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Preclinical Study of Novel Gene Silencer Pyrrole-Imidazole Polyamide Targeting Human TGF-β1 Promoter for Hypertrophic Scars in a Common Marmoset Primate Model
We report a preclinical study of a pyrrole-imidazole (PI) polyamide that targets the human transforming growth factor (hTGF)-β1 gene as a novel transcriptional gene silencer in a common marmoset primate model. We designed and then synthesized PI polyamides to target the hTGF-β1 promoter. We examined...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4418757/ https://www.ncbi.nlm.nih.gov/pubmed/25938472 http://dx.doi.org/10.1371/journal.pone.0125295 |
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author | Igarashi, Jun Fukuda, Noboru Inoue, Takashi Nakai, Shigeki Saito, Kosuke Fujiwara, Kyoko Matsuda, Hiroyuki Ueno, Takahiro Matsumoto, Yoshiaki Watanabe, Takayoshi Nagase, Hiroki Bando, Toshikazu Sugiyama, Hiroshi Itoh, Toshio Soma, Masayoshi |
author_facet | Igarashi, Jun Fukuda, Noboru Inoue, Takashi Nakai, Shigeki Saito, Kosuke Fujiwara, Kyoko Matsuda, Hiroyuki Ueno, Takahiro Matsumoto, Yoshiaki Watanabe, Takayoshi Nagase, Hiroki Bando, Toshikazu Sugiyama, Hiroshi Itoh, Toshio Soma, Masayoshi |
author_sort | Igarashi, Jun |
collection | PubMed |
description | We report a preclinical study of a pyrrole-imidazole (PI) polyamide that targets the human transforming growth factor (hTGF)-β1 gene as a novel transcriptional gene silencer in a common marmoset primate model. We designed and then synthesized PI polyamides to target the hTGF-β1 promoter. We examined effects of seven PI polyamides (GB1101-1107) on the expression of hTGF-β1 mRNA stimulated with phorbol 12-myristate 13-acetate (PMA) in human vascular smooth muscle cells. GB1101, GB1105 and GB1106 significantly inhibited hTGF-β1 mRNA expression. We examined GB1101 as a PI polyamide to hTGF-β1 for hypertrophic scars in marmosets in vivo. Injection of GB1101 completely inhibited hypertrophic scar formation at 35 days post-incision and inhibited cellular infiltration, TGF-β1 and vimentin staining, and epidermal thickness. Mismatch polyamide did not affect hypertrophic scarring or histological changes. Epidermis was significantly thinner with GB1101 than with water and mismatch PI polyamides. We developed the PI polyamides for practical ointment medicines for the treatment of hypertrophic scars. FITC-labeled GB1101 with solbase most efficiently distributed in the nuclei of epidermal keratinocytes, completely suppressed hypertropic scarring at 42 days after incision, and considerably inhibited epidermal thickness and vimentin-positive fibroblasts. PI polyamides targeting hTGF-β1 promoter with solbase ointment will be practical medicines for treating hypertrophic scars after surgical operations and skin burns. |
format | Online Article Text |
id | pubmed-4418757 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-44187572015-05-12 Preclinical Study of Novel Gene Silencer Pyrrole-Imidazole Polyamide Targeting Human TGF-β1 Promoter for Hypertrophic Scars in a Common Marmoset Primate Model Igarashi, Jun Fukuda, Noboru Inoue, Takashi Nakai, Shigeki Saito, Kosuke Fujiwara, Kyoko Matsuda, Hiroyuki Ueno, Takahiro Matsumoto, Yoshiaki Watanabe, Takayoshi Nagase, Hiroki Bando, Toshikazu Sugiyama, Hiroshi Itoh, Toshio Soma, Masayoshi PLoS One Research Article We report a preclinical study of a pyrrole-imidazole (PI) polyamide that targets the human transforming growth factor (hTGF)-β1 gene as a novel transcriptional gene silencer in a common marmoset primate model. We designed and then synthesized PI polyamides to target the hTGF-β1 promoter. We examined effects of seven PI polyamides (GB1101-1107) on the expression of hTGF-β1 mRNA stimulated with phorbol 12-myristate 13-acetate (PMA) in human vascular smooth muscle cells. GB1101, GB1105 and GB1106 significantly inhibited hTGF-β1 mRNA expression. We examined GB1101 as a PI polyamide to hTGF-β1 for hypertrophic scars in marmosets in vivo. Injection of GB1101 completely inhibited hypertrophic scar formation at 35 days post-incision and inhibited cellular infiltration, TGF-β1 and vimentin staining, and epidermal thickness. Mismatch polyamide did not affect hypertrophic scarring or histological changes. Epidermis was significantly thinner with GB1101 than with water and mismatch PI polyamides. We developed the PI polyamides for practical ointment medicines for the treatment of hypertrophic scars. FITC-labeled GB1101 with solbase most efficiently distributed in the nuclei of epidermal keratinocytes, completely suppressed hypertropic scarring at 42 days after incision, and considerably inhibited epidermal thickness and vimentin-positive fibroblasts. PI polyamides targeting hTGF-β1 promoter with solbase ointment will be practical medicines for treating hypertrophic scars after surgical operations and skin burns. Public Library of Science 2015-05-04 /pmc/articles/PMC4418757/ /pubmed/25938472 http://dx.doi.org/10.1371/journal.pone.0125295 Text en © 2015 Igarashi et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Igarashi, Jun Fukuda, Noboru Inoue, Takashi Nakai, Shigeki Saito, Kosuke Fujiwara, Kyoko Matsuda, Hiroyuki Ueno, Takahiro Matsumoto, Yoshiaki Watanabe, Takayoshi Nagase, Hiroki Bando, Toshikazu Sugiyama, Hiroshi Itoh, Toshio Soma, Masayoshi Preclinical Study of Novel Gene Silencer Pyrrole-Imidazole Polyamide Targeting Human TGF-β1 Promoter for Hypertrophic Scars in a Common Marmoset Primate Model |
title | Preclinical Study of Novel Gene Silencer Pyrrole-Imidazole Polyamide Targeting Human TGF-β1 Promoter for Hypertrophic Scars in a Common Marmoset Primate Model |
title_full | Preclinical Study of Novel Gene Silencer Pyrrole-Imidazole Polyamide Targeting Human TGF-β1 Promoter for Hypertrophic Scars in a Common Marmoset Primate Model |
title_fullStr | Preclinical Study of Novel Gene Silencer Pyrrole-Imidazole Polyamide Targeting Human TGF-β1 Promoter for Hypertrophic Scars in a Common Marmoset Primate Model |
title_full_unstemmed | Preclinical Study of Novel Gene Silencer Pyrrole-Imidazole Polyamide Targeting Human TGF-β1 Promoter for Hypertrophic Scars in a Common Marmoset Primate Model |
title_short | Preclinical Study of Novel Gene Silencer Pyrrole-Imidazole Polyamide Targeting Human TGF-β1 Promoter for Hypertrophic Scars in a Common Marmoset Primate Model |
title_sort | preclinical study of novel gene silencer pyrrole-imidazole polyamide targeting human tgf-β1 promoter for hypertrophic scars in a common marmoset primate model |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4418757/ https://www.ncbi.nlm.nih.gov/pubmed/25938472 http://dx.doi.org/10.1371/journal.pone.0125295 |
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