CN116671632A - 储氢牡蛎钙抑制非小细胞肺癌的特殊医学用途食品、保健品及药品中的应用 - Google Patents
储氢牡蛎钙抑制非小细胞肺癌的特殊医学用途食品、保健品及药品中的应用 Download PDFInfo
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- C01B3/001—Reversible uptake of hydrogen by an appropriate medium, i.e. based on physical or chemical sorption phenomena or on reversible chemical reactions, e.g. for hydrogen storage purposes ; Reversible gettering of hydrogen; Reversible uptake of hydrogen by electrodes characterised by the uptaking medium; Treatment thereof
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Abstract
本发明公开了储氢牡蛎钙抑制非小细胞肺癌的特殊医学用途食品、保健品及药品中的应用,涉及生物学和医药学技术领域,储氢牡蛎钙抑制非小细胞肺癌的特殊医学用途食品、保健品及药品中的应用,使用储氢牡蛎钙作为固态的载氢剂,能够与水反应产生氢气,可持续释放高浓度氢气,对抑制非小细胞肺癌起到显著的效果。
Description
技术领域
本发明涉及生物学和医药学技术领域,具体是储氢牡蛎钙(hydrogen oysterpowder,HOP)抑制非小细胞肺癌的特殊医学用途食品、保健品及药品中的应用。
背景技术
1975年Dole M等人在《Science》发表了文章“Hyperbaric hydrogen therapy:apossible treatment for cancer”,研究结果报道了经过连续呼吸高压氢气2周后,皮肤恶性肿瘤动物模型中肿瘤体积较对照组明显减小,提示高压氢气治疗皮肤恶性肿瘤有一定效果,其机制可能与氢气的抗氧化作用有关。但气体氢具有危险性,富氢水饱和浓度低(0.8mmol/L),不便于贮存和易挥发等不足制约了氢的应用。且目前对非小细胞肺癌的氢治疗和抑制研究尚属空白。
发明内容
本发明的目的在于提供储氢牡蛎钙抑制非小细胞肺癌的特殊医学用途食品、保健品及药品中的应用,本发明中涉及的具有在消化道溶液环境中缓释氢分子的储氢牡蛎钙,对人非小细胞肺癌A549细胞株形成的瘤体的增殖具有显著的抑制效果,并解决了上述背景技术中提出的问题。
为实现上述目的,本发明提供如下技术方案:包括使用储氢牡蛎钙作为固态的载氢剂,能够与水反应产生氢气,可持续释放高浓度氢气。
进一步地,其储氢牡蛎钙制作的储氢牡蛎钙悬液浓度为100mg/k~2000mg/kg。
进一步地,其储氢牡蛎钙在制备抑制非小细胞肺癌细胞增殖的抑制剂中的应用。
进一步地,其储氢牡蛎钙在制备抑制线粒体融合进而抑制非小细胞肺癌细胞增殖的抑制剂中的应用。
进一步地,储氢牡蛎钙在特殊医学用途食品、保健品及药品中的应用。
与现有技术相比,本发明的有益效果是:
1.储氢牡蛎钙选用具有化痰软坚功效的中药材牡蛎作为储氢载体,对非小细胞肺癌移植瘤增殖具有显著的抑制作用;
2.所述储氢牡蛎钙在抑制非小细胞肺癌药物中的应用中储氢牡蛎钙无毒副作用;
3.储氢牡蛎钙通过RAS-MAPK-STAT3途径抑制非小细胞肺癌细胞增殖;
4.储氢牡蛎钙通过抑制线粒体融合进而抑制非小细胞肺癌细胞增殖。
附图说明
图1为储氢牡蛎钙(HOP)体外持续释放氢气情况;
图2为储氢牡蛎钙(HOP)抑制非小细胞肺癌细胞A549裸鼠移植瘤生长;
图3为储氢牡蛎钙(HOP)对荷瘤裸鼠无毒副作用;
图4为储氢牡蛎钙(HOP)通过抑制MAPK/STAT3通路促进肺癌细胞凋亡;
图5为储氢牡蛎钙(HOP)通过促进线粒体碎片化抑制线粒体功能。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
请参阅图1~5,本发明实施例中,非小细胞肺癌细胞A549培养及荷瘤裸鼠模型的建立
1)A549细胞培养
人非小细胞肺癌细胞系A549购于ATCC,使用含10%胎牛血清和1%双抗的RPMI-1640培养基培养于含5%CO2的37℃培养箱中。当汇合度达到90%左右,用0.25%胰蛋白酶消化,消化结束后加入新鲜完全培养基终止消化。
2)荷瘤动物模型建立
30只BALB/c nude雌性裸鼠(4-5周龄),体重约为20g,购买自北京维通利华实验动物技术有限公司。该批小鼠饲养于SPF动物房中EVC笼盒。其生存条件为:无特定病原体,温度为20-26℃,湿度为55%,光/暗循环时间为12h,可随意获取食物和水。小鼠适应一周后,右腿上方背部皮下注射2×106个细胞,体积为100μl。
3)荷瘤动物的分组与给药
裸鼠注射细胞一周后,随机分为①Control(对照组,灌胃与处理组等体积的水);②L-HOP(低剂量组,100mg/kg储氢牡蛎钙悬液)③M-HOP(中剂量组,500mg/kg储氢牡蛎钙悬液)④H-HOP(高剂量组,2000mg/kg储氢牡蛎钙悬液),每组6只,按照100μl/只的计量每天灌胃。观察裸鼠生长情况,每隔一天测量肿瘤体积和裸鼠体重。干预38天后,采用颈椎脱臼的方法使小鼠安乐死,取出肿瘤组织进行称重。
4)肿瘤组织和内脏的取材及制备
(1)处死裸鼠后立即将肿瘤取出,称重和拍照后进行分装:取一部分标本放进4%中性甲醛中固定;一部分标本提取蛋白做Western blot实验;一部分标本提取mRNA做qPCR实验;一部分标本测定ATP水平。
(2)取完瘤体后,立即取出小鼠的肝脏、肾脏和小肠标本放进4%中性甲醛中固定,石蜡包埋后做苏木精和伊红(Hematoxylin&eosin,HE)染色。
实验方法
1)HOP体外释放氢气的检测
准确称取不同剂量的储氢牡蛎钙粉末,用水分别配制浓度为30mg/mL,100mg/mL,300mg/mL的储氢牡蛎钙水溶液5mL置于20mL的小烧饼中,轻轻搅拌混合均匀后,密封烧杯口,待检测时打开烧杯,用氢电极检测水溶液中氢气的浓度。分别检测1h,4h,8h,24h,48h,72h,96h,120h,144h,168h,192h储氢牡蛎钙释放氢气的浓度,同时测定溶液的PH。
2)荧光定量逆转录-聚合酶链式反应(RT-PCR)
(1)RNA提取
肿瘤标本收集至无RNA酶的灭菌离心管中,加入1000μL Trizol裂解液后用匀浆机匀浆,匀浆条件为10s/次,间隙10秒,连续3次。然后加200μL预冷的氯仿,充分混匀15s,室温静置2~3min。待溶液出现明显分层后,12000g,4℃离心15min,小心转移上清约300μL至新的离心管中,注意避免吸到沉淀,使杂质污染RNA样品。加等体积预冷的异丙醇,上下颠倒40~60次,室温静置20min或-20℃静置1~3h。待RNA析出后,12000g,4℃离心10min,弃上清,得RNA沉淀。加100μL预冷的75%乙醇,上下颠倒20~30次,使RNA沉淀漂起。12000g,4℃离心10min,弃上清,置于超净工作台中挥干。待RNA沉淀由白色开始变透明时,加入适量的DEPC水,于60℃水浴加热10min溶解。以DEPC水调零,紫外分光光度法检测RNA浓度与纯度。
(2)RT-PCR
将RNA样品调成一致浓度,用AG反转录试剂盒按表1体系加样,混匀后旋转离心,使液体聚集于PCR管底,放入PCR仪,按表2程序进行反转录。
表1RT-PCR体系(/20μL)
表2RT-PCR程序
(3)实时定量PCR
目标基因的引物经设计、合成后,用灭菌超纯水溶解成100μM的储备液,-20℃保存。临用前将上、下游引物混合,稀释10倍后得终浓度为10μM的应用液。β-actin作为内参,实验所用的引物序列为:
将反转录所得的cDNA按表3反应体系加样,混匀后旋转离心,使液体聚集于PCR管底,放入PCR仪,按表4中的程序进行实时定量PCR。根据待测样品的Ct值计算目的基因的mRNA水平。
表3实时定量PCR体系(/10μL)
表4实时定量PCR程序
3)蛋白免疫印迹
(1)蛋白样品的制备
肿瘤标本收集至EP管中,加入300μL Ripa裂解液后用匀浆机匀浆,匀浆条件为10s/次,间隙10秒,连续3次。将蛋白裂解液于13000g,4℃离心6min,吸取上清至新的离心管中。用BCA试剂盒对上清进行蛋白定量,并将样品的蛋白浓度调成一致,随后加入样品体积1/4的加入5×loading buffer和β-巯基乙醇,混匀后于100℃加热10min,制好的样品即可用于电泳,或-20℃暂时保存。
(2)电泳
将SDS-PAGE凝胶置于电泳槽中,加入适当体积的电泳缓冲液,根据样品蛋白浓度,将适当体积的蛋白样品加入凝胶的加样孔中(10μg/孔),除蛋白marker加2.5μL外,所有孔的上样体积均相同。接通电源,以40mA恒流电泳至溴酚蓝指示剂距胶板底边5mm左右时停止。
(3)转膜
电泳结束后,将胶板取出,切除浓缩胶,于转膜液中小心剥离凝胶,同时将转膜所需的滤纸及硝酸纤维素膜置于转膜液中浸润,再将凝胶与硝酸纤维素膜紧密贴合,夹于滤纸和海绵中,放入转膜装置(胶向负极,膜向正极),加转膜液使其浸没凝胶。接通电源,以300mA恒流转膜120min。
(4)封闭
转膜结束后,取出硝酸纤维素膜,正面向上放入孵育盒中,加入封闭液(10~15mL/盒),置于摇床上,室温下摇动孵育1~2h或4℃封闭过夜。
(5)一抗孵育
将封闭后的膜用TBST漂洗三次,每次5min。将膜夹于两层保鲜膜中,参照marker的位置,按目的蛋白的分子量切取相应条带,置于孵育盒中。用TBST配制1%BSA溶液,并将一抗按比例稀释后加入相应蛋白的孵育盒内,置于摇床上,4℃摇动孵育过夜。一抗孵育完成后,回收一抗,用TBST洗膜三次,每次10min。
(6)二抗孵育
根据一抗的来源,将相对应的二抗用TBST按比例稀释,加入孵育盒内,室温下摇动孵育1h。二抗孵育完成后,用TBST洗膜三次,每次10min。
(7)检测
将膜从TBST中取出,吸去多余溶液,摆放于检测板上,将ECL发光剂的A液与B液等体积混合,均匀滴加到膜上。将检测板送入仪器内,按设定参数曝光并记录图像。用凝胶定量软件QuantityOne(Bio-red)对目的蛋白条带进行灰度分析。
4)ATP水平测定
肿瘤标本收集至EP管中,加入300μL ATP裂解液后用匀浆机匀浆,匀浆条件为10s/次,间隙10秒,连续3次。匀浆结束后在4℃下12000g离心5min。使用ATP试剂盒(碧云天#S0026)测量ATP水平。取裂解液上清加入反应混合液并在1min内用酶标仪(Spark10M,Tecan,Switzerland)测定化学发光值。每个样品的ATP水平通过对应孔的蛋白含量进行标准化。
5)组织石蜡包埋
固定:将肿瘤组织标本放进4%中性甲醛中固定72h。随后,把组织块标本块取出,应用0.1mol/L的PBS缓冲液清洗,共3次,每次30min;
组织脱水和石蜡包埋:将肿瘤组织标本浸泡在70%乙醇中1h,70%乙醇2h,80%乙醇处理30min,90%乙醇浸泡30min,95%乙醇中浸泡30min,95%乙醇中浸泡1h,无水乙醇中浸泡30min并重复两次,随后于二甲苯Ⅰ溶液中浸泡20min,二甲苯Ⅱ溶液中浸泡20min。以上步骤完成后将肿瘤组织置于蜡缸Ⅰ中浸泡1h,后蜡缸Ⅱ中浸泡1h。
包埋:包埋机使用时需提前开机预热,待机器中的蜡熔化后(大约1h)方可包埋。将脱水后的组织块放到包埋盒中央,滴蜡,然后盖上标本盒,最后用镊子将其夹到冷台上使其冷却后从包埋盒中取出标本盒,后将标本盒放在40C冰箱保存。
组织切片:将上述获得的石蜡组织块展平并置于冰上进行冷却,随后将组织块卡在切片机上,同时安装新的切割刀片,将组织块四周修整平整,将石蜡块切成4μm厚度的薄片,并把切下来的薄片平整的铺在45℃的水上,待褶皱完全摊开后,用防脱玻片将石蜡切片平整地捞起,用铅笔在载玻片的毛玻璃处标记组织名称、来源及获取时间。
烤片与烘片:将烤片机温度调到60℃,随后把载有组织切片的玻片置于烤片机上烘烤,时长2h,烘烤完成后将切片转移至70℃烘箱过夜。
6)苏木精和伊红(Hematoxylin&eosin,HE)染色
石蜡组织脱蜡:将上述获得的肿瘤组织石蜡切片依次置于以下溶液中。二甲苯I溶液中5min,二甲苯II溶液中浸泡5min,无水乙醇中浸泡3min,无水乙醇II中浸泡3min,95%乙醇中浸泡3min,90%乙醇酒精中浸泡3min,85%乙醇酒精中浸泡3min 75%的乙醇酒精中浸3min。随后用蒸馏水和PBS缓冲液各清洗两次。
染色:将脱蜡后的肿瘤组织标本置于苏木精溶液中孵育5min,随后用蒸馏水清洗5min,置于1%的盐酸酒精中分化10s,再水洗5min。随后将肿瘤组织切片置于伊红溶液中染色2min。显微镜下观察如果颜色过重的话可用75%乙醇进行脱色,并随时于显微镜下观察,染色合适后进行脱水。
脱水:染色后的标本切片进行梯度脱水,依次放入75%乙醇酒精1min,85%乙醇酒精浸泡1min,95%乙醇酒精1min,无水乙醇I中浸泡1min,无水乙醇II溶液中浸泡1min。晾干后将肿瘤组织切片分别置于二甲苯溶液I和II中各浸泡1min。
透明:晾干后将肿瘤组织切片置于二甲苯溶液I和II中各浸泡1min。
封片:中性树胶封片,滴一滴树胶于标本切片上,小心地盖上盖玻片,避免产生气泡,随后晾干室温保存。
显微镜下观察、拍照,评估肿瘤组织的病理学特征。
7)统计分析
使用Graphpad Prism 9软件进行统计分析。首先采用Shapiro-Wilk正态性检验检验样本的正态分布。如果符合正态分布,则进一步检验方差齐性。如果数据也通过了方差齐性检验,则使用双尾Student t-text或One-way ANOVA(Tukey事后检验)计算p值;否则,使用Welch t检验或Kruskal-Wallis检验计算p值。对于不符合正态分布的样本,使用Mann-Whitney或Kruskal-Wallis非参数检验。数据以平均值±SEM表示。显著统计学意义为*p<0.05,**p<0.01,***p<0.001。
相关结果
(一)储氢牡蛎钙(HOP)体外持续释放氢气的过程
为了明确储氢牡蛎钙在体外释放氢气的情况,首先准确称取不同剂量的储氢牡蛎钙粉末(HOP),用水分别配制浓度为30mg/mL,100mg/mL,300mg/mL的储氢牡蛎钙水溶液5mL置于20mL的小烧饼中,轻轻搅拌混合均匀后,密封烧杯口,待检测时打开烧杯,用氢电极检测水溶液中氢气的浓度。分别检测1h,4h,8h,24h,48h,72h,96h,120h,144h,168h,192h储氢牡蛎钙释放氢气的浓度,同时测定溶液的PH,检测结果如图1所示,图1(A)中我们发现30mg/mL,100mg/mL,300mg/mL的储氢牡蛎钙水溶液中氢气的浓度随着时间的增加先升高后降低,并且,30mg/mL,100mg/mL,300mg/mL的储氢牡蛎钙水溶液在8h氢气的浓度达到巅峰(氢气的峰值浓度分别为520ppb,600ppb,740ppb),随着储氢牡蛎钙浓度的增加,释放氢气的浓度也是增加的,300mg/ml储氢牡蛎钙水溶液释放氢气的浓度显著高于30mg/mL和100mg/mL,随着时间的延长,氢气的释放逐渐下降,30mg/mL储氢牡蛎钙水溶液在96h后氢气释放为0,100mg/mL的储氢牡蛎钙水溶液在120h后氢气释放为0,300mg/mL的储氢牡蛎钙水溶液在192h后氢气释放为0;PH检测检测结果如图1(B)所示,储氢牡蛎钙水溶液均呈现碱性(PH>8),且随着浓度的升高,储氢牡蛎钙水溶液的PH呈现显著性的升高,高剂量300mg/mL的储氢牡蛎钙水溶液PH大于13可以维持96h,然后开始降低,100mg/mL的储氢牡蛎钙水溶液PH大于12维持24h,之后开始逐渐降低,30mg/mL储氢牡蛎钙水溶液PH大于12维持8h,然后开始逐渐降低。
(二)HOP抑制非小细胞肺癌细胞A549裸鼠移植瘤增殖生长
非小细胞肺癌细胞A549移植到裸鼠一周后,开始监测肿瘤大小,肿瘤的生长情况如图2A所示,L-、M-、H-HOP组的肿瘤体积显著小于Control组。灌胃给药38天后处死小鼠(图2B),剥离下来的肿瘤如图2C所示,并且L-、M-、H-HOP组的肿瘤质量显著小于Control组(图2D)。Ki67标记的是处于生长周期中的细胞,Ki67的阳性率越高,说明处于生长期的肿瘤细胞比例越高,肿瘤生长越快。所以接下来我们对肿瘤组织进行石蜡包埋并用免疫组化的方法检测肿瘤细胞核抗原Ki-67,结果如图2E所示,L-、M-、H-HOP组中的Ki67阳性细胞显著少于Control组。综上所述,A549细胞在体实验表明,L-、M-、H-HOP组都能有效抑制肿瘤的生长,其中L-HOP的效果最显著。
(二)HOP对荷瘤裸鼠无毒副作用
接下来我们进一步观察灌胃给HOP是否有毒副作用。在给药过程中,我们除了连续监测肿瘤体积,同时也连续监测小鼠的体重、进食量和饮水量以观察HOP是否有毒副作用。结果如图3A所示,L-、M-、H-HOP组的小鼠体重略比Control组低,减少的体重大概为肿瘤所减少的重量,而且给药过程中各组小鼠的平均进食量和饮水量并无差异。进一步观察灌胃HOP是否会对代谢器官造成损伤,我们在处死小鼠后取肾脏、肝脏和小肠拍照观察和固定后做HE染色观察。图3B-D结果显示,L-、M-、H-HOP组给药均为对肾脏、肝脏和小肠造成损伤。上述结果表明,38天的连续给药后,HOP对荷瘤裸鼠并无毒副作用。
(三)HOP通过抑制MAPK/STAT3通路促进肺癌细胞凋亡
在明确HOP对A549细胞在体移植瘤的抑制作用后,我们接下来进一步探索其具体作用机制。非小细胞肺癌细胞A549属于K-Ras突变肺腺癌细胞系,RAS在许多重要细胞信号网络的轴上处于中心位置,而RAS下游一个主要的信号通路是MAPK级联磷酸化过程。MAPK是一组进化保守的丝氨酸-苏氨酸激酶,可分为4个亚族:ERK、p38、JNK和BMK1(也称:ERK5),分别代表四条经典的MAPK通路。如图4A所示,L-HOP组中JNK和P38的磷酸化也被显著抑制。表明A549细胞移植瘤中Ras通路被抑制。JNK、P38和ERK的活化可以进一步调节转录因子STAT3的磷酸化和转录活性,在细胞增殖、凋亡、迁移和周期等多种生理和病理过程中起重要作用。如图4B-C所示,STAT3的Tyr705位点磷酸化显著被抑制,同时其转录靶基因BCL2、CyclinD1和c-Myc的mRNA和蛋白水平都显著降低。综上所述,储氢牡蛎钙主要是通过RAS-MAPK-STAT3信号通路抑制K-Ras突变细胞A549移植瘤的增殖并促进其凋亡。
(四)HOP通过促进线粒体碎片化抑制线粒体能量生成功能
为了确定HOP对A549细胞线粒体形态和能量代谢的影响,我们首先评估了HOP对ATP水平的影响,结果表明L-、M-、H-HOP组给药均有效降低A549细胞中ATP水平(图5A)。作为细胞能量感受器,AMPK可对ATP低水平做出反应,在其激活后,可对补充细胞ATP供应的信号转导通路做出正向调控。接下来,我们进一步分析AMPK磷酸化水平的变化,并且结果显示,在HOP给药降低ATP水平的条件下,AMPK磷酸化水平显著升高(图5B)。线粒体形态会影响ATP的生产能力和/或效率,以应对能源需求和供应的变化。线粒体伸长是维持ATP产生和维持细胞活力所必需的,而线粒体碎片化与ATP产量下降、线粒体解偶联升高和营养物质储存增加有关。接下来我们进一步观察HOP对A549细胞线粒体形态的影响,图5C结果表明,线粒体融合蛋白MFN1、MFN2和OPA1显著抑制。上述结果表明,HOP通过抑制线粒体融合进而抑制ATP产生和损伤线粒体功能,从而抑制A549移植瘤的增殖。
对于本领域技术人员而言,显然本发明不限于上述示范性实施例的细节,而且在不背离本发明的精神或基本特征的情况下,能够以其他的具体形式实现本发明。因此,无论从哪一点来看,均应将实施例看作是示范性的,而且是非限制性的,本发明的范围由所附权利要求而不是上述说明限定,因此旨在将落在权利要求的等同要件的含义和范围内的所有变化囊括在本发明内,不应将权利要求中的任何附图标记视为限制所涉及的权利要求。
此外,应当理解,虽然本说明书按照实施方式加以描述,但并非每个实施方式仅包含一个独立的技术方案,说明书的这种叙述方式仅仅是为清楚起见,本领域技术人员应当将说明书作为一个整体,各实施例中的技术方案也可以经适当组合,形成本领域技术人员可以理解的其他实施方式。
Claims (5)
1.储氢牡蛎钙抑制非小细胞肺癌的特殊医学用途食品、保健品及药品中的应用,其特征在于,使用储氢牡蛎钙作为固态的载氢剂,能够与水反应产生氢气,可持续释放高浓度氢气。
2.根据权利要求1的应用,其特征在于,其储氢牡蛎钙制作的储氢牡蛎钙悬液浓度为100mg/k~2000mg/kg。
3.根据权利要求1的应用,其特征在于,其储氢牡蛎钙在制备抑制非小细胞肺癌细胞增殖的抑制剂中的应用。
4.根据权利要求1的应用,其特征在于,其储氢牡蛎钙在制备抑制线粒体融合进而抑制非小细胞肺癌细胞增殖的抑制剂中的应用。
5.储氢牡蛎钙在特殊医学用途食品、保健品及药品中的应用。
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