皂荚抗心肌缺血活性成分筛选及机理研究
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摘要
本课题根据中医理论对心肌缺血及心绞痛病因病机的认识,基于已有研究基础,以传统中药皂荚为研究对象,采用现代药理学、植物化学及分子生物学研究方法,深入探讨皂荚抗心肌缺血物质基础、活性成分的生物利用度及其作用机理。结果表明:
1.皂荚总皂苷具有抗心肌缺血作用,其水解产物皂荚总皂苷元具有更强的药理活性,结合肠道菌群代谢理论及血清药理学相关研究提示皂荚总皂苷元为皂荚总皂苷体内抗心肌缺血的主要活性部位。
2.皂荚总皂苷元主要由刺囊酸及齐墩果酸组成,二者经静脉注射给药均能产生良好的抗心肌缺血作用,且强度相当。提示皂荚抗心肌缺血的物质基础为刺囊酸及齐墩果酸。
3.建立高效液相测定血浆样品中刺囊酸含量的方法,该方法稳定可行,操作简便,线性范围宽,定量限达到46ng/ml,满足生物利用度研究需要。
4.采用CaCo-2细胞模型及大鼠体内生物利用度研究方法比较了刺囊酸及刺囊酸钠盐的生物利用度,结果显示,刺囊酸钠盐生物利用度明显高于刺囊酸。
5.在整体动物、细胞、基因水平对刺囊酸抗心肌缺血作用进行研究,结果表明刺囊酸抗心肌缺血作用与增强心肌耐缺氧能力、保护心肌细胞、抗氧化及抑制心肌细胞凋亡有关。
综上,本论文深入阐明了皂荚抗心肌缺血的有效成分,并对刺囊酸的生物利用度及作用机理进行探索性研究,为中药皂荚在心肌缺血治疗专面提供了重要的实验依据,也为皂荚的开发利用及临床应用提供了重要参考。
Gleditsia sinensis Lam.was extensively used in the clinical practices of Traditional Chinese Medicine.Its anti-myocardial ischemia effects and the mechanisms were studied by the phytochemical, pharmacological and the molecular methods in the thesis,according to clinical experiences and the Tradional Chinese Medicial theories.The results showed as:
Firstly,the Gleditschia saponin had the anti-myocardial ischemia effects,which was not as good as that of the Gleditschia sapogenin.The result suggested that the Gleditschia sapogenin was the mainly active fraction of the Gleditschia saponin in vivo,according to theories of intestinal flora metabolism and serum pharmacological study.
Secondly,the Gleditschia sapogenin mainly include the echinocystic acid(EA) and the oleanolic acid(OA),both of which had the similar anti-myocardial ischemia activity.It was the first time that the EA and the OA were reported as the main components with anti-myocardial ischemia activity of Gleditsia sinensis Lam.
Thirdly,a high performance liquid chromatographic method had been established to study the bioavailability of the EA.The quantitative limitation,linearity and repeatability of the method were satisfactory.
Fourthly,the CaCo-2 cell model and the rat pharmacokinetic model were employed to compare the bioavailability of the EA and its sodium salt. The resuts revealed that the sodium salt of EA had the better bioavailability than EA.
Fifthly,the anti-myocardial ischemia mechanisms of EA were investigated at the animal,cell,and gene levels respectively.The results showed that the mechanisms were related with improving resistance to anoxia,protecting myocardial cell,antioxygen activity and inhibiting myocardial apoptosis.
To sum up,the study revealed the effects of Gleditsia sinensis Lam. on myocardial ischemia,also explored the bioavailability and mechanisms of the main active component(EA) of Gleditsia sinensis Lam.profoundly, which provided the experimental basis for the development and the clinlc use of Gleditsia sinensis Lam..
1.皂荚总皂苷具有抗心肌缺血作用,其水解产物皂荚总皂苷元具有更强的药理活性,结合肠道菌群代谢理论及血清药理学相关研究提示皂荚总皂苷元为皂荚总皂苷体内抗心肌缺血的主要活性部位。
2.皂荚总皂苷元主要由刺囊酸及齐墩果酸组成,二者经静脉注射给药均能产生良好的抗心肌缺血作用,且强度相当。提示皂荚抗心肌缺血的物质基础为刺囊酸及齐墩果酸。
3.建立高效液相测定血浆样品中刺囊酸含量的方法,该方法稳定可行,操作简便,线性范围宽,定量限达到46ng/ml,满足生物利用度研究需要。
4.采用CaCo-2细胞模型及大鼠体内生物利用度研究方法比较了刺囊酸及刺囊酸钠盐的生物利用度,结果显示,刺囊酸钠盐生物利用度明显高于刺囊酸。
5.在整体动物、细胞、基因水平对刺囊酸抗心肌缺血作用进行研究,结果表明刺囊酸抗心肌缺血作用与增强心肌耐缺氧能力、保护心肌细胞、抗氧化及抑制心肌细胞凋亡有关。
综上,本论文深入阐明了皂荚抗心肌缺血的有效成分,并对刺囊酸的生物利用度及作用机理进行探索性研究,为中药皂荚在心肌缺血治疗专面提供了重要的实验依据,也为皂荚的开发利用及临床应用提供了重要参考。
Gleditsia sinensis Lam.was extensively used in the clinical practices of Traditional Chinese Medicine.Its anti-myocardial ischemia effects and the mechanisms were studied by the phytochemical, pharmacological and the molecular methods in the thesis,according to clinical experiences and the Tradional Chinese Medicial theories.The results showed as:
Firstly,the Gleditschia saponin had the anti-myocardial ischemia effects,which was not as good as that of the Gleditschia sapogenin.The result suggested that the Gleditschia sapogenin was the mainly active fraction of the Gleditschia saponin in vivo,according to theories of intestinal flora metabolism and serum pharmacological study.
Secondly,the Gleditschia sapogenin mainly include the echinocystic acid(EA) and the oleanolic acid(OA),both of which had the similar anti-myocardial ischemia activity.It was the first time that the EA and the OA were reported as the main components with anti-myocardial ischemia activity of Gleditsia sinensis Lam.
Thirdly,a high performance liquid chromatographic method had been established to study the bioavailability of the EA.The quantitative limitation,linearity and repeatability of the method were satisfactory.
Fourthly,the CaCo-2 cell model and the rat pharmacokinetic model were employed to compare the bioavailability of the EA and its sodium salt. The resuts revealed that the sodium salt of EA had the better bioavailability than EA.
Fifthly,the anti-myocardial ischemia mechanisms of EA were investigated at the animal,cell,and gene levels respectively.The results showed that the mechanisms were related with improving resistance to anoxia,protecting myocardial cell,antioxygen activity and inhibiting myocardial apoptosis.
To sum up,the study revealed the effects of Gleditsia sinensis Lam. on myocardial ischemia,also explored the bioavailability and mechanisms of the main active component(EA) of Gleditsia sinensis Lam.profoundly, which provided the experimental basis for the development and the clinlc use of Gleditsia sinensis Lam..
引文
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