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Liver fibrosis is characterized by changes in tissue architecture and extracellular matrix composition. Liver fibrosis affects not only hepatocytes but also the non-parenchymal cells such as hepatic stellate cells (HSCs), which are essential for maintaining an intact liver structure and function. Transforming growth factor β1 (TGF-β1) is a multifunctional cytokine that induces liver fibrosis through activation of Smad signaling pathways. To improve a new therapeutic approach, synthetic TGF-β1/Smad oligodeoxynucleotide (ODN) was used to suppress both TGF-β1 expression and Smad transcription factor using a combination of antisense ODN and decoy ODN. The aims of this study are to investigate the anti-fibrotic effects of TGF-β1/Smad ODN on simultaneous suppressions of both Smad transcription factor and TGF-β1 mRNA expression in the hepatic fibrosis model in vitro and in vivo. Synthetic TGF-β1/Smad ODN effectively inhibits Smad binding activity and TGF-β1 expression. TGF-β1/Smad ODN attenuated the epithelial mesenchymal transition (EMT) and activation of HSCs in TGF-β1-induced AML12 and HSC-T6 cells. TGF-β1/Smad ODN prevented the fibrogenesis and deposition of collagen in CCl4-treated mouse model. Synthetic TGF-β1/Smad ODN demonstrates anti-fibrotic effects that are mediated by the suppression of fibrogenic protein and inflammatory cytokines. Therefore, synthetic TGF-β1/Smad ODN has substantial therapeutic feasibility for the treatment of liver fibrotic diseases. Keywords: oligodeoxynucleotide, decoy, antisense, liver fibrosis, TGF-β1, Smad