BACKGROUND & AIMS: BACKGROUND:Despite familial clustering of nephropathy and retinopathy severity in type 1 diabetes, few gene variants have been consistently associated with these outcomes. RESEARCH DESIGN AND METHODS:We performed an individual-based genetic association study with time to renal and retinal outcomes in 1,362 white probands with type 1 diabetes from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. Specifically, we genotyped 1,411 SNPs that capture common variations in 212 candidate genes for long-term complications and analyzed them for association with the time from DCCT baseline to event for renal and retinal outcomes using multivariate Cox proportion hazards models. To address multiple testing and assist interpretation of the results, false discovery rate q values were calculated separately for each outcome. RESULTS:We observed association between rs17880135 in the 3' region of superoxide dismutase 1 (SOD1) and the incidence of both severe nephropathy (hazard ratio [HR] 2.62 [95% CI 1.64-4.18], P = 5.6 x 10(-5), q = 0.06) and persistent microalbuminuria (1.82 [1.29-2.57], P = 6.4 x 10(-4), q = 0.46). Sequencing and fine-mapping identified additional SOD1 variants, including rs202446, rs9974610, and rs204732, which were also associated (P < 10(-3)) with persistent microalbuminuria, whereas rs17880135 and rs17881180 were similarly associated with the development of severe nephropathy. Attempts to replicate the findings in three cross-sectional case-control studies produced equivocal results. We observed no striking differences between risk genotypes in serum SOD activity, serum SOD1 mass, or SOD1 mRNA expression in lymphoblastoid cell lines. CONCLUSIONS:Multiple variations in SOD1 are significantly associated with persistent microalbuminuria and severe nephropathy in the DCCT/EDIC study.

背景与目标：

BACKGROUND & AIMS: :In a search for iron-regulated proteins of Aspergillus nidulans and Aspergillus fumigatus a 16-kDa protein was identified which is about 5-fold upregulated during iron starvation in both species and which can be approximately 500-fold enriched by simple one-step chromatography on Amberlite XAD-16 resin. N-terminal protein sequence analysis and cloning of the respective A. nidulans cDNA identified this protein as a Cu/Zn-superoxide dismutase (SODA). Northern analysis revealed that upregulation of sodA expression occurs at the level of transcript accumulation. This seems to be a specific low iron response and not a general starvation answer since sodA transcript levels do not respond to carbon or nitrogen starvation. In contrast, copper depletion leads to transcriptional downregulation of sodA. Furthermore, sodA expression was found still to be subject to iron regulation in an A. nidulans mutant lacking SREA, a regulator of iron homeostasis, indicating that sodA expression is regulated by an SREA-independent mechanism. The data presented suggest that SODA plays a protective role under iron deplete conditions.

背景与目标： : 在寻找构巢曲霉和烟曲霉的铁调节蛋白时，鉴定出一种16 kDa蛋白，该蛋白在两种物种的铁饥饿期间上调约5倍，并且可以通过简单的一步色谱法富集约500倍在Amberlite XAD-16树脂上。N末端蛋白序列分析和相应的A.Niddulans cDNA的克隆将该蛋白鉴定为Cu/Zn-超氧化物歧化酶 (SODA)。Northern分析表明，苏打表达的上调发生在转录本积累的水平上。这似乎是一种特定的低铁反应，而不是一般的饥饿答案，因为苏打水转录水平对碳或氮的饥饿没有反应。相反，铜的耗竭导致苏打的转录下调。此外，在缺乏铁稳态调节剂SREA的A.Niddulans突变体中，发现苏打表达仍受铁调节，这表明苏打表达受SREA独立机制的调节。提供的数据表明，苏打在铁耗尽条件下起着保护作用。

BACKGROUND & AIMS: BACKGROUND:Diffuse panbronchiolitis (DPB) is characterized by chronic neutrophil-mediated inflammation of the airway mediated by oxygen radical production. DPB can be controlled with low-dose and long-term erythromycin therapy based on its anti-inflammatory effect. OBJECTIVE:In this study, the antioxidant levels were analyzed as an anti-inflammatory effect of erythromycin in the patients. METHODS:We investigated the activity and protein level of an antioxidant enzyme, Cu, Zn-superoxide dismutase (SOD) in alveolar macrophages (AMs) of patients with DPB before and after erythromycin therapy. AMs were obtained from bronchoalveolar lavage fluid. RESULTS:There was no significant difference in the activity of Cu, Zn-SOD between normal subjects and untreated patients. Erythromycin therapy (600 mg/day) significantly increased the activity of the enzyme relative to that before therapy and normal subjects [18.2 units/10(6) cells (9.2-26.2) vs. 4.4 units/10(6) cells (1.1-9.3), p < 0.01 and 10.4 units/10(6) cells (2.4-20.6), p < 0.05, respectively]. Furthermore, the protein level of Cu, Zn-SOD in AMs in treated patients was significantly higher than in the other two groups [69.4 ng/10(6) cells (34.2-147.1) vs. 20.1 ng/ 10(6) cells (16.9-39.8) for untreated patients, p < 0.01 and 43.2 ng/10(6) cells (32.6-68.2) for normal subjects, p < 0.01], but the levels in the latter groups were not different. CONCLUSION:Our results suggest that one of the anti-inflammatory effects of erythromycin in DPB may be, in part, mediated by enhancement of antioxidant activity in AMs.

背景与目标：

BACKGROUND & AIMS: :Cationic fraction III from the lysosomes of normal human peripheral blood polymorphonuclear cells (PMNs) was found to contain superoxide generation enhancing protein (SGEP). Herein, we report on the influence of partially purified SGEP obtained from fraction III (subfractions III-5 and III-6), on various phagocytic functions of human PMNs. SGEP markedly enhanced intracellular bactericidal activity of human peripheral PMNs. The enhancement was time and dose dependent. It also reduced adhesiveness of the PMNs. SGEP did not influence chemotaxis, phagocytosis or phagocytic index. These findings are compatible with our original observation regarding superoxide generation enhancement properties of SGEP.

背景与目标： : 发现正常人外周血多形核细胞 (pmn) 溶酶体中的阳离子级分III含有超氧化物生成增强蛋白 (SGEP)。在本文中，我们报告了从级分III (亚级分III-5和III-6) 获得的部分纯化的SGEP对人pmn的各种吞噬功能的影响。SGEP显着增强了人外周pmn的细胞内杀菌活性。增强是时间和剂量依赖性的。它还降低了pmn的粘附性。SGEP不影响趋化性，吞噬作用或吞噬指数。这些发现与我们关于SGEP的超氧化物生成增强特性的原始观察结果兼容。

BACKGROUND & AIMS: :The phytochemical resveratrol, which is found in grapes and red wine, has been reported to have a variety of biological properties. It was shown in our previous research that introduction of additional hydroxyl groups into the stilbene structure increases the biological activity of resveratrol. In this study, the activity of 3,3',4,4',5,5'-hexahydroxystilbene (M8) was investigated in ZR-75-1, MDA-MB-231 and T47D human breast cancer cells. For evaluation of cytotoxic activity of M8, clonogenic and cell proliferation assays were used. The IC50 values obtained in the clonogenic assay were 0.846 microM for T47D, 8.53 microM for ZR-75-1 cells and 25.5 microM for MDA-MB-231, while IC50 values obtained in the cell proliferation assay were significantly higher: 90.1 microM, 98.4 microM, 127.8 microM for T47D, ZR-75-1 and MDA-MB-231 cells, respectively. Compound M8 caused the activation of caspase-8 in MDA-MB-231 cells (marker of extrinsic apoptotic pathway), while activities of caspase-9 (marker of intrinsic apoptotic pathway) and caspase-3 were increased in all 3 tested cell lines. Activation of caspase-9 and caspase-3 was connected with loss of mitochondrial potential and increase of p53, which could have an impact on downregulation of mitochondrial superoxide dismutase (MnSOD) seen in our experiments. MnSOD is a key enzyme providing antioxidative defense in mitochondria - the cellular center of reactive oxygen species' generation. Downregulation of MnSOD can therefore cause a significant decrease of antioxidant defense in cancer cells. An increase of oxidative stress conditions was suggested by loss of reduced glutathione in tested cells. Since cancer cells are usually under permanent oxidative stress, additional increased ROS generation as a result of the interaction of M8 with the mitochondrial respiratory chain and a decrease in oxidative defense can therefore be a promising method for selective elimination of cancer cells.

背景与目标： : 据报道，在葡萄和红酒中发现的植物化学白藜芦醇具有多种生物学特性。在我们先前的研究中表明，在二苯乙烯结构中引入额外的羟基可以提高白藜芦醇的生物活性。在这项研究中，在ZR-75-1，MDA-MB-231和T47D人乳腺癌细胞中研究了3,3 '，4,4'，5,5 '-六羟基二苯乙烯 (M8) 的活性。为了评估M8的细胞毒性活性，使用了克隆形成和细胞增殖测定法。在克隆形成测定中获得的IC50值为T47D的0.846微m、ZR-75-1细胞的8.53微m和MDA-MB-231的25.5微m，而在细胞增殖测定中获得的IC50值显著更高: 分别为T47D的90.1微m、98.4微m、127.8微m、ZR-75-1和MDA-MB-231细胞。化合物M8引起MDA-MB-231细胞中caspase-8的激活 (外源性凋亡途径的标记)，而caspase-9 (内源性凋亡途径的标记) 和caspase-3的活性在所有3种测试细胞系中均增加。caspase-9和caspase-3的激活与线粒体潜能的丧失和p53的增加有关，这可能对我们实验中看到的线粒体超氧化物歧化酶 (MnSOD) 的下调产生影响。MnSOD是在线粒体中提供抗氧化防御的关键酶-活性氧物种产生的细胞中心。因此，MnSOD的下调会导致癌细胞中抗氧化防御的显着降低。测试细胞中还原型谷胱甘肽的丢失提示氧化应激条件增加。由于癌细胞通常处于永久性氧化应激状态，因此，由于M8与线粒体呼吸链的相互作用以及氧化防御能力的降低，额外增加的ROS生成可能是选择性消除癌细胞的有希望的方法。

BACKGROUND & AIMS: :We have isolated a codominant Arabidopsis mutant, radical-induced cell death1 (rcd1), in which ozone (O(3)) and extracellular superoxide (O(2)(*)-), but not hydrogen peroxide, induce cellular O(2)(*)- accumulation and transient spreading lesions. The cellular O(2)(*)- accumulation is ethylene dependent, occurs ahead of the expanding lesions before visible symptoms appear, and is required for lesion propagation. Exogenous ethylene increased O(2)(*)--dependent cell death, whereas impairment of ethylene perception by norbornadiene in rcd1 or ethylene insensitivity in the ethylene-insensitive mutant ein2 and in the rcd1 ein2 double mutant blocked O(2)(*)- accumulation and lesion propagation. Exogenous methyl jasmonate inhibited propagation of cell death in rcd1. Accordingly, the O(3)-exposed jasmonate-insensitive mutant jar1 displayed spreading cell death and a prolonged O(2)(*)- accumulation pattern. These results suggest that ethylene acts as a promoting factor during the propagation phase of developing oxyradical-dependent lesions, whereas jasmonates have a role in lesion containment. Interaction and balance between these pathways may serve to fine-tune propagation and containment processes, resulting in alternate lesion size and formation kinetics.

背景与目标： : 我们已经分离出一个共显性的拟南芥突变体，自由基诱导的细胞死亡1 (rcd1)，其中臭氧 (O(3)) 和细胞外超氧化物 (O(2)(*)-)，但不是过氧化氢，诱导细胞O(2)(*) 积累和短暂扩散病变。细胞O(2)(*) 的积累是乙烯依赖性的，在可见症状出现之前发生在扩大的病变之前，并且是病变传播所必需的。外源乙烯增加了O(2)(*)-依赖性细胞死亡，而降冰片二烯在rcd1或乙烯不敏感突变体ein2和rcd1 ein2双突变体中的乙烯不敏感性对乙烯感知的损害阻止了O(2)(*)-积累和病变传播。外源茉莉酸甲酯抑制rcd1细胞死亡的传播。因此，暴露于O(3) 的茉莉酸酯不敏感的突变体jar1显示出扩散的细胞死亡和延长的O(2)(*) 积累模式。这些结果表明，在发展为氧自由基依赖性病变的传播阶段，乙烯起促进作用，而茉莉酸酯在病变遏制中起作用。这些途径之间的相互作用和平衡可能有助于微调传播和遏制过程，从而导致交替的病变大小和形成动力学。

BACKGROUND & AIMS: -2

背景与目标： -2

BACKGROUND & AIMS: :Extracellular superoxide dismutase (EC-SOD) is a major superoxide scavenger and may be important to normal vascular function and cardiovascular health. We analyzed family data from 610 healthy Australians to detect and quantify the effects of genes on normal variation in plasma levels of EC-SOD and to test for pleiotropy with plasma nitric oxide (NO) and apolipoprotein A-I (apoA-I). Using maximum-likelihood-based variance decomposition methods, we determined that sex, age, and plasma levels of HDL cholesterol, apoA-I, and creatinine accounted for 38.6% of the variance in plasma EC-SOD levels and that additive genes accounted for 35% (P<0.00002). Multivariate analyses of plasma levels of EC-SOD, NO(x) (a measure of basal NO production), and apoA-I detected significant genetic correlations, indicating pleiotropy between EC-SOD and apoA-I (genetic correlation [rho(G)]=-0.45) and between NO(x) and apoA-I (rho(G)=0.58) but not between EC-SOD and NO(x). Genes shared by EC-SOD and apoA-I account for 20% of the genetic variance and, respectively, 7% and 9% of the phenotypic variance in both traits. Shared genes also account for >33% of the genetic variance and 5% and 15% of the respective phenotypic variance in NO(x) and apoA-I. In healthy individuals, over a third of the variance in EC-SOD plasma levels is due to the additive effects of genes. Some genes influence EC-SOD and apoA-I levels. The same is true of NO(x) and apoA-I but not of EC-SOD and NO(x). These patterns of pleiotropy can guide subsequent attempts to identify the genes and physiological mechanisms underlying them.

背景与目标： : 细胞外超氧化物歧化酶 (ec-sod) 是主要的超氧化物清除剂，可能对正常的血管功能和心血管健康很重要。我们分析了来自610名健康澳大利亚人的家庭数据，以检测和量化基因对血浆ec-sod水平正常变化的影响，并测试血浆一氧化氮 (NO) 和载脂蛋白a-i (apoA-I) 的多效性。使用基于最大似然的方差分解方法，我们确定了性别，年龄和血浆HDL胆固醇，apoA-I和肌酐水平占血浆ec-sod水平方差的38.6%，而加性基因占35% (P<0.00002)。血浆ec-sod，NO(x) (基础NO产生的量度) 和apoa-i的血浆水平的多变量分析检测到显着的遗传相关性，指示ec-sod和apoa-i之间的多效性 (遗传相关性 [rho(G)]=-0.45) 和NO(x) 和apoa-i之间的多效性 (rho(G)= 0.58)，但不是ec-sod和NO(x) 之间的多效性。EC-SOD和apoA-I共有的基因分别占两个性状中遗传变异的20% 以及表型变异的7% 和9%。共享基因还占NO(x) 和apoA-I中遗传变异的> 33% 和各自表型变异的5% 和15%。在健康个体中，ec-sod血浆水平的变化超过三分之一是由于基因的加性作用。一些基因影响EC-SOD和apoA-I水平。NO(x) 和apoA-I也是如此，但EC-SOD和NO(x) 则不是。这些多效性模式可以指导随后尝试鉴定其基础的基因和生理机制。

BACKGROUND & AIMS: :Hydrogen peroxide production in yeast cells undergoing programmed cell death in response to acetic acid occurred in the majority of live cells 15 min after death induction and was no longer detectable after 60 min. Superoxide anion production was found later, 60 and 90 min after death induction when cells viability was 60 and 30%, respectively. In cells protected from death due to acid stress adaptation neither hydrogen peroxide nor superoxide anion could be observed after acetic acid treatment. The early production of hydrogen peroxide in cells in which survival was 100% could play a major role in acetic acid-induced programmed cell death signaling. Superoxide anion is assumed to be generated in cells already en route to acetic acid-induced programmed cell death.

背景与目标： : 在诱导死亡后15分钟，大多数活细胞都发生了对乙酸进行程序性细胞死亡的酵母细胞中过氧化氢的产生，并且在60分钟后不再检测到。当细胞活力分别为60和30% 时，在死亡诱导后60和90分钟发现超氧阴离子产生。在因酸胁迫适应而免于死亡的细胞中，乙酸处理后均未观察到过氧化氢和超氧阴离子。在100% 存活的细胞中早期产生过氧化氢可能在乙酸诱导的程序性细胞死亡信号传导中起主要作用。假定已经在乙酸诱导的程序性细胞死亡途中的细胞中产生了超氧阴离子。

BACKGROUND & AIMS: :The cellular and molecular mechanisms that underlie cardioprotection against I/R by anesthetic-induced preconditioning (APC) require further elucidation. Using isoflurane as a representative anesthetic, we evaluated the hypothesis that APC induces myocardial protection against I/R by attenuation of excessive reactive oxygen species and restoration of mitochondrial bioenergetics through postischemic up-regulation of manganese superoxide dismutase (MnSOD) expression and preservation of respiratory enzyme activity. Pentobarbital anesthetized open-chest Sprague-Dawley rats were subject to 30-min left coronary artery occlusion, followed by 120-min reperfusion. Before ischemia, rats were randomly assigned to receive 0.9% saline, two cycles of brief coronary artery occlusion and reperfusion, or a 30-min exposure to 1.0 minimum alveolar concentration isoflurane in the absence or presence of a specific mitochondrial adenosine triphosphate-sensitive potassium (KATP) channel blocker, 5-hydroxydecanoate; a membrane-permeable superoxide scavenger, 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl; or a NOS inhibitor, N(G)-nitro-L-arginine methyl ester. Isoflurane exposure induced an initial increase in myocardial superoxide (O2-), but not NO level. It also significantly decreased infarct size and restored mitochondrial respiratory enzyme activity or ATP production in I/R rat hearts, along with suppression of the O2- surge at reperfusion and increase in MnSOD expression or enzyme activity. These protective effects were abrogated by 5-hydroxydecanoate or 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl, but not by N(G)-nitro-L-arginine methyl ester pretreatment. These results suggest that opening of mitochondrial KATP channel, followed by O2- signaling, induces postischemic augmentation of MnSOD and preservation of mitochondrial respiratory enzyme activities, leading to attenuated cardiac O2- surge and restored ATP production during reperfusion, and underlie APC-induced cardioprotection.

背景与目标： : 麻醉诱导的预处理 (APC) 对I/R心脏保护的细胞和分子机制需要进一步阐明。使用异氟烷作为代表性麻醉剂，我们评估了以下假设: APC通过抑制过多的活性氧种类和线粒体生物能的恢复来诱导心肌对I/R的保护。通过有计划后上调锰超氧化物歧化酶 (MnSOD) 的表达和保留呼吸酶活性。对戊巴比妥麻醉的开胸Sprague-Dawley大鼠进行30分钟的左冠状动脉闭塞，然后进行120分钟的再灌注。缺血前，将大鼠随机分配接受0.9% 生理盐水，两个周期的短暂冠状动脉闭塞和再灌注，或在不存在或存在特定线粒体三磷酸腺苷敏感钾 (KATP) 通道阻滞剂5-羟基癸酸盐的情况下暴露于1.0最低肺泡浓度异氟烷30分钟; 膜可渗透的超氧化物清除剂，4-羟基-2,6，6-四甲基哌啶氧基; 或NOS抑制剂，N(G)-硝基-L-精氨酸甲酯。异氟烷暴露导致心肌超氧化物 (O2-) 的初始增加，但没有水平。它还显着减少了I/R大鼠心脏的梗塞面积并恢复了线粒体呼吸酶活性或ATP产生，并抑制了再灌注时的O2激增并增加了MnSOD表达或酶活性。这些保护作用通过5-羟基癸酸酯或4-羟基-2,6，6-四甲基哌啶氧基消除，但不通过N(G)-硝基-L-精氨酸甲酯预处理消除。这些结果表明，线粒体KATP通道的开放，随后是O2信号传导，可诱导MnSOD的缺血后增强和线粒体呼吸酶活性的保留，从而导致心脏O2激增减弱并在再灌注过程中恢复ATP的产生，并成为APC诱导的心脏保护的基础。

BACKGROUND & AIMS: :Besides nitric oxide (NO), NO synthases (NOS) also produce superoxide ((*)O(2)()), a primary reactive oxygen species involved in both cell injury and signaling. Neuronal NOS was first found to produce (*)O(2)(-) in vitro. Subsequent studies revealed (*)O(2)(-) generation as a common property of all NOS isoforms. Although NOS was originally shown to produce (*)O(2)(-) under defined conditions such as substrate or cofactor depletion, recent enzymatic studies found that the reduction of oxygen to (*)O(2)(-) is an obligatory step in NO synthesis. Tetrahydrobiopterin appears to play a key role in preventing (*)O(2)(-) release from the NOS oxygenase domain. On the other hand, the NOS reductase domain is also capable of producing significant amounts of (*)O(2)(-). Increasing evidence demonstrates that (*)O(2)(-) generation is involved in both physiological and pathological actions of NOS.

背景与目标： : 除一氧化氮 (NO) 外，NO合酶 (NOS) 还产生超氧化物 ((*)O(2)())，这是一种参与细胞损伤和信号传导的主要活性氧。首先发现神经元NOS在体外产生 (*)O(2)(-)。随后的研究表明 (*)O(2)(-) 生成是所有NOS亚型的共同属性。尽管最初显示NOS在定义的条件下 (例如底物或辅因子消耗) 产生 (*)O(2)(-)，但最近的酶研究发现，将氧还原为 (*)O(2)(-) 是NO合成的强制性步骤。四氢生物蝶呤似乎在防止 (*)O(2)(-) 从NOS加氧酶结构域释放中起关键作用。另一方面，NOS还原酶结构域也能够产生大量的 (*)O(2)(-)。越来越多的证据表明，(*)O(2)(-) 的产生与NOS的生理和病理作用有关。

BACKGROUND & AIMS: :The effects of physiological changes in estrogens and androgens on the erythrocyte antioxidant superoxide dismutase, catalase and glutathione peroxidase enzyme activities during the menstrual cycle were investigated in healthy eumenorrheic women. Blood samples were taken on alternate days from twelve normally cyclic women (age range: 20 to 27 years; mean age: 24.1 years) from the first day of one menstrual cycle until the first day of the subsequent one. Plasma was analyzed for FSH, LH, estradiol, progesterone, testosterone, free testosterone and androstenedione concentrations. Erythrocyte superoxide dismutase, catalase and glutathione peroxidase activities were evaluated on the same days and cycle length was standardized on the basis of the preovulatory estradiol peak. Significant cyclic phase-related changes were observed in glutathione peroxidase (P<0.05), with higher glutathione peroxidase activity levels from the late follicular to the early luteal phase compared with those found in the early follicular phase (P<0.001 and P<0.002 respectively). A significant positive correlation was observed between mean estradiol and glutathione peroxidase cycle-related variations (r=0.80, P<0.001), whereas no significant cycle phase-dependent changes were seen in superoxide dismutase and catalase. No effect of progesterone and androgens on the erythrocyte antioxidant enzyme system was documented. The findings indicate that physiological ovarian estradiol production during the menstrual cycle may have an important role in regulating erythrocyte glutathione peroxidase activity.

背景与目标： : 在健康的经期妇女中，研究了雌激素和雄激素的生理变化对月经周期中红细胞抗氧化超氧化物歧化酶，过氧化氢酶和谷胱甘肽过氧化物酶活性的影响。从一个月经周期的第一天到下一个月经周期的第一天，每隔几天从十二个正常周期的女性 (年龄范围: 20至27岁; 平均年龄: 24.1岁) 采集血液样本。分析血浆中FSH，LH，雌二醇，孕酮，睾丸激素，游离睾丸激素和雄烯二酮的浓度。在同一天评估红细胞超氧化物歧化酶，过氧化氢酶和谷胱甘肽过氧化物酶的活性，并根据排卵前雌二醇峰对周期长度进行标准化。在谷胱甘肽过氧化物酶中观察到显着的周期相关变化 (P<0.05)，与卵泡期早期相比，从卵泡晚期到黄体早期的谷胱甘肽过氧化物酶活性水平更高 (分别为P<0.001和P<0.002)。在平均雌二醇和谷胱甘肽过氧化物酶周期相关变化之间观察到显着的正相关 (r = 0.80，P<0.001)，而在超氧化物歧化酶和过氧化氢酶中未观察到显着的周期相依赖性变化。没有记录孕酮和雄激素对红细胞抗氧化酶系统的影响。研究结果表明，月经周期中生理性卵巢雌二醇的产生可能在调节红细胞谷胱甘肽过氧化物酶活性中起重要作用。

BACKGROUND & AIMS: :Cytosolic Cu/Zn superoxide dismutase (SOD1) is a ubiquitous small cytosolic metalloenzyme that catalyzes the conversion of superoxide anion to hydrogen peroxide (H(2)O(2)). Mutations in the SOD1 gene cause a familial form of amyotrophic lateral sclerosis (fALS). The mechanism by which mutant SOD1s causes ALS is not understood. Transgenic mice expressing multiple copies of fALS-mutant SOD1s develop an ALS-like motoneuron disease resembling ALS. Here we report that transgenic mice expressing a high concentration of wild-type human SOD1 (hSOD1(WT)) develop an array of neurodegenerative changes consisting of (1) swelling and vacuolization of mitochondria, predominantly in axons in the spinal cord, brain stem, and subiculum; (2) axonal degeneration in a number of long fiber tracts, predominantly the spinocerebellar tracts; and (3) at 2 years of age, a moderate loss of spinal motoneurons. Parallel to the development of neurodegenerative changes, hSOD1(WT) mice also develop mild motor abnormalities. Interestingly, mitochondrial vacuolization was associated with accumulation of hSOD1 immunoreactivity, suggesting that the development of mitochondrial pathology is associated with disturbed SOD1 turnover. In this study we also crossed hSOD1(WT) mice with a line of fALS-mutant SOD1 mice (hSOD1(G93A)) to generate "double" transgenic mice that express high levels of both wild-type and G93A mutant hSOD1. The "double" transgenic mice show accelerated motoneuron death, earlier onset of paresis, and earlier death as compared with hSOD1(G93A) littermates. Thus in vivo expression of high levels of wild-type hSOD1 is not only harmful to neurons in itself, but also increases or facilitates the deleterious action of a fALS-mutant SOD1. Our data indicate that it is important for motoneurons to control the SOD1 concentration throughout their processes, and that events that lead to improper synthesis, transport, or breakdown of SOD1 causing its accumulation are potentially dangerous.

背景与目标： : 胞质Cu/Zn超氧化物歧化酶 (SOD1) 是一种普遍存在的小胞质金属酶，催化超氧阴离子转化为过氧化氢 (H(2)O(2))。SOD1基因的突变会导致家族形式的肌萎缩性侧索硬化症 (fars)。突变体SOD1s引起ALS的机制尚不清楚。表达多个fALS突变体sod1的转基因小鼠会发展出类似于ALS的ALS样运动神经元疾病。在这里，我们报告了表达高浓度野生型人SOD1 (hSOD1(WT)) 的转基因小鼠会发生一系列神经退行性变化，包括 (1) 线粒体的肿胀和空泡化，主要在脊髓，脑干和下丘的轴突中; (2) 许多长纤维区的轴突变性，主要是脊髓小脑区; (3) 在2岁时，脊髓运动神经元的中度丧失。与神经退行性改变的发展平行，hSOD1(WT) 小鼠也发展为轻度运动异常。有趣的是，线粒体空泡化与hSOD1免疫反应性的积累有关，这表明线粒体病理的发展与干扰的SOD1转换有关。在这项研究中，我们还将hSOD1(WT) 小鼠与fALS突变型SOD1小鼠 (hSOD1(G93A)) 杂交，以产生 “双” 转基因小鼠，该小鼠同时表达高水平的野生型和G93A突变型hSOD1。与同窝hSOD1(G93A) 相比，“双” 转基因小鼠显示出加速的运动神经元死亡，轻瘫发作较早和死亡较早。因此，高水平的野生型hSOD1的体内表达不仅对神经元本身有害，而且还会增加或促进fars突变体sod1的有害作用。我们的数据表明，运动神经元在整个过程中控制SOD1浓度很重要，并且导致SOD1合成，运输或分解不当导致其积累的事件具有潜在的危险。

BACKGROUND & AIMS: :Red tide phytoplankton Chattonella marina is known to produce reactive oxygen species (ROS), such as superoxide anion (O(2)(-)), hydrogen peroxide (H(2)O(2)) and hydroxyl radical (&z.rad;OH), under normal physiological conditions. Although several lines of evidence suggest that ROS are involved in the mortality of fish exposed to C. marina, the mechanism of ROS generation in C. marina remains to be clarified. In this study, we found that the cell-free supernatant prepared from C. marina cells showed NAD(P)H-dependent O(2)(-) generation, and this response was inhibited by diphenyleneiodonium, an inhibitor of mammalian NADPH oxidase. When the cell-free supernatant of C. marina was analyzed by immunoblotting using antibody raised against the human neutrophil cytochrome b558 large subunit (gp91phox), a main band of approximately 110 kDa was detected. The cell surface localization of the epitope recognized with this antibody was also demonstrated in C. marina by indirect immunofluorescence. Furthermore, Southern blot analysis performed on genomic DNA of C. marina with a probe covering the C-terminal region of gp91phox suggested the presence of a single-copy gene coding for gp91phox homologous protein in C. marina. These results provide evidence for the involvement of an enzymatic system analogous to the neutrophil NADPH oxidase as a source of O(2)(-) production in C. marina.

背景与目标： : 赤潮浮游植物Chattonella marina已知在正常生理条件下会产生活性氧 (ROS)，例如超氧阴离子 (O(2)(-))，过氧化氢 (H(2)O(2)) 和羟基自由基 (& z.rad;OH)。尽管有几条证据表明ROS与暴露于C. marina的鱼类的死亡率有关，但C. marina中ROS生成的机制仍有待阐明。在这项研究中，我们发现由C. marina细胞制备的无细胞上清液显示NAD(P)H依赖性O(2)(-) 生成，并且这种反应被哺乳动物NADPH氧化酶的抑制剂二苯基乙二胺抑制。当使用针对人中性粒细胞细胞色素b558大亚基 (gp91phox) 产生的抗体通过免疫印迹分析C. marina的无细胞上清液时，检测到约110 kDa的主要条带。通过间接免疫荧光在C. marina中也证明了用该抗体识别的表位的细胞表面定位。此外，用覆盖gp91phox C末端区域的探针对C. marina的基因组DNA进行的Southern印迹分析表明，C. marina中存在编码gp91phox同源蛋白的单拷贝基因。这些结果为类似中性粒细胞NADPH氧化酶的酶系统作为C. marina中O(2)(-) 产生的来源的参与提供了证据。

BACKGROUND & AIMS: :The effect of human C-reactive protein (CRP) on macrophage function was studied in an assay of superoxide anion (O2-) production. Peritoneal exudate macrophages (PEM) of guinea pigs exposed in vitro to various doses of CRP for 72 hr resulted in the development of O2- production dose-dependently, measured by increases in superoxide dismutase-inhibitable nitro blue tetrazolium reduction. The O2--producing activity of PEM cultured without CRP, used as a control, decreased markedly in proportion to incubation time. The O2- production by PEM exposed to CRP for 18 hr when control PEM were still high in O2- production, was decreased by larger doses of CRP, while PEM cultured without CRP for 72 hr, when O2- production by control PEM was very low, followed by incubation with CRP for another 18 hr, produced O2- CRP-dose-dependently as in the case of that observed after 72-hr incubation with CRP. These results indicate that CRP is capable of activating macrophages and acts on macrophage function as a modulator. CRP possesses migration inhibitory factor (MIF)-like activity (as reported in the preceding paper) and also macrophage-activating factor (MAF)-like activity, indicating that CRP may play a functional role at the site of inflammation and tissue damage by accumulating and activating macrophages.

背景与目标： : 在超氧阴离子 (O2-) 产生的测定中研究了人C反应蛋白 (CRP) 对巨噬细胞功能的影响。豚鼠的腹膜渗出巨噬细胞 (PEM) 在体外暴露于各种剂量的CRP下72小时会导致剂量依赖性地产生O2，这是通过超氧化物歧化酶抑制硝基蓝四唑减少量的增加来衡量的。作为对照，没有CRP培养的PEM的O2产生活性与孵育时间成比例显着降低。当对照PEM的O2产生量仍然很高时，PEM暴露于CRP 18小时的O2产生量被较大剂量的CRP降低，而PEM在没有CRP的情况下培养了72小时，当对照PEM的O2产生量非常低，然后与CRP再孵育18小时，与CRP孵育72小时后观察到的情况一样，产生O2- CRP剂量依赖性。这些结果表明，CRP能够激活巨噬细胞，并作为调节剂作用于巨噬细胞功能。CRP具有迁移抑制因子 (MIF) 样活性 (如前一篇论文所述) 和巨噬细胞激活因子 (MAF) 样活性，表明CRP可能在炎症和组织损伤部位发挥功能作用通过积累和激活巨噬细胞。