CN111603464B - 仙鹤草内酯在拮抗缺氧引起的心肌细胞损伤中的用途 - Google Patents
仙鹤草内酯在拮抗缺氧引起的心肌细胞损伤中的用途 Download PDFInfo
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Abstract
本发明公开了仙鹤草内酯在拮抗缺氧引起的心肌细胞损伤中的用途。本发明研究发现,仙鹤草内酯能够通过促进心肌细胞增殖、抑制缺氧引起的细胞凋亡、维持细胞形态的完整性和增强线粒体的功能,从而实现对缺氧引起的心肌细胞损伤的保护作用,为开发新的治疗心肌梗死的药物提供了理论支持。
Description
技术领域
本发明属于仙鹤草内酯的医药用途领域,具体涉及仙鹤草内酯在拮抗缺氧引起的心肌细胞损伤中的医药用途。
背景技术
缺氧,是指由于供氧不足或氧功能障碍导致组织代谢,功能和形态结构发生异常变化的病理过程。缺氧是各种临床疾病中非常常见的一种病理过程,可损伤心肌细胞,诱导细胞凋亡。心肌梗死(MI)是由心脏急性和持续缺血或缺氧引起的一种常见的临床心血管疾病。虽然MI的治疗取得了很大的进展,但心肌梗死的发病率和死亡率仍然很高,严重威胁着人类的健康。心肌细胞凋亡和损伤是MI的主要特征,因此,寻找一种有效的减轻心肌细胞损伤和凋亡的新药物将有助于MI的治疗。
仙鹤草是一种传统中草药,收敛止血作用最早被古人发现。仙鹤草的主要成分有仙鹤草素,木犀草素-7-葡萄糖苷,香豆素,单宁,甾醇等。这些提取物具有抗氧化,抗炎,抗病毒,降血糖,抗肿瘤等药理活性。最近的研究发现,仙鹤草提取物可清除DPPH自由基,提示仙鹤草具有较强的抗氧化活性;在链脲佐菌素糖尿病发展过程中,仙鹤草降低了高血糖水平,延缓了小鼠糖尿病的发展;用仙鹤草乙醇提取物处理HepG2细胞,可抑制细胞增殖,激活细胞凋亡相关蛋白,如XIAP、BIK、MCL-1、bcl-xl、bcl-2、BID、caspase-9、caspase-3和PARP,表明仙鹤草乙醇提取物可诱导细胞凋亡;仙鹤草多糖及其硫酸化衍生物通过激活Wnt/β-catenin信号通路和抑制细胞凋亡,保护MC3T3-E1细胞免受DEX诱导的细胞损伤。
仙鹤草内酯(Agrimonolide,AM)是从仙鹤草中分离提取的一种异香豆素类化合物,现有研究发现:仙鹤草内酯具有保肝、抗炎、降血糖、抗肿瘤等药理活性。但目前还未有关于仙鹤草内酯对缺氧诱导的心肌细胞损伤作用方面的报道。
发明内容
针对上述现有技术,本发明的目的是提供仙鹤草内酯在保护缺氧引起的心肌细胞损伤方面的新的医药用途。
为实现上述目的,本发明采用如下技术方案:
本发明的第一方面,提供仙鹤草内酯在制备治疗由缺氧引起的心肌细胞损伤的药物中的应用。
上述应用中,所述仙鹤草内酯通过如下(1)-(4)至少一条途径来拮抗缺氧引起的心肌细胞损伤:
(1)降低G0/G1期细胞所占的比例;
(2)提高PCNA蛋白的水平;
(3)抑制缺氧诱导的细胞凋亡;
(4)增强线粒体功能。
上述应用中,优选的,所述心肌细胞为H9C2细胞。
本发明的第二方面,提供仙鹤草内酯在制备治疗由缺氧引起的心肌梗死的药物中的应用。
本发明的第三方面,提供一种治疗由缺氧引起的心肌细胞损伤的药物,所述药物以15μM的仙鹤草内酯为有效成分。
本发明的第四方面,提供仙鹤草内酯在制备用于提高缺氧条件下G0/G1期心肌细胞所占比例的药物中的应用。
本发明的第五方面,提供仙鹤草内酯在制备用于提高缺氧条件下PCNA蛋白表达水平的药物中的应用。
本发明的第六方面,提供仙鹤草内酯在制备用于增强缺氧条件下线粒体功能的药物中的应用。
本发明的有益效果:
本发明研究发现,仙鹤草内酯能够通过促进心肌细胞增殖、抑制缺氧引起的细胞凋亡、维持细胞形态的完整性和增强线粒体的功能,从而实现对缺氧引起的心肌细胞损伤的保护作用,为开发新的治疗心肌梗死的药物提供了理论支持。
附图说明
图1:不同浓度的AM处理H9C2细胞24小时后对细胞活力的影响。
图2:不同处理组对H9C2细胞形态变化的影响(倒置显微镜,×200);其中,Con:对照组;Hypoxia:缺氧处理组;Hypoxia+AM(15μM):缺氧+AM处理组;AM:AM处理组。
图3:不同处理组对H9C2细胞周期的影响;其中,A:PI染色,流式细胞仪分析细胞周期谱;B:不同处理组G0/G1期细胞和S+G2/M期细胞比例;C:PCNA蛋白Western Blot检测结果;D:不同处理组PCNA蛋白的表达水平;Con(或NC):对照组;Hypoxia:缺氧处理组;Hypoxia+AM(15μM):缺氧+AM处理组;AM:AM处理组。
图4:不同处理组对H9C2细胞凋亡的影响;其中,A:Annexin V-FITC/PI染色,流式细胞仪检测细胞凋亡率;B:流式细胞仪检测的细胞凋亡率结果;C:用TdT和DAPI染色,免疫荧光显微镜观察凋亡细胞,图像放大倍数为400倍;D:免疫荧光检测的细胞凋亡率结果;Con:对照组;Hypoxia:缺氧处理组;Hypoxia+AM(15μM):缺氧+AM处理组;AM:AM处理组。
图5:不同处理组对H9C2细胞凋亡蛋白的影响;其中,A:Western Blot检测结果;B:不同处理组Bcl2蛋白表达水平;C:不同处理组Bax蛋白表达水平;D:不同处理组Cleavedcaspase3蛋白表达水平;Con:对照组;Hypoxia:缺氧处理组;Hypoxia+AM(15μM):缺氧+AM处理组;AM:AM处理组。
图6:不同处理组对H9C2细胞ROS的影响;其中,Con:对照组;Hypoxia:缺氧处理组;Hypoxia+AM(15μM):缺氧+AM处理组;AM:AM处理组。
图7:不同处理组对H9C2细胞MMP的影响;其中,Con:对照组;Hypoxia:缺氧处理组;Hypoxia+AM(15μM):缺氧+AM处理组;AM:AM处理组。
图8:不同处理组对H9C2细胞线粒体功能蛋白的影响;其中,A:Western Blot检测结果;B:不同处理组DRP1蛋白表达水平;C:不同处理组OPA1蛋白表达水平;D:不同处理组MFN1蛋白表达水平;E:不同处理组MFN2蛋白表达水平;F:不同处理组Tom20蛋白表达水平;Con:对照组;Hypoxia:缺氧处理组;Hypoxia+AM(15μM):缺氧+AM处理组;AM:AM处理组。
具体实施方式
应该指出,以下详细说明都是例示性的,旨在对本申请提供进一步的说明。除非另有指明,本文使用的所有技术和科学术语具有与本申请所属技术领域的普通技术人员通常理解的相同含义。
正如背景部分所介绍的,仙鹤草由于具有广泛的药理学作用,而被国内外医药学家所关注。目前从仙鹤草各个部位分离得到的化学成分主要可分为:黄酮类、三萜类、间苯三酚衍生物类、异香豆素类、鞣质类、有机酸类、甾体类及脂肪族类。
仙鹤草内酯(Agrimonolide,AM)是从仙鹤草中分离提取的一种异香豆素类化合物,其结构式如下:
目前报道的仙鹤草内酯的药理活性主要有:保肝、抗炎、降血糖、抗肿瘤等,但还未有关于仙鹤草内酯对缺氧诱导的心肌细胞损伤作用方面的研究。
基于此,本发明探究了仙鹤草内酯对缺氧诱导H9C2细胞损伤的调节作用。首先考察了仙鹤草内酯对细胞活性的影响,结果显示,一定浓度范围的仙鹤草内酯处理H9C2细胞能够增强细胞活力,促进细胞增殖,呈剂量依赖效应,且增殖效果在15μM时达到峰值(图1),表明仙鹤草在低浓度时能够促进H9C2细胞增殖。
缺氧能够造成H9C2细胞损伤,使细胞形态发生改变,细胞皱缩,数量减少。本发明研究发现,采用AM干预后,能够缓解缺氧造成的这种变化,保持细胞的完整性(图2)。由此,推测AM对缺氧诱导的H9C2细胞损伤具有调节作用。
为进一步证实该调节作用,本发明研究了AM对细胞周期调控的影响。研究发现,缺氧会将细胞周期阻滞于G1期,抑制细胞的增殖,从而降低细胞活性;结果显示缺氧处理处于G1期的细胞占70%,叫正常组的62%显著增加,采用AM干预后能够降低G1期细胞的比率至64%。增殖细胞核抗原(PCNA)参与DNA复制、DNA修复和细胞周期控制,是反映细胞增殖状态的良好指标。我们的结果显示,缺氧处理PCNA水平下降,AM干预后能够提高PCNA蛋白的水平,AM单独处理能够增加PCNA的表达,证明AM能够通过调节细胞周期和PCNA的表达抑制缺氧诱导的H9C2周期的改变。
缺氧能够诱导心肌细胞凋亡引起心肌损伤,因此我们检测了凋亡相关指标的变化。Annexin V-FITC/PI染色流式检测,结果显示,缺氧处理能够使细胞凋亡率上升至19%,AM干预后能够降低细胞凋亡率至12%。TUNEL染色结果也显示,缺氧处理出现凋亡的细胞显著增加,AM干预后能够减少凋亡细胞数量。Cleaved caspase、Bax、Bcl2蛋白参与细胞凋亡进程,在凋亡的发生和发展中发挥着重要的作用,因此我们检测了它们的表达情况,结果显示,缺氧处理能够使Bax、Cleaved caspase3蛋白水平升高,Bcl2蛋白水平下降;AM干预后能够调节这种变化,降低Bax、cleaved caspase3蛋白水平,提高Bcl2蛋白水平。证明了AM能够降低细胞凋亡率,调节相关蛋白表达抑制细胞凋亡。
缺氧会引起线粒体氧化应激,促进ROS的生成,使线粒体功能发生改变,因此线粒体的功能障碍是缺氧造成心肌细胞损伤的主要原因之一。ROS是含氧的化学反应性化学物质,在细胞信号传导和生长发育过程中具有重要作用,当受到外界环境压力时,ROS水平会急剧增加,对细胞造成损害。本研究结果显示,缺氧处理H9C2细胞大量ROS被生成,AM干预后,ROS的水平被降低。表明AM能够减少被缺氧引起的ROS生成。线粒体在呼吸氧化过程中,将所产生的能量以电化学势能储存于线粒体内膜,在内膜两侧造成质子及其他离子浓度的不对称分布而形成线粒体膜电位(Mitochondrial membrane potential,MMP)。正常的MMP是维持线粒体进行氧化磷酸化、产生三磷酸腺苷的先决条件,有利于维持细胞的正常生理功能。本研究结果显示,缺氧处理细胞内MMP降低,AM干预后MMP被显著升高。线粒体稳态对于维持细胞的正常生理功能发挥着重要的作用,线粒体融合与分裂的平衡对于线粒体的稳态具有重要作用,而DRP1,MFN1,MFN2,OPA1参与调节线粒体裂变与融合,Tom20定位于线粒体外膜,并以前导序列启动前体蛋白识别,以帮助蛋白跨线粒体外膜导入线粒体,维持线粒体的正常功能。我们的结果显示,缺氧使DRP1蛋白水平被上升,MFN1、MFN2、OPA1和Tom20水平下降;AM干预后相关蛋白的表达被调节,使DRP1蛋白水平下降,MFN1、MFN2、OPA1和Tom20水平上升。AM组与control组对比,JC-1和ROS水平没有发生显著的变化,表明AM单独处理不会引起细胞的氧化应激损伤,但是在线粒体功能蛋白水平上,AM单独处理,能够显著调节相关蛋白的表达。
综上,仙鹤草内酯(AM)通过调节细胞周期促进H9C2细胞的增殖,抑制缺氧诱导的H9C2凋亡,维持细胞形态的完整性,调节相关凋亡蛋白的表达——降低cleaved caspase-3和Bax水平,增加Bcl-2水平。此外,AM的干预可恢复线粒体膜电位,抑制活性氧的产生,增强MFN1、MFN2、OPA1和Tom20等线粒体功能蛋白,从而实现了对缺氧诱导H9C2细胞损伤的保护作用。
为了使得本领域技术人员能够更加清楚地了解本申请的技术方案,以下将结合具体的实施例详细说明本申请的技术方案。
本发明实施例中所用的未进行具体说明试验材料均为本领域常规的试验材料,均可通过商业渠道购买得到。其中:
仙鹤草内酯(AM)购自上海源叶生物科技有限公司(中国,上海);DMEM培养基购自Hyclone Company(Logan City,Utah,USA);胎牛血清(FBS)购自浙江天杭生物科技股份有限公司(浙江德清);细胞周期与凋亡分析试剂盒(C1052)、MMP检测试剂盒(C2006)、ROS检测试剂盒(S0033)、TUNEL检测试剂盒(C1086)、DAPI染色液(C1005),均由碧云天生物技术研究所提供;Annexin V-FITC/PI凋亡检测试剂盒(A211-01)购自南京诺唯赞生物技术有限公司;Bax(A15646)和Bcl-2(A0208)抗体购自ABclonal Biotechnology Co.,Ltd.(Oxfordshire,UK);β-Actin抗体由武汉塞维尔生物技术有限公司提供;GAPDH(10494-1-AP)抗体购自武汉三鹰生物技术有限公司;Caspase3(#9662)、DRP1(#5391)、OPA1(#80471)、MFN2(#11925)和Tom20(#42406)抗体购自Cell Signaling Technology.,Inc.(Beverly,MA,USA);MFN1(ab104274)抗体购自Abcam(Cambridge,UK)。
H9C2细胞购自赛百慷(上海)生物技术股份有限公司(中国,上海)。
实施例1:仙鹤草内脂对缺氧诱导的H9C2心肌细胞损伤的保护作用研究
1.试验方法:
1.1细胞培养及处理:
将H9C2细胞在添加有10%胎牛血清的DMEM培养基中进行培养,培养条件为37℃、5%CO2的湿化环境。
当细胞培养至融合率为50%时,进行分组处理,将细胞分为4个处理组,分别为:
(1)对照组:常规条件下孵育24h;(2)缺氧处理组:在缺氧条件下,即三气培养箱(1%O2,5%CO2,94%N2)中孵育24h;(3)缺氧+AM处理组:在缺氧条件下,即三气培养箱(1%O2,5%CO2,94%N2)中,添加AM(15μM)孵育24h;(4)AM处理组:在常规条件下添加AM(15μM)孵育24h。
24h后收集H9C2细胞进行分析。
1.2细胞活性测定:
在96孔板中培养H9C2细胞,将不同浓度的AM(0、3.25、7.5、15、30和60μM)添加到孔板中,在37℃分别孵育24h。
采用MTT法测定细胞活性,并用显微镜观察细胞形态。
1.3细胞周期检测:
将各处理组的细胞消化收集于1.5mL离心管中。4℃1000g离心5min,预冷PBS洗涤一次,4℃预冷75%乙醇1ml重悬过夜。4℃1000g离心5min,预冷PBS洗涤一次。丢弃上清后,加入0.5mL PI染色液,37℃暗箱孵育30min,流式细胞仪检测(LSRFortessa,BD,USA)。
1.4TUNEL免疫荧光检测:
将1×105个细胞接种到24孔板的载玻片中。当细胞达到50%融合时,开始缺氧和/或AM处理24h。PBS洗涤1次,4%多聚甲醛固定30min,PBS洗涤1次。加入0.3%Triton X-100处理细胞5min,PBS洗涤2次。然后加入50μL TUNEL检测液,37℃避光孵育60min。孵育后,PBS洗涤2次,加入50μL DAPI染色液处理10min,PBS重洗2次,在徕卡TCS SPE共聚焦显微镜下观察图像。观察并计数显示绿色荧光的细胞。
1.5Annexin V-FITC/PI法检测细胞凋亡:
采用Annexin V-FITC/PI细胞双染色检测细胞凋亡率。在缺氧和/或AM处理24小时后,用不含EDTA的胰蛋白酶收集H9C2细胞。将细胞用预冷的PBS洗涤3次,用100μL的1×binding buffer重悬,然后在含有5μL Annexin V-FITC和5μL PI的1×binding buffer中室温暗孵育15分钟。最后在检测前加入400μL 1×binding buffe。然后用流式细胞仪((LSRFortessa,BD,USA))分析细胞样本。
1.6活性氧(ROS)检测:
采用荧光探针DCFH-DA法检测ROS的变化。H9C2细胞经缺氧和/或AM处理24小时后,收集细胞,用无血清培养基洗涤1次,用500μL的DCFH-DA工作液重悬,37℃暗箱孵育30min。孵育后用无血清细胞培养液洗涤3次。处理后的细胞样品采用流式细胞仪进行分析。
1.7线粒体膜电位(MMP)测量:
H9C2细胞经缺氧和/或AM处理24小时后,收集细胞,将细胞重悬于500μL的培养基中,然后再加入500μL JC-1试剂,37℃避光孵育15分钟。离心弃上清后,用JC-1缓冲液洗涤细胞3次,用500μL的JC-1缓冲液重悬细胞,处理后的细胞样品采用流式细胞仪进行分析。
1.8免疫印迹分析:
用RIPA缓冲液提取H9C2细胞总蛋白,用BCA蛋白检测试剂盒定量蛋白浓度后,用蛋白和5倍上样缓冲液制备蛋白样品。用SDS-PAGE将蛋白分离并转移到PVDF膜上。用5%脱脂奶粉封闭1.5小时后,与一抗4℃孵育过夜。次日室温下,PVDF与二抗孵育1h,用增强化学发光检测ECL试剂显影,最后定量。
1.9统计学分析:
所有数据均以至少三个独立实验的均数±标准差(SD)表示。实验数据采用SPSS25.0软件进行分析。p值采用单因素方差分析(ANOVA)(Scheffe’s F检验)计算;P<0.05为差异有统计学意义。
2.试验结果:
2.1AM对细胞增殖的影响:
采用MTT法检测一系列AM浓度(0、3.25、7.5、15、30和60μM)对H9C2细胞活性的影响,结果如图1所示,当采用0-15μM的AM处理细胞24h,细胞增殖率呈剂量依赖效应,随AM处理浓度的增大细胞增殖率提高;但当AM浓度增加到30和60μM时,细胞生存能力显著降低(P<0.01)。结果表明,低浓度的AM对细胞增殖有促进作用,高浓度的AM对细胞有抑制和损伤作用。因此,在后续的实验条件下,AM浓度选择为15μM。
2.2AM能够缓解缺氧引起的H9C2细胞损伤:
4个处理组的细胞孵育24h后的显微镜观察结果如图2所示。由图2可以看出:缺氧处理24h后,H9C2细胞的形态发生了变化,即细胞萎缩,结构受损,细胞体积减小。而在缺氧+AM处理组中,上述形态变化不明显,说明AM对缺氧诱导的H9C2细胞具有保护作用。
2.3AM能够调节缺氧诱导的细胞周期变化:
如图3A和B所示,缺氧处理24h后,G0/G1期细胞数量显著增加(P<0.01,与对照组比较),S期细胞数量显著减少(P<0.05,与对照组比较)。AM(15μM)与缺氧共同处理可以显著减少G0/G1期的细胞数量(P<0.05)。与对照组相比,单独使用AM(15μM)可减少G0/G1期细胞数(P<0.05)。
如图3C、D所示,缺氧处理降低了PCNA蛋白水平(P<0.01,与对照组比较)。经AM(15μM)干预后,PCNA蛋白水平较缺氧组升高(P<0.01)。与对照组相比,单用AM处理可提高PCNA蛋白水平(P<0.05)。
这一结果表明AM通过调节细胞周期来抑制缺氧诱导的细胞损伤。
2.4AM降低了缺氧诱导的凋亡细胞的数量:
流式细胞仪结果如图4A和B所示。从图中可以看出,缺氧诱导的细胞凋亡率增加(P<0.01,与对照组比较),AM(15μM)干预后显著降低了细胞凋亡率(P<0.01,与缺氧处理组比较)。与此同时,在图4C和图D的免疫荧光结果中,缺氧处理后TUNEL阳性细胞比例显著增加(P<0.01,与对照组比较),AM(15μM)干预后降低了TUNEL阳性细胞比例(P<0.01,与缺氧处理组比较)。这一结果表明AM降低了缺氧诱导的凋亡细胞的数量。
2.5AM降低了缺氧诱导的细胞凋亡蛋白的表达水平:
通过检测细胞凋亡蛋白,进一步研究AM对缺氧诱导的H9C2细胞凋亡的影响,结果如图5所示,缺氧处理24小时后,Bax和Cleaved caspase3蛋白水平升高,Bcl2蛋白水平降低(P<0.01,与对照组相比)。AM(15μM)干预后,Bax和Cleaved caspase3蛋白水平降低,Bcl2蛋白水平升高(P<0.01,与缺氧处理组比较),说明AM通过调控凋亡蛋白表达抑制了缺氧诱导的细胞凋亡。
2.6AM降低了缺氧诱导的活性氧的产生:
缺氧是一种氧化应激反应,刺激ROS的产生。如图6所示,缺氧处理24小时后,流量峰右移,表明产生了大量ROS(P<0.01,与对照组相比),ROS水平升高。AM(15μM)干预后,ROS水平下降(P<0.01,与缺氧处理组比较)。这一结果表明AM降低了缺氧诱导的ROS的水平。
2.7AM拮抗缺氧引起的MMP损失:
线粒体膜电位(MMP)是反映线粒体功能的重要指标。如图7所示,缺氧处理24h后,MMP显著降低(P<0.01,与对照组比较)。AM(15μM)干预后,能够拮抗缺氧引起的MMP降低,使其上升(P<0.01,与缺氧处理组比较),这表明AM可以对抗缺氧诱导MMP的损失。
2.8AM对线粒体功能蛋白的影响:
Western blotting检测线粒体相关蛋白的表达。如图8所示,缺氧处理24h后,DRP1的表达显著升高(P<0.01,与对照组相比),而OPA1、MFN1、MFN2和Tom20的表达显著降低(P<0.01,与对照组相比)。AM(15μM)干预后,显著抑制了缺氧诱导的OPA1、MFN1、MFN2和Tom20蛋白水平的降低(P<0.01,与缺氧处理组比较),降低了DRP1蛋白水平(P<0.01,与缺氧处理组比较)。此外,单独使用AM(15μM)处理后,OPA1、MFN2和Tom20蛋白水平升高(P<0.01)。这些结果表明AM可以通过调节线粒体功能蛋白来显著改善线粒体功能。
以上所述仅为本申请的优选实施例而已,并不用于限制本申请,对于本领域的技术人员来说,本申请可以有各种更改和变化。凡在本申请的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本申请的保护范围之内。
Claims (3)
1.仙鹤草内酯作为唯一活性成分在制备治疗由缺氧引起的心肌细胞损伤的药物中的应用。
2.根据权利要求1所述的应用,其特征在于,所述心肌细胞为H9C2细胞。
3.仙鹤草内酯作为唯一活性成分在制备治疗由缺氧引起的心肌梗死的药物中的应用。
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