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American Journal of Physiology. Cell... Oct 2008Free radical-induced macromolecular damage has been studied extensively as a mechanism of oxidative stress, but large-scale intervention trials with free radical... (Review)
Review
Free radical-induced macromolecular damage has been studied extensively as a mechanism of oxidative stress, but large-scale intervention trials with free radical scavenging antioxidant supplements show little benefit in humans. The present review summarizes data supporting a complementary hypothesis for oxidative stress in disease that can occur without free radicals. This hypothesis, which is termed the "redox hypothesis," is that oxidative stress occurs as a consequence of disruption of thiol redox circuits, which normally function in cell signaling and physiological regulation. The redox states of thiol systems are sensitive to two-electron oxidants and controlled by the thioredoxins (Trx), glutathione (GSH), and cysteine (Cys). Trx and GSH systems are maintained under stable, but nonequilibrium conditions, due to a continuous oxidation of cell thiols at a rate of about 0.5% of the total thiol pool per minute. Redox-sensitive thiols are critical for signal transduction (e.g., H-Ras, PTP-1B), transcription factor binding to DNA (e.g., Nrf-2, nuclear factor-kappaB), receptor activation (e.g., alphaIIbbeta3 integrin in platelet activation), and other processes. Nonradical oxidants, including peroxides, aldehydes, quinones, and epoxides, are generated enzymatically from both endogenous and exogenous precursors and do not require free radicals as intermediates to oxidize or modify these thiols. Because of the nonequilibrium conditions in the thiol pathways, aberrant generation of nonradical oxidants at rates comparable to normal oxidation may be sufficient to disrupt function. Considerable opportunity exists to elucidate specific thiol control pathways and develop interventional strategies to restore normal redox control and protect against oxidative stress in aging and age-related disease.
Topics: Free Radicals; Oxidants; Oxidative Stress
PubMed: 18684987
DOI: 10.1152/ajpcell.00283.2008 -
Physiological Reviews Jan 2002At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At... (Review)
Review
At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, however, nitric oxide (NO), superoxide anion, and related reactive oxygen species (ROS) play an important role as regulatory mediators in signaling processes. Many of the ROS-mediated responses actually protect the cells against oxidative stress and reestablish "redox homeostasis." Higher organisms, however, have evolved the use of NO and ROS also as signaling molecules for other physiological functions. These include regulation of vascular tone, monitoring of oxygen tension in the control of ventilation and erythropoietin production, and signal transduction from membrane receptors in various physiological processes. NO and ROS are typically generated in these cases by tightly regulated enzymes such as NO synthase (NOS) and NAD(P)H oxidase isoforms, respectively. In a given signaling protein, oxidative attack induces either a loss of function, a gain of function, or a switch to a different function. Excessive amounts of ROS may arise either from excessive stimulation of NAD(P)H oxidases or from less well-regulated sources such as the mitochondrial electron-transport chain. In mitochondria, ROS are generated as undesirable side products of the oxidative energy metabolism. An excessive and/or sustained increase in ROS production has been implicated in the pathogenesis of cancer, diabetes mellitus, atherosclerosis, neurodegenerative diseases, rheumatoid arthritis, ischemia/reperfusion injury, obstructive sleep apnea, and other diseases. In addition, free radicals have been implicated in the mechanism of senescence. That the process of aging may result, at least in part, from radical-mediated oxidative damage was proposed more than 40 years ago by Harman (J Gerontol 11: 298-300, 1956). There is growing evidence that aging involves, in addition, progressive changes in free radical-mediated regulatory processes that result in altered gene expression.
Topics: Aging; Animals; Cell Physiological Phenomena; Disease; Free Radicals; Humans; Oxidation-Reduction; Oxidative Stress; Signal Transduction; Stress, Physiological
PubMed: 11773609
DOI: 10.1152/physrev.00018.2001 -
Cell Feb 2005The free radical theory of aging postulates that the production of intracellular reactive oxygen species is the major determinant of life span. Numerous cell culture,... (Review)
Review
The free radical theory of aging postulates that the production of intracellular reactive oxygen species is the major determinant of life span. Numerous cell culture, invertebrate, and mammalian models exist that lend support to this half-century-old hypothesis. Here we review the evidence that both supports and conflicts with the free radical theory and examine the growing link between mitochondrial metabolism, oxidant formation, and the biology of aging.
Topics: Aging; Animals; Free Radicals; Mitochondria; Mutation; Nutritional Physiological Phenomena; Oxidants; Reactive Oxygen Species; Yeasts
PubMed: 15734681
DOI: 10.1016/j.cell.2005.02.001 -
Oxidative Medicine and Cellular... 2016
Topics: Aging; Animals; Antioxidants; Exercise; Free Radicals; Humans; Killer Cells, Natural; Rats
PubMed: 26949447
DOI: 10.1155/2016/3813680 -
Proceedings of the National Academy of... Jun 2018Oxygen-derived free radicals and related oxidants are ubiquitous and short-lived intermediates formed in aerobic organisms throughout life. These reactive species... (Review)
Review
Oxygen-derived free radicals and related oxidants are ubiquitous and short-lived intermediates formed in aerobic organisms throughout life. These reactive species participate in redox reactions leading to oxidative modifications in biomolecules, among which proteins and lipids are preferential targets. Despite a broad array of enzymatic and nonenzymatic antioxidant systems in mammalian cells and microbes, excess oxidant formation causes accumulation of new products that may compromise cell function and structure leading to cell degeneration and death. Oxidative events are associated with pathological conditions and the process of normal aging. Notably, physiological levels of oxidants also modulate cellular functions via homeostatic redox-sensitive cell signaling cascades. On the other hand, nitric oxide (NO), a free radical and weak oxidant, represents a master physiological regulator via reversible interactions with heme proteins. The bioavailability and actions of NO are modulated by its fast reaction with superoxide radical ([Formula: see text]), which yields an unusual and reactive peroxide, peroxynitrite, representing the merging of the oxygen radicals and NO pathways. In this Inaugural Article, I summarize early and remarkable developments in free radical biochemistry and the later evolution of the field toward molecular medicine; this transition includes our contributions disclosing the relationship of NO with redox intermediates and metabolism. The biochemical characterization, identification, and quantitation of peroxynitrite and its role in disease processes have concentrated much of our attention. Being a mediator of protein oxidation and nitration, lipid peroxidation, mitochondrial dysfunction, and cell death, peroxynitrite represents both a pathophysiologically relevant endogenous cytotoxin and a cytotoxic effector against invading pathogens.
Topics: Animals; Biomedical Research; Free Radicals; Humans; Molecular Medicine; Nitric Oxide; Oxidation-Reduction; Peroxynitrous Acid; Proteins; Superoxide Dismutase; Tyrosine
PubMed: 29802228
DOI: 10.1073/pnas.1804932115 -
International Journal of Molecular... Feb 2021Since the discovery in 1922 of 2,2-diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl stable free radical (DPPH), the chemistry of such open-shell compounds has developed... (Review)
Review
Since the discovery in 1922 of 2,2-diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl stable free radical (DPPH), the chemistry of such open-shell compounds has developed continuously, allowing for both theoretical and practical advances in the free radical chemistry area. This review presents the important, general and modern aspects of the chemistry of hydrazyl free radicals and the science behind it.
Topics: Electron Spin Resonance Spectroscopy; Free Radicals; Halogens; Models, Chemical; Molecular Structure; Nitrogen Dioxide
PubMed: 33546504
DOI: 10.3390/ijms22041545 -
Molecules (Basel, Switzerland) Mar 2022Some of the most interesting aspects of free radical chemistry that emerged in the last two decades are radical enzyme mechanisms, cell signaling cascades, antioxidant...
Some of the most interesting aspects of free radical chemistry that emerged in the last two decades are radical enzyme mechanisms, cell signaling cascades, antioxidant activities, and free radical-induced damage of biomolecules. In addition, identification of modified biomolecules opened the way for the evaluation of in vivo damage through biomarkers. When studying free radical-based chemical mechanisms, it is very important to establish biomimetic models, which allow the experiments to be performed in a simplified environment, but suitably designed to be in strict connection with cellular conditions. The 28 papers (11 reviews and 17 articles) published in the two Special Issues of on "Biomimetic Radical Chemistry and Applications (2019 and 2021)" show a remarkable range of research in this area. The biomimetic approach is presented with new insights and reviews of the current knowledge in the field of radical-based processes relevant to health, such as biomolecular damages and repair, signaling and biomarkers, biotechnological applications, and novel synthetic approaches.
Topics: Biomarkers; Biomimetics; Free Radicals
PubMed: 35408441
DOI: 10.3390/molecules27072042 -
Analytical Chemistry Oct 2020The inherent structural complexity and diversity of glycans pose a major analytical challenge to their structural analysis. Radical chemistry has gained considerable...
The inherent structural complexity and diversity of glycans pose a major analytical challenge to their structural analysis. Radical chemistry has gained considerable momentum in the field of mass spectrometric biomolecule analysis, including proteomics, glycomics, and lipidomics. Herein, seven isomeric disaccharides and two isomeric tetrasaccharides with subtle structural differences are distinguished rapidly and accurately via one-step radical-induced dissociation. The free-radical-activated glycan-sequencing reagent (FRAGS) selectively conjugates to the unique reducing terminus of glycans in which a localized nascent free radical is generated upon collisional activation and simultaneously induces glycan fragmentation. Higher-energy collisional dissociation (HCD) and collision-induced dissociation (CID) are employed to provide complementary structural information for the identification and discrimination of glycan isomers by providing different fragmentation pathways to generate informative, structurally significant product ions. Furthermore, multiple-stage tandem mass spectrometry (MS CID) provides supplementary and valuable structural information through the generation of characteristic parent-structure-dependent fragment ions.
Topics: Chromatography, High Pressure Liquid; Disaccharides; Free Radicals; Isomerism; Polysaccharides; Tandem Mass Spectrometry
PubMed: 32935980
DOI: 10.1021/acs.analchem.0c02213 -
The FEBS Journal Nov 2022Molecular oxygen possesses a dual nature due to its highly reactive free radical property: it is capable of oxidizing metabolic substrates to generate cellular energy,... (Review)
Review
Molecular oxygen possesses a dual nature due to its highly reactive free radical property: it is capable of oxidizing metabolic substrates to generate cellular energy, but can also serve as a substrate for genotoxic reactive oxygen species generation. As a labile substance upon which aerobic life depends, the mechanisms for handling cellular oxygen have been fine-tuned and orchestrated in evolution. Protection from atmospheric oxygen toxicity as originally posited by the Endosymbiotic Theory of the Mitochondrion is likely to be one basic principle underlying oxygen homeostasis. We briefly review the literature on oxygen homeostasis both in vitro and in vivo with a focus on the role of the mitochondrion where the majority of cellular oxygen is consumed. The insights gleaned from these basic mechanisms are likely to be important for understanding disease pathogenesis and developing strategies for maintaining health.
Topics: Mitochondria; Free Radicals; Oxygen; Homeostasis; Reactive Oxygen Species; Oxidative Stress
PubMed: 34235856
DOI: 10.1111/febs.16115 -
Nicotine & Tobacco Research : Official... Aug 2019Free radicals and carbonyls produced by electronic cigarettes (e-cigs) have the potential to inflict oxidative stress. Recently, Juul e-cigs have risen drastically in...
INTRODUCTION
Free radicals and carbonyls produced by electronic cigarettes (e-cigs) have the potential to inflict oxidative stress. Recently, Juul e-cigs have risen drastically in popularity; however, there is no data on nicotine and oxidant yields from this new e-cig design.
METHODS
Aerosol generated from four different Juul flavors was analyzed for carbonyls, nicotine, and free radicals. The e-liquids were analyzed for propylene glycol (PG) and glycerol (GLY) concentrations. To determine the effects of e-liquid on oxidant production, Juul pods were refilled with nicotine-free 30:70 or 60:40 PG:GLY with or without citral.
RESULTS
No significant differences were found in nicotine (164 ± 41 µg/puff), free radical (5.85 ± 1.20 pmol/puff), formaldehyde (0.20 ± 0.10 µg/puff), and acetone (0.20 ± 0.05 µg/puff) levels between flavors. The PG:GLY ratio in e-liquids was ~30:70 across all flavors with GLY being slightly higher in tobacco and mint flavors. In general, when Juul e-liquids were replaced with nicotine-free 60:40 PG:GLY, oxidant production increased up to 190% and, with addition of citral, increased even further.
CONCLUSIONS
Juul devices produce free radicals and carbonyls, albeit, at levels substantially lower than those observed in other e-cig products, an effect only partially because of a low PG:GLY ratio. Nicotine delivery by these devices was as high as or higher than the levels previously reported from cigarettes.
IMPLICATIONS
These findings suggest that oxidative stress and/or damage resulting from Juul use may be lower than that from cigarettes or other e-cig devices; however, the high nicotine levels are suggestive of a greater addiction potential.
Topics: Electronic Nicotine Delivery Systems; Flavoring Agents; Free Radicals; Humans; Nicotine; Oxidative Stress; Propylene Glycol
PubMed: 30346584
DOI: 10.1093/ntr/nty221