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Manganese Superoxide Dismutase (manganese + superoxide_dismutase)
Selected AbstractsBetulinic acid-mediated inhibitory effect on hepatitis B virus by suppression of manganese superoxide dismutase expressionFEBS JOURNAL, Issue 9 2009Dachun Yao The betulinic acid (BetA) purified from Pulsatilla chinensis (PC) has been found to have selective inhibitory effects on hepatitis B virus (HBV). In hepatocytes from HBV-transgenic mice, we showed that BetA substantially inhibited HBV replication by downregulation of manganese superoxide dismutase (SOD2) expression, with subsequent reactive oxygen species generation and mitochondrial dysfunction. Also, the HBV X protein (HBx) is suppressed and translocated into the mitochondria followed by cytochrome c release. Further investigation revealed that SOD2 expression was suppressed by BetA-induced cAMP-response element-binding protein dephosphorylation at Ser133, which subsequently prevented SOD2 transcription through the cAMP-response element-binding protein-binding motif on the SOD2 promoter. SOD2 overexpression abolished the inhibitory effect of BetA on HBV replication, whereas SOD2 knockdown mimicked this effect, indicating that BetA-mediated HBV clearance was due to modulation of the mitochondrial redox balance. This observation was further confirmed in HBV-transgenic mice, where both BetA and PC crude extracts suppressed SOD2 expression, with enhanced reactive oxygen species generation in liver tissues followed by substantial HBV clearance. We conclude that BetA from PC could be a good candidate for anti-HBV drug development. [source] Mitochondrial superoxide dismutase and glutathione peroxidase in idiosyncratic drug-induced liver injury,,HEPATOLOGY, Issue 1 2010M. Isabel Lucena Drug-induced liver injury (DILI) susceptibility has a potential genetic basis. We have evaluated possible associations between the risk of developing DILI and common genetic variants of the manganese superoxide dismutase (SOD2 Val16Ala) and glutathione peroxidase (GPX1 Pro200Leu) genes, which are involved in mitochondrial oxidative stress management. Genomic DNA from 185 DILI patients assessed by the Council for International Organizations of Medical Science scale and 270 sex- and age-matched controls were analyzed. The SOD2 and GPX1 genotyping was performed using polymerase chain reaction restriction fragment length polymorphism and TaqMan probed quantitative polymerase chain reaction, respectively. The statistical power to detect the effect of variant alleles with the observed odds ratio (OR) was 98.2% and 99.7% for bilateral association of SOD2 and GPX1, respectively. The SOD2 Ala/Ala genotype was associated with cholestatic/mixed damage (OR = 2.3; 95% confidence interval [CI] = 1.4-3.8; corrected P [Pc] = 0.0058), whereas the GPX1 Leu/Leu genotype was associated with cholestatic injury (OR = 5.1; 95%CI = 1.6-16.0; Pc = 0.0112). The presence of two or more combined risk alleles (SOD2 Ala and GPX1 Leu) was more frequent in DILI patients (OR = 2.1; 95%CI = 1.4-3.0; Pc = 0.0006). Patients with cholestatic/mixed injury induced by mitochondria hazardous drugs were more prone to have the SOD2 Ala/Ala genotype (OR = 3.6; 95%CI = 1.4-9.3; Pc = 0.02). This genotype was also more frequent in cholestatic/mixed DILI induced by pharmaceuticals producing quinone-like or epoxide metabolites (OR = 3.0; 95%CI = 1.7-5.5; Pc = 0.0008) and S-oxides, diazines, nitroanion radicals, or iminium ions (OR = 16.0; 95%CI = 1.8-146.1; Pc = 0.009). Conclusion: Patients homozygous for the SOD2 Ala allele and the GPX1 Leu allele are at higher risk of developing cholestatic DILI. SOD2 Ala homozygotes may be more prone to suffer DILI from drugs that are mitochondria hazardous or produce reactive intermediates. (HEPATOLOGY 2010) [source] Molecular relaxation and metalloenzyme active site modelingINTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, Issue 4-5 2002James W. Whittaker Abstract Metalloenzymes represent a broad class of important biomolecules containing an essential metal ion cofactor in their catalytic active sites, forming biologic metal complexes that perform a wide range of important functions: activation of small molecules (O2, N2, H2, CO), atom transfer chemistry, and the control of oxidation equivalents. The structures of many metalloenzyme active sites have been defined by X-ray crystallography, revealing transition metal ions in unique low-symmetry environments. These bioinorganic complexes present significant challenges for computational studies aimed at going beyond crystal structures to develop a detailed understanding of the catalytic mechanisms. Considerable progress has been made in the theoretical characterization of these sites in recent years, supported by the availability of efficient computational tools, in particular density functional methods. However, the ultimate success of a theoretical model depends on a number of factors independent of the specific computational method used, including the quality of the initial structural data, the identification of important environmental perturbations and constraints, and experimental validation of theoretical predictions. We explore these issues in detail and illustrate the effects of molecular relaxation in calculations of two metalloenzymes, manganese superoxide dismutase and galactose oxidase. © 2002 Wiley Periodicals, Inc. Int J Quantum Chem, 2002 [source] Molecular mechanism of preconditioningIUBMB LIFE, Issue 4 2008Manika Das Abstract During the last 20 years, since the appearance of the first publication on ischemic preconditioning (PC), our knowledge of this phenomenon has increased exponentially. PC is defined as an increased tolerance to ischemia and reperfusion induced by previous sublethal period ischemia. This is the most powerful mechanism known to date for limiting the infract size. This adaptation occurs in a biphasic pattern (i) early preconditioning (lasts for 2,3 h) and (ii) late preconditioning (starting at 24 h lasting until 72,96 h after initial ischemia). Early preconditioning is more potent than delayed preconditioning in reducing infract size. Late preconditioning attenuates myocardial stunning and requires genomic activation with de novo protein synthesis. Early preconditioning depends on adenosine, opioids and to a lesser degree, on bradykinin and prostaglandins, released during ischemia. These molecules activate G-protein-coupled receptor, initiate activation of KATP channel and generate oxygen-free radicals, and stimulate a series of protein kinases, which include protein kinase C, tyrosine kinase, and members of MAP kinase family. Late preconditioning is triggered by a similar sequence of events, but in addition essentially depends on newly synthesized proteins, which comprise iNOS, COX-2, manganese superoxide dismutase, and possibly heat shock proteins. The final mechanism of PC is still not very clear. The present review focuses on the possible role signaling molecules that regulate cardiomyocyte life and death during ischemia and reperfusion. © 2008 IUBMB IUBMB Life, 60(4): 199,203, 2008 [source] Oxidative stress: A cause and therapeutic target of diabetic complicationsJOURNAL OF DIABETES INVESTIGATION, Issue 3 2010Eiichi Araki Abstract Oxidative stress is defined as excessive production of reactive oxygen species (ROS) in the presence of diminished anti-oxidant substances. Increased oxidative stress could be one of the common pathogenic factors of diabetic complications. However, the mechanisms by which hyperglycemia increases oxidative stress are not fully understood. In this review, we focus on the impact of mitochondrial derived ROS (mtROS) on diabetic complications and suggest potential therapeutic approaches to suppress mtROS. It has been shown that hyperglycemia increases ROS production from mitochondrial electron transport chain and normalizing mitochondrial ROS ameliorates major pathways of hyperglycemic damage, such as activation of polyol pathway, activation of PKC and accumulation of advanced glycation end-products (AGE). Additionally, in subjects with type 2 diabetes, we found a positive correlation between HbA1c and urinary excretion of 8-hydroxydeoxyguanosine (8-OHdG), which reflects mitochondrial oxidative damage, and further reported that 8-OHdG was elevated in subjects with diabetic micro- and macro- vascular complications. We recently created vascular endothelial cell-specific manganese superoxide dismutase (MnSOD) transgenic mice, and clarified that overexpression of MnSOD in endothelium could prevent diabetic retinopathy in vivo. Furthermore, we found that metformin and pioglitazone, both of which have the ability to reduce diabetic vascular complications, could ameliorate hyperglycemia-induced mtROS production by the induction of PPAR, coactivator-1, (PGC-1,) and MnSOD and/or activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK). We also found that metformin and pioglitazone promote mitochondrial biogenesis through the same AMPK,PGC-1, pathway. Taking these results, mtROS could be the key initiator of and a therapeutic target for diabetic vascular complications. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00013.x, 2010) [source] The overexpression of major antioxidant enzymes does not extend the lifespan of miceAGING CELL, Issue 1 2009Viviana I. Pérez Summary We evaluated the effect of overexpressing antioxidant enzymes on the lifespans of transgenic mice that overexpress copper zinc superoxide dismutase (CuZnSOD), catalase, or combinations of either CuZnSOD and catalase or CuZnSOD and manganese superoxide dismutase (MnSOD). Our results show that the overexpression of these major antioxidant enzymes, which are known to scavenge superoxide and hydrogen peroxide in the cytosolic and mitochondrial compartments, is insufficient to extend lifespan in mice. [source] Cell-specific expression of manganese superoxide dismutase protein in the lungs of patients with respiratory distress syndrome, chronic lung disease, or persistent pulmonary hypertension,PEDIATRIC PULMONOLOGY, Issue 3 2001Tiina M. Asikainen MD Abstract The developmental profile of manganese superoxide dismutase (MnSOD) and its regulation in hyperoxia vary between species. We hypothesized that MnSOD increases in human lung in response to oxygen treatment, although this response could be restricted to certain cell types and depend on gestational age. Therefore, the cell-specific expression of pulmonary immunoreactive MnSOD protein was investigated during development, and in patients with respiratory distress syndrome (RDS), chronic lung disease (CLD), or persistent pulmonary hypertension (PPHN). Throughout ontogenesis, all cell types expressed MnSOD, but the most intense positivity was found in bronchiolar epithelium and (pre-) type-II pneumocytes. MnSOD protein did not increase during development. The MnSOD staining pattern in arterial endothelium was more intense in RDS patients than in age-matched controls, but this may be related to induction of MnSOD by increased blood flow rather than by oxygen. MnSOD expression in other cell types of RDS, CLD, or PPHN patients did not differ from that in age-matched controls. We conclude that, in terms of mitochondrial enzymatic superoxide scavenging capacity, preterm infants are not more vulnerable than term infants to oxygen-induced lung injury at physiological oxygen concentrations. However, the inability to induce MnSOD in response to oxygen treatment may result in a poor outcome. Pediatr Pulmonol. 2001; 32:193,200. © 2001 Wiley-Liss, Inc. [source] Response of anti-oxidant enzymes mRNA in the neonatal rat liver exposed to 1,2,3,4-tetrachlorodibenzo- p -dioxin via lactationPEDIATRICS INTERNATIONAL, Issue 5 2002Yumi Kono Abstract Background: The aim of this study was to assess the response to dioxin-induced oxidative stress in neonates via lactation in the model we have described previously. Methods: Maternal rats were treated with a single dose of 50 or 100 µmol/kg 1,2,3,4-tetrachlorodibenzo- p -dioxin (TCDD) on the first day postpartum (day 1). Messenger RNA levels of the key anti-oxidant enzymes (AOE), phospholipid hydroperoxide-glutathione peroxidase (PH-GPx), cellular-glutathione peroxidase (cell-GPx), copper-zinc superoxide dismutase (CuZn SOD), manganese superoxide dismutase (Mn SOD) and catalase (CAT) in the neonatal and maternal livers were determined by a competitive reverse transcription, polymerase chain reaction method. Results: Lactational transfer of 1,2,3,4-TCDD induced an inhibition of PH-GPx and cell-GPx mRNA in the neonatal liver on day 2 to 68 (P < 0.01) and 62% (P < 0.05) of the control at 100 µmol/kg, respectively. Both GPx mRNA returned to control levels on day 6 and thereafter increased to levels higher than the controls on day 10. In the dam rat, 10 days after the treatment, no remarkable change of PH-GPx or cell-GPx mRNA was observed. Copper-zinc superoxide dismutase and CAT mRNA of neonates on day 2 were also suppressed at 100 µmol/kg and then slightly increased on day 10. However, Mn SOD mRNA was not suppressed, but increased to a 2.1-fold level of the control (P < 0.05) on day 10 with 100 µmol/kg 1,2,3,4-TCDD. Conclusion: Quantitative analysis of AOE mRNA showed that PH-GPx and cell-GPx mRNA, as well as CuZn SOD and CAT mRNA in the neonatal liver were suppressed for a short period of time by 1,2,3,4-TCDD exposure via lactation. Dioxin induced oxidative stress by lactational transfer may alter pretranslation regulation of protective AOE in neonates. [source] Comparative proteomic analysis of mesenchymal stem cells derived from human bone marrow, umbilical cord, and placenta: Implication in the migrationPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 1 2009Guo Li Abstract Umbilical cord (UC) and placenta (P) have been suggested as alternatives to bone marrow (BM) as sources of mesenchymal stem cells (MSC) for cell therapy, with both UC- and P-MSC possess immunophenotypic and functional characteristics similar to BM-MSC. However, their migration capacity, which is indispensable during tissue regeneration process, is unclear. Under defined conditions, the migration capacity of BM- and P-MSC was found 5.9- and 3.2-folds higher than that of UC-MSC, respectively. By the use of 2-DE and combined MS and MS/MS analysis, six differentially expressed proteins were identified among these MSC samples, with five of them known to be involved in cell migration as migration enhancing or inhibiting proteins. Consistent with their migration capacity, the levels of migration enhancing proteins including cathepsin B, cathepsin D and prohibitin,were significantly lower in UC-MSC when compared with those in BM- and P-MSC. For the migration inhibiting proteins such as plasminogen activator inhibitor-1 (PAI-1) and manganese superoxide dismutase, higher expression was found in the UC-MSC. We also showed that the overexpression of the PAI-1 impaired the migration capacity of BM- and P-MSC while silencing of PAI-1 enhanced the migration capacity of UC-MSC. Our study indicates that PAI-1 and other migration-related proteins are pivotal in governing the migration capacity of MSC. [source] Proteome analysis of hepatocellular carcinoma cell strains, MHCC97-H and MHCC97-L, with different metastasis potentialsPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 4 2004Shi-Jian Ding Abstract To better understand the mechanism underlying hepatocellular carcinoma (HCC) metastasis and to search for potential markers for HCC prognosis, differential proteome analysis on two HCC cell strains with high and low metastatic potentials, MHCC97-H and MHCC97-L, was conducted using two-dimensional (2-D) gel electrophoresis followed by matrix-assisted laser desorption/time of flight mass spectrometry and liquid chromatography ion trap mass spectrometry. Image analysis of silver-stained 2-D gels revealed that 56 protein spots showed significant differential expression in MHCC97-H and MHCC97-L cells (Student's t -test, P < 0.05) and 4 protein spots were only detected in MHCC97-H cells. Fourteen protein spots were further identified using in-gel tryptic digestion, peptide mass fingerprinting and tandem mass spectrometry. The expressions of pyruvate kinase M2, ubiquitin carboxy-terminal hydrolase L1, laminin receptor 67 kDa, S100 calcium-binding protein A4, thioredoxin and cytokeratin 19 were elevated in MHCC97-H cells. However, manganese superoxide dismutase, calreticulin precursor, cathepsin D, lactate dehydrogenase B, non-metastatic cell protein 1, cofilin 1 and calumenin precursor were down-regulated in MHCC97-H cells. Intriguingly, most of these identified proteins have been reported to be associated with tumor metastasis. The functional implications of alterations in the levels of these proteins are discussed. [source] Comparative Proteomics Analysis of the Proteins Associated With Laryngeal Carcinoma-Related Gene 1,THE LARYNGOSCOPE, Issue 2 2006Xiaopeng Zhang PhD Abstract Objectives: A novel gene, laryngeal carcinoma-related gene 1 (LCRG1), had the characteristics of tumor-suppressor genes. It was cloned in our laboratory. The objective was to find and characterize the proteins related to LCRG1 and to elucidate the molecular mechanism of LCRG1. Study Design: We used the established cell lines of Hep-2/LCRG1 (Hep-2 cells transfected by recombinant plasmid pcDNA3.1[+]/LCRG1) and Hep-2/pcDNA3.1(+) (Hep-2 cells transfected by control vector pcDNA3.1[+]) as cell models. Methods: Two-dimensional gel electrophoresis (2-DE) technology was performed to separate the proteins of Hep-2/LCRG1 and Hep-2/pcDNA3.1(+) cell lines, respectively. The differential protein spots were analyzed by software analysis, subject to in-gel digestion, and identified by Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and electrospray ionization,quadruple time-of-flight MS/MS (ESI-Q-TOF MS/MS). Then the differential expression levels of partial identified proteins were determined by Western blotting analysis and quantitative real-time reverse transcriptase,polymerase chain reaction. Results: The results showed the attained 2-DE patterns of the two cell lines were well-resolved and reproducible. There were 1075 ± 43 and 1027 ± 23 protein spots observed in Hep-2/LCRG1 and Hep-2/pcDNA3.1(+) cell lines, respectively. The average matching rate of the two cell lines was 91%. Twenty-six differentially expressed protein spots were identified (twenty spots for MALDI-TOF-MS, six spots for ESI-Q-TOF MS/MS). Most of the characterized proteins were characterized as the members of enzymes (phosphoglycerate mutase, manganese superoxide dismutase, and so on), transcription proteins (rho gdp dissociation inhibitor), and so on. Those identified proteins might contribute to the tumor-suppressive function of LCRG1. The differential expression levels of the partial proteins were confirmed by real-time polymerase chain reaction and Western blotting. Conclusions: We tentatively proposed those differentially expressed proteins were involved in the tumor-suppressive process related to LCRG1. These data will be helpful to elucidate the molecular mechanism of LCRG1. [source] Diabetic rat testes: morphological and functional alterationsANDROLOGIA, Issue 6 2009G. Ricci Summary Reproductive dysfunction is a consequence of diabetes, but the underlying mechanisms are poorly understood. This study investigated the histological and molecular alterations in the testes of rats injected with streptozotocin at prepuperal (SPI rats) and adult age (SAI rats) to understand whether diabetes affects testicular tissue with different severity depending on the age in which this pathological condition starts. The testes of diabetic animals showed frequent abnormal histology, and seminiferous epithelium cytoarchitecture appeared altered as well as the occludin distribution pattern. The early occurrence of diabetes increased the percentage of animals with high number of damaged tubules. The interstitial compartment of the testes was clearly hypertrophic in several portions of the organs both in SPI and SAI rats. Interestingly, fully developed Leydig cells were present in all the treated animals although abnormally distributed. Besides the above-described damages, we found a similar decrease in plasma testosterone levels both in SPI and SAI rats. Oxidative stress (OS) is involved in the pathogenesis of various diabetic complications, and in our experimental models we found that manganese superoxide dismutase was reduced in diabetic animals. We conclude that in STZ-induced diabetes, the altered spermatogenesis, more severe in SPI animals, is possibly due to the effect of OS on Leydig cell function which could cause the testosterone decrease responsible for the alterations found in the seminiferous epithelium of diabetic animals. [source] Structures of two superoxide dismutases from Bacillus anthracis reveal a novel active centreACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 7 2005Ian W. Boucher The BA4499 and BA5696 genes of Bacillus anthracis encode proteins homologous to manganese superoxide dismutase, suggesting that this organism has an expanded repertoire of antioxidant proteins. Differences in metal specificity and quaternary structure between the dismutases of prokaryotes and higher eukaryotes may be exploited in the development of therapeutic antibacterial compounds. Here, the crystal structure of two Mn superoxide dismutases from B. anthracis solved to high resolution are reported. Comparison of their structures reveals that a highly conserved residue near the active centre is substituted in one of the proteins and that this is a characteristic feature of superoxide dismutases from the B. cereus/B. anthracis/B. thuringiensis group of organisms. [source] Comparative proteomic analysis between normal skin and keloid scarBRITISH JOURNAL OF DERMATOLOGY, Issue 6 2010C.T. Ong Summary Background, Keloids are pathological scars and, despite numerous available treatment modalities, continue to plague physicians and patients. Objectives, Identification of molecular mediators that contribute to this fibrotic phenotype. Methods, Two-dimensional gel electrophoresis, MALDI-TOF, Mascot online database searching algorithm and Melanie 5 gel analysis software were employed for comparative proteomic analysis between normal skin (NS) and keloid scar (KS) tissue extracts. Results, Seventy-nine protein spots corresponding to 23 and 32 differentially expressed proteins were identified in NS and KS, respectively. Isoforms of heat shock proteins, gelsolin, carbonic anhydrase and notably keratin 10 were strongly expressed in NS along with manganese superoxide dismutase, immune components, antitrypsin, prostatic binding protein and crystalline. Various classes of proteins were found either to be present or to be upregulated in keloid tissue: (i) inflammatory/differentiated keratinocyte markers: S100 proteins, peroxiredoxin I; (ii) wound healing proteins: gelsolin-like capping protein; (iii) fibrogenetic proteins: mast cell ,-tryptase, macrophage migration inhibitory factor (MIF); (iv) antifibrotic proteins: asporin; (v) tumour suppressor proteins: stratifin, galectin-1, maspin; and (vi) antiangiogenic proteins: pigment epithelium-derived factor. Significant increases in expression of asporin, stratifin, galectin-1 and MIF were observed by Western blot analysis in KS. Conclusions, This work has identified differentially expressed proteins specific to KS tissue extracts which can potentially be used as specific targets for therapeutic intervention. [source] Stochasticity of Manganese Superoxide Dismutase mRNA Expression in Breast Carcinoma Cells by Molecular Beacon ImagingCHEMBIOCHEM, Issue 11 2005Timothy J. Drake Abstract Visual and quantitative monitoring of cell-to-cell variation in the expression of manganese superoxide dismutase (MnSOD) mRNA by using novel ratiometric imaging with molecular beacons (MB) reveals a distinct change in patterns following induction of human breast-carcinoma cells with lipopolysaccharide. Interestingly, the pattern of cell-to-cell variation in a cell line stably transfected with a plasmid bearing a cDNA clone of MnSOD and overproducing the enzyme is significantly different from the pattern associated with MnSOD induction. The levels and the patterns of cell-population heterogeneity for ,-actin mRNA expression do not show distinct changes either following induction or in stably transfected cells. These results are significant in light of the reported relationship between this enzyme and malignant phenotype of breast-carcinoma cells. Use of MBs in ratiometric image analyses for cytoplasmic mRNAs represents a novel means of directly examining the stochasticity of transcription of MnSOD and other genes implicated in cellular phenotype regulation. [source] Functional analysis of mutants of the optineurin gene, associated with some forms of glaucomaACTA OPHTHALMOLOGICA, Issue 2008D BALASUBRAMANIAN Purpose Mutations in the gene OPTN are associated with normal tension and open angle glaucomas. We have studied the effects of some of these mutations on the cellular biology of retinal ganglion cells, and tried to infer the role of the protein optineurin. Methods We transfected plasmids expressing normal or wild-type (WT) and E50K, R545Q, H26D, and H486R mutant optineurin into a variety of cells such as HeLa, COS-1, retinal pigment epithelial (RPE), and the rat retinal ganglion cell (RGC) line RGC-5, and followed their effects on cell survival by morphologic observation of cells. Expression of optineurin and its mutants was monitored by immunofluorescence staining of cells and by Western blotting. Results The E50K mutant of optineurin, which is associated with the severest phenotype, was seen to selectively induce the death of retinal ganglion cells but not of the other cell lines tested. Neither the wild type cDNA nor the other mutants have any such effect. This cell death induced by E50K OPTN was inhibited by the antioxidants N-acetylcysteine and Trolox. E50K was seen to generate reactive oxygen species (ROS), which were reduced by antioxidants. Coexpression of manganese superoxide dismutase with the E50K mutant abolished ROS production and inhibited cell death. Conclusion E50K optineurin is a gain of function mutant, which has acquired the ability to induce cell death selectively in retinal ganglion cells. This cell death was mediated by oxidative stress. The present findings suggest the possibility of antioxidant use for delaying or controlling some forms of glaucoma. [source] | ||||||||||||||||