Selective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model
Abstract Chronic hepatitis C virus (HCV) infection is one of the major causes of serious liver diseases, including liver cirrhosis. There are no anti-fibrotic drugs with efficacy against liver cirrhosis. Wnt/β-catenin signaling has been implicated in the pathogenesis of a variety of tissue fibrosis....
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Nature Portfolio
2017
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oai:doaj.org-article:a5328ca8ed1a462090583dbee4a72a392021-12-02T16:07:46ZSelective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model10.1038/s41598-017-00282-w2045-2322https://doaj.org/article/a5328ca8ed1a462090583dbee4a72a392017-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00282-whttps://doaj.org/toc/2045-2322Abstract Chronic hepatitis C virus (HCV) infection is one of the major causes of serious liver diseases, including liver cirrhosis. There are no anti-fibrotic drugs with efficacy against liver cirrhosis. Wnt/β-catenin signaling has been implicated in the pathogenesis of a variety of tissue fibrosis. In the present study, we investigated the effects of a β-catenin/CBP (cyclic AMP response element binding protein) inhibitor on liver fibrosis. The anti-fibrotic activity of PRI-724, a selective inhibitor of β-catenin/CBP, was assessed in HCV GT1b transgenic mice at 18 months after HCV genome expression. PRI-724 was injected intraperitoneally or subcutaneously in these mice for 6 weeks. PRI-724 reduced liver fibrosis, which was indicated by silver stain, Sirius Red staining, and hepatic hydroxyproline levels, in HCV mice while attenuating αSMA induction. PRI-724 led to increased levels of matrix metalloproteinase (MMP)-8 mRNA in the liver, along with elevated levels of intrahepatic neutrophils and macrophages/monocytes. The induced intrahepatic neutrophils and macrophages/monocytes were identified as the source of MMP-8. In conclusion, PRI-724 ameliorated HCV-induced liver fibrosis in mice. We hypothesize that inhibition of hepatic stellate cells activation and induction of fibrolytic cells expressing MMP-8 contribute to the anti-fibrotic effects of PRI-724. PRI-724 is a drug candidate which possesses anti-fibrotic effect.Yuko TokunagaYosuke OsawaTakahiro OhtsukiYukiko HayashiKenzaburo YamajiDaisuke YamaneMitsuko HaraKeisuke MunekataKyoko Tsukiyama-KoharaTsunekazu HishimaSoichi KojimaKiminori KimuraMichinori KoharaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017) |
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Medicine R Science Q Yuko Tokunaga Yosuke Osawa Takahiro Ohtsuki Yukiko Hayashi Kenzaburo Yamaji Daisuke Yamane Mitsuko Hara Keisuke Munekata Kyoko Tsukiyama-Kohara Tsunekazu Hishima Soichi Kojima Kiminori Kimura Michinori Kohara Selective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model |
| description |
Abstract Chronic hepatitis C virus (HCV) infection is one of the major causes of serious liver diseases, including liver cirrhosis. There are no anti-fibrotic drugs with efficacy against liver cirrhosis. Wnt/β-catenin signaling has been implicated in the pathogenesis of a variety of tissue fibrosis. In the present study, we investigated the effects of a β-catenin/CBP (cyclic AMP response element binding protein) inhibitor on liver fibrosis. The anti-fibrotic activity of PRI-724, a selective inhibitor of β-catenin/CBP, was assessed in HCV GT1b transgenic mice at 18 months after HCV genome expression. PRI-724 was injected intraperitoneally or subcutaneously in these mice for 6 weeks. PRI-724 reduced liver fibrosis, which was indicated by silver stain, Sirius Red staining, and hepatic hydroxyproline levels, in HCV mice while attenuating αSMA induction. PRI-724 led to increased levels of matrix metalloproteinase (MMP)-8 mRNA in the liver, along with elevated levels of intrahepatic neutrophils and macrophages/monocytes. The induced intrahepatic neutrophils and macrophages/monocytes were identified as the source of MMP-8. In conclusion, PRI-724 ameliorated HCV-induced liver fibrosis in mice. We hypothesize that inhibition of hepatic stellate cells activation and induction of fibrolytic cells expressing MMP-8 contribute to the anti-fibrotic effects of PRI-724. PRI-724 is a drug candidate which possesses anti-fibrotic effect. |
| format |
article |
| author |
Yuko Tokunaga Yosuke Osawa Takahiro Ohtsuki Yukiko Hayashi Kenzaburo Yamaji Daisuke Yamane Mitsuko Hara Keisuke Munekata Kyoko Tsukiyama-Kohara Tsunekazu Hishima Soichi Kojima Kiminori Kimura Michinori Kohara |
| author_facet |
Yuko Tokunaga Yosuke Osawa Takahiro Ohtsuki Yukiko Hayashi Kenzaburo Yamaji Daisuke Yamane Mitsuko Hara Keisuke Munekata Kyoko Tsukiyama-Kohara Tsunekazu Hishima Soichi Kojima Kiminori Kimura Michinori Kohara |
| author_sort |
Yuko Tokunaga |
| title |
Selective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model |
| title_short |
Selective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model |
| title_full |
Selective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model |
| title_fullStr |
Selective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model |
| title_full_unstemmed |
Selective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model |
| title_sort |
selective inhibitor of wnt/β-catenin/cbp signaling ameliorates hepatitis c virus-induced liver fibrosis in mouse model |
| publisher |
Nature Portfolio |
| publishDate |
2017 |
| url |
https://doaj.org/article/a5328ca8ed1a462090583dbee4a72a39 |
| work_keys_str_mv |
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1718384734876205056 |