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SHR Neuro Cancer Cardio Lipid Metab Microb

Veres, B; Radnai, B; Gallyas, F; Varbiro, G; Berente, Z; Osz, E; Sumegi, B.
Regulation of kinase cascades and transcription factors by a poly(ADP-ribose) polymerase-1 inhibitor, 4-hydroxyquinazoline, in lipopolysaccharide-induced inflammation in mice.
J Pharmacol Exp Ther. 2004; 310(1): 247-255. Doi: 10.1124/jpet.104.065151
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Co-authors Med Uni Graz: Radnai Balazs
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Abstract:: Activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) is involved in numerous pathophysiological conditions. Because PARP-1 knockout mice are resistant to endotoxin-induced shock and inhibitors of the enzyme were reported to have similar beneficial properties, we investigated the effect of 4-hydroxyquinazoline (4-HQN), a potent PARP-1 inhibitor, on the modulation of kinase cascades and the regulation of transcription factors in a rodent septic shock model. T2-weighted magnetic resonance imaging showed the pattern of anatomical localization of the inflammatory response in bacterial lipopolysaccharide (LPS)-treated mice and the anti-inflammatory effect of the PARP-1 inhibitor. We have found that 4-HQN activated the phosphatidylinositol 3 (PI3)-kinase/Akt pathway in lung, liver, and spleen, and down-regulated two elements of the MAP kinase system. Namely, it dramatically attenuated the activation of the LPS-induced extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein (MAP) kinase in a tissue-specific manner. Furthermore, phosphorylation of p90RSK, a downstream target of ERK1/2, showed a similar pattern of down-regulation as did the phosphorylation of ERK1/2 and p38 after LPS and 4-HQN treatment. As a consequence of the aforementioned effects on the kinase pathways, 4-HQN decreased the activation of transcription factor nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1) in LPS-induced endotoxic shock. Our results provide evidence for the first time that the beneficial effects of PARP inhibition in endotoxic shock, such as attenuation of NF-kappaB- and AP-1 transcription factor activation, are mediated, at least partially, through the regulation of the PI3-kinase/Akt pathway and MAP kinase cascades.
Find related publications in this database (using NLM MeSH Indexing): Animals -; HeLa Cells -; Humans -; Inflammation - chemically induced Inflammation - metabolism; Kidney - drug effects Kidney - enzymology; Lipopolysaccharides - pharmacology; Liver - drug effects Liver - enzymology; Magnetic Resonance Imaging -; Mice -; Mice, Inbred BALB C -; Mitogen-Activated Protein Kinases - metabolism; NF-kappa B - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation - drug effects; Phosphotransferases - metabolism; Poly(ADP-ribose) Polymerases - antagonists & inhibitors; Quinazolines - pharmacology; Quinazolinones -; Spleen - drug effects Spleen - enzymology; Transcription Factor AP-1 - metabolism; Tumor Necrosis Factor-alpha - metabolism