CN112656797A - chaetocin在制备抑制动脉粥硬化药物中的应用 - Google Patents
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Abstract
本发明提供了chaetocin在制备抑制动脉粥硬化药物中的应用,更具体为在制备抑制血管平滑肌细胞增殖、迁移进而抑制动脉粥样硬化药物中的应用。本发明通过实验证明了chaetocin抑制VSMCs的增殖和迁移,以及可显著抑制westerndiet诱导的ApoE‑/‑小鼠动脉粥样硬化的形成,在抑制动脉粥样硬化方面具有广阔的临床应用前景。
Description
技术领域
本发明涉及生物医药技术领域,尤其涉及chaetocin在制备抑制动脉粥硬化药物中的应用。
背景技术
糖尿病是严重危害人类健康的全身性代谢疾病,糖尿病大血管病变是糖尿病患者致死、致残的主要原因,其病理表现主要为动脉粥样硬化。因此阐明糖尿病动脉粥样硬化的致病机制意义重大。
血管平滑肌细胞(VSMCs)是主动脉中层含量最为丰富的细胞成分,在血管相关疾病如动脉粥样硬化等中都发挥重要作用。在生理状态下,VSMCs在维持主动脉的正常生理功能方面发挥重要作用。此时VSMCs呈收缩型,高表达VSMCs特异性收缩蛋白,如α-SMA、SM22α、SM-MHC和calponin等,而增殖和迁移能力有限。经典的VSMCs表型转化理论认为,当VSMCs受到外界刺激如低氧、损伤等,VSMCs可以发生表型转化,由“收缩表型”转化为“合成表型”。此时VSMCs特异性收缩蛋白的表达水平显著下调,而表现出较强的增殖和迁移能力。
Chaetocin是由毛壳素中分离的天然小分子化合物,是组蛋白甲基转移酶。chaetocin作为SUV39H1的抑制剂,可抑制组蛋白H3K9me3修饰,进而使染色质呈常染色质状态,促进基因的表达。研究发现chaetocin具有广谱抗癌作用,chaetocin可通过诱导肿瘤细胞坏死与凋亡,抑制肿瘤细胞增殖,进而发挥抑癌作用。chaetocin还可依赖于SIRT1发挥抗心肌梗死作用。然而chaetocin在动脉粥样硬化中的作用尚无研究报道。
发明内容
本发明针对现有技术的不足,提供了chaetocin在制备抑制动脉粥硬化药物中的应用。
为实现上述目的,本发明采用以下技术方案:
第一方面,本发明提供了chaetocin在制备抑制动脉粥硬化药物中的应用;该药物的主要有效成分为chaetocin,其结构式如下:
进一步地,上述药物还包括药学上可接受的载体。
进一步地,上述载体选自注射用水和冻干粉剂辅料。
第二方面,本发明提供了chaetocin在制备抑制血管平滑肌细胞增殖和迁移的药物中的应用;该药物的主要有效成分为chaetocin,其结构式如下:
第三方面,本发明提供了一种抑制动脉粥硬化的药物,该药物包括chaetocin和药学上接受的载体;该药物的主要有效成分为chaetocin,其结构式如下:
进一步地,上述载体选自注射用水和冻干粉剂辅料。
进一步地,上述药物施用后,血管平滑肌细胞的增殖和迁移能力被抑制,以及斑块稳定性增加。
进一步地,chaetocin的体内有效剂量为0.25mg/kg。
本发明采用以上技术方案,与现有技术相比,具有如下技术效果:
本发明通过实验证明了chaetocin抑制VSMCs的增殖和迁移,以及可显著抑制western diet诱导的ApoE-/-小鼠动脉粥样硬化的形成,在抑制动脉粥样硬化方面具有广阔的临床应用前景。
附图说明
图1显示了本发明一实施例中CCK-8比色法测定chaetocin作用于小鼠主动脉血管平滑肌细胞(Movas)浓度-相对增殖率结果图;
图2显示了本发明一实施例中CCK-8比色法测定chaetocin作用于Movas细胞时间-相对增殖率结果图;
图3显示了本发明一实施例中chaetocin作用于Movas细胞的EdU染色结果图;
图4显示了本发明一实施例中CCK-8比色法chaetocin作用于C57BL/6小鼠原代主动脉平滑肌细胞(PVSMCs)浓度-相对增殖率结果图;
图5显示了本发明一实施例中chaetocin作用于PVSMCs细胞的EdU染色结果图(图A)及其统计图(图B);
图6显示了本发明一实施例中chaetocin对Movas细胞迁移的影响Transwell结果图;
图7显示了本发明一实施例中chaetocin对PVSMCs细胞迁移的影响Transwell结果图;
图8显示了本发明一实施例中DMSO组(图A)和chaetocin组(图B)小鼠主动脉组织整体油红O染色图;
图9显示了本发明一实施例中chaetocin组和DMSO组小鼠小鼠主动脉组织整体油红O染色定量统计比较图;
图10显示了本发明一实施例中chaetocin组和DMSO组小鼠小鼠主动脉组织根部苏木精和伊红(H&E)染色、油红O染色、Masson染色、免疫组化染色图及其对应的统计图。
具体实施方式
本发明提供了chaetocin在制备抑制血管平滑肌细胞增殖、迁移进而抑制动脉粥样硬化药物中的应用,其中,chaetocin的结构式如下:
下面通过具体实施例和附图对本发明进行详细和具体的介绍,以使更好的理解本发明,但是下述实施例并不限制本发明范围。
实施例中方法如无特殊说明的采用常规方法,使用的试剂如无特殊说明的使用常规市售试剂或按常规方法配制的试剂。
实施例1
本实施例验证chaetocin对VSMCs(Movas细胞和PVSMCs)增殖的抑制作用,具体的操作步骤和结果如下:
(1)Movas细胞
Movas细胞饥饿24小时后,分别以0nM、50nM、100nM、150nM和200nM的chaetocin刺激Movas细胞24小时,以CCK-8试剂盒检测Movas细胞OD值。如图1所示,chaetocin可显著抑制Movas细胞增殖且呈浓度依赖性。
Movas细胞饥饿24小时后,以100nM chaetocin刺激Movas细胞24小时、48小时和72小时,以CCK-8试剂盒检测Movas细胞OD值。如图2所示,chaetocin可显著抑制Movas细胞增殖且呈时间依赖性。
Movas细胞饥饿24小时后,分别以0nM、50nM、100nM和150nM的chaetocin刺激Movas细胞24h,以EdU染色法检测Movas细胞增殖情况,以EdU阳性信号(EdU+)/Hoechst33342阳性信号(Hoechst33342+)反映细胞试剂增殖水平。如图3所示,随着chaetocin浓度增加,EdU+/Hoechst33342+逐步减少,chaetocin可显著抑制Movas细胞增殖且呈浓度依赖性。
(2)PVSMCs
PVSMCs饥饿24小时后,分别以0nM、20nM、30nM和50nM的chaetocin刺激PVSMCs 24小时,以CCK-8试剂盒检测PVSMCs OD值。如图4所示,随着chaetocin浓度增加,PVSMCs增殖被显著抑制且呈浓度依赖性。
PVSMCs饥饿24小时后,分别以0nM、20nM、30nM和50nM的chaetocin刺激PVSMCs 24小时,以EdU染色法检测PVSMCs增殖水平。如图5所示,随着chaetocin浓度增殖,EdU+/Hoechst33342+逐步减少,chaetocin可显著抑制PVSMCs增殖且呈浓度依赖性。
实施例2
本实施例验证chaetocin对VSMCs(Movas细胞和PVSMCs)迁移的抑制作用,具体的操作步骤和结果如下:
Movas细胞PVSMCs饥饿24小时后,以100nM的chaetocin或DMSO溶剂(对照组)作用细胞18小时,以Transwell法检测Movas细胞的迁移情况;PVSMCs饥饿24小时后,以30nM的chaetocin或DMSO溶剂作用细胞18小时,以Transwell法检测PVSMCs迁移情况。其中,结晶紫染色结果代表迁移至上层小室下层小室面的细胞,即实际发生迁移的细胞。如图6-7所示,与对照组相比,chaetocin刺激后的Movas细胞和PVSMCs迁移至下层小室面的细胞显著减少,chaetocin可显著抑制Movas细胞和PVSMCs迁移。
实施例3
本实施例探究chaetocin在体内抑制动脉粥样硬化,具体的操作步骤和结果如下:
ApoE-/-小鼠以标准饲料饲养8周。在8周龄时,小鼠改用westerndiet(D12079B,Research Diets,Inc.),持续20周。Apo E-/-小鼠年龄达到20周时,接受腹腔隔日注射chaetocin(0.25mg/kg)或DMSO 8周。在28周龄时,将小鼠麻醉后处死,并取组织样本作进一步研究。获取主动脉,用油红O染色法分析病变大小。
如图8和9所示,ApoE-/-小鼠经chaetocin治疗后,主动脉表面的动脉粥样硬化病变面积较对照组小鼠明显减少。
实施例4
在实施例3的基础上,本实施例证明chaetocin增加斑块稳定性,具体的操作步骤和结果如下:
形态和免疫组织化学分析:从主动脉上剖开chaetocin组或对照组的小鼠心脏后,将主动脉根部嵌入OCT化合物中,苏木精和伊红(H&E)染色分析坏死核心大小、纤维帽含量;油红O染色用于评估脂质的积累;Masson's Trichrome染色用于计算胶原蛋白含量;免疫组化染色用鼠F4/80、TER-119。
如图10所示,chaetocin治疗后主动脉纤维帽厚度增加,坏死核心区减少,脂质积累减少;Masson Trichrome染色法比较了chaetocin组与DMSO组ApoE-/-小鼠主动脉根部的胶原蛋白组成;在chaetocin处理的小鼠中观察到主动脉根部的胶原蛋白增加;F4/80染色评估巨噬细胞浸润减少;TER119染色评估瓣膜内出血减少。
以上对本发明的具体实施例进行了详细描述,但其只是作为范例,本发明并不限制于以上描述的具体实施例。对于本领域技术人员而言,任何对本发明进行的等同修改和替代也都在本发明的范畴之中。因此,在不脱离本发明的精神和范围下所作的均等变换和修改,都应涵盖在本发明的范围内。
Claims (8)
2.根据权利要求1所述的应用,其特征在于,所述药物还包括药学上可接受的载体。
3.根据权利要求2所述的应用,其特征在于,所述载体选自注射用水和冻干粉剂辅料。
6.根据权利要求5所述的药物,其特征在于,所述载体选自注射用水和冻干粉剂辅料。
7.根据权利要求5所述的药物,其特征在于,所述药物施用后,血管平滑肌细胞的增殖和迁移能力被抑制,以及斑块稳定性增加。
8.根据权利要求5所述的药物,其特征在于,所述chaetocin的体内有效剂量为0.25mg/kg。
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JPH09227371A (ja) * | 1996-02-23 | 1997-09-02 | Kissei Pharmaceut Co Ltd | 粥状動脈硬化抑制剤 |
CN103550222A (zh) * | 2013-11-05 | 2014-02-05 | 南京医科大学 | 毛壳素在制备预防和治疗糖尿病药物中的应用 |
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CN108143735A (zh) * | 2018-02-11 | 2018-06-12 | 中国人民解放军陆军军医大学 | 毛壳素在制备预防和治疗低氧性肺动脉高压药物中的应用 |
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JPH09227371A (ja) * | 1996-02-23 | 1997-09-02 | Kissei Pharmaceut Co Ltd | 粥状動脈硬化抑制剤 |
CN105229013A (zh) * | 2013-05-24 | 2016-01-06 | 梨花女子大学校产学协力团 | 桥二硫双氧代哌嗪化合物或它的衍生物,及其用途 |
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