CN112972454B - 大蒜素在制备预防或治疗遗传性心肌病产品中的用途 - Google Patents
大蒜素在制备预防或治疗遗传性心肌病产品中的用途 Download PDFInfo
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Abstract
本发明涉及医药技术领域,特别是涉及大蒜素在制备预防或治疗遗传性心肌病产品中的用途,大蒜素包括大蒜素前体物质、大蒜素代谢物以及二者的衍生物,遗传性心肌病包括扩张型心肌病、肥厚型心肌病、限制型心肌病,扩张型心肌病包括杜氏肌营养不良症并发的心肌病。本发明基于DMD hiPSC‑CMs作为药物筛选平台筛选出中草药中的活性化合物,并验证出大蒜素对DMD hiPSC‑CMs的影响,为遗传性心肌病防治药物的开发提供了新的选择,开拓了大蒜素作为中草药提取物的应用范围,为临床治疗遗传性心肌病提供新的方向,也为中草药物质的临床应用带来新的生机。
Description
技术领域
本发明涉及医药技术领域,特别是涉及大蒜素在制备预防或治疗遗传性心肌病产品中的用途。
背景技术
遗传性扩张型心肌病(dilated cardiomyopathy,DCM)的特点是心室扩张、心脏收缩功能下降。其中,DCM病患随着心力衰竭而承受着生活质量下降、高额的经济负担以及心脏猝死的风险。目前我国特发性/家族性心衰患者在使用β-受体阻滞剂(β-blocker)以及血管紧张素转换酶抑制剂(Angiotensin-Converting Enzyme Inhibitors,ACEI)等药暂缓了心衰的进展,然而除了少数的心脏移植患者,大多数患者的病情仍然持续恶化。
杜氏肌营养不良症(DMD)由营养不良蛋白(Dystrophin)表达缺失引起,是一种X-连锁遗传疾病,在世界范围内有大约1:3500至1:5000的男性受到影响。Dystrophin通过与糖蛋白形成复合物(DGC)把细胞内骨架锚定到细胞外基质,在骨骼肌和心肌的机械稳定性、细胞信号传导和细胞完整性维持中起到重要的作用。DMD患者会经历进行性肌肉丧失,导致肌肉无力,到了20多岁时,伴发扩张性心肌病和呼吸衰竭的发生。呼吸机的使用在一定程度上延长了患者生存率,然而,DMD并发的心肌病作为DMD患者的主要死亡原因,迫切需要开发有效的治疗DMD并发的心肌病和预防心力衰竭的方法。
目前,DMD并发的心肌病的治疗方法主要是使用类固醇(用以减缓肌肉退化)和β受体阻滞剂(用以缓解心功能衰竭),但是慢性类固醇使用具有包括体重增加、生长阻滞和骨折风险在内的显著副作用。
发明内容
鉴于以上所述现有技术的缺点,本发明的目的在于提供大蒜素在制备预防或治疗遗传性心肌病产品中的用途,用于解决现有技术中的问题。
为实现上述目的及其他相关目的,本发明提供大蒜素或大蒜素的衍生物在制备预防或治疗遗传性心肌病产品中的用途。
本发明还提供大蒜素或大蒜素的衍生物在制备提高VCAM1蛋白表达的产品、增加DMD hiPSC-CMs细胞面积或肌小节宽度的产品中的用途。
优选地,所述大蒜素选自天然化合物或人工合成化合物。
优选地,所述大蒜素的衍生物选自以大蒜素为母核的化合物、大蒜素前体物质、以大蒜素前体物质为母核的化合物、大蒜素代谢物、以大蒜素代谢物为母核的化合物中的一种或多种。
优选地,大蒜素前体物质为蒜氨酸。
优选地,大蒜素代谢物包括二烯丙基二硫醚、二烯丙基三硫醚、烯丙基二甲基砜和烯丙基二甲基亚砜。
优选地,所述遗传性心肌病包括扩张型心肌病、肥厚型心肌病、限制型心肌病。
优选地,所述扩张型心肌病包括杜氏肌营养不良症并发的心肌病。
如上所述,本发明的大蒜素在制备防治遗传性心肌病产品中的用途,具有以下有益效果:本发明基于DMD hiPSC-CMs作为药物筛选平台来筛选出中草药中的活性化合物,并验证出化合物对DMD hiPSC-CMs的影响,为遗传性扩张型心肌病的防治药物的开发提供了新的选择,开拓大蒜素作为中草药提取物的应用范围,为临床治疗遗传性扩张型心肌病及DMD心肌病提供新的方向,也为中草药物质的临床应用带来新的生机。
附图说明
图1A显示为不同组心肌细胞VCAM1蛋白染色情况,图1B是图1A中VCAM1蛋白荧光量的数字化统计结果。
图2A显示为不同组心肌细胞肌小节宽度的检测结果,图2B为不同组心肌细胞细胞面积的检测结果。
图3显示为不同组心肌细胞使用透射电镜对超微结构的检测结果。
具体实施方式
本发明提供大蒜素或大蒜素的衍生物在制备预防或治疗遗传性心肌病产品中的用途。
所述大蒜素(Allicin)可选自天然化合物或人工合成化合物。
大蒜素(Allicin)学名为二烯丙基硫代亚磺酸酯。大蒜素是天然存在于葱科葱属植物大蒜的鳞茎、洋葱和其他葱科植物中提取的硫代烯丙醚类化合物,为淡黄色粉末或淡黄色油状液体,一般有较浓的气味。大蒜素具有除头皮屑、抗瘙痒、防止神经痛、治疗汞中毒、抗辐射、抗氧化、保护生物膜、抗衰老、防治蚊虫叮咬、抗感冒等医疗保健作用。
所述大蒜素的衍生物选自以大蒜素为母核的化合物、大蒜素前体物质、以大蒜素前体物质为母核的化合物、大蒜素代谢物、以大蒜素代谢物为母核的化合物中的一种或多种。
大蒜素前体物质为蒜氨酸。
大蒜素代谢物包括二烯丙基二硫醚(大蒜辣素,diallyl disulfide,DADS)、二烯丙基三硫醚(大蒜新素,dially trisulfied,DATS)、烯丙基二甲基砜(Allyl methylsulfone)、和烯丙基二甲基亚砜(Allyl methyl sulfoxide)等。
当本发明中的大蒜素、大蒜素的衍生物选自天然化合物时,所述天然化合物均为分离的化合物,即是从植物中单独分离出而不与植物中其他有效成分混同的化合物。
在一种实施方式中,大蒜素、大蒜素的衍生物作为预防或治疗遗传性心肌病产品的唯一有效成分。即各分离的化合物作为有效成分单独作用于遗传性心肌病的样本或患者后即能够起到预防或治疗遗传性心肌病的作用。在另一种实施方式中,大蒜素、大蒜素的衍生物也可作为预防或治疗遗传性心肌病产品的有效成分之一。此时,所述大蒜素、大蒜素的衍生物可与其他可预防或治疗遗传性心肌病的有效成分共同发挥防治遗传性心肌病的作用。
本发明中所使用的大蒜素购买自SelleckChemicals公司,大蒜素Allicin(Diallyl Thiosulfinate,二烯丙基硫代亚磺酸酯),货号S3860。
所述遗传性心肌病包括扩张型心肌病、肥厚型心肌病、限制型心肌病。遗传性心肌病的第一表现是心源性猝死。
以上种类为按病因和病理予以分类的,三种遗传性心肌病的特征如下:
(1)扩张型心肌病(DCM),以心室扩张且功能受损为特征。常发生充血性心力衰竭,所以也有称之为充血型心肌病。至少25%的扩张型心肌病是家族性的或由多样化基因突变引起。核纤层蛋白A/C突变是家族性DCM患者中最常见的基因异常情况;但目前至少有30余种基因突变与该病相关。在DCM形成过程中,心肌细胞会发生活性氧积累、电生理失常,及DNA损伤并导致张缩功能的下降。
(2)肥厚型心肌病(HCM),以心室肥厚为特征。由于不少患者有室间隔不对称肥厚而造成心室流出道梗阻,故以往称之为梗阻型心肌病,实际上还有部分患者虽有心肌肥厚但并不造成梗阻。
(3)限制型心肌病,以心内膜心肌瘢痕形成为特征,心室腔可能闭塞。过去以心肌瘢痕形成而无肥厚者为限制型心肌病;心室腔因纤维增生及附壁血栓而闭塞者为闭塞型心肌病,现在将这两种情况合并成限制型心肌病。
所述扩张型心肌病包括杜氏肌营养不良症(DMD)并发的心肌病。
DMD并发的心肌病是进行性发展的,主要的心脏表型包括:心律失常、心电图异常、舒张功能障碍、纤维化、心室逐渐扩张、收缩功能障碍和终末期心力衰竭。
本发明通过对杜氏肌营养不良症病人诱导多能干细胞来源的心肌细胞(DMDhiPSC-CMs)的结构与功能的检测,证明大蒜素靶向于VCAM1蛋白,提高VCAM1蛋白表达,增加DMD hiPSC-CMs细胞面积和肌小节宽度,进而稳定心肌细胞结构。
本发明还提供大蒜素或大蒜素的衍生物在制备提高VCAM1蛋白表达的产品、增加DMD hiPSC-CMs细胞面积或肌小节宽度产品中的用途。
所述预防或治疗遗传性心肌病产品、增加DMD hiPSC-CMs细胞面积或肌小节宽度的产品为药物、保健品或食品。
进一步的,以上产品的有效成分包括大蒜素或其衍生物。
所述药物还包括药学上可接受的药物载体或辅料。
“药学上可接受的”是指当分子本体和组合物适当地给予动物或人时,它们不会产生不利的、过敏的或其它不良反应。
更进一步的,所述药学上可接受的药物载体包含肠溶衣制剂、胶囊、微球/囊、脂质体、微乳液、复乳液、纳米颗粒、磁颗粒、明胶或凝胶中的一种或一种以上。
更进一步的,药学上可接受的辅料应当与所述有效成分相容,即能与其共混而不会在通常情况下大幅度降低药物的效果。可作为药学上可接受的载体或辅料的一些物质的具体例子是糖类,如乳糖、葡萄糖和蔗糖;淀粉,如玉米淀粉和土豆淀粉;纤维素及其衍生物,如甲基纤维素钠、乙基纤维素和甲基纤维素;西黄蓍胶粉末;麦芽;明胶;滑石;固体润滑剂,如硬脂酸和硬脂酸镁;硫酸钙;植物油,如花生油、棉籽油、芝麻油、橄榄油、玉米油和可可油;多元醇,如丙二醇、甘油、山梨糖醇、甘露糖醇和聚乙二醇;海藻酸;乳化剂,如Tween;润湿剂,如月桂基硫酸钠;着色剂;调味剂;压片剂、稳定剂;抗氧化剂;防腐剂;无热原水;等渗盐溶液;和磷酸盐缓冲液等。这些物质根据需要用于帮助配方的稳定性或有助于提高活性或它的生物有效性或在口服的情况下产生可接受的口感或气味。
以下通过特定的具体实例说明本发明的实施方式,本领域技术人员可由本说明书所揭露的内容轻易地了解本发明的其他优点与功效。本发明还可以通过另外不同的具体实施方式加以实施或应用,本说明书中的各项细节也可以基于不同观点与应用,在没有背离本发明的精神下进行各种修饰或改变。
在进一步描述本发明具体实施方式之前,应理解,本发明的保护范围不局限于下述特定的具体实施方案;还应当理解,本发明实施例中使用的术语是为了描述特定的具体实施方案,而不是为了限制本发明的保护范围;在本发明说明书和权利要求书中,除非文中另外明确指出,单数形式“一个”、“一”和“这个”包括复数形式。
当实施例给出数值范围时,应理解,除非本发明另有说明,每个数值范围的两个端点以及两个端点之间任何一个数值均可选用。除非另外定义,本发明中使用的所有技术和科学术语与本技术领域技术人员通常理解的意义相同。除实施例中使用的具体方法、设备、材料外,根据本技术领域的技术人员对现有技术的掌握及本发明的记载,还可以使用与本发明实施例中所述的方法、设备、材料相似或等同的现有技术的任何方法、设备和材料来实现本发明。
以下实施例利用DMD患者来源的人类诱导多能干细胞(hiPSC)来源的心肌细胞(DMD hiPSC-CMs)进行了单方有效成分对DMD心肌功能的药效评估。在DCM形成过程中,心肌细胞会发生结构紊乱并导致张缩功能的下降。通过细胞实验证明大蒜素对遗传性扩张型心肌病及DMD心肌病具有明显的作用效果。
实施例1IPS细胞(iPSC)的培养及心肌细胞分化
1.将健康人的诱导多能干细胞(hiPSC)、杜氏肌营养不良症患者的诱导多能干细胞(DMD hiPSC)分别在包被了Matrigel(购自Corning公司)的培养板中使用NutristemhPSC XF培养基(购自Biological Industries公司)培养,生长至70-90%的密度时进行心肌方向分化。
2.提前配好培养基:RPMI1640培养基+B27 minus insulin(按照10ml B27+500mlRPMI1640的比例配制)。取部分RPMI1640培养基+B27minus insulin加入CHIR(购自SelleckChemicals公司)至于终浓度6μM。
3.弃掉IPS细胞培养皿内培养基,加入提前配制好的含有CHIR的RPMI1640+B27minus insulin培养基,连续培养48小时。
4.之后更换为RPMI1640+B27 minus insulin培养基并加入IWR-1(购自sigma公司)至终浓度5μM,继续分化48小时。
5.更换为基础RPMI1640+B27 minus insulin培养基培养两天后换RPMI1640+B27with insulin培养基培养4天。
6.使用无葡萄糖RPMI1640+B27with insulin培养基和4mM d-乳酸钠(购自sigma公司)培养4天。培养基每2天更换一次,以维持健康人的心肌细胞和DMD心肌细胞(DMDhiPSC-CMs)心肌细胞正常生长。
7.进行以下实施例中的各项检测前将两种心肌细胞按照以下设置分成两组:对照组(Vehicle)、大蒜素组。对照组使用0.01%的DMSO处理DMD心肌细胞,大蒜素组使用溶解于DMSO的10μM的大蒜素处理DMD心肌细胞5天。
实施例2心肌细胞VCAM1蛋白定量
1.两种心肌细胞分别在室温下用含4%的甲醛PBS固定10分钟,PBS洗涤3次后,用染色液(含0.1%Triton X-100)和含20%胎牛血清的PBS在室温下渗透并封闭细胞1小时。
2.用染色液1:200稀释兔多克隆抗体anti-VCAM1(购自Proteintech公司),4℃孵育过夜。
3.除去抗体,孵育后的细胞用染色液洗涤3次,每次10分钟。
4.用1:1000稀释的二抗(购自Invitrogen公司)室温孵育1-2小时。
5.除去二抗,用染色液洗涤样品3次,然后用含有DAPI的PBS孵育10分钟。
6.VECTASHIELD(购自Vector公司)封片,使用蔡司LSM880显微镜进行图像采集。
7.使用ZEN软件进行图像分析。
结果如图1所示,大蒜素可以作用于VCAM1并显著增加VCAM1蛋白。
实施例3
1.将两种心肌细胞在通风柜内室温下用2.5%戊二醛溶液固定2小时。
2.PBS洗涤三次后,用1%四氧化锇在4℃下固定1h。PBS洗涤3次,依次用25%、50%、75%、95%的乙醇在蒸馏水中脱水10分钟。
3.在纯乙醇中脱水2次(每次30分钟),然后用环氧812(2:1,1:1,1:2,每次30分钟)渗透乙醇。
4.用纯环氧812浸渍过夜然后将样品埋入环氧812中。
5.树脂块在65℃下聚合48h后,用金刚石刀进行超微切片,切成70nm厚的薄片。薄片安装在formva涂层的铜栅格上,用3%醋酸铀在70%甲醇和30%水中计数7分钟,然后用柠檬酸铅计数3分钟。
6.在120千伏的FEI(Tecnai G2 Spirit 120kV)电子显微镜下观察。
结果如附图2和3所示,大蒜素处理能增加DMD hiPSC-CMs细胞面积和肌小节宽度,稳定细胞结构。
因此,本发明首次描述和证实大蒜素对遗传性扩张型心肌病中的DMD并发心肌病具有令人满意的疗效,提示从中草药中提取的天然化合物大蒜素在遗传性扩张型心肌病预防和治疗中具有良好的应用前景,为其治疗提供新的选择和药物研发思路。
以上的实施例是为了说明本发明公开的实施方案,并不能理解为对本发明的限制。此外,本文所列出的各种修改以及发明中方法的变化,在不脱离本发明的范围和精神的前提下对本领域内的技术人员来说是显而易见的。虽然已结合本发明的多种具体优选实施例对本发明进行了具体的描述,但应当理解,本发明不应仅限于这些具体实施例。事实上,各种如上所述的对本领域内的技术人员来说显而易见的修改来获取发明都应包括在本发明的范围内。
Claims (5)
1.大蒜素在制备治疗杜氏肌营养不良症并发的心肌病产品中的用途。
2.根据权利要求1所述的用途,其特征在于,大蒜素通过提高VCAM1蛋白表达、增加DMDhiPSC-CMs细胞面积或肌小节宽度治疗杜氏肌营养不良症并发的心肌病。
3.根据权利要求1所述的用途,其特征在于,所述大蒜素选自天然化合物或人工合成化合物。
4.根据权利要求1所述的用途,其特征在于,所述治疗杜氏肌营养不良症并发的心肌病产品为药物。
5.根据权利要求4所述的用途,其特征在于,所述治疗杜氏肌营养不良症并发的心肌病产品的有效成分包括大蒜素。
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