NO signaling in ARE-mediated gene expression.
ABSTRACT Nitric oxide (NO) and peroxynitrite, which serve as cell signal molecules, activate the antioxidant response element (ARE) for the induction of phase II antioxidant enzymes as an adaptive response. The reactive nitrogen species plays an essential role in Nrf2 activation and Nrf2 binding to the ARE present in the target genes. In this chapter, we describe the system by which the NO signaling pathway regulates ARE-mediated gene expression, which includes immunochemical assessment and gel shift analysis of Nrf2 activation.
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ABSTRACT: NO, produced from l-arginine in a reaction catalyzed by NO synthase, is an endogenous free radical with multiple functions in mammalian cells. Here, we demonstrate that endogenously produced NO can suppress c-Jun N-terminal kinase (JNK) activation in intact cells. Treatment of BV-2 murine microglial cells with IFN-γ induced endogenous NO production, concomitantly suppressing JNK1 activation. Similarly, IFN-γ induced suppression of JNK1 activation in RAW264.7 murine macrophage cells and rat alveolar macrophages. The IFN-γ-induced suppression of JNK1 activation in BV-2, RAW264.7, or rat alveolar macrophage cells was completely prevented by NG-nitro-l-arginine, a NO synthase inhibitor. Interestingly, the IFN-γ-induced suppression of JNK1 activation was not affected by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, an inhibitor of guanylyl cyclase. 8-Bromo-cGMP, a membrane-permeant analogue of cGMP, did not change JNK1 activation in intact cells either. In contrast, S-nitro-N-acetyl-dl-penicillamine (SNAP), a NO donor, inhibited JNK1 activity in vitro. Furthermore, a thiol reducing agent, DTT, reversed not only the in vitro inhibition of JNK1 activity by SNAP but also the in vivo suppression of JNK1 activity by IFN-γ. Substitution of serine for cysteine-116 in JNK1 abolished the inhibitory effect of IFN-γ or SNAP on JNK1 activity in vivo or in vitro, respectively. Moreover, IFN-γ enhanced endogenous S-nitrosylation of JNK1 in RAW264.7 cells. Collectively, our data suggest that endogenous NO mediates the IFN-γ-induced suppression of JNK1 activation in macrophage cells by means of a thiol-redox mechanism.Proceedings of the National Academy of Sciences 01/2001; · 9.74 Impact Factor
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ABSTRACT: NO is considered to be an ubiquitous endogenous system which takes part in body's homeostatic regulations and in pathological events. NO derives from a) the actions of enzymes, the NO Synthases (NOS), which are constitutives (endothelial NOS (eNOS) and nervous NOS (nNOS)) and generate small amounts of NO and have homeostatic functions: and b) from the actions of inducible NOS (iNOS), which generate large amounts of NO and exert protective actions against noxious agents but also toxic effects (e.g. inhibition of enzymes) through the production of peroxynitrite (ONOO-). Modulation of the L-Arg/NO system may be used to obtain favourable therapeutic results, either by promoting (e.g. with NO donors) or by reducing (e.g. with NOS inhibitors) the production of NO. The present chapter will consider two approaches and four groups of potential therapeutic agents: 1) The stimulation of NO production with; a) agents which improve the efficiency of the Kallikrein-Kinin System; b) NO donors. 2) The reduction of excessive NO production with: a) inhibitors of NO Synthases; b) agents that reduce the formation of reactive nitrogen/ oxygen species (RNS / ROS).Current Pharmaceutical Design 02/2004; 10(14):1667-76. · 3.31 Impact Factor
- 07/2009; 58(4):725-725.