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| superoxide |
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| CHEBI:18421 |
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This entity has been manually annotated by the ChEBI Team.
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CHEBI:7710, CHEBI:15143, CHEBI:26839
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| No supplier information found for this compound. |
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Molfile
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SDF
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more structures >>
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| In chemistry, a superoxide is a compound that contains the superoxide ion, which has the chemical formula O−2. The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature. Molecular oxygen (dioxygen) is a diradical containing two unpaired electrons, and superoxide results from the addition of an electron which fills one of the two degenerate molecular orbitals, leaving a charged ionic species with a single unpaired electron and a net negative charge of −1. Both dioxygen and the superoxide anion are free radicals that exhibit paramagnetism. Superoxide was historically also known as "hyperoxide". |
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Read full article at Wikipedia
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| InChI=1S/HO2/c1-2/h1H/p-1 |
| OUUQCZGPVNCOIJ-UHFFFAOYSA-M |
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Mus musculus
(NCBI:txid10090)
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Source: BioModels - MODEL1507180067
See:
PubMed
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Escherichia coli
(NCBI:txid562)
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See:
PubMed
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Homo sapiens
(NCBI:txid9606)
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See:
DOI
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Escherichia coli metabolite
Any bacterial metabolite produced during a metabolic reaction in Escherichia coli.
human metabolite
Any mammalian metabolite produced during a metabolic reaction in humans (Homo sapiens).
mouse metabolite
Any mammalian metabolite produced during a metabolic reaction in a mouse (Mus musculus).
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View more via ChEBI Ontology
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dioxidanidyl
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dioxide(•1−)
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(O2)•−
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IUPAC
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Dioxid(1−)
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ChEBI
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dioxide(1−)
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IUPAC
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hiperóxido
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ChEBI
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Hyperoxid
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ChEBI
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hyperoxide
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IUPAC
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O2•−
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IUPAC
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O2−
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IUPAC
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O2-
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KEGG COMPOUND
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O2.-
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KEGG COMPOUND
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superoxide
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IUPAC
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superoxide
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UniProt
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Superoxide anion
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KEGG COMPOUND
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superoxide anion radical
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ChemIDplus
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superoxide radical
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ChEBI
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superoxide radical anion
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ChEBI
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superóxido
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ChEBI
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superoxyde
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ChEBI
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11062-77-4
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CAS Registry Number
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ChemIDplus
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11062-77-4
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CAS Registry Number
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NIST Chemistry WebBook
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487
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Gmelin Registry Number
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Gmelin
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Jie Z, Liu J, Shu M, Ying Y, Yang H (2022)
Detection strategies for superoxide anion: A review.
Talanta 236, 122892 [PubMed:34635271]
[show Abstract]
Reactive oxygen species (ROS) play an essential role in regulating various physiological functions of living organisms. Superoxide anion (O2-.), one kind of ROS, is the single-electron reduction product of oxygen molecules, which mainly exists in plants and animals, and is closely related to many inflammatory diseases. In the field of biomedicine, with the deepening understanding of superoxide anion, more and more detection methods have been developed. This review mainly introduces the detection techniques for superoxide anion in recent years. | Trist BG, Hilton JB, Hare DJ, Crouch PJ, Double KL (2021)
Superoxide Dismutase 1 in Health and Disease: How a Frontline Antioxidant Becomes Neurotoxic.
Angewandte Chemie (International ed. in English) 60, 9215-9246 [PubMed:32144830]
[show Abstract]
Cu/Zn superoxide dismutase (SOD1) is a frontline antioxidant enzyme catalysing superoxide breakdown and is important for most forms of eukaryotic life. The evolution of aerobic respiration by mitochondria increased cellular production of superoxide, resulting in an increased reliance upon SOD1. Consistent with the importance of SOD1 for cellular health, many human diseases of the central nervous system involve perturbations in SOD1 biology. But far from providing a simple demonstration of how disease arises from SOD1 loss-of-function, attempts to elucidate pathways by which atypical SOD1 biology leads to neurodegeneration have revealed unexpectedly complex molecular characteristics delineating healthy, functional SOD1 protein from that which likely contributes to central nervous system disease. This review summarises current understanding of SOD1 biology from SOD1 genetics through to protein function and stability. | Sonis ST (2021)
Superoxide Dismutase as an Intervention for Radiation Therapy-Associated Toxicities: Review and Profile of Avasopasem Manganese as a Treatment Option for Radiation-Induced Mucositis.
Drug design, development and therapy 15, 1021-1029 [PubMed:33716500]
[show Abstract]
Toxicities associated with radiation therapy are common, symptomatically devastating, and costly. The best chance to effectively mitigate radiation-associated normal tissue side effects are interventions aimed at disrupting the biological cascade, which is the basis for toxicity development, while simultaneously not reducing the beneficial impact of radiation on tumor. Oxidative stress is a key initiator of radiation-associated normal tissue injury as physiologic antioxidant mechanisms are overwhelmed by the accumulation of effects produced by fractionated treatment regimens. And fundamental to this is the generation of superoxide, which is normally removed by superoxide dismutases (SODs). Attempts to supplement the activity of endogenous SOD to prevent radiation-induced normal tissue injury have included the administration of bovine-derived SOD and increasing SOD production using gene transfer, neither of which has resulted in a clinically acceptable therapy. A third approach has been to develop synthetic small molecule dismutase mimetics. This approach has led to the creation and development of avasopasem manganese, a unique and specific dismutase mimetic that, in clinical trials, has shown promising potential to reduce the incidence, severity and duration of severe oral mucositis amongst patients being treated with concomitant chemoradiation for cancers of the head and neck. Further, avasopasem and related analogues have demonstrated mechanism-related antitumor synergy in combination with high dose per fraction radiotherapy, an observation that is also being tested in clinical trials. An ongoing Phase 3 trial seeks to confirm avasopasem manganese as an effective intervention for severe oral mucositis associated with chemoradiation in head and neck cancer patients. | Costa TJ, Barros PR, Arce C, Santos JD, da Silva-Neto J, Egea G, Dantas AP, Tostes RC, Jiménez-Altayó F (2021)
The homeostatic role of hydrogen peroxide, superoxide anion and nitric oxide in the vasculature.
Free radical biology & medicine 162, 615-635 [PubMed:33248264]
[show Abstract]
Reactive oxygen and nitrogen species are produced in a wide range of physiological reactions that, at low concentrations, play essential roles in living organisms. There is a delicate equilibrium between formation and degradation of these mediators in a healthy vascular system, which contributes to maintaining these species under non-pathological levels to preserve normal vascular functions. Antioxidants scavenge reactive oxygen and nitrogen species to prevent or reduce damage caused by excessive oxidation. However, an excessive reductive environment induced by exogenous antioxidants may disrupt redox balance and lead to vascular pathology. This review summarizes the main aspects of free radical biochemistry (formation, sources and elimination) and the crucial actions of some of the most biologically relevant and well-characterized reactive oxygen and nitrogen species (hydrogen peroxide, superoxide anion and nitric oxide) in the physiological regulation of vascular function, structure and angiogenesis. Furthermore, current preclinical and clinical evidence is discussed on how excessive removal of these crucial responses by exogenous antioxidants (vitamins and related compounds, polyphenols) may perturb vascular homeostasis. The aim of this review is to provide information of the crucial physiological roles of oxidation in the endothelium, vascular smooth muscle cells and perivascular adipose tissue for developing safer and more effective vascular interventions with antioxidants. | Rosa AC, Corsi D, Cavi N, Bruni N, Dosio F (2021)
Superoxide Dismutase Administration: A Review of Proposed Human Uses.
Molecules (Basel, Switzerland) 26, 1844 [PubMed:33805942]
[show Abstract]
Superoxide dismutases (SODs) are metalloenzymes that play a major role in antioxidant defense against oxidative stress in the body. SOD supplementation may therefore trigger the endogenous antioxidant machinery for the neutralization of free-radical excess and be used in a variety of pathological settings. This paper aimed to provide an extensive review of the possible uses of SODs in a range of pathological settings, as well as describe the current pitfalls and the delivery strategies that are in development to solve bioavailability issues. We carried out a PubMed query, using the keywords "SOD", "SOD mimetics", "SOD supplementation", which included papers published in the English language, between 2012 and 2020, on the potential therapeutic applications of SODs, including detoxification strategies. As highlighted in this paper, it can be argued that the generic antioxidant effects of SODs are beneficial under all tested conditions, from ocular and cardiovascular diseases to neurodegenerative disorders and metabolic diseases, including diabetes and its complications and obesity. However, it must be underlined that clinical evidence for its efficacy is limited and consequently, this efficacy is currently far from being demonstrated. | Xiao H, Zhang W, Li P, Zhang W, Wang X, Tang B (2020)
Versatile Fluorescent Probes for Imaging the Superoxide Anion in Living Cells and In Vivo.
Angewandte Chemie (International ed. in English) 59, 4216-4230 [PubMed:31254369]
[show Abstract]
The superoxide anion (O2.- ) is widely engaged in the regulation of cell functions and is thereby intimately associated with the onset and progression of many diseases. To ascertain the pathological roles of O2.- in related diseases, developing effective methods for monitoring O2.- in biological systems is essential. Fluorescence imaging is a powerful tool for monitoring bioactive molecules in cells and in vivo owing to its high sensitivity and high temporal-spatial resolution. Therefore, increasing numbers of fluorescent imaging probes have been constructed to monitor O2.- inside live cells and small animals. In this minireview, we summarize the methods for design and application of O2.- -responsive fluorescent probes. Moreover, we present the challenges for detecting O2.- and suggestions for constructing new fluorescent probes that can indicate the production sites and concentration changes in O2.- as well as O2.- -associated active molecules in living cells and in vivo. | Pierini A, Brutti S, Bodo E (2020)
Superoxide Anion Disproportionation Induced by Li+ and H+ : Pathways to 1 O2 Release in Li-O2 Batteries.
Chemphyschem : a European journal of chemical physics and physical chemistry 21, 2060-2067 [PubMed:32667121]
[show Abstract]
We explore the disproportionation reaction of superoxide anions in the presence of H+ and Li+ cations with high quality multiconfigurational ab-initio methods. This reaction is of paramount importance in Li-O2 battery chemistry as it represents the source of a major degrading impurity, singlet molecular oxygen. For the first time, the thermodynamic and kinetic data of the reaction are drawn from an accurate theoretical model where the electronic structure of the reactant and products is treated at the necessary level of theory. Overall, the H+ catalyzed O2 - +O2 - disproportionation follows a very efficient thermodynamic and kinetic reaction path leading to neutral 3 O2 , 1 O2 and peroxide anions. On the contrary, we have found that the Li+ catalysis promotes only the release of 3 O2 whereas the 1 O2 formation is energetically unfeasible at room temperature. | Altobelli GG, Van Noorden S, Balato A, Cimini V (2020)
Copper/Zinc Superoxide Dismutase in Human Skin: Current Knowledge.
Frontiers in medicine 7, 183 [PubMed:32478084]
[show Abstract]
Superoxide dismutase is widespread in the human body, including skin and its appendages. Here, we focus on human skin copper/zinc superoxide dismutase, the enzyme that protects skin and its appendages against reactive oxygen species. Human skin copper/zinc superoxide dismutase resides in the cytoplasm of keratinocytes, where up to 90% of cellular reactive oxygen species is produced. Factors other than cell type, such as gender, age and diseased state influence its location in skin tissues. We review current knowledge of skin copper/zinc superoxide dismutase including recent studies in an attempt to contribute to solving the question of its remaining unexplained functions. The research described here may be applicable to pathologies associated with oxidative stress. However, recent studies on copper/zinc superoxide dismutase in yeast reveal that its predominant function may be in signaling pathways rather than in scavenging superoxide ions. If confirmed in the skin, novel approaches might be developed to unravel the enzyme's remaining mysteries. | Kitada M, Xu J, Ogura Y, Monno I, Koya D (2020)
Manganese Superoxide Dismutase Dysfunction and the Pathogenesis of Kidney Disease.
Frontiers in physiology 11, 755 [PubMed:32760286]
[show Abstract]
The mitochondria are a major source of reactive oxygen species (ROS). Superoxide anion (O2 •-) is produced by the process of oxidative phosphorylation associated with glucose, amino acid, and fatty acid metabolism, resulting in the production of adenosine triphosphate (ATP) in the mitochondria. Excess production of reactive oxidants in the mitochondria, including O2 •-, and its by-product, peroxynitrite (ONOO-), which is generated by a reaction between O2 •- with nitric oxide (NO•), alters cellular function via oxidative modification of proteins, lipids, and nucleic acids. Mitochondria maintain an antioxidant enzyme system that eliminates excess ROS; manganese superoxide dismutase (Mn-SOD) is one of the major components of this system, as it catalyzes the first step involved in scavenging ROS. Reduced expression and/or the activity of Mn-SOD results in diminished mitochondrial antioxidant capacity; this can impair the overall health of the cell by altering mitochondrial function and may lead to the development and progression of kidney disease. Targeted therapeutic agents may protect mitochondrial proteins, including Mn-SOD against oxidative stress-induced dysfunction, and this may consequently lead to the protection of renal function. Here, we describe the biological function and regulation of Mn-SOD and review the significance of mitochondrial oxidative stress concerning the pathogenesis of kidney diseases, including chronic kidney disease (CKD) and acute kidney injury (AKI), with a focus on Mn-SOD dysfunction. | Damiano S, Sozio C, La Rosa G, Guida B, Faraonio R, Faraonio R, Santillo M, Mondola P (2020)
Metabolism Regulation and Redox State: Insight into the Role of Superoxide Dismutase 1.
International journal of molecular sciences 21, E6606 [PubMed:32927603]
[show Abstract]
Energy metabolism and redox state are strictly linked; energy metabolism is a source of reactive oxygen species (ROS) that, in turn, regulate the flux of metabolic pathways. Moreover, to assure redox homeostasis, metabolic pathways and antioxidant systems are often coordinately regulated. Several findings show that superoxide dismutase 1 (SOD1) enzyme has effects that go beyond its superoxide dismutase activity and that its functions are not limited to the intracellular compartment. Indeed, SOD1 is secreted through unconventional secretory pathways, carries out paracrine functions and circulates in the blood bound to lipoproteins. Striking experimental evidence links SOD1 to the redox regulation of metabolism. Important clues are provided by the systemic effects on energy metabolism observed in mutant SOD1-mediated amyotrophic lateral sclerosis (ALS). The purpose of this review is to analyze in detail the involvement of SOD1 in redox regulation of metabolism, nutrient sensing, cholesterol metabolism and regulation of mitochondrial respiration. The scientific literature on the relationship between ALS, mutated SOD1 and metabolism will also be explored, in order to highlight the metabolic functions of SOD1 whose biological role still presents numerous unexplored aspects that deserve further investigation. | Yan Z, Spaulding HR (2020)
Extracellular superoxide dismutase, a molecular transducer of health benefits of exercise.
Redox biology 32, 101508 [PubMed:32220789]
[show Abstract]
Extracellular superoxide dismutase (EcSOD) is the only extracellular scavenger of superoxide anion (O2.-) with unique binding capacity to cell surface and extracellular matrix through its heparin-binding domain. Enhanced EcSOD activity prevents oxidative stress and damage, which are fundamental in a variety of disease pathologies. In this review we will discuss the findings in humans and animal studies supporting the benefits of EcSOD induced by exercise training in reducing oxidative stress in various tissues. In particularly, we will highlight the importance of skeletal muscle EcSOD, which is induced by endurance exercise and redistributed through the circulation to the peripheral tissues, as a molecular transducer of exercise training to confer protection against oxidative stress and damage in various disease conditions. | Picón-Pagès P, Garcia-Buendia J, Muñoz FJ (2019)
Functions and dysfunctions of nitric oxide in brain.
Biochimica et biophysica acta. Molecular basis of disease 1865, 1949-1967 [PubMed:30500433]
[show Abstract]
Nitric oxide (NO) works as a retrograde neurotransmitter in synapses, allows the brain blood flow and also has important roles in intracellular signaling in neurons from the regulation of the neuronal metabolic status to the dendritic spine growth. Moreover NO is able to perform post-translational modifications in proteins by the S-nitrosylation of the thiol amino acids, which is a physiological mechanism to regulate protein function. On the other hand, during aging and pathological processes the behavior of NO can turn harmful when reacts with superoxide anion to form peroxynitrite. This gaseous compound can diffuse easily throughout the neuronal membranes damaging lipid, proteins and nucleic acids. In the case of proteins, peroxynitrite reacts mostly with the phenolic ring of the tyrosines forming nitro-tyrosines that affects dramatically to the physiological functions of the proteins. Protein nitrotyrosination is an irreversible process that also yields to the accumulation of the modified proteins contributing to the onset and progression of neurodegenerative processes such as Alzheimer's disease or Parkinson's disease. | Imlay JA (2019)
Where in the world do bacteria experience oxidative stress?
Environmental microbiology 21, 521-530 [PubMed:30307099]
[show Abstract]
Reactive oxygen species - superoxide, hydrogen peroxide and hydroxyl radicals - have long been suspected of constraining bacterial growth in important microbial habitats and indeed of shaping microbial communities. Over recent decades, studies of paradigmatic organisms such as Escherichia coli, Salmonella typhimurium, Bacillus subtilis and Saccharomyces cerevisiae have pinpointed the biomolecules that oxidants can damage and the strategies by which microbes minimize their injuries. What is lacking is a good sense of the circumstances under which oxidative stress actually occurs. In this MiniReview several potential natural sources of oxidative stress are considered: endogenous ROS formation, chemical oxidation of reduced species at oxic-anoxic interfaces, H2 O2 production by lactic acid bacteria, the oxidative burst of phagocytes and the redox-cycling of secreted small molecules. While all of these phenomena can be reproduced and verified in the lab, the actual quantification of stress in natural habitats remains lacking - and, therefore, we have a fundamental hole in our understanding of the role that oxidative stress actually plays in the biosphere. | Matsuoka K, Nakatani Y, Yoshimura T, Akasaki T (2019)
Superoxide Scavenging Activity of Gold, Silver, and Platinum Nanoparticles Capped with Sugar-based Nonionic Surfactants.
Journal of oleo science 68, 847-854 [PubMed:31484901]
[show Abstract]
Metal nanoparticles have the ability to remove superoxide via changes in the surface electronic states at the large surface area. Gold, silver, and platinum nanoparticles were prepared in the presence of three sugar-based nonionic surfactants using NaBH4 as a reducing agent. The surfactants (glycosyloxyethyl methacrylate: xGEMA) contain sugar oligomers of various lengths (x), are biodegradable, and act as protecting groups for the nanoparticles. Three types of xGEMA were used: dodecyl and hexadecyl chains containing amphiphilic oligomers (C12-3.0GEMA and C16-3.2GEMA) and multi-dodecyl chain with multiple sugar side chains (1.8C12-4.7GEMA). We found that the type of nonionic surfactant affected the size of the nanoparticles. The average size of the gold, silver, and platinum nanoparticles ranged from 1.9 to 6.6 nm depending on the surfactant. The trend in the size of gold nanoparticles in relation to the chosen surfactants was different from that for the silver and platinum nanoparticles. Moreover, the gold nanoparticles did not show effective antioxidant activity for superoxide, whereas the silver and platinum nanoparticles removed superoxide to a certain extent. The general order for superoxide scavenging activity increased in the following order: gold < platinum < silver. In particular, the largest size of silver nanoparticles capped with C16-3.2GEMA had a similar ability for the removal of superoxide as superoxide dismutase (ca. 3999 unit/mg) on the basis of the mass concentration. | Li J, Lei J, He L, Fan X, Yi F, Zhang W (2019)
Evaluation and Monitoring of Superoxide Dismutase (SOD) Activity and its Clinical Significance in Gastric Cancer: A Systematic Review and Meta-Analysis.
Medical science monitor : international medical journal of experimental and clinical research 25, 2032-2042 [PubMed:30886134]
[show Abstract]
BACKGROUND This systematic review of the literature and meta-analysis aimed to review the evaluation and monitoring of superoxide dismutase (SOD) activity and its clinical significance in gastric cancer. MATERIAL AND METHODS Systematic review involved searching the PubMed, Embase, Ovid, and the China National Knowledge Infrastructure (CNKI) databases. Search terms included 'superoxide dismutase,' and 'gastric cancer.' Studies that included measurements of SOD activity in peripheral blood samples in patients with SOD activity compared with healthy controls. The study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS Ten controlled clinical studies were identified that included six studies that measured SOD in serum, three in erythrocytes, and one study that measured SOD on whole blood. Meta-analysis, using the standardized mean difference (SMD) and the 95% confidence interval (CI), showed that patients with gastric cancer had significantly decreased SOD activity when compared with the healthy controls (SMD, -0.840; 95% CI, -1.463 to -0.218; p=0.008). Subgroup analysis was conducted on SOD distribution in the blood (erythrocyte: SMD, -1.773; 95% CI, -2.504 to -1.042; p=0.000) (serum SMD, -0.322; 95% CI, -1.006-0.361; p=0.355) (whole blood: SMD, -1.251; 95% CI, -1.731 to -0.771; p=0.000) and for male subjects (SMD, -2.090; 95% CI, -2.725 to -1.456; p<0.001). CONCLUSIONS Meta-analysis showed that SOD measurements from blood samples, especially in erythrocytes, had potential as a diagnostic and monitoring parameter in patients with gastric cancer. | Mapuskar KA, Anderson CM, Spitz DR, Batinic-Haberle I, Allen BG, E Oberley-Deegan R (2019)
Utilizing Superoxide Dismutase Mimetics to Enhance Radiation Therapy Response While Protecting Normal Tissues.
Seminars in radiation oncology 29, 72-80 [PubMed:30573187]
[show Abstract]
Symptomatic normal tissue injury is a common side effect following definitive therapeutic radiation and chemotherapy treatment for a variety of malignancies. These cancer therapy related toxicities may occur acutely during treatment resulting in reduced or missed therapy agent administration or after the completion of therapy resulting in significant chronic morbidities that significantly diminish patient quality of life. Radiation and chemotherapy induce the formation of reactive oxygen species (ROS) both in normal tissues and tumor cells. One type of ROS common to both chemotherapy and radiation therapy is the formation of superoxide (O2•-). Fortunately, due to metabolic differences between cancer and normal cell metabolism, as well as improved targeting techniques, ROS generation following radiation and chemotherapy is generally greater in cancer cells compared to normal tissues. However, the levels of ROS generated in normal tissues are capable of inducing significant toxicity. Thus, several groups are focusing on metabolism-based approaches to mitigate normal tissue effects occurring both during and following cancer therapy. This review will summarize the most current preclinical and clinical data available demonstrating the efficacy of small molecule, superoxide dismutase mimetics in minimizing radiation and chemotherapy-induced normal tissue injury, resulting in enhanced patient outcomes. | Azadmanesh J, Borgstahl GEO (2018)
A Review of the Catalytic Mechanism of Human Manganese Superoxide Dismutase.
Antioxidants (Basel, Switzerland) 7, E25 [PubMed:29385710]
[show Abstract]
Superoxide dismutases (SODs) are necessary antioxidant enzymes that protect cells from reactive oxygen species (ROS). Decreased levels of SODs or mutations that affect their catalytic activity have serious phenotypic consequences. SODs perform their bio-protective role by converting superoxide into oxygen and hydrogen peroxide by cyclic oxidation and reduction reactions with the active site metal. Mutations of SODs can cause cancer of the lung, colon, and lymphatic system, as well as neurodegenerative diseases such as Parkinson's disease and amyotrophic lateral sclerosis. While SODs have proven to be of significant biological importance since their discovery in 1968, the mechanistic nature of their catalytic function remains elusive. Extensive investigations with a multitude of approaches have tried to unveil the catalytic workings of SODs, but experimental limitations have impeded direct observations of the mechanism. Here, we focus on human MnSOD, the most significant enzyme in protecting against ROS in the human body. Human MnSOD resides in the mitochondrial matrix, the location of up to 90% of cellular ROS generation. We review the current knowledge of the MnSOD enzymatic mechanism and ongoing studies into solving the remaining mysteries. | Shalan H, Kato M, Cheruzel L (2018)
Keeping the spotlight on cytochrome P450.
Biochimica et biophysica acta. Proteins and proteomics 1866, 80-87 [PubMed:28599858]
[show Abstract]
This review describes the recent advances utilizing photosensitizers and visible light to harness the synthetic potential of P450 enzymes. The structures of the photosensitizers investigated to date are first presented along with their photophysical and redox properties. Functional photosensitizers range from organic and inorganic complexes to nanomaterials as well as the biological photosystem I complex. The focus is then on the three distinct approaches that have emerged for the activation of P450 enzymes. The first approach utilizes the in situ generation of reactive oxygen species entering the P450 mechanism via the peroxide shunt pathway. The other two approaches are sustained by electron injections into catalytically competent heme domains either facilitated by redox partners or through direct heme domain reduction. Achievements as well as pitfalls of each approach are briefly summarized. This article is part of a Special Issue entitled: Cytochrome P450 biodiversity and biotechnology, edited by Erika Plettner, Gianfranco Gilardi, Luet Wong, Vlada Urlacher, Jared Goldstone. | Younus H (2018)
Therapeutic potentials of superoxide dismutase.
International journal of health sciences 12, 88-93 [PubMed:29896077]
[show Abstract]
Superoxide dismutases (SODs) constitute a very important antioxidant defense against oxidative stress in the body. The enzyme acts as a good therapeutic agent against reactive oxygen species-mediated diseases. The present review describes the therapeutic effects of SOD in various physiological and pathological conditions such as cancer, inflammatory diseases, cystic fibrosis, ischemia, aging, rheumatoid arthritis, neurodegenerative diseases, and diabetes. However, the enzyme has certain limitations in clinical applications. Therefore, SOD conjugates and mimetics have been developed to increase its therapeutic efficiency. Here, an overview is provided of some in vivo therapeutic effects observed with SOD. | Robinett NG, Peterson RL, Culotta VC (2018)
Eukaryotic copper-only superoxide dismutases (SODs): A new class of SOD enzymes and SOD-like protein domains.
The Journal of biological chemistry 293, 4636-4643 [PubMed:29259135]
[show Abstract]
The copper-containing superoxide dismutases (SODs) represent a large family of enzymes that participate in the metabolism of reactive oxygen species by disproportionating superoxide anion radical to oxygen and hydrogen peroxide. Catalysis is driven by the redox-active copper ion, and in most cases, SODs also harbor a zinc at the active site that enhances copper catalysis and stabilizes the protein. Such bimetallic Cu,Zn-SODs are widespread, from the periplasm of bacteria to virtually every organelle in the human cell. However, a new class of copper-containing SODs has recently emerged that function without zinc. These copper-only enzymes serve as extracellular SODs in specific bacteria (i.e. Mycobacteria), throughout the fungal kingdom, and in the fungus-like oomycetes. The eukaryotic copper-only SODs are particularly unique in that they lack an electrostatic loop for substrate guidance and have an unusual open-access copper site, yet they can still react with superoxide at rates limited only by diffusion. Copper-only SOD sequences similar to those seen in fungi and oomycetes are also found in the animal kingdom, but rather than single-domain enzymes, they appear as tandem repeats in large polypeptides we refer to as CSRPs (copper-only SOD-repeat proteins). Here, we compare and contrast the Cu,Zn versus copper-only SODs and discuss the evolution of copper-only SOD protein domains in animals and fungi. | Wang Y, Branicky R, Noë A, Hekimi S (2018)
Superoxide dismutases: Dual roles in controlling ROS damage and regulating ROS signaling.
The Journal of cell biology 217, 1915-1928 [PubMed:29669742]
[show Abstract]
Superoxide dismutases (SODs) are universal enzymes of organisms that live in the presence of oxygen. They catalyze the conversion of superoxide into oxygen and hydrogen peroxide. Superoxide anions are the intended product of dedicated signaling enzymes as well as the byproduct of several metabolic processes including mitochondrial respiration. Through their activity, SOD enzymes control the levels of a variety of reactive oxygen species (ROS) and reactive nitrogen species, thus both limiting the potential toxicity of these molecules and controlling broad aspects of cellular life that are regulated by their signaling functions. All aerobic organisms have multiple SOD proteins targeted to different cellular and subcellular locations, reflecting the slow diffusion and multiple sources of their substrate superoxide. This compartmentalization also points to the need for fine local control of ROS signaling and to the possibility for ROS to signal between compartments. In this review, we discuss studies in model organisms and humans, which reveal the dual roles of SOD enzymes in controlling damage and regulating signaling. | Wilkes JG, Alexander MS, Cullen JJ (2017)
Superoxide Dismutases in Pancreatic Cancer.
Antioxidants (Basel, Switzerland) 6, E66 [PubMed:28825637]
[show Abstract]
The incidence of pancreatic cancer is increasing as the population ages but treatment advancements continue to lag far behind. The majority of pancreatic cancer patients have a K-ras oncogene mutation causing a shift in the redox state of the cell, favoring malignant proliferation. This mutation is believed to lead to nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and superoxide overproduction, generating tumorigenic behavior. Superoxide dismutases (SODs) have been studied for their ability to manage the oxidative state of the cell by dismuting superoxide and inhibiting signals for pancreatic cancer growth. In particular, manganese superoxide dismutase has clearly shown importance in cell cycle regulation and has been found to be abnormally low in pancreatic cancer cells as well as the surrounding stromal tissue. Likewise, extracellular superoxide dismutase expression seems to favor suppression of pancreatic cancer growth. With an increased understanding of the redox behavior of pancreatic cancer and key regulators, new treatments are being developed with specific targets in mind. This review summarizes what is known about superoxide dismutases in pancreatic cancer and the most current treatment strategies to be advanced from this knowledge. | Kalyanaraman B, Hardy M, Podsiadly R, Cheng G, Zielonka J (2017)
Recent developments in detection of superoxide radical anion and hydrogen peroxide: Opportunities, challenges, and implications in redox signaling.
Archives of biochemistry and biophysics 617, 38-47 [PubMed:27590268]
[show Abstract]
In this review, some of the recent developments in probes and assay techniques specific for superoxide (O2-) and hydrogen peroxide (H2O2) are discussed. Over the last decade, significant progress has been made in O2- and H2O2 detection due to syntheses of new redox probes, better understanding of their chemistry, and development of specific and sensitive assays. For superoxide detection, hydroethidine (HE) is the most suitable probe, as the product, 2-hydroxyethidium, is specific for O2-. In addition, HE-derived dimeric products are specific for one-electron oxidants. As red-fluorescent ethidium is always formed from HE intracellularly, chromatographic techniques are required for detecting 2-hydroxyethidium. HE analogs, Mito-SOX and hydropropidine, exhibit the same reaction chemistry with O2- and one-electron oxidants. Thus, mitochondrial superoxide can be unequivocally detected using HPLC-based methods and not by fluorescence microscopy. Aromatic boronate-based probes react quantitatively with H2O2, forming a phenolic product. However, peroxynitrite and hypochlorite react more rapidly with boronates, forming the same product. Using ROS-specific probes and HPLC assays, it is possible to screen chemical libraries to discover specific inhibitors of NADPH oxidases. We hope that rigorous detection of O2- and H2O2 in different cellular compartments will improve our understanding of their role in redox signaling. | Griess B, Tom E, Domann F, Teoh-Fitzgerald M (2017)
Extracellular superoxide dismutase and its role in cancer.
Free radical biology & medicine 112, 464-479 [PubMed:28842347]
[show Abstract]
Reactive oxygen species (ROS) are increasingly recognized as critical determinants of cellular signaling and a strict balance of ROS levels must be maintained to ensure proper cellular function and survival. Notably, ROS is increased in cancer cells. The superoxide dismutase family plays an essential physiological role in mitigating deleterious effects of ROS. Due to the compartmentalization of ROS signaling, EcSOD, the only superoxide dismutase in the extracellular space, has unique characteristics and functions in cellular signal transduction. In comparison to the other two intracellular SODs, EcSOD is a relatively new comer in terms of its tumor suppressive role in cancer and the mechanisms involved are less well understood. Nevertheless, the degree of differential expression of this extracellular antioxidant in cancer versus normal cells/tissues is more pronounced and prevalent than the other SODs. A significant association of low EcSOD expression with reduced cancer patient survival further suggests that loss of extracellular redox regulation promotes a conducive microenvironment that favors cancer progression. The vast array of mechanisms reported in mediating deregulation of EcSOD expression, function, and cellular distribution also supports that loss of this extracellular antioxidant provides a selective advantage to cancer cells. Moreover, overexpression of EcSOD inhibits tumor growth and metastasis, indicating a role as a tumor suppressor. This review focuses on the current understanding of the mechanisms of deregulation and tumor suppressive function of EcSOD in cancer. | Gosalvez J, Tvrda E, Agarwal A (2017)
Free radical and superoxide reactivity detection in semen quality assessment: past, present, and future.
Journal of assisted reproduction and genetics 34, 697-707 [PubMed:28341974]
[show Abstract]
Oxidative stress is a well-established cause of male infertility, with reactive oxygen species (ROS) impairing sperm production, motility, membrane, and DNA integrity. Currently, most clinics do not test infertile patients for the imbalance between ROS generation and the ability of the antioxidants to scavenge them, although there is a clear need for andrology laboratories to be able to identify and/or quantify seminal oxidative stress. As such there is a clinical urgency for an inexpensive and easy-to-perform assay able to identify oxidative stress in semen. The aim of this review is to provide information on the currently available methods to assess and quantify ROS and particularly superoxide in male reproductive cells, tissues, and fluids which may have a significant clinical utility in identifying men with impaired fertility associated with oxidative stress. Through a deeper understanding of oxidative stress and its assessment options, clinical andrology labs may better assist patients to achieve increased rates of fertility and pregnancy. | Wong HS, Dighe PA, Mezera V, Monternier PA, Brand MD (2017)
Production of superoxide and hydrogen peroxide from specific mitochondrial sites under different bioenergetic conditions.
The Journal of biological chemistry 292, 16804-16809 [PubMed:28842493]
[show Abstract]
Mitochondrial production of superoxide and hydrogen peroxide is potentially important in cell signaling and disease. Eleven distinct mitochondrial sites that differ markedly in capacity are known to leak electrons to oxygen to produce O2̇̄ and/or H2O2 We discuss their contributions to O2̇̄/H2O2 production under native conditions in mitochondria oxidizing different substrates and in conditions mimicking physical exercise and the changes in their capacities after caloric restriction. We review the use of S1QELs and S3QELs, suppressors of mitochondrial O2̇̄/H2O2 generation that do not inhibit oxidative phosphorylation, as tools to characterize the contributions of specific sites in situ and in vivo. | Hayyan M, Hashim MA, AlNashef IM (2016)
Superoxide Ion: Generation and Chemical Implications.
Chemical reviews 116, 3029-3085 [PubMed:26875845]
[show Abstract]
Superoxide ion (O2(•-)) is of great significance as a radical species implicated in diverse chemical and biological systems. However, the chemistry knowledge of O2(•-) is rather scarce. In addition, numerous studies on O2(•-) were conducted within the latter half of the 20th century. Therefore, the current advancement in technology and instrumentation will certainly provide better insights into mechanisms and products of O2(•-) reactions and thus will result in new findings. This review emphasizes the state-of-the-art research on O2(•-) so as to enable researchers to venture into future research. It comprises the main characteristics of O2(•-) followed by generation methods. The reaction types of O2(•-) are reviewed, and its potential applications including the destruction of hazardous chemicals, synthesis of organic compounds, and many other applications are highlighted. The O2(•-) environmental chemistry is also discussed. The detection methods of O2(•-) are categorized and elaborated. Special attention is given to the feasibility of using ionic liquids as media for O2(•-), addressing the latest progress of generation and applications. The effect of electrodes on the O2(•-) electrochemical generation is reviewed. Finally, some remarks and future perspectives are concluded. | Che M, Wang R, Li X, Wang HY, Zheng XFS (2016)
Expanding roles of superoxide dismutases in cell regulation and cancer.
Drug discovery today 21, 143-149 [PubMed:26475962]
[show Abstract]
Reactive oxygen species (ROS) have important roles in normal physiology and diseases, particularly cancer. Under normal physiological conditions, they participate in redox reactions and serve as second messengers for regulatory functions. Owing to aberrant metabolism, cancer cells accumulate excessive ROS, thus requiring a robustly active antioxidant system to prevent cellular damage. Superoxide dismutases (SODs) are enzymes that catalyze the removal of superoxide free radicals. There are three distinct members of this metalloenzyme family in mammals: SOD1 (Cu/ZnSOD), SOD2 (MnSOD) and SOD3 (ecSOD). SODs are increasingly recognized for their regulatory functions in growth, metabolism and oxidative stress responses, which are also crucial for cancer development and survival. Growing evidence shows that SODs are also potentially useful anticancer drug targets. This review will focus on recent research of SODs in cellular regulation, with emphasis on their roles in cancer biology and therapy. | Brand MD (2016)
Mitochondrial generation of superoxide and hydrogen peroxide as the source of mitochondrial redox signaling.
Free radical biology & medicine 100, 14-31 [PubMed:27085844]
[show Abstract]
This review examines the generation of reactive oxygen species by mammalian mitochondria, and the status of different sites of production in redox signaling and pathology. Eleven distinct mitochondrial sites associated with substrate oxidation and oxidative phosphorylation leak electrons to oxygen to produce superoxide or hydrogen peroxide: oxoacid dehydrogenase complexes that feed electrons to NAD+; respiratory complexes I and III, and dehydrogenases, including complex II, that use ubiquinone as acceptor. The topologies, capacities, and substrate dependences of each site have recently clarified. Complex III and mitochondrial glycerol 3-phosphate dehydrogenase generate superoxide to the external side of the mitochondrial inner membrane as well as the matrix, the other sites generate superoxide and/or hydrogen peroxide exclusively in the matrix. These different site-specific topologies are important for redox signaling. The net rate of superoxide or hydrogen peroxide generation depends on the substrates present and the antioxidant systems active in the matrix and cytosol. The rate at each site can now be measured in complex substrate mixtures. In skeletal muscle mitochondria in media mimicking muscle cytosol at rest, four sites dominate, two in complex I and one each in complexes II and III. Specific suppressors of two sites have been identified, the outer ubiquinone-binding site in complex III (site IIIQo) and the site in complex I active during reverse electron transport (site IQ). These suppressors prevent superoxide/hydrogen peroxide production from a specific site without affecting oxidative phosphorylation, making them excellent tools to investigate the status of the sites in redox signaling, and to suppress the sites to prevent pathologies. They allow the cellular roles of mitochondrial superoxide/hydrogen peroxide production to be investigated without catastrophic confounding bioenergetic effects. They show that sites IIIQo and IQ are active in cells and have important roles in redox signaling (e.g. hypoxic signaling and ER-stress) and in causing oxidative damage in a variety of biological contexts. | Mondola P, Damiano S, Sasso A, Santillo M (2016)
The Cu, Zn Superoxide Dismutase: Not Only a Dismutase Enzyme.
Frontiers in physiology 7, 594 [PubMed:27965593]
[show Abstract]
The Cu,Zn superoxide dismutase (SOD1) is an ubiquitary cytosolic dimeric carbohydrate free molecule, belonging to a family of isoenzymes involved in the scavenger of superoxide anions. This effect certainly represents the main and well known function ascribed to this enzyme. Here we highlight new aspects of SOD1 physiology that point out some inedited effects of this enzyme in addition to the canonic role of oxygen radical enzymatic dismutation. In the last two decades our research group produced many data obtained in in vitro studies performed in many cellular lines, mainly neuroblastoma SK-N-BE cells, indicating that this enzyme is secreted either constitutively or after depolarization induced by high extracellular K+ concentration. In addition, we gave many experimental evidences showing that SOD1 is able to stimulate, through muscarinic M1 receptor, pathways involving ERK1/2, and AKT activation. These effects are accompanied with an intracellular calcium increase. In the last part of this review we describe researches that link deficient extracellular secretion of mutant SOD1G93A to its intracellular accumulation and toxicity in NSC-34 cells. Alternatively, SOD1G93A toxicity has been attributed to a decrease of Km for H2O2 with consequent OH radical formation. Interestingly, this last inedited effect of SOD1G93A could represent a gain of function that could be involved in the pathogenesis of familial Amyotrophic Lateral Sclerosis (fALS). | Jiménez-Quesada MJ, Traverso JÁ, Alché Jde D (2016)
NADPH Oxidase-Dependent Superoxide Production in Plant Reproductive Tissues.
Frontiers in plant science 7, 359 [PubMed:27066025]
[show Abstract]
In the life cycle of a flowering plant, the male gametophyte (pollen grain) produced in the anther reaches the stigmatic surface and initiates the pollen-pistil interaction, an important step in plant reproduction, which ultimately leads to the delivery of two sperm cells to the female gametophyte (embryo sac) inside the ovule. The pollen tube undergoes a strictly apical expansion characterized by a high growth rate, whose targeting should be tightly regulated. A continuous exchange of signals therefore takes place between the haploid pollen and diploid tissue of the pistil until fertilization. In compatible interactions, theses processes result in double fertilization to form a zygote (2n) and the triploid endosperm. Among the large number of signaling mechanisms involved, the redox network appears to be particularly important. Respiratory burst oxidase homologs (Rbohs) are superoxide-producing enzymes involved in a broad range of processes in plant physiology. In this study, we review the latest findings on understanding Rboh activity in sexual plant reproduction, with a particular focus on the male gametophyte from the anther development stages to the crowning point of fertilization. Rboh isoforms have been identified in both the male and female gametophyte and have proven to be tightly regulated. Their role at crucial points such as proper growth of pollen tube, self-incompatibility response and eventual fertilization is discussed. | Shen X, Wang Q, Liu Y, Xue W, Ma L, Feng S, Wan M, Wang F, Mao C (2016)
Manganese Phosphate Self-assembled Nanoparticle Surface and Its application for Superoxide Anion Detection.
Scientific reports 6, 28989 [PubMed:27357008]
[show Abstract]
Quantitative analysis of superoxide anion (O2(·-)) has increasing importance considering its potential damages to organism. Herein, a novel Mn-superoxide dismutase (MnSOD) mimics, silica-manganous phosphate (SiO2-Mn3(PO4)2) nanoparticles, were designed and synthesized by surface self-assembly processes that occur on the surface of silica-phytic acid (SiO2-PA) nanoparticles. The composite nanoparticles were characterized by fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), scanning electronic microscopy (SEM), electron diffraction pattern, energy dispersive spectroscopy (EDS) and elemental mapping. Then the electrochemical measurements of O2(·-) based on the incorporation of SiO2-Mn3(PO4)2 onto the surface of electrodes were performed, and some satisfactory results were obtained. This is the first report that manganous phosphate (Mn3(PO4)2) nanoparticles with shape-controlled, but not multilayer sheets, were utilized for O2(·-) detection. The surface self-assembly technology we proposed will offer the ideal material to construct more types biosensor and catalytic system for its nanosized effect. | Kawano T, Kagenishi T, Kadono T, Bouteau F, Hiramatsu T, Lin C, Tanaka K, Tanaka L, Mancuso S, Uezu K, Okobira T, Furukawa H, Iwase J, Inokuchi R, Baluška F, Yokawa K (2015)
Production and removal of superoxide anion radical by artificial metalloenzymes and redox-active metals.
Communicative & integrative biology 8, e1000710 [PubMed:27066179]
[show Abstract]
Generation of reactive oxygen species is useful for various medical, engineering and agricultural purposes. These include clinical modulation of immunological mechanism, enhanced degradation of organic compounds released to the environments, removal of microorganisms for the hygienic purpose, and agricultural pest control; both directly acting against pathogenic microorganisms and indirectly via stimulation of plant defense mechanism represented by systemic acquired resistance and hypersensitive response. By aiming to develop a novel classes of artificial redox-active biocatalysts involved in production and/or removal of superoxide anion radicals, recent attempts for understanding and modification of natural catalytic proteins and functional DNA sequences of mammalian and plant origins are covered in this review article. | Zeinali F, Homaei A, Homaei A, Kamrani E (2015)
Sources of marine superoxide dismutases: Characteristics and applications.
International journal of biological macromolecules 79, 627-637 [PubMed:26047895]
[show Abstract]
The ability of marine organism to cope with oxidative stress is one of the main factors that influence its survival in the marine environment, when senescence conditions prevail. The antioxidative defense system includes enzymatic and non-enzymatic components. Among the enzymatic system, superoxide dismutases are the first and most important of the antioxidant metalloenzymes. Four different types of metal centers have been detected in SODs, dividing this family into Cu/Zn, Ni, Mn and Fe-SODs. Its use was limited to non-drug applications in humans (include: cosmetic, food, agriculture, and chemical industries) and drug applications in animals. This paper is a review of the recent literatures on sources of marine SODs, the need for SOD and different applications in industry, covering the last decades. The most recent paper, patents and reviews on characterization and application are reviewed. | Nauseef WM (2014)
Detection of superoxide anion and hydrogen peroxide production by cellular NADPH oxidases.
Biochimica et biophysica acta 1840, 757-767 [PubMed:23660153]
[show Abstract]
BackgroundThe recent recognition that isoforms of the cellular NADPH-dependent oxidases, collectively known as the NOX protein family, participate in a wide range of physiologic and pathophysiologic processes in both the animal and plant kingdoms has stimulated interest in the identification, localization, and quantitation of their products in biological settings. Although several tools for measuring oxidants released extracellularly are available, the specificity and selectivity of the methods for reliable analysis of intracellular oxidants have not matched the enthusiasm for studying NOX proteins.Scope of reviewFocusing exclusively on superoxide anion and hydrogen peroxide produced by NOX proteins, this review describes the ideal probe for analysis of O2(-) and H2O2 generated extracellularly and intracellularly by NOX proteins. An overview of the components, organization, and topology of NOX proteins provides a rationale for applying specific probes for use and a context in which to interpret results and thereby construct plausible models linking NOX-derived oxidants to biological responses. The merits and shortcomings of methods currently in use to assess NOX activity are highlighted, and those assays that provide quantitation of superoxide or H2O2 are contrasted with those intended to examine spatial and temporal aspects of NOX activity.Major conclusionsAlthough interest in measuring the extracellular and intracellular products of the NOX protein family is great, robust analytical probes are limited.General significanceThe widespread involvement of NOX proteins in many biological processes requires rigorous approaches to the detection, localization, and quantitation of the oxidants produced. This article is part of a Special Issue entitled Current methods to study reactive oxygen species - pros and cons and biophysics of membrane proteins. Guest Editor: Christine Winterbourn. | Kalyanaraman B, Dranka BP, Hardy M, Michalski R, Zielonka J (2014)
HPLC-based monitoring of products formed from hydroethidine-based fluorogenic probes--the ultimate approach for intra- and extracellular superoxide detection.
Biochimica et biophysica acta 1840, 739-744 [PubMed:23668959]
[show Abstract]
BackgroundNearly ten years ago, we demonstrated that superoxide radical anion (O2⋅¯) reacts with the hydroethidine dye (HE, also known as dihydroethidium, DHE) to form a diagnostic marker product, 2-hydroxyethidium (2-OH-E(+)). This particular product is not derived from reacting HE with other biologically relevant oxidants (hydrogen peroxide, hydroxyl radical, or peroxynitrite). This discovery negated the longstanding view that O2⋅¯ reacts with HE to form the other oxidation product, ethidium (E(+)). It became clear that due to the overlapping fluorescence spectra of E(+) and 2-OH-E(+), fluorescence-based techniques using the "red fluorescence" are not suitable for detecting and measuring O2⋅¯ in cells using HE or other structurally analogous fluorogenic probes (MitoSOX(TM) Red or hydropropidine). However, using HPLC-based assays, 2-OH-E(+) and analogous hydroxylated products can be easily detected and quickly separated from other oxidation products.Scope of reviewThe principles discussed in this chapter are generally applicable in free radical biology and medicine, redox biology, and clinical and translational research. The assays developed here could be used to discover new and targeted inhibitors for various superoxide-producing enzymes, including NADPH oxidase (NOX) isoforms.Major conclusionsHPLC-based approaches using site-specific HE-based fluorogenic probes are eminently suitable for monitoring O2⋅¯ in intra- and extracellular compartments and in mitochondria. The use of fluorescence-microscopic methods should be avoided because of spectral overlapping characteristics of O2⋅¯-derived marker product and other, non-specific oxidized fluorescent products formed from these probes.General significanceMethodologies and site-specific fluorescent probes described in this review can be suitably employed to delineate oxy radical dependent mechanisms in cells under physiological and pathological conditions. This article is part of a Special Issue entitled Current methods to study reactive oxygen species - pros and cons and biophysics of membrane proteins. Guest Editor: Christine Winterbourn. | Chiu WK, Towheed A, Palladino MJ (2014)
Genetically encoded redox sensors.
Methods in enzymology 542, 263-287 [PubMed:24862271]
[show Abstract]
Endogenous redox sensors detect fluctuations in the intracellular redox equilibrium and are critical for the maintenance of homeostasis. Such systems have been exploited to engineer genetically encoded redox sensors to detect dynamic oxidative changes within a cellular environment. Most genetically encoded redox sensors detect reactive oxygen species (ROS) such as superoxide anion, hydrogen peroxide and hydroxyl radical. Technical hurdles including the limited temporal and spatial resolution as well as tissue heterogeneity have complicated the realization of the full potential of genetically encoded redox sensors in animals until recently. Alterations in the concentration and subcellular localization of ROS are integral to numerous disorders, including neurodegenerative diseases and cancer. Thus, genetically encoded redox sensors are useful for the study of the pathogenesis and progression of multiple diseases. Moreover, the ultimate generation of genetically encoded redox sensors provides substantial advantages over conventional methods such as ROS-sensitive fluorescent probes. Here, we review examples of genetically encoded redox sensors, present their application to various fields of biomedical investigation, including the study of oncometabolism, discuss their drawbacks and explore future developments. | Lanciano P, Khalfaoui-Hassani B, Selamoglu N, Ghelli A, Rugolo M, Daldal F (2013)
Molecular mechanisms of superoxide production by complex III: a bacterial versus human mitochondrial comparative case study.
Biochimica et biophysica acta 1827, 1332-1339 [PubMed:23542447]
[show Abstract]
In this mini review, we briefly survey the molecular processes that lead to reactive oxygen species (ROS) production by the respiratory complex III (CIII or cytochrome bc1). In particular, we discuss the "forward" and "reverse" electron transfer pathways that lead to superoxide generation at the quinol oxidation (Qo) site of CIII, and the components that affect these reactions. We then describe and compare the properties of a bacterial (Rhodobacter capsulatus) mutant enzyme producing ROS with its mitochondrial (human cybrids) counterpart associated with a disease. The mutation under study is located at a highly conserved tyrosine residue of cytochrome b (Y302C in R. capsulatus and Y278C in human mitochondria) that is at the heart of the quinol oxidation (Qo) site of CIII. Similarities of the major findings of bacterial and human mitochondrial cases, including decreased catalytic activity of CIII, enhanced ROS production and ensuing cellular responses and damages, are remarkable. This case illustrates the usefulness of undertaking parallel and complementary studies using biologically different yet evolutionarily related systems, such as α-proteobacteria and human mitochondria. It progresses our understanding of CIII mechanism of function and ROS production, and underlines the possible importance of supra-molecular organization of bacterial and mitochondrial respiratory chains (i.e., respirasomes) and their potential disease-associated protective roles. This article is part of a Special Issue entitled: Respiratory complex III and related bc complexes. | Li YL (2013)
Angiotensin II-Superoxide Signaling and Arterial Baroreceptor Function in Type-1 Diabetes Mellitus.
Journal of diabetes & metabolism Suppl 12, 1-6 [PubMed:24567847]
[show Abstract]
Diabetes is a major world health problem. Growing evidence from both clinical trials and animal experiments has clearly confirmed that arterial baroreflex dysfunction is a feature of type 1 diabetes, which links to prognosis and mortality of the type 1 diabetic patients. The arterial baroreflex normally regulates the blood pressure and heart rate through sensing changes of arterial vascular tension by the arterial baroreceptors in the aortic arch and carotid sinus. The aortic baroreceptor neuron located in the nodose ganglia is a primary afferent component of the arterial baroreflex. The functional changes of these neurons are involved in the arterial baroreflex dysfunction in the type 1 diabetes. Type 1 diabetes causes the overexpression and hyperactivation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and further reduces cell excitability of the aortic baroreceptor neurons. The alterations of the HCN channels are regulated by angiotensin II-NADPH oxidase-superoxide signaling in the aortic baroreceptor neurons. From the present review, we can understand the possible mechanisms responsible for the attenuated arterial baroreflex in the type 1 diabetes. These findings are beneficial for improving quality of life and prognosis in patients with the type 1 diabetes mellitus. | Fridovich I (2013)
Oxygen: how do we stand it?.
Medical principles and practice : international journal of the Kuwait University, Health Science Centre 22, 131-137 [PubMed:22759590]
[show Abstract]
The electronic structure of ground state oxygen, which is essential for the life of all aerobic organisms, makes it potentially dangerous for those organisms. Atmospheric oxygen contains two unpaired electrons with parallel spin states, which predisposes it to reduction by a univalent pathway. As a consequence, normal aerobic metabolism generates dangerous reactive intermediates of the reduction of O2. These include superoxide radical (O2*-), hydrogen peroxide (H2O2), and hydroxyl radical (HO*). These reactive oxygen species and others that they can engender can damage all cellular macromolecules and unless opposed by cellular defenses, would make aerobic life impossible. Such defenses include superoxide dismutases, catalases, and peroxidases, enzymes that decrease the concentration of the reactive oxygen species that are their substrates, and others that repair or recycle oxidatively damaged macromolecules. Any factor that stimulates reactive oxygen species production or suppresses the antioxidant systems would inevitably cause cell damage. The role of such oxidative damage in various diseases is well documented. In vivo detection of O2- and other reactive oxygen species is however hampered by the lack of easy, specific, and sensitive analytical methods. Potential artifacts and limitations of the most common detection methods currently in use are briefly discussed. | Dröse S, Brandt U (2012)
Molecular mechanisms of superoxide production by the mitochondrial respiratory chain.
Advances in experimental medicine and biology 748, 145-169 [PubMed:22729857]
[show Abstract]
The mitochondrial respiratory chain is a major source of reactive oxygen species (ROS) in eukaryotic cells. Mitochondrial ROS production associated with a dysfunction of respiratory chain complexes has been implicated in a number of degenerative diseases and biological aging. Recent findings suggest that mitochondrial ROS can be integral components of cellular signal transduction as well. Within the respiratory chain, complexes I (NADH:ubiquinone oxidoreductase) and III (ubiquinol:cytochrome c oxidoreductase; cytochrome bc (1) complex) are generally considered as the main producers of superoxide anions that are released into the mitochondrial matrix and the intermembrane space, respectively. The primary function of both respiratory chain complexes is to employ energy supplied by redox reactions to drive the vectorial transfer of protons into the mitochondrial intermembrane space. This process involves a set of distinct electron carriers designed to minimize the unwanted leak of electrons from reduced cofactors onto molecular oxygen and hence ROS generation under normal circumstances. Nevertheless, it seems plausible that superoxide is derived from intermediates of the normal catalytic cycles of complexes I and III. Therefore, a detailed understanding of the molecular mechanisms driving these enzymes is required to understand mitochondrial ROS production during oxidative stress and redox signalling. This review summarizes recent findings on the chemistry and control of the reactions within respiratory complexes I and III that result in increased superoxide generation. Regulatory contributions of other components of the respiratory chain, especially complex II (succinate:ubiquinone oxidoreductase) and the redox state of the ubiquinone pool (Q-pool) will be briefly discussed. | Miriyala S, Spasojevic I, Tovmasyan A, Salvemini D, Vujaskovic Z, St Clair D, Batinic-Haberle I (2012)
Manganese superoxide dismutase, MnSOD and its mimics.
Biochimica et biophysica acta 1822, 794-814 [PubMed:22198225]
[show Abstract]
Increased understanding of the role of mitochondria under physiological and pathological conditions parallels increased exploration of synthetic and natural compounds able to mimic MnSOD - endogenous mitochondrial antioxidant defense essential for the existence of virtually all aerobic organisms from bacteria to humans. This review describes most successful mitochondrially-targeted redox-active compounds, Mn porphyrins and MitoQ(10) in detail, and briefly addresses several other compounds that are either catalysts of O(2)(-) dismutation, or its non-catalytic scavengers, and that reportedly attenuate mitochondrial dysfunction. While not a true catalyst (SOD mimic) of O(2)(-) dismutation, MitoQ(10) oxidizes O(2)(-) to O(2) with a high rate constant. In vivo it is readily reduced to quinol, MitoQH(2), which in turn reduces ONOO(-) to NO(2), producing semiquinone radical that subsequently dismutes to MitoQ(10) and MitoQH(2), completing the "catalytic" cycle. In MitoQ(10), the redox-active unit was coupled via 10-carbon atom alkyl chain to monocationic triphenylphosphonium ion in order to reach the mitochondria. Mn porphyrin-based SOD mimics, however, were designed so that their multiple cationic charge and alkyl chains determine both their remarkable SOD potency and carry them into the mitochondria. Several animal efficacy studies such as skin carcinogenesis and UVB-mediated mtDNA damage, and subcellular distribution studies of Saccharomyces cerevisiae and mouse heart provided unambiguous evidence that Mn porphyrins mimic the site and action of MnSOD, which in turn contributes to their efficacy in numerous in vitro and in vivo models of oxidative stress. Within a class of Mn porphyrins, lipophilic analogs are particularly effective for treating central nervous system injuries where mitochondria play key role. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease. | Katsuyama M, Matsuno K, Yabe-Nishimura C (2012)
Physiological roles of NOX/NADPH oxidase, the superoxide-generating enzyme.
Journal of clinical biochemistry and nutrition 50, 9-22 [PubMed:22247596]
[show Abstract]
NADPH oxidase is a superoxide (O(2) (•-))-generating enzyme first identified in phagocytes, essential for their bactericidal activities. Later, in non-phagocytes, production of O(2) (•-) was also demonstrated in an NADPH-dependent manner. In the last decade, several non-phagocyte-type NADPH oxidases have been identified. The catalytic subunit of these oxidases, NOX, constitutes the NOX family. There are five homologs in the family, NOX1 to NOX5, and two related enzymes, DUOX1 and DUOX2. Transgenic or gene-disrupted mice of the NOX family have also been established. NOX/DUOX proteins possess distinct features in the dependency on other components for their enzymatic activities, tissue distributions, and physiological functions. This review summarized the characteristics of the NOX family proteins, especially focused on their functions clarified through studies using gene-modified mice. | Gómez LA, Hagen TM (2012)
Age-related decline in mitochondrial bioenergetics: does supercomplex destabilization determine lower oxidative capacity and higher superoxide production?
Seminars in cell & developmental biology 23, 758-767 [PubMed:22521482]
[show Abstract]
Mitochondrial decay plays a central role in the aging process. Although certainly multifactorial in nature, defective operation of the electron transport chain (ETC) constitutes a key mechanism involved in the age-associated loss of mitochondrial energy metabolism. Primarily, mitochondrial dysfunction affects the aging animal by limiting bioenergetic reserve capacity and/or increasing oxidative stress via enhanced electron leakage from the ETC. Even though the important aging characteristics of mitochondrial decay are known, the molecular events underlying inefficient electron flux that ultimately leads to higher superoxide appearance and impaired respiration are not completely understood. This review focuses on the potential role(s) that age-associated destabilization of the macromolecular organization of the ETC (i.e. supercomplexes) may be important for development of the mitochondrial aging phenotype, particularly in post-mitotic tissues. | Hempel N, Carrico PM, Melendez JA (2011)
Manganese superoxide dismutase (Sod2) and redox-control of signaling events that drive metastasis.
Anti-cancer agents in medicinal chemistry 11, 191-201 [PubMed:21434856]
[show Abstract]
Manganese superoxide dismutase (Sod2) has emerged as a key enzyme with a dual role in tumorigenic progression. Early studies were primarily directed at defining the tumor suppressive function of Sod2 based on its low level expression in many tumor types. It is now commonly held that loss of Sod2 expression is likely an early event in tumor progression allowing for further propagation of the tumorigenic phenotype resulting from steady state increases in free radical production. Increases in free radical load have also been linked to defects in mitochondrial function and metastatic disease progression. It was initially believed that Sod2 loss may propagate metastatic disease progression, in reality both epidemiologic and experimental evidence indicate that Sod2 levels increase in many tumor types as they progress from early stage non-invasive disease to late stage metastatic disease. Sod2 overexpression in many instances enhances the metastatic phenotype that is reversed by efficient H(2)O(2) scavenging. This review evaluates the many sequelae associated with increases in Sod2 that impinge on the metastatic phenotype. The ability to use Sod2 to modulate the cellular redox-environment has allowed for the identification of redox-responsive signaling events that drive malignancy, such as invasion, migration and prolonged tumor cell survival. Further studies of these redox-driven events will help in the development of targeted therapeutic strategies to efficiently restrict redox-signaling essential for malignant progression. | Fukai T, Ushio-Fukai M (2011)
Superoxide dismutases: role in redox signaling, vascular function, and diseases.
Antioxidants & redox signaling 15, 1583-1606 [PubMed:21473702]
[show Abstract]
Excessive reactive oxygen species Revised abstract, especially superoxide anion (O₂•-), play important roles in the pathogenesis of many cardiovascular diseases, including hypertension and atherosclerosis. Superoxide dismutases (SODs) are the major antioxidant defense systems against (O₂•-), which consist of three isoforms of SOD in mammals: the cytoplasmic Cu/ZnSOD (SOD1), the mitochondrial MnSOD (SOD2), and the extracellular Cu/ZnSOD (SOD3), all of which require catalytic metal (Cu or Mn) for their activation. Recent evidence suggests that in each subcellular location, SODs catalyze the conversion of (O₂•-), H2O2, which may participate in cell signaling. In addition, SODs play a critical role in inhibiting oxidative inactivation of nitric oxide, thereby preventing peroxynitrite formation and endothelial and mitochondrial dysfunction. The importance of each SOD isoform is further illustrated by studies from the use of genetically altered mice and viral-mediated gene transfer. Given the essential role of SODs in cardiovascular disease, the concept of antioxidant therapies, that is, reinforcement of endogenous antioxidant defenses to more effectively protect against oxidative stress, is of substantial interest. However, the clinical evidence remains controversial. In this review, we will update the role of each SOD in vascular biologies, physiologies, and pathophysiologies such as atherosclerosis, hypertension, and angiogenesis. Because of the importance of metal cofactors in the activity of SODs, we will also discuss how each SOD obtains catalytic metal in the active sites. Finally, we will discuss the development of future SOD-dependent therapeutic strategies. | Hines IN, Grisham MB (2011)
Divergent roles of superoxide and nitric oxide in liver ischemia and reperfusion injury.
Journal of clinical biochemistry and nutrition 48, 50-56 [PubMed:21297912]
[show Abstract]
Liver ischemia and reperfusion-induced injury is a major clinical complication associated with hemorrhagic or endotoxin shock and thermal injury as well as liver transplantation and resectional surgery. Data obtained from several different studies suggest that an important initiating event in the pathophysiology of ischemia and reperfusion-induced tissue injury is enhanced production of superoxide concomitant with a decrease in the bioavailability of endothelial cell-derived nitric oxide. This review will summarize the evidence supporting the hypothesis that the redox imbalance induced by alterations in superoxide and nitric oxide generation creates a more oxidative environment within the different cells of the liver that enhances the nuclear transcription factor-κB-dependent expression of a variety of different cytokines and mediators that may promote as well as limit ischemia and reperfusion-induced hepatocellular injury. In addition, the evidence implicating endothelial cell nitric oxide synthase-dependent and -independent generation of nitric oxide as important regulatory pathways that act to limit ischemia and reperfusion-induced liver injury and inflammation is also presented. | Pinto AF, Rodrigues JV, Teixeira M (2010)
Reductive elimination of superoxide: Structure and mechanism of superoxide reductases.
Biochimica et biophysica acta 1804, 285-297 [PubMed:19857607]
[show Abstract]
Superoxide anion is among the deleterious reactive oxygen species, towards which all organisms have specialized detoxifying enzymes. For quite a long time, superoxide elimination was thought to occur through its dismutation, catalyzed by Fe, Cu, and Mn or, as more recently discovered, by Ni-containing enzymes. However, during the last decade, a novel type of enzyme was established that eliminates superoxide through its reduction: the superoxide reductases, which are spread among anaerobic and facultative microorganisms, from the three life kingdoms. These enzymes share the same unique catalytic site, an iron ion bound to four histidines and a cysteine that, in its reduced form, reacts with superoxide anion with a diffusion-limited second order rate constant of approximately 10(9) M(-1) s(-1). In this review, the properties of these enzymes will be thoroughly discussed. | Perry JJ, Shin DS, Getzoff ED, Tainer JA (2010)
The structural biochemistry of the superoxide dismutases.
Biochimica et biophysica acta 1804, 245-262 [PubMed:19914407]
[show Abstract]
The discovery of superoxide dismutases (SODs), which convert superoxide radicals to molecular oxygen and hydrogen peroxide, has been termed the most important discovery of modern biology never to win a Nobel Prize. Here, we review the reasons this discovery has been underappreciated, as well as discuss the robust results supporting its premier biological importance and utility for current research. We highlight our understanding of SOD function gained through structural biology analyses, which reveal important hydrogen-bonding schemes and metal-binding motifs. These structural features create remarkable enzymes that promote catalysis at faster than diffusion-limited rates by using electrostatic guidance. These architectures additionally alter the redox potential of the active site metal center to a range suitable for the superoxide disproportionation reaction and protect against inhibition of catalysis by molecules such as phosphate. SOD structures may also control their enzymatic activity through product inhibition; manipulation of these product inhibition levels has the potential to generate therapeutic forms of SOD. Markedly, structural destabilization of the SOD architecture can lead to disease, as mutations in Cu,ZnSOD may result in familial amyotrophic lateral sclerosis, a relatively common, rapidly progressing and fatal neurodegenerative disorder. We describe our current understanding of how these Cu,ZnSOD mutations may lead to aggregation/fibril formation, as a detailed understanding of these mechanisms provides new avenues for the development of therapeutics against this so far untreatable neurodegenerative pathology. | Queisser N, Fazeli G, Schupp N (2010)
Superoxide anion and hydrogen peroxide-induced signaling and damage in angiotensin II and aldosterone action.
Biological chemistry 391, 1265-1279 [PubMed:20868230]
[show Abstract]
The formation of reactive oxygen species (ROS) can be induced by xenobiotic substances, such as redox cycling molecules, but also by endogenous substances such as hormones and cytokines. Recent research shows the importance of ROS in cellular signaling. Here, the signaling pathways of the two blood pressure-regulating hormones angiotensin II and aldosterone are presented, focusing on both their physiological effects and the change of signaling owing to the action of increased concentrations or prolonged exposure. When present in high concentrations, both angiotensin II and aldosterone, as various other endogenous substances, activate NADPH oxidase, which produces superoxide. In this review the generation of superoxide anions and hydrogen peroxide in cells stimulated with angiotensin II or aldosterone, as well as the subsequently induced signaling processes and DNA damage is discussed. | Vásquez-Vivar J (2009)
Tetrahydrobiopterin, superoxide, and vascular dysfunction.
Free radical biology & medicine 47, 1108-1119 [PubMed:19628033]
[show Abstract]
(6R)-5,6,7,8-Tetrahydrobiopterin (BH(4)) is an endogenously produced pterin that is found widely distributed in mammalian tissues. BH(4) works as a cofactor of aromatic amino acid hydroxylases and nitric oxide synthases. In the vasculature a deficit of BH(4) is implicated in the mechanisms of several diseases including atherosclerosis, hypertension, diabetic vascular disease, and vascular complications from cigarette smoking and environmental pollution. These ill-effects are connected to the ability of BH(4) to regulate reactive oxygen species levels in the endothelium. The possibility of using BH(4) as a therapeutical agent in cardiovascular medicine is becoming more compelling and many biochemical and physiological aspects involved in this application are currently under investigation. This review summarizes our current understanding of BH(4) reactivity and some aspects of cellular production and regulation. | Afanasev I (2009)
Detection of superoxide in cells, tissues and whole organisms.
Frontiers in bioscience (Elite edition) 1, 153-160 [PubMed:19482633]
[show Abstract]
The radical anion of dioxygen superoxide (O2.-) is a physiological free radical formed in various enzymatic processes. On the one hand superoxide is a precursor of reactive oxygen and nitrogen species (hydroxyl radicals, peroxy radicals, hydrogen peroxide, peroxynitrite, etc.), -the initiators of cellular damage; on the other hand it is a signaling molecule regulating numerous physiological processes including apoptosis, aging, and senescence. Therefore, the detection and measurement of superoxide in cells, tissues, and whole organisms is of a vital importance for in vitro and in vivo studies of many physiological and pathophysiological processes. At present different efficient methods were developed, which allow to identificate and measure superoxide in biological systems. In present review the credibility and efficiency of principal mostly applied methods of superoxide detection based on one-electron transfer and nucleophilic reactions are discussed, and spectrophotometrical, chemiluminescent, fluorescent, and ESR spin trapping methods are compared. | Afanas'ev I (2009)
Superoxide and nitric oxide in senescence and aging.
Frontiers in bioscience (Landmark edition) 14, 3899-3912 [PubMed:19273321]
[show Abstract]
In this review some aspects of free radical theory of aging are discussed. Many new and interesting findings concerning the role of physiological free radicals superoxide and nitric oxide in senescence and aging development are considered and the mechanisms of processes mediated by these radicals are discussed. It has been known for a long time that being themselves mostly harmless species, superoxide and NO are precursors of really reactive species hydroxyl radicals and peroxynitrite, the initiators of aging and various pathologies. However, contemporary studies demonstrate the other maybe more important ways of damaging activity of physiological free radicals. Numerous studies show that lessening of NO production and its bioavailability could be a starting point of aging development. It results in a decrease in NO inhibition of mitochondrial cytochrome c oxidase and an increase in dioxygen consumption. That in its turn leads to an increase in the production of superoxide and the other reactive oxygen and nitrogen species and initiation of apoptosis, In conclusion the possibilities of pharmacological intervention with antioxidants and other antiradical procedures to suppress aging and senescence or even to expand the life span of animals are considered. | Ivanović-Burmazović I, van Eldik R (2008)
Metal complex-assisted activation of small molecules. From NO to superoxide and peroxides.
Dalton transactions (Cambridge, England : 2003)5259-5275 [PubMed:18827931]
[show Abstract]
Transition metal centres are one of the primary targets for nitric oxide (NO), superoxide (O2(-)) and hydrogen peroxide (H2O2), which are small molecules present in a biological milieu, and of industrial and environmental interest. Coordination to a metal centre modulates their redox behaviour in such a way that they become activated for an inner-sphere oxidation or reduction, depending on the electronic and redox properties of a particular transition metal ion. Since the related redox reactions play multiple roles in physiological and pathophysiological processes, as well as in chemical catalysis in terms of synthetic applications and exhaust gas purification, the elucidation of the mechanisms of the elementary reaction steps behind these complex processes is of fundamental importance. This review concentrates on our work in this area, where by applying low temperature and high pressure kinetic and thermodynamic techniques we shed more light on the mechanisms of the particular reaction steps involved in the activation of NO, O2(-) and various peroxides. The studies include work on solvent exchange reactions that control the binding of small molecules to the metal centre and subsequent electron-transfer processes. We paid special attention to different iron and manganese complexes with heme and non-heme ligand systems. | Bréchard S, Tschirhart EJ (2008)
Regulation of superoxide production in neutrophils: role of calcium influx.
Journal of leukocyte biology 84, 1223-1237 [PubMed:18519744]
[show Abstract]
Upon stimulation, activation of NADPH oxidase complexes in neutrophils produces a burst of superoxide anions contributing to oxidative stress and the development of inflammatory process. Store-operated calcium entry (SOCE), whereby the depletion of intracellular stores induces extracellular calcium influx, is known to be a crucial element of NADPH oxidase regulation. However, the mechanistic basis mediating SOCE is still only partially understood, as is the signal-coupling pathway leading to modulation of store-operated channels. This review emphasizes the role of calcium influx in the control of the NADPH oxidase and summarizes the current knowledge of pathways mediating this extracellular calcium entry in neutrophils. Such investigations into the cross-talk between NADPH oxidase and calcium might allow the identification of novel pharmacological targets with clinical use, particularly in inflammatory diseases. | Mayorov DN (2007)
Brain superoxide as a key regulator of the cardiovascular response to emotional stress in rabbits.
Experimental physiology 92, 471-479 [PubMed:17303648]
[show Abstract]
Cardiovascular reactivity, an abrupt increase in blood pressure and heart rate in response to emotional stress, is a risk factor for hypertension and heart disease. Brain angiotensin II (Ang II) type 1 (AT(1)) receptor is increasingly recognized as an important regulator of cardiovascular reactivity. Given that a wide variety of AT(1) receptor signalling pathways exists in neurones, the precise molecular mechanisms that underlie central cardiovascular actions of Ang II during emotional stress are yet to be determined. Growing evidence, however, indicates that reactive oxygen species, and in particular superoxide (.O(2)(-)), are important intracellular messengers of many actions of brain Ang II. In particular, studies employing microinjection of .O(2)(-) scavengers directly into the rostral ventrolateral medulla (RVLM) and dorsomedial hypothalamus of rabbits have shown that the activation of AT(1) receptor-.O(2)(-) signalling is required for full manifestation of the cardiovascular response to emotional stress. This role of .O(2)(-) appears to be highly specific, because .O(2)(-) scavengers in the RVLM do not alter the sympathoexcitatory response to baroreceptor unloading or sciatic nerve stimulation. The subcellular mechanisms for the stress-induced .O(2)(-) production are likely to include the activation of NADPH oxidase and are essentially independent of nitric oxide. This review summarizes current knowledge of redox-sensitive signalling mechanisms in the brain that regulate cardiovascular effects of stress. Additionally, it presents initial evidence that .O(2)(-) may be less important in the activation of central pressor pathways mediating cardiovascular arousal associated with appetitive events, such as food anticipation and feeding. | Pervaiz S, Clement MV (2007)
Superoxide anion: oncogenic reactive oxygen species?
The international journal of biochemistry & cell biology 39, 1297-1304 [PubMed:17531522]
[show Abstract]
Recent evidence linking intracellular reactive oxygen species to cell survival and/or proliferation signals has resulted in a paradigm shift from the age-old dogma implicating reactive oxygen species exclusively in cell damage and death. It is now accepted that reactive oxygen species play important roles in normal physiological states and that depending on the species involved the effect could be highly varied. In this regard, the effects of the two major reactive oxygen species, superoxide and hydrogen peroxide have been extensively studied. During normal cell growth a tight balance between the two species is kept under check by the cells' anti-oxidant defense systems. Deficiency or defect in this defense armory is invariably associated with neoplasia, thus rendering the intracellular redox status in a state of imbalance and generating a "pro-oxidant" milieu. A variety of model systems have underscored the relationship between a pro-oxidant state and cancer promotion and progression. In this review, we present evidence to support the hypothesis that the effect of intracellular reactive oxygen species on oncogenesis is dependent on the ratio of intracellular superoxide to hydrogen peroxide in that a predominant increase in superoxide supports cell survival and promotes oncogenesis whereas a tilt in favor of hydrogen peroxide prevents carcinogenesis by facilitating cell death signaling. | Furukawa Y, O'Halloran TV (2006)
Posttranslational modifications in Cu,Zn-superoxide dismutase and mutations associated with amyotrophic lateral sclerosis.
Antioxidants & redox signaling 8, 847-867 [PubMed:16771675]
[show Abstract]
Activation of the enzyme Cu,Zn-superoxide dismutase (SOD1) involves several posttranslational modifications including copper and zinc binding, as well as formation of the intramolecular disulfide bond. The copper chaperone for SOD1, CCS, is responsible for intracellular copper loading in SOD1 under most physiological conditions. Recent in vitro and in vivo assays reveal that CCS not only delivers copper to SOD1 under stringent copper limitation, but it also facilitates the stepwise conversion of the disulfide-reduced immature SOD1 to the active disulfide-containing enzyme. The two new functions attributed to CCS, (i.e., O(2)-dependent sulfhydryl oxidase- and disulfide isomerase-like activities) indicate that this protein has attributes of the larger class of molecular chaperones. The CCS-dependent activation of SOD1 is dependent upon oxygen availability, suggesting that the cell only loads copper and activates this enzyme when O(2)-based oxidative stress is present. Thiol/disulfide status as well as metallation state of SOD1 significantly affects its structure and protein aggregation, which are relevant in pathologies of a neurodegenerative disease, amyotrophic lateral sclerosis (ALS). The authors review here a mechanism for posttranslational activation of SOD1 and discuss models for ALS in which the most immature forms of the SOD1 polypeptide exhibits propensity to form toxic aggregates. | Salvemini D, Doyle TM, Cuzzocrea S (2006)
Superoxide, peroxynitrite and oxidative/nitrative stress in inflammation.
Biochemical Society transactions 34, 965-970 [PubMed:17052238]
[show Abstract]
A considerable body of evidence suggests that formation of potent reactive oxygen species and resulting oxidative/nitrative stress play a major role in acute and chronic inflammation and pain. Much of the knowledge in this field has been gathered by the use of pharmacological and genetic approaches. In this mini review, we will evaluate recent advances made towards understanding the roles of reactive oxygen species in inflammation, focusing in particular on superoxide and peroxynitrite. Given the limited space to cover this broad topic, here we will refer the reader to comprehensive review articles whenever possible. | Rakhit R, Chakrabartty A (2006)
Structure, folding, and misfolding of Cu,Zn superoxide dismutase in amyotrophic lateral sclerosis.
Biochimica et biophysica acta 1762, 1025-1037 [PubMed:16814528]
[show Abstract]
Fourteen years after the discovery that mutations in Cu, Zn superoxide dismutase (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS), the mechanism by which mutant SOD1 exerts toxicity remains unknown. The two principle hypotheses are (a) oxidative damage stemming from aberrant SOD1 redox chemistry, and (b) misfolding of the mutant protein. Here we review the structure and function of wild-type SOD1, as well as the changes to the structure and function in mutant SOD1. The relative merits of the two hypotheses are compared and a common unifying principle is outlined. Lastly, the potential for therapies targeting SOD1 misfolding is discussed. | Valentine JS, Doucette PA, Zittin Potter S (2005)
Copper-zinc superoxide dismutase and amyotrophic lateral sclerosis.
Annual review of biochemistry 74, 563-593 [PubMed:15952898]
[show Abstract]
Copper-zinc superoxide dismutase (CuZnSOD, SOD1 protein) is an abundant copper- and zinc-containing protein that is present in the cytosol, nucleus, peroxisomes, and mitochondrial intermembrane space of human cells. Its primary function is to act as an antioxidant enzyme, lowering the steady-state concentration of superoxide, but when mutated, it can also cause disease. Over 100 different mutations have been identified in the sod1 genes of patients diagnosed with the familial form of amyotrophic lateral sclerosis (fALS). These mutations result in a highly diverse group of mutant proteins, some of them very similar to and others enormously different from wild-type SOD1. Despite their differences in properties, each member of this diverse set of mutant proteins causes the same clinical disease, presenting a challenge in formulating hypotheses as to what causes SOD1-associated fALS. In this review, we draw together and summarize information from many laboratories about the characteristics of the individual mutant SOD1 proteins in vivo and in vitro in the hope that it will aid investigators in their search for the cause(s) of SOD1-associated fALS. | Andreyev AY, Kushnareva YE, Starkov AA (2005)
Mitochondrial metabolism of reactive oxygen species.
Biochemistry. Biokhimiia 70, 200-214 [PubMed:15807660]
[show Abstract]
Oxidative stress is considered a major contributor to etiology of both "normal" senescence and severe pathologies with serious public health implications. Mitochondria generate reactive oxygen species (ROS) that are thought to augment intracellular oxidative stress. Mitochondria possess at least nine known sites that are capable of generating superoxide anion, a progenitor ROS. Mitochondria also possess numerous ROS defense systems that are much less studied. Studies of the last three decades shed light on many important mechanistic details of mitochondrial ROS production, but the bigger picture remains obscure. This review summarizes the current knowledge about major components involved in mitochondrial ROS metabolism and factors that regulate ROS generation and removal. An integrative, systemic approach is applied to analysis of mitochondrial ROS metabolism, which is now dissected into mitochondrial ROS production, mitochondrial ROS removal, and mitochondrial ROS emission. It is suggested that mitochondria augment intracellular oxidative stress due primarily to failure of their ROS removal systems, whereas the role of mitochondrial ROS emission is yet to be determined and a net increase in mitochondrial ROS production in situ remains to be demonstrated. | Evans RG, Fitzgerald SM (2005)
Nitric oxide and superoxide in the renal medulla: a delicate balancing act.
Current opinion in nephrology and hypertension 14, 9-15 [PubMed:15586010]
[show Abstract]
Purpose of reviewEndothelial nitric oxide synthase (eNOS) and nicotinamide adenine dinucleotide (phosphate) oxidase [NAD(P)H oxidase] are both expressed in tubular epithelial cells within the renal medulla, particularly the thick ascending limb of the loop of Henle (mTALH). Thick ascending limbs contribute to long-term blood pressure control, both because they reabsorb approximately 30% of filtered sodium, and because they produce paracrine factors like nitric oxide (NO) that control medullary blood flow (MBF), which in turn has a major impact on tubular sodium reabsorption. Herein, we review recent evidence for roles of NO and superoxide (O2*-) in autocrine control of tubular sodium reabsorption, and in paracrine control of MBF.Recent findingsO2*- can have a direct action to reduce MBF, and to enhance sodium reabsorption from mTALH. These actions oppose those of NO produced in mTALH, which inhibits tubular sodium reabsorption (autocrine) and increases MBF (paracrine). NO and O2*- also oppose each other's actions through chemical combination to produce peroxynitrite. Thus, interactions between NO and O2*-, at both the chemical and cellular levels, likely contribute to long-term blood pressure control. This hypothesis is supported by recent data showing that sodium retention and hypertension can develop when the balance of production of these free radicals is tipped towards O2*-, such as in diabetes, atherosclerosis and renin-angiotensin-system activation.SummaryInteractions between O2*- and NO produced within the mTALH regulate tubular and vascular function in the renal medulla. Dysregulation of these systems in states of oxidative stress likely promotes salt and water retention, and thus hypertension. | Ferdinandy P, Schulz R (2003)
Nitric oxide, superoxide, and peroxynitrite in myocardial ischaemia-reperfusion injury and preconditioning.
British journal of pharmacology 138, 532-543 [PubMed:12598407]
[show Abstract]
There appears to be a controversy in the study of myocardial ischaemia-reperfusion injury and preconditioning whether nitric oxide (NO) plays a protective or detrimental role. A number of findings and the interpretation of the results to date do not support such a controversy. An understanding of the latest developments in NO, superoxide (O(2)(-)*) and peroxynitrite (ONOO(-)) biology, as well as the various ischaemic animal models utilized is necessary to resolve the apparent controversy. NO is an important cardioprotective molecule via its vasodilator, antioxidant, antiplatelet, and antineutrophil actions and it is essential for normal heart function. However, NO is detrimental if it combines with O(2)(-)* to form ONOO(-) which rapidly decomposes to highly reactive oxidant species. There is a critical balance between cellular concentrations of NO, O(2)(-)*, and superoxide dismutase which physiologically favour NO production but in pathological conditions such as ischaemia and reperfusion result in ONOO(-) formation. In contrast, exposure of the heart to brief episode(s) of ischaemia markedly enhances its ability to withstand a subsequent ischaemic injury. The triggering of this endogenous cardioprotective mechanism known as preconditioning requires both NO and O(2)(-)* synthesis. However, preconditioning in turn attenuates the overproduction of NO, O(2)(-)* and ONOO(-) during a subsequent episode of ischaemia and reperfusion, thereby protecting the heart. Here we review the roles of NO, O(2)(-)*, and ONOO(-) in both ischaemia-reperfusion injury and preconditioning. | Ingold KU (2003)
Reactions of water-soluble alkylperoxyl radicals and superoxide with DNA, lipoproteins and phospholipid vesicles: the role played by electrostatic forces.
Current medicinal chemistry 10, 2631-2642 [PubMed:14529453]
[show Abstract]
The role of electrostatic forces in free radical biology is very important but it is all too often overlooked. The radicals discussed in this review include positively-charged, negatively-charged and neutral water-soluble alkylperoxyls and superoxide. Important scientific insights have been gained by generating these radicals in known quantities by the thermal decomposition of simple, "clean", chemical precursors in the presence of potential bio-targets. For example, the abilities of these radicals to damage double-stranded DNA, a polyanion, are dictated by Coulombic forces with only the positively-charged peroxyls being capable of directly producing single-strand breaks. The Coulombic control of the reactions and reaction rates of water-soluble peroxyl radicals which are so evident with DNA do not manifest themselves with all electrostatically charged bio-targets, e.g., low density lipoprotein (LDL), probably because the charge on the surface of the LDL is not uniformly distributed. | Saran M (2003)
To what end does nature produce superoxide? NADPH oxidase as an autocrine modifier of membrane phospholipids generating paracrine lipid messengers.
Free radical research 37, 1045-1059 [PubMed:14703794]
[show Abstract]
Production of superoxide anion O2*- by the membrane-bound enzyme NADPH oxidase of phagocytes is a long-known phenomenon; it is generally assumed that O2*-helps phagocytes kill bacterial intruders. The details and the chemistry of the killing process have, however, remained a mystery. Isoforms of NADPH oxidase exist in membranes of nearly every cell, suggesting that reactive oxygen species (ROS) participate in intra- and intercellular signaling processes. What the nature of the signal is exactly, how it is transmitted, and what structural characteristics a receptor of a "radical message" must have, have not been addressed convincingly. This review discusses how the action of messengers is in agreement with radical-specific behavior. In search for the smallest common denominator of cellular free radical activity we hypothesize that O2*- and its conjugate acid, HO2*, may have evolved under primordial conditions as regulators of membrane mechanics and that isoprostanes, widely used markers of "oxidative stress", may be an adventitious correlate of this biologic activity of O2*-/HO2*. An overall picture is presented that suggests that O2*-/HO2* radicals, by modifying cell membranes, help other agents gain access to the hydrophobic region of phospholipid bilayers and hence contribute to lipid-dependent signaling cascades. With this, O2*-/HO2* are proposed as indispensable adjuvants for the generation of cellular signals, for membrane transport, channel gating and hence, in a global sense, for cell viability and growth. We also suggest that many of the allegedly O2*- dependent bacterial pathologies and carcinogenic derailments are due to membrane-modifying activity rather than other chemical reactions of O2*-/HO2*. A consequence of this picture is the potential evolution of the "radical theory of ageing" to a "lipid theory of aging". | Guzik TJ, Korbut R, Adamek-Guzik T (2003)
Nitric oxide and superoxide in inflammation and immune regulation.
Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 54, 469-487 [PubMed:14726604]
[show Abstract]
Nitric oxide (NO) and reactive oxygen species exert multiple modulating effects on inflammation and play a key role in the regulation of immune responses. They affect virtually every step of the development of inflammation. Low concentrations of nitric oxide produced by constitutive and neuronal nitric oxide synthases inhibit adhesion molecule expression, cytokine and chemokine synthesis and leukocyte adhesion and transmigration. Large amounts of NO, generated primarily by iNOS can be toxic and pro-inflammatory. Actions of nitric oxide are however not dependent primarily on the enzymatic source, but rather on the cellular context, NO concentration (dependent on the distance from NO source) and initial priming of immune cells. These observations may explain difficulties in determining the exact role of NO in Th1 and Th2 lymphocyte balance in normal immune responses and in allergic disease. Similarly superoxide anion produced by NAD(P)H oxidases present in all cell types participating in inflammation (leukocytes, endothelial and other vascular cells etc) may lead to toxic effects, when produced at high levels during oxidative burst, but may also modulate inflammation in a far more discrete way, when continuously produced at low levels by NOXs (non-phagocytic oxidases). The effects of both nitric oxide and superoxide in immune regulation are exerted through multiple mechanisms, which include interaction with cell signalling systems like cGMP, cAMP, G-protein, JAK/STAT or MAPK dependent signal transduction pathways. They may also lead to modification of transcription factors activity and in this way modulate the expression of multiple other mediators of inflammation. Moreover genetic polymorphisms exist within genes encoding enzymes producing both NO and superoxide. The potential role of these polymorphisms in inflammation and susceptibility to infection is discussed. Along with studies showing increasing role of NO and free radicals in mediating inflammatory responses drugs which interfere with these systems are being introduced in the treatment of inflammation. These include statins, angiotensin receptor blockers, NAD(P)H oxidase inhibitors, NO-aspirin and others. In conclusion in this mini-review we discuss the mechanisms of nitric oxide and superoxide dependent modulation of inflammatory reactions in experimental animals and humans. We also discuss potential roles of nitric oxide as a mediator of allergic inflammation. | Salvemini D, Cuzzocrea S (2002)
Superoxide, superoxide dismutase and ischemic injury.
Current opinion in investigational drugs (London, England : 2000) 3, 886-895 [PubMed:12137408]
[show Abstract]
Oxidative stress results from an oxidant/antioxidant imbalance: an excess of oxidants relative to the antioxidant capacity. Recent evidence strongly suggests that oxidant stress plays a major role in several aspects of ischemia and reperfusion. Immunohistochemical and biochemical evidence demonstrate the significant role of reactive oxygen species, in particular superoxide and its reaction product peroxynitrite, formed by the interaction of superoxide and nitric oxide, in endothelial and tissue injury associated with ischemia and reperfusion. Endothelial cell damage, neutrophil activation and infiltration into tissues, lipid peroxidation, direct inhibition of mitochondrial respiratory chain enzymes, inactivation of glyceraldehyde-3-phosphate dehydrogenase, inhibition of membrane sodium/potassium ATPase activity, inactivation of membrane sodium channels and other oxidative protein modifications contribute to the cytotoxic effect of superoxide and peroxynitrite. In addition, superoxide and peroxynitrite trigger DNA strand breakage, with subsequent activation of the nuclear enzyme poly-ADP ribosyl synthetase, a pathway which contributes to the cellular injury in ischemia and reperfusion. In vivo, removal of superoxide (and thus of peroxynitrite) by superoxide dismutase mimetics (SODm), which mimic the catalytic activity of the human superoxide dismutase enzymes, prevent the cellular energetic failure and tissue damage associated with ischemia and reperfusion and exert an overall beneficial effect in this situation. The role(s) of superoxide and the potential utility of SODm will be discussed in this review. | Wolin MS, Gupte SA, Oeckler RA (2002)
Superoxide in the vascular system.
Journal of vascular research 39, 191-207 [PubMed:12097818]
[show Abstract]
Oxidant production and regulation is becoming increasingly important in the study of vascular signaling mechanisms, and recent reviews have characterized some of the possible roles for known downstream products of superoxide formation. In this review, we will examine current research in the field, with a special emphasis on the role of the superoxide molecule itself and its place amongst the slightly better understood roles of peroxide and peroxynitrite. The regulatory roles of oxidant species are wide-ranging, and their involvement in processes ranging from intracellular and receptor signaling mechanisms that regulate endothelial mediator release and vascular contractile function to processes that control cellular growth and apoptosis has been implied. Cellular sources of superoxide production and metabolism and the chemical interaction of oxidant species with specific components of cellular signaling mechanisms are considered important factors which determine physiological responses that control vascular function. | Tarpey MM, Fridovich I (2001)
Methods of detection of vascular reactive species: nitric oxide, superoxide, hydrogen peroxide, and peroxynitrite.
Circulation research 89, 224-236 [PubMed:11485972]
[show Abstract]
The evanescent nature of reactive oxygen and nitrogen species, the multiple cellular mechanisms evolved to maintain these substances at low (submicromolar) concentrations within the vascular system, and the often multifaceted nature of their reactivities have made measurement of these compounds within the vasculature problematic. This review attempts to provide a critical description of some of the most common approaches to quantification of nitric oxide, superoxide, hydrogen peroxide, and peroxynitrite, with attention to key issues that may influence the utility of a particular assay when adapted for use in vascular cells and tissues. | Kobayashi T, Tsunawaki S, Seguchi H (2001)
Evaluation of the process for superoxide production by NADPH oxidase in human neutrophils: evidence for cytoplasmic origin of superoxide.
Redox report : communications in free radical research 6, 27-36 [PubMed:11333112]
[show Abstract]
We present an up-to-date insight into the function of NADPH oxidase in human neutrophils, the signalling pathways involved in activation of this enzyme and the process of association of its components with the cytoskeleton. We also discuss the functional implications of morphological studies revealing localization of the sites of NADPH oxidase activity. An original model of the process of superoxide (O2*-) production in human neutrophils is shown. Organization of NADPH oxidase is associated with several components. Upon stimulation, tri-phox cytosolic components of NADPH oxidase (p40-phox, p47-phox and p67-phox) bind to actin filaments. This process involves other actin-binding proteins, such as cofilin and coronin. Activated protein kinase C, translocated from the plasma membrane, phosphorylates cytosolic components at a scaffold of cytoskeleton. Subsequently, p40-phox, responsible for maintaining the resting state of NADPH oxidase, is separated from other two cytosolic phox proteins following an attachment of the active form of small GTP-binding protein Rac to p67-phox. Cytosolic duo-phox proteins (p47-phox and p67-phox) conjugate with membrane components (gp91-phox, p22-phox and Rapla) of NADPH oxidase residing within membranes of intracellular compartments. This chain of events triggers production of O2*-. Then, oxidant-producing intracellular compartments associate with the plasma membrane. Eventually, intracellularly produced O2*- is released to the extracellular environment through the orifice formed by fusion of oxidant-producing compartments with the plasma membrane. Intracellular movement of the oxidant-producing compartments may be regulated by myosin light chain kinase. The review emphasizes that functional assembly of NADPH oxidase and, therefore, generation of O2*- is accomplished essentially within the intracellular compartments. Upon neutrophil stimulation, intracellularly generated O2*- is transported to the plasma membrane to be released and to ensure host defense against infection. | Lynch M, Kuramitsu H (2000)
Expression and role of superoxide dismutases (SOD) in pathogenic bacteria.
Microbes and infection 2, 1245-1255 [PubMed:11008114]
[show Abstract]
This review will be limited to the expression and roles of the family of metalloenzymes superoxide dismutases in pathogenic bacteria. Only animal pathogens will be described, with particular emphasis on those causing disease in man. | Graier WF, Posch K, Fleischhacker E, Wascher TC, Kostner GM (1999)
Increased superoxide anion formation in endothelial cells during hyperglycemia: an adaptive response or initial step of vascular dysfunction?
Diabetes research and clinical practice 45, 153-160 [PubMed:10588368]
[show Abstract]
In diabetes mellitus, the risk for cardiovascular complications and development of atherosclerosis is increased compared with healthy individuals. Recently evidence was provided that increased production of superoxide anions occurs in endothelial cells during hyperglycemia. In order to evaluate the potential impact of the enhanced formation of this oxygen radical for vascular cell dysfunction and its role in tissue adaptation, it is essential to assess the effect of superoxide anions on endothelial cell function. Here, we present new data and review our previous work on the effects of superoxide anions on endothelial vascular function, such as intracellular Ca2+ signal cascade, formation and bioactivity of nitric oxide. Based on the presented data we discuss superoxide anion production as a two faced phenomenon. In lower concentrations, superoxide anions are mediators of an endothelium adaptation to ensure endothelial vasomotion control. However, in higher concentrations superoxide anions disrupt endothelial-smooth muscle crosstalk resulting in vessel wall dysfunction and vascular wall dysfunction. | Goldschmidt-Clermont PJ, Moldovan L (1999)
Stress, superoxide, and signal transduction.
Gene expression 7, 255-260 [PubMed:10440226]
[show Abstract]
A variety of stressful events can trigger the production of free radicals by exposed cells. For years, the effect of such highly reactive radicals was expected to be damaging to cells, altering their biology irreversibly. However, many recent reports have shown that reactive oxygen species can have additional functions, and contribute to important signaling pathways to regulate key biological responses, including cell migration, mitosis, and apoptosis. With this review, we address the role of the small GTP binding protein, Rac, as a regulatory protein that controls superoxide production, and the effect of superoxide and derived oxidants in cell signaling. | McIntyre M, Bohr DF, Dominiczak AF (1999)
Endothelial function in hypertension: the role of superoxide anion.
Hypertension (Dallas, Tex. : 1979) 34, 539-545 [PubMed:10523323]
[show Abstract]
Much attention has been focused on the role of nitric oxide in hypertension and cardiovascular disease. More recently, the role of superoxide anion and its interaction with nitric oxide has been investigated in this context. This review will concentrate on the role of superoxide in human and experimental hypertension, paying particular attention to the potential sources of superoxide within the vasculature and discussing some of the molecular mechanisms surrounding its production and dismutation. We discuss what is known about the human superoxide dismutase enzymes. We conclude that the balance between nitric oxide and superoxide is more important than the absolute levels of either alone. | Liu SS (1997)
Generating, partitioning, targeting and functioning of superoxide in mitochondria.
Bioscience reports 17, 259-272 [PubMed:9337481]
[show Abstract]
Recently, we proposed a hypothetical model of coexistence of "Reactive oxygen cycle" with Q cycle and H+ cycle in mitochondrial respiratory chain to combine both processes of univalent electron leak for production of superoxide and of proton leak across inner mitochondrial membrane. This review presents a more detailed description of this model and summaries the supporting experimental evidence obtained. | Nunoshiba T (1996)
Two-stage gene regulation of the superoxide stress response soxRS system in Escherichia coli.
Critical reviews in eukaryotic gene expression 6, 377-389 [PubMed:8959373]
[show Abstract]
All organisms have adapted to environmental changes by acquiring various functions controlled by gene regulation. In bacteria, a number of specific responses have been found to confer cell survival in various nutrient-limited conditions, and under physiological stresses such as high or low temperature, extreme pH, radiation, and oxidation (for review, see Neidhardt et al., 1987). In this article, I introduce an Escherichia coli (E. coli) global response induced by superoxide stress, the soxRS regulon. The functions controlled by this system consist of a wide variety of enzymes such as manganese-containing SOD (Mn-SOD); glucose 6-phosphate dehydrogenase (G6PD), the DNA repair enzyme endonuclease IV, fumarase C, NADPH:ferredoxin oxidoreductase, and aconitase. This response is positively regulated by a two-stage control system in which SoxR iron-sulfur protein senses exposure to superoxide and nitric oxide, and then activates transcription of the soxS gene, whose product stimulates the expression of the regulon genes. Our recent finding indicates that soxS transcription is initiated in a manner dependent on the rpoS gene encoding RNA polymerase sigma factor, theta s, in response to entering the stationary phase of growth. With this information, mechanisms for prokaryotic coordinating gene expression in response to superoxide stress and in stationary phase are discussed. | Katusic ZS (1996)
Superoxide anion and endothelial regulation of arterial tone.
Free radical biology & medicine 20, 443-448 [PubMed:8720916]
[show Abstract]
Evidence continues to accumulate on the importance of paracrine substances formed in the endothelium in regulation of the vascular system. Mechanisms that govern the balance between relaxing and contracting factors are important for understanding the regulation of blood vessel tone in health and disease. Chemical antagonism between superoxide anions and nitric oxide has been recognized as a potentially important modulator of vascular reactivity as well as being a source of peroxynitrite, a potent oxidant. In several models of vascular diseases, impairment of endothelium-dependent relaxations and promotion of endothelium-dependent contractions has been ascribed to increased production of superoxide anions. In pathologic conditions, increased production of superoxide anions may be responsible for an impairment of balance between relaxing and contracting factors favoring an increase in arterial tone. In this review the role of superoxide anions in modulation of endothelial mechanisms responsible for regulation of arterial tone will be discussed. | Reid GM, Tervit H (1995)
Sudden infant death syndrome and superoxide/nitric oxide.
Medical hypotheses 45, 395-397 [PubMed:8577306]
[show Abstract]
In a sudden infant death syndrome review Valdès-Dapena describes Naeye's report of increased medial muscle mass in walls of small pulmonary arteries and increased weight of cardiac right ventricles. These findings point to cardiorespiratory insufficiency, a problem in fast growing chicks raised at high altitudes. The vascular epithelium lining all blood vessels synthesises nitric oxide which induces relaxation of smooth muscle in vessel walls, and is possibly an important neurotransmitter. Others demonstrate that nitric oxide is involved in regulating vessel calibre, blood pressure and blood flow, as well as falls in ventricular outputs. Superoxide interacts with nitric oxide and removes it from the circulation. Superoxide is thus a vasoconstrictor. Superoxide is produced by activated phagocytes and possibly lymphocytes and other cell types in the immune response. Elevated immunoglobulins in mucus secretions are a hallmark in sudden infant death syndrome and hypoxic chicks. Our approach therefore is that cardiorespiratory insufficiency may be induced by superoxide in small pulmonary arteries preventing nitric oxide from acting as a muscle relaxant in vascular walls. | Nohl H (1994)
Generation of superoxide radicals as byproduct of cellular respiration.
Annales de biologie clinique 52, 199-204 [PubMed:7998676]
[show Abstract]
Cell respiration is associated with the risk of formation of oxygen radicals. Although various conditions of respiration have been described under which O2-radicals are generated it is not clear whether oxygen radical generation is an inevitable side effect of respiration. The answer is necessarily linked to an understanding of the mechanism and molecular site of oxygen radical generation. Redox-cycling ubiquinones of the mitochondrial respiratory chain have often been suggested to account for cellular O2-radical formation. However, there is an increasing body of evidence which refutes this assumption on thermodynamic grounds. The discovery of a novel respiratory enzyme of heart mitochondria, exogenous NADH-dehydrogenase, some years ago, has considerably aided understanding of mitochondrial O2-radical generation and the role of ubiquinones therein. This mitochondrial enzyme can be directly activated by cytosolic NADH. It has been shown that NADH consumption via this enzyme not only stimulates electron flow along components of the respiratory chain but that its activity is also linked to the release O2-. or the single electron reduction of adequate non-physiological oxidants. Anthraquinones which are increasingly used as antitumor drugs can enter this redox-shuttle and initiate radical chain reactions which may be partially responsible for the selective cardiotoxicity of these compounds. Metabolic conditions, causing abnormally high NADH levels in the cytosol, such as ischemia have been found to irreversibly transform intact mitochondria to active radical generators. The present review elucidates the finding of a general phenomenon which gives more insight into the mechanism and the site of O2-radical formation during normal cell respiration.(ABSTRACT TRUNCATED AT 250 WORDS) | Bielski BH, Cabelli DE (1991)
Highlights of current research involving superoxide and perhydroxyl radicals in aqueous solutions.
International journal of radiation biology 59, 291-319 [PubMed:1671684]
[show Abstract]
Selected topics of current research on HO2/O2- radical reactions in aqueous solutions are described. The subject is introduced by a brief review of the fundamental background chemistry of HO2/O2-, including a description of the rates and mechanisms of formation and decay as well as their spectral properties, current research on self-exchange rates, etc. This is followed by examples of their reactivity with simple metal complexes of iron, manganese and copper and extended to some biological significant metal-containing systems such as porphyrins, haem enzymes and superoxide dismutases. Some recent results on the interaction of these oxy-radicals with antioxidants, specifically vitamin C and E, are discussed. A brief review of some topical chemistry describing HO2/O2- involvement in atmospheric and aquatic chemistry is given. Finally, some new trends in the areas of heterogeneous catalysis and reactor chemistry that involve these species are described. | Heyworth PG, Badwey JA (1990)
Protein phosphorylation associated with the stimulation of neutrophils. Modulation of superoxide production by protein kinase C and calcium.
Journal of bioenergetics and biomembranes 22, 1-26 [PubMed:2160451]
[show Abstract]
Neutrophils and other phagocytic cells of the immune system possess a superoxide-generating oxidase system which is essential for the efficient killing of microbes. The system is activated by a wide variety of stimuli, some of which operate through pathways involving protein kinase C (PKC), while others appear not to. The PKC-dependent pathway is probably the major signal transduction route for most of the stimuli. Alterations in cellular Ca2+ and diglyceride levels can have a pronounced stimulatory effect on this pathway by their ability to synergistically activate PKC. This review discusses PKC, the different interactions of this kinase with the plasmalemma that are important in superoxide production, the synergy between Ca2+ and diglyceride, and the nature of the phosphoproteins involved. Evidence supporting the existence of the PKC-independent pathway is also reviewed. | Sohal RS, Svensson I, Sohal BH, Brunk UT (1989)
Superoxide anion radical production in different animal species.
Mechanisms of ageing and development 49, 129-135 [PubMed:2552230]
[show Abstract]
The general objective of this study was to examine the relationship between oxygen free radicals and the aging process. The rate of superoxide anion radical (O2.-) generation was measured in liver sub-mitochondrial particles from mouse, rat, rabbit, pig and cow, and in flight muscle sub-mitochondrial particles from the housefly. The rate of O2.- generation was determined as superoxide dismutase inhibitable reduction of ferricytochrome c in the presence of antimycin A and KCN. O2.- generation was inversely related to maximum species life span potential (MLSP) (r = -0.92). A 24-fold difference in the rate of O2.- production was observed between the cow and the fly while a 6-fold difference existed among the mammals. The results are interpreted to indicate that under identical conditions, mitochondria from organisms with low MLSP have a relatively greater propensity to generate O2.-. This may be suggestive of innate differences in the molecular organization of the inner mitochondrial membrane among different species. | Oberley LW, Buettner GR (1979)
Role of superoxide dismutase in cancer: a review.
Cancer research 39, 1141-1149 [PubMed:217531]
[show Abstract]
Diminished amounts of manganese-containing superoxide dismutase have been found in all the tumors examined to date. Lowered amounts of the copper-zinc-containing superoxide dismutase have been found in many, but not all, tumors. At the same time, tumors have been shown to produce superoxide radicals. It is shown how diminished enzyme activities along with radical production may lead to many of the observed properties of cancer cells. The apparent exploitation of the differences between normal and cancer cell superoxide dismutase activity in the treatment of cancer is discussed. |
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2022-03-29
