Selective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2017 |
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| Erschienen: |
2017 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:7 |
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| Enthalten in: |
Scientific reports - 7(2017), 1 vom: 23. März, Seite 325 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Tokunaga, Yuko [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 24.08.2018 Date Revised 13.11.2018 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41598-017-00282-w |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM270258469 |
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| 245 | 1 | 0 | |a Selective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model |
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| 520 | |a 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 | ||
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| 700 | 1 | |a Osawa, Yosuke |e verfasserin |4 aut | |
| 700 | 1 | |a Ohtsuki, Takahiro |e verfasserin |4 aut | |
| 700 | 1 | |a Hayashi, Yukiko |e verfasserin |4 aut | |
| 700 | 1 | |a Yamaji, Kenzaburo |e verfasserin |4 aut | |
| 700 | 1 | |a Yamane, Daisuke |e verfasserin |4 aut | |
| 700 | 1 | |a Hara, Mitsuko |e verfasserin |4 aut | |
| 700 | 1 | |a Munekata, Keisuke |e verfasserin |4 aut | |
| 700 | 1 | |a Tsukiyama-Kohara, Kyoko |e verfasserin |4 aut | |
| 700 | 1 | |a Hishima, Tsunekazu |e verfasserin |4 aut | |
| 700 | 1 | |a Kojima, Soichi |e verfasserin |4 aut | |
| 700 | 1 | |a Kimura, Kiminori |e verfasserin |4 aut | |
| 700 | 1 | |a Kohara, Michinori |e verfasserin |4 aut | |
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