Katrina M Miranda

Abstract:

The function of nitric oxide (^•NO) in pathophysiology remains confounding as both protective and cytotoxic effects of ^•NO have been demonstrated in many disease processes. Nitric oxide chemistry culminating in the generation of oxidative as well as nitrosative intermediates have generally been proposed as mediators of pathophysiology and have overshadowed the antioxidant capabilities of ^•NO. However, the counteracting role of ^•NO in providing a balance under conditions of oxidative and nitrosative stress has been underappreciated. The purpose of this review is the discussion of the role of ^•NO as an antioxidant and interceptor of more potent reactive intermediates in normal physiology and disease. © 2004 Bentham Science Publishers Ltd.

PMID: 14642390;Abstract:

The poly(ADP-ribose) polymerase (PARP) family of nuclear enzymes is involved in the detection and signaling of single strand breaks induced either directly by ionizing radiation or indirectly by the sequential action of various DNA repair proteins. Therefore, PARP plays an important role in maintaining genome stability. Because PARP proteins contain two zinc finger motifs, these enzymes can be targets for reactive nitrogen oxide intermediates (RNOS) generated as a result of nitric oxide (NO) biosynthesis in an aerobic environment. The effects of RNOS on the activity of purified PARP were examined using donor compounds. Both NO and nitroxyl (HNO) donors were found to be inhibitory in a similar time and concentration manner, indicating that PARP activity can be modified under both nitrosative and oxidative conditions. Moreover, these RNOS donors elicited comparable PARP inhibition in Sf21 insect cell extract and intact human MCF-7 cancer cells. The concentrations of donor required for 90% inhibition of PARP activity produce RNOS at a similar magnitude to those generated in the cellular microenvironment of activated leukocytes, suggesting that cellular scavenging of RNOS may not be protective against PARP modification and that inhibition of PARP may be significant under inflammatory conditions. © 2003 Elsevier Inc.

PMID: 20666387;PMCID: PMC2912650;Abstract:

The formation and interconversion of nitrogen oxides has been of interest in numerous contexts for decades. Early studies focused on gas-phase reactions, particularly with regard to industrial and atmospheric environments, and on nitrogen fixation. Additionally, investigation of the coordination chemistry of nitric oxide (NO) with hemoglobin dates back nearly a century. With the discovery in the early 1980s that NO is blosynthesized as a molecular signaling agent, the literature has been focused on the biological effects of nitrogen oxides, but the original concerns remain relevant. For instance, hemoglobin has long been known to react with nitrite, but this reductase activity has recently been considered to be important to produce NO under hypoxic conditions. The association of nitrosyl hydride (HNO; also commonly referred to as nitroxyl) with heme proteins can also produce NO by reductive nitrosylation. Furthermore, HNO is considered to be an intermediate in bacterial denitrification, but conclusive identification has been elusive. The authors of this article have approached the bioinorganic chemistry of HNO from different perspectives, which have converged because heme proteins are important biological targets of HNO. © 2010 American Chemical Society.

PMID: 14977040;Abstract:

This review addresses many of the chemical aspects of nitrosative stress mediated by N2O3. From a cellular perspective, N2O3 and the resulting reactive nitrogen oxide species target specific motifs such as thiols, lysine active sites, and zinc fingers and is dependant upon both the rates of production as well as consumption of NO and must be taken into account in order to access the nitrosative environment. Since production and consumption are integral parts of N2O3 generation, we predict that nitrosative stress occurs under specific conditions, such as chronic inflammation. In contrast to conditions of stress, nitrosative chemistry may also provide cellular protection through the regulation of critical signaling pathways. Therefore, a careful evaluation of the chemistry of nitrosation based upon specific experimental conditions may provide a better understanding of how the subtle balance between oxidative and nitrosative stress may be involved in the etiology and control of various disease processes. Copyright © by Walter de Gruyter.

PMID: 10863541;Abstract:

Many cellular functions in physiology are regulated by the direct interaction of NO with target biomolecules. In many pathophysiologic and toxicologic mechanisms, NO first reacts with oxygen, superoxide or other nitrogen oxides to subsequently elicit indirect effects. The balance between nitrosative stress and oxidative stress within a specific biological compartment can determine whether the presence of NO will be ultimately deleterious or beneficial. Nitrosative stress can be defined primarily through reactions mediated by N2O3, a reactive nitrogen oxide species generated by high fluxes of NO in an aerobic environment. In contrast, oxidative stress is mediated primarily by superoxide and peroxides. In addition to reactive oxygen species, several reactive nitrogen oxide species such as peroxynitrite, nitroxyl, and nitrogen dioxide can also impose oxidative stress to a cell. We here describe how the mechanisms of cell death are interwoven in the balance between the different chemical intermediates involved in nitrosative and oxidative stress.