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Cell Reports Jul 2023The present study examines whether there is a mechanism beyond the current concept of post-translational modifications to regulate the function of a protein. A small gas...
The present study examines whether there is a mechanism beyond the current concept of post-translational modifications to regulate the function of a protein. A small gas molecule, hydrogen sulfide (HS), was found to bind at active-site copper of Cu/Zn-SOD using a series of methods including radiolabeled binding assay, X-ray absorption near-edge structure (XANES), and crystallography. Such an HS binding enhanced the electrostatic forces to guide the negatively charged substrate superoxide radicals to the catalytic copper ion, changed the geometry and energy of the frontier molecular orbitals of the active site, and subsequently facilitated the transfer of an electron from the superoxide radical to the catalytic copper ion and the breakage of the copper-His61 bridge. The physiological relevance of such an HS effect was also examined in both in vitro and in vivo models where the cardioprotective effects of HS were dependent on Cu/Zn-SOD.
Topics: Copper; Superoxide Dismutase; Catalytic Domain; Hydrogen Sulfide; Superoxides; Zinc
PubMed: 37421623
DOI: 10.1016/j.celrep.2023.112750 -
The Cochrane Database of Systematic... Oct 2023Free oxygen radicals have been implicated in the pathogenesis of bronchopulmonary dysplasia (BPD) in preterm infants. Superoxide dismutase (SOD) is a naturally occurring... (Review)
Review
BACKGROUND
Free oxygen radicals have been implicated in the pathogenesis of bronchopulmonary dysplasia (BPD) in preterm infants. Superoxide dismutase (SOD) is a naturally occurring enzyme which provides a defense against such oxidant injury. Providing supplementary SOD has been tested in clinical trials to prevent BPD in preterm infants.
OBJECTIVES
To determine the efficacy and safety of SOD in the prevention and treatment of BPD on mortality and other complications of prematurity in infants at risk for, or having BPD.
SEARCH METHODS
We searched CENTRAL, PubMed, Embase, and three trials registers on 22 September 2022 together with reference checking, citation searching and contact with study authors to identify additional studies.
SELECTION CRITERIA
Randomized, quasi-randomized and cluster-randomized controlled trials (RCTs) where the participants were preterm infants who had developed, or were at risk of developing BPD, and who were randomly allocated to receive either SOD (in any form, by any route, any dose, anytime) or placebo, or no treatment.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methods. Our primary outcomes were BPD defined as an oxygen requirement at 28 days, BPD defined as oxygen at 36 weeks' postmenstrual age, neonatal mortality, mortality prior to discharge, and BPD or death at 36 weeks' postmenstrual age. We reported risk ratio (RR) and risk difference (RD) with 95% confidence intervals (CIs) for the dichotomous outcomes. We used GRADE to assess certainty of evidence for each outcome.
MAIN RESULTS
We included three RCTs (380 infants) on SOD administration in preterm infants at risk for BPD, and no studies in preterm infants with evolving BPD / early respiratory insufficiency. The evidence is very uncertain about the effect of SOD on BPD defined as an oxygen requirement at 28 days (RR 1.09, 95% CI 0.94 to 1.26; RD 0.06, 95% CI -0.05 to 0.16, 1 study, 302 infants; I for RR and RD not applicable), BPD defined as oxygen at 36 weeks' postmenstrual age (RR 0.96, 95% CI 0.72 to 1.29; RD -0.01, 95% CI -0.11 to 0.09, 2 studies, 335 infants; I for RR and RD = 0%), neonatal mortality (RR 0.98, 95% CI 0.57 to 1.68; RD -0.00, 95% CI -0.08 to 0.07, 2 studies, 335 infants; I for RR and RD = 0%), and mortality prior to discharge (RR 1.20, 95% CI 0.53 to 2.71; RD 0.04, 95% CI -0.14 to 0.23, 2 studies, 78 infants; I for RR and RD = 0%). No studies reported BPD or death at 36 weeks' postmenstrual age. The evidence is very uncertain about the effect of SOD on retinopathy of prematurity any stage (RR 0.95, 95% CI 0.78 to 1.15; RD -0.03, 95% CI -0.15 to 0.08, 2 studies, 335 infants; Ifor RR = 0%, I for RD = 8%), and severe retinopathy of prematurity (ROP) (RR 0.97, 95% CI 0.57 to 1.65; RD -0.01, 95% CI -0.10 to 0.09, 1 study, 244 infants; I for RR and RD not applicable). No studies reported moderate to severe neurodevelopmental outcome at 18 to 24 months. Certainty of evidence was very low for all outcomes. We identified no ongoing trials.
AUTHORS' CONCLUSIONS
The evidence is very uncertain about the effect of SOD on BPD defined as an oxygen requirement at 28 days, BPD defined as oxygen at 36 weeks' postmenstrual age, neonatal mortality and mortality prior to discharge compared to placebo. No studies reported BPD or death at 36 weeks' postmenstrual age and need for supplemental oxygen. The evidence is very uncertain about the effect of SOD on retinopathy of prematurity any stage and severe retinopathy of prematurity. No studies reported moderate to severe neurodevelopmental outcome at 18 to 24 months. The effects of SOD in preterm infants has not been reported in any trial in the last few decades, considering that the most recent trial on SOD in preterm infants was conducted in 1997/1998, and no new studies are ongoing. In the light of the limited available evidence, new data from preclinical and observational studies are needed to justify the conduction of new RCTs. Observational studies might report how SOD is administered, including indication, dose and association with relevant outcomes such as mortality, BPD and long-term neurodevelopment.
Topics: Infant, Newborn; Infant; Humans; Retinopathy of Prematurity; Bronchopulmonary Dysplasia; Infant, Premature; Oxygen; Superoxide Dismutase; Randomized Controlled Trials as Topic
PubMed: 37811631
DOI: 10.1002/14651858.CD013232.pub2 -
Journal of Biological Inorganic... Oct 2023Superoxide dismutases (SODs) are enzymes that catalyze the dismutation of the superoxide radical anion into O and HO in a two-step reaction. They are ubiquitous to all...
Superoxide dismutases (SODs) are enzymes that catalyze the dismutation of the superoxide radical anion into O and HO in a two-step reaction. They are ubiquitous to all forms of life and four different types of metal centers are detected, dividing this class of enzymes into Cu-/Zn-, Ni-, Mn-, and Fe-SODs. In this study, a superoxide dismutase from the thermophilic bacteria Thermobifida fusca (TfSOD) was cloned and expressed before the recombinant enzyme was characterized. The enzyme was found to be active for superoxide dismutation measured by inhibition of cytochrome c oxidation and the inhibition of the autoxidation of pyrogallol. Its pH-optimum was determined to be 7.5, while it has a broad temperature optimum ranging from 20 to 90 °C. Combined with the T that was found to be 78.5 ± 0.5 °C at pH 8.0, TfSOD can be defined as a thermostable enzyme. Moreover, the crystal structure of TfSOD was determined and refined to 1.25 Å resolution. With electron paramagnetic resonance spectroscopy, it was confirmed that iron is the metal co-factor of TfSOD. The cell potential (E) for the TfSOD-Fe/TfSOD-Fe redox couple was determined to be 287 mV.
Topics: Superoxide Dismutase; Superoxides; Hydrogen Peroxide; Thermobifida
PubMed: 37725277
DOI: 10.1007/s00775-023-02019-9 -
Free Radical Biology & Medicine Feb 2024Oxidative stress has been implicated in the etiology of skeletal muscle weakness following joint injury. We investigated longitudinal patient muscle samples following...
Oxidative stress has been implicated in the etiology of skeletal muscle weakness following joint injury. We investigated longitudinal patient muscle samples following knee injury (anterior cruciate ligament tear). Following injury, transcriptomic analysis revealed downregulation of mitochondrial metabolism-related gene networks, which were supported by reduced mitochondrial respiratory flux rates. Additionally, enrichment of reactive oxygen species (ROS)-related pathways were upregulated in muscle following knee injury, and further investigation unveiled marked oxidative damage in a progressive manner following injury and surgical reconstruction. We then investigated whether antioxidant protection is effective in preventing muscle atrophy and weakness after knee injury in mice that overexpress Mn-superoxide dismutase (MnSOD). MnSOD mice showed attenuated oxidative damage, atrophy, and muscle weakness compared to wild type littermate controls following ACL transection surgery. Taken together, our results indicate that ROS-related damage is a causative mechanism of muscle dysfunction after knee injury, and that mitochondrial antioxidant protection may hold promise as a therapeutic target to prevent weakness and development of disability.
Topics: Humans; Mice; Animals; Anterior Cruciate Ligament Injuries; Antioxidants; Reactive Oxygen Species; Muscular Atrophy; Muscle Weakness; Knee Injuries; Oxidative Stress; Superoxide Dismutase
PubMed: 38154571
DOI: 10.1016/j.freeradbiomed.2023.12.037 -
Nature Communications Oct 2023Psoriasis is a common inflammatory disease of especially high recurrence rate (90%) which is suffered by approximately 3% of the world population. The overexpression of...
Psoriasis is a common inflammatory disease of especially high recurrence rate (90%) which is suffered by approximately 3% of the world population. The overexpression of reactive oxygen species (ROS) plays a critical role in psoriasis progress. Here we show that biomimetic iron single-atom catalysts (FeNO-SACs) with broad-spectrum ROS scavenging capability can be used for psoriasis treatment and relapse prevention via related gene restoration. FeNO-SACs demonstrate attractive multiple enzyme-mimicking activities based on atomically dispersed Fe active structures, which are analogous to those of natural antioxidant enzymes, iron superoxide dismutase, human erythrocyte catalase, and ascorbate peroxidase. Further, in vitro and in vivo experiments show that FeNO-SACs can effectively ameliorate psoriasis-like symptoms and prevent the relapse with augmented efficacy compared with the clinical drug calcipotriol. Mechanistically, estrogen receptor 1 (ESR1) is identified as the core protein upregulated in psoriasis treatment through RNA sequencing and bioinformatic analysis. Together, this study provides a proof of concept of psoriasis catalytic therapy (PCT) and multienzyme-inspired bionics (MIB).
Topics: Humans; Reactive Oxygen Species; Secondary Prevention; Estrogen Receptor alpha; Superoxide Dismutase; Psoriasis
PubMed: 37880231
DOI: 10.1038/s41467-023-42477-y -
Psychiatry Research Aug 2023NMDAR hypofunction and oxidative stress are implicated in the pathogenesis of Alzheimer's disease. D-amino acid oxidase (DAO) regulates NMDAR function. Glutathione,...
NMDAR hypofunction and oxidative stress are implicated in the pathogenesis of Alzheimer's disease. D-amino acid oxidase (DAO) regulates NMDAR function. Glutathione, superoxide dismutase, and catalase are three first-line endogenous antioxidants. This study explored the associations of these potential biomarkers with mild cognitive impairment. Cognitive function and blood levels of DAO, glutathione, superoxide dismutase, and catalase were measured in 63 mild cognitive impairment patients and 24 healthy individuals every 6 months for 2 years. Among the patients, DAO and glutathione levels at baseline contributed to the cognitive decline 2 years later. Among the healthy individuals, only glutathione levels were associated with cognitive change. The four biomarkers differed in change directions (upward vs. downward) in the patients and in the healthy individuals. Among patients, glutathione levels were negatively correlated with superoxide dismutase and positively correlated with catalase, and DAO levels were negatively correlated with superoxide dismutase. To our knowledge, this is the first study to demonstrate the differential associations of NMDAR hypofunction and oxidative stress with cognitive change between the mild cognitive impairment patients and healthy people. Glutathione may be regarded as an aging marker for both mild cognitive impairment and normal aging; and DAO, a biomarker exclusively for mild cognitive impairment.
Topics: Humans; Catalase; Cognitive Dysfunction; Oxidative Stress; Biomarkers; Glutathione; Superoxide Dismutase; Alzheimer Disease; Receptors, N-Methyl-D-Aspartate
PubMed: 37343463
DOI: 10.1016/j.psychres.2023.115288 -
Science Advances Nov 2023Repulsive guidance molecule A (RGMa) was originally identified as a neuronal growth cone-collapsing factor. Previous reports have demonstrated the multifunctional roles...
Repulsive guidance molecule A (RGMa) was originally identified as a neuronal growth cone-collapsing factor. Previous reports have demonstrated the multifunctional roles of RGMa mediated by neogenin1. However, the pathogenic involvement of RGMa in amyotrophic lateral sclerosis (ALS) remains unclear. Here, we demonstrated that RGMa concentration was elevated in the cerebrospinal fluid of both patients with ALS and transgenic mice overexpressing the mutant human superoxide dismutase1 (mSOD1 mice). Treatment with humanized anti-RGMa monoclonal antibody ameliorated the clinical symptoms in mSOD1 mice. Histochemical analysis revealed that the anti-RGMa antibody significantly decreased mutant SOD1 protein accumulation in the motor neurons of mSOD1 mice via inhibition of actin depolymerization. In vitro analysis revealed that the anti-RGMa antibody inhibited the cellular uptake of the mutant SOD1 protein, presumably by reinforcing the neuronal actin barrier. Collectively, these data suggest that RGMa leads to the collapse of the neuronal actin barrier and promotes aberrant protein deposition, resulting in exacerbation of the ALS pathology.
Topics: Animals; Humans; Mice; Actins; Amyotrophic Lateral Sclerosis; Antibodies; Mice, Transgenic; Motor Neurons; Superoxide Dismutase; Superoxide Dismutase-1
PubMed: 37992159
DOI: 10.1126/sciadv.adg3193 -
Current Opinion in Neurology Aug 2023Amyotrophic lateral sclerosis (ALS) is a severe disease characterized by the degeneration of motor neurons. Large-scale genetic studies have now identified over 60 genes... (Review)
Review
PURPOSE OF REVIEW
Amyotrophic lateral sclerosis (ALS) is a severe disease characterized by the degeneration of motor neurons. Large-scale genetic studies have now identified over 60 genes that are associated with ALS, which in large part have also been functionally characterized. The purpose of this review is to outline how these advances are being translated into novel therapeutic strategies.
RECENT FINDINGS
The emergence of techniques that allow the specific therapeutic targeting of a (mutant) gene, in particular antisense oligonucleotide therapy (ASOs), have led to the first successful gene therapy for SOD1-ALS and multiple other gene-targeted trials are underway. This includes genetic variants that modify the disease phenotype as well as causal mutations.
SUMMARY
Technological and methodological advances are enabling researchers to unravel the genetics of ALS. Both causal mutations and genetic modifiers are viable therapeutic targets. By performing natural history studies, the phenotype-genotype correlations can be characterized. In conjunction with biomarkers for target engagement and international collaboration, this makes performing gene-targeted trials ALS feasible. The first effective treatment has now been developed for SOD1-ALS and, with multiple studies underway, it seems realistic that more therapies will follow.
Topics: Humans; Amyotrophic Lateral Sclerosis; Genes, Modifier; Superoxide Dismutase-1; Motor Neurons; Mutation
PubMed: 37338820
DOI: 10.1097/WCO.0000000000001178 -
Ecotoxicology and Environmental Safety Aug 2023Fluoranthene (Flu) uptake by plants is affected by plant growth and environmental concentration. Although plant growth processes, including substance synthesis and...
Fluoranthene (Flu) uptake by plants is affected by plant growth and environmental concentration. Although plant growth processes, including substance synthesis and antioxidant enzyme activities, have been reported to regulate Flu uptake, their contributions have been poorly evaluated. Moreover, the effect of Flu concentration is little known. Here, low concentrations (0, 1, 5, and 10 mg/L) and high concentrations (20, 30, and 40 mg/L) of Flu were set to compare the changes in Flu uptake by ryegrass (Lolium multiflorum Lam.). Indices of plant growth (biomass, root length, root area, root tip number, and photosynthesis and transpiration rates), substance synthesis (indole acetic acid [IAA] content), and antioxidant enzyme activities (superoxide dismutase [SOD], peroxidase [POD], and catalase [CAT]) were recorded to unravel the mechanism of Flu uptake. Findings suggested that the Langmuir model fitted Flu uptake by ryegrass well. Flu absorption capacity in the root was stronger than that that in the leaf. Flu bioconcentration and translocation factors increased then reduced with the increase in Flu concentration and reached the maximum value under 5 mg/L Flu treatment. Plant growth and IAA content had the same pattern as before bioconcentration factor (BCF). SOD and POD activities increased then decreased with Flu concentration and reached their highest levels under 30 and 20 mg/L Flu treatments, respectively, whereas CAT activity decreased continuously and reached its lowest level under 40 mg/L Flu treatment. Variance partitioning analysis indicated that IAA content had the greatest significant effect on Flu uptake under low-concentration Flu treatments, whereas antioxidant enzyme activities had the greatest significant effect on Flu uptake under high-concentration Flu treatments. Revealing the concentration-dependent mechanisms of Flu uptake could provide a basis for regulating pollutant accumulation in plants.
Topics: Antioxidants; Lolium; Peroxidase; Superoxide Dismutase
PubMed: 37285675
DOI: 10.1016/j.ecoenv.2023.115088 -
Biomedicine & Pharmacotherapy =... Dec 2023Superoxide dismutase (SOD) can convert active oxygen to oxygen or hydrogen peroxide, and recent research has suggested that it can protect against lung damage and...
Superoxide dismutase (SOD) can convert active oxygen to oxygen or hydrogen peroxide, and recent research has suggested that it can protect against lung damage and fibrosis. Clinical applications based on SOD remain limited however due to costs and low stability. We here investigated a potential new therapeutic delivery system for this enzyme in the form of SOD-overexpressing Bacillus amyloliquefaciens spores which we introduced into a bleomycin-induced pulmonary fibrosis mouse model. This treatment significantly alleviated the disease, as quantified using a hydroxyproline assay, at 10 colony forming unit (CFU) of Bacillus spores per day. Exposure of the mice to the spores was further found to decrease the lung mRNA levels of CTGF, Col1a1, α-SMA, TGF-β, TNF-α, and IL-6, and the protein levels of TGF-β, Smad2/3, αSMA and Col1a1, all major indicators of pulmonary fibrosis. Survival benefits, and reduced byproducts of lipid peroxidase such as malondialdehyde and 4-hydroxynen, were also noted in the treated animals. The beneficial effects of these Bacillus spores on pulmonary fibrosis were further found to be greater than the equivalent free SOD concentration. Immunofluorescence staining of primary pulmonary fibroblasts extracted from the bleomycin-induced model showed decreased αSMA expression following the in vivo treatment with SOD-overexpressing Bacillus. Our treatment approach SOD through Bacillus spores shows beneficial effects against pulmonary fibrosis, combined with the suppression of the SMAD/TGF-β pathway, suggesting that it is an effective novel delivery route for antioxidants.
Topics: Mice; Animals; Pulmonary Fibrosis; Bacillus amyloliquefaciens; Spores, Bacterial; Lung; Superoxide Dismutase; Transforming Growth Factor beta; Bleomycin; Transforming Growth Factor beta1
PubMed: 37826939
DOI: 10.1016/j.biopha.2023.115647