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利用环状Sp1诱饵寡脱氧核苷酸通过调控转录因子对四氯化碳诱导的肝纤维化的抗纤维化作用

Antifibrotic effect through the regulation of transcription factor using ring type-Sp1 decoy oligodeoxynucleotide in carbon tetrachloride-induced liver fibrosis.

作者信息

Park Ji-Hyun, Jo Ji-Ho, Kim Kyung-Hyun, Kim Soo-Jung, Lee Woo-Ram, Park Kwan-Kyu, Park Jae-Bok

机构信息

Department of Pathology, Catholic University of Daegu, College of Medicine, Nam-gu, Daegu, Republic of Korea.

出版信息

J Gene Med. 2009 Sep;11(9):824-33. doi: 10.1002/jgm.1355.

Abstract

BACKGROUND

Liver fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM). Recent advances in the knowledge about the cellular, molecular and genetic aspects of fibrosis have opened a new era of research on liver cirrhosis. A transcription factor, Sp1, originally described as a ubiquitous transcription factor, is involved in the basal expression of ECM genes and may be important in the fibrotic processes.

METHODS

The chronic hepatic damage received intraperitoneal injection of carbon tetrachloride (2 mg/kg) dissolved in corn oil (1 : 3 ratio) three times a weekly for 8 weeks. The delivery of decoy oligodeoxynucleotide (ODN) was performed by injection of 10 microg of scrambled decoy ODN or 10 microg of ring type (R)-Sp1 decoy ODN through the mouse tail vein. All animals of each group were sacrificed, DNA binding activity, expression of cytokines and histological analysis were measured.

RESULTS

We have generated a R-Sp1 decoy ODN that effectively blocks Sp1 binding to the promoter region for transcription regulation of transforming growth factor (TGF)-beta1. The expression of fibrotic cytokines and inflammatory cytokines was decreased by using the R-Sp1 decoy ODN in liver cirrhosis.

CONCLUSIONS

The present study demonstrates that the R-Sp1 decoy ODN inhibits TGF-beta1 expression in liver cirrhosis. These results indicate that targeting Sp1 can efficiently block ECM expression, and suggest that such an approach may represent an interesting therapeutic alternative towards the treatment of cirrhosis.

摘要

背景

肝纤维化的特征是细胞外基质(ECM)过度积聚。关于纤维化的细胞、分子和遗传方面知识的最新进展开启了肝硬化研究的新时代。转录因子Sp1最初被描述为一种普遍存在的转录因子,它参与ECM基因的基础表达,可能在纤维化过程中起重要作用。

方法

对慢性肝损伤小鼠每周3次腹腔注射溶解于玉米油(比例为1:3)中的四氯化碳(2mg/kg),持续8周。通过小鼠尾静脉注射10μg随机序列诱饵寡脱氧核苷酸(ODN)或10μg环型(R)-Sp1诱饵ODN来进行诱饵寡脱氧核苷酸的递送。每组所有动物均处死后,检测DNA结合活性、细胞因子表达及进行组织学分析。

结果

我们制备了一种R-Sp1诱饵ODN,它能有效阻断Sp1与转化生长因子(TGF)-β1转录调控启动子区域的结合。在肝硬化中使用R-Sp1诱饵ODN可降低纤维化细胞因子和炎性细胞因子的表达。

结论

本研究表明R-Sp1诱饵ODN可抑制肝硬化中TGF-β1的表达。这些结果表明靶向Sp1可有效阻断ECM表达,并提示这种方法可能是治疗肝硬化的一种有前景的治疗选择。

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