A novel nonsteroidal antifibrotic oligo decoy containing the TGF-beta element found in the COL1A1 gene which regulates murine schistosomiasis liver fibrosis.
A novel nonsteroidal antifibrotic oligo decoy containing the TGF-beta element found in the COL1A1 gene which regulates murine schistosomiasis liver fibrosis.
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一种新型非甾体抗纤维化寡核苷酸诱饵，含有在 COL1A1 基因中发现的 TGF-β 元件，可调节小鼠血吸虫病肝纤维化。
DOI：
10.1002/jcp.20412
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发表时间：
2005
影响因子：
5.6
通讯作者：
Cutroneo,KR
中科院分区：
文献类型：
--
作者：
Boros,DL;Singh,KP;Gerard,HC;Hudson,AP;White,SL;Cutroneo,KR
曼氏血吸虫病在小鼠和人类中传播的虫卵会诱发肉芽肿性炎症和累积性纤维化，导致发病甚至可能死亡。在这项研究中，肝内和静脉注射含有TGF-β调节元件的双链寡脱氧核苷酸诱饵到蠕虫感染的小鼠中，发现在COL 1A 1基因的远端启动子中抑制TGF-β1，COL 1A 1，金属蛋白酶的组织抑制剂-1，并在较小程度上减少COL 3A 1 mRNA。小鼠基因组内的序列比较发现了COL 3A 1、TGF-β1和TIMP-1 5′侧翼区域内的同源序列。冷竞争凝胶迁移率变动分析使用这些同源序列与5′和3′侧翼区发现在naturalCOL 1A 1基因显示竞争。在单独实验中的竞争性凝胶迁移率测定显示，使用5个碱基突变或乱序序列没有竞争。从盐水注射的小鼠中取出的肝肉芽肿将10.45 ± 1.7%的3 H-脯氨酸掺入到新合成的胶原中，而诱饵处理的小鼠显示没有胶原合成。与生理盐水对照组相比，硫代磷酸双链寡脱氧核苷酸治疗的血吸虫病小鼠的总肝胶原蛋白含量（即羟基-4-脯氨酸）降低了34%。这种新的分子方法有可能被用作一种新的抗纤维化治疗方式。© 2005 Wiley利斯公司
Schistosomiasis mansoni disseminated worm eggs in mice and humans induce granulomatous inflammations and cumulative fibrosis causing morbidity and possibly mortality. In this study, intrahepatic and I.V. injections of a double‐stranded oligodeoxynucleotide decoy containing the TGF‐β regulatory element found in the distal promoter of theCOL1A1gene into worm‐infected mice suppressed TGF‐β1, COL1A1, tissue inhibitor of metalloproteinase‐1, and decreased COL3A1 mRNAs to a lesser extent. Sequence comparisons within the mouse genome found homologous sequences within the COL3A1, TGF‐β1, and TIMP‐1 5′ flanking regions. Cold competition gel mobility shift assays using these homologous sequences with 5′ and 3′ flanking regions found in the naturalCOL1A1gene showed competition. Competitive gel mobility assays in a separate experiment showed no competition using a 5‐base mutated or scrambled sequence. Explanted liver granulomas from saline‐injected mice incorporated 10.45 ± 1.7%3H‐proline into newly synthesized collagen, whereas decoy‐treated mice showed no collagen synthesis. Compared with the saline control schistosomiasis mice phosphorothioate double‐stranded oligodeoxynucleotide treatment decreased total liver collagen content (i.e. hydroxy‐4‐proline) by 34%. This novel molecular approach has the potential to be employed as a novel antifibrotic treatment modality. © 2005 Wiley‐Liss, Inc.