课题基金基金详情
基于p38MAPK及ERK2通路研究蛭芎胶囊治疗动脉粥样硬化斑块的药效成分与药理机制
结题报告
批准号:
81903930
项目类别:
青年科学基金项目
资助金额:
20.0 万元
负责人:
翟健秀
依托单位:
学科分类:
H3219.中药学研究新技术与新方法
结题年份:
2022
批准年份:
2019
项目状态:
已结题
项目参与者:
--
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中文摘要
蛭芎胶囊(ZXC)临床上用于治疗眩晕及头痛,近期发现有患者服用该药后颈部动脉粥样硬化(AS)斑块减小。前期实验发现ZXC可显著预防兔颈动脉内形成AS斑块,上述作用与ERK2及p38MAPK通路相关。考虑到临床通常在AS斑块形成后进行治疗,以预实验初步证明ZXC能够降低已形成AS斑块的覆盖面积,并拟在本研究中使用大鼠体内AS模型系统考察ZXC对已形成AS斑块的药理作用;同时,通过UPLC-QTOF-MS法检测ZXC的入血成分,基于入血成分以网络药理学技术预测ZXC的关键药效成分及作用靶点,并分析各靶点与上述信号通路的关联;最后以生物分析技术检测体内药效实验中所得大鼠动脉组织,对预测靶点进行验证。通过上述工作,可明确ZXC能否用于治疗已形成AS斑块,并初步揭示其药效物质基础及药理机制,为增加ZXC的适应症提供数据支持,并填补目前对临床对AS治疗的用药空白。
英文摘要
Chinese patent medicine Zhixiong Capsule is widely applied in clinic to treat dizziness and headache. Recently, clinical observations indicated that ZXC may reduce the size of atherosclerosis (AS) plaque in patients. Results from previous experiments showed that ZXC could significantly prevent the formation of AS plaque while administrated during model establishment. Further mechanism investigations indicated that ZXC could inhibit AS plaque formation by blocking ERK2 and p38MAPK signaling pathways. Considering that treatment against AS plaque were usually applied after plaque formation, an preliminary experiment has been performed, and it was found that ZXC significantly reduced the formed AS plaque in rats. In this project, the the pharmacodynamics effects of ZXC against formed AS plaque will be further investigated using an established rat model. Meanwhile, the blood-dissolving components of ZXC will be determined by an UPLC-QTOF-MS method. Then, blood-dissolving components-based network pharmacology method will be applied to analysis the key components and targets of ZXC in the treatment against formed AS plaque. Also, the targets would be further analyzed to find their relationships with ERK2 and p38MAPK signaling pathways. Finally, the attended targets will be verified by biological analysis techniques to give a comprehensive understanding of the involved pharmacological mechanisms. By accomplishing the above works, this project is expected to find out the effects of ZXC on formed AS plaques, to illustrate the effective components and pharmacological mechanisms of ZXC, which can provide data support for extending the clinical application of ZXC, and may response to the urgent need for AS plaque- scanvenging drug in clinic treatments.
动脉粥样硬化(AS)斑块的形成、发展是众多心脑血管疾病的基础,患者可能产生心绞痛、肢体麻木等症状,甚至发生心肌梗死、脑卒中等急重症,生命安全受到严重威胁。蛭芎胶囊(ZXC)临床上用于治疗眩晕及头痛,通过前期实验,发现ZXC可显著预防兔颈动脉内AS斑块的形成。本研究进一步考察了ZXC对已形成AS斑块的治疗效果及药理机制,并有以下主要发现:(1)ZXC对大鼠胸主动脉中已形成斑块确有治疗效果:低、高剂量(相当于临床剂量、二倍临床剂量)的ZXC给药可使AS斑块覆盖率分别降低为11.3%和5.3% (p<0.01),且显著改善了血管组织中胶原沉积和斑块矿化程度、降低大鼠血脂水平;(2)初步阐释了ZXC治疗AS斑块的潜在关键成分及关键靶标:基于入血成分进行网络药理学分析,发现水蛭及部分黄酮类化合物可能为疗效的关键成分,MAPK1、MAPK14、PTGS2和c -jun可能为关键靶标,IL-4和IL-13信号传导通路为关键干涉通路;(3)对上述靶标进行了验证:AS模型组大鼠胸动脉中IL-4和IL-13含量明显降低,而MAPK1和MAPK14含量呈升高趋势。低剂量ZXC能有效逆转上述变化,IL-4和IL-13含量较模型对照组分别增加79.3%和48.6% (p<0.05);高剂量ZXC给药使MAPK1、MAPK14和c-jun水平分别降低了44%、65.6%和47.0%。Western blot分析结果表明,模型组大鼠p53表达水平产生显著下降(-95.3%)。与模型对照组相比,低剂量ZXC给药、高剂量ZXC给药均能够使p53表达水平产生显著回复(1.9-和0.4倍);(4)ZXC中所含水蛭、川芎嗪及部分黄酮类成分可有效延缓巨噬细胞泡沫化进程:以染料木苷、异鼠李素以及槲皮素降低胆固醇酯(CE)的作用最为显著(p<0.001,与模型组相比分别降低44.47%、40.55%以及50.34%);君药成分中川芎嗪、水蛭乙醇提取物(LAEE)以及水蛭50%乙醇提取物(LEE)都能不同程度降低细胞内CE含量,以LEE组对CE的降低作用最为显著(p<0.01,降低28.28%)。.通过上述实验结果,本研究证明了ZXC确能有效治疗已形成AS斑块,并初步明确了其药效物质基础及可能涉及的药理机制,对于扩大ZXC适应症、为AS斑块治疗提供备选有效药物提供了重要理论及数据支持。
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DOI:10.1016/j.jep.2019.112523
发表时间:2020-05-23
期刊:JOURNAL OF ETHNOPHARMACOLOGY
影响因子:5.4
作者:Zhai,Jianxiu;Ren,Zhaohui;Yin,Jun
通讯作者:Yin,Jun
国内基金
海外基金