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活性双过氧钒化合物的生物活性研究
时间:2011-02-28 浏览次数:1693次 无忧论文网
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生物医学工程
钒化合物的生物评价钒化合物的生物评价
    钒是一种自然界广泛存在的微量元素,也是人体所必需的一种微量元素。近20年来,钒化合物生物活性及药理作用成为各国学者研究的热点之一,特别是在抗糖尿病、改善胰岛素抵抗等方面。近年来,钒化合物作为广谱的抗癌药物也倍受关注。本课题围绕双过氧钒化合物的生物活性开展研究,在合成表征的基础上,研究了5种双过氧钒化合物{bpV(ox),potassium bisperoxo(oxalato)oxovanadate、bpV(bipy),sodium bisperoxo(2,2’bipyridine)oxovanadate、bpV(phen),potassium bisperoxo(1,10-phenanthroline)oxovanadate、bpV(pic),potassium bisperoxo (piclinato) oxovanadate、bpv(Imi-py),ammonium bisperoxo[2-(2′-pyridyl)-imidazole] oxovanadate}对脂肪细胞糖代谢的影响和bpV(Imi-py)对肝癌的影响。
        本研究在水溶液中合成了4种典型的双过氧钒化合物bpV(ox)、bpV(bipy)、bpV(phen)和bpV(pic)和1种新型双过氧钒化合物bpV(Imi-py),并对这五种化合物进行了谱学表征;为了研究它们的模拟胰岛素活性,本研究以诱导分化成熟的脂肪细胞3T3-L1为细胞模型,用葡萄糖氧化酶法检测了5种双过氧钒化合物对葡萄糖消耗的影响;通过半定量RT-PCR分析了双过氧钒化合物对过氧化物酶体增生物激活受体(PPARγ)、抵抗素(Resistin)和葡萄糖转运蛋白-4(GLUT-4) mRNA表达的影响,通过western blot方法研究了双过氧钒化合物对GLUT-4蛋白转位的影响;为了研究双过氧钒的抗癌作用,体外实验采用MTT法、荧光染色、流式细胞仪和DNA凝胶电泳等方法检测了bpV(Imi-py)对肝癌细胞Bel-7402形态学和生化学的改变,并初步探讨了其作用机理,检测了Caspase-3、-8、-9酶的催化活性,体内实验观测了双过氧钒化合物bpV(Imi-py)对H22小鼠肿瘤模型的治疗作用。
        本研究结果表明:5种双过氧钒化合物均能不同程度地促进脂肪细胞的葡萄糖消耗,上调PPARγ和GLUT-4 mRNA的基因表达,下调Resistin基因表达,促进GLUT-4蛋白的转位。bpV(phen)和bpV(Imi-py)表现出较强的模拟胰岛素作用,优于阳性对照VOSO4。bpV(Imi-py)能诱导Bel-7402细胞凋亡,呈剂量依赖性,并上调Caspase-3、-8、-9的酶活性。体内实验显示,bpV(Imi-py)能抑制肿瘤生长,诱导肿瘤细胞凋亡。
    总之,本研究新合成的双过氧钒化合物bpV(Imi-py)在脂肪细胞模型中表现出良好的模拟胰岛素作用,显示出潜在的抗糖尿病应用前景;bpV(Imi-py)还具有明显的抗肝癌作用,其抗肿瘤作用部分与其促进肝癌细胞凋亡机制有关。 [英文摘要]:     Vanadium is a trace element that is ubiquitous in nature and essential for human. In the past 20 years, biological activity and pharmacology of vanadium compounds are one of the hot research topics around the world, especially their potential in anti-diabetes and insulin resistance. In recent years, vanadium compounds as broad-spectrum anti-cancer drug have also attracted much attention. In this thesis, five diperoxovanadate compounds {bpV(ox),potassium bisperoxo(oxalato)oxovanadate、bpV(bipy),sodium bisperoxo(2,2’bipyridine)oxovanadate、bpV(phen),potassium bisperoxo (1,10-phenanthroline)oxovanadate、bpV(pic),potassium bisperoxo (piclinato) oxovanadate、bpv(Imi-py),ammonium bisperoxo[2-(2′-pyridyl)-imidazole] oxovanadate} were synthesized and characterized. Their impacts on glucose metabolism in adipocyte and antitumor effect in hepatocellular carcinoma were investigated.
    Four typical diperoxovanadate compounds [bpV(ox), bpV(bipy) bpV(phen), bpV(pic)] and a new diperoxovanadate compound bpV(Imi-py) were synthesized in water solution, and their spectral characters were analyzed. In order to study their insulin-like activity, glucose oxidase method was used to investigate the influence of the five diperoxovanadate compounds on glucose consumption in 3T3-L1 adipocytes which were fully differentiated. Influence of diperoxovanadate compounds on PPARγ, GLUT-4 and Resistin mRNA expression was analyzed by semi-quantitative RT-PCR. At the same time, Influence of diperoxovanadate compounds on GLUT-4 protein translocation was analyzed by western blot method. In order to study the anticancer effect of the diperoxovanadates, MTT, staining, DNA flow cytometry and gel electrophoresis methods were used in vitro to detect the influence of bpV(Imi-py) on morphological and biochemical changes of hepatoma cells Bel-7402. In addition, we investigated the mechanism by testing its catalytic activity on Caspase-3, -8, -9 and by observing the therapeutic effects of bpV(Imi-py) on H22 mouse tumor model, in vivo.
    Our results show that all of the five diperoxovanadate compounds can promote the adipocyte glucose consumption, upregulate GLUT-4 and PPARγ mRNA gene expression, downregulate Resistin gene expression and promote GLUT-4 protein translocation. BpV(phen) and bpV(Imi-py) show strong insulin-like activity, superior to the positive control VOSO4. BpV(Imi-py) can induce Bel-7402 apoptosis in a dose-dependent manner, and improve the catalytic activities of Caspase-3, -8, -9. In vivo, bpV(Imi-py) can inhibit tumor growth and induce tumor apoptosis.
    In conclusion, the new diperoxovanadate bpV(Imi-py) shows good insulin-like activity in adipocyte model, possible for anti-diabetes application. BpV(Imi-py) also has significant anti-tumor effect, which may be relevant to liver cell apoptosis mechanism.    
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