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首页> 外文期刊>Life sciences >Inhibitory effect of dicationic diphenylfurans on production of type I collagen by human fibroblasts and activated hepatic stellate cells.
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Inhibitory effect of dicationic diphenylfurans on production of type I collagen by human fibroblasts and activated hepatic stellate cells.

机译：二苯基呋喃二甲酸对人成纤维细胞和活化的肝星状细胞产生I型胶原的抑制作用。

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Excessive production of extracellular matrix is responsible for clinical manifestations of fibroproliferative disorders and drugs which can inhibit excessive synthesis of type I collagen are needed for the therapy. Several dicationic diphenylfurans were synthesized and were found to bind RNA. Two of these type compounds were able to reduce synthesis of type I collagen by human fibroblasts and human activated hepatic stellate cells (HSCs). Activated HSCs are responsible for collagen production in liver fibrosis. When added at 40 microM compound 588 reduced intracellular level and secretion of procollagen alpha1(I) by 50%, while compound 654 reduced these parameters by more than 80% at 20 microM. 654 also significantly reduced secretion of fibronectin. Toxic effects were observed at 80 microM for 588 and 40 microM for 654. 654 reduced expression of a reporter gene with collagen signal peptide, while expression of the same gene without signal peptide was unaffected. Also, expression of intracellular proteins tubulin and calnexin was unchanged. 654 accumulated inside the cell in the cytoplasm and did not change the steady-state level of collagen mRNAs. Treatment of cells with proteosome inhibitor MG132 did not change the inhibitory effect of 654, suggesting that 654 acts as suppressor of translation of proteins containing a signal peptide. Most secreted proteins of fibroblasts and activated HSCs are components of extracellular matrix. Therefore inhibition of their production, as shown here for procollagen alpha1(I) and fibronectin, may be a useful property of some of diphenylfurans, making these compounds a basis for development of antifibrotic drugs.
机译：细胞外基质的过量产生是纤维增生性疾病的临床表现的原因，该疗法需要能够抑制I型胶原过度合成的药物。合成了几种二苯基呋喃二甲酸酯，发现它们结合了RNA。这些类型化合物中的两种能够减少人类成纤维细胞和人类活化的肝星状细胞（HSC）合成I型胶原的能力。活化的HSC负责肝纤维化中胶原蛋白的产生。当以40 microM加入时，化合物588将细胞内水平和前胶原α1（I）的分泌降低了50％，而化合物654在20 microM时将这些参数降低了80％以上。 654还显着减少了纤连蛋白的分泌。在80 microM对588和40 microM对654处观察到了毒性作用。654带有胶原蛋白信号肽的报告基因表达降低，而不含信号肽的相同基因的表达不受影响。另外，细胞内蛋白微管蛋白和钙连接蛋白的表达未改变。 654在细胞质中积累在细胞内，并且没有改变胶原蛋白mRNA的稳态水平。用蛋白体抑制剂MG132处理细胞不会改变654的抑制作用，这表明654可以作为含有信号肽的蛋白质翻译的抑制物。成纤维细胞和活化的HSC分泌最多的蛋白质是细胞外基质的组成部分。因此，如前所示，对胶原蛋白α1（I）和纤连蛋白的抑制作用可能是某些二苯呋喃的有用特性，使这些化合物成为开发抗纤维化药物的基础。

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