The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.

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Nitric Oxide and Peroxynitrite in Health and Disease

The brain and nervous system are prone to oxidative stress, and are inadequately equipped with antioxidant defense systems to prevent 'ongoing' oxidative damage, let alone the extra oxidative damage imposed by the neurodegenerative diseases. Indeed, increased oxidative damage, mitochondrial dysfunction, accumulation of oxidized aggregated proteins, inflammation, and defects in protein clearance constitute complex intertwined pathologies that conspire to kill neurons. After a long lag period, therapeutic and other interventions based on a knowledge of redox biology are on the horizon for at least some of the neurodegenerative diseases.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1471-4159.2006.03907.x

Oxidative stress and neurodegeneration: where are we now?

The occurrence of protein tyrosine nitration under disease conditions is now firmly established and represents a shift from the signal transducing physiological actions of (.)NO to oxidative and potentially pathogenic pathways. Tyrosine nitration is mediated by reactive nitrogen species such as peroxynitrite anion (ONOO(-)) and nitrogen dioxide ((.)NO2), formed as secondary products of (.)NO metabolism in the presence of oxidants including superoxide radicals (O2(.-)), hydrogen peroxide (H2O2), and transition metal centers. The precise interplay between (.)NO and oxidants and the identification of the proximal intermediate(s) responsible for nitration in vivo have been under controversy. Despite the capacity of peroxynitrite to mediate tyrosine nitration in vitro, its role on nitration in vivo has been questioned, and alternative pathways, including the nitrite/H2O2/hemeperoxidase and transition metal-dependent mechanisms, have been proposed. A balanced analysis of existing evidence indicates that (i) different nitration pathways can contribute to tyrosine nitration in vivo, and (ii) most, if not all, nitration pathways involve free radical biochemistry with carbonate radicals (CO3(.-)) and/or oxo-metal complexes oxidizing tyrosine to tyrosyl radical followed by the diffusion-controlled reaction with (.)NO2 to yield 3-nitrotyrosine. Although protein tyrosine nitration is a low-yield process in vivo, 3-nitrotyrosine has been revealed as a relevant biomarker of (.)NO-dependent oxidative stress; additionally, site-specific nitration focused on particular protein tyrosines may result in modification of function and promote a biological effect. Tissue distribution and quantitation of protein 3-nitrotyrosine, recognition of the predominant nitration pathways and individual identification of nitrated proteins in disease states open new avenues for the understanding and treatment of human pathologies.

https://www.pnas.org/content/pnas/101/12/4003.full.pdf

Nitric oxide, oxidants, and protein tyrosine nitration

Mitochondria and reactive oxygen species.

Reactive oxygen (ROS) and nitrogen (RNS) species cause oxidative and nitrosative stresses, respectively. These stresses are implicated not only in diverse physiological processes but also in various pathological processes, including cancer and neurodegenerative disorders. In addition, some ROS and RNS in the environment are pollutants that threaten human health. As a consequence of these effects, sensitive methods, which can be employed to selectively monitor ROS and RNS in live cells, tissues and organisms as well as in environmental samples, are needed so that their biological roles can be understood and their concentrations in environmental samples can be determined. In this review, fluorescent, luminescent and colorimetric ROS and RNS probes, which have been developed since 2011, are comprehensively discussed.

Célio C.X. Santos

Papers

Nitrogen dioxide and carbonate radical anion: two emerging radicals in biology.

Ischemic preconditioning requires increases in reactive oxygen release independent of mitochondrial K+ channel activity.