内质网应激与氧化应激:恶性循环还是双刃剑?

目的综述内质网应激与氧化应激之间相互作用关系的研究进展。探讨氧化应激与内质网应激相互作用诱发相关疾病的机制。方法阅读国内外文献数据库中相关文献,尤其是近年来关于氧化应激与内质网之间关系的文献,结合临床,从疾病诱发机制等方面对文献进行整理和综述。结果根据疾病背景,促进细胞存活的治疗策略主要在于加强保护未折叠蛋白反应(UPR)信号响应,衰减内质网应激水平,或者灭活UPR促凋亡化合物;而从氧化应激出发,控制氧化应激水平,减弱内质网应激是控制疾病发作的重要方法。结论本文对两种应激关系的研究近况进行整理总结,为相关疾病发病机制的深入研究和临床应用提供理论依据。     

一体化护理对局部麻醉术患者心理及疼痛应激的影响

目的：探讨一体化护理对局部麻醉术患者心理及疼痛应激的影响。方法选取2010年10月~2013年12月本院收治的80例局部麻醉术患者为研究对象,将入选者随机分为对照组（常规手术护理组）40例和观察组（一体化护理组）40例,比较两组干预前后的Zung自评量表与疼痛自我评估结果。结果观察组护理干预后的Zung自评量表抑郁和焦虑评分分别为（46.21±4.96）分和（46.25±4.04）分,阳性率分别为50.00%和52.50%;术中及术后即刻的轻度疼痛率分别为95.00%和97.50%,均显著优于对照组,差异有统计学意义（P〈0.05）。结论一体化护理对局部麻醉术患者心理应激及疼痛应激的影响较大,更适用于局部麻醉术患者。     

单程延迟性应激诱导雌性大鼠创伤后应激障碍模型的建立

目的 采用雌性SD大鼠建立单程长时应激(SPS)模型,从表观效度和预测效度2方面考察其是否能作为创伤性应激障碍的动物模型。方法 雌性大鼠依次连续给予固定束缚(2 h)、强迫游泳(20 min)和乙醚麻醉各1次作为应激因子制备SPS模型,随后连续2周内每天1次ig 给予舍曲林10 mg·kg^-1。2周后给予足底电击刺激,次日环境重现,测定呆滞行为时间;高架十字迷宫实验测定进入开臂次数百分比和开臂滞留时间百分比;开场实验观察爬格次数和站立次数。结果 与正常对照组比较,模型组大鼠呆滞行为时间明显延长(P<0.01),进入开臂次数百分比和开臂滞留时间百分比显著降低(P<0.01);与模型组相比,舍曲林组大鼠呆滞行为时间显著降低,进入开臂次数百分比和开臂滞留时间百分比显著增加(P<0.05, P<0.01); 各组爬格次数和站立数与正常对照组无显著性差异。结论 通过SPS成功诱导建立雌性大鼠创伤性应激障碍动物模型。     

Enhanced oxidative stress in hypertrophic cardiomyopathy

Elevated plasma levels of inflammation and endothelial dysfunction markers have been reported in patients with hypertrophic cardiomyopathy (HCM). The aim of the current study was to determine whether HCM is associated with enhanced oxidative stress. We enrolled 54HCMpatients with sinus rhythm, including 21 subjects with a left ventricular outflow tract (LVOT) obstruction (gradient ≥ 30 mmHg), and 54 age- and sex-matched controls without cardiovascular diseases. Serum levels of 8-isoprostaglandin F_2α (8-iso-PGF_2α), a stable marker of oxidative stress, were determined.Serum 8-iso-PGF_2α levels were elevated in HCM patients compared with controls (35.4 ± 10.2 vs. 29.9 ± 9.9 pg/ml, p < 0.001). Patients with obstructiveHCMdisplayed higher 8-iso-PGF_2α levels compared with the non-obstructiveHCMsubgroup (41.6 ± 12.7 vs. 31.4 ± 5.4 pg/ml, p < 0.0001). Both anatomic (mitral-septal distance) and hemodynamic (subaortic gradient) indexes of LVOT obstruction, but not other echocardiographic variables, correlated with 8-iso-PGF_2α levels (r = –0.43; p < 0.05 and r = 0.39; p < 0.05, respectively).This study is the first to show that HCM is characterized by enhanced oxidative stress as evidenced by higher 8-iso-PGF_2α, which achieves its highest values in the presence of LVOT obstruction in HCM patients.     

Oxidative stress and stress signaling： menace of diabetic cardiomyopathy

Cardiovascular disease is the most common cause of death in the diabetic population and is currently one of the leading causes of death in the United States and other industrialized countries. The health care expenses associated with cardiovascular disease are staggering, reaching more than 350 billion dollars in 2003. The risk factors for cardiovascular disease include high fat/cholesterol levels, alcoholism, smoking, genetics, environmental factors and hypertension, which are commonly used to gauge an individual's risk of cardiovascular disease and to track their progress during therapy. Most recently, these factors have become important in the early prevention of cardiovascular diseases. Oxidative stress, the imbalance between reactive oxygen species production and breakdown by endogenous antioxidants, has been implicated in the onset and progression of cardiovascular diseases such as congestive heart failure and diabetes-associated heart dysfunction (diabetic cardiomyopathy). Antioxidant therapy has shown promise in preventing the development of diabetic heart complications. This review focuses on recent advances in oxidative stress theory and antioxidant therapy in diabetic cardiomyopathy, with an emphasis on the stress signaling pathways hypothesized to be involved. Many of these stress signaling pathways lead to activation of reactive oxygen species, major players in the development and progression of diabetic cardiomyopathy.     

Nicotine enantiomers and oxidative stress

Nicotine affects a variety of cellular processes ranging from induction of gene expression to secretion of hormones and modulation of enzymatic activities. The objective of this study was to characterize the toxicity of nicotine enantiomers as well as their ability to induce oxidative stress in an in vitro model using Chinese hamster ovary (CHO) cells. Colony formation assay has demonstrated that (−)-nicotine is the more toxic of the enantiomers. At 6 mM concentrations, (−)-nicotine was found to be ≈28- and 19-fold more potent than (+)-, and (±)-nicotine (racemic), respectively. Results also indicated that the toxicity of (±)-nicotine is higher than that of (+)-nicotine. (−)-Nicotine at a 10 mM concentration substantially decreased glutathione (GSH) levels (46% decrease). In addition, a 3-fold increase in malondialdehyde (MDA) level was evident in cells after exposure to 10 mM (−)-nicotine. Increased lactate dehydrogenase (LDH) activities in the media demonstrated that cellular membrane integrity was disturbed in nicotine treated cells. In the presence of superoxide dismutase (SOD) and catalase (CAT), the LDH activities returned to control value in 24 h with all concentrations of (−)-, (+)-, and (±)-nicotine. The decreases in LDH activities in the presence of the radical scavenging enzymes SOD and CAT suggest that membrane damage may be due to free radical generation.     

Thymoquinone protects rat liver after partial hepatectomy under ischaemia/reperfusion through oxidative stress and endoplasmic reticulum stress prevention

Ischaemia reperfusion (I/R) is associated with liver injury and impaired regeneration during partial hepatectomy (PH). The aim of this study was to investigate the effect of thymoquinone (TQ), the active compound of essential oil obtained from Nigella sativa seeds, on rat liver after PH. Male Wistar rats were divided equally into four groups (n = 6) receiving an oral administration of either vehicle solution (sham and PH groups) or TQ at 30 mg/kg (TQ and TQ + PH groups) for 10 consecutive days. Then, rats underwent PH (70%) with 60 minutes of ischaemia followed by 24 hours of reperfusion (PH and TQ + PH groups). Alanine aminotransferase (ALT) activity and histopathological damage were determined. Also, antioxidant parameters, liver regeneration index, hepatic adenosine triphosphate (ATP) content, endoplasmic reticulum (ER) stress and apoptosis were assessed. In response to PH under I/R, liver damage was significantly alleviated by TQ treatment as evidenced by the decrease in ALT activity (P < .01) and histological findings (P < .001). In parallel, TQ preconditioning increased hepatic antioxidant capacities. Moreover, TQ improved mitochondrial function (ATP, P < .05), attenuated ER stress parameters and repressed the expression of apoptotic effectors. Taken together, our results suggest that TQ preconditioning could be an effective strategy to reduce liver injury after PH under I/R. The protective effects were mediated by the increase of antioxidant capacities and the decrease of ER stress and apoptosis.     

Targeting oxidative stress in cancer

Importance of the field: Reactive oxygen species (ROS) occur as natural by-products of oxygen metabolism and have important cellular functions. Normally, the cell is able to maintain an adequate balance between the formation and removal of ROS either via anti-oxidants or through the use specific enzymatic pathways. However, if this balance is disturbed, oxidative stress may occur in the cell, a situation linked to the pathogenesis of many diseases, including cancer.

Areas covered in this review: HDACs are important regulators of many oxidative stress pathways including those involved with both sensing and coordinating the cellular response to oxidative stress. In particular aberrant regulation of these pathways by histone deacetylases may play critical roles in cancer progression.

What the reader will gain: In this review we discuss the notion that targeting HDACs may be a useful therapeutic avenue in the treatment of oxidative stress in cancer, using chronic obstructive pulmonary disease (COPD), NSCLC and hepatocellular carcinoma (HCC) as examples to illustrate this possibility.

Take home message: Epigenetic mechanisms may be an important new therapeutic avenue for targeting oxidative stress in cancer.     

Urinary biomarkers of oxidative/nitrosative stress in healthy smokers

Objective: To evaluate the effect of cigarette smoking on oxidative and nitrosative stress, we assessed urinary levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG), isoprostane 15-F_2t-IsoP, thiobarbituric acid-reacting substances (TBARS), advanced glycation end-products (AGEs), dityrosine (diTyr), hydrogen peroxide, total nitrite and nitrate and trolox equivalent antioxidant capacity (TEAC) in healthy smokers.

Methods: Fluorimetric and spectrophotometric assays were performed in urine samples of 33 healthy smokers and 58 age-matched controls.

Results: Levels of 8-OHdG, 15-F_2t-IsoP and AGES were found significantly higher in smokers than in controls (10.7?ng/mg Cr vs. 8.3?ng/mg Cr, 1.41?ng/mg Cr vs. 1.01?ng/mg Cr and 189 AFU/mg Cr vs. 143 AFU/mg Cr, respectively; P?<?0.05 for all). Positive correlations were found between age and levels of AGEs and diTyr in smokers (r?=?0.380, P?<?0.035 and r?=?0.418, P?<?0.019, respectively) and also between age and AGEs, diTyr and TEAC in controls (r?=?0.474, P?<?0.001, r?=?0.463, P?<?0.001 and r?=?0.576, P?<?0.001, respectively), being this correlation negative for 8-OHdG in controls (r?=??0.295, P?=?0.041). Positive correlation between the number of cigarettes smoked per day and AGEs was also found (r?=?0.355, P?=?0.044).

Conclusion: Urinary 8-OHdG, 15-F_2t-IsoP and AGEs may represent a non-invasive quantitative index of oxidant stress in healthy smokers, being AGEs a possible indicator of tobacco toxin exposure. The increased oxidative stress in healthy smokers observed may be generated because of an excessive production of reactive oxygen species and not by exhaustion of antioxidant defenses.     

Chronic life stress,acute stress events,and substance availability in relapse

This study evaluated additive and interactive models of the effects of acute stressful life events, chronic life stressors, and immediate substance availability on substance use following alcohol and drug treatment. One hundred and two veterans meeting DSM-IV criteria for alcohol, cannabis, or stimulant dependence at treatment entry completed quarterly interviews for one year. Severe chronic stressors and substance availability predicted an increased risk of initiating substance use posttreatment (OR?=?5.18 and 3.18, respectively). However, the chronic stressors and immediate substance availability were associated with less protracted substance use (F (2, 67)?=17.30, p?<?0.001). Substance availability also predicted fewer total drinks consumed. In contrast to chronic stressors, recent stressful life events were not predictive of posttreatment substance initiation or severity. None of the interactions between stress and substance availability were significant. These findings support a model where chronic stressors and substance availability independently add to the risk for alcohol or drug use following treatment.     

代谢型谷氨酸受体与应激损伤

代谢型谷氨酸受体 (mGluRs)在应激性损伤中的作用日益受到重视 ,它可参与GC水平的调节 ,影响谷氨酸神经毒性作用和突触可塑性 (LTP、LTD)的诱导 ,由此表明mGluRs在应激性损伤中可能占有重要的地位。由于不同类型的mGluRs具有不同的作用 ,机制较为复杂 ,因此 ,今后还需进一步加强mGluRs与应激性损伤关系的研究     

Diabetes mellitus: oxidative stress and wine

SUMMARY

This review focuses on the link between diabetes mellitus and oxidative stress and, in particular, on the role that moderate wine consumption may play in preventing diabetic complications and the onset of diabetes. With this aim, a search of PubMed was carried out for literature published up to March

In diabetes mellitus, oxidative stress results both from exposure to hyperglycaemia through glycoxidation and sorbitol system activation, and from functional limitation of the hexose monophosphate shunt, leading to a decrease in glutathione synthesis.

Oxidative stress alters the plasma lipoprotein profile (particularly low- density lipoproteins), the coagulative parameters (with an increased thrombotic risk), the endothelium (with a decrease in prostacyclin synthesis and an increase of thromboxane production) and the cell membranes (which undergo peroxidation). In diabetic patients, an altered oxidative pattern is present not only in the fasting state but also especially after food intake. In particular, food intake induces a decrease

in the total radical-trapping antioxidant parameter (TRAP) and an elevation of hydroperoxides and thiobarbituric acid reactive substances (TBARS).

Previously several clinical trials tried to improve the diabetic oxidative status using α-tocopherol, ascorbic acid and β-carotene supplementation. Some authors found, in normal subjects, a reduction of hydroperoxides postprandially when the meal included red wine. Other authors showed that the oxidative pattern present in type 2 diabetic patients was mitigated by red wine. These actions may reduce cardiovascular risk. Moreover, an inverse relationship was observed between alcohol consumption and the incidence of type 2 diabetes; this relationship was valid for a light to moderate intake and it seemed to depend on drinking regularly and to be independent of the type of alcoholic beverage.

In conclusion, moderate and regular wine consumption could ameliorate the diabetic oxidative status. This lifestyle measure might contribute to preventing diabetic complications and the onset of diabetes.     

Oxidative stress status in patients with melasma

Background: Melasma is an acquired skin disease characterized clinically by development of gray–brown macules or patches. The lesions have geographic borders and most often seen on face and less frequently on the neck and forearms. Pathogenesis has not been completely understood yet. Although the disease constitutes a very disturbing cosmetic problem, it has not obtained an efficient treatment. There were not any studies in the literature that evaluates the role of oxidative stress in melasma.

Objectives: The evaluation of the role of oxidative stress in melasma.

Methods: Fifty melasma patients and 50 healthy volunteers were included in the study. The diagnosis was made clinically and the patients were evaluated by Melasma Area Severity Index. Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) enzyme activities and malondialdehyde, nitric oxide, protein carbonyl levels were measured both in the melasma group and the control group.

Results: SOD and GSH-Px enzyme activities were significantly higher in the patient group in comparison with the control group (p?p?Conclusion: The results show that the balance between oxidant and anti-oxidants was disrupted and the oxidative stress increased in melasma. These results improve the understanding of etiology–pathogenesis of the disease and its treatment.     

Endocrine and cardiovascular responses to a series of graded physical and psychological stress stimuli in healthy volunteers

To investigate the endocrine and cardiovascular responses to a series of psychological and physical stress stimuli and to investigate the possibility of a stimulus intensity-response relation of endocrine and cardiovascular reactivity, 18 healthy volunteers were exposed to psychological and physical stimuli of increasing intensity. Each volunteer participated in three experimental sessions on separate days. The sequence of the sessions was such that all volunteers first participated in a session in which they were not exposed to a stress stimulus, i.e. the control session. Then they were randomly assigned to enter two trial sessions in which they were consecutively exposed to a series of psychological stressors and a series of physical stressors. During each session blood pressure (BP) and heart rate (HR) were assessed and blood samples were taken, to determine cortisol and noradrenaline levels.

During the physical stress session increments in systolic and diastolic blood pressure and noradrenaline were observed, proportional to the intensity of the stimuli. In contrast, during the psychological stress session pronounced increments in heart rate were observed, with maximum responses at the second and third stimuli. Diastolic blood pressure responses showed a similar pattern, whereas no changes in noradrenaline were observed. Plasma cortisol was not increased by the psychological stressor, whereas it was stimulated by the physical stressor but at the highest stimulus intensity only. Although the size of the study population precludes any firm conclusions, the results suggest that a stimulus intensity approach in human stress research is possible. Furthermore, the results also appear to indicate that the cardiovascular and pituitary-adrenal systems may display stress-specific responses.     

Endothelial cationic amino acid transporter‐1 overexpression blunts the effects of oxidative stress on pressor responses to behavioural stress in mice

Observational studies indicate that psychological stress may contribute to the pathogenesis of hypertension and this may be further accentuated by factors such as endothelial dysfunction. On this basis, we aimed to determine whether oxidative stress enhances pressor responses to stressful stimuli and whether augmenting endothelial function by increasing the transport of l ‐arginine can counter the effects of oxidative stress. Telemetry probes were used to measure mean arterial pressure (MAP) in wild‐type (WT; n = 6) and endothelial cationic amino acid transporter‐1 (CAT‐1)‐overexpressing (CAT+) mice (n = 6) before and during an aversive (restraint) and non‐aversive (almond feeding) stressor. The superoxide dismutase inhibitor diethyldithiocarbamic acid (DETCA; 30 mg/kg per day; 14 days) was then administered via a minipump to induce oxidative stress. Stress responses to feeding and restraint were repeated during Days 11–12 of DETCA infusion. In WT mice, pressor responses to restraint and feeding were augmented during infusion of DETCA (35 ± 1 and 28 ± 1 mmHg, respectively) compared with respective pretreatment responses (28 ± 2 and 24 ± 1 mmHg, respectively; P ≤ 0.01). In CAT+ mice, pressor responses to feeding were blunted during DETCA (20 ± 1 mmHg) compared with the control response (23 ± 1 mmHg; P = 0.03). In these mice, pressor responses to restraint were similar before (28 ± 1 mmHg) and during (26 ± 1 mmHg) DETCA infusion (P = 0.26). We conclude that endothelial CAT‐1 overexpression can counter the ability of oxidative stress to augment pressor responses to behavioural stress.     

DON shares a similar mode of action as the ribotoxic stress inducer anisomycin while TBTO shares ER stress patterns with the ER stress inducer thapsigargin based on comparative gene expression profiling in Jurkat T cells

Previously, we studied the effects of deoxynivalenol (DON) and tributyltin oxide (TBTO) on whole genome mRNA expression profiles of human T lymphocyte Jurkat cells. These studies indicated that DON induces ribotoxic stress and both DON and TBTO induced ER stress which resulted into T-cell activation and apoptosis. The first goal of the present study was to provide final proof for these mode of actions by comparing the effects of 6 h exposure to DON and TBTO on mRNA expression to those of positive controls of ribotoxic stress (anisomycin), ER stress (thapsigargin) and T cell activation (ionomycin). Genes affected by anisomycin and the majority of genes affected by thapsigargin were affected in the same direction by DON and TBTO, respectively, confirming the expected modes of action. Pathway analysis further sustained that DON induces ribotoxic stress and both DON and TBTO induce unfolded protein response (UPR), ER stress, T cell activation and apoptosis. The second goal was to assess whether DON and/or TBTO affect other pathways above those detected before. TBTO induced groups of genes that are involved in DNA packaging and heat shock response that were not affected by thapsigargin. DON did not affect other genes than anisomycin indicating the effect of DON to be restricted to ribotoxic stress. This study also demonstrates that comparative gene expression analysis is a very promising tool for the identification of modes of action of immunotoxic compounds.     

Hypertension and oxidative stress

1. Oxidative stress has been suggested to be involved in the pathogenesis of hypertension. This may be via a number of possible mechanisms, including quenching of the important vasodilator nitric oxide. 2. Animal studies have generally supported the hypothesis that increased blood pressure is associated with increased oxidative stress. However, human studies have been inconsistent and may differ owing to the populations studied and the various methods used. Treatment with anti-oxidants has been suggested to lower oxidative stress and, therefore, blood pressure. However, to date, studies investigating single or combination supplements have failed to show any consistent benefit. 3. Overall, the evidence supporting the link between hypertension and oxidative stress remains inconclusive, with methodological and population differences possibly confounding results. Further studies investigating this relationship are warranted.     

心理应激对心率变异影响的研究

目的观察应用小剂量倍他乐克对部队战士心理应激心率变异的影响,评价小剂量倍他乐克对心理应激心血管自主神经的调节作用。方法被试者为800名部队新、老战士,年龄18～22岁,均衡分为betaloc组(服用倍他乐克6.25mg/次,2次/d,共1周),对照组(服用安慰剂)。服药前和应急训练前应用SCL-90症状自评量表测评,采用Holter记录服药前30min及应急训练前30min的心电信号,进行心率变异(HRV)分析。结果新、老战士在应急训练前SCL-90症状自评量表总分和阳性项目数显著升高,LF均升高,HF下降,LF/HF升高,有显著性差异,且二者有相关性。对照组较betaloc组LF升高更显著穴P<0.05雪,服用倍他乐克使心理应激时HF降低幅度显著减少。结论心理应激使心脏交感神经兴奋、迷走神经抑制,心率变异性降低,小剂量倍他乐克可提高心理应激时的心率变异性,使心脏交感神经和迷走神经的平衡调节改善。