| In Vitro | In vitro activity: Pirfenidone (< 300 μg/mL) suppresses the proinflammatory cytokine tumor necrosis factor-α (TNF-α) by a translational mechanism in RAW264.7 cells, which is independent of activation of the mitogen-activated protain kinase (MAPK) 2, p38 MAP kinase, and c-Jun N-terminal kinase (JNK). Pirfenidone (< 10 mM) leads to reduced glioma cell density in concentration-dependent manner in LN-18, T98G, LNT-229 and LN-308 cell lines. Pirfenidone (< 5 mM) reduces TGF-β bioactivity by affecting TGF-β2 mRNA expression and processing of pro-TGF-β in CCL-64 cells. Pirfenidone (< 8.3 mM) inhibits the activity of recombinant furin and downregulates the expression of MMP-11 in a dose-dependent manner in LN-308 cells.
Kinase Assay:
Cell Assay: In RAW264.7 cells, Pirfenidone (< 300 μg/mL) suppressed the proinflammatory cytokine tumor necrosis factor-α (TNF-α) through a translational mechanism, which was independent of activation of the mitogen-activated protein kinase (MAPK)2, p38 MAP kinase, and c-Jun N-terminal kinase (JNK). In LN-18, T98G, LNT-229 and LN-308 cell lines, Pirfenidone (< 10 mM) reduced glioma cell density in a concentration-dependent manner. In CCL-64 cells, Pirfenidone (< 5 mM) reduced TGF-β bioactivity by affecting TGF-β2 mRNA expression and processing of pro-TGF-β. Pirfenidone (< 8.3 mM) inhibited the activity of recombinant furin and downregulated the expression of MMP-11 in a dose-dependent manner in LN-308 cells. In cultured myometrial and leiomyoma smooth muscle cells, pirfenidone inhibited serum-stimulated increases in DNA synthesis and cell proliferation in a dose-dependent manner. |
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| In Vivo | Pirfenidone (250 mg/kg) potently inhibits the production of the proinflammatory cytokines, TNF-alpha, interferon-gamma, and interleukin-6, but enhances the production of the anti-inflammatory cytokine, interleukin-10, in mice. Pirfenidone (250 mg/kg/day) ameliorates cyclosporine-induced fibrosis by about 50% and decreases TGF-beta1 protein expression by 80% in Sprague-Dawley rats receiving a low-salt diet. Pirfenidone (400 mg/kg/day) inhibits heat shock protein 47-positive cells and myofibroblasts, the principal cells responsible for the accumulation and deposition of extracellular matrix seen in pulmonary fibrosis in ICR mice intravenously injected with bleomycin. Pirfenidone (0.5%, liquid diet) treatment reduces the degree of liver injury in rats, as determined by alanine aminotransferase values and necro-inflammatory score, which is associated with reduced hepatic stellate cells proliferation and collagen deposition. Pirfenidone (0.5%, liquid diet) administration downregulates dimethylnitrosamine induced transcripts levels of procollagen alpha1(I), TIMP-1 and MMP-2 by 50-60% in rats, and this is associated with a 70% reduction in collagen deposition. |
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