In vitro and ex vivo anti-fibrotic effects of LY2109761, a small molecule inhibitor against TGF-β
| Autor: | Henricus A. M. Mutsaers, Chuthamanee Suthisisang, Adhyatmika Adhyatmika, Theerut Luangmonkong, Koert P. de Jong, S. Suriguga, Dorenda Oosterhuis, Peter Olinga, Amirah Adlia |
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| Přispěvatelé: | Pharmaceutical Technology and Biopharmacy, Nanomedicine & Drug Targeting, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Groningen Institute for Organ Transplantation (GIOT), Biopharmaceuticals, Discovery, Design and Delivery (BDDD) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine TGF-β Down-Regulation Gene Expression Smad2 Protein In Vitro Techniques Toxicology Collagen Type I Cell Line Smad1 Protein 03 medical and health sciences Adenosine Triphosphate In vitro Transforming Growth Factor beta Fibrosis Gene expression medicine Animals Humans Pyrroles Protein phosphorylation Phosphorylation Rats Wistar Pharmacology Tissue Inhibitor of Metalloproteinase-2 biology Chemistry Transforming growth factor beta medicine.disease Rats Cell biology Ex vivo 030104 developmental biology Liver LY2109761 biology.protein Pyrazoles Signal transduction |
| Zdroj: | Luangmonkong, T, Suriguga, S, Adhyatmika, A, Adlia, A, Oosterhuis, D, Suthisisang, C, de Jong, K P, Mutsaers, H A M & Olinga, P 2018, ' In vitro and ex vivo anti-fibrotic effects of LY2109761, a small molecule inhibitor against TGF-β ', Toxicology and Applied Pharmacology, vol. 355, pp. 127-137 . https://doi.org/10.1016/j.taap.2018.07.001 Toxicology and Applied Pharmacology, 355, 127-137. ACADEMIC PRESS INC ELSEVIER SCIENCE |
| ISSN: | 0041-008X |
| DOI: | 10.1016/j.taap.2018.07.001 |
| Popis: | Fibrosis is a pathophysiological state characterized by the excessive formation/deposition of fibrous extracellular matrix. Transforming growth factor-beta (TGF-β) is a central profibrotic mediator, and targeting TGF-β is a promising strategy in the development of drugs for the treatment of fibrosis. Therefore, the effect of LY2109761, a small molecule inhibitor against TGF-β with targets beyond TGF-β signaling, on fibrogenesis was elucidated in vitro (HepG2 cells and LX-2 cells) and ex vivo (human and rat precision-cut liver slices). Our results displayed an anti-fibrotic effect of LY2109761, as it markedly down-regulated gene and protein expression of collagen type 1, as well as gene expression of the inhibitor of metalloproteinases 1. This effect on fibrosis markers was partially mediated by targeting TGF-β signaling, seeing that LY2109761 inhibited TGF-β1 gene expression and SMAD2 protein phosphorylation. Interestingly, particularly at a high concentration, LY2109761 decreased SMAD1 protein phosphorylation and gene expression of the inhibitor of DNA binding 1, which appeared to be TGF-β-independent effects. In conclusion, LY2109761 exhibited preclinical anti-fibrotic effects via both TGF-β-dependent and -independent pathways. These results illustrate that small molecule inhibitors directed against TGF-β could possibly influence numerous signaling pathways and thereby mitigate fibrogenesis. |
| Databáze: | OpenAIRE |
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