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Cu/Zn Superoxide Dismutase (cu + superoxide_dismutase)
Selected AbstractsStabilization of mutant Cu/Zn superoxide dismutase (SOD1) protein by coexpressed wild SOD1 protein accelerates the disease progression in familial amyotrophic lateral sclerosis miceEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2001Kei Fukada Abstract Transgenic mice carrying familial amyotrophic lateral sclerosis (FALS)-linked mutant Cu/Zn superoxide dismutase (SOD1) genes such as G93A (G93A-mice) and G85R (G85R-mice) genes develop limb paresis. Introduction of human wild type SOD1 (hWT-SOD1) gene, which does not cause motor impairment by itself, into different FALS mice resulted in different effects on their clinical courses, from no effect in G85R-mice to acceleration of disease progression in G93A-mice. However, the molecular mechanism which causes the observed difference, has not been clarified. We hypothesized that the difference might be caused by the stability of mutant SOD1 proteins. Using a combination of mass spectrometry and enzyme-linked immunosorbent assay, we found that the concentration of G93A-SOD1 protein was markedly elevated in tissues of transgenic mice carrying both G93A - and hWT-SOD1 genes (G93A/hWT-mice) compared to that in G93A-mice, and also found that the concentration of G93A-SOD1 protein had a close relation to the disease duration. The concentration of metallothionein-I/II in the spinal cord, reflecting the degree of copper-mediated oxidative stress, was highest in G93A/hWT-mice, second in G93A-mice, and normal in the mice carrying hWT-SOD1 gene. These results indicated that the increase of G93A-SOD1 protein was responsible for the increase of oxidative stress and disease acceleration in G93A/hWT-mice. We speculate that coexpression of hWT-SOD1 protein is deleterious to transgenic mice carrying a stable mutant such as G93A-SOD1, because this mutant protein is stabilized by hWT-SOD1 protein, but not to transgenic mice carrying an unstable mutant such as G85R-SOD1, because this mutant protein is not stabilized by hWT-SOD1. [source] Down-regulation of endothelial adhesion molecules and leukocyte adhesion by treatment with superoxide dismutase is beneficial in chronic immune experimental colitisINFLAMMATORY BOWEL DISEASES, Issue 10 2005Joaquim Seguí PhD Abstract Modulation of adhesion molecule expression that govern trafficking of leukocytes into the inflamed intestine is envisioned as a new strategy for treatment of inflammatory bowel disease (IBD). This study was designed to determine the impact of reducing oxidative stress on adhesion molecules expression and leukocyte recruitment in experimental chronic colitis. For that purpose, colitic interleukin-10 knockout and wild-type mice were studied. Groups of animals were treated with Cu/Zn superoxide dismutase (SOD1) 13 mg/kg/d or vehicle for either 7 or 14 days. Expression of vascular cell adhesion molecule-1 and mucosal addressin cell adhesion molecule-1 were determined; leukocyte-endothelial cell interactions in colonic venules were studied with intravital microscopy; and changes in colon pathology and biomarkers of colitis severity were determined. Development of colitis was associated with a marked increase in endothelial vascular cell adhesion molecule-1 and mucosal addressin cell adhesion molecule-1 expression, which were significantly reduced by treatment with SOD1. The increase in leukocyte rolling and adhesion in colonic venules of colitic mice were significantly reduced by administration of SOD1. This treatment markedly reduced colonic lipid hydroperoxidation, myeoloperoxidase activity, and plasma levels of serum amyloid A protein and resulted in significant, although modest, reductions in histologic damage score. The therapeutic value of SOD1 when administered prophylactically was assessed in the dextran sulfate sodium model of colitis with similar positive results. These results indicate that SOD1 affords significant amelioration of colonic inflammatory changes in experimental colitis. Down-regulation of adhesion molecule expression, reduction of lipid hydroperoxidation, and recruitment of leukocytes into the inflamed intestine contribute to this beneficial effect. [source] Comprehensive Analysis of Expressed Sequence Tags from the Pulp of the Red Mutant ,Cara Cara' Navel Orange (Citrus sinensis Osbeck)JOURNAL OF INTEGRATIVE PLANT BIOLOGY, Issue 10 2010Jun-Li Ye Expressed sequence tag (EST) analysis of the pulp of the red-fleshed mutant ,Cara Cara' navel orange provided a starting point for gene discovery and transcriptome survey during citrus fruit maturation. Interpretation of the EST datasets revealed that the mutant pulp transcriptome held a high section of stress responses related genes, such as the type III metallothionein-like gene (6.0%), heat shock protein (2.8%), Cu/Zn superoxide dismutase (0.8%), late embryogenesis abundant protein 5 (0.8%), etc. 133 transcripts were detected to be differentially expressed between the red mutant and its orange-color wild genotype ,Washington' via digital expression analysis. Among them, genes involved in metabolism, defense/stress and signal transduction were statistical overrepresented. Fifteen transcription factors, composed of NAM, ATAF, and CUC transcription factor (NAC); myeloblastosis (MYB); myelocytomatosis (MYC); basic helix-loop-helix (bHLH); basic leucine zipper (bZIP) domain members, were also included. The data reflected the distinct expression profile and the unique regulatory module associated with these two genotypes. Eight differently expressed genes analyzed in digital were validated by quantitative real-time polymerase chain reaction. For structural polymorphism, both simple sequence repeats and single nucleotide polymorphisms (SNP) loci were surveyed; dinucleotide presentation revealed a bias toward AG/GA/TC/CT repeats (52.5%), against GC/CG repeats (0%). SNPs analysis found that transitions (73%) outnumbered transversions (27%). Seventeen potential cultivar-specific and 387 heterozygous SNP loci were detected from ,Cara Cara' and ,Washington' EST pool. [source] Amyotrophic lateral sclerosis: all roads lead to RomeJOURNAL OF NEUROCHEMISTRY, Issue 5 2007Jose-Luis Gonzalez de Aguilar Abstract Amyotrophic lateral sclerosis (ALS) is the most frequent adult-onset motor neuron disease characterized by degeneration of upper and lower motor neurons, generalized weakness and muscle atrophy. Most cases of ALS appear sporadically but some forms of the disease result from mutations in the gene encoding the antioxidant enzyme Cu/Zn superoxide dismutase (SOD1). Several other mutated genes have also been found to predispose to ALS including, among others, one that encodes the regulator of axonal retrograde transport dynactin. As all roads lead to the proverbial Rome, we discuss here how distinct molecular pathways may converge to the same final result that is motor neuron death. We critically review the basic research on SOD1-linked ALS to propose a pioneering model of a ,systemic' form of the disease, causally involving multiple cell types, either neuronal or non-neuronal. Contrasting this, we also postulate that other neuron-specific defects, as those triggered by dynactin dysfunction, may account for a primary motor neuron disease that would represent ,pure' neuronal forms of ALS. Identifying different disease subtypes is an unavoidable step toward the understanding of the physiopathology of ALS and will hopefully help to design specific treatments for each subset of patients. [source] Therapeutic benefits of intrathecal protein therapy in a mouse model of amyotrophic lateral sclerosisJOURNAL OF NEUROSCIENCE RESEARCH, Issue 13 2008Yasuyuki Ohta Abstract When fused with the protein transduction domain (PTD) derived from the human immunodeficiency virus TAT protein, proteins can cross the blood,brain barrier and cell membrane and transfer into several tissues, including the brain, making protein therapy feasible for various neurological disorders. We have constructed a powerful antiapoptotic modified Bcl-XL protein (originally constructed from Bcl-XL) fused with PTD derived from TAT (TAT-modified Bcl-XL), and, to examine its clinical effectiveness in a mouse model of familial amyotrophic lateral sclerosis (ALS), transgenic mice expressing human Cu/Zn superoxide dismutase (SOD1) bearing a G93A mutation were treated by intrathecal infusion of TAT-modified Bcl-XL. We demonstrate that intrathecally infused TAT-fused protein was effectively transferred into spinal cord neurons, including motor neurons, and that intrathecal infusion of TAT-modified Bcl-XL delayed disease onset, prolonged survival, and improved motor performance. Histological studies show an attenuation of motor neuron loss and a decrease in the number of cleaved caspase 9-, cleaved caspase 3-, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells in the lumbar cords of TAT-modified Bcl-XL -treated G93A mice. Our results indicate that intrathecal protein therapy using a TAT-fused protein is an effective clinical tool for the treatment of ALS. © 2008 Wiley-Liss, Inc. [source] Protective effects of atypical antipsychotic drugs on PC12 cells after serum withdrawalJOURNAL OF NEUROSCIENCE RESEARCH, Issue 2 2002Ou Bai Abstract Atypical antipsychotic drugs are widely used in the treatment of schizophrenia, and clinical evidence has shown that early and prolonged intervention with these drugs will improve the long-term outcome. It is still unclear, however, whether the atypical antipsychotic drugs are also neuroprotective. To clarify this matter, we used PC12 cell cultures and the MTT assay for cell viability to determine whether various concentrations of the atypical antipsychotics clozapine, quetiapine, and risperidone are neuroprotective after serum withdrawal. In addition, to explore the drugs' actions, Northern blot was used to examine the gene expression of SOD1 (Cu/Zn superoxide dismutase) and p75NTR (p75 neurotrophin receptor). The results demonstrated that 1) the antipsychotic drugs can protect PC12 cells from death after serum withdrawal; cell viability in these drug treatment groups is significantly different from that in the groups without serum in the medium (P < 0.01); and 2) these drugs up-regulated the SOD1 gene expression to more than 120% (P < 0.05) and also down-regulated p75NTR mRNA levels to less than 65% of their respective control values (P < 0.05). These findings suggest that the atypical antipsychotics clozapine, quetiapine, and risperidone may exert a neuroprotective function through the modulation of SOD1 and p75NTR expression. © 2002 Wiley-Liss, Inc. [source] Japanese familial amyotrophic lateral sclerosis family with a two-base deletion in the superoxide dismutase-1 geneNEUROPATHOLOGY, Issue 1 2001Yasuhiro Watanabe The clinical characteristics of members of a familial amyotrophic lateral sclerosis (FALS) family from Oki Island, whose members have a 2-bp deletion at codon 126 of Cu/Zn superoxide dismutase (SOD1) gene, are presented here. Mean age of the onset in the members was 42 years. Mean disease duration among the members who had not been placed on a respirator was approximately 2 years. Long-term survivors with respiratory support presented disturbances in eye movement and urination toward the end stages of the disease. They predominantly exhibited lower motor neuron symptoms. In addition, the authors focused on frameshift, nonsense and non-amino-acid-altering mutations. Frameshift and nonsense mutations were all found within exon 4, exon 5 and intron 4. These amyotrophic lateral sclerosis cases were likely to have shorter disease duration than the FALS patients with single substitution. Several hypotheses were presented on the pathogenesis of FALS with SOD1 mutation. [source] Mechanism of DNA Damage Photosensitized by Trisbipyrazyl Ruthenium Complex.PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 5 2000Unusual Role of Cu/Zn Superoxide Dismutase ABSTRACT Trisbipyrazyl ruthenium(II) (Ru[bpz]32+) was examined as DNA photosensitizer. Damage resulting from the photolysis of synthetic oligonucleotides has been monitored by polyacrylamide gel electrophoresis. Photoadduct formation is found on both single- and double-stranded oligonucleotides. On oligonucleotide duplex, oxidative damage occurs selectively at the 5,G of the 5,GG3, site and to a lesser extent at the 5,G of a GA sequence. These findings suggest the involvement of electron transfer and show that this mechanism is the main DNA damaging process involved in Ru(bpz)32+ photosensitization. In addition, photoadducts and oxidative damage are both highly affected by an increase of salt concentration in the reaction medium, stressing the importance of direct interactions between nucleic acid bases and the excited ruthenium complex for efficient electron transfer. On single-stranded oligonucleotides, all the guanines are oxidized to the same extent. In this case, oxidative damage, which is not affected by an increase of salt in the solution, has been attributed, in part, to singlet oxygen. More importantly, Cu/Zn superoxide dismutase (SOD) strongly enhances the yield of all damage, correlated to an increase of both electron transfer and singlet oxygen production. This original activity of SOD is the first example of bioactivation of a polyazaaromatic ruthenium complex. [source] Current hypotheses for the underlying biology of amyotrophic lateral sclerosis,ANNALS OF NEUROLOGY, Issue S1 2009Jeffrey D. Rothstein MD The mechanisms involved in selective motor neuron degeneration in amyotrophic lateral sclerosis remain unknown more than 135 years after the disease was first described. Although most cases have no known cause, mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) have been implicated in a fraction of familial cases of the disease. Transgenic mouse models with mutations in the SOD1 gene and other ALS genes develop pathology reminiscent of the disorder, including progressive death of motor neurons, and have provided insight into the pathogenesis of the disease but have consistently failed to predict therapeutic efficacy in humans. However, emerging research has demonstrated that mutations and pathology associated with the TDP-43 gene and protein may be more common than SOD1 mutations in familial and sporadic ALS. Putative mechanisms of toxicity targeting motor neurons include oxidative damage, accumulation of intracellular aggregates, mitochondrial dysfunction, defects in axonal transport, growth factor deficiency, aberrant RNA metabolism, glial cell pathology, and glutamate excitotoxicity. Convergence of these pathways is likely to mediate disease onset and progression. Ann Neurol 2009;65 (suppl):S3,S9 [source] Managing amyotrophic lateral sclerosis: Slowing disease progression and improving patient quality of life,ANNALS OF NEUROLOGY, Issue S1 2009Benjamin Rix Brooks MD It is now possible to slow the disease progression of amyotrophic lateral sclerosis (ALS), but documented improvement in the quality of life of ALS patients has been difficult to quantitate. Putative mechanisms involved in motor neuron degeneration in ALS include oxidative damage, mitochondrial dysfunction, neuroinflammation, growth factor deficiency, and glutamate excitotoxicity. Several pharmacological agents that target these potential targets have demonstrated therapeutic potential in animal models with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Many treatments that have been moderately effective in this animal model have not been successfully translated into effective treatments for humans with ALS. Only the glutamate modulator riluzole has demonstrated efficacy in clinical trials and is approved for treating ALS. Combination treatments may represent a potential therapeutic strategy to more robustly prolong life and preserve function, but only vitamin E with riluzole has been formally studied in clinical trials, and to date, no combination treatments have been found to be more effective than currently available single agents. Ann Neurol 2009;65 (suppl):S17,S23 [source] Contractile activity of ATP and diadenosine tetraphosphate on urinary bladder in the rats: role of superoxide anion and urotheliumAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 2 2006M. M. Khattab Summary 1 Both ATP and diadenosine tetraphosphate (AP4A) produced a dose-dependent contraction of rat isolated urinary bladder rings. The AP4A dose,response curve was to the left of that of ATP, and the maximum response was greater than that produced by ATP. 2 Mechanical removal of the urothelium increased the contractile response to ATP by between 53% and 71%, and that to AP4A by 42% (at highest AP4A concentration) to 68% at lower concentration. 3 Inhibition of Cu/Zn superoxide dismutase with diethylthiocarbamate (DETCA, 5 mm) significantly reduced the ATP-evoked contraction by 31% (at high ATP concentration) to 40% at low ATP concentration. Similarly, the AP4A-induced contractions were significantly decreased by 27% at low AP4A level to 38% at higher concentrations. 4 Induction of exogenous superoxide anion stress by the use of the superoxide anion generator, pyrogallol (0.5 mm), significantly decreased both ATP- and AP4A-induced contractions of the rat urinary bladder over the whole dose range. Contractile responses to ATP decreased by 36,40%, and those to AP4A by 44,49%. 5 In conclusion, the urinary bladder urothelium exerts an inhibitory control over the purinergic contractility produced by adenine mononucleotides and dinucleotides. Superoxide anion stress, whether endogenous or exogenous, attenuates the ATP-induced as well as AP4A-induced contractility. [source] Purification and crystallization of human Cu/Zn superoxide dismutase recombinantly produced in the protozoan Leishmania tarentolaeACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 8 2010Emerich Mihai Gazdag The rapid and inexpensive production of high-quality eukaryotic proteins in recombinant form still remains a challenge in structural biology. Here, a protein-expression system based on the protozoan Leishmania tarentolae was used to produce human Cu/Zn superoxide dismutase (SOD1) in recombinant form. Sequential integration of the SOD1 expression cassettes was demonstrated to lead to a linear increase in expression levels to up to 30,mg per litre. Chromatographic purification resulted in 90% pure recombinant protein, with a final yield of 6.5,mg per litre of culture. The protein was crystallized and the structures of two new crystal forms were determined. These results demonstrate the suitability of the L. tarentolae expression system for structural research. [source] Importance of calcitonin gene-related peptide, adenosine and reactive oxygen species in cerebral autoregulation under normal and diseased conditionsCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1-2 2004Hwa Kyoung Shin Summary 1.,Mechanisms regulating cerebral circulation, including autoregulation of cerebral blood flow (CBF), have been widely investigated. Vasodilators such as nitric oxide, prostacyclin, calcitonin gene-related peptide (CGRP) and K+ channel openers are well known to have important roles in the physiological and pathophysiological control of CBF autoregulation. In the present review, the focus is on the mechanism(s) of altered CBF autoregulation after traumatic brain injury and subarachnoid haemorrhage (SAH) and on the effect of adenovirus-mediated transfer of Cu/Zn superoxide dismutase (SOD)-1 in amelioration of impaired CBF autoregulation. 2.,The roles of CGRP and adenosine are particularly emphasized, both being implicated in the autoregulatory vasodilation of the pial artery in response to hypotension. 3.,After fluid percussion injury, production of NADPH oxidase-derived superoxide anion and activation of tyrosine kinase links the inhibition of K+ channels to impaired autoregulatory vasodilation in response to acute hypotension and alterations in CBF autoregulation in rat pial artery. 4.,Subarachnoid haemorrhage during the acute stage causes an increase in NADPH oxidase-dependent superoxide formation in cerebral vessels in association with activated tyrosine phosphorylation-coupled increased expression of gp91phox mRNA and membrane translocation of Rac protein, thereby resulting in a significant reduction of autoregulatory vasodilation. 5.,Fluid percussion injury and SAH-induced overproduction of superoxide anion in cerebral vessels contributes to the impairment of CBF autoregulation and administration of recombinant adenovirus-mediated transfer of the Cu/Zn SOD-1 gene effectively ameliorates the impairment of CBF autoregulation of the pial artery. 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