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首页> 外文学位 >In vitro and in vivo Mechanistic Studies of the Wound-healing Effects of Astragali Radix and Phytochemical Analysis of Its Active Fractions/Components Isolated Using Bioassay-guided Fractionation.
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In vitro and in vivo Mechanistic Studies of the Wound-healing Effects of Astragali Radix and Phytochemical Analysis of Its Active Fractions/Components Isolated Using Bioassay-guided Fractionation.

机译：黄芪的伤口愈合作用的体外和体内机制研究以及使用生物测定引导的分馏方法分离的其有效成分/成分的植物化学分析。

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摘要

Wound healing process is typically divided into three sequential but overlapping phases, namely inflammation, proliferation, and remodeling. Chronic wounds fail to proceed through an orderly and timely healing process, and hence cannot be recovered due to the underlying pathology. They may lead to ulceration such as diabetic foot ulcers. In our recent study, a simplified diabetic foot ulcer herbal formula NF3 was shown to enhance diabetic wound healing in rats, and Astragali Radix (AR) was demonstrated as the principal herb in NF3. Therefore, the wound healing effects of AR would be further investigated in this study.;We aimed to (1) isolate the AR major active fraction(s) or pure compound(s) which were responsible for the three wound healing related mechanism of actions (antiinflammation, angiogenesis and fibroblast proliferation) by bioassay-guided fractionation; (2) further investigate their underlying mechanisms using different in vitro and in vivo models; (3) identify their chemical constituent(s); (4) investigate their in vivo wound healing effects; and (5) examine their oral bioavailability in in vitro model.;Several AR major active fractions including anti-inflammatory active fractions (P2-3-2-2-2 and P2-3-2-2-3), angiogenic active fraction (P1-1-1) and fibroblast proliferative active fraction (P2-2-3), had been successfully isolated.;Thirteen known AR compounds including five flavonoids and eight triterpenoid saponins were found in P2-3-2-2-2 and P2-3-2-2-3. Formononetin and ononin were the active components which partially contributed to its anti-inflammatory activity due to their mild effects and minute amounts (less than 5 %). MAF (combined fraction of P2-3- 2-2-2 and P2-3-2-2-3) was shown to display anti-inflammatory effects by reducing the release of inflammatory mediators and inactivation of NFeB through MAPK signalling pathway.;P1-1-1 was identified to consist of glycoprotein. It stimulated angiogenesis in zebrafish embryos via up-regulating expression of VEGF and its tyrosine kinase receptors, and proliferation of endothelial cells (HMEC-1) by increasing cell viability, DNA synthesis and the S phase population.;P2-2-3 was found to have trace of adenine, adenosine and guanosine (0.1 %) which were shown to have no proliferative activities. The proliferative property of P2-2-3 was further verified by the increase in cellular DNA synthesis and S phase population in cell cycle analysis.;To investigate their wound healing effects in diabetic foot ulcer rat model, the AR combined fraction which should consist of the three major active fractions (MAF, P1-1- 1 and P2-2-3 in 1:1:1 ratio) was replaced by their corresponding mother active fractions (P2-3, P1-1 and P2-2) due to their low extraction yields. Unfortunately, the AR combined fraction was found to have no significant promoting effect in wound healing when compared with that of the control group.;The oral bioavailability of the three major active fractions were investigated in in vitro Caco-2 model. Among them, only MAF was proved to display in vivo biological activity due to the presence of its absorbable active components (formononetin and ononin).;In conclusion, we had successfully isolated several major AR active fractions which exhibited anti-inflammatory, angiogenic and proliferative properties, by bioassayguided fractionation. The anti-inflammatory active fractions could contribute greatly to the overall wound healing effects when compared with the other two fractions due to their confirmed in vivo biological effects. The wound healing effects of the major active fractions which were combined in different ratios, would be further investigated in the future.
机译：伤口愈合过程通常分为三个连续但重叠的阶段，即炎症，增殖和重塑。慢性伤口无法通过有序及时的愈合过程进行，因此由于潜在的病理原因而无法恢复。它们可能导致溃疡，例如糖尿病性足溃疡。在我们最近的研究中，简化的糖尿病足溃疡草药配方NF3被证明可以增强大鼠的糖尿病伤口愈合，而黄芪（AR）被证明是NF3中的主要草药。因此，本研究将进一步研究AR的伤口愈合作用。；我们的目的是（1）分离引起三种伤口愈合相关作用机理的AR主要活性成分或纯化合物。通过生物测定指导的分级分离（抗炎，血管生成和成纤维细胞增殖）； （2）使用不同的体内和体外模型进一步研究其潜在机制； （3）确定其化学成分； （4）研究其体内伤口愈合作用； （5）在体外模型中检查它们的口服生物利用度。几个AR主要活性成分包括抗炎活性成分（P2-3-2-2-2和P2-3-2-2-3），血管生成活性成分（P1-1-1）和成纤维细胞增殖活性级分（P2-2-3）已被成功分离。;在P2-3-2-2-2和P2-3-2中发现了13种已知的AR化合物，包括5种类黄酮和8种三萜类皂苷。 P2-3-2-2-3。 Formononetin和ononin是活性成分，由于其温和的作用和微量的作用（少于5％），部分有助于其抗炎活性。 MAF（P2-3-2-2-2和P2-3-2-2-3的组合部分）显示出通过减少炎症介质的释放和通过MAPK信号通路使NFeB失活而显示出抗炎作用。鉴定出P1-1-1由糖蛋白组成。它通过上调VEGF及其酪氨酸激酶受体的表达，并通过增加细胞活力，DNA合成和S期种群来刺激内皮细胞（HMEC-1）的增殖，从而刺激斑马鱼胚胎中的血管生成。; P2-2-3具有痕量的腺嘌呤，腺苷和鸟苷（0.1％），被证明没有增殖活性。在细胞周期分析中，通过细胞DNA合成的增加和S期群体的增加，进一步证实了P2-2-3的增殖特性。为了研究其在糖尿病足溃疡大鼠模型中的伤口愈合作用，AR结合部分应包括：三种主要活性成分（MAF，P1-1-1和P2-2-3以1：1：1的比例）被其相应的母体活性成分（P2-3，P1-1和P2-2）取代，原因是它们的提取率低。不幸的是，与对照组相比，发现AR结合部分对伤口愈合没有明显的促进作用。；在体外Caco-2模型中研究了三种主要活性部分的口服生物利用度。其中，仅MAF被证明具有可吸收的活性成分（甲羟吗啡酮和ononin），因此具有体内生物活性。结论：我们成功地分离出了几种主要的AR活性成分，这些成分具有抗炎，血管生成和增殖作用通过生物分析引导分级分离与其他两个组分相比，抗炎活性组分由于其已证实的体内生物学作用，可对整体伤口愈合效果做出很大贡献。未来将进一步研究以不同比例组合的主要活性成分的伤口愈合效果。

著录项

  • 作者

    Lai, Kwok Kin.;

  • 作者单位

    The Chinese University of Hong Kong (Hong Kong).;

  • 授予单位 The Chinese University of Hong Kong (Hong Kong).;
  • 学科 Health Sciences Pharmacology.;Chemistry Analytical.;Health Sciences Alternative Medicine.
  • 学位 Ph.D.
  • 年度 2013
  • 页码 279 p.
  • 总页数 279
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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