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Brain : a Journal of Neurology Nov 2023The current strategies to mitigate the toxicity of misfolded superoxide dismutase 1 (SOD1) in familial amyotrophic lateral sclerosis via blocking SOD1 expression in the...
The current strategies to mitigate the toxicity of misfolded superoxide dismutase 1 (SOD1) in familial amyotrophic lateral sclerosis via blocking SOD1 expression in the CNS are indiscriminative for misfolded and intact proteins, and as such, entail a risk of depriving CNS cells of their essential antioxidant potential. As an alternative approach to neutralize misfolded and spare unaffected SOD1 species, we developed scFv-SE21 antibody that blocks the β6/β7 loop epitope exposed exclusively in misfolded SOD1. The β6/β7 loop epitope has previously been proposed to initiate amyloid-like aggregation of misfolded SOD1 and mediate its prion-like activity. The adeno-associated virus-mediated expression of scFv-SE21 in the CNS of hSOD1G37R mice rescued spinal motor neurons, reduced the accumulation of misfolded SOD1, decreased gliosis and thus delayed disease onset and extended survival by 90 days. The results provide evidence for the role of the exposed β6/β7 loop epitope in the mechanism of neurotoxic gain-of-function of misfolded SOD1 and open avenues for the development of mechanism-based anti-SOD1 therapeutics, whose selective targeting of misfolded SOD1 species may entail a reduced risk of collateral oxidative damage to the CNS.
Topics: Mice; Animals; Superoxide Dismutase-1; Amyotrophic Lateral Sclerosis; Superoxide Dismutase; Epitopes; Phenotype; Protein Folding; Disease Models, Animal; Mice, Transgenic
PubMed: 37394908
DOI: 10.1093/brain/awad222 -
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 -
Biochimica Et Biophysica Acta.... Dec 2023Different SOD1 proteoforms are implicated## in both familial and sporadic cases of Amyotrophic Lateral Sclerosis (ALS), an aging-associated disease that affects motor...
Different SOD1 proteoforms are implicated## in both familial and sporadic cases of Amyotrophic Lateral Sclerosis (ALS), an aging-associated disease that affects motor neurons. SOD1 is crucial to neuronal metabolism and health, regulating the oxidative stress response and the shift between oxidative-fermentative metabolism, which is important for astrocyte-neuron metabolic cooperation. Neurons have a limited capacity to metabolize methylglyoxal (MGO), a potentially toxic side product of glycolysis. MGO is highly reactive and can readily posttranslationally modify proteins, in a reaction known as glycation, impacting their normal biology. Here, we aimed to investigate the effect of glycation on the aggregation and toxicity of human SOD1WT (hSOD1WT). Cells with deficiency in MGO metabolism showed increased levels of hSOD1WT inclusions, displaying also reduced hSOD1WT activity and viability. Strikingly, we also found that the presence of hSOD1WT in stress granules increased upon MGO treatment. The treatment of recombinant hSOD1WT with MGO resulted in the formation of SDS-stable oligomers, specially trimers, and thioflavin-T positive aggregates, which can promote cell toxicity and TDP-43 pathology. Together, our results suggest that glycation may play a still underappreciated role on hSOD1WT and TDP-43 pathologies in sporadic ALS, which could open novel perspectives for therapeutic intervention.
Topics: Humans; Superoxide Dismutase-1; Amyotrophic Lateral Sclerosis; Superoxide Dismutase; Maillard Reaction; Magnesium Oxide; Motor Neurons; DNA-Binding Proteins
PubMed: 37558009
DOI: 10.1016/j.bbadis.2023.166835 -
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 -
Free Radical Research Jan 2022Superoxide dismutase 3 (SOD3), one of SOD isozymes, maintains extracellular redox homeostasis through the dismutation reaction of superoxide. Loss of SOD3 in tumor cells...
Superoxide dismutase 3 (SOD3), one of SOD isozymes, maintains extracellular redox homeostasis through the dismutation reaction of superoxide. Loss of SOD3 in tumor cells induces oxidative stress and exacerbates tumor progression; however, interestingly, overexpression of SOD3 also promotes cell proliferation through the production of hydrogen peroxide. In this study, we investigated the functional role of SOD3 in human breast cancer MDA-MB-231 cell migration and the molecular mechanisms involved in high expression of SOD3 in MDA-MB-231 cells and human monocytic THP-1 cells. The level of histone H3 trimethylation at lysine 27 (H3K27me3), a marker of gene silencing, was decreased in 12--tetra-decanoylphorbol-13-acetate (TPA)-treated THP-1 cells. Also, that reduction was observed within the promoter region. We then investigated the involvement of H3K27 demethylase JMJD3 in SOD3 induction. The induction of SOD3 and the reduction of H3K27me3 were inhibited in the presence of JMJD3 inhibitor, GSK-J4. Additionally, it was first determined that the knockdown of the transcription factor forkhead box O1 (FOXO1) significantly suppressed TPA-elicited SOD3 induction. FOXO1-mediated SOD3 downregulation was also observed in MDA-MB-231 cells, and knockdown of FOXO1 and SOD3 suppressed cell migration. Our results provide a novel insight into epigenetic regulation of SOD3 expression in tumor-associated cells, and high expression of FOXO1 and SOD3 would participate in the migration of MDA-MB-231 cells.
Topics: Cell Movement; Epigenesis, Genetic; Forkhead Box Protein O1; Histones; Humans; Oxidation-Reduction; Superoxide Dismutase
PubMed: 35271779
DOI: 10.1080/10715762.2022.2049770 -
Blood Advances Sep 2019Sickle cell disease (SCD) is an inherited hemoglobinopathy caused by a single point mutation in the β-globin gene. As a consequence, deoxygenated hemoglobin polymerizes... (Review)
Review
Sickle cell disease (SCD) is an inherited hemoglobinopathy caused by a single point mutation in the β-globin gene. As a consequence, deoxygenated hemoglobin polymerizes triggering red blood cell sickling and hemolysis, vaso-occlusion, and ischemia/reperfusion. Allied to these pathologies is the overproduction of reactive oxygen species driven by hemoglobin Fenton chemistry and peroxidase reactions as well as by secondary activation of vascular oxidases, including NAD(P)H oxidase and xanthine oxidase. In addition, hypoxia, produced by sickle red blood cell occlusion, disrupts mitochondrial metabolism and generates excess superoxide through electron leak from the mitochondrial respiratory chain. Superoxide dismutase 2 (SOD2) is a mitochondrial-specific antioxidant enzyme that dismutates superoxide to hydrogen peroxide, which is then converted to water by catalase and glutathione peroxidase. In SCD, the antioxidant defense system is significantly diminished through decreased expression and activity levels of antioxidant enzymes, including superoxide dismutase, catalase, and glutathione peroxidase. From a translational perspective, genetic variants including a missense variant in SOD2 (valine to alanine at position 16) are present in 45% of people with African ancestry and are associated with increased sickle complications. While it is known that there is an imbalance between oxidative species and antioxidant defenses in SCD, much more investigation is warranted. This review summarizes our current understanding of antioxidant defense systems in SCD, particularly focused on SOD2, and provides insight into challenges and opportunities as the field moves forward.
Topics: Anemia, Sickle Cell; Antioxidants; Humans; Hypoxia; Mitochondria; Mutation, Missense; Reactive Oxygen Species; Superoxide Dismutase
PubMed: 31506286
DOI: 10.1182/bloodadvances.2019000527 -
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 -
Free Radical Biology & Medicine Feb 2021Superoxide dismutase 3 (SOD3) is an extracellular protein with the capacity to convert superoxide into hydrogen peroxide, an important secondary messenger in redox...
Superoxide dismutase 3 (SOD3) is an extracellular protein with the capacity to convert superoxide into hydrogen peroxide, an important secondary messenger in redox regulation. To investigate the utility of zebrafish in functional studies of SOD3 and its relevance for redox regulation, we have characterized the zebrafish orthologues; Sod3a and Sod3b. Our analyses show that both recombinant Sod3a and Sod3b express SOD activity, however, only Sod3b is able to bind heparin. Furthermore, RT-PCR analyses reveal that sod3a and sod3b are expressed in zebrafish embryos and are present primarily in separate organs in adult zebrafish, suggesting distinct functions in vivo. Surprisingly, both RT-PCR and whole mount in situ hybridization showed specific expression of sod3b in skeletal tissue. To further investigate this observation, we compared femoral bone obtained from wild-type and SOD3 mice to determine whether a functional difference was apparent in healthy adult mice. Here we report, that bone from SOD3 mice is less mineralized and characterized by significant reduction of cortical and trabecular thickness in addition to reduced mechanical strength. These analyses show that SOD3 plays a hitherto unappreciated role in bone development and homeostasis.
Topics: Animals; Bone and Bones; Homeostasis; Mice; Mice, Knockout; Oxidation-Reduction; Superoxide Dismutase; Zebrafish
PubMed: 33476796
DOI: 10.1016/j.freeradbiomed.2021.01.027 -
International Journal of Biological... Dec 2023Superoxide dismutase 1 (SOD1) is a vital enzyme responsible for controlling cellular oxidative stress. Any dysregulation of SOD1 activity is linked with cancer...
Superoxide dismutase 1 (SOD1) is a vital enzyme responsible for controlling cellular oxidative stress. Any dysregulation of SOD1 activity is linked with cancer pathogenesis and neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS). Among the inhibitors known to be effective against SOD1, LCS-1 stands out; however, its efficacy, specificity, and safety profiles are somewhat restricted. In this study, we used PubChem library to retrieve compounds that exhibited a structural similarity of at least 90 % with LCS-1. These compounds underwent molecular docking analyses to examine their interaction patterns and binding affinities with SOD1. Further, we applied filters based on physicochemical and ADMET properties, refining the selection process. Our analysis revealed that selected compounds interact with crucial residues of SOD1 active site. To gain further insights into conformational stability and dynamics of the SOD1-ligand complexes, we conducted all-atom molecular dynamics (MD) simulations for 100 ns. We identified two compounds, CID:133306073 and CID:133446715, as potential scaffolds with promising inhibitory properties against SOD1. Both compounds hold significant potential for further exploration as therapeutic SOD1 inhibitors. Further studies are warranted to fully harness their therapeutic potential in targeting SOD1 for cancer and ALS treatment, offering new avenues for improved patient outcomes and disease management.
Topics: Humans; Superoxide Dismutase-1; Molecular Docking Simulation; Amyotrophic Lateral Sclerosis; Oxidation-Reduction; Neoplasms; Superoxide Dismutase; Mutation
PubMed: 37666395
DOI: 10.1016/j.ijbiomac.2023.126684 -
Molecular Biology Reports Nov 2022Incomplete combustion of wood releases toxic chemicals. Exposure to these chemicals during charcoal production can modulate redox status of cellular system which may...
BACKGROUND
Incomplete combustion of wood releases toxic chemicals. Exposure to these chemicals during charcoal production can modulate redox status of cellular system which may further lead to genomic instability and of antioxidant enzymes. Genetic polymorphism may alter the functioning properties of these enzymes and modulate the response to oxidative stress.
METHODS
In this study, we analyzed the link between genetic polymorphism and enzyme activity for antioxidant enzymes: MnSOD and GPx-1 in charcoal workers and control population. This study included 77 charcoal workers and 79 demographically matched healthy control subjects. This association was studied using multiple linear regression, adjusted for confounding factors viz. age, consumption habits and exposure duration.
RESULTS
SOD activity was lower for TT genotype (3.47 ± 0.66; 5.92 ± 1.08) versus CC genotype (3.47 ± 0.66; 6.67 ± 1.60) in control and charcoal workers respectively. Significant lower GPx-1 activity was found in leu/leu genotype (7.25 ± 0.38; 3.59 ± 0.57) when compared to pro/pro genotype (7.78 ± 0.59; 4.28 ± 0.71) and pro/leu genotype (8.48 ± 0.34; 4.30 ± 0.76) in control population and charcoal workers respectively. A significant difference in the levels of 1-Hydroxypyrene (biomarker of exposure) and SOD and GPx-1 activity (biomarkers of oxidative stress) was evident in exposed group in comparison to the control one.
CONCLUSION
Collectively, our findings suggested that PAH influenced the mode of action of SOD and GPx-1 which were impacted by polymorphism in SOD and GPx-1 gene. Hence, polymorphism of MnSOD and GPx-1 genes were found to play a modulatory role in human susceptibility to oxidative damage induced by wood smoke in charcoal workers.
Topics: Humans; Glutathione Peroxidase; Antioxidants; Charcoal; Superoxide Dismutase; Polymorphism, Genetic; Oxidative Stress; Superoxide Dismutase-1; Biomarkers; Catalase
PubMed: 36074229
DOI: 10.1007/s11033-022-07779-2