CN110022880B - 包含胆汁酸的用于预防或治疗缺血性再灌注损伤的药学组合物 - Google Patents
包含胆汁酸的用于预防或治疗缺血性再灌注损伤的药学组合物 Download PDFInfo
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Abstract
本发明涉及包含胆汁酸的用于预防、治疗或改善缺血性再灌注损伤的组合物。根据本发明,胆汁酸具有提高β‑连环蛋白在细胞核中的水平,阻碍线粒体通透性转换孔(mitochondria permeable transition pore)的开放,在缺血性再灌注损伤动物模型中改善组织的损伤,并减小梗塞大小的优异效果,因而可有效适用于缺血性再灌注损伤的预防、治疗或改善。
Description
技术领域
本发明涉及包含胆汁酸或其药学上可接受的盐的用于预防、治疗或改善缺血性再灌注损伤的组合物。
背景技术
血液起到将氧或营养成分输送到身体的各个组织或细胞的作用,由于向身体器官、组织或部位供血的血管狭窄、收缩或者未充分生成正常的血管造成血液供应不足而引起缺氧的状态称之为缺血(ischemia)。缺血不可逆地损伤细胞并导致组织的坏死(necrosis)。尤其,大脑或心脏是对于血流供应不足最为敏感的身体器官,例如,若因脑卒中或头部损伤等而在组织中发生缺血、则会触发称之为缺血级联反应(ischemic cascade)的一系列过程,从而导致组织永久受损。为了防止这种组织损伤而在发生缺血后再次血流称之为再灌注(reperfusion)。
对于缺血及由此引起的缺氧症的常规疗法是通过增加全身供氧或消除血管闭塞的原因来使血流及氧传递恢复正常水平。但是,随着血流及氧传递的恢复,与因缺血或缺氧症而引起的损伤无关地,导致额外的细胞死亡或功能丧失。随着血流及氧传递恢复而引起的额外损伤被公知为再灌注损伤。由再灌注损伤引起的组织损伤类似于由炎性细胞附着于再灌注的组织、这些炎性细胞的活化以及后续的自由基的形成引起的急性炎症状态。在再灌注的组织中生成的自由基及其他细胞毒性生物分子可能导致坏死或由激活凋亡途径而引起的细胞死亡。
另一方面,线粒体通透性转换孔(mPTP,mitochondrial permeabilitytransition pore)形成于线粒体内膜,当线粒体通透性转换孔开放时,可使1500Da以下的分子进入线粒体膜内。线粒体通透性转换孔开放的结果,与氧化磷酸化的解偶联、被储存的钙及前凋亡因子的后续释放一同导致线粒体外膜的肿胀以及最终破裂。被储存的钙的释放可能导致钙过载、活性氧类(ROS)的生成以及在通过细胞引起链式反应的附近的线粒体中的线粒体通透性转换(MPT,mitochondrial permeability transition)。接着,根据细胞的能量状态,发生诱导不可逆的组织及器官损伤的凋亡或坏死。
线粒体介导的凋亡及坏死的作用在多数疾病的病历中已经确立无误,在急性心肌梗塞、脑卒中及神经疾病、肝炎等几种疾病的病历及进展中已知导致这些发病的原因为线粒体通透性转换孔。
尤其,在心肌梗塞的情况下,在缺血性心脏疾病中,通过坏死和/或凋亡引起心肌细胞死亡而发生顺序性缺血再灌注。认为致死性再灌注损伤(作为组织再灌注的直接结果的心肌细胞死亡)占比高达最终心肌梗塞大小的50%,并且已知依赖于再灌注损伤补救激酶(RISK,Reperfusion Injury Salvage Kinase)途径及线粒体通透性转换孔开放。
到目前为止,还没有有关起到这种功能的线粒体通透性转换孔与胆汁酸之间的关联性的报道。如上所述,实际情况为缺乏有效治疗作为发病率高的重要疾病的缺血性再灌注损伤的方法,因此若出现利用胆汁酸来有效预防和治疗缺血性再灌注损伤的治疗方法,则其波及效果将会非常大。
发明内容
发明问题
据此,本发明人在研究线粒体通透性转换孔与胆汁酸之间的关联性的过程中,确认到可通过胆汁酸中的脱氧胆酸、胆酸及石胆酸来抑制缺血性再灌注损伤,从而完成了本发明。
因此,本发明的目的在于,提供包含胆汁酸(bile acid)或其药学上可接受的盐的用于预防或治疗缺血性再灌注损伤的药学组合物及用于预防或改善缺血性再灌注损伤的食品组合物。
解决问题的方案
为了实现上述目的,本发明提供包含胆汁酸(bile acid)或其药学上可接受的盐的用于预防或治疗缺血性再灌注损伤的药学组合物。
并且,本发明提供包含胆汁酸或其药学上可接受的盐的用于预防或改善缺血性再灌注损伤的食品组合物。
发明效果
根据本发明,胆汁酸具有提高β-连环蛋白在细胞核中的水平,阻碍线粒体通透性转换孔(mitochondria permeable transition pore)的开放,在缺血性再灌注损伤动物模型中改善组织的损伤,并减小梗塞大小的优异效果,因而可有效适用于缺血性再灌注损伤的预防、治疗或改善。
附图说明
图1为示出通过细胞核的β-连环蛋白荧光素酶试验(nuclear beta-cateninLuciferase assay)确认胆酸、石胆酸、脱氧胆酸是否提高细胞核中的β-连环蛋白水平的结果的图。
图2为示出在使用脱氧胆酸(DCA)进行处理后通过蛋白质印迹法(western blot)按照不同时间确认β-连环蛋白在细胞核中的迁移的结果的图。
图3为示出通过四甲基罗丹明甲酯高氯酸盐(TMRM,Tetramethylrhodamine,Methyl Ester,Perchlorate)染色法确认胆酸、石胆酸、脱氧胆酸是否具有保护线粒体的效果的结果的图。
图4为示出在使用胆汁酸中的牛磺胆酸、胆酸及石胆酸进行处理后在人脐静脉内皮细胞(human umbrical vein endothelial cell)中通过细胞计数(counting)方法(图4A)以及利用细胞计数试剂盒(CCK-8)(图4B)的染色法确认细胞增殖效果的结果的图。
图5为在使用胆汁酸中的牛磺胆酸(TauroCA)、胆酸及石胆酸进行处理后在人脐静脉内皮细胞(HUVEC,human umbrical vein endothelial cell)中通过染色法确认细胞迁移效果的结果的图(图5A)以及示出利用博伊登室(Boyden chamber)对经过膜的细胞数量进行计数的结果的图(图5B)。
图6为示出确认胆汁酸的小鼠再灌注损伤抑制效果的小鼠模型的组织照片的图(图6A)以及示出在上述组织照片中相对于总面积,以百分比对梗塞组织的面积进行定量的结果的图(图6B)。
图7为示出为了确认胆汁酸中的脱氧胆酸对因再灌注损伤而引起的心肌坏死的抑制效果而利用Annexin-Vivo750荧光染料染色的结果的图(图7A)以及示出不同浓度的脱氧胆酸的心肌死亡减少效果的结果的图(图7B)。
具体实施方式
以下,详细说明本发明。
本发明提供包含胆汁酸或其药学上可接受的盐的用于预防或治疗缺血性再灌注损伤的药学组合物。
在本发明中,胆汁酸具有提高β-连环蛋白在细胞核中的水平,阻碍线粒体通透性转换孔的开放,在缺血性再灌注损伤动物模型中改善组织的损伤,并减小梗塞大小的优异效果,因而可有效适用于缺血性再灌注损伤的预防、治疗或改善。
在本发明中,胆汁酸可以为选自由熊去氧胆酸(ursodeoxycholic acid)、甘氨鹅脱氧胆酸(GlycochenDCA,glycochenodeoxycholic acid)、牛磺脱氧胆酸(TauroDCA,Taurodeoxycholic acid)、甘氨胆酸(Glycocholic acid)、牛磺胆酸(Taurocholic acid)、鹅去氧胆酸(ChenoDCA,Chenodeoxycholic acid)、胆酸(Cholic acid)、脱氢胆酸(Dehydrocholic acid)、石胆酸(Lithocholic acid)及脱氧胆酸(Deoxycholic acid,DCA)组成的组中的一种以上,优选为胆酸、石胆酸或脱氧胆酸,但不限于此。
本发明的胆酸、石胆酸及脱氧胆酸即使在低浓度下也可有效预防及治疗缺血性再灌注损伤。
除非另有说明,胆汁酸的药学上可接受的盐包括可存在于胆汁酸的酸性或碱性基团的盐。例如,药学上可接受的盐包括羟基的钠盐、钙盐及钾盐,氨基的其他药学上可接受的盐包括氢溴酸盐、硫酸盐、硫酸氢盐、磷酸盐、磷酸氢盐、磷酸二氢盐、乙酸盐、琥珀酸盐、柠檬酸盐、酒石酸盐、乳酸盐、扁桃酸盐、甲磺酸盐及p-甲苯磺酸盐,可通过本技术领域中所公知的盐的制备方法或制备过程来制备。优选为葡萄糖酸钠盐、牛磺酸钠盐,但不限于此。
在本发明中,“缺血性损伤”是指在心脏、脑、肾等需要血流供应的器官中因血液循环被阻塞引起氧传递减少而发生的损伤,包括可能导致组织的功能损伤及细胞死亡的致死性损伤。可能引起缺血性损伤的原因包括血管疾病、冠状动脉血栓形成、脑血管血栓形成、动脉瘤破裂、全身出血、挤压伤、败血症、严重皮肤烧伤、血管闭塞性手术方法(例,胸腹动脉瘤手术过程中的脊髓缺血)、心肺分流方法、器官移植、心肺衰竭(急性心原性猝死)及窒息等,但不限于此。
并且,在本发明中,“缺血性损伤”除了通常可能发生的缺血性损伤之外,还包括因器官移植等而可能发生的缺血再灌注损伤。
在本发明中,“缺血性再灌注损伤”可能由选自由心肌缺血、脑血管缺血、肾缺血、肝缺血、缺血再灌注心肌病,皮肤缺血、肠道缺血、肠缺血、胃缺血、肺缺血、胰腺缺血、骨骼肌缺血、腹肌缺血、四肢缺血、缺血再灌注结肠炎,肠系膜缺血及无症状性缺血组成的组中的一种以上的缺血引起,但不限于此。
上述缺血性再灌注损伤由外伤引起,例如,可能由在急性心肌梗塞后经历过血流的恢复等自然事件或血液供应减少的组织或器官中的血流的恢复或再灌注手术,例如,经历过血液供应减少的组织或器官中用于恢复血流的一种以上的外科手术,其他治疗干预(therapeutic intervention)或器官移植手术过程引起。上述外科手术包括诸如冠状动脉旁路移植术、冠状动脉形成术、器官移植手术等。
例如,急性心肌梗塞是指随着心脏的一个血管闭合而未能形成氧及营养的供应,从而导致心肌死亡、坏死的现象,在此情况下,通常,若访问医院并在1小时之内再灌注血管,则可将死亡率降低10%之内。但是,在大约10%的患者中,随着被阻塞的血管再灌注,因快速供氧而导致心肌细胞受损,这称为再灌注损伤。由于再灌注损伤,导致大约10%的患者在手术后30天内死亡,而存活的患者中30%左右会得心力衰竭等症状。
在本发明中,术语“再灌注手术”是指用于切除血管内生成的血栓并使血流重新流动的手术或治疗,包括外科血栓切除术以及通过使用支架(stent)等来进行的再灌注操作诱导法等,但不限于此。再灌注手术可用于弥补再灌注治疗剂(例:组织型纤溶酶原激活剂(tPA)等纤溶酶原激活剂)的缺点。
再灌注手术包括通过施加负压来吸入血栓的方法(近端血栓切除术:proximalthrombectomy)、钩上线圈来取出血栓的方法(远端血栓切除术:distal thrombectomy)、以及插入支架来扩张变窄的血管并移除支架的同时一同切除血栓的方法(支架回收器:Stentretriever)等。近端血栓切除术作为通过接近血栓的近端来施加负压并切除血栓的方法,主要利用吸入装置,例如半暗带系统(Penumbra system)。远端血栓切除术作为经过血栓并从远端钩上线来去除血栓的方法,主要利用线圈装置,例如取栓器(Merci system)。利用支架回收器的方法为与冠状动脉一样通过放入支架来诱导血管的再灌注的方法。本发明的组合物除了上述所提及的手术之外,还可适用于以再灌注为目的的多种再灌注手术。
在本发明中,再灌注手术是指为了治疗脑血管疾病、动脉硬化症、心血管疾病等而实施的手术或治疗,但不限于此。
上述脑血管疾病包括脑卒中、脑梗塞、脑血栓、脑栓塞等,但不限于此。上述心血管疾病包括心肌梗塞、心绞痛等,但不限于此。
本发明的药学组合物可以在缺血性再灌注损伤发生之前、发生的同时或发生后给药,例如,可以是再灌注手术预处理用。本发明的药学组合物在血管再灌注手术之前给药患者的血管内,从而更加有利于预防、治疗或改善再灌注之后引起的组织,例如心肌的损伤。
并且,如本发明中所记载,由缺血引起的病情以及缺血或由缺血再灌注引起的损伤可在患病的细胞、组织或器官中诱导细胞死亡,这导致损伤及功能障碍。本发明提供缺血性再灌注损伤的预防或治疗方法,上述缺血性再灌注损伤的预防或治疗方法包括使胆汁酸或其药学上可接受的盐与所需的细胞、组织、器官相接触或者给药所需的个体的步骤。为了缺血性损伤或缺血性再灌注损伤的预防或治疗,例如,可将本发明的胆汁酸或其药学上可接受的盐给药所要接受再灌注手术的个体,例如,可在再灌注手术的约5分钟之前、约10分钟之前、约15分钟之前、约20分钟之前、约30分钟之前、约45分钟之前、约1小时之前、约2小时之前、约3小时之前、约4小时之前、约5小时之前、约12小时之前、约24小时之前或约48小时之前给药,优选地,可在约2小时之前给药。
代替或额外地,本发明的胆汁酸或其药学上可接受的盐可在再灌注手术之后或再灌注手术期间给药个体。例如,胆汁酸或其药学上可接受的盐可在再灌注手术期间按规定的间隔投一次以上。代替性地,胆汁酸可在再灌注手术的持续时间内连续给药。并且,例如,本发明的胆汁酸可在再灌注手术之后向接受再灌注手术的个体进行给药。本发明的胆汁酸可在例如,再灌注手术的约5分钟之后、约10分钟之后、约15分钟之后、约20分钟之后、约30分钟之后、约45分钟之后、约1小时之后、约2小时之后、约3小时之后、约4小时之后、约5小时之后、约12小时之后、约24小时之后或约48小时之后向接受再灌注手术的个体进行给药。本发明的胆汁酸或其可接受的盐还可在再灌注手术之前用于抑制离体细胞、组织或器官(例如,移植手术中所使用的组织、器官移植术中所使用的器官)的缺血或缺血性再灌注损伤。例如,在将器官移植到宿主个体之前(例如,无菌环境内器官的储存或运输期间),可通过使器官与胆汁酸相接触(例如,浸泡在本发明的包含胆汁酸的组合物中)来抑制缺血或缺血性再灌注损伤,优选地,在具有急性心肌梗塞的个体的再灌注手术之前,可通过实施一次静脉注射来抑制因再灌注手术而引起的心脏损伤。
并且,本发明的药学组合物还可包含再灌注治疗剂(therapeutic agent forrecanalization)。并且,本发明的药学组合物可与再灌注治疗剂同时使用。
本发明的胆汁酸或其药学上可接受的盐为线粒体通透性转换孔的开放抑制剂。
本发明的胆汁酸或其药学上可接受的盐为β-连环蛋白(β-catenin)的激动剂(agonist)。
本发明的胆汁酸或其药学上可接受的盐用于保护线粒体。
本发明的胆汁酸或其药学上可接受的盐抑制组织的梗塞。
本发明的胆汁酸或其药学上可接受的盐作为β-连环蛋白的激动剂,显著减少随着被堵塞的血管再灌注而发生氧的快速流入,因而使线粒体通透性转换孔开放,从而引起心肌死亡或坏死的现象。由此,在再灌注手术之后30天内减少高达10%的死亡率,并可减少手术后30%左右的患者所经受的心力衰竭症状。线粒体通透性转换孔形成于线粒体内膜,当线粒体通透性转换孔开放时,会诱导线粒体去极化,从而引起线粒体的功能不全。胆汁酸起到β-连环蛋白的激动剂的作用,从而通过阻碍线粒体通透性转换孔的开放来抑制线粒体的去极化,进而保护线粒体并防止线粒体的氧化损伤来抑制组织的梗塞。由此呈现出预防、治疗或改善缺血性再灌注损伤的效果。
本发明的包含胆汁酸或其药学上可接受的盐的药学组合物能够以注射用制剂或口服用制剂的形式进行剂型化。并且,包含本发明的药学组合物的注射用制剂可通过包括口服、经皮、皮下、静脉或肌肉在内的多种途径给药,优选地,可通过静脉给药。可使用本技术领域中所公知的方法来对包含本发明的药学组合物的注射用制剂进行剂型化,以便可在给药个体后快速、持续或延迟释放活性成分。优选地,上述注射用制剂向皮下、肌肉或静脉内给药,最为优选地,可向静脉内给药。在向静脉内给药的情况下,可在再灌注手术之前通过一次静脉注射给药,仅通过一次静脉注射,也可有效改善因再灌注手术而引起的心脏等器官的损伤。并且,上述口服用制剂可选自由片剂、丸剂、粉剂、颗粒剂、胶囊剂、混悬剂、溶液剂、油剂、糖浆剂及冻干剂组成的组中,但不限于此。
本发明的胆汁酸或其药学上可接受的盐可通过腹腔内给药、鼻腔内给药、静脉注射、皮下注射、脑脊髓腔内注射、吸入给药、或口服给药来向个体给药。并且,本发明的药学组合物的有效成分可根据所要给药的个体的年龄、性别、体重、病理状态及其严重程度、投药途径或处方者的判断而变化。基于这种因素确定适当剂量,这在本技术领域的普通技术人员的水平之内,但能够以与美国食品药品监督管理局(FDA)批准的浓度类似的浓度或比美国食品药品监督管理局批准的浓度低的浓度使用。更加具体地,其日剂量可以为例如0.1mg/kg/日至10mg/kg/日,具体地,可以为0.5mg/kg/日至5mg/kg/日,更加具体地,可以为0.8mg/kg/日至3mg/kg/日,进一步具体地,可以为1mg/kg/日至2mg/kg/日,但不限于此。本发明的药学组合物可以每日给药1次至3次,但不限于此。
用于非口服投药的本发明的药学组合物的剂型可以为注射剂、注射滴剂、乳剂、软膏剂、凝胶剂、乳青剂、混悬剂、油剂、栓剂、贴剂或喷雾剂,但不限于此。并且,根据需要,本发明的药学组合物可包含稀释剂、赋形剂、润滑剂、结合剂、崩解剂、缓冲剂、分散剂、表面活性剂、着色剂、香料或甜味剂等添加剂。本发明的药学组合物可通过本技术领域的常规方法来制备。
本发明的药学组合物可单独或与一种以上的其他治疗剂一同给药,可在其他治疗剂之前、之后或与其同时给药。本发明的胆汁酸及上述其他治疗剂作为分离的剂型或共同剂型,可同时(例如,一同)共同给药。代替性地,作用剂可在由熟练的临床医生确定的合理的时间范围内(例如,足以允许疗法的药物效果的重叠)作为分离的组合物依次给药。本发明的胆汁酸及一种以上的其他治疗剂可按适合于达到所需治疗效果(例如,减少和/或抑制缺血、减少和/或抑制缺血性损伤;减少和/或抑制缺血性再灌注损伤)的顺序以及时间安排以单剂量或多剂量给药。合适的剂量及给药疗法可由临床医生确定,并依赖于所选的(多个)作用剂、药学剂型及给药途径、多种患者因素以及除此之外的考虑因素。
可与本发明的药学组合物一同给药的合适的其他治疗剂包括钙通道阻滞剂、β受体阻滞剂、硝酸甘油、阿司匹林、抗炎剂、钠利尿因子、血管扩张剂、血栓溶解剂及抗血栓剂(antithrombolic agent),但不限于此。
并且,本发明提供包含胆汁酸或其药学上可接受的盐的用于预防或改善缺血性再灌注损伤的食品组合物。
上述食品组合物可用于保健食品,在本发明中,保健食品可按原样添加胆汁酸或与其他食品或食品成分一同使用,可通过常规方法合理地使用。
上述食品的种类不受特殊限制。作为上述食品的例子,包括饮剂、肉类、香肠、面包、小饼干、年糕、巧克力、糖类、零食类、饼干类、比萨、拉面、其他面类、口香糖类、包括冰淇淋类的乳制品、各种汤、饮料、酒精饮料及维生素复合剂等,将传统意义上的保健食品均包括在内。
本发明的胆汁酸或其药学上可接受的盐可按原样添加于食品中或与其他食品或食品成分一同使用,可根据常规方法合理地使用。有效成分的混合量可根据其使用目的(预防或改善用)适当地确定。一般情况下,保健食品中的胆汁酸能够以食品总重量的0.01至15重量百分比添加,保健饮料组合物能够以100ml为基准施加0.02至5g,优选地,能够以0.3至1g的比率添加。但是,在以健康及卫生为目的或以调节健康为目的的长期摄入的情况下,上述量可以为上述范围以下。由于在安全性方面无任何问题,因而还能过以上述范围以上的量使用有效成分。
本发明的健康功能性饮料组合物除了按指示的比率作为必要成分含有胆汁酸之外,其他成分不受特殊限制,可像普通饮料那样含有多种香味剂或天然碳水化合物等作为追加成分。上述天然碳水化合物的例子包括:单糖,例如葡萄糖、果糖等;二糖,例如麦芽糖、蔗糖等;多糖,例如糊精、环糊精等常规糖;以及糖醇,例如木糖醇、山梨糖醇、赤藓糖醇等。作为除上述之外的香味剂,可有效使用天然香味剂(奇异果甜蛋白、甜叶菊提取物(例如,莱鲍迪甙A、甘草甜素等)及合成香味剂(糖精、阿斯巴甜等)。
除上述之外,本发明的食品组合物可含有多种营养剂、维生素、矿物质(电解质)、合成风味剂及天然风味剂等风味剂、着色剂及重剂(奶酪、巧克力等)、果胶酸及其盐、海藻酸及其盐、有机酸、保护胶体增稠剂、pH调节剂、稳定剂、防腐剂、甘油、醇、用于碳酸饮料的碳酸化剂等。
本说明书中未另外定义的术语具有本发明所属技术领域中通常所使用的含义。
以下,通过实施例详细说明本发明。但是,下述实施例仅用于例示本发明,本发明的内容并不局限于下述实施例。
实施例1.针对胆汁酸对细胞核中的β-连环蛋白水平产生的影响的试验
1.1用于挖掘β-连环蛋白(β-catenin)亢进药物的筛选
进行了用于通过分析多种胆汁酸对细胞核中的β-连环蛋白水平产生的影响来挖掘具有β-连环蛋白亢进效果的药物的试验。通过细胞核的β-连环蛋白荧光素酶试验对使用熊去氧胆酸、甘氨鹅脱氧胆酸、牛磺脱氧胆酸、甘氨胆酸、牛磺胆酸、鹅去氧胆酸、胆酸、脱氢胆酸、石胆酸及脱氧胆酸进行的处理对细胞核中β-连环蛋白的水平变化产生的影响进行了观察。
具体地,利用了T细胞因子/淋巴增强因子报告基因(TCF/LEF reporter)_HEK293细胞株(BPS bioscience)。T细胞因子/淋巴增强因子报告基因_HEK293细胞株作为在细胞核内T细胞因子/淋巴增强因子启动子(β-连环蛋白结合启动子)中克隆有荧光素酶的稳定的细胞株,若经过药物处理后测量荧光素酶的水平,则可观察细胞核中的β-连环蛋白水平。将T细胞因子/淋巴增强因子报告基因_HEK293细胞株(BPS Bioscience)分株于24个孔(well)(2×105个)或96个孔(2×104个)中并培养至细胞粘附于板底部。为了形成休止期状态的细胞,以1%的胎牛血清培养基(FBS)替换10%的胎牛血清的达尔伯克改良伊格尔培养基培养基(FBS DMEM)并培养一天。在以1μm或10μm的上述等胆汁酸处理细胞并培养24小时之后,利用光度计(luminometer)测出荧光素酶的活性度。将测量结果示出于图1中。
如图1所示,确认到在10种胆汁酸中,牛磺胆酸、胆酸、石胆酸、脱氧胆酸显著提高细胞核中的β-连环蛋白水平。
1.2确认脱氧胆酸增加β-连环蛋白在细胞核中的迁移
为了观察与β-连环蛋白通过在上述实施例1.1中所确认的脱氧胆酸在细胞核中迁移有关的印迹,进行了蛋白质印迹法(western blot)。在例用1μm的脱氧胆酸(DCA)处理细胞后针对30分钟、1小时、2小时、4小时、8小时之后的细胞进行了蛋白质印迹法,并将其结果示出于图2中。
如图2中所确认,在处理脱氧蛋白之后,从30分钟后开始在细胞核中观察到β-连环蛋白的增加,在经过2小时之后,确认到细胞核中β-连环蛋白的量形成最大峰值(peak)的结果。
因此,确认到牛磺胆酸、胆酸、石胆酸、脱氧胆酸提高阻碍线粒体通透性转换孔(mitochondrial permeability trasition pore)开放的β-连环蛋白的水平,并由此呈现出抑制再灌注损伤的效果,从而具有作为具有β-连环蛋白亢进效果的药物候选者的可能性。
实施例2.确认胆汁酸对线粒体的保护效果-抑制线粒体通透性转换孔的开放
为了对在上述实施例1中确认到具有提高β-连环蛋白水平的效果的胆酸、石胆酸、脱氧胆酸是否具有保护线粒体的效果进行确认,执行了四甲基罗丹明甲酯高氯酸盐染色法。四甲基罗丹明甲酯高氯酸盐为可对正常线粒体染色的荧光标记物。
具体地,用1μm及10μm的胆酸、石胆酸、脱氧胆酸处理293T细胞,并经过1小时之后,对线粒体诱导与再灌注类似的刺激来开放线粒体通透性转换孔,并使用作为诱导极化的物质的羰基氰化物间氯苯腙(CCCP,chlorophenylhydrazone,50μm)进行处理来诱导出线粒体通透性转换孔的开放以及线粒体的去极化。在45分钟之后,使用磷酸盐缓冲液(PBS)进行清洗并使用四甲基罗丹明甲酯高氯酸盐进行了染色,之后利用荧光度数器测出数值。将测量结果示出于图3中。作为阳性对照组,使用了环孢菌素A(Cyp,cyclosporine A),其为抑制线粒体通透性转换孔开放的代表性物质。
如图3所示,在使用作为阳性对照组的环孢菌素来经过处理的组中,环孢菌素抑制线粒体损伤约50%左右,石胆酸也以与阳性对照组类似的水平抑制了线粒体的损伤。尤其,在胆酸及脱氧胆酸的情况下,确认到具有可抑制线粒体损伤约90%的效果。
因此,确认到通过抑制使用胆酸、脱氧胆酸、石胆酸进行处理并抑制被诱导的线粒体通透性转换孔的开放来抑制线粒体的去极化,从而具有保护线粒体的优异效果。因此,确认到胆酸、脱氧胆酸及石胆酸可通过抑制由再灌注引起的线粒体的损伤来抑制诱导不可逆组织及器官损伤的凋亡或坏死。
实施例3.确认胆汁酸的体外(in vitro)细胞增殖效果及细胞迁移效果
3.1确认胆汁酸的体外细胞增殖效果
使用胆汁酸中的牛磺胆酸、胆酸及石胆酸1μm进行处理后进行了用于确认在人脐静脉内皮细胞(human umbrical vein endothelial cell)中是否呈现出细胞增殖效果的试验。在利用细胞计数方法及细胞计数试剂盒的染色法处理牛磺胆酸、胆酸及石胆酸之后,确认了24小时之后的细胞增殖效果。上述试验结果示出于图4A及4B中。
如图4A所示,通过细胞增殖试验(Proliferation assay)确认到胆酸及石胆酸具有比对照组更显著的细胞增殖效果。如图4B所示,通过细胞计数试剂盒试验确认到胆酸的显著的细胞增殖效果。因此,确认到胆酸及石胆酸使细胞增殖并由此呈现出缺血性再灌注损伤的抑制效果。
3.2确认胆汁酸的体外细胞迁移效果
为了在使用胆汁酸中的牛磺胆酸、胆酸及石胆酸1μm进行处理后确认是否在人脐静脉内皮细胞(human umbrical vein endothelial cell)中呈现出细胞迁移效果,利用博伊登室确认了细胞数量。在处理牛磺胆酸、胆酸及石胆酸之后确认到细胞的迁移效果,将上述试验结果示出于图5A及5B中。
如图5A所示,确认到若使用胆酸、牛磺胆酸及石胆酸进行处理,则细胞的迁移比对照组更为明显。并且,如图5B所示,通过迁移试验(migration assay)确认到在使用胆酸及石胆酸处理的情况下,相对于对照组,具有细胞的迁移以显著的水平增加的效果。尤其,确认到胆酸具有对照组的约2倍左右的细胞迁移效果,因而具有最为优异的迁移效果。
因此,确认到胆酸及石胆酸使细胞迁移,由此呈现出缺血性再灌注损伤的抑制效果。
实施例4.制造再灌注损伤小鼠模型以及确认胆汁酸对小鼠再灌注损伤的抑制效果
为了制造再灌注损伤小鼠模型,利用氯胺酮对Balb/C小鼠(8周龄)进行了麻醉。将管插入气道内并与呼吸器相连接之后,将小鼠矫正至其左侧边朝上并切开了皮肤。张开第3肋骨与第4肋骨之间来以露出心脏的方式进行固定,并通过血管注射方式按浓度(2mg/kg、10mg/kg、50mg/kg)向左心室注射脱氧胆酸或在筛选及体外试验中呈现出最优异效果的胆酸,之后结扎左冠状动脉,在40分钟之后松开并进行了缝合。在经过24小时之后摘取心脏并在-20℃的温度下冷冻4小时,之后以2mm的厚度将心脏分成4块并将各个组织放入2%的四唑红(TTC)(磷酸盐缓冲液中)溶液中,之后培养40分钟后进行了染色。然后转移到10%的福尔马林溶液中并保管一天后拍下照片,将其结果示出于图6A中。并且,图6B示出了在组织照片中相对于总面积,以百分比对梗塞组织的面积进行定量的结果。作为阳性对照组,使用了环孢菌素,其为抑制线粒体通透性转换孔开放的物质。
如图6A所示,确认到存活的组织被染成红色,而梗塞组织被染成白色。并且确认到相对于对照组,使用2mg/kg的脱氧胆酸进行处理的组织及使用2mg/kg、10mg/kg的胆酸进行处理的组织中的大部分被染成红色,而几乎没有被染成白色的部分。
并且,如图6B所示,在作为阳性对照组的环孢菌素(5mg/kg)的情况下,梗塞面积减少了20%左右,相反,在使用2mg/kg的脱氧胆酸进行处理的情况下,确认到梗塞面积减少了50%以上,在使用2mg/kg的胆酸进行处理的情况下,梗塞面积减少了约50%,在使用10mg/kg的胆酸进行处理的情况下,梗塞面积减少了约40%左右。但是,在脱氧胆酸的情况下,在10mg/kg以上的浓度下导致个体死亡,在2mg/kg以下的浓度下呈现出效果。在胆酸的情况下,在图2mg/kg下呈现出最佳功效。因此,确认到以低浓度使用的情况下,再灌注损伤的抑制效果优异。
因此,确认到可将低浓度的脱氧胆酸和胆酸用作再灌注之后的心脏损伤抑制剂。
实施例5.在再灌注损伤小鼠模型的制造中确认胆汁酸对小鼠心肌坏死的抑制效果
为了确认胆汁酸中的脱氧胆酸对由上述再灌注损伤引起的心肌坏死的抑制效果,利用Annexin-Vivo750荧光染料进行了小鼠心肌坏死确认试验。对于在上述实施例3中制造的小鼠模型,在经过24小时之后投入Annexin-Vivo750荧光染料来按不同浓度观察了脱氧胆酸(1mg/kg、2mg/kg、5mg/kg(mpk))的效果,并将其结果示出于图7A及7B中。已知膜联蛋白(Annexin)染料通过在发生细胞凋亡的位置结合来显示荧光。
如图7A所示,确认到在未接受再灌注手术的对照组的情况下,心脏未被染色,但是经过再灌注手术的对照组显示出强荧光。并且,如图7B所示,确认到在1mpk、2mpk浓度的脱氧胆酸的情况下,相对于再灌注手术对照组,具有减少心肌死亡40%以上的效果。因此,确认到可将低浓度的脱氧胆酸有效地用作由抑制缺血性再灌注损伤引起的再灌注损伤的抑制剂。
虽然通过上述所提及的优选实施例对本发明进行了说明,但可在不脱离发明主旨及范围的情况下进行多种修改或变形。并且,所附的发明要求保护范围包括属于本发明主旨的这种修改或变形。
制剂例1:药品的制备
1.1胶囊剂的制备
胆汁酸100ml
玉米淀粉100mg
乳糖100mg
硬脂酸镁2mg
按照通常的胶囊剂制备方法混和上述成分并填充于明胶胶囊中来制备胶囊剂。
1.2注射剂的制备
胆汁酸100ml
注射用灭菌蒸馏水适量
pH调节剂适量
按照通常的注射剂制备方法来以每1安瓶(2ml)以上述含量含有上述成分的方式进行制备。
1.3液体制剂的制备
胆汁酸100ml
糖20g
异构化糖20g
柠檬香适量
加入纯净水来使总容量达到1000ml。按照通常的液体制剂制备方法混合上述成分之后,填充于棕色瓶中并经过灭菌来制备出液体制剂。
制剂例2:食品的制作
2.1面类食品的制作
将0.1~10.0重量份的本发明的食品组合物添加于面粉中,并利用该混合物通过常规方法制作出面包、蛋糕、饼干、面条及面食类,从而制作出用于改善健康的食品。
2.2乳制品(dairy products)的制作
将0.1~1.0重量份的本发明的食品组合物添加于牛奶中,并使用上述牛奶通过常规方法制作出黄油及冰淇淋等多种乳制品。
Claims (8)
1.胆汁酸或其药学上可接受的盐在制备用于预防或治疗心肌缺血性再灌注损伤的药物中的用途,其特征在于,所述胆汁酸为选自由脱氧胆酸、胆酸和石胆酸组成的组中的一种以上。
2.根据权利要求1所述的用途,其特征在于,所述心肌缺血性再灌注损伤由缺血性再灌注心肌病引起。
3.根据权利要求1所述的用途,其特征在于,所述药物用于再灌注手术的预处理。
4.根据权利要求1所述的用途,其特征在于,所述胆汁酸或其药学上可接受的盐为线粒体通透性转换孔的开放抑制剂。
5.根据权利要求1所述的用途,其特征在于,所述胆汁酸或其药学上可接受的盐为β-连环蛋白的激动剂。
6.根据权利要求1所述的用途,其特征在于,所述胆汁酸或其药学上可接受的盐用于保护线粒体。
7.根据权利要求1所述的用途,其特征在于,将所述药物以口服用制剂或注射用制剂的形式进行剂型化。
8.根据权利要求1所述的用途,其特征在于,将所述胆汁酸或其药学上可接受的盐以0.1mg/kg/日至10mg/kg/日进行给药。
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