CN108785320A - 异毛蕊花糖苷在制备激活Nrf2-ARE信号通路的保健品/药品中的应用 - Google Patents
异毛蕊花糖苷在制备激活Nrf2-ARE信号通路的保健品/药品中的应用 Download PDFInfo
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Abstract
本发明涉及医药保健领域;具体而言,本发明公开了一种异毛蕊花糖苷在制备激活Nrf2‑ARE信号通路的保健品/药品中的应用。可以激活Nrf2‑ARE信号通路的异毛蕊花糖苷作为活性成分可应用于健康食品或药品中,特别是应用于具有抗氧化、抗肿瘤、神经保护功能的健康食品或药品中。
Description
技术领域
本发明涉及医药保健领域;更具体地涉及一种能激活Nrf2-ARE信号通路的异毛蕊花糖苷及其在健康食品或药品中的用途。
背景技术
Nrf2-ARE信号通路是机体内重要的抗氧化应激信号通路,研究证明在抗肿瘤、抗氧化应激、抗凋亡、抗炎症反应以及调节心脑血管应激、神经保护等方面发挥着广泛的作用。具体而言,Nrf2/ARE信号通路是细胞氧化应激反应中的关键通路,其调控的下游抗氧化蛋白和Ⅱ相解毒酶在细胞防御保护中发挥重要作用。现有研究显示Nrf2/ARE通路在抗炎、抗肿瘤、神经保护、抗凋亡等多方面具有重要作用,以Nrf2为靶点的药物有望用于多发性硬化、糖尿病、神经退行性疾病、肿瘤等多种疾病的治疗,其中已有富马酸二甲酯、巴多克沙龙等多个新药进入临床研究阶段。目前公认的能激活Nrf2-ARE信号通路的物质有表儿茶素、黄芩黄素、圣草酚、染料木素、鼠尾草酸等等。
研究表明,毛蕊花糖苷具有多种生物活性如:抗氧化、抗肿瘤、抗衰老、提高免疫力、神经保护等。
发明内容
本发明要解决的技术问题是提供一种异毛蕊花糖苷在健康食品或药品中的新用途。
为了解决上述技术问题,本发明提供一种异毛蕊花糖苷在制备激活Nrf2-ARE信号通路的保健品/药品中的应用。
作为本发明的异毛蕊花糖苷在制备激活Nrf2-ARE信号通路的保健品/药品中的应用的改进:可以激活Nrf2-ARE信号通路的异毛蕊花糖苷作为活性成分应用于健康食品或药品中。
作为本发明的异毛蕊花糖苷在制备激活Nrf2-ARE信号通路的保健品/药品中的应用的进一步改进:可以激活Nrf2-ARE信号通路的异毛蕊花糖苷作为活性成分应用于具有抗氧化、抗肿瘤、神经保护功能的健康食品或药品中。
即,发明公开了一种能激活Nrf2-ARE信号通路的异毛蕊花糖苷及其在健康食品或药品中的用途。本发明的异毛蕊花糖苷可以用于制备与Nrf2-ARE信号通路相关疾病的健康食品或药品中。本发明提供了异毛蕊花糖苷在相关疾病模型中对Nrf2-ARE信号通路的激活作用。
异毛蕊花糖苷与毛蕊花糖苷都是苯乙醇苷类化合物并且是同分异构体,也已被报道具有抗氧化能力,本研究基于前期对该类化合物的研究基础,认为其与毛蕊花糖苷具有相似的生物活性。
本发明的问世基于本课题组前期研究结果认为:异毛蕊花糖苷是Nrf2-ARE信号通路的有效激活剂,并且在Nrf2-ARE信号通路相关的疾病如抗氧化、抗肿瘤、神经保护等方面具有很好的防治效果。因此,有望用于制备与Nrf2-ARE信号通路相关疾病的健康食品或药品中。
本发明所用的化合物异毛蕊花糖苷,中文别名:异麦角甾苷、异类叶升麻苷,分子量624.59,分子式C29H36O15,CAS号:61303-13-7,结构式如下:
本发明的化合物毛蕊花糖苷可以通过商业途径购买获得,亦可以用常规方法从木犀科植物桂花Osmanthus fragrans(Thunb.)Lour.的花朵中提取获得。
本发明的异毛蕊花糖苷可以单独使用或以药物组合物的形式使用。药物组合物包括作为活性成分的本发明的异毛蕊花糖苷及可药用载体。该载体不会破坏本发明的异毛蕊花糖苷的药学活性,同时其有效用量,即能发挥药物载体作用同时的用量可以在一定程度上提高异毛蕊花糖苷的稳定性并且对人体无害。
所述可用药物载体包括但不限于:软磷脂、自乳化药物传递系统、食用胶、环状糊精、纤维素衍生物、明胶、酪蛋白等。
本发明的毛蕊花糖苷以及其药物组合物可按本领域常规方法制备并可以通过肠道或非肠道或局部途径给药。口服制剂包括胶囊剂、片剂、口服液、颗粒剂、丸剂、散剂、丹剂、等;非肠道给药制剂包括注射液等;局部给药制剂包括霜剂、贴剂、软膏剂、喷雾剂、稀释剂、湿润剂等。优选为口服制剂。
本发明的异毛蕊花糖苷及其药物组合物的给药途径可以口服、舌下、经皮、经肌肉或皮下、皮肤粘膜、静脉、尿道、阴道等。用量(有效成分的用量)可参照常规用量;例如,动物实验时,大鼠为500-1000mg/kg。
需要说明的是:Nrf2-ARE信号通路是重要的抗氧化应激信号通路,在很多疾病中都具有重要的保护作用,但是不同疾病的发病机制各有不同,具有抗肿瘤、抗衰老等作用的物质作用机制很多都是通过细胞凋亡途径实现,神经保护作用的物质很多表现在对神经营养因子或者免疫因子的调控。因此,具有抗氧化、抗肿瘤、抗衰老、提高免疫力、神经保护等功能与激活Nrf2-ARE信号通路之间没有必然关系。
作为公知技术,竹叶黄酮已证实其具有抗氧化、抗衰老、抗肿瘤、保护心血管疾病等生物活性,但是发明人针对竹叶黄酮进行了针对Nrf2-ARE信号通路的相应研究,没有得到如同本发明所述的其可以激活Nrf2-ARE信号通路的证据;迄今为止,也没有竹叶黄酮可以激活Nrf2-ARE信号通路这样的研究被报道过。
附图说明
下面结合附图对本发明的具体实施方式作进一步详细说明。
图1为不同处理组对斑马鱼运动轨迹的影响对比图;
CK:正常对照组;Model:模型组;PC:阳性对照组;AL:异毛蕊花糖苷低剂量组;
AM:异毛蕊花糖苷中剂量组;AH:异毛蕊花糖苷高剂量组;
图2为斑马鱼全标本包埋酪氨酸羟化酶免疫染色对比图;
CK:正常对照组;Model:模型组;PC:阳性对照组;AL:异毛蕊花糖苷低剂量组;
AM:异毛蕊花糖苷中剂量组;AH:异毛蕊花糖苷高剂量组;
图3为毛蕊花糖苷对PD斑马鱼体内Nrf2基因mRNA表达水平的影响对比图;
CK:对照组;Model:模型组;PC:阳性对照组;AL:异毛蕊花糖苷低浓度组;AM:异毛蕊花糖苷中浓度组;AH:异毛蕊花糖苷高浓度组;
#:与模型组差异显著,p<0.05;##:与模型组差异极显著,p<0.01;
图4为毛蕊花糖苷对PD斑马鱼体内Nrf2下游Ⅱ相解毒酶基因mRNA表达水平的影响对比图;
CK:对照组;Model:模型组;PC:阳性对照组;AL:异毛蕊花糖苷低浓度组;AM:异毛蕊花糖苷中浓度组;AH:异毛蕊花糖苷高浓度组;
#:与模型组差异显著,p<0.05;##:与模型组差异极显著,p<0.01。
具体实施方式
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。
实施实例1、异毛蕊花糖苷抗氧化作用
(1)DPPH法
实验前精确称取20mg的DPPH溶于适量甲醇中,定容至500mL。以25-800μM Trolox为对照品,取稀释一定倍数的样品或对照品溶液100uL,加入3.9mL DPPH,37℃避光反应60min,于515nm波长处测吸光度。以Trolox浓度为横坐标,吸光值为纵坐标作标准曲线,根据标准曲线计算样品抗氧化能力,结果以每克提取物中Trolox当量表示(mmol Trolox/gDW)。
(2)ABTS法
分别配置7.4mM ABTS以及2.6mM过硫酸钾,临用前等体积混合,37℃避光反应12h,稀释27倍后使用。以25-800μM Trolox为对照品,取稀释一定倍数后的样品或对照品溶液100uL,加入3.0mL ABTS反应液,37℃避光反应60min后于734nm处测吸光度。以Trolox浓度为横坐标,吸光值为纵坐标作标准曲线,根据标准曲线计算样品抗氧化能力,结果以每克提取物中Trolox当量表示(mmol Trolox/g DW)。
(3)FRAP法
以40mM HCl为溶剂配置10mM TPTZ溶液,20mM FeCl3水溶液,300mM,pH=3.6乙酸钠缓冲液,三者以1:1:10(v/v/v)混合得FRAP。以FeSO4为对照品,取稀释一定倍数后的样品或对照品溶液100uL,加入3.0mL FRAP反应液,37℃避光反应60min后于595nm处测吸光度。以FeSO4浓度为横坐标,吸光值为纵坐标作标准曲线,根据标准曲线计算样品抗氧化能力,结果以每克提取物中FeSO4当量表示(mmol FeSO4/g DW)。
(4)ORAC法
配置pH 7.4,浓度为75mM磷酸盐缓冲液,以其为溶剂配制荧光素及AAPH溶液。以0-80μM Trolox为对照品,分别向黑色酶标96孔板中加入20uL样品(稀释一定倍数后)、120uL荧光素,37℃保温5min后加入60uL AAPH,使荧光素和AAPH终浓度分别为70nM和12mM,立即进入荧光酶标仪测定。测定条件为每2min测定一次,持续3h,激发波长及发射波长分别为485nm、530nm。以Trolox浓度为横坐标,吸光值为纵坐标作标准曲线,根据标准曲线计算样品抗氧化能力,结果以每克提取物中Trolox当量表示(mmol Trolox/g DW)。
结果如表1所示,异毛蕊花糖苷有较强的清除自由基、抗氧化的能力。
表1、异毛蕊花糖苷清除自由基能力
实施实例2、异毛蕊花糖苷抗肿瘤细胞作用
(1)细胞培养
细胞复苏:从液氮保存罐中取出冻存管,立即放入37℃水浴中,快速摇晃,直至冻存液完全融化,1,200r/min离心5-10min收集细胞,用细胞培养液悬液混悬沉淀细胞,调整细胞浓度,置于培养箱中,在37℃、5%CO2条件下培养,定时观察细胞生长状态。
细胞传代:超净工作台经紫外照射30min以上后使用,倒出旧培养液,用PBS清洗两遍后加入200μL胰蛋白酶(经PBS稀释5倍后的稀释液),使其覆盖细胞表面后反应约1min,待细胞消化至开始皱缩,立即加入细胞培养液终止反应,将贴壁细胞吹打脱落并均匀分布于培养液中,1,200r/min离心5-10min收集细胞,用细胞培养液悬液混悬沉淀细胞,补加培养液,根据需要按一定比例分装于新的培养瓶。
细胞冻存:取对数生长期的细胞,消化后装于离心管中收集细胞,弃去培养液后加入适量冻存液,取1.0mL分装于冻存管中,封口膜封口,标明细胞名称、细胞代数、保存时间、保存者姓名等,逐级降温,4℃下恒温放置2h,-20℃下恒温放置2h,最后放入液氮罐中长期保存。
(2)细胞活力检测
将处于对数期的细胞消化后,用血球计数板计数,调整细胞浓度至1×105个/mL,每孔接180μL于96孔板中,周边用PBS代替以避免边缘效应。实验组分为正常对照组(不做处理)和样品处理组,每组设3个复孔。待细胞贴壁后,样品组加入不同浓度的异毛蕊花糖苷24h,干预结束后移除旧培养液并用PBS洗涤,每孔加含MTT终浓度为0.5mg/mL的培养液200μL,4h后终止培养,小心吸去孔内培养液,每孔加入150uL二甲基亚砜,置摇床上低速振荡10min,使结晶物充分溶解。在酶标仪490nm处测量各孔的吸光值。测定前设置含细胞培养液、MTT和二甲基亚砜的调零孔。
结果如表2所示,异毛蕊花糖苷可以显著降低人宫颈癌细胞Hala,人肝癌细胞HepG2,人乳腺癌细胞MCF-7和T47D,人前列腺癌细胞LNCap、PC3和DU145的增值率,浓度越高抑制效果越显著。
表2、三种不同浓度的异毛蕊花糖苷抑制肿瘤细胞增殖能力
实施实例3、异毛蕊花糖苷对6-OHDA诱导的斑马鱼帕金森疾病(PD)防治作用
(1)斑马鱼的饲养
选用野生型AB品系斑马鱼,养殖在循环系统内,循环系统内养殖水由反渗透净水机制备,系统温度保持在28.0℃,电导率维持在450-550μS,盐浓度维持在0.25-0.75‰,pH值保持在7.2-7.6,光强度维持在52-350LX,溶氧度不低于6mg/L,氨氮浓度低于0.02ppm,光周期(光照/黑暗):10h/14h。每日早8:00-9:00、晚19:00-20:00各喂薄片鱼粮一次,早11:30-12:30、晚15:30-16:30各喂丰年虫一次。
(2)配鱼与鱼卵收集
取卵前一天,按照雌:雄为1:1的比例将斑马成鱼放置于底部带有筛孔隔离层的交配盒,中间用垂直隔板将雌雄隔开。次日早晨8:30-9:00拔除隔板,2h后收集鱼卵,将收集的卵置于盛有Holt Buffer的培养皿中,去除死卵及其他杂物,转移到28.5℃恒温培养箱中培育。每日更换Holt Buffer并及时去除死卵,直至加药处理。
(3)斑马鱼行为学研究
收集鱼卵孵化至72hpf(受精后72小时)时,选择已破膜并且发育正常的幼鱼,随机分为6组,分别为:正常对照组、250μM 6-OHDA处理组、诺米芬新阳性对照组、100μg/mL异毛蕊花糖苷处理组、200μg/mL异毛蕊花糖苷处理组、400μg/mL异毛蕊花糖苷处理组,每组10条幼鱼。正常对照组用正常孵化液处理,250μM 6-OHDA处理组用含有250μM 6-OHDA的孵化液浸泡处理,诺米芬新阳性对照组用含有250μM 6-OHDA和3μM的诺米芬新的孵化液浸泡处理,异毛蕊花糖苷处理组用含有250μM 6-OHDA和100、200、400μg/mL异毛蕊花糖苷的孵化液浸泡处理,处理4d。实验结束,将幼鱼移至96孔板(每孔1条鱼),待其适应1h后,分别拍摄10min内运动情况,用Any-maze 4.73软件分析其运动轨迹、运动距离等参数。
(4)黑质多巴胺能神经元凋亡检测
收集鱼卵孵化至24hpf,人工破膜后随机分为6组,分别为:正常对照组、6-OHDA处理组、诺米芬新阳性对照组、100μg/mL异毛蕊花糖苷处理组、200μg/mL异毛蕊花糖苷处理组、400μg/mL异毛蕊花糖苷处理组,每组10条幼鱼。正常对照组用正常孵化液处理,250μM6-OHDA处理组用含有250μM 6-OHDA的孵化液浸泡处理,诺米芬新阳性对照组用含有250μM 6-OHDA和3μM的诺米芬新的孵化液浸泡处理,异毛蕊花糖苷处理组用含有250μM6-OHDA和100、200、400μg/mL异毛蕊花糖苷的孵化液浸泡处理,处理2d,收集幼鱼置于冰上处死后用于后续实验。将幼鱼置于4%多聚甲醛于常温1h或4℃过夜固定,PBST冲洗5min。加入50%乙醇常温下脱水5min,脱水后的样品可置于100%乙醇中于-20℃长期保存,也可以直接用于实验。取脱水或者保存的样品,用PBST冲洗5min,加入0.0125%胰酶常温处理40min,用PBST冲洗5min,加入-20℃预冷的丙酮,并置于-20℃处理7min,用TBST冲洗3次,每次5min。用含2%山羊血清和0.1%BSA的封闭液常温封闭1h,孵育一抗(用封闭液配制,稀释倍数为1:200),常温孵育2h或者4℃孵育过夜。用TBST冲洗6次,每次30min,参照试剂盒说明孵育二抗。着色后用3.5%甲基纤维素固定样品进行观察拍照。
结果如图1和表3所示,异毛蕊花糖苷可以显著改善PD斑马鱼的运动距离和运动轨迹,如图2所示,异毛蕊花糖苷可以显著减少PD斑马鱼多巴胺能神经元的凋亡。
表3、不同处理组对斑马鱼运动距离的影响
注:**表示与正常对照组比较,p<0.01,#表示与模型组比较,p<0.05,##表示与模型组比较,p<0.01。
实施实例4:异毛蕊花糖苷对Nrf2-ARE信号通路的激活作用
(1)斑马鱼的饲养
参照实施案例3
(2)配鱼与鱼卵收集
参照实施案例3
(3)组织内谷胱甘肽过氧化物酶酶活检测、过氧化氢酶酶活检测及超氧化物岐化酶酶活力检测
收集鱼卵孵化至72hpf时,选择已破膜并且发育正常的幼鱼,随机分为6组,分别为:正常对照组、250μM 6-OHDA处理组、诺米芬新阳性对照组、100μg/mL异毛蕊花糖苷处理组、200μg/mL异毛蕊花糖苷处理组、400μg/mL异毛蕊花糖苷处理组,每组200条幼鱼。正常对照组用正常孵化液处理,250μM 6-OHDA处理组用含有250μM 6-OHDA的孵化液浸泡处理,诺米芬新阳性对照组用含有250μM 6-OHDA和3μM的诺米芬新的孵化液浸泡处理,异毛蕊花糖苷处理组用含有250μM 6-OHDA和100、200、400μg/mL异毛蕊花糖苷的孵化液浸泡处理,处理4d。实验结束后,置于冰上处死幼鱼,按照每条幼鱼加入0.5μL裂解液的比例进行加入裂解液(含10mM PMSF),电动研磨棒研磨10s,冰上放置30min,随后4℃,12,000g离心10min。取上清进行谷胱甘肽过氧化物酶酶活检测、过氧化氢酶酶活检测及超氧化物岐化酶的活性检测。
超氧化物歧化酶:
按照每个反应160μL均匀混合151μL SOD检测缓冲液、8μL WST-8和1μL酶溶液配置WST-8/酶工作液。样品测定时分为空白对照组和样品组,把试剂盒中的反应启动液(40×)融解后混匀,按照每1μL反应启动液(40×)加入39μL SOD检测缓冲液的比例进行稀释;使用96孔板设置样品孔和各种空白对照孔,并依次加入待测样品20μL(空白对照1、2用SOD检测缓冲液代替)、160μL WST-8/酶工作液和20μL反应启动工作液(空白对照2用SOD检测缓冲液代替)后充分混匀,37℃孵育30min,测定A450。样品中总SOD活力的计算:抑制百分率=(A空白对照1-A样品)/(A空白对照1-A空白对照2)×100%,待测样品中SOD酶活力单位=检测体系中SOD酶活力单位=抑制百分率/(1-抑制百分率)units。
过氧化氢酶:
配制250mM过氧化氢溶液、5mM过氧化氢溶液,取适当量的过氧化物酶,按照1:1000的比例用显色底物稀释,配制成显色工作液。取0、12.5、25、50或75μL(5mM)过氧化氢溶液至1.5mL或0.5mL塑料离心管中,分别加入过氧化氢酶检测缓冲液至最后体积为100μL,混匀,各取4μL,加入到96孔板中的一个孔内,加入200μL显色工作液,25℃孵育15min后测定A520,制作标准曲线。样品测定时分为空白对照组和样品组,取10μL样品至1.5mL塑料离心管中(空白对照组用等量过氧化氢酶检测缓冲液替代),加过氧化氢酶检测缓冲液至体积为40μL,再加入10μL 250mM过氧化氢溶液,用移液器迅速混匀,25℃反应5min,加入450μL过氧化氢酶反应终止液,颠倒混匀或涡旋混匀以终止反应;在一洁净的塑料离心管内加入40μL过氧化氢酶检测缓冲液,再加入10μL已终止并混匀的上述反应体系,混匀,从上一步骤的50μL体系中取10μL加入到96孔板中的一个孔内,加入200μL显色工作液,25℃孵育15min,测定A520。由标准曲线A520=k[过氧化氢微摩尔数]+b计算出k和b的值。样品中残余的过氧化氢摩尔数=(A520-b)/k,[样品过氧化氢酶酶活力]=[消耗过氧化氢微摩尔数]×[稀释倍数250]/([反应分钟数5]×[样品体积10]×[蛋白浓度])。
谷胱甘肽过氧化物酶:
配制10mM NADPH、84mM GSH溶液、15mM过氧化物试剂溶液;GPx检测工作液的配制:5μL 10mM NADPH、5μL 84mM GSH、0.4μL谷胱甘肽还原酶/样品(所有试剂使用前须在水浴到25℃)。样品测定时分为空白对照组、样品本底对照组和样品组,依次加入186μL谷胱甘肽过氧化物酶检测缓冲液、2-10μL待测样品(空白对照组用等量谷胱甘肽过氧化物酶检测缓冲液替代)、10μL GPx检测工作液和4μL 15mM过氧化物试剂溶液(样品本底对照组用等量谷胱甘肽过氧化物酶检测缓冲液替代),混匀,使用适当的酶标仪或微量紫外分光光度计测定A340;连续测定3min或自动每隔30s测定一次A340。[样品中谷胱甘肽过氧化物酶活力]=[检测体系中谷胱甘肽过氧化物酶活力]X[稀释倍数]/[样品中的蛋白浓度][样品中谷胱甘肽过氧化物酶活力],单位:U/mg蛋白。
(4)组织内MDA水平检测
收集鱼卵孵化至72hpf时,选择已破膜并且发育正常的幼鱼,随机分为6组,分别为:正常对照组、250μM 6-OHDA处理组、诺米芬新阳性对照组、100μg/mL异毛蕊花糖苷处理组、200μg/mL异毛蕊花糖苷处理组、400μg/mL异毛蕊花糖苷处理组,每组200条幼鱼。正常对照组用正常孵化液处理,250μM 6-OHDA处理组用含有250μM 6-OHDA的孵化液浸泡处理,诺米芬新阳性对照组用含有250μM 6-OHDA和3μM的诺米芬新的孵化液浸泡处理,异毛蕊花糖苷处理组用含有250μM 6-OHDA和100、200、400μg/mL异毛蕊花糖苷的孵化液浸泡处理,处理4d。实验结束后,置于冰上处死幼鱼,按照每条幼鱼加入0.5μL裂解液的比例进行加入裂解液(含10mM PMSF),电动研磨棒研磨10s,冰上放置30min,随后4℃,12,000g离心10min。取上清进行脂质过氧化物水平检测。
配制浓度为0.37%的TBA储存液,MDA检测工作液的配制:TBA稀释液150μL、TBA储存液50μL、抗氧化剂3μL/样品。取适量标准品用蒸馏水稀释至1、2、5、10、20、50μM,加入0.1mL不同浓度标准品,随后加入0.2mL MDA检测工作液;混匀后,100℃金属浴加热15min,水浴冷却至室温,1,000g室温离心10min;取200μL上清加入到96孔板中,测定A532。用于制作标准曲线。样品测定时分为空白对照组和样品组,TBA稀释液150μL、TBA储存液50μL、抗氧化剂3μL/样品,加入0.1mL样品(空白对照组用等量PBS溶液替代),随后加入0.2mL MDA检测工作液;混匀后,100℃金属浴加热15min,水浴冷却至室温,1,000g室温离心10min;取200μL上清加入到96孔板中,测定A532。MDA含量的计算:根据标准曲线计算获得MDA的摩尔浓度,通过单位重量的蛋白含量来表示最初样品中的MDA含量(mol/mg蛋白)。以上指标检测过程中使用的所有试剂均现配现用,所有操作均在冰上进行。
结果如表4所示,毛蕊花糖苷可以提高PD斑马鱼组织内抗氧化酶活力同时减少MDA产生,即提高了斑马鱼的抗氧化能力,这可能是其改善PD症状的原因。
表4不同处理组斑马鱼组织内抗氧化酶活力、MDA水平
注:**表示与正常对照组比较,p<0.01,#表示与模型组比较,p<0.05,##表示与模型组比较,p<0.01。
(5)斑马鱼体内Nrf2-ARE信号通路的激活情况
总RNA提取
收集鱼卵孵化至72hpf时,选择已破膜并且发育正常的幼鱼,随机分为6组,分别为:正常对照组、250μM 6-OHDA处理组、诺米芬新阳性对照组、100μg/mL异毛蕊花糖苷处理组、200μg/mL异毛蕊花糖苷处理组、400μg/mL异毛蕊花糖苷处理组,每组10条幼鱼。正常对照组用正常孵化液处理,250μM 6-OHDA处理组用含有250μM 6-OHDA的孵化液浸泡处理,诺米芬新阳性对照组用含有250μM 6-OHDA和3μM的诺米芬新的孵化液浸泡处理,异毛蕊花糖苷处理组用含有250μM 6-OHDA和100、200、400μg/mL异毛蕊花糖苷的孵化液浸泡处理,处理4d。实验结束,收集各组样品至1.5mL离心管中,加入1mL的RNAiso Plus,使用电动研磨棒研磨均匀。室温静置5min;加入1/5RNAiso Plus体积的氯仿,剧烈振荡30s混匀,使水相和有机相充分接触,室温静置5min;4℃14,000g离心15min,上层水相移至新的RNase free EP管。加入1倍RNAiso Plus体积的异丙醇,轻柔混匀,室温静置10min;4℃14,000g离心10min,小心弃去上清,切勿触及沉淀。加入1倍RNAiso Plus体积的75%乙醇清洗沉淀,4℃7,500g离心5min后小心弃去上清,切勿触及沉淀,重复此步骤操作1次;打开离心管盖,室温干燥。沉淀干燥后,加入适量的RNase free水溶解沉淀。将RNA样品置于-80℃保存,以用于后续检测。
使用前利用Nanodrop ND-2000超微量核酸蛋白测定仪测定RNA浓度和纯度。
去除基因组DNA反应
按照2.0μL 5×gDNAEraser Buffer+1.0μL gDNAEraser/样品,配制反应体系,体系配好后置于冰上配制反应混合液,分装反应体系每个反应管中,最后加入RNA样品(每个体系<1μg),加RNase Free dH2O补至10μL,混匀,42℃放置2min,4℃保存。
反转录反应
按照1.0μL PrimeScript RT Enzyme Mix I+1.0μL RT Primer Mix+4.0μL5×PrimeScript Buffer 2+4.0μL RNase Free dH2O/样品,配制反应体系,体系配好后置于冰上,分装反应体系到已经去除基因组DNA的反应液中,轻柔混匀,37℃放置15min,85℃放置5s,-20℃保存备用。
RT-PCR
按照12.5μL SYBR Premix Ex TaqⅡ(2×)、1.0μL上游引物(10μM)、1.0μL下游引物(10μM)、3.0μL DNA模板、8.0μL灭菌水、0.5μL ROX Reference Dye/样品,配制反应体系。轻柔混匀,上机检测。PCR反应程序:95℃,30s;95℃,5s,引物退火温度,30s,共40个循环;并添加融解曲线。
引物及退火温度如下:
β-Actin Forward primer:CACTGAGGCTCCCCTGAATC
Reverse primer:GGGTCACACCATCACCAGAG
Nrf2Forward primer:CTGCTGTCACTCCCAGAGTT
Reverse primer:GCCGTAGTTTTGGGTTGGTG
HO1Forward primer:AAGAGCTGGACAGAAACGCA
Reverse primer:AGAAGTGCTCCAAGTCCTGC
GCLC Forward primer:CTCCTCACAGTCACGGCATT
Reverse primer:TGAATGGAGACGGGGTGTTG
GCLM Forward primer:AAGCCAGACACTGACACACC
Reverse primer:ATCTGGAGGCATCACACAGC
NQO1Forward primer:AAGCCTCTGTCCTTTGCTCC
Reverse primer:TGCTGTGGTAATGCCGTAGG
如图3所示,6-OHDA处理后,斑马鱼体内Nrf2水平较正常对照组明显降低,毛蕊花糖苷可以显著提高Nrf2基因的表达水平,具有增强机体抗氧化能力的潜能。
如图4所示,6-OHDA导致Nrf2下游Ⅱ相解毒酶HO-1、GCLC、GCLM基因在mRNA水平表达量显著降低(p<0.01),异毛蕊花糖苷则可以提高其表达量,表明异毛蕊花糖苷可以激活Nrf2-ARE信号通路。
最后,还需要注意的是,以上列举的仅是本发明的若干个具体实施例。显然,本发明不限于以上实施例,还可以有许多变形。本领域的普通技术人员能从本发明公开的内容直接导出或联想到的所有变形,均应认为是本发明的保护范围。
序列表
<110> 浙江大学
<120> 异毛蕊花糖苷在制备激活Nrf2-ARE信号通路的保健品/药品中的应用
<160> 12
<170> SIPOSequenceListing 1.0
<210> 1
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 1
cactgaggct cccctgaatc 20
<210> 2
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 2
gggtcacacc atcaccagag 20
<210> 3
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 3
ctgctgtcac tcccagagtt 20
<210> 4
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 4
gccgtagttt tgggttggtg 20
<210> 5
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 5
aagagctgga cagaaacgca 20
<210> 6
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 6
agaagtgctc caagtcctgc 20
<210> 7
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 7
ctcctcacag tcacggcatt 20
<210> 8
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 8
tgaatggaga cggggtgttg 20
<210> 9
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 9
aagccagaca ctgacacacc 20
<210> 10
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 10
atctggaggc atcacacagc 20
<210> 11
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 11
aagcctctgt cctttgctcc 20
<210> 12
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 12
tgctgtggta atgccgtagg 20
Claims (3)
1.异毛蕊花糖苷在制备激活Nrf2-ARE信号通路的保健品/药品中的应用。
2.根据权利要求1所述的异毛蕊花糖苷在制备激活Nrf2-ARE信号通路的保健品/药品中的应用,其特征是:可以激活Nrf2-ARE信号通路的异毛蕊花糖苷作为活性成分应用于健康食品或药品中。
3.根据权利要求2所述的异毛蕊花糖苷在制备激活Nrf2-ARE信号通路的保健品/药品中的应用,其特征是:可以激活Nrf2-ARE信号通路的异毛蕊花糖苷作为活性成分应用于具有抗氧化、抗肿瘤、神经保护功能的健康食品或药品中。
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