title: Pretranscriptional regulation of Tgf-beta1 by PI polyamide prevents scarring and accelerates wound healing of the cornea after exposure to alkali.
abstract: Corneal alkali burns are a serious clinical problem that often leads to permanent visual impairment. In this process, transforming growth factor (Tgf)-beta1 is upregulated and involved in the response to corneal injury and the process of corneal stromal scarring. To develop an efficient compound to inhibit Tgf-beta1 in the cornea, we designed GB1201, a pyrrole-imidazole (PI) polyamide targeting rat Tgf-beta1 gene promoter to the activator protein-1 (AP-1) binding site. GB1201 showed a high binding affinity to the target DNA sequence in the gel mobility shift and Biacore assays. GB1201 significantly inhibited the rat Tgf-beta1 gene promoter activity in HEK (human embryonic kidney) 293 cells in a concentration-dependent manner. Topically administrated GB1201 was distributed immediately to the nuclei of all cell layers of the cornea and remained for 24 hours. A corneal alkali burn model in rats was used to evaluate the therapeutic efficacy of GB1201. GB1201 suppressed the upregulation of Tgf-beta1 in the burned cornea, both in the mRNA and protein levels. Moreover, daily treatment with GB1201 for a week significantly improved the corneal tissue wound healing, reduced corneal stromal scarring, and prevented corneal haze formation. Our data suggest that PI polyamide may open new opportunities for therapeutic intervention in the treatment of chemically burned corneas.
authors.affiliation: Life Science, Advanced Research Institute for the Sciences and Humanities (ARISH), Nihon University, Tokyo, Japan.
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Matsuda
authors.forename: Linghua
authors.initials: L
authors.lastname: Wang
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Makoto T
authors.initials: MT
authors.lastname: Kimura
authors.forename: Jun
authors.initials: J
authors.lastname: Igarashi
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Wang
authors.forename: Tohru
authors.initials: T
authors.lastname: Sakimoto
authors.forename: Noboru
authors.initials: N
authors.lastname: Fukuda
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Sawa
authors.forename: Hiroki
authors.initials: H
authors.lastname: Nagase
mesh_terms: D000818:Animals; D001665:Binding Sites; D002921:Cicatrix / Q000517:prevention & control; D003315:Cornea / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D009757:Nylons / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011758:Pyrroles / Q000737:chemistry* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014945:Wound Healing
chemical_list: D007093:Imidazoles; D009757:Nylons; D011758:Pyrroles; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1