フルテキストファイル
著者
Sakaguchi, Takuki Department of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medical Sciences, Tottori University / Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine
Kono, Yohei Department of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medical Sciences, Tottori University
Itaba, Noriko Department of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medical Sciences, Tottori University 研究者総覧 KAKEN
Morimoto, Minoru Research Initiative Center, Tottori University 研究者総覧 KAKEN
Isomoto, Hajime Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine 研究者総覧 KAKEN
Shiota, Goshi Department of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medical Sciences, Tottori University 研究者総覧 KAKEN
キーワード
deactivation
hepatic stellate cells
liver fibrosis
small-molecule compound
抄録
Background: Liver fibrosis progresses to decompensated liver cirrhosis, for which medical needs remain unmet. We recently developed IC-2, a small-molecule compound that suppresses Wnt/β-catenin signaling, and found that IC-2 also suppresses liver fibrosis. In this study, we performed three-step screening of newly synthesized IC-2 derivatives to identify other small-molecule compounds that suppress liver fibrosis.

Methods: The screening system consisted of three steps: a cell viability assay, a transcription factor 4 (TCF4) reporter assay, and induction of α-smooth muscle actin (α-SMA) and collagen 1α1 (Col1A1) expression in response to each compound. Screening using human LX-2 hepatic stellate cells (HSCs) was performed to target HSCs, which are the driver cells of liver fibrosis.

Results: In the first step, since 9b and 9b-CONH2 at 100 μM did not have any effects on cell viability, they were omitted in the next screening. Additionally, the conditions that led to > 40% inhibition of the controls were also excluded in subsequent screening. The second step was performed under 31 conditions for 19 small-molecule compounds. Sixteen small-molecule compounds caused significant reduction of TCF4 activity relative to that of 0.1% DMSO. Of the 16 compounds, the 10 showing the greatest suppression of TCF4 activity were selected for the third step. Expressions of mRNA for α-SMA and Col1A1 were significantly reduced by seven and three small-molecule compounds, respectively. The greatest reductions in the α-SMA and Col1A1 mRNA expressions were observed in the cells treated with IC-2-F. Protein expressions of α-SMA and Col1A1 caused by IC-2-F were also comparable to those caused by IC-2.

Conclusion: IC-2-F was identified as a novel deactivating small-molecule compound for HSCs in vitro. These data suggest that IC-2-F is a promising medicine for liver fibrosis.
出版者
Tottori University Medical Press
資料タイプ
学術雑誌論文
外部リンク
ISSN
05135710
書誌ID
AA00892882
掲載誌名
Yonago Acta Medica
最新掲載誌名
Yonago Acta Medica
63
1
開始ページ
79
終了ページ
87
Original Article
発行日
2020-02-20
出版者DOI
著者版フラグ
出版社版
著作権表記
注があるものを除き、この著作物は日本国著作権法により保護されています。 / This work is protected under Japanese Copyright Law unless otherwise noted.
掲載情報
Takuki Sakaguchi, Yohei Kono, Noriko Itaba, Minoru Morimoto, Hajime Isomoto, Goshi Shiota, Identification of a Novel Deactivating Small-Molecule Compound for Fibrogenic Hepatic Stellate Cells, Yonago Acta Medica, 2020, Volume 63, Issue 1, Pages 79-87, Released February 20, 2020
部局名
医学部・医学系研究科・医学部附属病院
言語
英語