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
2017-03-01
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Series: | Scientific Reports |
Online Access: | https://doi.org/10.1038/s41598-017-00282-w |
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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 |
collection | DOAJ |
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. |
first_indexed | 2024-12-19T03:58:55Z |
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id | doaj.art-a5328ca8ed1a462090583dbee4a72a39 |
institution | Directory Open Access Journal |
issn | 2045-2322 |
language | English |
last_indexed | 2024-12-19T03:58:55Z |
publishDate | 2017-03-01 |
publisher | Nature Portfolio |
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series | Scientific Reports |
spelling | doaj.art-a5328ca8ed1a462090583dbee4a72a392022-12-21T20:36:44ZengNature PortfolioScientific Reports2045-23222017-03-017111110.1038/s41598-017-00282-wSelective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse modelYuko Tokunaga0Yosuke Osawa1Takahiro Ohtsuki2Yukiko Hayashi3Kenzaburo Yamaji4Daisuke Yamane5Mitsuko Hara6Keisuke Munekata7Kyoko Tsukiyama-Kohara8Tsunekazu Hishima9Soichi Kojima10Kiminori Kimura11Michinori Kohara12Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical ScienceDivision of Hepatology, Tokyo Metropolitan Komagome HospitalDepartment of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical ScienceDepartment of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical ScienceDepartment of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical ScienceDepartment of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical ScienceMicro-signaling Regulation Technology Unit, RIKEN Center for Life Science TechnologiesDepartment of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical ScienceTransboundary Animal Diseases Center, Joint Faculty of Veterinary Medicine, Kagoshima UniversityDepartment of Pathology, Tokyo Metropolitan Komagome HospitalMicro-signaling Regulation Technology Unit, RIKEN Center for Life Science TechnologiesDivision of Hepatology, Tokyo Metropolitan Komagome HospitalDepartment of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical ScienceAbstract 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.https://doi.org/10.1038/s41598-017-00282-w |
spellingShingle | 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 Scientific Reports |
title | 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_short | 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 |
url | https://doi.org/10.1038/s41598-017-00282-w |
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