1、材料和方法
1.1、实验动物
采用14d的昆明品系雌性小鼠,购自吉林省长春市亿斯实验动物技术有限责任公司。小鼠生活在温控的房间(21±2℃),12h光照/12h黑暗的光照周期。自由饮水和采食。小鼠的处理方法经吉林医药学院伦理委员会同意。
1.2、BPA和虾青素的准备
利用二甲基亚砜(DMSO,D2650,Sigma)溶解双酚A(BPA,239658,Sigma)和虾青素(Asta,SML0982,Sigma),分别配制成浓度25mmol/L的BPA储存液及浓度2.5μmol/L的虾青素储存液。使用前,将1μL BPA或虾青素的储存液加入至1mL卵泡的体外培养液中,使BPA的工作浓度为25μmol/L、虾青素的工作浓度为2.5nmol/L。同时配制溶剂组:将2μL DMSO加入到1mL卵泡的体外培养液中,使其在培养液中的浓度为0.2%。
1.3、小鼠腔前卵泡体外培养
14d昆明雌性小鼠,颈椎脱臼处死,迅速取其双侧卵巢于L-15工作液(含10%胎牛血清,11415114,Gibco)中。利用26G针头机械分离出卵泡,选取4级或5a级卵泡。将选取的腔前卵泡置于α-MEM培养液滴(12571063,Gibco)中,培养液中包含5%胎牛血清(FBS,10091155,Gibco)、1%胰岛素-转铁蛋白-硒(ITS,41400045,Gibco)和0.1IU/ml重组卵泡刺激素(r-FSH,Gonal-F,Serono),于37℃、5%CO2的培养箱中培养10天。第10天,加入含有浓度为2.5U/ml人绒毛膜促性腺激素(hCG,丽珠集团丽珠制药厂)的α-MEM培养液。14-16h后,成熟卵泡破裂排卵。向上述α-MEM培养液中分别添加BPA或DMSO或BPA+Asta,得到BPA组、DMSO组及BPA+Asta 3个不同观察组。其中,BPA组是在上述α-MEM培养液中添加25μmol/L的BPA,DMSO组是在上述α-MEM培养液中添加0.2%的DMSO,BPA+Asta组是在上述α-MEM培养液中添加25μmol/L的BPA和2.5nmol/L虾青素。隔天半定量换液,观察记录各组卵泡生长情况,利用日本奥林巴斯IX-83显微镜的cellSens显微图像软件拍摄各个发育阶段的卵泡照片,使用Image J图像处理软件分析卵泡在培养皿上的贴壁面积,每组分析10个卵泡。
1.4、激素水平检测
分析D10卵泡培养液中雌激素和孕激素的含量。采用雌激素和孕激素的ELISA检测试剂盒(BPE20376 and BPE20381,Shanghai Lengton Bioscience Co.,LTD)按照说明书进行分析。简要地,样品和检测试剂分别加到一个96孔板中,在37℃孵育30min。洗板,然后在各个反应孔中加入显色液,37℃避光孵育10min。使用SpectraMax Absorbance Reader(Molecular Devices)在450nm处测定样品的OD值。
1.5、蛋白印迹分析
每个实验组从40个体外培养第8天或第10天的卵泡获取颗粒细胞,用RIPA强裂解液(含1%PMSF)(P0013B和P1006,Beyotime)提取蛋白。将蛋白转移到聚偏二氟乙烯膜(PVDF)膜上,5%脱脂奶粉封闭1h,对转移颗粒细胞蛋白的PVDF膜进行增殖细胞核抗原(PCNA,ab92552,Abcam)、雌激素受体-α(ER-α,ab32063,Abcam)或β-肌动蛋白(β-actin,ab8226,Abcam)的一抗孵育,4℃过夜。PBST洗膜后,膜在山羊抗兔的辣根过氧化物酶标记的二抗(31210,Thermo Scientific Pierce)中室温孵育2h,然后进行增强的化学发光显色。使用ChemiDOC XRS+imaging systems(Bio-Rad Laboratories,Hercules,CA,USA)对膜进行扫描。重复3次后,用Image J图像分析软件分析PCNA和ER-α的相对表达水平。
1.6、丙二醛(MDA)含量测定
为检测卵泡培养液中MDA的含量,采用MDA检测试剂盒(Beyotime,S0131S),使硫代巴比妥酸(TBA)和MDA反应形成红色的MDA-TBA加和物。使用SpectraMax AbsorbanceReader(Molecular Devices)在532nm处测定样品的光密度(OD)值。结果以每升培养液中所含的μmol MDA量表示。
1.7、活性氧自由基(ROS)水平检测
将卵泡在添加hCG的α-MEM培养液中培养14-16h后,获取COCs,脱去卵丘细胞后,将获得的卵母细胞在含10mM carboxy-H2DCF diacetate(Cat#S0033,Beyotime)的M2液体中37℃孵育30min。阳性组的卵母细胞在含Rosup(1:1000稀释,Cat#S0033;Beyotime)的M2培养液中37度孵育20min,然后在10mM carboxy-H2DCF diacetate(Cat#S0033;Beyotime)37度孵育30min。用M2液体将卵母细胞洗3遍后,利用日本奥林巴斯IX-83显微镜的cellSens显微图像软件对卵母细胞进行拍摄,所有的图片均在相同的设置下拍摄。使用Image J图像处理软件分析每个卵母细胞的荧光强度。每组分析10个卵母细胞。
1.8、线粒体膜电位(Δψm)测定
线粒体膜电位的改变是细胞凋亡的一个重要表现。将卵母细胞M2液洗3遍,然后放在含有0.5μmol/L JC-1(Invitrogen,Grand Island,NY,USA)的培养液中在37℃、5%CO2的培养箱中培养30min。细胞线粒体膜电位正常时,JC-1进入线粒体,聚集在线粒体基质中形成J-聚合体,产生红色荧光;如果细胞凋亡,线粒体膜电位下降或丧失,JC-1以J-单体的形式存在于胞质中,产生绿色荧光。使用日本奥林巴斯IX-83荧光显微镜的CellSense拍摄系统在相同的设置下对同一荧光进行拍摄。卵母细胞红色荧光强度和绿色荧光强度的比值反映线粒体的膜电位。每组分析10个卵母细胞。
1.9、qRT-PCR
每次60个卵母细胞进行实时荧光定量PCR分析。来自卵母细胞的RNAs使用RneasyMicro Kit(Qiagen,Hilden,Germany)提取,在20μL的反转录体系(1μL random primers,1μL Oligo dT Primer,4μL Reverse Transcription buffer,and 1IU/mL PrimeScriptTEMRT Enzyme MixⅠ(TaKaRa,Dalian,China))中进行反转录成cDNA.使用iQ5 MulticolorReal-time PCR Detection System(Bio-RAD)、利用SYBR Premix Ex Taq(Takara Dalian,China)通过定量实时PCR进行基因产物的定量分析,使用的特定引物见表1。Real-time PCR的反应系统包括Premix Ex TaqTMⅡ,forward/reverse primers and cDNA template.PCR反应条件为:95℃预变性30s,95℃变性5s,57-60℃(根据所用的引物而定,见表1)退火20s,72℃延伸30s,循环40次。β-actin被用来作为实验的内参。使用2-ΔΔCt方法计算目的基因相对表达水平。
表1引物序列
2、统计学分析
所有数据以均数±标准差表示,用SPSS 17.0统计软件分析,将数据均采用单因素方差分析(one-way ANOVA)进行处理分析。P<0.05认为差异有统计学意义。
3、结果
3.1、Asta缓解了BPA对卵泡发育和卵母细胞成熟的抑制作用
从D14的小鼠卵巢中分离出直径110-130μm的腔前卵泡,体外培养11天,分别于D2、D4、D6、D8和D10观察卵泡的发育状态(图1)。培养D2,卵泡开始贴壁生长,能看到向外生长的卵泡膜细胞。随后随着颗粒细胞增殖,卵泡的体积逐渐增大。D10在生长发育的卵泡中出现卵泡腔。添加hCG后14-16h,成熟卵泡会发生破裂排卵。统计各期卵泡的发育率,结果如表2所示。
表2小鼠卵泡的体外发育
注:存活率=存活卵泡数/培养卵泡数;成腔率=成腔卵泡数/存活卵泡数;排卵率=排卵的卵泡数/成腔的卵泡数;MⅡ期卵的比率=MⅡ期卵的数量/排出的卵的数量;*与对照组比较,p<0.05;#与25μM BPA组比较,p<0.05。
由表2可知,与正常组比较,BPA组卵泡的存活率、成腔率和MⅡ期卵母细胞比率显著下降,BPA+Asta组卵泡的存活率、成腔率和MⅡ期卵母细胞的比率较BPA组显著升高,0.2%DMSO对卵泡各期的发育率没有显著影响。各组卵泡的排卵率无显著差异。以上结果表明,Asta促进了卵泡发育和卵母细胞成熟。
3.2、Asta促进了颗粒细胞增殖
使用Image J图像分析软件测定D2、D4、D6、D8和D10卵泡的贴壁面积,如图2所示。
比较各组卵泡的贴壁面积,与正常组比较,BPA组D4、D6、D8和D10卵泡的贴壁面积显著降低(P<0.05,图2),BPA+Asta组D2、D4和D6卵泡的贴壁面积较BPA组无显著差异,但D8和D10卵泡的贴壁面积较BPA组显著增大(P<0.05,图2)。
收集D8和D10卵泡的颗粒细胞,进行PCNA的western blotting分析,结果如图3-4所示。
结果显示,与正常组和DMSO组比较,BPA组D8和D10颗粒细胞PCNA的表达显著降低(P<0.05),BPA+Asta组D8和D10颗粒细胞PCNA的表达较BPA组显著升高(P<0.05),但仍显著低于对照组。Asta提高了颗粒细胞PCNA的表达,促进了颗粒细胞增殖。
3.3、Asta提高了颗粒细胞对雌孕激素的分泌和对雌激素受体a的表达
分别收集D10卵泡的培养液,采用ELISA法测定培养液中卵泡所分泌的雌激素和孕激素的水平,结果参照图5-6。
结果所示,与对照组比较,BPA组培养液中雌激素和孕激素的水平显著降低(P<0.05),BPA+Asta组培养液中雌激素和孕激素的水平较BPA组显著升高(P<0.05),Asta提高了D10卵泡颗粒细胞对雌激素和孕激素的分泌。
分别收集D10卵泡的颗粒细胞,进行雌激素受体α(ERα)的蛋白印迹分析,如图7-8所示。
结果显示,与对照组比较,BPA组颗粒细胞对ERα的表达显著降低(P<0.05),BPA+Asta组颗粒细胞对ERα的表达较BPA组显著升高(P<0.05)。Asta刺激了卵泡发育晚期颗粒细胞对ERα的表达。
3.4、Asta降低了卵泡培养液和卵母细胞中MDA和ROS的水平
收集D10卵泡培养液,进行MDA试剂盒检测。结果如图9所示。
结果显示:与正常组相比,BPA组卵泡培养液中MDA的水平显著升高(P<0.05),BPA+Asta组培养液中MDA的水平较BPA组显著降低(P<0.05),Asta降低了卵泡中MDA的产生。
对D11排出的卵母细胞进行ROS染色检测,卵母细胞中绿色荧光越强代表ROS的含量越高,结果如图10所示(图中第二横排表示绿色荧光斑点)。
BPA组卵母细胞中ROS的平均荧光强度较正常组显著升高(P<0.05)(图11),BPA+Asta组卵母细胞中ROS的平均荧光强度较BPA组显著降低(P<0.05)(图11),Asta降低了卵母细胞中ROS的产生。
3.5、Asta提高了卵母细胞的线粒体膜电位和抗氧化基因的表达,降低了caspase3和cathepsin B基因的表达
利用JC-1探针检测卵母细胞的线粒体膜电位,红色荧光与绿色荧光的比值大,代表线粒体的膜电位正常,细胞处于健康状态(图12,图中第二横排荧光斑点表示红色荧光,第三横排荧光斑点表示绿色荧光)。
BPA组卵母细胞红色荧光和绿色荧光的比值较正常组卵母细胞红色荧光和绿色荧光的比值显著降低(P<0.05,图13),而BPA+Asta组卵母细胞红色荧光和绿色荧光的比值较BPA组卵母细胞红色荧光和绿色荧光的比值显著升高(P<0.05,图13),与正常组无显著差异。Asta提高了卵母细胞线粒体的膜电位。
利用qRT-PCR检测卵母细胞中抗氧化基因(CAT、SOD1和SOD2)、凋亡相关基因(caspase 3、Bcl-2)和cathepsin B的表达。结果如图14-15所示。
结果显示:BPA组卵母细胞中抗氧化基因(CAT、SOD1和SOD2)和抗凋亡基因Bcl-2的表达较正常组显著降低(P<0.05),caspase 3和cathepsin B的表达较正常组显著升高(P<0.05)。而BPA+Asta组卵母细胞中抗氧化基因(CAT、SOD1和SOD2)和抗凋亡基因Bcl-2的表达较BPA组显著升高(P<0.05),caspase 3和cathepsin B的表达较BPA组显著降低(P<0.05)。Asta促进了卵母细胞中抗氧化基因的表达,抑制了卵母细胞凋亡。
以上公开的仅为本发明的几个具体实施例,但是,本发明实施例并非局限于此,任何本领域的技术人员能思之的变化都应落入本发明的保护范围。
Claims (9)
1.虾青素在制备缓解卵泡氧化应激损伤的药物中的应用,其特征在于,所述卵泡氧化应激损伤是由双酚A引起。
2.根据权利要求1所述的应用,其特征在于,所述虾青素能够促进卵泡发育和卵母细胞成熟。
3.根据权利要求1所述的应用,其特征在于,所述虾青素能够促进颗粒细胞PCNA的表达及颗粒细胞的增殖。
4.根据权利要求1所述的应用,其特征在于,所述虾青素能够促进卵泡颗粒细胞对雌激素和孕激素的分泌,并促进颗粒细胞对ERα的表达。
5.根据权利要求1所述的应用,其特征在于,所述虾青素能够降低卵泡中MDA及卵母细胞中ROS的产生。
6.根据权利要求1所述的应用,其特征在于,所述虾青素用于制备卵母细胞的凋亡抑制剂。
7.根据权利要求1所述的应用,其特征在于,所述虾青素能够促进抗氧化基因CAT、SOD1、SOD2及抗凋亡基因Bcl-2的表达,并抑制caspase 3、cathepsin B的表达。
8.根据权利要求1所述的应用,其特征在于,所述虾青素能够提高卵母细胞线粒体的膜电位。
9.一种用于缓解BPA引起的卵泡氧化应激损伤的药物,其特征在于,其包括权利要求1-8任一项所述虾青素,以及药学上可接受的辅料或载体。
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