中药复方双龙方作用机理的系统生物学研究
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摘要
本文采用整合化学物质组学的系统生物学研究模式对中药复方双龙方进行了研究,旨在系统地探寻双龙方的作用机理和药效分子基础,并为其他中药复方的相关研究提供参考。
本研究首先通过大鼠骨髓间充质干细胞分化模型,采用免疫荧光技术鉴定心肌特异蛋白,鉴定及评价双龙方对骨髓间充质干细胞向心肌样细胞分化的作用效果,然后应用比较蛋白质组学的研究平台分析双龙方诱导分化过程中的差异蛋白表达,成功鉴定了13个差异表达蛋白。其中eEF2、Hspa8蛋白、Nme2、PKM2及Sl00A11等蛋白在双龙方诱导干细胞分化中具有重要作用,可能通过调节PI3K信号通路、MAPK信号通路及钙离子通路等途径参与干细胞的定向分化。
其次,采用心肌细胞缺氧复氧模型,运用MTT染色法考察双龙方对心肌细胞缺氧复氧损伤的保护作用。然后利用HPLC-MS技术,对实验组细胞破碎液进行分析,筛选及鉴定双龙方中可进入心肌细胞的活性成分。MTT染色法测定结果显示,模型组细胞存活率只有8%,而双龙方干预后细胞达70%,说明双龙方干预可以有效抵抗心肌缺氧复氧损伤。经HPLC-MS分析,进入细胞活性成分主要有Re、Rg1、Rf、Rb,及Rd,均具有显著抗氧化作用,并且主要通过调节钙离子通道来起作用。
再次,采用冠脉结扎致心肌梗死模型,利用基因芯片技术,寻找双龙方干预治疗心肌梗死模型大鼠的过程中差异表达基因,研究其基因水平作用机制。研究发现,双龙方干预组与模型组大鼠的差异基因表达主要与MAPK信号通路和碱基切除修复过程相关,双龙方可能通过调节MAPK通路和碱基切除修复过程起到减轻心肌损伤,保护心脏功能的作用。
最后,利用冠脉结扎致心肌梗死模型,运用已建立的比较基因组学研究平台,研究不同中药复方治疗心肌缺血作用的机理。双龙方、麝香保心丸及丹红注射液对冠心病等心脏病均具有很好的疗效,利用基因芯片技术研究其在治疗心肌梗死过程中的基因表达谱变化,筛选共同差异表达的基因,研究最终筛查出了Cfb、Nfil3、Arntl和Nppa等9个基因,其可能是治疗心肌梗死中药共同的靶基因,为后续深入研究提供了重要线索。
This paper studied Shuanglong Formula (SLF), a kind of traditional Chinese medicine, through systems biology integrated with chemomics. The aim of this paper was to systematically discuss the mechanism and pharmacodynamic molecular basis of SLF, and to offer the reference of technology for related investigation of other TCM formula.
First of all, on the rat bone marrow mesenchymal stem cells (MSCs) differentiation model, the cardiac-specific proteins were identified using immunofluorescence staining method to evaluate the effects of SLF on MSCs differentiation. And then differentially expressed proteins were screened during the process of MSCs differentiation induced by SLF. Finally, 13 differentially expressed proteins were successfully identified. During the process of MSCs differentiation, eEf-2, Hspa8, Nme2、PKM2 and S100A11 protein played an important role. They might direct MSCs differentiation through regulated PI3K signaling pathway, MAPK signaling pathway and calcium ion channels.
Secondly, a hypoxia/reoxygenation (H/R) myocardium model was established. The protective effect of SLF against H/R injury was investigated in this model using MTT method. Then the active ingredients, which existed inside cells, were screened and determined using HPLC-MS. The MTT staining results showed that SLF can improve cell survival up to 62%. It illustrated that SLF was effective in protecting cultured cardiomyocytes against H/R injury. The active ingredients mainly included Re, Rg1, Rf, Rb1 and Rd, all which had significant antioxidant to achieve by adjusting the calcium ion channel.
Thirdly, the rat model of myocardial infarction induced by ligation of coronary artery was established. After treatment by SLF, differential expressed genes were screened by cDNA microarray to investigate the molecular mechanism of SLF. The results showed that differential expressed gene mainly related MAPK pathway and the basic excision repair between the SLF group and the model group. So, SLF may regulate MAPK pathway and the basic excision repair process to achieve the effect of reducing myocardial injury and protecting cardiac function。
Finally, using the rat model of myocardial infarction and cDNA microarray technology, the mechanism of several kinds TCM was investigated. SLF, heart-protecting musk pill and Danhong injection all have effect on treatment myocardial infarction. The gene expression changes were observed and differentially expressed genes were screened from the chip data combined with all group. The results showed that 9 genes had very important roles, such as Cfb, Nfil3, Arntl, Nppa and so on. They may be the common target genes of TCM treatment of myocardial infarction and provided important clues for future research.
本研究首先通过大鼠骨髓间充质干细胞分化模型,采用免疫荧光技术鉴定心肌特异蛋白,鉴定及评价双龙方对骨髓间充质干细胞向心肌样细胞分化的作用效果,然后应用比较蛋白质组学的研究平台分析双龙方诱导分化过程中的差异蛋白表达,成功鉴定了13个差异表达蛋白。其中eEF2、Hspa8蛋白、Nme2、PKM2及Sl00A11等蛋白在双龙方诱导干细胞分化中具有重要作用,可能通过调节PI3K信号通路、MAPK信号通路及钙离子通路等途径参与干细胞的定向分化。
其次,采用心肌细胞缺氧复氧模型,运用MTT染色法考察双龙方对心肌细胞缺氧复氧损伤的保护作用。然后利用HPLC-MS技术,对实验组细胞破碎液进行分析,筛选及鉴定双龙方中可进入心肌细胞的活性成分。MTT染色法测定结果显示,模型组细胞存活率只有8%,而双龙方干预后细胞达70%,说明双龙方干预可以有效抵抗心肌缺氧复氧损伤。经HPLC-MS分析,进入细胞活性成分主要有Re、Rg1、Rf、Rb,及Rd,均具有显著抗氧化作用,并且主要通过调节钙离子通道来起作用。
再次,采用冠脉结扎致心肌梗死模型,利用基因芯片技术,寻找双龙方干预治疗心肌梗死模型大鼠的过程中差异表达基因,研究其基因水平作用机制。研究发现,双龙方干预组与模型组大鼠的差异基因表达主要与MAPK信号通路和碱基切除修复过程相关,双龙方可能通过调节MAPK通路和碱基切除修复过程起到减轻心肌损伤,保护心脏功能的作用。
最后,利用冠脉结扎致心肌梗死模型,运用已建立的比较基因组学研究平台,研究不同中药复方治疗心肌缺血作用的机理。双龙方、麝香保心丸及丹红注射液对冠心病等心脏病均具有很好的疗效,利用基因芯片技术研究其在治疗心肌梗死过程中的基因表达谱变化,筛选共同差异表达的基因,研究最终筛查出了Cfb、Nfil3、Arntl和Nppa等9个基因,其可能是治疗心肌梗死中药共同的靶基因,为后续深入研究提供了重要线索。
This paper studied Shuanglong Formula (SLF), a kind of traditional Chinese medicine, through systems biology integrated with chemomics. The aim of this paper was to systematically discuss the mechanism and pharmacodynamic molecular basis of SLF, and to offer the reference of technology for related investigation of other TCM formula.
First of all, on the rat bone marrow mesenchymal stem cells (MSCs) differentiation model, the cardiac-specific proteins were identified using immunofluorescence staining method to evaluate the effects of SLF on MSCs differentiation. And then differentially expressed proteins were screened during the process of MSCs differentiation induced by SLF. Finally, 13 differentially expressed proteins were successfully identified. During the process of MSCs differentiation, eEf-2, Hspa8, Nme2、PKM2 and S100A11 protein played an important role. They might direct MSCs differentiation through regulated PI3K signaling pathway, MAPK signaling pathway and calcium ion channels.
Secondly, a hypoxia/reoxygenation (H/R) myocardium model was established. The protective effect of SLF against H/R injury was investigated in this model using MTT method. Then the active ingredients, which existed inside cells, were screened and determined using HPLC-MS. The MTT staining results showed that SLF can improve cell survival up to 62%. It illustrated that SLF was effective in protecting cultured cardiomyocytes against H/R injury. The active ingredients mainly included Re, Rg1, Rf, Rb1 and Rd, all which had significant antioxidant to achieve by adjusting the calcium ion channel.
Thirdly, the rat model of myocardial infarction induced by ligation of coronary artery was established. After treatment by SLF, differential expressed genes were screened by cDNA microarray to investigate the molecular mechanism of SLF. The results showed that differential expressed gene mainly related MAPK pathway and the basic excision repair between the SLF group and the model group. So, SLF may regulate MAPK pathway and the basic excision repair process to achieve the effect of reducing myocardial injury and protecting cardiac function。
Finally, using the rat model of myocardial infarction and cDNA microarray technology, the mechanism of several kinds TCM was investigated. SLF, heart-protecting musk pill and Danhong injection all have effect on treatment myocardial infarction. The gene expression changes were observed and differentially expressed genes were screened from the chip data combined with all group. The results showed that 9 genes had very important roles, such as Cfb, Nfil3, Arntl, Nppa and so on. They may be the common target genes of TCM treatment of myocardial infarction and provided important clues for future research.
引文
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