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首页> 外文期刊>The Journal of toxicological sciences >Mechanisms of CCl4-induced liver fibrosis with combined transcriptomic and proteomic analysis
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Mechanisms of CCl4-induced liver fibrosis with combined transcriptomic and proteomic analysis

机译：CCL4诱导的肝纤维化机制组合转录组和蛋白质组学分析

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摘要

The classic toxicity of carbon tetrachloride (CCl4) is to induce liver lesion and liver fibrosis. Liver fibrosis is a consequence of chronic liver lesion, which can progress into liver cirrhosis even hepatocarcinoma. However, the toxicological mechanisms of CCl4-induced liver fibrosis remain not fully understood. We combined transcriptomic and proteomic analysis and biological network technology, predicted toxicological targets and regulatory networks of CCl4 in liver fibrosis. Wistar rats were treated with CCl4 for 9 weeks. Histopathological changes, hydroxyproline (Hyp) contents, serum ALT and AST in the CCl4-treated group were significantly higher than that of CCl4-untreated group. CCl4-treated and -untreated liver tissues were examined by microarray and iTRAQ. The results showed that 3535 genes (fold change >= 1.5, P < 0.05) and 1412 proteins (fold change >= 1.2, P < 0.05) were differentially expressed. Moreover, the integrative analysis of transcriptomics and proteomics data showed 523 overlapped proteins, enriched in 182 GO terms including oxidation reduction, response to oxidative stress, inflammatory response, extracellular matrix organization, etc. Furthermore, KEGG pathway analysis showed that 36 pathways including retinol metabolism, PPAR signaling pathway, glycolysis/gluconeogenesis, arachidonic acid metabolism, metabolism of xenobiotics by cytochrome P450 and drug metabolism. Network of protein-protein interaction (PPI) and key function with their related targets were performed and the degree of network was calculated with Cytoscape. The expression of key targets such as CYP4A3, ALDH2 and ALDH7A1 decreased after CCl4 treatment. Therefore, the toxicological mechanisms of CCl4-induced liver fibrosis may be related with multi biological process, pathway and targets which may provide potential protection reaction mechanism for CCl4 detoxication in the liver.
机译：四氯化碳（CCL4）的经典毒性是诱导肝病变和肝纤维化。肝纤维化是慢性肝病变的结果，它可以进入肝硬化甚至肝癌。然而，CCL4诱导的肝纤维化的毒理机制仍然没有完全理解。我们组合转录组和蛋白质组学分析和生物网络技术，预测CCL4在肝纤维化中的毒理学靶标和监管网络。 Wistar大鼠用CCl4处理9周。组织病理学变化，羟脯氨酸（哌啶），CCL4治疗组中的血清ALT和AST显着高于CCL4-未处理的基团。通过微阵列和ITRAQ检查CCL4治疗和 - 未解析的肝组织。结果表明，3535基因（折叠变化> = 1.5，P <0.05）和1412蛋白（折叠变化> = 1.2，P <0.05）差异地表达。此外，转录组和蛋白质组学数据的整合分析显示了523个重叠蛋白，其富集于182个阶段，包括氧化还原，响应氧化应激，炎症反应，细胞外基质基质组织等。此外，Kegg途径分析表明，36种途径包括视黄醇代谢，PPAR信号通路，糖酵解/葡糖生成，花生素酸代谢，细胞色素P450和药物代谢的异恶蛋白代谢。进行蛋白质 - 蛋白质相互作用（PPI）和具有相关靶标的关键功能，并用Cytoscape计算网络程度。在CCL4处理后，CYP4A3，AlDH2和AldH7a1的关键靶标的表达降低。因此，CCL4诱导的肝纤维化的毒理学机制可能与多生物学过程，途径和靶标有关，其可提供肝脏中CCL4毒物的潜在保护反应机制。

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  • 作者

    Dong Shu; Chen Qi-Long; Song Ya-Nan; Sun Yang; Wei Bin; Li Xiao-Yan; Hu Yi-Yang; Liu Ping; Su Shi-Bing;

  • 作者单位

    Shanghai Univ Tradit Chinese Med Res Ctr Tradit Chinese Med Complex Syst Shanghai 201203 Peoples;

    Shanghai Univ Tradit Chinese Med Res Ctr Tradit Chinese Med Complex Syst Shanghai 201203 Peoples;

    Shanghai Univ Tradit Chinese Med Res Ctr Tradit Chinese Med Complex Syst Shanghai 201203 Peoples;

    Shanghai Univ Tradit Chinese Med Res Ctr Tradit Chinese Med Complex Syst Shanghai 201203 Peoples;

    Shanghai Univ Tradit Chinese Med Res Ctr Tradit Chinese Med Complex Syst Shanghai 201203 Peoples;

    Shanghai Univ Tradit Chinese Med Res Ctr Tradit Chinese Med Complex Syst Shanghai 201203 Peoples;

    Shanghai Univ Tradit Chinese Med Inst Liver Dis Shuguang Hosp Shanghai 201203 Peoples R China;

    Shanghai Univ Tradit Chinese Med Inst E Shanghai 201203 Peoples R China;

    Shanghai Univ Tradit Chinese Med Res Ctr Tradit Chinese Med Complex Syst Shanghai 201203 Peoples;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药学;
  • 关键词

    Liver fibrosis; CCl4; Toxicity; Transcriptomics; Proteomics; Integrative analysis;

    机译：肝纤维化;CCL4;毒性;转录组织;蛋白质组学;综合分析;

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