Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P30044 (antioxidant enzyme)
8,037 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cells deficient in a major DNA double-strand break repair pathway (nonhomologous DNA end joining [NHEJ]) have increased spontaneous chromosome breaks; however, the source of these chromosome breaks has remained undefined. Here, we show that the observed spontaneous chromosome breaks are partially suppressed by reducing the cellular oxygen tension. Conversely, elevating the level of reactive oxygen species by overexpressing the antioxidant enzyme superoxide dismutase 1 (SOD1), in a transgenic mouse, increases chromosome breakage. The effect of SOD1 can also be modulated by cellular oxygen tension. The elevated chromosome breakage correlates histologically with a significant increase in the amount of neuronal cell death in Ku86(-/-) SOD1 transgenic embryos over that seen in Ku86(-/-) embryos. Therefore, oxygen metabolism is a major source of the genomic instability observed in NHEJ-deficient cells and, presumably, in all cells.
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PMID:Oxygen metabolism causes chromosome breaks and is associated with the neuronal apoptosis observed in DNA double-strand break repair mutants. 1193 46

Oxidative stress is implicated in both the deposition and pathogenesis of beta-amyloid (Abeta) protein in Alzheimer's disease (AD). Accordingly, overexpression of the antioxidant enzyme superoxide dismutase 1 (SOD1) in neuronal cells and transgenic AD mice reduces Abeta toxicity and accumulation. In contrast, mutations in SOD1 associated with amyotrophic lateral sclerosis (ALS) confer enhanced pro-oxidative enzyme activities. We therefore examined whether ALS-linked mutant SOD1 overexpression in motor neuronal cells or transgenic ALS mice modulates Abeta toxicity or its accumulation in the brain. Aggregated, but not freshly solubilised, substrate-bound Abeta peptides induced degenerative morphology and cytotoxicity in motor neuron-like NSC-34 cells. Transfection of NSC-34 cells with human wild-type SOD1 attenuated Abeta-induced toxicity, however this neuroprotective effect was also observed for ALS-linked mutant SOD1. Analysis of the cerebral cortex, brainstem, cerebellum and olfactory bulb from transgenic SOD1G93A mice using enzyme-linked immunosorbent assay of acid-guanidine extracts revealed age-dependent elevations in Abeta levels, although not significantly different from wild-type mouse brain. In addition, brain amyloid protein precursor (APP) levels remained unaltered as a consequence of mutant SOD1 expression. We therefore conclude that mutant SOD1 overexpression promotes neither Abeta toxicity nor brain accumulation in these ALS models.
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PMID:Brain beta-amyloid accumulation in transgenic mice expressing mutant superoxide dismutase 1. 1567 51

Peroxiredoxin-ll (Prxll) and glutathione peroxidase-l (GPxl) are regulators of the redox system that is one of the most crucial supporting systems in neurons. This system is an antioxidant enzyme defense system and is synchronously linked to other important cell supporting systems. To clarify the common self-survival mechanism of the residual motor neurons affected by amyotrophic lateral sclerosis (ALS), we examined motor neurons from 40 patients with sporadic ALS (SALS) and 5 patients with superoxide dismutase 1 (SOD1)-mutated familial ALS (FALS) from two different families (frame-shift 126 mutation and A4 V) as well as four different strains of the SOD1-mutated ALS models (H46R/G93A rats and G1H/G1L-G93A mice). We investigated the immunohistochemical expression of Prxll/GPxl in motor neurons from the viewpoint of the redox system. In normal subjects, Prxll/GPxl immunoreactivity in the anterior horns of the normal spinal cords of humans, rats and mice was primarily identified in the neurons: cytoplasmic staining was observed in almost all of the motor neurons. Histologically, the number of spinal motor neurons in ALS decreased with disease progression. Immunohistochemically, the number of neurons negative for Prxll/GPxl increased with ALS disease progression. Some residual motor neurons coexpressing Prxll/GPxl were, however, observed throughout the clinical courses in some cases of SALS patients, SOD1-mutated FALS patients, and ALS animal models. In particular, motor neurons overexpressing Prxll/GPxl, i.e., neurons showing redox system up-regulation, were commonly evident during the clinical courses in ALS. For patients with SALS, motor neurons overexpressing Prxll/GPxl were present mainly within approximately 3 years after disease onset, and these overexpressing neurons thereafter decreased in number dramatically as the disease progressed. For SOD1-mutated FALS patients, like in SALS patients, certain residual motor neurons without inclusions also overexpressed Prxll/GPxl in the short-term-surviving FALS patients. In the ALS animal models, as in the human diseases, certain residual motor neurons showed overexpression of Prxll/GPxl during their clinical courses. At the terminal stage of ALS, however, a disruption of this common Prxll/GPxl-overexpression mechanism in neurons was observed. These findings lead us to the conclusion that the residual ALS neurons showing redox system up-regulation would be less susceptible to ALS stress and protect themselves from ALS neuronal death, whereas the breakdown of this redox system at the advanced disease stage accelerates neuronal degeneration and/or the process of neuronal death.
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PMID:Redox system expression in the motor neurons in amyotrophic lateral sclerosis (ALS): immunohistochemical studies on sporadic ALS, superoxide dismutase 1 (SOD1)-mutated familial ALS, and SOD1-mutated ALS animal models. 1598 30

Oxidative stress has been implicated in the pathogenesis of preeclampsia. This study measured the relative mRNA expression of antioxidant proteins glutathione peroxidase 1 and 4, glutathione reductase, thioredoxin 1 and 2, thioredoxin reductase 1, thioredoxin peroxidase 3 and superoxide dismutase 1 and 2 in preeclamptic and non-preeclamptic placentae. Quantitative real-time PCR was conducted on placental mRNA isolated from preeclamptic and control patients. Cycle threshold numbers and fold differences were calculated as a measure of linear product amplification and used for comparison. The mRNA expression of glutathione reductase was significantly reduced (fold difference 0.41, p<0.05) in preeclamptic placenta when compared to controls while the expression of thioredoxin peroxidase 3 was significantly increased (fold difference 3.25, p<0.001) in the preeclamptic placentae. No significant difference in expression was observed for glutathione peroxidase 1 and 4, thioredoxin 1 and 2, thioredoxin reductase 1 and superoxide dismutase 1 and 2. These results suggest that it is the abnormal oxidative insult associated with preeclampsia not mRNA expression of antioxidant proteins that may be responsible for reduced antioxidant enzyme activity in preeclamptic placentae.
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PMID:Antioxidant gene expression in preeclamptic placentae: a preliminary investigation. 1839 94

Reactive oxygen species (ROS) and subsequent oxidative damage may contribute to the formation and persistence of multiple sclerosis (MS) lesions by acting on distinct pathological processes. ROS initiate lesion formation by inducing blood-brain barrier disruption, enhance leukocyte migration and myelin phagocytosis, and contribute to lesion persistence by mediating cellular damage to essential biological macromolecules of vulnerable CNS cells. Relatively little is known about which CNS cell types are affected by oxidative injury in MS lesions. Here, we show the presence of extensive oxidative damage to proteins, lipids, and nucleotides occurring in active demyelinating MS lesions, predominantly in reactive astrocytes and myelin-laden macrophages. Oxidative stress can be counteracted by endogenous antioxidant enzymes that confer protection against oxidative damage. Here, we show that antioxidant enzymes, including superoxide dismutase 1 and 2, catalase, and heme oxygenase 1, are markedly upregulated in active demyelinating MS lesions compared to normal-appearing white matter and white matter tissue from nonneurological control brains. Particularly, hypertrophic astrocytes and myelin-laden macrophages expressed an array of antioxidant enzymes. Enhanced antioxidant enzyme production in inflammatory MS lesions may reflect an adaptive defense mechanism to reduce ROS-induced cellular damage.
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PMID:Severe oxidative damage in multiple sclerosis lesions coincides with enhanced antioxidant enzyme expression. 1893 Aug 11

The antioxidant enzyme superoxide dismutase 1 (SOD1) is a critical player of the antioxidative defense whose activity is altered in several chronic diseases, including amyotrophic lateral sclerosis. However, how oxidative insult affects muscle homeostasis remains unclear. This study addresses the role of oxidative stress on muscle homeostasis and function by the generation of a transgenic mouse model expressing a mutant SOD1 gene (SOD1(G93A)) selectively in skeletal muscle. Transgenic mice developed progressive muscle atrophy, associated with a significant reduction in muscle strength, alterations in the contractile apparatus, and mitochondrial dysfunction. The analysis of molecular pathways associated with muscle atrophy revealed that accumulation of oxidative stress served as signaling molecules to initiate autophagy, one of the major intracellular degradation mechanisms. These data demonstrate that skeletal muscle is a primary target of SOD1(G93A) -mediated toxicity and disclose the molecular mechanism whereby oxidative stress triggers muscle atrophy.
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PMID:Skeletal muscle is a primary target of SOD1G93A-mediated toxicity. 1904 73

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by death of motor neurons leading to muscle wasting, paralysis, and death, usually within 2-3 years of symptom onset. The causes of ALS are not completely understood, and the neurodegenerative processes involved in disease progression are diverse and complex. There is substantial evidence implicating oxidative stress as a central mechanism by which motor neuron death occurs, including elevated markers of oxidative damage in ALS patient spinal cord and cerebrospinal fluid and mutations in the antioxidant enzyme superoxide dismutase 1 (SOD1) causing approximately 20% of familial ALS cases. However, the precise mechanism(s) by which mutant SOD1 leads to motor neuron degeneration has not been defined with certainty, and the ultimate trigger for increased oxidative stress in non-SOD1 cases remains unclear. Although some antioxidants have shown potential beneficial effects in animal models, human clinical trials of antioxidant therapies have so far been disappointing. Here, the evidence implicating oxidative stress in ALS pathogenesis is reviewed, along with how oxidative damage triggers or exacerbates other neurodegenerative processes, and we review the trials of a variety of antioxidants as potential therapies for ALS.
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PMID:Oxidative stress in ALS: key role in motor neuron injury and therapeutic target. 1996 67

The antioxidant activities of the thymoquinone-rich fraction (TQRF) extracted from Nigella sativa and its bioactive compound, thymoquinone (TQ), in rats with induced hypercholesterolemia were investigated. Rats were fed a semipurified diet supplemented with 1% (w/w) cholesterol and were treated with TQRF and TQ at dosages ranging from 0.5 to 1.5 g/kg and 20 to 100 mg/kg body wt, respectively, for 8 weeks. The hydroxyl radical (OH(.))-scavenging activity of plasma samples collected from experimental rats was measured by electron spin resonance. The GenomeLab Genetic Analysis System was used to study the molecular mechanism that mediates the antioxidative properties of TQRF and TQ. Plasma total cholesterol and low-density-lipoprotein cholesterol levels were significantly decreased in the TQRF- and TQ-treated rats compared to untreated rats. Feeding rats a 1% cholesterol diet for 8 weeks resulted in a significant decrease in plasma antioxidant capacity, as measured by the capacity to scavenge hydroxyl radicals. However, rats treated with TQRF and TQ at various doses showed significant inhibitory activity toward the formation of OH(.) compared to untreated rats. Upon examination of liver RNA expression levels, treatment with TQRF and TQ caused the up-regulation of the superoxide dismutase 1 (SOD1), catalase, and glutathione peroxidase 2 (GPX) genes compared to untreated rats (P<0.05). In support of this, liver antioxidant enzyme levels, including SOD1 and GPX, were also apparently increased in the TQRF- and TQ-treated rats compared to untreated rats (P<0.05). In conclusion, TQRF and TQ effectively improved the plasma and liver antioxidant capacity and enhanced the expression of liver antioxidant genes of hypercholesterolemic rats.
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PMID:Nigella sativa thymoquinone-rich fraction greatly improves plasma antioxidant capacity and expression of antioxidant genes in hypercholesterolemic rats. 2000 91

Inflammatory environment chronically activates bronchial epithelial cells to stimulate airway cells including epithelial cells themselves by secreting pro-inflammatory and regulatory factors. Proteomic approach is most relevant to screen the epithelial pathways following the inflammatory stimuli. We compared protein expression of the human bronchial epithelial cells exposed to leukotriene E(4) (LTE(4)) and transforming growth factor-beta(1) (TGF-beta(1)) with that of non-stimulated cells. The proteins were separated by 2-DE and the differentially expressed proteins were identified by MALDI-TOF MS and TOF/TOF tandem MS/MS. This approach allowed identification of 31 proteins, of which 26 corresponded to different proteins. beta-tubulin, significantly down-regulated by LTE(4), was confirmed as a ciliated cell marker beta-tubulin IV, whose decrease by LTE(4) was further corroborated by flow cytometry and RT-qPCR. This refers to a contribution of cysteinyl leukotrienes to epithelial remodelling and initiation of epithelial-mesenchymal transition in conducting airways. Of the affected proteins by TGF-beta(1), clinically most relevant ones were up-regulated antioxidant enzyme superoxide dismutase 1, pro-fibrotic enzyme protein disulfide-isomerase and heat shock 70 kDa protein 9B. The changed protein profiles from this study add novel aspects to improve our understanding of the airway pathobiology, provide hints for further directed airway research and may contribute to selecting targets for future therapeutics.
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PMID:Proteome changes of human bronchial epithelial cells in response to pro-inflammatory mediator leukotriene E4 and pro-remodelling factor TGF-beta1. 2021 18

Previous studies have demonstrated that N,N-diethyldithiocarbamate (DEDC) elevates copper and promotes oxidative stress within the nervous system. However, whether these effects resolve following cessation of exposure or have the potential to persist and result in cumulative injury has not been determined. In this study, an established model for DEDC myelin injury in the rat was used to determine whether copper levels, oxidative stress, and neuromuscular deficits resolve following the cessation of DEDC exposure. Rats were exposed to DEDC for 8 weeks and then either euthanized or maintained for 2, 6 or 12 weeks after cessation of exposure. At each time point copper levels were measured by inductively coupled mass spectrometry to assess the ability of sciatic nerve, brain, spinal cord and liver to eliminate excess copper post-exposure. The protein expression levels of glutathione transferase alpha, heme oxygenase 1 and superoxide dismutase 1 in peripheral nerve and brain were also determined by western blot to assess levels of oxidative stress as a function of post-exposure duration. As an initial assessment of the bioavailability of the excess copper in brain the protein expression levels of copper chaperone for superoxide dismutase 1, and prion protein were determined by western blot as a function of exposure and post-exposure duration. Neuromuscular function in peripheral nerve was evaluated using grip strengths, nerve conduction velocities, and morphologic changes at the light microscope level. The data demonstrated that in peripheral nerve, copper levels and oxidative stress return to control levels within several weeks after cessation of exposure. Neuromuscular function also showed a trend towards pre-exposure values, although the resolution of myelin lesions was more delayed. In contrast, total copper and antioxidant enzyme levels remained significantly elevated in brain for longer post-exposure periods. The persistence of effects observed in brain suggests that the central nervous system is more susceptible to long-term cumulative adverse effects from dithiocarbamates. Additionally, significant changes in expression levels of chaperone for superoxide dismutase 1, and prion protein were observed consistent with at least a portion of the excess copper being bioactive.
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PMID:Peripheral nerve and brain differ in their capacity to resolve N,N-diethyldithiocarbamate-mediated elevations in copper and oxidative injury. 2045 88


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