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Redox Biology May 2021In the open metabolic system, redox-related signaling requires continuous monitoring and fine-tuning of the steady-state redox set point. The ongoing oxidative... (Review)
Review
In the open metabolic system, redox-related signaling requires continuous monitoring and fine-tuning of the steady-state redox set point. The ongoing oxidative metabolism is a persistent challenge, denoted as oxidative eustress, which operates within a physiological range that has been called the 'Homeodynamic Space', the 'Goldilocks Zone' or the 'Golden Mean'. Spatiotemporal control of redox signaling is achieved by compartmentalized generation and removal of oxidants. The cellular landscape of HO, the major redox signaling molecule, is characterized by orders-of-magnitude concentration differences between organelles. This concentration pattern is mirrored by the pattern of oxidatively modified proteins, exemplified by S-glutathionylated proteins. The review presents the conceptual background for short-term (non-transcriptional) and longer-term (transcriptional/translational) homeostatic mechanisms of stress and stress responses. The redox set point is a variable moving target value, modulated by circadian rhythm and by external influence, summarily denoted as exposome, which includes nutrition and lifestyle factors. Emerging fields of cell-specific and tissue-specific redox regulation in physiological settings are briefly presented, including new insight into the role of oxidative eustress in embryonal development and lifespan, skeletal muscle and exercise, sleep-wake rhythm, and the function of the nervous system with aspects leading to psychobiology.
Topics: Homeostasis; Hydrogen Peroxide; Oxidants; Oxidation-Reduction; Oxidative Stress
PubMed: 33657525
DOI: 10.1016/j.redox.2021.101867 -
Nitric Oxide : Biology and Chemistry Aug 2011
Topics: Humans; Nitric Oxide; Oxidants; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species; Signal Transduction
PubMed: 21596152
DOI: 10.1016/j.niox.2011.05.002 -
The Journal of Biological Chemistry Sep 2013Peroxynitrite is the product of the diffusion-controlled reaction of nitric oxide and superoxide radicals. Peroxynitrite, a reactive short-lived peroxide with a pKa of... (Review)
Review
Peroxynitrite is the product of the diffusion-controlled reaction of nitric oxide and superoxide radicals. Peroxynitrite, a reactive short-lived peroxide with a pKa of 6.8, is a good oxidant and nucleophile. It also yields secondary free radical intermediates such as nitrogen dioxide and carbonate radicals. Much of nitric oxide- and superoxide-dependent cytotoxicity resides on peroxynitrite, which affects mitochondrial function and triggers cell death via oxidation and nitration reactions. Peroxynitrite is an endogenous toxicant but is also a cytotoxic effector against invading pathogens. The biological chemistry of peroxynitrite is modulated by endogenous antioxidant mechanisms and neutralized by synthetic compounds with peroxynitrite-scavenging capacity.
Topics: Animals; Humans; Hydrogen-Ion Concentration; Mitochondria; Nitric Oxide; Nitrogen; Oxidants; Oxidation-Reduction; Peroxynitrous Acid; Superoxide Dismutase; Superoxides; Tyrosine
PubMed: 23861390
DOI: 10.1074/jbc.R113.472936 -
The Journal of Biological Chemistry Oct 2019The free radical nitric oxide (NO) exerts biological effects through the direct and reversible interaction with specific targets ( soluble guanylate cyclase) or through... (Review)
Review
The free radical nitric oxide (NO) exerts biological effects through the direct and reversible interaction with specific targets ( soluble guanylate cyclase) or through the generation of secondary species, many of which can oxidize, nitrosate or nitrate biomolecules. The NO-derived reactive species are typically short-lived, and their preferential fates depend on kinetic and compartmentalization aspects. Their detection and quantification are technically challenging. In general, the strategies employed are based either on the detection of relatively stable end products or on the use of synthetic probes, and they are not always selective for a particular species. In this study, we describe the biologically relevant characteristics of the reactive species formed downstream from NO, and we discuss the approaches currently available for the analysis of NO, nitrogen dioxide (NO), dinitrogen trioxide (NO), nitroxyl (HNO), and peroxynitrite (ONOO/ONOOH), as well as peroxynitrite-derived hydroxyl (HO) and carbonate anion (CO) radicals. We also discuss the biological origins of and analytical tools for detecting nitrite (NO), nitrate (NO), nitrosyl-metal complexes, -nitrosothiols, and 3-nitrotyrosine. Moreover, we highlight state-of-the-art methods, alert readers to caveats of widely used techniques, and encourage retirement of approaches that have been supplanted by more reliable and selective tools for detecting and measuring NO-derived oxidants. We emphasize that the use of appropriate analytical methods needs to be strongly grounded in a chemical and biochemical understanding of the species and mechanistic pathways involved.
Topics: Free Radicals; Humans; Hydroxyl Radical; Nitrates; Nitric Oxide; Oxidants; Oxidation-Reduction; Peroxynitrous Acid; Reactive Nitrogen Species; Systems Biology
PubMed: 31409645
DOI: 10.1074/jbc.REV119.006136 -
Frontiers in Immunology 2021Redox medicine is a new therapeutic concept targeting reactive oxygen species (ROS) and secondary reaction products for health benefit. The concomitant function of ROS... (Review)
Review
Redox medicine is a new therapeutic concept targeting reactive oxygen species (ROS) and secondary reaction products for health benefit. The concomitant function of ROS as intracellular second messengers and extracellular mediators governing physiological redox signaling, and as damaging radicals instigating or perpetuating various pathophysiological conditions will require selective strategies for therapeutic intervention. In addition, the reactivity and quantity of the oxidant species generated, its source and cellular location in a defined disease context need to be considered to achieve the desired outcome. In inflammatory diseases associated with oxidative damage and tissue injury, ROS source specific inhibitors may provide more benefit than generalized removal of ROS. Contemporary approaches in immunity will also include the preservation or even elevation of certain oxygen metabolites to restore or improve ROS driven physiological functions including more effective redox signaling and cell-microenvironment communication, and to induce mucosal barrier integrity, eubiosis and repair processes. Increasing oxidants by host-directed immunomodulation or by exogenous supplementation seems especially promising for improving host defense. Here, we summarize examples of beneficial ROS in immune homeostasis, infection, and acute inflammatory disease, and address emerging therapeutic strategies for ROS augmentation to induce and strengthen protective host immunity.
Topics: Animals; Humans; Immune System Phenomena; Oxidants; Oxidation-Reduction; Reactive Oxygen Species
PubMed: 34149739
DOI: 10.3389/fimmu.2021.698042 -
Antioxidants & Redox Signaling Feb 2010Heme is an essential molecule in aerobic organisms. Heme consists of protoporphyrin IX and a ferrous (Fe(2+)) iron atom, which has high affinity for oxygen (O(2)).... (Review)
Review
Heme is an essential molecule in aerobic organisms. Heme consists of protoporphyrin IX and a ferrous (Fe(2+)) iron atom, which has high affinity for oxygen (O(2)). Hemoglobin, the major oxygen-carrying protein in blood, is the most abundant heme-protein in animals and humans. Hemoglobin consists of four globin subunits (alpha(2)beta(2)), with each subunit carrying a heme group. Ferrous (Fe(2+)) hemoglobin is easily oxidized in circulation to ferric (Fe(3+)) hemoglobin, which readily releases free hemin. Hemin is hydrophobic and intercalates into cell membranes. Hydrogen peroxide can split the heme ring and release "free" redox-active iron, which catalytically amplifies the production of reactive oxygen species. These oxidants can oxidize lipids, proteins, and DNA; activate cell-signaling pathways and oxidant-sensitive, proinflammatory transcription factors; alter protein expression; perturb membrane channels; and induce apoptosis and cell death. Heme-derived oxidants induce recruitment of leukocytes, platelets, and red blood cells to the vessel wall; oxidize low-density lipoproteins; and consume nitric oxide. Heme metabolism, extracellular and intracellular defenses against heme, and cellular cytoprotective adaptations are emphasized. Sickle cell disease, an archetypal example of hemolysis, heme-induced oxidative stress, and cytoprotective adaptation, is reviewed.
Topics: Anemia, Sickle Cell; Animals; Blood Vessels; Enzyme Activation; Heme; Heme Oxygenase-1; Hemin; Hemoglobins; Humans; Hydrogen Peroxide; Mice; Models, Biological; Oxidants; Oxidation-Reduction; Oxidative Stress
PubMed: 19697995
DOI: 10.1089/ars.2009.2822 -
Annals of the American Thoracic Society Mar 2016Research over the past 30 years has identified mechanistic biochemical oxidation pathways that contribute to asthma pathophysiology. Redox imbalance is present in asthma... (Review)
Review
Research over the past 30 years has identified mechanistic biochemical oxidation pathways that contribute to asthma pathophysiology. Redox imbalance is present in asthma and strongly linked to the pathobiology of airflow obstruction, airway hyperreactivity, and remodeling. High levels of reactive oxygen species, reactive nitrogen species, and oxidatively modified proteins in the lung, blood, and urine provide conclusive evidence for pathologic oxidation in asthma. Concurrent loss of antioxidants, such as superoxide dismutases and catalase, is attributed to redox modifications of the enzymes, and further amplifies the oxidative injury in the airway. The presence of high levels of urine bromotyrosine, an oxidation product of eosinophil peroxidase, identifies activated eosinophils, and shows promise for use as a noninvasive biomarker of poor asthma control.
Topics: Asthma; Humans; Lung; Oxidants; Oxidation-Reduction; Oxidative Stress; Reactive Nitrogen Species; Reactive Oxygen Species
PubMed: 27027950
DOI: 10.1513/AnnalsATS.201506-385MG -
Free Radical Biology & Medicine Jul 2022Beta-2-microglobulin (B2M) is synthesized by all nucleated cells and forms part of the major histocompatibility complex (MHC) class-1 present on cell surfaces, which...
Beta-2-microglobulin (B2M) is synthesized by all nucleated cells and forms part of the major histocompatibility complex (MHC) class-1 present on cell surfaces, which presents peptide fragments to cytotoxic CD8 T-lymphocytes, or by association with CD1, antigenic lipids to natural killer T-cells. Knockout of B2M results in loss of these functions and severe combined immunodeficiency. Plasma levels of this protein are low in healthy serum, but are elevated up to 50-fold in some pathologies including chronic kidney disease and multiple myeloma, where it has both diagnostic and prognostic value. High levels of the protein are associated with amyloid formation, with such deposits containing significant levels of modified or truncated protein. In the current study we examine the chemical and structural changes induced of B2M generated by both inflammatory oxidants (HOCl and ONOOH), and photo-oxidation (O) which is linked with immunosuppression. Oxidation results in oligomer formation, with this occurring most readily with HOCl and O, and a loss of native protein conformation. LC-MS analysis provided evidence for nitrated (from ONOOH), chlorinated (from HOCl) and oxidized residues (all oxidants) with damage detected at Tyr, Trp, and Met residues, together with cleavage of the disulfide (cystine) bond. An intermolecular di-tyrosine crosslink is also formed between Tyr10 and Tyr63. The pattern of these modifications is oxidant specific, with ONOOH inducing a greater range of modifications than HOCl. Comparison of the sites of modification with regions identified as amyloidogenic indicate significant co-localization, consistent with the hypothesis that oxidation may contribute, and predispose B2M, to amyloid formation.
Topics: Chromatography, Liquid; Hypochlorous Acid; Oxidants; Oxidation-Reduction; Protein Conformation; Tyrosine
PubMed: 35609861
DOI: 10.1016/j.freeradbiomed.2022.05.012 -
Pathogens and Disease Aug 2016Staphylococcus aureus is a ubiquitous, versatile and dangerous pathogen. It colonizes over 30% of the human population, and is one of the leading causes of death by an... (Review)
Review
Staphylococcus aureus is a ubiquitous, versatile and dangerous pathogen. It colonizes over 30% of the human population, and is one of the leading causes of death by an infectious agent. During S. aureus colonization and invasion, leukocytes are recruited to the site of infection. To combat S. aureus, leukocytes generate an arsenal of reactive species including superoxide, hydrogen peroxide, nitric oxide and hypohalous acids that modify and inactivate cellular macromolecules, resulting in growth defects or death. When S. aureus colonization cannot be cleared by the immune system, antibiotic treatment is necessary and can be effective. Yet, this organism quickly gains resistance to each new antibiotic it encounters. Therefore, it is in the interest of human health to acquire a deeper understanding of how S. aureus evades killing by the immune system. Advances in this field will have implications for the design of future S. aureus treatments that complement and assist the host immune response. In that regard, this review focuses on how S. aureus avoids host-generated oxidative stress, and discusses the mechanisms used by S. aureus to survive oxidative damage including antioxidants, direct repair of damaged proteins, sensing oxidant stress and transcriptional changes. This review will elucidate areas for studies to identify and validate future antimicrobial targets.
Topics: Animals; Gene Expression Regulation; Host-Pathogen Interactions; Humans; Microbial Viability; Neutrophils; Nitric Oxide; Oxidants; Oxidation-Reduction; Oxidative Stress; Respiratory Burst; Staphylococcal Infections; Staphylococcus aureus
PubMed: 27354296
DOI: 10.1093/femspd/ftw060 -
The Journal of Biological Chemistry Dec 2019Exposure of biological molecules to oxidants is inevitable and therefore commonplace. Oxidative stress in cells arises from both external agents and endogenous processes... (Review)
Review
Exposure of biological molecules to oxidants is inevitable and therefore commonplace. Oxidative stress in cells arises from both external agents and endogenous processes that generate reactive species, either purposely ( during pathogen killing or enzymatic reactions) or accidentally ( exposure to radiation, pollutants, drugs, or chemicals). As proteins are highly abundant and react rapidly with many oxidants, they are highly susceptible to, and major targets of, oxidative damage. This can result in changes to protein structure, function, and turnover and to loss or (occasional) gain of activity. Accumulation of oxidatively-modified proteins, due to either increased generation or decreased removal, has been associated with both aging and multiple diseases. Different oxidants generate a broad, and sometimes characteristic, spectrum of post-translational modifications. The kinetics (rates) of damage formation also vary dramatically. There is a pressing need for reliable and robust methods that can detect, identify, and quantify the products formed on amino acids, peptides, and proteins, especially in complex systems. This review summarizes several advances in our understanding of this complex chemistry and highlights methods that are available to detect oxidative modifications-at the amino acid, peptide, or protein level-and their nature, quantity, and position within a peptide sequence. Although considerable progress has been made in the development and application of new techniques, it is clear that further development is required to fully assess the relative importance of protein oxidation and to determine whether an oxidation is a cause, or merely a consequence, of injurious processes.
Topics: Amino Acids; Animals; Anions; Antioxidants; Free Radicals; Humans; Kinetics; Nitric Oxide; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxygen; Peptides; Protein Processing, Post-Translational; Proteins; Reactive Oxygen Species; Ultraviolet Rays
PubMed: 31672919
DOI: 10.1074/jbc.REV119.006217