-
Free Radical Biology & Medicine Aug 2009Numerous short-lived and highly reactive oxygen species (ROS) such as superoxide (O2(.-)), hydroxyl radical, and hydrogen peroxide are continuously generated in vivo.... (Review)
Review
Numerous short-lived and highly reactive oxygen species (ROS) such as superoxide (O2(.-)), hydroxyl radical, and hydrogen peroxide are continuously generated in vivo. Depending upon concentration, location, and intracellular conditions, ROS can cause toxicity or act as signaling molecules. The cellular levels of ROS are controlled by antioxidant enzymes and small-molecule antioxidants. As major antioxidant enzymes, superoxide dismutases (SODs), including copper-zinc superoxide dismutase (Cu/ZnSOD), manganese superoxide dismutase, and extracellular superoxide dismutase, play a crucial role in scavenging O2(.-). This review focuses on the regulation of the sod genes coding for these enzymes, with an emphasis on the human genes. Current knowledge about sod structure and regulation is summarized and depicted as diagrams. Studies to date on genes coding for Cu/ZnSOD (sod1) are mostly focused on alterations in the coding region and their associations with amyotrophic lateral sclerosis. Evaluation of nucleotide sequences reveals that regulatory elements of the sod2 gene reside in both the noncoding and the coding region. Changes associated with sod2 lead to alterations in expression levels as well as protein function. We also discuss the structural basis for the changes in SOD expression associated with pathological conditions and where more work is needed to establish the relationship between SODs and diseases.
Topics: Amyotrophic Lateral Sclerosis; Animals; Gene Expression Regulation, Enzymologic; Genetic Predisposition to Disease; Humans; Oxidative Stress; Polymorphism, Genetic; Reactive Oxygen Species; Regulatory Sequences, Nucleic Acid; Structure-Activity Relationship; Superoxide Dismutase; Superoxide Dismutase-1
PubMed: 19477268
DOI: 10.1016/j.freeradbiomed.2009.05.018 -
The Journal of Cell Biology Jun 2018Superoxide dismutases (SODs) are universal enzymes of organisms that live in the presence of oxygen. They catalyze the conversion of superoxide into oxygen and hydrogen... (Review)
Review
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.
Topics: Animals; Disease; Humans; Models, Animal; Oxidation-Reduction; Reactive Oxygen Species; Signal Transduction; Superoxide Dismutase
PubMed: 29669742
DOI: 10.1083/jcb.201708007 -
Proceedings of the National Academy of... Dec 2021Cytoglobin (Cygb) was discovered as a novel type of globin that is expressed in mammals; however, its functions remain uncertain. While Cygb protects against oxidant...
Cytoglobin (Cygb) was discovered as a novel type of globin that is expressed in mammals; however, its functions remain uncertain. While Cygb protects against oxidant stress, the basis for this is unclear, and the effect of Cygb on superoxide metabolism is unknown. From dose-dependent studies of the effect of Cygb on superoxide catabolism, we identify that Cygb has potent superoxide dismutase (SOD) function. Initial assays using cytochrome showed that Cygb exhibits a high rate of superoxide dismutation on the order of 10 M ⋅ s Spin-trapping studies also demonstrated that the rate of Cygb-mediated superoxide dismutation (1.6 × 10 M ⋅ s) was only ∼10-fold less than Cu,Zn-SOD. Stopped-flow experiments confirmed that Cygb rapidly dismutates superoxide with rates within an order of magnitude of Cu,Zn-SOD or Mn-SOD. The SOD function of Cygb was inhibited by cyanide and CO that coordinate to Fe-Cygb and Fe-Cygb, respectively, suggesting that dismutation involves iron redox cycling, and this was confirmed by spectrophotometric titrations. In control smooth-muscle cells and cells with siRNA-mediated Cygb knockdown subjected to extracellular superoxide stress from xanthine/xanthine oxidase or intracellular superoxide stress triggered by the uncoupler, menadione, Cygb had a prominent role in superoxide metabolism and protected against superoxide-mediated death. Similar experiments in vessels showed higher levels of superoxide in mice than wild type. Thus, Cygb has potent SOD function and can rapidly dismutate superoxide in cells, conferring protection against oxidant injury. In view of its ubiquitous cellular expression at micromolar concentrations in smooth-muscle and other cells, Cygb can play an important role in cellular superoxide metabolism.
Topics: Animals; Cell Line; Cytoglobin; Electron Spin Resonance Spectroscopy; Male; Mice; Mice, Knockout; Reactive Oxygen Species; Superoxide Dismutase
PubMed: 34930834
DOI: 10.1073/pnas.2105053118 -
Chemical Reviews Apr 2014
Review
Topics: Biocatalysis; Catalytic Domain; Hydrogen-Ion Concentration; Kinetics; Oxidoreductases; Superoxide Dismutase; Superoxides
PubMed: 24684599
DOI: 10.1021/cr4005296 -
Amino Acids Jan 2012Manganese superoxide dismutase (MnSOD) is a nuclear-encoded antioxidant enzyme that localizes to the mitochondria. Expression of MnSOD is essential for the survival of... (Review)
Review
Manganese superoxide dismutase (MnSOD) is a nuclear-encoded antioxidant enzyme that localizes to the mitochondria. Expression of MnSOD is essential for the survival of aerobic life. Transgenic mice expressing a luciferase reporter gene under the control of the human MnSOD promoter demonstrate that the level of MnSOD is reduced prior to the formation of cancer. Overexpression of MnSOD in transgenic mice reduces the incidences and multiplicity of papillomas in a DMBA/TPA skin carcinogenesis model. However, MnSOD deficiency does not lead to enhanced tumorigenicity of skin tissue similarly treated because MnSOD can modulate both the p53-mediated apoptosis and AP-1-mediated cell proliferation pathways. Apoptosis is associated with an increase in mitochondrial levels of p53 suggesting a link between MnSOD deficiency and mitochondrial-mediated apoptosis. Activation of p53 is preventable by application of a SOD mimetic (MnTE-2-PyP(5+)). Thus, p53 translocation to mitochondria and subsequent inactivation of MnSOD explain the observed mitochondrial dysfunction that leads to transcription-dependent mechanisms of p53-induced apoptosis. Administration of MnTE-2-PyP(5+) following apoptosis but prior to proliferation leads to suppression of protein carbonyls and reduces the activity of AP-1 and the level of the proliferating cellular nuclear antigen, without reducing the activity of p53 or DNA fragmentation following TPA treatment. Remarkably, the incidence and multiplicity of skin tumors are drastically reduced in mice that receive MnTE-2-PyP(5+) prior to cell proliferation. The results demonstrate the role of MnSOD beyond its essential role for survival and suggest a novel strategy for an antioxidant approach to cancer intervention.
Topics: Animals; Death; Humans; Life; Superoxide Dismutase
PubMed: 20454814
DOI: 10.1007/s00726-010-0600-9 -
PeerJ 2023Oxidative stress refers to the imbalance between oxidants and antioxidants in organisms and often induces hepatic inflammation. Supplementing exogenous superoxide...
BACKGROUND
Oxidative stress refers to the imbalance between oxidants and antioxidants in organisms and often induces hepatic inflammation. Supplementing exogenous superoxide dismutase is an effective way to alleviate oxidative stress; however, the effects and mechanisms by which superoxide dismutase alleviates hepatic inflammation remain unclear.
METHODS
This study established a Kunming mouse model to verify and investigate the oxidative stress and hepatic inflammation-alleviating effects of the superoxide dismutase oral supplement that was prepared by our research group in a previous study.
RESULTS
The superoxide dismutase product significantly restored the body weight and liver alanine transaminase, aspartate aminotransferase, superoxide dismutase, catalase, glutathione, and glutathione peroxidase levels of oxidative stress induced mice. Moreover, exogenous superoxide dismutase significantly inhibited interleukin 1 and interleukin 6 mRNA expression in the livers of mice with hepatic inflammation. Transcriptomic analysis indicated that superoxide dismutase had a significant inhibitory effect on expression, alleviating oxidative stress damage, and mediating liver cell apoptosis by regulating the expression of , , and .
CONCLUSION
Our research verified the oxidative stress remediation effects of superoxide dismutase and its therapeutic role against hepatic inflammation. This study can lay a foundation for investigating the mechanism by which superoxide dismutase alleviates hepatic disease.
Topics: Mice; Animals; Transcriptome; Liver; Oxidative Stress; Superoxide Dismutase; Inflammation
PubMed: 37583908
DOI: 10.7717/peerj.15829 -
Advanced Science (Weinheim,... Apr 2022Discography often destroys the hypoxic environment in the intervertebral disc and accelerates intervertebral disc degeneration (IVDD). Therefore, it often fails to meet...
Discography often destroys the hypoxic environment in the intervertebral disc and accelerates intervertebral disc degeneration (IVDD). Therefore, it often fails to meet the requirements for application in clinical practice. This technology mainly increases the reactive oxygen species (ROS) in the IVD. As so, it is particularly critical to develop strategies to avoid this degeneration mechanism. Prussian blue nanoparticles (PBNPs) are found to enhance development under magnetic resonance T1 and have antioxidant enzyme activity. The key results of the present study confirm that PBNPs alleviate intracellular oxidative stress and increase the intracellular activities of antioxidant enzymes, such as superoxide dismutase 1 (SOD1). PBNPs can rescue nucleus pulposus cell degeneration by increasing oxidoreductase system-related mRNA and proteins, especially by stabilizing SOD1 from ubiquitination-proteasome degradation, thus improving the mitochondrial structure to increase antioxidation ability, and finally rescuing ROS-induced IVDD in a rat model. Therefore, it is considered that PBNPs can be a potential antioxidation-protective discography contrast agent.
Topics: Animals; Ferrocyanides; Intervertebral Disc Degeneration; Nanoparticles; Proteasome Endopeptidase Complex; Rats; Superoxide Dismutase; Superoxide Dismutase-1; Ubiquitination
PubMed: 35128840
DOI: 10.1002/advs.202105466 -
Journal of Neuroinflammation Jan 2022Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor neuron system associated with both genetic and environmental risk factors....
BACKGROUND
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor neuron system associated with both genetic and environmental risk factors. Infection with enteroviruses, including poliovirus and coxsackievirus, such as coxsackievirus B3 (CVB3), has been proposed as a possible causal/risk factor for ALS due to the evidence that enteroviruses can target motor neurons and establish a persistent infection in the central nervous system (CNS), and recent findings that enteroviral infection-induced molecular and pathological phenotypes closely resemble ALS. However, a causal relationship has not yet been affirmed.
METHODS
Wild-type C57BL/6J and G85R mutant superoxide dismutase 1 (SOD1) ALS mice were intracerebroventricularly infected with a sublethal dose of CVB3 or sham-infected. For a subset of mice, ribavirin (a broad-spectrum anti-RNA viral drug) was given subcutaneously during the acute or chronic stage of infection. Following viral infection, general activity and survival were monitored daily for up to week 60. Starting at week 20 post-infection (PI), motor functions were measured weekly. Mouse brains and/or spinal cords were harvested at day 10, week 20 and week 60 PI for histopathological evaluation of neurotoxicity, immunohistochemical staining of viral protein, neuroinflammatory/immune and ALS pathology markers, and NanoString and RT-qPCR analysis of inflammatory gene expression.
RESULTS
We found that sublethal infection (mimicking chronic infection) of SOD1 ALS mice with CVB3 resulted in early onset and progressive motor dysfunction, and shortened lifespan, while similar viral infection in C57BL/6J, the background strain of SOD1 mice, did not significantly affect motor function and mortality as compared to mock infection within the timeframe of the current study (60 weeks PI). Furthermore, we showed that CVB3 infection led to a significant increase in proinflammatory gene expression and immune cell infiltration and induced ALS-related pathologies (i.e., TAR DNA-binding protein 43 (TDP-43) pathology and neuronal damage) in the CNS of both SOD1 and C57BL/6J mice. Finally, we discovered that early (day 1) but not late (day 15) administration of ribavirin could rescue ALS-like neuropathology and symptoms induced by CVB3 infection.
CONCLUSIONS
Our study identifies a new risk factor that contributes to early onset and accelerated progression of ALS and offers opportunities for the development of novel targeted therapies.
Topics: Amyotrophic Lateral Sclerosis; Animals; Disease Models, Animal; Disease Progression; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor Neurons; Neurodegenerative Diseases; Spinal Cord; Superoxide Dismutase; Superoxide Dismutase-1
PubMed: 35022041
DOI: 10.1186/s12974-022-02380-7 -
Molecular Metabolism Sep 2022Mutations in the copper-zinc superoxide dismutase (SOD1) gene cause familial amyotrophic lateral sclerosis (ALS), a progressive fatal neuromuscular disease characterized...
OBJECTIVE
Mutations in the copper-zinc superoxide dismutase (SOD1) gene cause familial amyotrophic lateral sclerosis (ALS), a progressive fatal neuromuscular disease characterized by motor neurons death and severe skeletal muscle degeneration. However, there is no effective treatment for this debilitating disease, since the underlying cause for the pathogenesis remains poorly understood. Here, we investigated a role of acyl-CoA:lysocardiolipin acyltransferase 1 (ALCAT1), an acyltransferase that promotes mitochondrial dysfunction in age-related diseases by catalyzing pathological remodeling of cardiolipin, in promoting the development of ALS in the SOD1 transgenic mice.
METHODS
Using SOD1 transgenic mice with targeted deletion of the ALCAT1 gene and treated with Dafaglitapin (Dafa), a very potent and highly selective ALCAT1 inhibitor, we determined whether ablation or pharmaceutical inhibition of ALCAT1 by Dafa would mitigate ALS and the underlying pathogenesis by preventing pathological remodeling of cardiolipin, oxidative stress, and mitochondrial dysfunction by multiple approaches, including lifespan analysis, behavioral tests, morphological and functional analysis of skeletal muscle, electron microscopic and Seahorse analysis of mitochondrial morphology and respiration, western blot analysis of the SOD1 protein aggregation, and lipidomic analysis of cardiolipin content and acyl composition in mice spinal cord.
RESULTS
ALCAT1 protein expression is potently upregulated in the skeletal muscle of the SOD1 mice. Consequently, ablation or pharmacological inhibition of ALCAT1 by Dafa attenuates motor neuron dysfunction, neuronal inflammation, and skeletal muscle atrophy in SOD1 mice by preventing SOD1 protein aggregation, mitochondrial dysfunction, and pathological CL remodeling, leading to moderate extension of lifespan in the SOD1 transgenic mice.
CONCLUSIONS
ALCAT1 promotes the development of ALS by linking SOD1 protein aggregation to mitochondrial dysfunction, implicating Dafa as a potential treatment for this debilitating disorder.
Topics: Acyltransferases; Amyotrophic Lateral Sclerosis; Animals; Cardiolipins; Disease Models, Animal; Mice; Mice, Transgenic; Protein Aggregates; Superoxide Dismutase; Superoxide Dismutase-1
PubMed: 35772643
DOI: 10.1016/j.molmet.2022.101536 -
British Journal of Pharmacology Oct 2003The list of pathophysiological conditions associated with the overproduction of superoxide expands every day. Much of the knowledge compiled on the role of this radical... (Review)
Review
The list of pathophysiological conditions associated with the overproduction of superoxide expands every day. Much of the knowledge compiled on the role of this radical in disease has been gathered using the native superoxide dismutase enzyme and, more recently, by the use of superoxide dismutase knockout models or transgenic models that overexpress the various isoforms of the enzyme. Although the native enzyme has shown promising anti-inflammatory properties in both preclinical and clinical studies, there were drawbacks and issues associated with its use as a therapeutic agent and pharmacological tool. Based on the concept that removal of superoxide modulates the course of inflammation, synthetic, low-molecular-weight mimetics of the superoxide dismutase enzymes that could overcome some of the limitations associated with the use of the native enzyme have been designed. In this review, we will discuss the advances made using various superoxide dismutase mimetics that led to the proposal that superoxide (and/or the product of its interaction with nitric oxide, peroxynitrite) is an important mediator of inflammation, and to the conclusion that superoxide dismutase mimetics can be utilized as therapeutic agents in diseases of various etiologies. The importance of the selectivity of such compounds in pharmacological studies will be discussed.
Topics: Animals; Biomimetic Materials; Drug Delivery Systems; Humans; Superoxide Dismutase
PubMed: 14522841
DOI: 10.1038/sj.bjp.0705430