title: Prevention of liver fibrosis by triple helix-forming oligodeoxyribonucleotides targeted to the promoter region of type I collagen gene.
abstract: Hepatic fibrosis leading to cirrhosis remains a global health problem. The most common etiologies are alcoholism and viral infections. Liver fibrosis is associated with major changes in both quantity and composition of extracellular matix and leads to disorganization of the liver architecture and irreversible damage to the liver function. As of now there is no effective therapy to control fibrosis. The end product of fibrosis is abnormal synthesis and accumulation of type I collagen in the extracellular matrix, which is produced by activated stellate or Ito cells in the damaged liver. Therefore, inhibition of transcription of type I collagen should in principle inhibit its production and accumulation in liver. Normally, DNA exists in a duplex form. However, under some circumstances, DNA can assume triple helical (triplex) structures. Intermolecular triplexes, formed by the addition of a sequence-specific third strand to the major groove of the duplex DNA, have the potential to serve as selective gene regulators. Earlier, we demonstrated efficient triplex formation between the exogenously added triplex-forming oligodeoxyribonucleotides (TFOs) and a specific sequence in the promoter region of the COL1A1 gene. In this study we used a rat model of liver fibrosis, induced by dimethylnitrosamine, to test whether these TFOs prevent liver fibrosis. Our results indicate that both the 25-mer and 18-mer TFOs, specific for the upstream nucleotide sequence from -141 to -165 (relative to the transcription start site) in the 5' end of collagen gene promoter, effectively prevented accumulation of liver collagen and fibrosis. We also observed improvement in liver function tests. However, mutations in the TFO that eliminated formation of triplexes are ineffective in preventing fibrosis. We believe that these TFOs can be used as potential antifibrotic therapeutic molecules.
authors.affiliation: Department of Molecular Sciences, The University of Tennessee Health Science Center , Memphis, TN, USA.
authors.forename: Subramaniyan
authors.initials: S
authors.lastname: Koilan
authors.forename: David
authors.initials: D
authors.lastname: Hamilton
authors.forename: Narina
authors.initials: N
authors.lastname: Baburyan
authors.forename: Mythili K
authors.initials: MK
authors.lastname: Padala
authors.forename: Karl T
authors.initials: KT
authors.lastname: Weber
authors.forename: Ramareddy V
authors.initials: RV
authors.lastname: Guntaka
mesh_terms: D000818:Animals; D024042:Collagen Type I / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000737:chemistry; D004195:Disease Models, Animal; D006801:Humans; D008103:Liver Cirrhosis / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage*; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D024042:Collagen Type I; D009838:Oligodeoxyribonucleotides; D004247:DNA
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