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A novel nonsteroidal antifibrotic oligo decoy containing the TGF‐β element found in the COL1A1 gene which regulates murine schistosomiasis liver fibrosis
Author(s) -
Boros D.L.,
Singh K.P.,
Gerard H.C.,
Hudson A.P.,
White S.L.,
Cutroneo K.R.
Publication year - 2005
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.20412
Subject(s) - decoy , biology , microbiology and biotechnology , fibrosis , schistosoma mansoni , gene , transforming growth factor , schistosomiasis , immunology , pathology , endocrinology , receptor , biochemistry , medicine , helminths
Schistosomiasis mansoni disseminated worm eggs in mice and humans induce granulomatous inflammations and cumulative fibrosis causing morbidity and possibly mortality. In this study, intrahepatic and I.V. injections of a double‐stranded oligodeoxynucleotide decoy containing the TGF‐β regulatory element found in the distal promoter of the COL1A1 gene into worm‐infected mice suppressed TGF‐β1, COL1A1, tissue inhibitor of metalloproteinase‐1, and decreased COL3A1 mRNAs to a lesser extent. Sequence comparisons within the mouse genome found homologous sequences within the COL3A1, TGF‐β1, and TIMP‐1 5′ flanking regions. Cold competition gel mobility shift assays using these homologous sequences with 5′ and 3′ flanking regions found in the natural COL1A1 gene showed competition. Competitive gel mobility assays in a separate experiment showed no competition using a 5‐base mutated or scrambled sequence. Explanted liver granulomas from saline‐injected mice incorporated 10.45 ± 1.7% 3 H‐proline into newly synthesized collagen, whereas decoy‐treated mice showed no collagen synthesis. Compared with the saline control schistosomiasis mice phosphorothioate double‐stranded oligodeoxynucleotide treatment decreased total liver collagen content (i.e. hydroxy‐4‐proline) by 34%. This novel molecular approach has the potential to be employed as a novel antifibrotic treatment modality. © 2005 Wiley‐Liss, Inc.