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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.

Igarashi J, Fukuda N, Inoue T, Nakai S, Saito K, Fujiwara K, Matsuda H, Ueno T, Matsumoto Y, Watanabe T, Nagase H, Bando T, Sugiyama H, Itoh T, Soma M - PLoS ONE (2015)

Bottom Line: GB1101, GB1105 and GB1106 significantly inhibited hTGF-β1 mRNA expression.Mismatch polyamide did not affect hypertrophic scarring or histological changes.Epidermis was significantly thinner with GB1101 than with water and mismatch PI polyamides.

View Article: PubMed Central - PubMed

Affiliation: Department of General Medicine, Nihon University School of Medicine, Tokyo, Japan.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Effects of injection of pyrrole-imidazole (PI) polyamide targeting human transforming growth factor (TGF)-β1 promoter (GB1101) on development of hypertrophic scars.Hypertrophic scars were created on marmoset abdomen skin by scalpel incision. A mixture of 100 μg of GB1101 and mismatch PI polyamides dissolved in 500 μl of H2O (Water) was subcutaneously injected into the wound site just before incision. (A) Typical macroscopic changes on post-incision days 21 and days 35 (two experiments) from 5 experiments. Arrows indicate hypertrophic scars. Bar = 5 mm. (B) Sections of 6 μm in thickness at 35 days post-incision from 4 experiments were stained with hematoxylin-eosin. Arrows indicate dermal thickness of hypertrophic scars. Bar = 500 μm. (C) Comparison of water, mismatch PI polyamide and GB1101 injection on epidermal thickness of hypertrophic scars at 35 days post-incision. Values are expressed as mean ± SE (n = 4). * p < 0.01 vs. Mismatch PI polyamide.
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pone.0125295.g004: Effects of injection of pyrrole-imidazole (PI) polyamide targeting human transforming growth factor (TGF)-β1 promoter (GB1101) on development of hypertrophic scars.Hypertrophic scars were created on marmoset abdomen skin by scalpel incision. A mixture of 100 μg of GB1101 and mismatch PI polyamides dissolved in 500 μl of H2O (Water) was subcutaneously injected into the wound site just before incision. (A) Typical macroscopic changes on post-incision days 21 and days 35 (two experiments) from 5 experiments. Arrows indicate hypertrophic scars. Bar = 5 mm. (B) Sections of 6 μm in thickness at 35 days post-incision from 4 experiments were stained with hematoxylin-eosin. Arrows indicate dermal thickness of hypertrophic scars. Bar = 500 μm. (C) Comparison of water, mismatch PI polyamide and GB1101 injection on epidermal thickness of hypertrophic scars at 35 days post-incision. Values are expressed as mean ± SE (n = 4). * p < 0.01 vs. Mismatch PI polyamide.

Mentions: Macroscopic changes in the incisional wounds in marmosets subcutaneously injected with GB1101 are shown in Fig 4A. One hundred micrograms of GB1101 and mismatch PI polyamides were subcutaneously injected into the wound site just before incision. On days 21 and 35, the incisional wound was elevated and obviously harder to the touch in comparison to the surrounding normal skin. Injection of GB1101 completely inhibited the formation of hypertrophic scars after incision compared to injection of water at 35 days post-incision. Mismatch polyamide did not affect the formation of hypertrophic scars (Fig 4A).


Preclinical Study of Novel Gene Silencer Pyrrole-Imidazole Polyamide Targeting Human TGF-β1 Promoter for Hypertrophic Scars in a Common Marmoset Primate Model.

Igarashi J, Fukuda N, Inoue T, Nakai S, Saito K, Fujiwara K, Matsuda H, Ueno T, Matsumoto Y, Watanabe T, Nagase H, Bando T, Sugiyama H, Itoh T, Soma M - PLoS ONE (2015)

Effects of injection of pyrrole-imidazole (PI) polyamide targeting human transforming growth factor (TGF)-β1 promoter (GB1101) on development of hypertrophic scars.Hypertrophic scars were created on marmoset abdomen skin by scalpel incision. A mixture of 100 μg of GB1101 and mismatch PI polyamides dissolved in 500 μl of H2O (Water) was subcutaneously injected into the wound site just before incision. (A) Typical macroscopic changes on post-incision days 21 and days 35 (two experiments) from 5 experiments. Arrows indicate hypertrophic scars. Bar = 5 mm. (B) Sections of 6 μm in thickness at 35 days post-incision from 4 experiments were stained with hematoxylin-eosin. Arrows indicate dermal thickness of hypertrophic scars. Bar = 500 μm. (C) Comparison of water, mismatch PI polyamide and GB1101 injection on epidermal thickness of hypertrophic scars at 35 days post-incision. Values are expressed as mean ± SE (n = 4). * p < 0.01 vs. Mismatch PI polyamide.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4418757&req=5

pone.0125295.g004: Effects of injection of pyrrole-imidazole (PI) polyamide targeting human transforming growth factor (TGF)-β1 promoter (GB1101) on development of hypertrophic scars.Hypertrophic scars were created on marmoset abdomen skin by scalpel incision. A mixture of 100 μg of GB1101 and mismatch PI polyamides dissolved in 500 μl of H2O (Water) was subcutaneously injected into the wound site just before incision. (A) Typical macroscopic changes on post-incision days 21 and days 35 (two experiments) from 5 experiments. Arrows indicate hypertrophic scars. Bar = 5 mm. (B) Sections of 6 μm in thickness at 35 days post-incision from 4 experiments were stained with hematoxylin-eosin. Arrows indicate dermal thickness of hypertrophic scars. Bar = 500 μm. (C) Comparison of water, mismatch PI polyamide and GB1101 injection on epidermal thickness of hypertrophic scars at 35 days post-incision. Values are expressed as mean ± SE (n = 4). * p < 0.01 vs. Mismatch PI polyamide.
Mentions: Macroscopic changes in the incisional wounds in marmosets subcutaneously injected with GB1101 are shown in Fig 4A. One hundred micrograms of GB1101 and mismatch PI polyamides were subcutaneously injected into the wound site just before incision. On days 21 and 35, the incisional wound was elevated and obviously harder to the touch in comparison to the surrounding normal skin. Injection of GB1101 completely inhibited the formation of hypertrophic scars after incision compared to injection of water at 35 days post-incision. Mismatch polyamide did not affect the formation of hypertrophic scars (Fig 4A).

Bottom Line: GB1101, GB1105 and GB1106 significantly inhibited hTGF-β1 mRNA expression.Mismatch polyamide did not affect hypertrophic scarring or histological changes.Epidermis was significantly thinner with GB1101 than with water and mismatch PI polyamides.

View Article: PubMed Central - PubMed

Affiliation: Department of General Medicine, Nihon University School of Medicine, Tokyo, Japan.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus