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1.
PLoS One ; 10(5): e0125295, 2015.
Article in English | MEDLINE | ID: mdl-25938472

ABSTRACT

We report a preclinical study of a pyrrole-imidazole (PI) polyamide that targets the human transforming growth factor (hTGF)-ß1 gene as a novel transcriptional gene silencer in a common marmoset primate model. We designed and then synthesized PI polyamides to target the hTGF-ß1 promoter. We examined effects of seven PI polyamides (GB1101-1107) on the expression of hTGF-ß1 mRNA stimulated with phorbol 12-myristate 13-acetate (PMA) in human vascular smooth muscle cells. GB1101, GB1105 and GB1106 significantly inhibited hTGF-ß1 mRNA expression. We examined GB1101 as a PI polyamide to hTGF-ß1 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-ß1 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-ß1 promoter with solbase ointment will be practical medicines for treating hypertrophic scars after surgical operations and skin burns.


Subject(s)
Cicatrix, Hypertrophic/therapy , Gene Silencing , Gene Targeting , Imidazoles/chemistry , Nylons/chemistry , Promoter Regions, Genetic , Pyrroles/chemistry , Transforming Growth Factor beta1/genetics , Animals , Base Sequence , Binding Sites , Callithrix , Disease Models, Animal , Humans , Injections , Male , Molecular Sequence Data , Ointments , RNA, Messenger/genetics , RNA, Messenger/metabolism
2.
Perit Dial Int ; 32(4): 462-72, 2012.
Article in English | MEDLINE | ID: mdl-22215658

ABSTRACT

OBJECTIVE: Encapsulating peritoneal sclerosis (EPS) is a devastating fibrotic complication in patients treated with peritoneal dialysis (PD). Transforming growth factor ß1 (TGF-ß1) is a pivotal factor in the induction of EPS. METHODS: To develop pyrrole-imidazole (PI) polyamide, a novel gene silencer, targeted to the TGF-ß1 promoter (Polyamide) for EPS, we examined the effects of Polyamide on messenger RNA (mRNA) expression of TGF-ß1, vascular endothelial growth factor (VEGF), and extracellular matrix (ECM) in mesothelial cells in vitro, and on the thickness of injured peritoneum evaluated by histology and high-resolution regional elasticity mapping in rats in vivo. RESULTS: Polyamide significantly lowered mRNA expression of TGF-ß1 and ECM in vitro. Polyamide labeled with fluorescein isothiocyanate was taken up into the injured peritoneum and was strongly localized in the nuclei of most cells. Polyamide 1 mg was injected intraperitoneally 1 or 3 times in rats receiving a daily intraperitoneal injection of chlorhexidine gluconate and ethanol (CHX) for 14 days. Polyamide significantly suppressed peritoneal thickening and the abundance of TGF-ß1 and fibronectin mRNA, but did not affect expression of VEGF mRNA in the injured peritoneum. Elasticity distribution mapping showed that average elasticity was significantly lower in Polyamide-treated rats than in rats treated solely with CHX. CONCLUSIONS: Polyamide suppressed the stiffness, ECM formation, and thickening of the injured peritoneum that occurs during EPS pathogenesis. These data suggest that PI polyamide targeted to the TGF-ß1 promoter will be a specific and feasible therapeutic strategy for patients with EPS.


Subject(s)
Imidazoles/pharmacology , Nylons/pharmacology , Peritoneal Dialysis/adverse effects , Peritoneal Fibrosis/metabolism , Peritoneum/metabolism , Pyrroles/pharmacology , Transforming Growth Factor beta1/metabolism , Vascular Endothelial Growth Factor A/metabolism , Animals , Cells, Cultured , Electrophoretic Mobility Shift Assay , Extracellular Matrix , Gene Silencing , Imidazoles/therapeutic use , Male , Peritoneal Fibrosis/genetics , Peritoneum/drug effects , Pyrroles/therapeutic use , RNA, Messenger/biosynthesis , Rats , Rats, Sprague-Dawley , Rats, Wistar , Transforming Growth Factor beta1/genetics , Vascular Endothelial Growth Factor A/genetics
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