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11.
Tumor necrosis factor a (TNFalpha) and manganese superoxide dismutase (MnSOD) are thought to play critical roles in the process of lung injury, repair, and disease. The induction of TNFalpha and MnSOD were examined in a model of progressive pulmonary fibrosis along the length of the alveolar duct in rats exposed for 1, 5, and 8 weeks to a combination of 0.8 ppm ozone and 14.4 ppm nitrogen dioxide. This oxidant injury model results in a triphasic response with an initial inflammatory stage during weeks 1-3, followed by a partial resolution at weeks 4-5, and a final stage of rapidly progressive fibrosis during weeks 6-8. Changes in TNFalpha and MnSOD labeling for the proximal and distal alveolar ducts of the lungs were quantified using immunohistochemistry and morphometric techniques at 1, 5, and 8 weeks of exposure. A significant elevation in MnSOD was noted in alveolar macrophages and interstitial cells of the proximal and distal portions of the alveolar duct following 8 weeks of exposure. Labeling for TNFalpha only in the proximal region of the alveolar duct, was significantly increased in alveolar macrophages after 1 and 8 weeks of exposure, while a significant increase in TNFalpha labeling of interstitial cells in proximal regions was noted at all time points. We conclude that MnSOD is elevated in areas of focal injury as well as the more distal protected areas of the lungs, while TNFalpha correlates strongly with both the temporal and spatial aspects of greatest cellular injury in the lungs. 相似文献
12.
Melissa M. Page Jean Richardson Brent E. Wiens Esther Tiedtke Craig W. Peters Paul A. Faure Gary Burness Jeffrey A. Stuart 《Age (Dordrecht, Netherlands)》2010,32(2):255-270
The free radical theory of ageing posits that accrual of oxidative damage underlies the increased cellular, tissue and organ
dysfunction and failure associated with advanced age. In support of this theory, cellular resistance to oxidative stress is
highly correlated with life span, suggesting that prevention or repair of oxidative damage might indeed be essential for longevity.
To test the hypothesis that the prevention of oxidative damage underlies longevity, we measured the activities of the five
major intracellular antioxidant enzymes in brain, heart and liver tissue of 14 mammalian and avian species with maximum life
spans (MLSPs) ranging from 3 years to over 100 years. Our data set included Snell dwarf mice in which life span is increased
by ∼50% compared to their normal littermates. We found that CuZn superoxide dismutase, the major cytosolic superoxide dismutase,
showed no correlation with MLSP in any of the three organs. Similarly, neither glutathione peroxidase nor glutathione reductase
activities correlated with MLSP. MnSOD, the sole mitochondrial superoxide dismutase in mammals and birds, was positively correlated
with MLSP only for brain tissue. This same trend was observed for catalase. For all correlational data, effects of body mass
and phylogenetic relatedness were removed using residual analysis and Felsenstein’s phylogenetically independent contrasts.
Our results are not consistent with a causal role for intracellular antioxidant enzymes in longevity, similar to recent reports
from studies utilising genetic modifications of mice (Pérez et al., Biochim Biophys Acta 1790:1005–1014, 2009). However, our results indicate a specific augmentation of reactive oxygen species neutralising activities in brain associated
with longevity. 相似文献
13.
Hitzeroth A Niehaus DJ Koen L Botes WC Deleuze JF Warnich L 《Progress in neuro-psychopharmacology & biological psychiatry》2007,31(3):664-672
Reactive oxygen species (ROS)-mediated damage has been hypothesized to play a role in the development and poor outcome of schizophrenia, as well as the development of neuroleptic-induced abnormal involuntary movements. Recently, the functional polymorphism (Ala-9Val) in the manganese superoxide dismutase (MnSOD) gene (part of the antioxidant defense mechanism) was found to be associated with schizophrenia in a Turkish population. This study was aimed at replicating this finding in a Xhosa population. In addition, the role of Ala-9Val in abnormal involuntary movement and tardive dyskinesia development in the Xhosa population was also investigated. The schizophrenic patient group (n=286) and a healthy control group (n=243) were genotyped for the Ala-9Val polymorphism using heteroduplex-single stranded conformational polymorphism (HEX-SSCP) analysis. No significant difference in genotype or allele frequency could be observed between the schizophrenia and control group (P=0.294 and P=0.528 respectively). In addition no association could be found between the polymorphism and symptom severity (SANS and SAPS). The Xhosa schizophrenia patient group with abnormal involuntary movements (n=54) and a subgroup with tardive dyskinesia (n=30) was found to significantly differ in Ala-9Val genotype frequency (P=0.008 and P=0.011 respectively) compared to the Xhosa schizophrenia patient group without abnormal involuntary movements (n=204). However, no significant difference was found for the allele frequencies (P=0.955 and P=0.161). Further, using ANCOVA no association was found between AIMS score and genotype in the group with abnormal involuntary movements (P=0.1234). However, in the patient group with tardive dyskinesia an association was observed between genotype and AIMS score (P=0.0365). These results do not support a major role of the MnSOD Ala-9Val polymorphism in the development of schizophrenia or symptom severity in the Xhosa population. Yet it seems to be involved in the development of abnormal involuntary movements and tardive dyskinesia and may even modulate the severity of tardive dyskinesia. 相似文献
14.
The role of obesity and related metabolic disturbances in cancers of the colon, prostate, and pancreas 总被引:1,自引:0,他引:1
Recent evidence indicates that obesity and related metabolic abnormalities are associated with increased incidence or mortality for a number of cancers, including those of the colon, prostate, and pancreas. Obesity, physical inactivity, visceral adiposity, hyperglycemia, and hyperinsulinemia are relatively consistent risk factors for colon cancer and adenoma. Also, patients with type 2 diabetes mellitus have a higher risk of colon cancer. For prostate cancer, the relationship to obesity appears more complex. Obesity seems to contribute to a greater risk of aggressive or fatal prostate cancer but perhaps to a lower risk of nonaggressive prostate cancer. Furthermore, men with type 2 diabetes mellitus are at lower risk of developing prostate cancer. Long-standing type 2 diabetes increases the risk of pancreatic cancer by approximately 50%. Furthermore, over the past 6 years, a large number of cohort studies have reported positive associations between obesity and pancreatic cancer. Together with data from prediagnostic blood specimens showing positive associations between glucose levels and pancreatic cancer up to 25 years later, sufficient evidence now supports a strong role for diabetes and obesity in pancreatic cancer etiology. The mechanisms for these associations, however, remain speculative and deserve further study. Hyperinsulinemia may be important, but the role of oxidative stress initiated by hyperglycemia also deserves further attention. 相似文献
15.
Zhang Y Qin X Zhang Y Zhao L Wang Y Liu X Yao L 《Journal of cancer research and clinical oncology》2008,134(2):219-226
Purpose ZD55-MnSOD is an E1B 55 kDa-deleted replication-competent adenovirus and armed with the therapeutic gene MnSOD. The expression
of the therapeutic gene MnSOD increases with the selective replication of the oncolytic adenovirus (ZD55) so that ZD55-MnSOD
has more significant activity than the replicate defective adenovirus Ad-MnSOD in vitro and in vivo. The tumor cannot be completely
eradicated only with ZD55-MnSOD, although ZD55-MnSOD has obvious antitumor activity. 5-fluorouracil (5-FU) is still the most
effective adjuvant therapy for patients with colorectal cancer.
Methods We reasoned that combined treatment of cancer cells with ZD55-MnSOD and 5-FU might have a synergistic effect. In vitro experiments
with SW620 colorectal carcinoma cell line demonstrated that it was sensitive to ZD55-MnSOD, especially most sensitive to ZD55-MnSOD
plus 5-FU treatment. Treatment with both ZD55-MnSOD and 5-FU could induce more significant apoptosis in cancer cells compared
with ZD55-MnSOD or 5-FU alone, respectively. A better antitumor activity was observed by ZD55-MnSOD plus 5-fluorouracil (5-FU)
treatment. Tumor growth was greatly inhibited by this combined treatment, and animal survival time increased.
Conclusion These results show that, by using the combination therapies, a significant decrease in tumor mass can be achieved, which suggest
that ZD55-MnSOD in combination with 5-FU may have potential clinical implications. 相似文献
16.
Uncoupling proteins (UCPs) are mitochondrial transporters present in the inner membrane of mitochondria. They belong to the family of anion mitochondrial carriers. UCPs could act as proton carriers activated by metabolites and create a shunt between complexes of the respiratory chain and ATP synthase. The increased leakiness of the mitochondrial inner membrane to protons may be to minimize superoxide production by limiting the maximum Deltamu(H+). The purpose of this study was to detect UCP expression in retinal capillary cells and their modification in high levels of glucose. The role of reactive oxygen species (ROS) of mitochondria and UCPs in pathogenesis of diabetic retinopathy was investigated. Bovine retinal capillary endothelial cells and pericytes were cultured with selective culture media, respectively. Passage cells were cultured in three different glucose concentrations (5, 23, 30 mM) until passage four. ROS changes in mitochondria of these cells in different glucose concentrations were detected with scanning laser confocal microscopy (SLCM). The mitochondria membrane potential (Deltapsi), cell death rate and apoptosis rate were measured with flowing cytometry. UCP expression in retinal capillary cells was detected by immunocytochemistry. Expression and modification of MnSOD and uncoupling proteins (UCPs) in different concentrations of glucose were detected by means of semi-quantitative RT-PCR. ROS in mitochondria of both endothelial cells and pericytes increased as the glucose concentration of media increased. Deltapsi and cell death rate of endothelial cells increased also. ROS was correlated to Deltapsi and cell death rate positively in endothelial cells. No difference in Deltapsi and cell death rate among different glucose levels was found in pericytes. Apoptosis rate of endothelial cells and pericytes in high glucose levels was higher than that in lower glucose levels. UCP1 and UCP2 were expressed in cultured retinal capillary cells whereas UCP3 was not. At high levels of glucose, expression of UCP1, UCP2 and MnSOD increased to accommodate ROS production compensatively. The compensative mechanism disappeared when glucose concentration was too high (30 mM). The results of this study showed that increasing mitochondrial ROS could be induced by high glucose concentration. Those proteins related to antioxidation mechanism, such as MnSOD and UCPs, could exert compensative action to a certain extent. This compensative action was insufficient when the glucose concentration was too high. 相似文献
17.
A neuronal model of Alzheimer's disease: an insight into the mechanisms of oxidative stress-mediated mitochondrial injury 总被引:2,自引:0,他引:2
Sompol P Ittarat W Tangpong J Chen Y Doubinskaia I Batinic-Haberle I Abdul HM Butterfield DA St Clair DK 《Neuroscience》2008,153(1):120-130
Alzheimer's disease (AD) is associated with beta-amyloid accumulation, oxidative stress and mitochondrial dysfunction. However, the effects of genetic mutation of AD on oxidative status and mitochondrial manganese superoxide dismutase (MnSOD) production during neuronal development are unclear. To investigate the consequences of genetic mutation of AD on oxidative damages and production of MnSOD during neuronal development, we used primary neurons from new born wild-type (WT/WT) and amyloid precursor protein (APP) (NLh/NLh) and presenilin 1 (PS1) (P264L) knock-in mice (APP/PS1) which incorporated humanized mutations in the genome. Increasing levels of oxidative damages, including protein carbonyl, 4-hydroxynonenal (4-HNE) and 3-nitrotyrosine (3-NT), were accompanied by a reduction in mitochondrial membrane potential in both developing and mature APP/PS1 neurons compared with WT/WT neurons suggesting mitochondrial dysfunction under oxidative stress. Interestingly, developing APP/PS1 neurons were significantly more resistant to beta-amyloid 1-42 treatment, whereas mature APP/PS1 neurons were more vulnerable than WT/WT neurons of the same age. Consistent with the protective function of MnSOD, developing APP/PS1 neurons have increased MnSOD protein and activity, indicating an adaptive response to oxidative stress in developing neurons. In contrast, mature APP/PS1 neurons exhibited lower MnSOD levels compared with mature WT/WT neurons indicating that mature APP/PS1 neurons lost the adaptive response. Moreover, mature APP/PS1 neurons had more co-localization of MnSOD with nitrotyrosine indicating a greater inhibition of MnSOD by nitrotyrosine. Overexpression of MnSOD or addition of MnTE-2-PyP(5+) (SOD mimetic) protected against beta-amyloid-induced neuronal death and improved mitochondrial respiratory function. Together, the results demonstrate that compensatory induction of MnSOD in response to an early increase in oxidative stress protects developing neurons against beta-amyloid toxicity. However, continuing development of neurons under oxidative damage conditions may suppress the expression of MnSOD and enhance cell death in mature neurons. 相似文献
18.
目的 探讨抗氧化剂白藜芦醇(Res)对低浓度H2 O2处理的佐剂性关节炎(AA)大鼠成纤维样滑膜细胞(FLS)增殖的抑制作用.方法 弗氏完全佐剂足趾皮下注射SD雄性大鼠,建立AA模型,14 d后股动脉放血处死AA大鼠,取血清检测氧化应激指标,组织块培养法培养大鼠滑膜细胞,CCK-8法观察不同浓度的H2O2对FLS的增殖影响,Western blot法检测氧化应激相关蛋白去乙酰化酶3(SIRT3)、锰超氧化物歧化酶(MnSOD)蛋白的表达.结果 AA模型大鼠血清氧化应激指标升高,体外实验表明,随着Res的浓度增加,低浓度H2O2处理的AA大鼠FLS增殖受抑制,SIRT3、MnSOD蛋白表达降低.结论 Res可减轻AA大鼠体内的氧化应激状态,机制与降低抗氧化应激蛋白SIDT3、MnSOD的表达有关. 相似文献
19.
20.
目的:研究肝切除术后小鼠肝再生过程中锰超氧化物歧化酶(MnSOD)的表达及其活性的变化,探讨MnSOD在肝再生中的作用。方法:采用经典小鼠肝切除模型,将38只雄性BALB/c小鼠,随机分为30%肝切除组(30% PH组)18只,70%肝切除组(70% PH组)18只,以及对照组2只。2个肝切除组分别于术后6 h和1、2、3、5、7 d这6个时间点随机各抽取3只小鼠处死,对照组小鼠在行假手术后即处死。取肝组织,制备冰冻切片使用DHE染色法在激光共聚焦显微镜下检测活性氧(ROS)水平,实时荧光定量PCR检测小鼠肝组织中MnSOD mRNA表达水平,Western blot检测小鼠肝组织中MnSOD蛋白的表达水平,采用MnSOD试剂盒检测小鼠肝组织中的MnSOD活性。结果:肝切除术后,与对照组相比,30% PH组小鼠肝组织ROS水平在术后6 h和1 d增加,MnSOD mRNA表达水平增加(P < 0.05),MnSOD蛋白含量无显著变化(P > 0.05);MnSOD的活性在术后第1和2天较高,第3和5天较低,第7天恢复。70% PH组小鼠肝组织ROS水平在术后第1~5天均升高,MnSOD mRNA的水平先下降后逐渐恢复,MnSOD的蛋白含量降低,MnSOD的活性在术后第6小时和1天增加,第2~7天均处于降低状态(P均 < 0.05)。结论:在肝切除术后小鼠的肝再生过程迅速启动,尤其是在70% PH后肝细胞迅速增殖,并在术后一段时间逐渐恢复到静息状态,其机制可能与MnSOD含量和活性的下调从而导致ROS升高有关。 相似文献