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Novel oral plasminogen activator inhibitor-1 inhibitor TM5275 attenuates hepatic fibrosis under metabolic syndrome via suppression of activated hepatic stellate cells in rats
An orally bioavailable small molecule inhibitor of plasminogen activator inhibitor-1 (PAI-1) is currently being clinically assessed as a novel antithrombotic agent. Although PAI-1 is known to serve a key role in the pathogenesis of metabolic syndrome (MetS) including nonalcoholic steatohepatitis (NA...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
D.A. Spandidos
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453658/ https://www.ncbi.nlm.nih.gov/pubmed/32945412 http://dx.doi.org/10.3892/mmr.2020.11360 |
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author | Noguchi, Ryuichi Kaji, Kosuke Namisaki, Tadashi Moriya, Kei Kawaratani, Hideto Kitade, Mitsuteru Takaya, Hiroaki Aihara, Yosuke Douhara, Akitoshi Asada, Kiyoshi Nishimura, Norihisa Miyata, Toshio Yoshiji, Hitoshi |
author_facet | Noguchi, Ryuichi Kaji, Kosuke Namisaki, Tadashi Moriya, Kei Kawaratani, Hideto Kitade, Mitsuteru Takaya, Hiroaki Aihara, Yosuke Douhara, Akitoshi Asada, Kiyoshi Nishimura, Norihisa Miyata, Toshio Yoshiji, Hitoshi |
author_sort | Noguchi, Ryuichi |
collection | PubMed |
description | An orally bioavailable small molecule inhibitor of plasminogen activator inhibitor-1 (PAI-1) is currently being clinically assessed as a novel antithrombotic agent. Although PAI-1 is known to serve a key role in the pathogenesis of metabolic syndrome (MetS) including nonalcoholic steatohepatitis (NASH), the pharmacological action of an oral PAI-1 inhibitor against the development of MetS-related liver fibrosis remains unclear. The current study was designed to explicate the effect of TM5275, an oral PAI-1 inhibitor, on MetS-related hepatic fibrogenesis. The in vivo antifibrotic effect of orally administered TM5275 was investigated in two different rat MetS models. Fischer 344 rats received a choline-deficient L-amino-acid-defined diet for 12 weeks to induce steatohepatitis with development of severe hepatic fibrosis. Otsuka Long-Evans Tokushima Fatty rats, used to model congenital diabetes, underwent intraperitoneal injection of porcine serum for 6 weeks to induce hepatic fibrosis under diabetic conditions. In each experimental model, TM5275 markedly ameliorated the development of hepatic fibrosis and suppressed the proliferation of activated hepatic stellate cells (HSCs). Additionally, the hepatic production of tumor growth factor (TGF)-β1 and total collagen was suppressed. In vitro assays revealed that TGF-β1 stimulated the upregulation of Serpine1 mRNA expression, which was inhibited by TM5275 treatment in cultured HSC-T6 cells, a rat HSC cell line. Furthermore, TM5275 substantially attenuated the TGF-β1-stimulated proliferative and fibrogenic activity of HSCs by inhibiting AKT phosphorylation. Collectively, TM5275 demonstrated an antifibrotic effect on liver fibrosis in different rat MetS models, suppressing TGF-β1-induced HSC proliferation and collagen synthesis. Thus, PAI-1 inhibitors may serve as effective future therapeutic agents against NASH-based hepatic fibrosis. |
format | Online Article Text |
id | pubmed-7453658 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | D.A. Spandidos |
record_format | MEDLINE/PubMed |
spelling | pubmed-74536582020-08-31 Novel oral plasminogen activator inhibitor-1 inhibitor TM5275 attenuates hepatic fibrosis under metabolic syndrome via suppression of activated hepatic stellate cells in rats Noguchi, Ryuichi Kaji, Kosuke Namisaki, Tadashi Moriya, Kei Kawaratani, Hideto Kitade, Mitsuteru Takaya, Hiroaki Aihara, Yosuke Douhara, Akitoshi Asada, Kiyoshi Nishimura, Norihisa Miyata, Toshio Yoshiji, Hitoshi Mol Med Rep Articles An orally bioavailable small molecule inhibitor of plasminogen activator inhibitor-1 (PAI-1) is currently being clinically assessed as a novel antithrombotic agent. Although PAI-1 is known to serve a key role in the pathogenesis of metabolic syndrome (MetS) including nonalcoholic steatohepatitis (NASH), the pharmacological action of an oral PAI-1 inhibitor against the development of MetS-related liver fibrosis remains unclear. The current study was designed to explicate the effect of TM5275, an oral PAI-1 inhibitor, on MetS-related hepatic fibrogenesis. The in vivo antifibrotic effect of orally administered TM5275 was investigated in two different rat MetS models. Fischer 344 rats received a choline-deficient L-amino-acid-defined diet for 12 weeks to induce steatohepatitis with development of severe hepatic fibrosis. Otsuka Long-Evans Tokushima Fatty rats, used to model congenital diabetes, underwent intraperitoneal injection of porcine serum for 6 weeks to induce hepatic fibrosis under diabetic conditions. In each experimental model, TM5275 markedly ameliorated the development of hepatic fibrosis and suppressed the proliferation of activated hepatic stellate cells (HSCs). Additionally, the hepatic production of tumor growth factor (TGF)-β1 and total collagen was suppressed. In vitro assays revealed that TGF-β1 stimulated the upregulation of Serpine1 mRNA expression, which was inhibited by TM5275 treatment in cultured HSC-T6 cells, a rat HSC cell line. Furthermore, TM5275 substantially attenuated the TGF-β1-stimulated proliferative and fibrogenic activity of HSCs by inhibiting AKT phosphorylation. Collectively, TM5275 demonstrated an antifibrotic effect on liver fibrosis in different rat MetS models, suppressing TGF-β1-induced HSC proliferation and collagen synthesis. Thus, PAI-1 inhibitors may serve as effective future therapeutic agents against NASH-based hepatic fibrosis. D.A. Spandidos 2020-10 2020-07-28 /pmc/articles/PMC7453658/ /pubmed/32945412 http://dx.doi.org/10.3892/mmr.2020.11360 Text en Copyright: © Noguchi et al. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
spellingShingle | Articles Noguchi, Ryuichi Kaji, Kosuke Namisaki, Tadashi Moriya, Kei Kawaratani, Hideto Kitade, Mitsuteru Takaya, Hiroaki Aihara, Yosuke Douhara, Akitoshi Asada, Kiyoshi Nishimura, Norihisa Miyata, Toshio Yoshiji, Hitoshi Novel oral plasminogen activator inhibitor-1 inhibitor TM5275 attenuates hepatic fibrosis under metabolic syndrome via suppression of activated hepatic stellate cells in rats |
title | Novel oral plasminogen activator inhibitor-1 inhibitor TM5275 attenuates hepatic fibrosis under metabolic syndrome via suppression of activated hepatic stellate cells in rats |
title_full | Novel oral plasminogen activator inhibitor-1 inhibitor TM5275 attenuates hepatic fibrosis under metabolic syndrome via suppression of activated hepatic stellate cells in rats |
title_fullStr | Novel oral plasminogen activator inhibitor-1 inhibitor TM5275 attenuates hepatic fibrosis under metabolic syndrome via suppression of activated hepatic stellate cells in rats |
title_full_unstemmed | Novel oral plasminogen activator inhibitor-1 inhibitor TM5275 attenuates hepatic fibrosis under metabolic syndrome via suppression of activated hepatic stellate cells in rats |
title_short | Novel oral plasminogen activator inhibitor-1 inhibitor TM5275 attenuates hepatic fibrosis under metabolic syndrome via suppression of activated hepatic stellate cells in rats |
title_sort | novel oral plasminogen activator inhibitor-1 inhibitor tm5275 attenuates hepatic fibrosis under metabolic syndrome via suppression of activated hepatic stellate cells in rats |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453658/ https://www.ncbi.nlm.nih.gov/pubmed/32945412 http://dx.doi.org/10.3892/mmr.2020.11360 |
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