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The compound LG283 inhibits bleomycin-induced skin fibrosis via antagonizing TGF-β signaling
BACKGROUND: Systemic sclerosis (SSc) is a collagen disease that exhibits intractable fibrosis and vascular injury of the skin and internal organs. Transforming growth factor-β (TGF-β)/Smad signaling plays a central role in extracellular matrix (ECM) production by α-SMA-positive myofibroblasts. Myofi...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9052694/ https://www.ncbi.nlm.nih.gov/pubmed/35488265 http://dx.doi.org/10.1186/s13075-022-02773-2 |
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author | Utsunomiya, Akira Chino, Takenao Kasamatsu, Hiroshi Hasegawa, Takumi Utsunomiya, Natsuko Luong, Vu Huy Matsushita, Takashi Sasaki, Yoko Ogura, Dai Niwa, Shin-ichiro Oyama, Noritaka Hasegawa, Minoru |
author_facet | Utsunomiya, Akira Chino, Takenao Kasamatsu, Hiroshi Hasegawa, Takumi Utsunomiya, Natsuko Luong, Vu Huy Matsushita, Takashi Sasaki, Yoko Ogura, Dai Niwa, Shin-ichiro Oyama, Noritaka Hasegawa, Minoru |
author_sort | Utsunomiya, Akira |
collection | PubMed |
description | BACKGROUND: Systemic sclerosis (SSc) is a collagen disease that exhibits intractable fibrosis and vascular injury of the skin and internal organs. Transforming growth factor-β (TGF-β)/Smad signaling plays a central role in extracellular matrix (ECM) production by α-SMA-positive myofibroblasts. Myofibroblasts may be partially derived from various precursor cells in addition to resident fibroblasts. Recently, our high-throughput in vitro screening discovered a small compound, LG283, that may disrupt the differentiation of epithelial cells into myofibroblasts. This compound was originally generated as a curcumin derivative. METHODS: In this study, we investigated the effect of LG283 on inhibiting fibrosis and its mechanism. The action of LG283 on TGF-β-dependent fibrogenic activity and epithelial-mesenchymal transition (EMT) was analyzed in vitro. The effects of LG283 were also examined in a bleomycin-induced skin fibrosis mouse model. RESULTS: LG283 suppressed TGF-β-induced expression of ECM, α-SMA, and transcription factors Snail 1 and 2, and Smad3 phosphorylation in cultured human dermal fibroblasts. LG283 was also found to block EMT induction in cultured human epithelial cells. During these processes, Smad3 phosphorylation and/or expression of Snail 1 and 2 were inhibited by LG283 treatment. In the bleomycin-induced skin fibrosis model, oral administration of LG283 efficiently protected against the development of fibrosis and decrease of capillary vessels without significantly affecting cell infiltration or cytokine concentrations in the skin. No apparent adverse effects of LG283 were found. LG283 treatment remarkably inhibited the enhanced expression of α-SMA and phosphorylated Smad3, as well as those of Snail 1 and 2, in the bleomycin-injected skin. CONCLUSIONS: The LG283 compound exhibits antagonistic activity on fibrosis and vascular injury through inhibition of TGF-β/Smad/Snail mesenchymal transition pathways and thus, may be a candidate therapeutic for the treatment of SSc. Although the involvement of EMT in the pathogenesis of SSc remains unclear, the screening of EMT regulatory compounds may be an attractive approach for SSc therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13075-022-02773-2. |
format | Online Article Text |
id | pubmed-9052694 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-90526942022-04-30 The compound LG283 inhibits bleomycin-induced skin fibrosis via antagonizing TGF-β signaling Utsunomiya, Akira Chino, Takenao Kasamatsu, Hiroshi Hasegawa, Takumi Utsunomiya, Natsuko Luong, Vu Huy Matsushita, Takashi Sasaki, Yoko Ogura, Dai Niwa, Shin-ichiro Oyama, Noritaka Hasegawa, Minoru Arthritis Res Ther Research Article BACKGROUND: Systemic sclerosis (SSc) is a collagen disease that exhibits intractable fibrosis and vascular injury of the skin and internal organs. Transforming growth factor-β (TGF-β)/Smad signaling plays a central role in extracellular matrix (ECM) production by α-SMA-positive myofibroblasts. Myofibroblasts may be partially derived from various precursor cells in addition to resident fibroblasts. Recently, our high-throughput in vitro screening discovered a small compound, LG283, that may disrupt the differentiation of epithelial cells into myofibroblasts. This compound was originally generated as a curcumin derivative. METHODS: In this study, we investigated the effect of LG283 on inhibiting fibrosis and its mechanism. The action of LG283 on TGF-β-dependent fibrogenic activity and epithelial-mesenchymal transition (EMT) was analyzed in vitro. The effects of LG283 were also examined in a bleomycin-induced skin fibrosis mouse model. RESULTS: LG283 suppressed TGF-β-induced expression of ECM, α-SMA, and transcription factors Snail 1 and 2, and Smad3 phosphorylation in cultured human dermal fibroblasts. LG283 was also found to block EMT induction in cultured human epithelial cells. During these processes, Smad3 phosphorylation and/or expression of Snail 1 and 2 were inhibited by LG283 treatment. In the bleomycin-induced skin fibrosis model, oral administration of LG283 efficiently protected against the development of fibrosis and decrease of capillary vessels without significantly affecting cell infiltration or cytokine concentrations in the skin. No apparent adverse effects of LG283 were found. LG283 treatment remarkably inhibited the enhanced expression of α-SMA and phosphorylated Smad3, as well as those of Snail 1 and 2, in the bleomycin-injected skin. CONCLUSIONS: The LG283 compound exhibits antagonistic activity on fibrosis and vascular injury through inhibition of TGF-β/Smad/Snail mesenchymal transition pathways and thus, may be a candidate therapeutic for the treatment of SSc. Although the involvement of EMT in the pathogenesis of SSc remains unclear, the screening of EMT regulatory compounds may be an attractive approach for SSc therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13075-022-02773-2. BioMed Central 2022-04-29 2022 /pmc/articles/PMC9052694/ /pubmed/35488265 http://dx.doi.org/10.1186/s13075-022-02773-2 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visithttp://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Article Utsunomiya, Akira Chino, Takenao Kasamatsu, Hiroshi Hasegawa, Takumi Utsunomiya, Natsuko Luong, Vu Huy Matsushita, Takashi Sasaki, Yoko Ogura, Dai Niwa, Shin-ichiro Oyama, Noritaka Hasegawa, Minoru The compound LG283 inhibits bleomycin-induced skin fibrosis via antagonizing TGF-β signaling |
title | The compound LG283 inhibits bleomycin-induced skin fibrosis via antagonizing TGF-β signaling |
title_full | The compound LG283 inhibits bleomycin-induced skin fibrosis via antagonizing TGF-β signaling |
title_fullStr | The compound LG283 inhibits bleomycin-induced skin fibrosis via antagonizing TGF-β signaling |
title_full_unstemmed | The compound LG283 inhibits bleomycin-induced skin fibrosis via antagonizing TGF-β signaling |
title_short | The compound LG283 inhibits bleomycin-induced skin fibrosis via antagonizing TGF-β signaling |
title_sort | compound lg283 inhibits bleomycin-induced skin fibrosis via antagonizing tgf-β signaling |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9052694/ https://www.ncbi.nlm.nih.gov/pubmed/35488265 http://dx.doi.org/10.1186/s13075-022-02773-2 |
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