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Regulación epigenética en la pancreatitis necrótica aguda

Authors
Publisher
Real Academia Nacional de Farmacia
Publication Date
Disciplines
  • Biology
  • Medicine
  • Pharmacology

Abstract

The acute necrotic pancreatitis (AP) produces, in serious clinical cases, a severe local necrosis, develops several systemic complications and elevate mortality. In the present work we analysed the complex and ordered temporal profile of gene expression of the most important genes related with the initiation of AP induced by taurocholate in rat. They include genes coding for transcriptional factors (f.i. egr-1), intracellular signalling network, adhesion molecules (f.i. icam-1), cytokines (f.i. tnfá) and oxidative stress genes. The analysis of regulation epigenetic mechanisms in three model genes (egr-1, icam-1y tnfá) showed the involvement of different pro-inflammatory transcriptional factors (EGR-1, ATF-2, NF-êB, C/EBPâ or SP1), binding of HAT complexes (CBP) and release of HDAC complexes (HDAC1/ 2-Sin3A-) and site-specific histone modification (H3K9ac, H3K14ac, H4K5ac y H3K4me3). Furthermore, the study of the mechanism of action of the potentially pharmacological agent pentoxyfiline showed that beneficial effect may be produced, at least partially, by repression of different genes, specially egr-1, icam-1 and tnfá, throughout regulation of pro-inflammatory transcriptional factors binding (NF-êB, SP1, C/EBPâ or EGR-1) and inhibition of signalling network ERK1/2 and JNK1/2 involved in the activation of those genes. The results support the potential therapeutic use of pentoxyfilline in the initial phases of AP, or as preventive treatment, since it blocks the pro-inflammatory stimulus generated in AP

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