CN112546042A - 表儿茶素在制备预防或治疗心肌纤维化的药物中的应用 - Google Patents
表儿茶素在制备预防或治疗心肌纤维化的药物中的应用 Download PDFInfo
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- CN112546042A CN112546042A CN202011530119.1A CN202011530119A CN112546042A CN 112546042 A CN112546042 A CN 112546042A CN 202011530119 A CN202011530119 A CN 202011530119A CN 112546042 A CN112546042 A CN 112546042A
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- epicatechin
- myocardial fibrosis
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Abstract
本发明涉及表儿茶素在制备预防或治疗心肌纤维化的药物中的应用，属于天然药物技术领域。本发明的目的在于提供一种表儿茶素的新用途，即表儿茶素在制备预防或治疗心肌纤维化的药物中的应用，其中表儿茶素的用量为0.001～15mg/Kg体重·天，所述药物含有有效量的表儿茶素和药学上可接受的载体和/或赋形剂。本发明通过小鼠实验证实表儿茶素能够改善小鼠心脏功能、对小鼠心脏结构起到保护作用，以及减轻AngⅡ诱导的肌成纤维细胞转化和胶原合成，表明其具有抑制心肌纤维化的作用，在对心肌纤维化的防治中具有较大应用前景，基于此，本发明首次提出将其用于制备预防或治疗心肌纤维化的药物中的新用途。
Description
技术领域
本发明属于天然药物技术领域，尤其涉及表儿茶素在制备预防或治疗心肌纤维化的药物中的应用。
背景技术
心肌纤维化(myocardial fibrosis，MF)是指心肌正常组织结构中出现的以细胞增殖、细胞外基质过度沉积为主要表现的疾病。心肌纤维化为心肌成纤维细胞(Cardiacfibroblasts，CFs)、异常增殖并分泌大量胶原蛋白，导致细胞外基质病理性积聚。近年来大量研究表明，心肌纤维化与许多心脏疾病有密切关系，如心房纤颤、心肌梗死、慢性心力衰竭、风湿性心瓣膜等。MF是多种心脏疾病发展至一定阶段具有的共同病理改变，也是引起心室重塑的关键原因，其主要病理表现有心计僵硬度增加、心肌收缩力下降、冠脉血流储备降低，甚至引起恶性心律失常和猝死。研究表明心肌纤维化程度与心室射血分数关系密切。有效防治心肌纤维化对心力衰竭的发生发展有重要意义。
表儿茶素(Epicatechin，EPI)为黄烷醇类化合物儿茶素类的家族成员，广泛存在于葡萄、茶叶和可可等食物中。表儿茶素类含有多个游离酚羟基，能提供氢质子与体内自由基结合，达到清除自由基的目的，并且在与自由基反应的过程中，分子内能形成氢键，生成稳定的自由基中间体，抑制原来的自由基链锁反应。表儿茶素对多元不饱和脂肪酸自由基、单线态氧、烷基过氧化物自由基等也都有清除作用。
研究表明表儿茶素能够对抗异丙肾上腺素诱导的氧化应激，减少心肌组织损伤，并且在冠状动脉闭塞疾病中能缩小梗死面积，保护心室结构和功能。表儿茶素治疗也改善了心力衰竭患者的线粒体结构，从而增强了心脏功能。但现有技术研究主要集中在表儿茶素对炎症及氧化应激诱发心血管疾病的干预作用，对于表儿茶素对心肌纤维化的治疗效果尚未见报道。
发明内容
本发明的目的在于提供一种表儿茶素的新用途，即表儿茶素在制备预防或治疗心肌纤维化的药物中的应用。
本发明的技术方案：
表儿茶素在制备预防或治疗心肌纤维化的药物中的应用。
进一步的，表儿茶素的用量为0.001～15mg/Kg体重·天。
进一步的，表儿茶素的用量为1mg/Kg体重·天。
进一步的，所述药物含有有效量的表儿茶素和药学上可接受的载体和/或赋形剂。
进一步的，所述药物的剂型为药剂学上允许的口服剂型或注射剂型。
进一步的，所述药物通过抑制心肌纤维化预防或治疗机体心脏心肌成纤维细胞转化。
进一步的，所述药物通过抑制心肌纤维化预防或治疗机体心肌胶原容积分数升高。
进一步的，所述药物通过抑制心肌纤维化预防或治疗慢性心衰。
进一步的，所述药物通过抑制心肌纤维化预防或治疗心脏重构，所述心脏重构包括心室扩张。
进一步的，表儿茶素能够减轻AngⅡ诱导的肌成纤维细胞转化和胶原合成。
本发明中所述的“预防或治疗心肌纤维化的药物”中包括表儿茶素以及药学上可接受的赋形剂，其可根据本领域常规方法制备，一般通过将表儿茶素与一种或多种药学上常规的赋形剂(可为固体赋形剂或液体赋形剂)和/或辅剂混合，制成适用于人或动物使用的剂型，例如普通制剂(片剂、胶囊剂、颗粒剂或注射剂等)、缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。表儿茶素在所述“预防或治疗心肌纤维化的药物”中的质量百分含量可为0.1～95％。
本发明中所述的“预防或治疗心肌纤维化的药物”可用任何公知的给药方法给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔黏膜、眼、肺和呼吸道、皮肤、阴道、直肠等。给药剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以使片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以使软膏剂、凝胶剂、糊剂等。
本发明中所述的“预防或治疗心肌纤维化的药物”可以使用本领域常规的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。上述片剂还可进一步制成包衣片，如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
本发明中所述的“预防或治疗心肌纤维化的药物”为胶囊剂时，为了将给药单元制成胶囊剂，可以将表儿茶素与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。上述片剂的各稀释剂、黏合剂、润湿剂、崩解剂和助流剂品种也可用于制备所述的胶囊剂中。
本发明中所述的“预防或治疗心肌纤维化的药物”为注射剂时，为将表儿茶素制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调节剂或渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调节剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。
本发明中所述的“预防或治疗心肌纤维化的药物”的给药剂量依照所要预防和/或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有大范围的变化。一般来讲，表儿茶素的每天的剂量范围可为0.001-15mg/Kg体重，优选为0.1-10mg/Kg体重，更优选为0.5-10mg/Kg体重，最优选为1-5mg/Kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明中所述的“预防或治疗心肌纤维化的药物”可单独服用或与其他治疗药物或对症药物合并使用。当表儿茶素与其它治疗药物存在协同作用时，应根据实际情况调整使用剂量。
本发明所述的应用中，所述的产品包括但不限定于药品和保健品。
本发明的有益效果：
本发明通过小鼠实验证实表儿茶素能够改善小鼠心脏功能、对小鼠心脏结构起到保护作用，以及减轻AngⅡ诱导的肌成纤维细胞转化和胶原合成，表明其具有抑制心肌纤维化的作用。由于表儿茶素是天然植物黄烷醇化合物，来源广泛、成本低廉，化学结构清楚、安全无毒副作用，在对心肌纤维化的防治中具有较大应用前景，基于此，本发明首次提出将其用于制备预防或治疗心肌纤维化的药物中的新用途。
附图说明
图1为实施例1中四组实验小鼠的代表心脏超声心动图；
图2为实施例1中四组实验小鼠的心脏参数对比图，
A图为LVEF：左室射血分数、
B图为LVFS：左室缩短分数、
C图为LVIDs：左室收缩内径、
D图为LVIDd：左室舒张内径、
E图为LVPWs：收缩期左室后壁厚度、
F图为LVPWd：舒张期左室后壁厚度、
G图为IVSs：收缩末期室间隔厚度、
H图为IVSd：舒张末期室间隔厚度；
图3为实施例1中四组实验小鼠的心肌切片显微照片；
A图为H&E法代表图、
B图为Masson法的代表图；
图4为实施例1中四组实验小鼠的胶原体积分数对比图；
图5为实施例1中四组实验小鼠的HW/BW指数对比图；
图6为实施例2各组细胞α-SMA抗体染色的免疫荧光强度统计图；
图7为实施例2中EPI或/和AngII孵育后的α-SMA、COLI和COLIII的Western blot条带及相对表达水平对比图，
A图为α-SMA的Western blot条带及相对表达水平对比图、
B图为COLI的Western blot条带及相对表达水平对比图、
C图为COLIII的Western blot条带及相对表达水平对比图。
具体实施方式
下面结合实施例对本发明的技术方案做进一步的说明，但并不局限于此，凡是对本发明技术方案进行修改或者等同替换，而不脱离本发明技术方案的精神和范围，均应涵盖在本发明的保护范围中。下列实施例中未具体注明的工艺设备或装置均采用本领域内的常规设备或装置，若未特别指明，本发明实施例中所用的原料等均可市售获得；若未具体指明，本发明实施例中所用的技术手段均为本领域技术人员所熟知的常规手段。本发明所用试剂和原料均市售可得。
实施例1
本实施例建立了TAC小鼠模型，利用超声影像学、病理组织学、显微观察和胶原沉积方面考察了表儿茶素(EPI)对小鼠心脏功能的改善效果。
本实施例的具体实验方法为：
正常的室温和湿度条件下，通过自由饮食喂养小鼠7天。用三溴乙醇(20mg/kg，美国MCE)麻醉小鼠。然后将小鼠随机分为对照组、主动脉弓狭窄术(TAC)组、表儿茶素组和TAC+表儿茶素组，表儿茶素组和TAC+表儿茶素的治疗组灌胃给予EPI 1mg/kg体重·天，连续灌胃28天。
(一)分别于TAC或治疗28天后采用超声心动图仪(visualonic Vevo 1100，加拿大)监测各组小鼠的心功能，监测结果如图1所示。
图1为本实施例中四组实验小鼠的心脏超声心动图；由图1可以看出，TAC导致了小鼠左室收缩内径及舒张内径扩大，而EPI能够逆转TAC的作用，降低心室扩张及室壁厚度，减少心肌肥厚，改善心脏功能。
(二)分别于TAC或治疗28天后检测各组5只小鼠的心脏参数——LVEF、LVFS、LVIDs、LVIDd、LVPWs、LVPWd、IVSs和IVSd，检测结果如图2所示。
图2为本实施例中四组实验小鼠的心脏参数对比图，A图为LVEF：左室射血分数、B图为LVFS：左室缩短分数、C图为LVIDs：左室收缩内径、D图为LVIDd：左室舒张内径、E图为LVPWs：收缩期左室后壁厚度、F图为LVPWd：舒张期左室后壁厚度、G图为IVSs：收缩末期室间隔厚度、H图为IVSd：舒张末期室间隔厚度。图2数据显示为平均值±SEM(n＝5)。*与对照组比较，P<0.05，**P<0.01；与TAC组比较，P<0.05，P<0.01
由图2可以看出，与对照组相比，TAC组小鼠的LVEF、LVFS降低，LVIDs、LVIDd增加；而TAC+表儿茶素的治疗组的小鼠经过EPI治疗后LVEF、LVFS明显升高，LVIDs、LVIDd降低，EPI能够改善小鼠心脏功能。
(三)分别于TAC或治疗28天后用H&E法或Masson法对小鼠心脏进行病理组织学进行分析，心肌切片用显微镜观察(美国卡尔蔡司有限公司)，显微照片如图3所示。
图3为本实施例中四组实验小鼠心肌切片的显微照片，A图为H&E法代表图、B图为Masson法的代表图，放大倍数为×200，比例尺＝20μm。由图3可以看出TAC导致了心肌细胞肥大及胶原沉积，EPI能够减少TAC引起的心肌细胞肥大及胶原沉积。
(四)分别于TAC或治疗28天后用胶原体积分数(CVF)评价胶原沉积，结果如图4所示。
图4为本实施例中四组实验小鼠的胶原体积分数对比图，数据显示为平均值±SEM(n＝5)。**与对照组比较P<0.01；与TAC组比较P<0.01；由图4对比可以看出，与对照组相比，TAC组的胶原体积分数升高，而TAC+表儿茶素的治疗组的小鼠经过EPI治疗后，胶原体积分数基本降至正常水平，这说明表儿茶素能够抑制小鼠心肌胶原沉积。
(五)HW/BW指数采用小鼠心脏重量体重比统计分析，分析结果如图5所示。
图5为本实施例中四组实验小鼠的HW/BW指数对比图，数据显示为平均值±SEM(n＝5)。**与对照组比较P<0.01；与TAC组比较P<0.01；由图5对比可以看出，与对照组相比，TAC组的HW/BW指数显著升高，而TAC+表儿茶素的治疗组的小鼠经过EPI治疗后，HW/BW指数基本降至正常水平，这说明表儿茶素能够保护小鼠的心脏结构。
实施例2
本实施例通过体外实验考察了EPI是否能保护心肌成纤维细胞(CFs)免受AngII诱导的心肌成纤维细胞转化。
本实施例用原代培养的新生大鼠心肌成纤维细胞作为体外心肌纤维化模型，具体实验方法为：
大鼠新生乳鼠(1-2d)在无菌条件下，开胸取出心脏，用D-Hanks液冲洗3次后剪成约1mm3的碎块，加入2ml的胰蛋白酶(1g/L)在37℃水浴锅中消化细胞2-3min，将含有细胞的胰蛋白酶液转移到含有10％胎牛血清的DMEM培养液中。重复上述操作直到心肌组织块颜色变透明为止。依据心肌细胞与成纤维细胞贴壁速度的不同，采用差速贴壁的方法，区分获得心肌成纤维细胞。将细胞悬液吸出，吹打均匀后，使用含10％胎牛血清的DMEM培养液，接种于培养皿中，置于37℃、5％CO2孵箱中培养。
将心肌成纤维细胞分为对照组，采用10μmol/L AngII孵育心肌成纤维细胞24h诱导心肌纤维化细胞模型组，用10μmol/L EPI孵育对照组的EPI组和用10μmol/L EPI孵育AngII孵育24h的心肌纤维化细胞模型组进行治疗干预的AngⅡ+EPI组。
(一)细胞免疫荧光实验使用α-SMA抗体染色各组细胞12h，用PBS洗涤细胞。然后加入二级抗体(分子探针，Invitrogen)1h，加入DAPI 3min，用显微镜(美国卡尔蔡司)检测免疫荧光，放大倍数为×200，比例尺为20μm，结果如图6所示。
图6为实施例2各组细胞α-SMA抗体染色的免疫荧光强度统计图；由图6对比可以看出，AngⅡ+EPI组荧光强度较模型组基本降至正常水平，这说明EPI能够抑制AngII诱导的成纤维细胞转化。
(二)为了进一步评价EPI对心肌纤维化的保护作用，用western blot检测α-SMA和collagenI/III(COLI/III)蛋白，具体实验方法如下：
细胞提取总蛋白，用BCA蛋白定量试剂盒测定蛋白浓度，取100μg蛋白加入5×上样缓冲液混合。用10％SDS-聚丙烯酰胺凝胶电泳进行分离并转到NC膜上，5％的脱脂奶粉室温下封闭2h，一抗包括α-SMA、COLI、COLIII和GAPDH，在4℃条件下，孵育24h。二抗室温避光孵育1h，使用美国LI-COR成像仪检测成像，各组的免疫印迹结果检测条带密度(面积×OD值)。Western blot条带、EPI或/和AngII孵育后的α-SMA、COLI和COLIII的相对表达水平对比结果如图7所示。
图7为实施例2中EPI或/和AngII孵育后的α-SMA、COLI和COLIII的Western blot条带及相对表达水平对比图；A图为α-SMA的Western blot条带及相对表达水平对比图、图为COLI的Western blot条带及相对表达水平对比图、C图为COLIII的Western blot条带及相对表达水平对比图。数据显示为平均值±SEM(n＝6)。**与对照组比较P<0.01；与AngII组比较P<0.01。
由图7的对比可以看出，AngII增加了α-SMA和COLI/III的蛋白表达，EPI能有效地抑制这些变化，证明EPI可以减轻AngII诱导的肌成纤维细胞转化和胶原合成。
Claims (10)
1.表儿茶素在制备预防或治疗心肌纤维化的药物中的应用。
2.根据权利要求1所述表儿茶素在制备预防或治疗心肌纤维化的药物中的应用，其特征在于，表儿茶素的用量为0.001～15mg/Kg体重·天。
3.根据权利要求2所述表儿茶素在制备预防或治疗心肌纤维化的药物中的应用，其特征在于，表儿茶素的用量为1mg/Kg体重·天。
4.根据权利要求3所述表儿茶素在制备预防或治疗心肌纤维化的药物中的应用，其特征在于，所述药物含有有效量的表儿茶素和药学上可接受的载体和/或赋形剂。
5.根据权利要求4所述表儿茶素在制备预防或治疗心肌纤维化的药物中的应用，其特征在于，所述药物的剂型为药剂学上允许的口服剂型或注射剂型。
6.根据权利要求1-5任一所述表儿茶素在制备预防或治疗心肌纤维化的药物中的应用，其特征在于，所述药物通过抑制心肌纤维化预防或治疗心肌成纤维细胞转化。
7.根据权利要求1-5任一所述表儿茶素在制备预防或治疗心肌纤维化的药物中的应用，其特征在于，所述药物通过抑制心肌纤维化预防或治疗机体心肌胶原容积分数升高。
8.根据权利要求1-5任一所述表儿茶素在制备预防或治疗心肌纤维化的药物中的应用，其特征在于，所述药物通过抑制心肌纤维化预防或治疗慢性心衰。
9.根据权利要求1-5任一所述表儿茶素在制备预防或治疗心肌纤维化的药物中的应用，其特征在于，所述药物通过抑制心肌纤维化预防或治疗心脏重构，所述心脏重构包括心室扩张。
10.根据权利要求1-5任一所述表儿茶素在制备预防或治疗心肌纤维化的药物中的应用，其特征在于，表儿茶素能够减轻AngⅡ诱导的肌成纤维细胞转化和胶原合成。
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| US20110021466A1 (en) * | 2008-03-13 | 2011-01-27 | The Regents Of The University Of California | Use of epicatechin and derivatives and salts thereof for cardiac protection of ischemic myocardium and to ameliorate adverse cardiac remodeling |
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| US20110021466A1 (en) * | 2008-03-13 | 2011-01-27 | The Regents Of The University Of California | Use of epicatechin and derivatives and salts thereof for cardiac protection of ischemic myocardium and to ameliorate adverse cardiac remodeling |
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