Superoxide Dismutase 1 in Health and Disease: How a Frontline Antioxidant Becomes Neurotoxic.
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ABSTRACT:
SUBMITTER: Trist BG
PROVIDER: S-EPMC8247289 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ImportanceX-linked adrenoleukodystrophy (ALD) may switch phenotype to the fatal cerebral form (ie, cerebral ALD [cALD]), the cause of which is unknown. Determining differences in antioxidant capacity and superoxide dismutase (SOD) levels between phenotypes may allow for the generation of a clinical biomarker for predicting the onset of cALD, as well as initiating a more timely lifesaving therapy.ObjectiveTo identify variations in the levels of antioxidant capacity and SOD activity between ALD phenotypes in patients with cALD or adrenomyeloneuropathy (AMN), heterozygote female carriers, and healthy controls and, in addition, correlate antioxidant levels with clinical outcome scores to determine a possible predictive value.Design, setting, and participantsSamples of monocytes and blood plasma were prospectively collected from healthy controls, heterozygote female carriers, and patients with AMN or cALD. We are counting each patient as 1 sample in our study. Because adrenoleukodystrophy is an X-linked disease, the affected group populations of cALD and AMN are all male. The heterozygote carriers are all female. The samples were assayed for total antioxidant capacity and SOD activity. The data were collected in an academic hospital setting. Eligibility criteria included patients who received a diagnosis of ALD and heterozygote female carriers, both of which groups were compared with age-matched controls. The prospective samples (n?=?30) were collected between January 2015 to January 2016, and existing samples were collected from tissue storage banks at the Kennedy Krieger Institute (n?=?30). The analyses were performed during the first 3 months of 2016.Main outcome and measuresCommercially available total antioxidant capacity and SOD assays were performed on samples of monocytes and blood plasma and correlated with magnetic resonance imaging severity score.ResultsA reduction in antioxidant capacity was shown between the healthy controls (0.225 mmol trolox equivalent) and heterozygote carriers (0.181 mmol trolox equivalent), and significant reductions were seen between healthy controls and patients with AMN (0.102 mmol trolox equivalent; P?<?.01), as well as healthy controls and patients with cALD (0.042 mmol trolox equivalent; P?<?.01). Superoxide dismutase activity in human blood plasma mirrored these reductions between prospectively collected samples from healthy controls (2.66 units/mg protein) and samples from heterozygote female carriers (1.91 units/mg protein), patients with AMN (1.39 units/mg protein; P?=?.01), and patients with cALD (0.8 units/mg protein; P?<?.01). Further analysis of SOD activity in biobank samples showed significant reductions between patients with AMN (0.89 units/mg protein) and patients with cALD (0.18 units/mg protein) (P?=?.03). Plasma SOD levels from patients with cALD demonstrated an inverse correlation to brain magnetic resonance imaging severity score (R2?=?0.75, P?<?.002). Longitudinal plasma SOD samples from the same patients (n?=?4) showed decreased activity prior to and at the time of cerebral diagnosis over a period of 13 to 42 months (mean period, 24 months).Conclusions and relevancePlasma SOD may serve as a potential biomarker for cerebral disease in ALD following future prospective studies.
| S-EPMC5822206 | biostudies-literature
Project description:Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease linked to misfolding of the ubiquitous enzyme Cu/Zn superoxide dismutase (SOD). In contrast to other protein-misfolding disorders with similar neuropathogenesis, ALS is not always associated with the in vivo deposition of protein aggregates. Thus, under the assumption that all protein-misfolding disorders share at primary level a similar disease mechanism, ALS constitutes an interesting disease model for identifying the yet-mysterious precursor states from which the cytotoxic pathway emerges. In this study, we have mapped out the conformational repertoire of the apoSOD monomer through analysis of its folding behavior. The results allow us to target the regions of the SOD structure that are most susceptible to unfolding locally under physiological conditions, leading to the exposure of structurally promiscuous interfaces that are normally hidden in the protein's interior. The structure of this putative ALS precursor is strikingly similar to those implicated in amyloid disease.
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Project description:The binding characteristics and superimposed antioxidant properties of caffeine combined with copper/zinc superoxide dismutase (SOD) were studied. The superimposed antioxidant activity of caffeine with SOD was investigated by detecting the concentration of malondialdehyde (MDA) present in cells, which was induced by hyperthermia and heavy metal exposure. The interactions between the SOD enzyme and caffeine were researched by ultraviolet spectrum, fluorescence spectrum, and molecular computation. The relative amounts of MDA contents of caffeine (0.1 mmol/L), SOD (0.1 mg/L), and caffeine (0.1 mmol/L) and SOD (0.1 mg/L) to water in cells were 0.70, 0.72, and 0.54, respectively, indicating that the antioxidant properties of caffeine combined with SOD may be superimposed. The fluorescence spectroscopy and molecular computation results show that the mixture of caffeine and SOD can result in the formation of a 1:1 complex through hydrogen bond and van der Waals forces spontaneously. The binding constant (K a) of caffeine with SOD at five different temperatures are 4.41 × 104, 3.30 × 104, 2.29 × 104, 1.71 × 104, and 1.17 × 104 L/mol. The changes of Gibbs-free energy (?G) are -26.50, -26.21, -25.71, -25.12, and -24.29 KJ/mol and the ?G of molecular docking calculation is -26.95 KJ/mol. The experimental results are in accordance with the results of theoretical calculations. The combination of caffeine with SOD can change the conformation and microenvironment of SOD but does not change the activity of SOD. In addition, the combination can superimpose the antioxidant activity of caffeine and SOD.
| S-EPMC6812128 | biostudies-literature
Project description:Extracellular superoxide dismutase (EC-SOD), also known as SOD3, is an antioxidant expressed at high levels in normal adult kidneys. Because oxidative stress contributes to a variety of kidney injuries, we hypothesized that EC-SOD may be protective in CKD progression. To study this hypothesis, we used a murine model of ADR nephropathy characterized by albuminuria and renal dysfunction. We found that levels of EC-SOD diminished throughout the course of disease progression and were associated with increased levels of NADPH oxidase and oxidative stress markers. EC-SOD null mice were sensitized to ADR injury, as evidenced by increases in albuminuria, serum creatinine, histologic damage, and oxidative stress. The absence of EC-SOD led to increased levels of NADPH oxidase and an increase in β-catenin signaling, which has been shown to be pathologic in a variety of kidney injuries. Exposure of EC-SOD null mice to either chronic angiotensin II infusion or to daily albumin injections also caused increased proteinuria. In contrast, EC-SOD null mice subjected to nonproteinuric CKD induced by unilateral ureteral obstruction exhibited no differences compared with wild-type mice. Finally, we also found a decrease in EC-SOD in human CKD biopsy samples, similar to our findings in mice. Therefore, we conclude that EC-SOD is protective in CKDs characterized by proteinuria.
| S-EPMC4587687 | biostudies-literature
Project description:Compelling evidence support an involvement of oxidative stress and intestinal inflammation as early events in the predisposition and development of obesity and its related comorbidities. Here we show that deficiency of the major mitochondrial antioxidant enzyme superoxide dismutase 2 (SOD2) in the gastrointestinal tract drives spontaneous obesity. Intestinal epithelium-specific Sod2 ablation in mice induced adiposity, inflammation and insulin resistance via phospholipase A2 (PLA2) activation and increased synthesis of omega-6 polyunsaturated fatty acid arachidonic acid. Remarkably, this obese and hyperinsulinemic phenotype was rescued when fed an essential fatty acid deficient diet, which abrogates de novo biosynthesis of arachidonic acid. Data from clinical samples revealed that the negative correlation between intestinal SOD2 mRNA levels and obesity features, such as body mass index and omega-6/omega-3 fatty acid ratio, appears to be conserved between mice and humans. Collectively, our findings suggest a role of intestinal SOD2 levels, PLA2 activity and arachidonic acid in obesity presenting new potential targets of therapeutic interest in the context of this metabolic disorder.
2021-12-31 | GSE158237 | GEO
Project description:Acute myocardial infarction (AMI) remains a dominant origin of morbidity, mortality and disability worldwide. Increases in reactive oxygen species (ROS) are key contributor to excessive cardiac injury after AMI. Here we developed an immobilized enzyme with Superoxide Dismutase (SOD) activity cross-link with Zr-based metal-organic framework (ZrMOF) (SOD-ZrMOF) for mitigate ROS-caused injury. In vitro and in vivo evidence indicates that SOD-ZrMOF exhibits excellent biocompatibility. By efficiently scavenging ROS and suppressing oxidative stress, SOD-ZrMOF can protect the function of mitochondria, reduce cell death and alleviate inflammation. More excitingly, long-term study using an animal model of AMI demonstrated that SOD-ZrMOF can reduce the infarct area, protect cardiac function, promote angiogenesis and inhibit pathological myocardial remodeling. Therefore, SOD-ZrMOF holds great potential as an efficacious and safe nanomaterial treatment for AMI.
| S-EPMC8636922 | biostudies-literature
Project description:BackgroundOxidative stress plays a pivotal role in the pathophysiology of sickle cell disease (SCD) and its associated disease complications. Superoxide Dismutases (SODs) are protective enzymes against oxidative stress. SOD2 deficiency results in the accumulation of oxidized red cell proteins, increased rate of hemoglobin oxidation, decreased red cell membrane deformability, and subsequently decreased red cells survival.ObjectiveThe current study was designed to determine the effect of SOD2 Val16Ala gene polymorphism (rs4880) on SOD2 level and their possible impact on SCD disease severity in a cohort of Egyptian SCD patients.MethodsGenotyping SOD2 Val16Ala polymorphism by TaqMan allelic discrimination assay for hundred SCD patients and a hundred age-sex matched healthy controls revealed the genotypic and allelic frequencies of the studied polymorphism in the SCD patients were close to that of the controls.ResultsSerum SOD2 level was significantly lower in those having the polymorphic genotypes (p=0.005). SOD2 level inversely correlates with the annual rate of hospitalization (r=-0.023, p= 0.038).ConclusionSOD2 Val16Ala polymorphism was associated with low serum SOD2 level that may predict disease severity.
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Project description: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.
| S-EPMC7109453 | biostudies-literature
Project description: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.
| S-EPMC7373076 | biostudies-literature
Project description:Oxidative stress is proposed as an important factor in osteoarthritis (OA).To investigate the expression of the three superoxide dismutase (SOD) antioxidant enzymes in OA.SOD expression was determined by real-time PCR and immunohistochemistry using human femoral head cartilage. SOD2 expression in Dunkin-Hartley guinea pig knee articular cartilage was determined by immunohistochemistry. The DNA methylation status of the SOD2 promoter was determined using bisulphite sequencing. RNA interference was used to determine the consequence of SOD2 depletion on the levels of reactive oxygen species (ROS) using MitoSOX and collagenases, matrix metalloproteinase 1 (MMP-1) and MMP-13, gene expression.All three SOD were abundantly expressed in human cartilage but were markedly downregulated in end-stage OA cartilage, especially SOD2. In the Dunkin-Hartley guinea pig spontaneous OA model, SOD2 expression was decreased in the medial tibial condyle cartilage before, and after, the development of OA-like lesions. The SOD2 promoter had significant DNA methylation alterations in OA cartilage. Depletion of SOD2 in chondrocytes increased ROS but decreased collagenase expression.This is the first comprehensive expression profile of all SOD genes in cartilage and, importantly, using an animal model, it has been shown that a reduction in SOD2 is associated with the earliest stages of OA. A decrease in SOD2 was found to be associated with an increase in ROS but a reduction of collagenase gene expression, demonstrating the complexities of ROS function.
| S-EPMC3789136 | biostudies-literature