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Zoidis, Evangelos, George Papadomichelakis, Athanasios C. Pappas, Georgios Theodorou, and Kostas Fegeros. "Effects of Selenium and Cadmium on Breast Muscle Fatty-Acid Composition and Gene Expression of Liver Antioxidant Proteins in Broilers." Antioxidants 8, no. 5 (May 27, 2019): 147. http://dx.doi.org/10.3390/antiox8050147.
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The present work was part of a project intended to evaluate whether organic selenium (Se) has the potential to protect against toxic effects exerted by cadmium (Cd). For this reason, 300 as-hatched, one-day-old broiler chickens were randomly allocated in four dietary treatments with five replicate pens per treatment. Chickens in T1 treatment, were offered a diet supplemented with 0.3 ppm Se (as Se-yeast), without added Cd; in T2 treatment, they were offered a diet with 0.3 ppm Se and 10 ppm Cd; in T3 treatment, they were offered a diet with 0.3 ppm Se and 100 ppm Cd; in T4 treatment, chickens were offered a diet supplemented with 3 ppm Se and 100 ppm Cd. Cadmium was added to the diets in T2, T3, and T4 as CdCl2. On the fourth and sixth weeks, liver and breast samples were obtained from two broilers per replicate pen. Relative gene expression levels of catalase (CAT), superoxide dismutase 1 (SOD1) and 2 (SOD2), methionine sulfoxide reductase A (MSRA) and B3 (MSRB3), iodothyronine deiodinase 1 (DIO1), 2 (DIO2), and 3 (DIO3), glutathione peroxidase 1 (GPX1) and 4 (GPX4), thioredoxin reductase 1 (TXNRD1) and 3 (TXNRD3), and metallothionein 3 (MT3) were analyzed by real-time quantitative PCR in liver, whereas the fatty-acid (FA) profile of breast muscle was determined by gas chromatography. Broilers supplemented with 0.3 ppm Se could tolerate low levels of Cd present in the diets, as there were no significant changes in the breast muscle FA profile, whereas excess Cd led to decreased polyunsaturated fatty acids (PUFAs), and in particular n-6 PUFA. Furthermore, treatments mainly affected the messenger RNA (mRNA) expression of SOD2, TXNRD3, and MT3, while age affected CAT, MSRB3, DIO2, DIO3, GPX4, TXNRD1, and MT3. In conclusion, dietary Se may help against the negative effects of Cd, but cannot be effective when Cd is present at excessive amounts in the diet.
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Bovio, Federica, Barbara Sciandrone, Chiara Urani, Paola Fusi, Matilde Forcella, and Maria Elena Regonesi. "Superoxide dismutase 1 (SOD1) and cadmium: A three models approach to the comprehension of its neurotoxic effects." NeuroToxicology 84 (May 2021): 125–35. http://dx.doi.org/10.1016/j.neuro.2021.03.007.
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Medicherla, Balasubrahmanyam, and Alfred L. Goldberg. "Heat shock and oxygen radicals stimulate ubiquitin-dependent degradation mainly of newly synthesized proteins." Journal of Cell Biology 182, no. 4 (August 25, 2008): 663–73. http://dx.doi.org/10.1083/jcb.200803022.
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Accumulation of misfolded oxidant-damaged proteins is characteristic of many diseases and aging. To understand how cells handle postsynthetically damaged proteins, we studied in Saccharomyces cerevisiae the effects on overall protein degradation of shifting from 30 to 38°C, exposure to reactive oxygen species generators (paraquat or cadmium), or lack of superoxide dismutases. Degradation rates of long-lived proteins (i.e., most cell proteins) were not affected by these insults, even when there was widespread oxidative damage to proteins. However, exposure to 38°C, paraquat, cadmium, or deletion of SOD1 enhanced two- to threefold the degradation of newly synthesized proteins. By 1 h after synthesis, their degradation was not affected by these treatments. Degradation of these damaged cytosolic proteins requires the ubiquitin–proteasome pathway, including the E2s UBC4/UBC5, proteasomal subunit RPN10, and the CDC48–UfD1–NPL4 complex. In yeast lacking these components, the nondegraded polypeptides accumulate as aggregates. Thus, many cytosolic proteins proceed through a prolonged “fragile period” during which they are sensitive to degradation induced by superoxide radicals or increased temperatures.
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Jiang, Shun Yao, and Pei Jiang Zhou. "Effects of Cadmium on the Expression of Antioxidant Enzymes, Oxidative Stress and Apoptosis in Primary Hepatocytes of Carassius Auratus." Advanced Materials Research 518-523 (May 2012): 341–46. http://dx.doi.org/10.4028/www.scientific.net/amr.518-523.341.
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The primary hepatocytes of Carassius auratus were incubated with 0, 0.01, 0.1, 1, 10 and 100 mg/l Cadmium(Cd2+) at 25°C for 8h in vitro. The results showed that the hepatocytes survival rate in the 1, 10 and 100 mg/l Cd2+ treated groups were significantly lower than that in the control, the percentage of apoptotic hepatocytes significantly increased in 0.1, 1 and 10 mg/l of Cd2+ treated groups, intracellular reactive oxygen species(ROS) and malondialdehyde (MDA) content significantly increased in 0.1, 1, 10 and 100 mg/l Cd2+ treated groups, typical DNA ladder was observed in 0.1, 1 and 10 mg/l Cd2+ treated groups, and ruleless DNA fragment occurred in 100 mg/l Cd2+ treated group. The activities of the antioxidant enzymes and the expression of their isozymes activities have similar change tendency, compared with the control group, the activities of superoxide dismutase (SOD) and their isozymes were activated by low concentration of Cd2+ (0.1 and 1 mg/l), however, their activities were inhibited by high concentration of Cd2+ (10 and 100 mg/l), especially, the special isozyme (SOD1) was found in the patterns of SOD isozymes in 0.1 and 1 mg/l Cd2+ treated groups, the activities of peroxidase(POD) and its isozymes significantly reduced with a concentration-dependent manner in all Cd Cd2+ treated groups, the activities of catalase(CAT) and its isozymes significantly decreased in higher concentration Cd2+ treated groups (1, 10 and 100mg/l). The results suggested that Cd2+ could damage the activities of the antioxidant enzymes and cause oxidative stress, lipid peroxidation, DNA fragmentation, apoptosis and necrosis in primary hepatocytes, contributing to the liver toxicity induced by Cd2+.
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Nikolic-Kokic, Aleksandra, Zorana Orescanin-Dusic, Ivan Spasojevic, Dusko Blagojevic, Zorica Stevic, Pavle Andjus, and Mihajlo Spasic. "The effects of wild-type and mutant SOD1 on smooth muscle contraction." Archives of Biological Sciences 67, no. 1 (2015): 187–92. http://dx.doi.org/10.2298/abs141006023n.
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In this work we compared the mutated liver copper zinc-containing superoxide dismutase (SOD1) protein G93A of the transgenic rat model of familial amyotrophic lateral sclerosis (FALS), to wild-type (WT) rat SOD1. We examined their enzymatic activities and effects on isometric contractions of uteri of healthy virgin rats. G93A SOD1 showed a slightly higher activity than WT SOD1 and, in contrast to WT SOD1, G93A SOD1 did not induce smooth muscle relaxation. This result indicates that effects on smooth muscles are not related to SOD1 enzyme activity and suggest that heterodimers of G93A SOD1 form an ion-conducting pore that diminishes the relaxatory effects of SOD1. We propose that this type of pathogenic feedback affects neurons in FALS.
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Sorrells, A. D., K. Corcoran-Gomez, K. A. Eckert, A. G. Fahey, B. L. Hoots, L. B. Charleston, J. S. Charleston, C. R. Roberts, and H. Markowitz. "Effects of environmental enrichment on the amyotrophic lateral sclerosis mouse model." Laboratory Animals 43, no. 2 (April 2009): 182–90. http://dx.doi.org/10.1258/la.2008.005090.
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The manner in which an animal's environment is furnished may have significant implications for animal welfare as well as research outcomes. We evaluated four different housing conditions to determine the effects of what has been considered standard rodent enrichment and the exercise opportunities those environments allow on disease progression in the amyotrophic lateral sclerosis mouse model. Forty-eight copper/zinc superoxide dismutase mice (strain: B6SJL-TgN [SOD1-G931]1Gur) (SOD1) and 48 control (C) (strain: B6SJL-TgN[SOD1]2Gur) male mice were randomly assigned to four different conditions where 12 SOD1 and 12 C animals were allotted to each condition ( n = 96). Conditions tested the effects of standard housing, a forced exercise regime, access to a mouse house and opportunity for ad libitum exercise on a running wheel. In addition to the daily all-occurrence behavioural sampling, mice were weighed and tested twice per week on gait and Rotor-Rod™ performance until the mice reached the age of 150 days (C) or met the criteria for our humane endpoint (SOD1). The SOD1 mice exposed to the forced exercise regime and wheel access did better in average lifespan and Rotor-Rod™ performance, than SOD1 mice exposed to the standard cage and mouse house conditions. In SOD1 mice, stride length remained longest throughout the progression of the disease in mice exposed to the forced exercise regime compared with other SOD1 conditions. Within the control group, mice in the standard cage and forced exercise regime conditions performed significantly less than the mice with the mouse house and wheels on the Rotor-Rod™. Alpha motor neuron counts were highest in mice with wheels and in mice exposed to forced exercise regime in both mouse strains. All SOD1 mice had significantly lower alpha neuron counts than controls ( P < 0.05). These data show that different enrichment strategies affect behaviour and disease progression in a transgenic mouse model, and may have implications for the effects of these strategies on experimental outcomes.
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Ying, Weihai, Christopher M. Anderson, Yongmei Chen, Becky A. Stein, Christian S. Fahlman, Jean-Christophe Copin, Pak H. Chan, and Raymond A. Swanson. "Differing Effects of Copper, Zinc Superoxide Dismutase Overexpression on Neurotoxicity Elicited by Nitric Oxide, Reactive Oxygen Species, and Excitotoxins." Journal of Cerebral Blood Flow & Metabolism 20, no. 2 (February 2000): 359–68. http://dx.doi.org/10.1097/00004647-200002000-00018.
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Overexpression of Cu,Zn superoxide dismutase (SOD1) reduces ischemic injury in some stroke models but exacerbates injury in a neonatal stroke model and in other settings. The current study used a SOD1 transgenic (SOD1-Tg) murine cortical culture system, derived from the same mouse strain previously used for the stroke models, to identify conditions that determine whether SOD1 overexpression in neurons is protective or detrimental. The nitric oxide (NO) donors S-nitroso- N-acetylpenicillamine, spermine-NONOate, and diethylamine-NONOate produced less death in SOD1-Tg neurons than in wild-type neurons ( p < 0.01). Also, NO produced markedly less 3-nitrotyosine in SOD1-Tg cells. In contrast, the superoxide generator menadione produced significantly greater death and nearly twice as much 2′7′-dichlorofluorescein fluorescence in SOD1-Tg neurons than in wild-type neurons, suggesting increased peroxide formation in the SOD1-Tg cells. No significant difference was observed in the vulnerability of the two cell types to H2O2, the product of the SOD reaction. Over-expression of SOD1 also had no effect on neuronal vulnerability to glutamate, N-methyl-D-aspartate, or kainate. These observations suggest that SOD1 overexpression can reduce neuronal death under conditions where peroxynitrite formation is a significant factor, but may exacerbate neuronal death under conditions of rapid intracellular superoxide formation or impaired H2O2 disposal.
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Nikolić-Kokić, Aleksandra, Zorana Oreščanin-Dušić, Marija Slavić, Ivan Spasojević, Zorica Stević, Mihajlo Spasić, and Duško Blagojević. "The Effects of Human Wild-Type and Fals Mutant L144P SOD1 on Non-Vascular Smooth Muscle Contractions / EFEKTI HUMANE NORMALNE I FALS MUTIRANE L144P SOD1 NA NEVASKULARNE KONTRAKCIJE GLATKIH MIŠIĆA." Journal of Medical Biochemistry 32, no. 4 (October 1, 2013): 375–79. http://dx.doi.org/10.2478/jomb-2013-0032.
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Summary Background: Mutated copper, zinc-containing superoxide dismutase (SOD1) may self-aggregate, an event that could also be an initial cause of motor neuron malfunction leading to disease onset. The effects of human mutated SOD1 pro- tein from the blood of familial amyotrophic lateral sclerosis (FALS) patients bearing Leu144Phe (L144F) mutation were compared to wild-type (WT) human SOD1 derived from healthy examinees, for enzymatic activity and the effects on isometric contractions of non-vascular smooth muscle. Methods: We isolated WT and L144F SOD1 enzymes from eight patients with FALS, L144F mutation in exon 5 and eight healthy controls. We then investigated SOD1 activities in the obtained samples by the adrenaline method and pro- filed them electrophoretically. Finally, we applied WT and L144F SOD1 on the isolated rat uterus. Results: L144F SOD1 showed lower superoxide-dismutating activity compared to WT human SOD1. We found that, in contrast to WT human SOD1, mutated L144F does not induce smooth muscle relaxation. Conclusions: Our data suggest that the lack of relaxation of muscle tonus in the presence of mutated SOD1 may have pathogenic feedback effects in FALS.
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Culik, Robert M., Ashok Sekhar, Jayashree Nagesh, Harmeen Deol, Jessica A. O. Rumfeldt, Elizabeth M. Meiering, and Lewis E. Kay. "Effects of maturation on the conformational free-energy landscape of SOD1." Proceedings of the National Academy of Sciences 115, no. 11 (February 26, 2018): E2546—E2555. http://dx.doi.org/10.1073/pnas.1721022115.
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Amyotrophic lateral sclerosis (ALS) is a devastating fatal syndrome characterized by very rapid degeneration of motor neurons. A leading hypothesis is that ALS is caused by toxic protein misfolding and aggregation, as also occurs in many other neurodegenerative disorders, such as prion, Alzheimer’s, Parkinson’s, and Huntington’s diseases. A prominent cause of familial ALS is mutations in the protein superoxide dismutase (SOD1), which promote the formation of misfolded SOD1 conformers that are prone to aberrant interactions both with each other and with other cellular components. We have shown previously that immature SOD1, lacking bound Cu and Zn metal ions and the intrasubunit disulfide bond (apoSOD12SH), has a rugged free-energy surface (FES) and exchanges with four other conformations (excited states) that have millisecond lifetimes and sparse populations on the order of a few percent. Here, we examine further states of SOD1 along its maturation pathway, as well as those off-pathway resulting from metal loss that have been observed in proteinaceous inclusions. Metallation and disulfide bond formation lead to structural transformations including local ordering of the electrostatic loop and native dimerization that are observed in rare conformers of apoSOD12SH; thus, SOD1 maturation may occur via a population-switch mechanism whereby posttranslational modifications select for preexisting structures on the FES. Metallation and oxidation of SOD1 stabilize the native, mature conformation and decrease the number of detected excited conformational states, suggesting that it is the immature forms of the protein that contribute to misfolded conformations in vivo rather than the highly stable enzymatically active dimer.
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Pytte, Julia, Loren L. Flynn, Ryan S. Anderton, Frank L. Mastaglia, Frances Theunissen, Ian James, Abigail Pfaff, et al. "Disease-modifying effects of an SCAF4 structural variant in a predominantly SOD1 ALS cohort." Neurology Genetics 6, no. 4 (July 1, 2020): e470. http://dx.doi.org/10.1212/nxg.0000000000000470.
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ObjectiveTo test the hypothesis that rs573116164 will have disease-modifying effects in patients with superoxide dismutase 1 (SOD1) familial amyotrophic lateral sclerosis (fALS), we characterized rs573116164 within a cohort of 190 patients with fALS and 560 healthy age-matched controls to assess the variant for association with various measures of disease.MethodsUsing a previously described bioinformatics evaluation algorithm, a polymorphic short structural variant associated with SOD1 was identified according to its theoretical effect on gene expression. An 12–18 poly-T repeat (rs573116164) within the 3′ untranslated region of serine and arginine rich proteins-related carboxy terminal domain associated factor 4 (SCAF4), a gene that is adjacent to SOD1, was assessed for disease association and influence on survival and age at onset in an fALS cohort using PCR, Sanger sequencing, and capillary separation techniques for allele detection.ResultsIn a North American cohort of predominantly SOD1 fALS patients (n =190) and age-matched healthy controls (n = 560), we showed that carriage of an 18T SCAF4 allele was associated with disease within this cohort (odds ratio [OR] 6.6; 95% confidence interval [CI] 3.9–11.2; p = 4.0e-11), but also within non-SOD1 cases (n = 27; OR 5.3; 95% CI 1.9–14.5; p = 0.0014). This finding suggests genetically SOD1-independent effects of SCAF4 on fALS susceptibility. Furthermore, carriage of an 18T allele was associated with a 26-month reduction in survival time (95% CI 6.6–40.8; p = 0.014), but did not affect age at onset of disease.ConclusionsThe findings in this fALS cohort suggest that rs573116164 could have SOD1-independent and broader relevance in ALS, warranting further investigation in other fALS and sporadic ALS cohorts, as well as studies of functional effects of the 18T variant on gene expression.
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Pereira, Gabriel Rodrigues Coutinho, Bárbara de Azevedo Abrahim Vieira, and Joelma Freire De Mesquita. "Comprehensive in silico analysis and molecular dynamics of the superoxide dismutase 1 (SOD1) variants related to amyotrophic lateral sclerosis." PLOS ONE 16, no. 2 (February 25, 2021): e0247841. http://dx.doi.org/10.1371/journal.pone.0247841.
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Amyotrophic Lateral Sclerosis (ALS) is the most frequent motor neuron disorder, with a significant social and economic burden. ALS remains incurable, and the only drugs approved for its treatments confers a survival benefit of a few months for the patients. Missense mutations in superoxide dismutase 1 (SOD1), a major cytoplasmic antioxidant enzyme, has been associated with ALS development, accounting for 23% of its familial cases and 7% of all sporadic cases. This work aims to characterize in silico the structural and functional effects of SOD1 protein variants. Missense mutations in SOD1 were compiled from the literature and databases. Twelve algorithms were used to predict the functional and stability effects of these mutations. ConSurf was used to estimate the evolutionary conservation of SOD1 amino-acids. GROMACS was used to perform molecular dynamics (MD) simulations of SOD1 wild-type and variants A4V, D90A, H46R, and I113T, which account for approximately half of all ALS-SOD1 cases in the United States, Europe, Japan, and United Kingdom, respectively. 233 missense mutations in SOD1 protein were compiled from the databases and literature consulted. The predictive analyses pointed to an elevated rate of deleterious and destabilizing predictions for the analyzed variants, indicating their harmful effects. The ConSurf analysis suggested that mutations in SOD1 mainly affect conserved and possibly functionally essential amino acids. The MD analyses pointed to flexibility and essential dynamics alterations at the electrostatic and metal-binding loops of variants A4V, D90A, H46R, and I113T that could lead to aberrant interactions triggering toxic protein aggregation. These alterations may have harmful implications for SOD1 and explain their association with ALS. Understanding the effects of SOD1 mutations on protein structure and function facilitates the design of further experiments and provides relevant information on the molecular mechanism of pathology, which may contribute to improvements in existing treatments for ALS.
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Joyce, Peter I., Philip Mcgoldrick, Rachele A. Saccon, William Weber, Pietro Fratta, Steven J. West, Ning Zhu, et al. "A novel SOD1-ALS mutation separates central and peripheral effects of mutant SOD1 toxicity." Human Molecular Genetics 24, no. 7 (December 2, 2014): 1883–97. http://dx.doi.org/10.1093/hmg/ddu605.
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Ma, Delin, Jeffrey M. Shuler, Aishwarya Kumar, Quincy R. Stanford, Sudheer Tungtur, Hiroshi Nishimune, and John A. Stanford. "Effects of Tongue Force Training on Bulbar Motor Function in the Female SOD1-G93A Rat Model of Amyotrophic Lateral Sclerosis." Neurorehabilitation and Neural Repair 31, no. 2 (September 24, 2016): 147–56. http://dx.doi.org/10.1177/1545968316666956.
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Background. The use of exercise in amyotrophic lateral sclerosis (ALS) is controversial. Although moderate exercise appears to be beneficial for limb muscles in ALS, the effects of exercise on bulbar muscles such as the tongue have not been studied. Objective. To determine the effects of tongue force training on bulbar motor function in the SOD1-G93A rat model of ALS. Methods. We compared the effects of tongue force training on bulbar motor function and neuromuscular junction innervation in female SOD1-G93A rats and age-matched female wild-type controls. Half of each group underwent afternoon tongue force training sessions, and all rats were tested under minimal force conditions in the mornings. Results. Tongue force did not differ between the SOD1-G93A rats and healthy controls during the morning testing sessions, nor was it affected by training. Surprisingly, decreases in tongue motility, the number of licks per session, and body weight were greater in the tongue force–trained SOD1-G93A rats. Forelimb grip force, survival, and denervation of the genioglossus (GG) muscle did not differ between the trained and untrained SOD1-G93A rats. GG innervation was correlated with changes in tongue force but not tongue motility in SOD1-G93A rats at end stage. Conclusions. The results indicate a potential deleterious effect of tongue force training on tongue motility in female SOD1-G93A rats. The lack of a relationship between GG innervation and tongue motility suggests that factors other than lower–motor neuron integrity likely accounted for this effect.
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Muratet, François, Elisa Teyssou, Aude Chiot, Séverine Boillée, Christian S. Lobsiger, Delphine Bohl, Beata Gyorgy, et al. "Impact of a frequent nearsplice SOD1 variant in amyotrophic lateral sclerosis: optimising SOD1 genetic screening for gene therapy opportunities." Journal of Neurology, Neurosurgery & Psychiatry 92, no. 9 (March 30, 2021): 942–49. http://dx.doi.org/10.1136/jnnp-2020-325921.
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ObjectiveMutations in superoxide dismutase 1 gene (SOD1), encoding copper/zinc superoxide dismutase protein, are the second most frequent high penetrant genetic cause for amyotrophic lateral sclerosis (ALS) motor neuron disease in populations of European descent. More than 200 missense variants are reported along the SOD1 protein. To limit the production of these aberrant and deleterious SOD1 species, antisense oligonucleotide approaches have recently emerged and showed promising effects in clinical trials. To offer the possibility to any patient with SOD1-ALS to benefit of such a gene therapy, it is necessary to ascertain whether any variant of unknown significance (VUS), detected for example in SOD1 non-coding sequences, is pathogenic.MethodsWe analysed SOD1 mutation distribution after SOD1 sequencing in a large cohort of 470 French familial ALS (fALS) index cases.ResultsWe identified a total of 27 SOD1 variants in 38 families including two SOD1 variants located in nearsplice or intronic regions of the gene. The pathogenicity of the c.358–10T>G nearsplice SOD1 variant was corroborated based on its high frequency (as the second most frequent SOD1 variant) in French fALS, the segregation analysis confirmed in eight affected members of a large pedigree, the typical SOD1-related phenotype observed (with lower limb onset and prominent lower motor neuron involvement), and findings on postmortem tissues showing SOD1 misaccumulation.ConclusionsOur results highlighted nearsplice/intronic mutations in SOD1 are responsible for a significant portion of French fALS and suggested the systematic analysis of the SOD1 mRNA sequence could become the method of choice for SOD1 screening, not to miss these specific cases.
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Agbas, Abdulbaki, Dongwei Hui, Xinsheng Wang, Vekalet Tek, Asma Zaidi, and Elias K. Michaelis. "Activation of brain calcineurin (Cn) by Cu-Zn superoxide dismutase (SOD1) depends on direct SOD1–Cn protein interactions occurring in vitro and in vivo." Biochemical Journal 405, no. 1 (June 13, 2007): 51–59. http://dx.doi.org/10.1042/bj20061202.
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Cn (calcineurin) activity is stabilized by SOD1 (Cu-Zn superoxide dismutase), a phenomenon attributed to protection from superoxide (O2•−). The effects of O2•− on Cn are still controversial. We found that O2•−, generated either in vitro or in vivo did not affect Cn activity. Yet native bovine, recombinant human or rat, and two chimaeras of human SOD1–rat SOD1, all activated Cn, but SOD2 (Mn-superoxide dismutase) did not affect Cn activity. There was also a poor correlation between SOD1 dismutase activity and Cn activation. A chimaera of human N-terminal SOD1 and rat C-terminal SOD1 had little detectable dismutase activity, yet stimulated Cn activity the same as full-length human or rat SOD1. Nevertheless, there was evidence that the active site of SOD1 was involved in Cn activation based on the loss of activation following chelation of Cu from the active site of SOD1. Also, SOD1 engaged in the catalysis of O2•− dismutation was ineffective in activating Cn. SOD1 activation of Cn resulted from a 90-fold decrease in phosphatase Km without a change in Vmax. A possible mechanism for the activation of Cn was identified in our studies as the prevention of Fe and Zn losses from the active site of Cn, suggesting a conformation-dependent SOD1–Cn interaction. In neurons, SOD1 and Cn were co-localized in cytoplasm and membranes, and SOD1 co-immunoprecipitated with Cn from homogenates of brain hippocampus and was present in immunoprecipitates as large multimers. Pre-incubation of pure SOD1 with Cn caused SOD1 multimer formation, an indication of an altered conformational state in SOD1 upon interaction with Cn.
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Beni, Sara M., Jeanna Tsenter, Alexander G. Alexandrovich, Nili Galron-Krool, Ari Barzilai, Ron Kohen, Nikolas Grigoriadis, Constantina Simeonidou, and Esther Shohami. "CuZn-SOD Deficiency, Rather than Overexpression, is Associated with Enhanced Recovery and Attenuated Activation of NF-κB After Brain Trauma in Mice." Journal of Cerebral Blood Flow & Metabolism 26, no. 4 (August 10, 2005): 478–90. http://dx.doi.org/10.1038/sj.jcbfm.9600209.
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Superoxide-dismutases (SOD) catalyze O2− conversion to hydrogen peroxide (H2O2) and with other antioxidant enzymes and low molecular weight antioxidants (LMWA) constitute endogenous defense mechanisms. We first assessed the effects of SOD1 levels on outcome after closed head injury (CHI) and later, based on these results, the effects of SOD−/- deficiency on cellular redox homeostasis. Superoxide-dismutase 1-deficient (SOD1−/-) and -overexpressing (transgenic (Tg)) mice and matched wild-type (WT) controls were subjected to CHI and outcome (neurobehavioral and memory functions) was assessed during 14 days. Brain edema, LMWA, and SOD2 activity were measured along with histopathological analysis. Transactivation of nuclear factor-kappa B (NF- κB) was evaluated by electromobility shift assay. Mortality, motor, and cognitive outcome of Tg and WT mice were comparable. Mortality and edema were similar in SOD1−/- and WT mice, yet, unexpectedly, SOD1−/- displayed better neurobehavioral recovery ( P < 0.05) at 14 days after CHI. Basal LMWA were higher in the cortex and liver of SOD1−/- mice ( P < 0.05) and similar to WT in the cerebellum. Five minutes after CHI, cortical LMWA decreased only in SOD1−/- mice. One week after CHI, SOD2 activity decreased fourfold in WT cortex ( P < 0.001), but was preserved in the SOD1−/- . Constitutive NF- κB transactivation was comparably low in SOD1−/- and WT; however, CHI induced a robust NF- κB activation that was absent in SOD1−/- cortices ( P > 0.005 versus WT). At the same time, immunohistochemical analysis of brain sections revealed that astrogliosis and neurodegeneration were of lesser severity in SOD1−/- mice. We suggest that SOD1 deficiency impairs H2O2-mediated activation of NF- κB, decreasing death-promoting signals, and leading to better outcome.
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Damiano, Simona, Concetta Sozio, Giuliana La Rosa, Bruna Guida, Raffaella Faraonio, Mariarosaria Santillo, and Paolo Mondola. "Metabolism Regulation and Redox State: Insight into the Role of Superoxide Dismutase 1." International Journal of Molecular Sciences 21, no. 18 (September 10, 2020): 6606. http://dx.doi.org/10.3390/ijms21186606.
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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.
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Sato, Atsushi, Yasunaga Shiraishi, Toyokazu Kimura, Ayumu Osaki, Kazuki Kagami, Yasuo Ido, and Takeshi Adachi. "Resistance to Obesity in SOD1 Deficient Mice with a High-Fat/High-Sucrose Diet." Antioxidants 11, no. 7 (July 19, 2022): 1403. http://dx.doi.org/10.3390/antiox11071403.
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Metabolic syndrome (Mets) is an important condition because it may cause stroke and heart disease in the future. Reactive oxygen species (ROSs) influence the pathogenesis of Mets; however, the types of ROSs and their localization remain largely unknown. In this study, we investigated the effects of SOD1, which localize to the cytoplasm and mitochondrial intermembrane space and metabolize superoxide anion, on Mets using SOD1 deficient mice (SOD1−/−). SOD1−/− fed on a high-fat/high-sucrose diet (HFHSD) for 24 weeks showed reduced body weight gain and adipose tissue size compared to wild-type mice (WT). Insulin secretion was dramatically decreased in SOD1−/− fed on HFHSD even though blood glucose levels were similar to WT. Ambulatory oxygen consumption was accelerated in SOD1−/− with HFHSD; however, ATP levels of skeletal muscle were somewhat reduced compared to WT. Reflecting the reduced ATP, the expression of phosphorylated AMPK (Thr 172) was more robust in SOD1−/−. SOD1 is involved in the ATP production mechanism in mitochondria and may contribute to visceral fat accumulation by causing insulin secretion and insulin resistance.
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Peggion, Caterina, Valeria Scalcon, Maria Lina Massimino, Kelly Nies, Raffaele Lopreiato, Maria Pia Rigobello, and Alessandro Bertoli. "SOD1 in ALS: Taking Stock in Pathogenic Mechanisms and the Role of Glial and Muscle Cells." Antioxidants 11, no. 4 (March 23, 2022): 614. http://dx.doi.org/10.3390/antiox11040614.
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the loss of motor neurons in the brain and spinal cord. While the exact causes of ALS are still unclear, the discovery that familial cases of ALS are related to mutations in the Cu/Zn superoxide dismutase (SOD1), a key antioxidant enzyme protecting cells from the deleterious effects of superoxide radicals, suggested that alterations in SOD1 functionality and/or aberrant SOD1 aggregation strongly contribute to ALS pathogenesis. A new scenario was opened in which, thanks to the generation of SOD1 related models, different mechanisms crucial for ALS progression were identified. These include excitotoxicity, oxidative stress, mitochondrial dysfunctions, and non-cell autonomous toxicity, also implicating altered Ca2+ metabolism. While most of the literature considers motor neurons as primary target of SOD1-mediated effects, here we mainly discuss the effects of SOD1 mutations in non-neuronal cells, such as glial and skeletal muscle cells, in ALS. Attention is given to the altered redox balance and Ca2+ homeostasis, two processes that are strictly related with each other. We also provide original data obtained in primary myocytes derived from hSOD1(G93A) transgenic mice, showing perturbed expression of Ca2+ transporters that may be responsible for altered mitochondrial Ca2+ fluxes. ALS-related SOD1 mutants are also responsible for early alterations of fundamental biological processes in skeletal myocytes that may impinge on skeletal muscle functions and the cross-talk between muscle cells and motor neurons during disease progression.
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Bradman, Matthew J. G., Richard Morris, Anne McArdle, Malcolm J. Jackson, and Thimmasettappa Thippeswamy. "The effects of L-NAME on neuronal NOS and SOD1 expression in the DRG–spinal cord network of axotomised Thy 1.2 eGFP mice." Neuron Glia Biology 7, no. 2-4 (May 2011): 129–41. http://dx.doi.org/10.1017/s1740925x12000051.
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Nitric oxide (NO) plays an important role in pathophysiology of the nervous system. Copper/zinc superoxide dismutase (SOD1) reacts with superoxide, which is also a substrate for NO, to provide antioxidative protection. NO production is greatly altered following nerve injury, therefore we hypothesised that SOD1 and NO may be involved in modulating axotomy responses in dorsal root ganglion (DRG)–spinal network. To investigate this interaction, adult Thy1.2 enhanced membrane-bound green fluorescent protein (eGFP) mice underwent sciatic nerve axotomy and received NG-nitro- <l-arginine methylester (L-NAME) or vehicle 7–9 days later. L4–L6 spinal cord and DRG were harvested for immunohistochemical analyses. Effect of injury was confirmed by axotomy markers; small proline-rich repeat protein 1A (SPRR1A) was restricted to ipsilateral neuropathology, while Thy1.2 eGFP revealed also contralateral crossover effects. L-NAME, but not axotomy, increased neuronal NO synthase (nNOS) and SOD1 immunoreactive neurons, with no colocalisation, in a lamina-dependent manner in the dorsal horn of the spinal cord. Axotomy and/or L-NAME had no effect on total nNOS+and SOD1+neurons in DRG. However, L-NAME altered SOD1 expression in subsets of axotomised DRG neurons. These findings provide evidence for differential distribution of SOD1 and its modulation by NO, which may interact to regulate axotomy-induced changes in DRG–spinal network.
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Carlström, Mattias, Russell D. Brown, Johan Sällström, Erik Larsson, Mihkel Zilmer, Sheller Zabihi, Ulf J. Eriksson, and A. Erik G. Persson. "SOD1 deficiency causes salt sensitivity and aggravates hypertension in hydronephrosis." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 297, no. 1 (July 2009): R82—R92. http://dx.doi.org/10.1152/ajpregu.90843.2008.
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Hydronephrosis causes renal dysfunction and salt-sensitive hypertension, which is associated with nitric oxide deficiency and abnormal tubuloglomerular feedback (TGF) response. We investigated the role of oxidative stress for salt sensitivity and for hypertension in hydronephrosis. Hydronephrosis was induced in superoxide dismutase 1-transgenic (SOD1-tg), SOD1-deficient (SOD1-ko), and wild-type mice and in rats. In mice, telemetric measurements were performed during normal (0.7% NaCl) and high-sodium (4% NaCl) diets and with chronic tempol supplementation. The 8-iso-prostaglandin-F2α (F2-IsoPs) and protein excretion profiles and renal histology were investigated. The acute effects of tempol on blood pressure and TGF were studied in rats. In hydronephrosis, wild-type mice developed salt-sensitive hypertension (114 ± 1 to 120 ± 2 mmHg), which was augmented in SOD1-ko (125 ± 3 to 135 ± 4 mmHg) but abolished in SOD1-tg (109 ± 3 to 108 ± 3 mmHg). SOD1-ko controls displayed salt-sensitive blood pressure (108 ± 1 to 115 ± 2 mmHg), which was not found in wild types or SOD1-tg. Chronic tempol treatment reduced blood pressure in SOD1-ko controls (−7 mmHg) and in hydronephrotic wild-type (−8 mmHg) and SOD1-ko mice (−16 mmHg), but had no effect on blood pressure in wild-type or SOD1-tg controls. SOD1-ko controls and hydronephrotic wild-type and SOD1-ko mice exhibited increased fluid excretion associated with increased F2-IsoPs and protein excretion. The renal histopathological changes found in hydronephrotic wild-type were augmented in SOD1-ko and diminished in SOD-tg mice. Tempol attenuated blood pressure and normalized TGF response in hydronephrosis [ΔPSF: 15.2 ± 1.2 to 9.1 ± 0.6 mmHg, turning point: 14.3 ± 0.8 to 19.7 ± 1.4 nl/min]. Oxidative stress due to SOD1 deficiency causes salt sensitivity and plays a pivotal role for the development of hypertension in hydronephrosis. Increased superoxide formation may enhance TGF response and thereby contribute to hypertension.
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Maier, Marcel, Tobias Welt, Fabian Wirth, Fabio Montrasio, Daniel Preisig, Jordan McAfoose, Fernando G. Vieira, et al. "A human-derived antibody targets misfolded SOD1 and ameliorates motor symptoms in mouse models of amyotrophic lateral sclerosis." Science Translational Medicine 10, no. 470 (December 5, 2018): eaah3924. http://dx.doi.org/10.1126/scitranslmed.aah3924.
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Mutations in the gene encoding superoxide dismutase 1 (SOD1) lead to misfolding and aggregation of SOD1 and cause familial amyotrophic lateral sclerosis (FALS). However, the implications of wild-type SOD1 misfolding in sporadic forms of ALS (SALS) remain unclear. By screening human memory B cells from a large cohort of healthy elderly subjects, we generated a recombinant human monoclonal antibody (α-miSOD1) that selectively bound to misfolded SOD1, but not to physiological SOD1 dimers. On postmortem spinal cord sections from 121 patients with ALS, α-miSOD1 antibody identified misfolded SOD1 in a majority of cases, regardless of their SOD1 genotype. In contrast, the α-miSOD1 antibody did not bind to its epitope in most of the 41 postmortem spinal cord sections from non-neurological control (NNC) patients. In transgenic mice overexpressing disease-causing human SOD1G37R or SOD1G93A mutations, treatment with the α-miSOD1 antibody delayed the onset of motor symptoms, extended survival by up to 2 months, and reduced aggregation of misfolded SOD1 and motor neuron degeneration. These effects were obtained whether α-miSOD1 antibody treatment was administered by direct brain infusion or peripheral administration. These results support the further development of α-miSOD1 antibody as a candidate treatment for ALS involving misfolding of SOD1.
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Wang, Xiao-lu, Liang Wang, Fo-lan Lin, Si-si Li, Ting-xuan Lin, and Ren-wang Jiang. "Protective Effect of Penetratin Analogue-Tagged SOD1 on Cisplatin-Induced Nephrotoxicity through Inhibiting Oxidative Stress and JNK/p38 MAPK Signaling Pathway." Oxidative Medicine and Cellular Longevity 2021 (August 21, 2021): 1–13. http://dx.doi.org/10.1155/2021/5526053.
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Copper/zinc superoxide dismutase (SOD1) can clear cisplatin- (CP-) induced excessive reactive oxygen species (ROS), but exogenous SOD1 cannot enter cells because of its low biomembrane permeability. Cell-penetrating peptides (CPPs) can rapidly cross plasma membranes. This study is aimed at identifying an efficient and stable CPP-SOD1 and investigating its effects on CP-induced nephrotoxicity. We recombined SOD1 with 14 different CPPs and purified them using an NTA-Ni2+ column. In in vitro experiments, CPPs-SOD1 cell membrane penetration ability and JNK/p38 MAPK signaling pathway were evaluated using Western blotting. ROS production, mitochondrial membrane potential (MMP), and cell apoptosis were determined using flow cytometry and immunofluorescence staining in VERO and HK-2 cells. For in vivo experiments, mice were administered PSF-SOD1 for 2 h before cotreatment with a single CP injection for an additional 4 days. Blood and kidney samples were collected for renal function assessment (creatinine, urea nitrogen, histopathology, TUNEL assay, and JNK/p38 MAPK signaling pathway). Compared with TAT-SOD1, we found that PSF-SOD1 is more efficient at crossing the cell membrane and is stable after transduction into cells. Pretreatment with PSF-SOD1 inhibited CP-induced apoptosis, ROS generation, and JNK/p38 MAPK activation and restored CP-induced MMP loss in VERO and HK-2 kidney cells. Treatment of mice with PSF-SOD1 inhibited CP-induced serum creatinine, blood urea nitrogen elevation, and JNK/p38 MAPK activation. H&E staining and TUNEL assay indicated that kidney tissue damage was alleviated following PSF-SOD1 pretreatment. Overall, PSF-SOD1 ameliorated CP-induced renal damage by partially reducing oxidative stress and cell apoptosis by regulating JNK/p38 MAPK signaling pathway and might be a better cytoprotective agent than TAT-SOD1.
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Dayal, Sanjana, Katina M. Wilson, Ryan Hutchins, and Steven R. Lentz. "Deficiency of Superoxide Dismutase Impairs Generation of Activated Protein C and Enhances Susceptibility to Experimental Thrombosis in Mice." Blood 118, no. 21 (November 18, 2011): 535. http://dx.doi.org/10.1182/blood.v118.21.535.535.
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Abstract Abstract 535 In vitro studies have suggested that reactive oxygen species such as superoxide can produce several potentially prothrombotic effects, including enhanced platelet activation, increased tissue factor (TF) expression, and an oxidative modification in thrombomodulin that impairs its capacity to enhance the generation of activated protein C (APC) by thrombin. It is not known, however, if elevated levels of superoxide accelerate susceptibility to experimental thrombosis in vivo. Using a murine model that is genetically deficient in superoxide dismutase-1 (SOD1, an antioxidant enzyme that dismutates superoxide to hydrogen peroxide), we tested the hypothesis that lack of superoxide dismutase enhances susceptibility to thrombosis. Additionally, we investigated the mechanisms of superoxide-enhanced thrombosis. First, we examined the susceptibility to carotid artery thrombosis in a photochemical injury model. We found that Sod1−/− mice formed stable occlusions significantly faster than Sod1+/+ or Sod1+/− mice (P<0.05). Further, using an inferior vena cava (IVC) stasis method we observed that Sod1−/− mice developed significantly larger thrombi 48 hours after IVC ligation (P<0.05 compared with Sod1+/+ or Sod1+/− mice). These findings suggest that deficiency of SOD1 leads to increased susceptibility to both arterial and venous thrombosis in mice. To address the mechanism of accelerated thrombosis, we first examined activation of platelets in response to multiple agonists using flow cytometry. After activation by thrombin (0.5 U/ml) and convulxin (200 ng/ml), no differences in surface expression of P-selectin or binding of fibrinogen to activated platelets were observed between Sod1−/−, Sod1+/+, or Sod1+/− mice, suggesting that increased susceptibility to thrombosis in Sod1−/− mice is not platelet mediated. Next, we measured expression of TF mRNA in lung by real time qPCR. TF mRNA levels in Sod1−/− mice were similar to those in Sod1+/+ mice, suggesting that deficiency of SOD1 does not influence TF expression in mice. Finally, we measured the activation of protein C in vivo in response to infusion of thrombin (40 U/Kg). Generation of activated protein C was significantly lower in Sod1−/− mice compared with Sod1+/+ mice (P<0.05). No differences in mRNA levels for thrombomodulin or endothelial protein C receptor were detected in Sod1−/− mice compared with Sod1+/+ mice (P=0.4 and 0.6 respectively), suggesting that altered generation of activated protein C in Sod1−/− mice may be related to a direct oxidative effect on thrombomodulin rather than to decreased expression of thrombomodulin or EPCR. We conclude that lack of SOD1 in mice accelerates thrombosis and impairs the protein C anticoagulant response to thrombin. Disclosures: No relevant conflicts of interest to declare.
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Sakowski, Stacey A., J. Lunn, Angela S. Busta, Sang Oh, Grettel Zamora-Berridi, Madeline Palmer, Andrew A. Rosenberg, Stephen G. Philip, James J. Dowling, and Eva L. Feldman. "Neuromuscular effects of G93A-SOD1 expression in zebrafish." Molecular Neurodegeneration 7, no. 1 (2012): 44. http://dx.doi.org/10.1186/1750-1326-7-44.
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Davidovic-Plavsic, Biljana, Natasa Lukic, Aleksandra Nikolic-Kokic, and Biljana Kukavica. "Effects of hemazin SC 500 (terbuthylazine) on antioxidative enzymes in human erythrocytes in vitro." Journal of the Serbian Chemical Society 84, no. 5 (2019): 455–65. http://dx.doi.org/10.2298/jsc181011115d.
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The aim of this work was to investigate the effect of the commercial formulation hemazin SC 500, an herbicide containing terbuthylazine as the active compound, on the isoenzyme patterns and activities of Cu-Zn superoxide dismutase (SOD1) and catalase (CAT), as well as on the glutathione S-transferase (GST) activity, in human erythrocytes in vitro. The human erythrocytes were treated with hemazin SC 500 over a broad range of terbuthylazine concentrations (37 nmol L-1? ?37 ?mol L-1) for 1 and 3 h at a temperature of 37?C. Native electrophoresis of the control and treated samples revealed two SOD1 and one CAT isoform. Treatment did not affect the SOD1 and CAT isoenzyme profile, but induced a change in their activities. Terbuthylazine at lower concentration induced a significant increase of the total SOD1 activity and decreased the GST activity in samples incubated for 1 and 3 h. On the other hand, the highest increase in the CAT activity was observed for the sample treated for 1 h with a higher concentration of terbuthylazine. Hemazin SC 500 containing terbuthylazine induces changes in the erythrocyte antioxidative system whereby the response of individual enzymatic antioxidants depends on the concentration of the pesticide and the incubation time.
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Dash, Banaja P., Axel Freischmidt, Jochen H. Weishaupt, and Andreas Hermann. "Downstream Effects of Mutations in SOD1 and TARDBP Converge on Gene Expression Impairment in Patient-Derived Motor Neurons." International Journal of Molecular Sciences 23, no. 17 (August 25, 2022): 9652. http://dx.doi.org/10.3390/ijms23179652.
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Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disease marked by death of motor neurons (MNs) present in the spinal cord, brain stem and motor cortex. Despite extensive research, the reason for neurodegeneration is still not understood. To generate novel hypotheses of putative underlying molecular mechanisms, we used human induced pluripotent stem cell (hiPSCs)-derived motor neurons (MNs) from SOD1- and TARDBP (TDP-43 protein)-mutant-ALS patients and healthy controls to perform high-throughput RNA-sequencing (RNA-Seq). An integrated bioinformatics approach was employed to identify differentially expressed genes (DEGs) and key pathways underlying these familial forms of the disease (fALS). In TDP43-ALS, we found dysregulation of transcripts encoding components of the transcriptional machinery and transcripts involved in splicing regulation were particularly affected. In contrast, less is known about the role of SOD1 in RNA metabolism in motor neurons. Here, we found that many transcripts relevant for mitochondrial function were specifically altered in SOD1-ALS, indicating that transcriptional signatures and expression patterns can vary significantly depending on the causal gene that is mutated. Surprisingly, however, we identified a clear downregulation of genes involved in protein translation in SOD1-ALS suggesting that ALS-causing SOD1 mutations shift cellular RNA abundance profiles to cause neural dysfunction. Altogether, we provided here an extensive profiling of mRNA expression in two ALS models at the cellular level, corroborating the major role of RNA metabolism and gene expression as a common pathomechanism in ALS.
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Zhu, Cheng, Matthew V. Beck, Jack D. Griffith, Mohanish Deshmukh, and Nikolay V. Dokholyan. "Large SOD1 aggregates, unlike trimeric SOD1, do not impact cell viability in a model of amyotrophic lateral sclerosis." Proceedings of the National Academy of Sciences 115, no. 18 (April 16, 2018): 4661–65. http://dx.doi.org/10.1073/pnas.1800187115.
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Aberrant accumulation of misfolded Cu, Zn superoxide dismutase (SOD1) is a hallmark of SOD1-associated amyotrophic lateral sclerosis (ALS), an invariably fatal neurodegenerative disease. While recent discovery of nonnative trimeric SOD1-associated neurotoxicity has suggested a potential pathway for motor neuron impairment, it is yet unknown whether large, insoluble aggregates are cytotoxic. Here we designed SOD1 mutations that specifically stabilize either the fibrillar form or the trimeric state of SOD1. The designed mutants display elevated populations of fibrils or trimers correspondingly, as demonstrated by gel filtration chromatography and electron microscopy. The trimer-stabilizing mutant, G147P, promoted cell death, even more potently in comparison with the aggressive ALS-associated mutants A4V and G93A. In contrast, the fibril-stabilizing mutants, N53I and D101I, positively impacted the survival of motor neuron-like cells. Hence, we conclude the SOD1 oligomer and not the mature form of aggregated fibril is critical for the neurotoxic effects in the model of ALS. The formation of large aggregates is in competition with trimer formation, suggesting that aggregation may be a protective mechanism against formation of toxic oligomeric intermediates.
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Renzini, Alessandra, Eva Pigna, Marco Rocchi, Alessia Cedola, Giuseppe Gigli, Viviana Moresi, and Dario Coletti. "Sex and HDAC4 Differently Affect the Pathophysiology of Amyotrophic Lateral Sclerosis in SOD1-G93A Mice." International Journal of Molecular Sciences 24, no. 1 (December 21, 2022): 98. http://dx.doi.org/10.3390/ijms24010098.
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Amyotrophic Lateral Sclerosis (ALS) is a devastating adult-onset neurodegenerative disease, with ineffective therapeutic options. ALS incidence and prevalence depend on the sex of the patient. Histone deacetylase 4 (HDAC4) expression in skeletal muscle directly correlates with the progression of ALS, pointing to the use of HDAC4 inhibitors for its treatment. Contrarily, we have found that deletion of HDAC4 in skeletal muscle worsened the pathological features of ALS, accelerating and exacerbating skeletal muscle loss and negatively affecting muscle innervations in male SOD1-G93A (SOD1) mice. In the present work, we compared SOD1 mice of both sexes with the aim to characterize ALS onset and progression as a function of sex differences. We found a global sex-dependent effects on disease onset and mouse lifespan. We further investigated the role of HDAC4 in SOD1 females with a genetic approach, and discovered morpho-functional effects on skeletal muscle, even in the early phase of the diseases. The deletion of HDAC4 decreased muscle function and exacerbated muscle atrophy in SOD1 females, and had an even more dramatic effect in males. Therefore, the two sexes must be considered separately when studying ALS.
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Bian, Xinyu, Xiaoyu Zhuang, Junpeng Xing, Shu Liu, Zhiqiang Liu, and Fengrui Song. "Native Mass Spectrometry Coupled to Spectroscopic Methods to Investigate the Effect of Soybean Isoflavones on Structural Stability and Aggregation of Zinc Deficient and Metal-Free Superoxide Dismutase." Molecules 27, no. 21 (October 27, 2022): 7303. http://dx.doi.org/10.3390/molecules27217303.
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The deficiency or wrong combination of metal ions in Cu, Zn-superoxide dismutase (SOD1), is regarded as one of the main factors causing the aggregation of SOD1 and then inducing amyotrophic lateral sclerosis (ALS). A ligands-targets screening process based on native electrospray ionization ion mobility mass spectrometry (ESI-IMS-MS) was established in this study. Four glycosides including daidzin, sophoricoside, glycitin, and genistin were screened out from seven soybean isoflavone compounds and were found to interact with zinc-deficient or metal-free SOD1. The structure and conformation stability of metal-free and zinc-deficient SOD1 and their complexes with the four glycosides was investigated by collision-induced dissociation (CID) and collision-induced unfolding (CIU). The four glycosides could strongly bind to the metal-free and copper recombined SOD1 and enhance the folding stability of these proteins. Additionally, the ThT fluorescence assay showed that these glycosides could inhibit the toxic aggregation of the zinc-deficient or metal-free SOD1. The competitive interaction experiments together with molecular docking indicate that glycitin, which showed the best stabilizing effects, binds with SOD1 between β-sheet 6 and loop IV. In short, this study provides good insight into the relationship between inhibitors and different SOD1s.
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Zhao, Zhu-fen, Ye Zhang, Yang Sun, Chun-hai Zhang, and Ming-wei Liu. "Protective effects of baicalin on caerulein-induced AR42J pancreatic acinar cells by attenuating oxidative stress through miR-136-5p downregulation." Science Progress 104, no. 2 (April 2021): 003685042110261. http://dx.doi.org/10.1177/00368504211026118.
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Baicalin, the main active component of Scutellaria baicalensis, has antioxidant and anti-apoptotic effects and is used to treat acute pancreatitis; however, its specific mechanism is unclear. This study aims to determine the protective effect and underlying mechanism of baicalin on AR42J pancreatic acinar cell injury. AR42J acinar cells (caerulein, 10 nmol/L) were induced in vitro to establish a cell model for acute pancreatitis. Cell relative survival was measured by thiazolyl blue tetrazolium bromide, and cell apoptosis and death were examined by flow cytometry. The expression levels of superoxide dismutase1 (SOD1), Bax, survivin, Bcl-2, caspase-3, and caspase-7 proteins were analyzed by Western blot, and those of SOD1 mRNA and miR-136-5p were determined by RT-PCR. The activities of GSH, SOD1, ROS, and MDA were also investigated. Compared with those of the caerulein group, the relative survival rate and activity of AR42J pancreatic acinar cells with different baicalin concentrations were significantly increased ( p < 0.05), and the supernatant amylase level was markedly decreased ( p < 0.05). In addition, the ROS and MDA activities and mir-136-5p expression were significantly decreased, and the GSH activities and SOD1 gene and protein expression levels were markedly increased ( p < 0.05). These results suggest that baicalin reduced the caerulein-induced death of AR42J acinar cells and alleviated the caerulein-induced injury in pancreatic acinar cells by inhibiting oxidative stress. The mechanism may be related to the decreased expression of Mir-136-5p and the increased expression of SOD1 gene and protein.
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Bouldin, Samantha D., Maxwell A. Darch, P. John Hart, and Caryn E. Outten. "Redox properties of the disulfide bond of human Cu,Zn superoxide dismutase and the effects of human glutaredoxin 1." Biochemical Journal 446, no. 1 (July 27, 2012): 59–67. http://dx.doi.org/10.1042/bj20120075.
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The intramolecular disulfide bond in hSOD1 [human SOD1 (Cu,Zn superoxide dismutase 1)] plays a key role in maintaining the protein's stability and quaternary structure. In mutant forms of SOD1 that cause familial ALS (amyotrophic lateral sclerosis), this disulfide bond is more susceptible to chemical reduction, which may lead to destabilization of the dimer and aggregation. During hSOD1 maturation, disulfide formation is catalysed by CCS1 (copper chaperone for SOD1). Previous studies in yeast demonstrate that the yeast GSH/Grx (glutaredoxin) redox system promotes reduction of the hSOD1 disulfide in the absence of CCS1. In the present study, we probe further the interaction between hSOD1, GSH and Grxs to provide mechanistic insight into the redox kinetics and thermodynamics of the hSOD1 disulfide. We demonstrate that hGrx1 (human Grx1) uses a monothiol mechanism to reduce the hSOD1 disulfide, and the GSH/hGrx1 system reduces ALS mutant SOD1 at a faster rate than WT (wild-type) hSOD1. However, redox potential measurements demonstrate that the thermodynamic stability of the disulfide is not consistently lower in ALS mutants compared with WT hSOD1. Furthermore, the presence of metal cofactors does not influence the disulfide redox potential. Overall, these studies suggest that differences in the GSH/hGrx1 reaction rate with WT compared with ALS mutant hSOD1 and not the inherent thermodynamic stability of the hSOD1 disulfide bond may contribute to the greater pathogenicity of ALS mutant hSOD1.
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Ting, Hsiao-Chien, Hui-I. Yang, Horng-Jyh Harn, Ing-Ming Chiu, Hong-Lin Su, Xiang Li, Mei-Fang Chen, et al. "Coactivation of GSK3β and IGF-1 Attenuates Amyotrophic Lateral Sclerosis Nerve Fiber Cytopathies in SOD1 Mutant Patient-Derived Motor Neurons." Cells 10, no. 10 (October 16, 2021): 2773. http://dx.doi.org/10.3390/cells10102773.
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Amyotrophic lateral sclerosis (ALS) is a progressive nervous system disease that causes motor neuron (MN) degeneration and results in patient death within a few years. To recapitulate the cytopathies of ALS patients’ MNs, SOD1G85R mutant and corrected SOD1G85G isogenic-induced pluripotent stem cell (iPSC) lines were established. Two SOD1 mutant ALS (SOD1G85R and SOD1D90A), two SOD1 mutant corrected (SOD1G85G and SOD1D90D), and one sporadic ALS iPSC lines were directed toward MNs. After receiving ~90% purity for MNs, we first demonstrated that SOD1G85R mutant ALS MNs recapitulated ALS-specific nerve fiber aggregates, similar to SOD1D90A ALS MNs in a previous study. Moreover, we found that both SOD1 mutant MNs showed ALS-specific neurite degenerations and neurotransmitter-induced calcium hyperresponsiveness. In a small compound test using these MNs, we demonstrated that gastrodin, a major ingredient of Gastrodia elata, showed therapeutic effects that decreased nerve fiber cytopathies and reverse neurotransmitter-induced hyperresponsiveness. The therapeutic effects of gastrodin applied not only to SOD1 ALS MNs but also to sporadic ALS MNs and SOD1G93A ALS mice. Moreover, we found that coactivation of the GSK3β and IGF-1 pathways was a mechanism involved in the therapeutic effects of gastrodin. Thus, the coordination of compounds that activate these two mechanisms could reduce nerve fiber cytopathies in SOD1 ALS MNs. Interestingly, the therapeutic role of GSK3β activation on SOD1 ALS MNs in the present study was in contrast to the role previously reported in research using cell line- or transgenic animal-based models. In conclusion, we identified in vitro ALS-specific nerve fiber and neurofunctional markers in MNs, which will be useful for drug screening, and we used an iPSC-based model to reveal novel therapeutic mechanisms (including GSK3β and IGF-1 activation) that may serve as potential targets for ALS therapy.
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Broom, Helen R., Jessica A. O. Rumfeldt, and Elizabeth M. Meiering. "Many roads lead to Rome? Multiple modes of Cu,Zn superoxide dismutase destabilization, misfolding and aggregation in amyotrophic lateral sclerosis." Essays in Biochemistry 56 (August 18, 2014): 149–65. http://dx.doi.org/10.1042/bse0560149.
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ALS (amyotrophic lateral sclerosis) is a fatal neurodegenerative syndrome characterized by progressive paralysis and motor neuron death. Although the pathological mechanisms that cause ALS remain unclear, accumulating evidence supports that ALS is a protein misfolding disorder. Mutations in Cu,Zn-SOD1 (copper/zinc superoxide dismutase 1) are a common cause of familial ALS. They have complex effects on different forms of SOD1, but generally destabilize the protein and enhance various modes of misfolding and aggregation. In addition, there is some evidence that destabilized covalently modified wild-type SOD1 may be involved in disease. Among the multitude of misfolded/aggregated species observed for SOD1, multiple species may impair various cellular components at different disease stages. Newly developed antibodies that recognize different structural features of SOD1 represent a powerful tool for further unravelling the roles of different SOD1 structures in disease. Evidence for similar cellular targets of misfolded/aggregated proteins, loss of cellular proteostasis and cell–cell transmission of aggregates point to common pathological mechanisms between ALS and other misfolding diseases, such as Alzheimer's, Parkinson's and prion diseases, as well as serpinopathies. The recent progress in understanding the molecular basis for these devastating diseases provides numerous avenues for developing urgently needed therapeutics.
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Shteinfer-Kuzmine, Anna, Shirel Argueti-Ostrovsky, Marcel F. Leyton-Jaimes, Uttpal Anand, Salah Abu-Hamad, Ran Zalk, Varda Shoshan-Barmatz, and Adrian Israelson. "Targeting the Mitochondrial Protein VDAC1 as a Potential Therapeutic Strategy in ALS." International Journal of Molecular Sciences 23, no. 17 (September 1, 2022): 9946. http://dx.doi.org/10.3390/ijms23179946.
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Impaired mitochondrial function has been proposed as a causative factor in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), caused by motor neuron degeneration. Mutations in superoxide dismutase (SOD1) cause ALS and SOD1 mutants were shown to interact with the voltage-dependent anion channel 1 (VDAC1), affecting its normal function. VDAC1 is a multi-functional channel located at the outer mitochondrial membrane that serves as a mitochondrial gatekeeper controlling metabolic and energetic crosstalk between mitochondria and the rest of the cell and it is a key player in mitochondria-mediated apoptosis. Previously, we showed that VDAC1 interacts with SOD1 and that the VDAC1-N-terminal-derived peptide prevented mutant SOD1 cytotoxic effects. In this study, using a peptide array, we identified the SOD1 sequence that interacts with VDAC1. Synthetic peptides generated from the identified VDAC1-binding sequences in SOD1 directly interacted with purified VDAC1. We also show that VDAC1 oligomerization increased in spinal cord mitochondria isolated from mutant SOD1G93A mice and rats. Thus, we used the novel VDAC1-specific small molecules, VBIT-4 and VBIT-12, inhibiting VDAC1 oligomerization and subsequently apoptosis and associated processes such as ROS production, and increased cytosolic Ca2+. VBIT-12 was able to rescue cell death induced by mutant SOD1 in neuronal cultures. Finally, although survival was not affected, VBIT-12 administration significantly improved muscle endurance in mutant SOD1G93A mice. Therefore, VBIT-12 may represent an attractive therapy for maintaining muscle function during the progression of ALS.
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Apolloni, Savina, Francesca Caputi, Annabella Pignataro, Susanna Amadio, Paola Fabbrizio, Martine Ammassari-Teule, and Cinzia Volonté. "Histamine Is an Inducer of the Heat Shock Response in SOD1-G93A Models of ALS." International Journal of Molecular Sciences 20, no. 15 (August 3, 2019): 3793. http://dx.doi.org/10.3390/ijms20153793.
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(1) Background: Amyotrophic lateral sclerosis (ALS) is a multifactorial non-cell autonomous disease where activation of microglia and astrocytes largely contributes to motor neurons death. Heat shock proteins have been demonstrated to promote neuronal survival and exert a strong anti-inflammatory action in glia. Having previously shown that the pharmacological increase of the histamine content in the central nervous system (CNS) of SOD1-G93A mice decreases neuroinflammation, reduces motor neuron death, and increases mice life span, here we examined whether this effect could be mediated by an enhancement of the heat shock response. (2) Methods: Heat shock protein expression was analyzed in vitro and in vivo. Histamine was provided to primary microglia and NSC-34 motor neurons expressing the SOD1-G93A mutation. The brain permeable histamine precursor histidine was chronically administered to symptomatic SOD1-G93A mice. Spine density was measured by Golgi-staining in motor cortex of histidine-treated SOD1-G93A mice. (3) Results: We demonstrate that histamine activates the heat shock response in cultured SOD1-G93A microglia and motor neurons. In SOD1-G93A mice, histidine augments the protein content of GRP78 and Hsp70 in spinal cord and cortex, where the treatment also rescues type I motor neuron dendritic spine loss. (4) Conclusion: Besides the established histaminergic neuroprotective and anti-inflammatory effects, the induction of the heat shock response in the SOD1-G93A model by histamine confirms the importance of this pathway in the search for successful therapeutic solutions to treat ALS.
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Deng, Binbin, Wenjing Lv, Weisong Duan, Yakun Liu, Zhongyao Li, Yanqin Ma, Guisen Zhang, et al. "Progressive Degeneration and Inhibition of Peripheral Nerve Regeneration in the SOD1-G93A Mouse Model of Amyotrophic Lateral Sclerosis." Cellular Physiology and Biochemistry 46, no. 6 (2018): 2358–72. http://dx.doi.org/10.1159/000489627.
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Background: Myelination, degeneration and regeneration are implicated in crucial responses to injury in the peripheral nervous system. Considering the progression of amyotrophic lateral sclerosis (ALS), we used the superoxide dismutase 1 (SOD1)-G93A transgenic mouse model of ALS to investigate the effects of mutant SOD1 on the peripheral nerves. Methods: Changes in peripheral nerve morphology were analyzed in SOD1 mutant mice at various stages of the disease by toluidine blue staining and electron microscopy (EM). Schwann cell proliferation and recruitment of inflammatory factors were detected by immunofluorescence staining and quantitative reverse transcription PCR and were compared between SOD1 mutant mice and control mice. Furthermore, western blotting (WB) and TUNEL staining were used to investigate axonal damage and Schwann cell survival in the sciatic nerves of mice in both groups. Results: An analysis of the peripheral nervous system in SOD1-G93A mice revealed the following novel features: (i) Schwann cells and axons in mutant mice underwent changes that were similar to those seen in the control mice during the early development of peripheral nerves. (ii) The peripheral nerves of SOD1-G93A mice developed progressive neuropathy, which presented as defects in axons and myelin, leading to difficulty in walking and reduced locomotor capacity at a late stage of the disease. (iii) Macrophages were recruited and accumulated, and nerve injury and a deficit in the blood-nerve barrier were observed. (iv) Proliferation and the inflammatory micro-environment were inhibited, which impaired the regeneration and remyelination of axons after crush injury in the SOD1-G93A mice. Conclusions: The mutant human SOD1 protein induced axonal and myelin degeneration during the progression of ALS and participated in axon remyelination and regeneration in response to injury.
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Alkhaddur, A., and E. V. Mashkina. "EFFECT OF PHITOCHEMICAL EXTRACTS ON EXPRESSION OF GENES NFE2L2, JUN, SOD1 IN HUMAN CELLS." Aerospace and Environmental Medicine 56, no. 3 (2022): 40–46. http://dx.doi.org/10.21687/0233-528x-2022-56-3-40-46.
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Investigations of the effects of phitochemical compounds from extracts of pomegranate, grape seeds and garlic on expression of NFE2L2, JUN, SOD1 in cultivated cells of the human blood showed that transcription of SOD1 increased in the presence of pomegranate and grape seed extracts. Level of mRNA in NFE2L2 and JUN rose briskly only under the influence of a high concentration of the grape seed extract. Level of JUN mRNA correlated with NFE2L2 mRNA. Garlic extract had no effect on transcription of NFE2L2, JUN, SOD1. Activation of the transcription of all 3 genes under study by the grape seeds extract can contribute to controlling the free radical processes in human cells.
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Noblanc, Anaīs, Alicia Klaassen, and Bernard Robaire. "The Exacerbation of Aging and Oxidative Stress in the Epididymis of Sod1 Null Mice." Antioxidants 9, no. 2 (February 11, 2020): 151. http://dx.doi.org/10.3390/antiox9020151.
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There is growing evidence that the quality of spermatozoa decreases with age and that children of older fathers have a higher incidence of birth defects and genetic mutations. The free radical theory of aging proposes that changes with aging are due to the accumulation of damage induced by exposure to excess reactive oxygen species. We showed previously that absence of the superoxide dismutase 1 (Sod1) antioxidant gene results in impaired mechanisms of repairing DNA damage in the testis in young Sod1−/− mice. In this study, we examined the effects of aging and the Sod−/− mutation on mice epididymal histology and the expression of markers of oxidative damage. We found that both oxidative nucleic acid damage (via 8-hydroxyguanosine) and lipid peroxidation (via 4-hydroxynonenal) increased with age and in Sod1−/− mice. These findings indicate that lack of SOD1 results in an exacerbation of the oxidative damage accumulation-related aging phenotype.
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Kimura, Shintaro, Yuji O. Kamatari, Yukina Kuwahara, Hideaki Hara, Osamu Yamato, Sadatoshi Maeda, Hiroaki Kamishina, and Ryo Honda. "Canine SOD1 harboring E40K or T18S mutations promotes protein aggregation without reducing the global structural stability." PeerJ 8 (July 15, 2020): e9512. http://dx.doi.org/10.7717/peerj.9512.
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Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease associated with aggregation of superoxide dismutase 1 (SOD1) protein. More than 160 mutations in human SOD1 have been identified in familial ALS and extensively characterized in previous studies. Here, we investigated the effects of T18S and E40K mutations on protein aggregation of canine SOD1. These two mutations are exclusively found in canine degenerative myelopathy (an ALS-like neurodegenerative disease in dogs), whose phenotype is unknown at the level of protein folding. Interestingly, the T18S and E40K mutations did not alter far-UV CD spectrum, enzymatic activity, or global structural stability of canine SOD1. However, thioflavin-T assay and transmission electron microscopy analysis revealed that these mutations promote formation of fibrous aggregates, in particular in the Cu2+/Zn2+-unbound state. These evidence suggested that the T18S and E40K mutations promote protein aggregation through a unique mechanism, possibly involving destabilization of the local structure, reduction of net negative charge, or production of disulfide-linked oligomers.
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Lobsiger, Christian S., Séverine Boillée, and Don W. Cleveland. "Toxicity from different SOD1 mutants dysregulates the complement system and the neuronal regenerative response in ALS motor neurons." Proceedings of the National Academy of Sciences 104, no. 18 (April 26, 2007): 7319–26. http://dx.doi.org/10.1073/pnas.0702230104.
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Global, age-dependent changes in gene expression from rodent models of inherited ALS caused by dominant mutations in superoxide-dismutase 1 (SOD1) were identified by using gene arrays and RNAs isolated from purified embryonic and adult motor neurons. Comparison of embryonic motor neurons expressing a dismutase active ALS-linked mutant SOD1 with those expressing comparable levels of wild-type SOD1 revealed the absence of mutant-induced mRNA changes. An age-dependent mRNA change that developed presymptomatically in adult motor neurons collected by laser microdissection from mice expressing dismutase active ALS-linked mutants was dysregulation of the d/l-serine biosynthetic pathway, previously linked to both excitotoxic and neurotrophic effects. An unexpected dysregulation common to motor neurons expressing either dismutase active or inactive mutants was induction of neuronally derived components of the classic complement system and the regenerative/injury response. Alteration of these mutant SOD1-induced pathways identified a set of targets for therapies for inherited ALS.
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Liochev, Stefan I., and Irwin Fridovich. "CO2 enhanced peroxidase activity of SOD1: the effects of pH." Free Radical Biology and Medicine 36, no. 11 (June 2004): 1444–47. http://dx.doi.org/10.1016/j.freeradbiomed.2004.03.006.
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Somalinga, Balajee R., Gregory A. Miller, Hiba T. Malik, W. Christian Wigley, and Philip J. Thomas. "A Screen to Identify Cellular Modulators of Soluble Levels of an Amyotrophic Lateral Sclerosis (ALS)–Causing Mutant SOD1." Journal of Biomolecular Screening 16, no. 9 (August 29, 2011): 974–85. http://dx.doi.org/10.1177/1087057111418505.
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The molecular pathology of many protein misfolding, toxic gain-of-function diseases, such as amyotrophic lateral sclerosis (ALS), is not well understood. Although protein misfolding and aggregation are common themes in these diseases, efforts to identify cellular factors that regulate this process in an unbiased fashion and on a global scale have been lacking. Using an adapted version of an extant β-gal-based protein solubility assay, an expression screen for cellular modulators of solubility of an ALS-causing mutant SOD1 was carried out in mammalian cells. Following fluorescence-activated cell sorting enrichment of a mouse spinal cord cDNA library for gene products that increased SOD1 solubility, high-throughput screening of the cDNA pools from this enriched fraction was employed to identify pools containing relevant modulators. Positive pools, containing approximately 10 cDNA clones each, were diluted and rescreened iteratively until individual clones that improved SOD1 folding/solubility were identified. Genes with profound effects in the solubility assay were selected for validation by independent biochemical assays. Six of 10 validated genes had a significant effect on SOD1 solubility and folding in a SOD1 promoter-driven β-gal assay, indicating that global screening of cellular targets using such protein solubility/folding assay is viable and can be adapted for other misfolding diseases.
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Wiwanitkit, Viroj. "Cadmium related health effects." Environmental Research 112 (January 2012): 236. http://dx.doi.org/10.1016/j.envres.2011.12.005.
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Young, Brent, Chad Purcell, Yi-Qun Kuang, Nicholle Charette, and Denis J. Dupré. "Superoxide Dismutase 1 Regulation of CXCR4-Mediated Signaling in Prostate Cancer Cells is Dependent on Cellular Oxidative State." Cellular Physiology and Biochemistry 37, no. 6 (2015): 2071–84. http://dx.doi.org/10.1159/000438566.
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Background/Aims: CXCL12, acting via one of its G protein-coupled receptors, CXCR4, is a chemoattractant for a broad range of cell types, including several types of cancer cells. Elevated expression of CXCR4, and its ligand CXCL12, play important roles in promoting cancer metastasis. Cancer cells have the potential for rapid and unlimited growth in an area that may have restricted blood supply, as oxidative stress is a common feature of solid tumors. Recent studies have reported that enhanced expression of cytosolic superoxide dismutase (SOD1), a critical enzyme responsible for regulation of superoxide radicals, may increase the aggressive and invasive potential of malignant cells in some cancers. Methods: We used a variety of biochemical approaches and a prostate cancer cell line to study the effects of SOD1 on CXCR4 signaling. Results: Here, we report a direct interaction between SOD1 and CXCR4. We showed that SOD1 interacts directly with the first intracellular loop (ICL1) of CXCR4 and that the CXCL12/CXCR4-mediated regulation of AKT activation, apoptosis and cell migration in prostate cancer (PCa) cells is differentially modulated under normal versus hypoxic conditions when SOD1 is present. Conclusions: This study highlights a potential new regulatory mechanism by which a sensor of the oxidative environment could directly regulate signal transduction of a receptor involved in cancer cell survival and migration.
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Lewandowski, Łukasz, Marta Kepinska, and Halina Milnerowicz. "Alterations in Concentration/Activity of Superoxide Dismutases in Context of Obesity and Selected Single Nucleotide Polymorphisms in Genes: SOD1, SOD2, SOD3." International Journal of Molecular Sciences 21, no. 14 (July 17, 2020): 5069. http://dx.doi.org/10.3390/ijms21145069.
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Little is known about the contribution of each of the three superoxide dismutase isozymes (SODs) to the total SOD activity in extracellular fluids. This study was aimed to investigate the alterations in concentration/activity of (SODs) in plasma, in context of sex, obesity, exposition to cigarette smoke, and genotypic variability of five selected single nucleotide polymorphisms (SNPs) in genes SOD1, SOD2, SOD3. Men showed higher SOD1 concentration, lower SOD3 concentration and higher total antioxidative capacity (TAC) values. Intersexual variability was observed in concentration of copper, zinc, and cadmium. The obese showed higher total oxidative capacity regardless of sex. An increase in SOD2 activity was coexistent with obesity in men, and exposition to cigarette smoke in non-obese individuals. Additionally, in state of this exposition, Cu,Zn-SOD contribution to the total SOD was lower. Interestingly, over 90% of the obese were of C/T genotype of rs4880 (SOD2). Non-obese of T/T genotype (rs4880) were of lower total SOD activity due to decrease in both Cu,Zn-SOD and Mn-SOD activities. SNP rs2234694 was associated with differences in concentration of SODs, depending on obesity status. Correlations indicate that both TAC and SODs, together, may adapt to insulin resistance and inflammation-derived oxidative stress found in obesity. This topic should be further investigated.
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Vidonja-Uzelac, Teodora, Nikola Tatalovic, Milica Mijovic, Aleksandra Nikolic-Kokic, Zorana Orescanin-Dusic, Mara Bresjanac, and Dusko Blagojevic. "Effects of ibogaine per os treatment on redox homeostasis in rat kidney." Archives of Biological Sciences 71, no. 2 (2019): 245–52. http://dx.doi.org/10.2298/abs190208006v.
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Our previous results showed that a single oral dose (1 or 20 mg/kg body weight) of the anti-addiction agent ibogaine induced in rats 6 and 24 h after administration glycogenolytic activity in hepatocytes, followed by a mild oxidative stress. In this work, we examined the in vivo effect of the same doses of ibogaine on rat kidney morphology, antioxidant enzyme (superoxide dismutases (SOD1 and 2), catalase, glutathione peroxidase, glutathione reductase (GR) and glutathione- S-transferase) activities, and oxidative stress (TBARS) and redox (-SH groups) parameters. The dose of 1 mg/kg ibogaine induced an elevation in SOD1 activity and decreased GR activity after 6 and 24 h. GR activity was decreased at 6 and 24 h after 20 mg/kg ibogaine administration, suggesting changed redox homeostasis. After 24 h, we observed an increase in moderate morphological changes, without changes in urinalyses, indicating that kidney function was not measurably affected. Nevertheless, kidney-function monitoring during and following ibogaine use in human subjects is advisable.
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Zhang, Yunyan, Yuzhi Yang, Mingxue Xu, Jingwen Zheng, Yuchan Xu, Guoqing Chen, Qiang Guo, Weidong Tian, and Weihua Guo. "The Dual Effects of Reactive Oxygen Species on the Mandibular Alveolar Bone Formation in SOD1 Knockout Mice: Promotion or Inhibition." Oxidative Medicine and Cellular Longevity 2021 (February 3, 2021): 1–15. http://dx.doi.org/10.1155/2021/8847140.
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The status of reactive oxygen species (ROS) correlates closely with the normal development of the oral and maxillofacial tissues. Oxidative stress caused by ROS accumulation not only affects the development of enamel and dentin but also causes pathological changes in periodontal tissues (periodontal ligament and alveolar bone) that surround the root of the tooth. Although previous studies have shown that ROS accumulation plays a pathologic role in some oral and maxillofacial tissues, the effects of ROS on alveolar bone development remain unclear. In this study, we focused on mandibular alveolar bone development of mice deficient in superoxide dismutase1 (SOD1). Analyses were performed using microcomputerized tomography (micro-CT), TRAP staining, immunohistochemical (IHC) staining, and enzyme-linked immunosorbent assay (ELISA). We found for the first time that slightly higher ROS in mandibular alveolar bone of SOD1(-/-) mice at early ages (2-4 months) caused a distinct enlargement in bone size and increased bone volume fraction (BV/TV), trabecular thickness (Tb.Th), and expression of alkaline phosphatase (ALP), Runt-related transcription factor 2 (Runx2), and osteopontin (OPN). With ROS accumulation to oxidative stress level, increased trabecular bone separation (Tb.Sp) and decreased expression of ALP, Runx2, and OPN were found in SOD1(-/-) mice at 6 months. Additionally, dosing with N-acetylcysteine (NAC) effectively mitigated bone loss and normalized expression of ALP, Runx2, and OPN. These results indicate that redox imbalance caused by SOD1 deficiency has dual effects (promotion or inhibition) on mandibular alveolar bone development, which is closely related to the concentration of ROS and the stage of growth. We present a valuable model here for investigating the effects of ROS on mandibular alveolar bone formation and highlight important roles of ROS in regulating tissue development and pathological states, illustrating the complexity of the redox signal.
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Modrick, Mary L., Sean P. Didion, Cynthia M. Lynch, Sanjana Dayal, Steven R. Lentz, and Frank M. Faraci. "Role of Hydrogen Peroxide and the Impact of Glutathione Peroxidase-1 in Regulation of Cerebral Vascular Tone." Journal of Cerebral Blood Flow & Metabolism 29, no. 6 (April 8, 2009): 1130–37. http://dx.doi.org/10.1038/jcbfm.2009.37.
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Although arachidonic acid (AA) has diverse vascular effects, the mechanisms that mediate these effects are incompletely defined. The goal of our study was to use genetic approaches to examine the role of hydrogen peroxide (H2O2), glutathione peroxidase (Gpx1, which degrades H2O2), and CuZn-superoxide dismutase (SOD1, which produces H2O2 from superoxide) in mediating and in determining vascular responses to AA. In basilar arteries in vitro, AA produced dilation in nontransgenic mice, and this response was reduced markedly in transgenic mice overexpressing Gpx1 (Gpx1 Tg) or in those genetically deficient in SOD1. For example, AA (1 nmol/L to 1 μmol/L) dilated the basilar artery and this response was reduced by ∼90% in Gpx1 Tg mice ( P<0.01), although responses to acetylcholine were not altered. Dilation of cerebral arterioles in vivo in response to AA was inhibited by ∼50% by treatment with catalase (300 U/mL) ( P<0.05) and reduced by as much as 90% in Gpx1 Tg mice compared with that in controls ( P<0.05). These results provide the first evidence that Gpx1 has functional effects in the cerebral circulation, and that AA-induced vascular effects are mediated by H2O2 produced by SOD1. In contrast, cerebral vascular responses to the endothelium-dependent agonist acetylcholine are not mediated by H2O2.
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Di Paola, Davide, Enrico Gugliandolo, Fabiano Capparucci, Marika Cordaro, Carmelo Iaria, Rosalba Siracusa, Ramona D’Amico, et al. "Early Exposure to Environmental Pollutants: Imidacloprid Potentiates Cadmium Toxicity on Zebrafish Retinal Cells Death." Animals 12, no. 24 (December 9, 2022): 3484. http://dx.doi.org/10.3390/ani12243484.
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In the present study, we analyzed the combination of non-toxic concentrations per se, of Cd and a pesticide the imidacloprid (IMI) (10 and 50 μM for Cd and 195 μM for IMI), to highlight early developmental toxicity and possible damage to retinal cells. Co-exposure to Cd and IMI showed a toxic effect in zebrafish larval development, with lowered degrees of survival and hatching, and in some cases the induction of structural alterations and edema. In addition, co-exposure to 50 and 195 μM, respectively, for Cd and IMI, also showed increased apoptosis in eye cells, accompanied by up regulation of genes associated with antioxidant markers (cat, sod1, nrf2 and ho-1). Thus, the present study aims to highlight how the presence of multiple contaminants, even at low concentrations, can be a risk factor in a model of zebrafish (Danio rerio). The presence of other contaminants, such as IMI, can cause an enhancement of the toxic action of Cd on morphological changes in the early life stage of zebrafish, but more importantly disrupt the normal development of the retina, eventually triggering apoptosis.