CN114404403A - 山姜素在制备治疗心梗和心梗后心肌重构药物中的应用 - Google Patents
山姜素在制备治疗心梗和心梗后心肌重构药物中的应用 Download PDFInfo
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Abstract
本发明公开了山姜素在制备治疗心梗和心梗后心肌重构药物中的新应用,所述山姜素通过调控TLR4/MyD88/NF‑κB信号通路发挥对心梗和心梗后心肌重构的保护作用。本发明通过山姜素对心血管疾病整体水平的研究,发现山姜素对于心梗和心梗后心肌重构具有良好的保护作用,为心梗和心梗后心肌重构提供了新的药物选择,且同时为山姜素的新应用提供了新的方向。
Description
技术领域
本发明涉及山姜素的一种新应用,尤其是山姜素对心梗和心梗后心肌重构具有保护作用的新应用。
背景技术
山姜素是一种黄酮类化合物,在姜科和双子叶植物中分布广泛。姜科植物的药用历史悠久,有祛风散寒,健脾暖胃的功效。虽然黄酮类化合物药理活性多样,然而山姜素的相关研究却有限。目前的研究表明,山姜素有抗炎、抗肿瘤、和肝肾保护等作用,最重要的是毒性低,安全性好。目前,山姜素对心血管方面的作用研究非常少,因此,亟需对山姜素在心血管方面的作用进行整体研究,为山姜素提供新的应用方向。
发明内容
本发明的目的在于克服上述现有技术中存在的问题而提供山姜素在制备治疗心梗和心梗后心肌重构药物中的新应用。
为实现上述目的,本发明采取的技术方案为:山姜素在制备治疗心梗和心梗后心肌重构药物中的应用。
本申请发明人通过山姜素对心血管疾病整体水平的研究,发现山姜素对于心梗和心梗后心肌重构具有良好的保护作用,为心梗和心梗后心肌重构提供了新的药物选择,且同时为山姜素的新应用提供了新的方向。
作为本发明所述山姜素在制备治疗心梗和心梗后心肌重构药物中的应用的优选实施方式,所述山姜素通过调控TLR4/MyD88/NF-κB信号通路发挥对心梗和心梗后心肌重构的保护作用。本申请通过对心血管疾病整体水平的研究,采用大鼠急性心梗的动物模型,研究得知山姜素对心梗及心梗后心肌重构的保护作用及其机制,所述山姜素通过调控TLR4/MyD88/NF-κB信号通路发挥对心梗和心梗后心肌重构的保护作用。
作为本发明所述山姜素在制备治疗心梗和心梗后心肌重构药物中的应用的优选实施方式,所述药物为固体制剂或液体制剂。
作为本发明所述山姜素在制备治疗心梗和心梗后心肌重构药物中的应用的优选实施方式,所述药物的剂型为片剂、丸剂、胶囊剂或注射剂。
本发明所述山姜素在制备治疗心梗和心梗后心肌重构的药物时,按照现有技术制备成常见固体制剂和液体制剂均可,包括不限于片剂、丸剂、胶囊剂、注射剂等。
作为本发明所述山姜素在制备治疗心梗和心梗后心肌重构药物中的应用的优选实施方式,所述药物用于治疗心梗和心梗后心肌重构时,山姜素的使用剂量为0.8-8mg/kg。作为本发明所述山姜素在制备治疗心梗和心梗后心肌重构药物中的应用的优选实施方式,所述药物用于治疗心梗和心梗后心肌重构时,山姜素的使用剂量为1.6-6.3mg/kg。本申请发明人在试验中发现,当所述山姜素制备成用于治疗心梗和心梗后心肌重构的药物,所述药物在用于治疗心梗和心梗后心肌重构时,山姜素的有效使用剂量为0.8-8mg/kg,优选地,山姜素的有效使用剂量为1.6-6.3mg/kg。
作为本发明所述山姜素在制备治疗心梗和心梗后心肌重构药物中的应用的优选实施方式,所述药物中还含有具有治疗心梗和心梗后心肌重构效果的中药和西药。本申请发明人通过试验研究发现,当所述山姜素与现有技术中具有治疗心梗和心梗后心肌重构效果的中药和西药联合应用时,它们之间可以产生协同作用,对于治疗心梗和心梗后心肌重构效果具有更好的效果。
作为本发明所述山姜素在制备治疗心梗和心梗后心肌重构药物中的应用的优选实施方式,所述具有治疗心梗和心梗后心肌重构效果的中药包括丹参、人参、姜黄中的至少一种。本申请中所述的现有技术中具有治疗心梗和心梗后心肌重构效果的中药包括但不限于丹参、人参和姜黄。
作为本发明所述山姜素在制备治疗心梗和心梗后心肌重构药物中的应用的优选实施方式,所述具有治疗心梗和心梗后心肌重构效果的西药包括血管紧张素转化酶抑制剂(ACEI)、血管静张素受体阻滞剂(ARBs)、阿司匹林中的至少一种。本申请中所述的现有技术中具有治疗心梗和心梗后心肌重构效果的西药包括但不限于血管紧张素转化酶抑制剂(ACEI)、血管静张素受体阻滞剂(ARBs)和阿司匹林。
本发明通过山姜素对心血管疾病整体水平的研究,发现山姜素对于心梗和心梗后心肌重构具有良好的保护作用,为心梗和心梗后心肌重构提供了新的药物选择,且同时为山姜素的新应用提供了新的方向。
附图说明
图1为本发明山姜素对心梗和心梗后心肌重构保护作用的试验流程图;
图2为心梗大鼠心电图变化图;
图3为各组大鼠心功能超声图像对比图;
图4为各组大鼠心功能超声结果对比图;
图5为各组大鼠心脏重量指标检测结果对比图;
图6为各组大鼠HE染色结果对比图;
图7为各组大鼠天狼猩红染色对比图;
图8为各组大鼠天狼猩红染色后胶原面积和胶原类型结果对比图;
图9为各组大鼠Western Blot检测TLR4/MyD88/NF-κB信号通路对比图;
图10为各组大鼠进行ELISA检测的血清TNF-α、TL-6的含量对比图;
图11为各组大鼠心肌成纤维细胞活力对比图;
图4中,Sham:假手术组;AMI:心梗组;ALP:山姜素组;与Sham组比较:*表示P<0.05,**表示P<0.01;与AMI组比较:#表示P<0.05,##表示P<0.01,n=8;
图5中,Sham:假手术组;AMI:心梗组;ALP:山姜素组;与Sham组比较:*表示P<0.05,**表示P<0.01;与AMI组比较:#表示P<0.05,##表示P<0.01,n=8;
图8中,Sham:假手术组;AMI:心梗组;ALP:山姜素组;与Sham组比较:*表示P<0.05,**表示P<0.01;与AMI组比较:#表示P<0.05,##表示P<0.01,n=3;
图10中,Sham:假手术组;AMI:心梗组;ALP:山姜素组;与Sham组比较:*表示P<0.05,**表示P<0.01;与AMI组比较:#表示P<0.05,##表示P<0.01,n=8;
图11中,Con:正常对照组;DMSO:溶媒对照组;LPS:脂多糖组;ALP10:10μg/ml;ALP20:20μg/ml;ALP40:40μg/ml;与Con组比较:**表示P<0.01;与LPS组比较:#表示P<0.05,##表示P<0.01,n=5。
具体实施方式
为更好的说明本发明的目的、技术方案和有益效果,下面将结合附图和具体实施例对本发明作进一步说明。
本发明所述山姜素可直接购于市场或者采用本领域常规方法制备而成。
实施例1本发明所述山姜素对心梗和心梗后心肌重构的保护效果试验
本实施例中采用SD大鼠为试验对象,通过将SD大鼠分成假手术组、心梗组和给药组三组,通过对各组大鼠进行超声心电图、心脏标本形态学分析、心脏组织病理学分析、生化指标和分子生物学检测等进行检测(如附图1所示),研究本发明所述山姜素对于心梗和心梗后心肌重构的保护作用。
一、动物分组及心梗造模
1.1动物分组
选取8~10周龄的SD雄性大鼠作为试验对象,随机分为:假手术组、模型和山姜素组,每组15只。
1.2心梗造模
心梗造模方法:将大鼠经50mg/kg戊巴比妥钠腹腔注射麻醉,气管插管,连接心电图和小动物呼吸机。胸部备皮,于胸骨左侧纵向切口,钝性分离第三四肋间肌,打开胸腔、撕开心包充分暴露心脏,用7号丝线结扎左冠状动脉前降支,观察到心电图S-T段显著抬高,心室前壁变白,运动减弱,清除腔内淤血和气体后逐层关胸。
三组分别进行如下处理:
心梗组:结扎冠状动脉左前降支,生理盐水灌胃21天;
假手术组:穿线不结扎,生理盐水灌胃21天;
山姜素组:结扎大鼠冠状动脉左前降支,山姜素(20mg/kg)灌胃21天。
所有动物标准饮食,饲养条件相同。术后21天动物处死取材检测相关指标。
二、试验方法
2.1超声心动图
用2%异氟醚气体麻醉大鼠,流速为2~2.5ml/min。体温维持在37℃,心率维持在350次/分左右。采用超高分辨率小动物超声影像系统(Vevo2100),通过胸骨旁长轴和短轴切面分析左心室舒张末期内径、左心室收缩末期内径、左心室舒张末期容积、左心室收缩末期容积、射血分数和缩短分数等参数。
2.2心脏标本形态学分析
各组大鼠饲养21天后处死,电子天平精确称取全心质量(THW),去除心房、血管及周围结缔组织,保留左心室,预冷PBS冲洗后吸干残余水分,称取左心室质量(LVW),分别与体质量(BW)相比,以心脏质量指数(THW/BW)及左心室质量指数(LVW/BW)作为心肌肥厚的定量指标。
2.3心脏组织病理学分析
在垂直于心脏长轴中点处分割,取心脏组织经4%多聚甲醛固定后常规石蜡包埋,连续进行5μm厚度切片,采用HE及天狼猩红染色检测心肌的损伤程度和心肌胶原纤维的面积作为评价心梗后纤维化的指标。
2.4生化指标和分子生物学检测
①ELISA
收集各组大鼠血清样本,参照试剂盒操作说明,采用酶标仪在450nm波长检测吸光值,评价TNF-α、IL-6、IL-1β等炎症因子的水平。
②WesternBlot
取各组大鼠心脏标本,采用Western Blot检测梗死周边区TLR4、NF-κB p65、NF-κBpp65、IkBα、p-IkBα、TGF-β1蛋白的表达。
③qRT-PCR
参照试剂盒说明,提取各组心肌样本总RNA,逆转录获得cDNA,检测各组心肌样本TLR4 mRNA的表达。
2.5乳鼠原代心肌成纤维细胞分离与培养
取1~3日龄SD乳鼠,浸泡在75%酒精中后迅速剪开胸腔,摘取心脏后用预冷PBS清洗两次。切除多余的血管,剪碎心脏至1mm3左右大小。加入0.1%胶原酶II,37℃水浴消化,消化5min,消化8~10次。消化后取上清加入10%FBS的DMEM,用100目细胞筛过滤混合液。混合液1000r/min,5min离心,弃上清加入培养基。差速贴壁90min,得到心肌成纤维细胞,心肌成纤维细胞3~5代用于试验。
2.6统计方法
三、试验结果
(一)功能学指标结果
①心电图的变化
以心电图(ECG)S-T段显著抬高作为衡量造模成功与否的标志。如图2所示,从ECG中对比,结扎冠状动脉左前降支后出现S-T段显著抬高及QRS波与T波融合。
②心脏超声心动图的变化
分别对假手术组、心梗组和山姜素组的大鼠进行心功能超声检测,得出各组的心脏超声心动图,如附图3和附图4所示,为冠状动脉左前降支结扎后21天心脏超声心动图的代表性图像和分析结果。
由附图3和附图4可知,与假手术(sham)组相比,心梗组(AMI)心脏的左心室收缩末期内径、舒张末期内径和左心室舒张末期容积显著升高(P<0.01),并且射血分数和缩短分数显著降低(P<0.01),由此说明急性心肌梗死的模型建模成功。
由附图4可知,与心梗(AMI)组相比,山姜素(ALP)治疗组心脏的左心室收缩末期内径和左心室收缩末期容积明显降低(P<0.05),射血分数和缩短分数明显增加(P<0.05)。
这些结果表明山姜素显著减轻了急性心肌梗死后的心脏功能障碍,尤其是收缩功能障碍,且减弱了心脏重构。
(二)形态学指标结果
①心重指数和左室质量指数
分别检测假手术组、心梗组和山姜素组大鼠的心重指数和左室质量指数,检测结果如附图5所示。由附图5可知,与对照(Sham)组相比,心梗(AMI)组左心室重量明显升高(P<0.05),左心室质量指数显著升高(P<0.01)。此外,与心梗(AMI)组相比,山姜素(ALP)治疗组左心室重量和左心室质量指数明显降低(P<0.05)。
②病理检测结果
1)HE染色
分别对假手术组、心梗组和山姜素组大鼠心脏组织进行HE染色,染色结果如附图6所示。由附图6可知,假手术(Sham)组大鼠心肌细胞排列整齐,无炎性细胞浸润;与假手术(Sham)组比较,心梗(AMI)组梗死区心肌细胞数量减少,较多炎性细胞浸润,细胞淡染,心肌纤维内颗粒样变性,存在溶解断裂、排列紊乱,核周空泡(黑色箭头);山姜素(ALP)组梗死区内心肌细胞排列较为整齐,肌纹较明显,较少炎性细胞浸润或炎性程度降低,提示山姜素(ALP)治疗后大鼠心肌组织炎症程度有所降低。
2)天狼猩红染色
分别对假手术组、心梗组和山姜素组大鼠进行天狼猩红染色,结果如附图7和8所示。由附图7和8可知,与假手术(Sham)组相比,心梗(AMI)组胶原蛋白面积和Ⅰ型/Ⅲ型胶原蛋白显著增加(P<0.01)。与心梗(AMI)组相比,山姜素(ALP)组胶原蛋白面积和Ⅰ型/Ⅲ型胶原蛋白比例明显降低。提示山姜素(ALP)治疗后大鼠的胶原沉积降低。
(三)分子生物学指标结果
分别对假手术组、心梗组和山姜素组大鼠心肌进行WesternBlot检测,结果如附图9所示。由附图9可知,心梗组大鼠心肌TLR4/MyD88/NF-κB信号通路的蛋白表达明显上调,而山姜素(ALP)抑制了此通路的激活。提示山姜素(ALP)治疗后大鼠的炎症信号通路明显被抑制。
(四)生化指标结果
分别对假手术组、心梗组和山姜素组大鼠血清进行ELISA检测,结果如附图10所示。由附图10可知,与对照(sham)组相比,心梗(AMI)组大鼠血清中TNF-α、IL-6含量均显著增加(P<0.01),炎症反应增强。而与AMI组相比,给予山姜素(ALP)治疗的大鼠血清中TNF-α含量显著降低(P<0.01),IL-6含量明显降低(P<0.05)。这些结果表明,心梗组大鼠TLR4/MyD88/NF-κB信号通路下游的炎症因子表达上调。反之,山姜素显著抑制了AMI大鼠的炎症反应。
(五)细胞试验
分别对各组大鼠原代心肌成纤维细胞的增殖进行CCK-8检测,结果如附图11所示,由附图11可知,与对照组相比,脂多糖(LPS)组心肌成纤维细胞的活力显著升高(P<0.01)。与LPS组相比,山姜素(ALP)呈浓度依赖性抑制了心肌成纤维细胞的增殖。
最后所应当说明的是,以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制,尽管参照较佳实施例对本发明作了详细说明,本领域的普通技术人员应当理解,可以对本发明的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实质和范围。
Claims (9)
1.山姜素在制备治疗心梗和心梗后心肌重构药物中的应用。
2.如权利要求1所述山姜素在制备治疗心梗和心梗后心肌重构药物中的应用,其特征在于,所述山姜素通过调控TLR4/MyD88/NF-κB信号通路发挥对心梗和心梗后心肌重构的保护作用。
3.如权利要求1或2所述山姜素在制备治疗心梗和心梗后心肌重构药物中的应用,其特征在于,所述药物为固体制剂或液体制剂。
4.如权利要求3所述山姜素在制备治疗心梗和心梗后心肌重构药物中的应用,其特征在于,所述药物的剂型为片剂、丸剂、胶囊剂或注射剂。
5.如权利要求3所述山姜素在制备治疗心梗和心梗后心肌重构药物中的应用,其特征在于,所述药物用于治疗心梗和心梗后心肌重构时,山姜素的使用剂量为0.8-8mg/kg。
6.如权利要求5所述山姜素在制备治疗心梗和心梗后心肌重构药物中的应用,其特征在于,所述药物用于治疗心梗和心梗后心肌重构时,山姜素的使用剂量为1.6-6.3mg/kg。
7.如权利要求1所述山姜素在制备治疗心梗和心梗后心肌重构药物中的应用,其特征在于,所述药物中还含有具有治疗心梗和心梗后心肌重构效果的中药和西药。
8.如权利要求7所述山姜素在制备治疗心梗和心梗后心肌重构药物中的应用,其特征在于,所述具有治疗心梗和心梗后心肌重构效果的中药包括丹参、人参、姜黄中的至少一种。
9.如权利要求7所述山姜素在制备治疗心梗和心梗后心肌重构药物中的应用,其特征在于,所述具有治疗心梗和心梗后心肌重构效果的西药包括血管紧张素转化酶抑制剂(ACEI)、血管紧张素受体阻滞剂(ARBs)、阿司匹林中的至少一种。
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