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题名: 七种抗骨质疏松与抗肿瘤生物活性筛选模型的建立、活性筛选及相关机制研究
作者: 曾广智
学位类别: 博士
答辩日期: 2007-01-24
授予单位: 中国科学院昆明植物研究所
授予地点: 昆明植物研究所
导师: 谭宁华
关键词: 骨质疏松 ; 肿瘤 ; 体外筛选模型 ; 天然抑制剂 ; 作用机制
学位专业: 植物学
中文摘要: 本论文包含以下内容:(1)破骨细胞是调节骨吸收、导致骨质疏松症形成的关键因素。针对其中的三个关键蛋白——整合素V3、组织蛋白酶K及基质金属蛋白酶9,我们建立了相应的体外活性筛选模型并开展了6254个/次样品的批量筛选工作,发现了9个活性化合物及87个活性提取物。活性化合物均为相应蛋白的新型天然抑制剂。(2)组织蛋白酶B能够促进肿瘤细胞的迁徙转移,Cdc25蛋白能促进肿瘤细胞的增殖,I型纤溶酶原激活剂抑制剂能够抑制血栓的溶解,I型蛋白磷酸酶对多种细胞功能具有调节作用。针对这四个蛋白,我们从Bayer公司引建了相应的靶标筛选模型,进行了9738个/次样品批量筛选。分别发现了17个和292个对酶有抑制活性的化合物及提取物。(3)通过多底物活性筛选、酶动力学测定及分子对接等方法,我们发现6个双黄酮抑制剂Amentoflavone及其衍生物对组织蛋白酶B的内切酶活性具有选择性抑制作用,它们可能对肿瘤迁徙转移过程中组织蛋白酶B的活性异常具有治疗作用。通过显微成像、流式细胞术等方法,我们首次报道了倍半萜类化合物Bigelovin及6-Deoxymexicanin在体外对人白血病细胞株U937的细胞凋亡过程具有一定的诱导作用。(4)针对破骨细胞及成骨细胞,对目前骨质疏松症治疗中的治疗靶点及其药物作了详细综述。
英文摘要: This dissertation included four parts: (1) Osteoclast is the pivotal cell that mediates bone resorption and leads to osteoporosis. Integrin V3, cathepsin K (CatK) and matrix metalloproteinase 9 (MMP-9) are the key regulators in osteoclast-mediated bone resorption. In order to find natural inhibitors of these three enzymes, we performed their inhibition assays in vitro, and screened 6254 samples. Results indicated that 9 compounds and 87 extracts exhibited inhibitory activities against these three enzymes, in which these 9 compounds are novel natural inhibitors for them. (2) Cathepsin B is a protein which can promote tumor invasion and metastasis by degradation of extracellular matrix and basement membrane. Cdc25 is the protein that plays an important role in tumor proliferation. Plasminogen activator inhibitor 1 is the physiological regulator that inhibits the process of fibrinolysis. Type I protein phosphatase is a major eukaryotic protein that regulates an enormous variety of cellular functions. In order to find natural inhibitors of these four enzymes, we performed their inhibition assays in vitro based on the methods transferred from Bayer AG (Germany). 9738 samples were screened, and 17 compounds and 292 extracts were found with inhibitory activities against these four enzymes. (3) Inhibitory, kinetic and docking research results indicated that six inhibitors of cathepsin B, amentoflavone and its derivatives, are more specific to CatB endopeptidase, which makes them may be more potential in pathological state like tumor progression. Furthermore, by the results from micrography and cytoflow research, we first reported that anti-tumor bigelovin and 6-deoxymexicanin could induce apoptosis of cancer cell line U937. (4) Based on the research about osteoclast and osteoblast, its targets and related agents in osteoporosis therapy were summarized.
语种: 中文
内容类型: 学位论文
URI标识: http://ir.kib.ac.cn/handle/151853/292
Appears in Collections:昆明植物所硕博研究生毕业学位论文_学位论文

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Recommended Citation:
七种抗骨质疏松与抗肿瘤生物活性筛选模型的建立、活性筛选及相关机制研究.曾广智[d].中国科学院昆明植物研究所,2007.20-25
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