分子氢——医学气体研究的新视角

 医学气体在临床中有着广泛的应用，以往被认为是生理性惰性气体的氢气(H2)，最近研究表明它不仅具有抗氧化作用，同时具有抗炎和抗细胞凋亡作用，在缺血再灌注损伤、动脉粥样硬化、代谢综合征等多种系统性疾病中发挥保护作用，其生物学意义值得深入研究，并可能启动了一种新的生物医学研究领域。     

L-肉毒碱抗缺血再灌注损伤机制研究进展

L肉毒碱是一种类维生素,能够促进脂肪代谢,具有抗氧化和促进造血功能。临床主要用于调节血脂和抗贫血治疗。近来大量文献报道,L肉毒碱能够减轻组织器官缺血再灌注损伤,主要机制为:抗氧自由基损伤、促进血流灌注和能量代谢、抗凋亡作用。因此,L肉毒碱可能在防治缺血再灌注损伤的疾病中有较好的应用前景。本文就L肉毒碱抗缺血再灌注损伤作用机制研究进展作一综述。     

大鼠肾缺血再灌注损伤肝内过氧化酶Ⅰ、过氧化氢酶、细胞外超氧化物歧化酶的表达变化

目的:观察大鼠肾缺血再灌注损伤模型肝的功能、形态、氧化应激水平以及抗氧化酶过氧化酶Ⅰ(PrxⅠ)、过氧化氢酶(CAT)、细胞外超氧化物歧化酶(EC-SOD)的表达变化,探讨肾缺血再灌注损伤对肝的影响及PrxⅠ、CAT、EC-SOD的抗氧化作用.方法:通过无损伤动脉夹钳夹肾动脉法建立肾缺血再灌注损伤模型.再灌注24 h后取血、肝和肾.血清ALT活性采用速率法测定,血清SCr含量采用苦味酸法测定;血清BUN含量采用酶耦联速率法测定.采用H-E染色观察肝、肾的形态学改变.肝组织MDA含量采用硫代巴比妥酸比色法测定;肝组织H2O2含量采用分光光度法测定.抗氧化酶PrxⅠ、CAT、EC-SOD mRNA表达水平采用RT-PCR的方法测定,其蛋白水平的表达变化采用免疫印迹测定.结果:肾缺血再灌注损伤组大鼠血清SCr含量、BUN含量和ALT活性均高于对照组;H-E染色结果显示模型组大鼠肾组织、肝组织形态结构均明显受损.肝组织内的MDA含量和H2O2含量明显高于对照组,PrxⅠ、CAT、EC-SOD的mRNA和蛋白表达水平与对照组相比也明显升高.结论:肾缺血再灌注损伤可导致肝遭受过氧化损伤,形态结构和功能受损,PrxⅠ、CAT、EC-SOD在此过程中可能发挥了抗氧化应激作用,对肝具有保护功能.     

银杏内酯A对中枢神经系统作用及机制的研究进展

银杏叶提取物在心脑血管方面得到广泛应用,其中银杏内酯A(GA)具有很强的药理活性,主要是通过抗炎、抗凋亡、抗氧化损伤、清除自由基,以及抑制Aβ聚集来产生神经保护作用。对脑缺血、缺血/再灌注损伤、Aβ损伤、胆碱能损伤方面具有改善作用。本文就GA对中枢神经系统的影响作一综述。     

天麻对大鼠肾缺血再灌注损伤中SOD、MDA作用的研究

目的探讨天麻在大鼠肾缺血再灌注损伤中的抗氧化作用.方法通过建立大鼠急性肾缺血再灌注损伤模型,测定天麻对肾缺血再灌注后肾组织SOD活力与MDA含量的变化.结果与对照组相比,使用天麻后,在再灌注6h、12h和24h后肾组织SOD活力明显升高(p值分别<0.01,0.05,0.01),MDA含量明显降低(p值分别<0.05,0.01,0.05).结论天麻在大鼠肾缺血再灌注损伤模型中,有抗自由基损伤和减轻脂质过氧化的作用.     

血红素氧化酶1对移植肝脏缺血再灌注损伤的保护

背景：在肝移植过程中,肝脏的缺血再灌注损伤导致的移植肝原发性无功能一直困扰着广大移植专家学者。血红素氧化酶1参与多种疾病及病理过程,通过抗氧化、抗炎、抗凋亡等多种机制发挥组织器官保护作用。 目的：对血红素氧化酶1对移植肝缺血再灌注损伤的保护作用进行综述。 方法：由第一作者应用计算机检索PubMed数据库1992年1月至2009年12月及中国期刊网全文数据库2003年1月至2010年12月有关血红素氧化酶1对移植肝缺血再灌注损伤保护作用的文章,英文检索词为“heme oxygenase-1,ischemia-reperfusion injury,liver graft”,中文检索词为“血红素氧化酶1,移植肝,缺血再灌注损伤”。排除研究目的与课题无关及内容重复的研究,共保留34篇文献进行综述。 结果与结论：血红素氧化酶1可能是哺乳动物体内分布最广、保护作用最重要的基因。血红素氧化酶1及其催化产物组成了机体重要的内源性保护系统,参与多种疾病及病理过程,通过抗氧化、抗炎、抗凋亡等多种机制发挥组织器官保护作用,具有重要的临床应用潜能。血红素氧化酶1对移植肝的缺血再灌注损伤具有明显的保护作用,如何通过转基因手段将其应用于临床,保护移植肝减轻缺血再灌注损伤,提高移植肝成活率,有着广阔的临床应用前景,也是未来所要研究的方向。     

天麻对大鼠肾缺血再灌注损伤中SOD、MDA作用的研究

目的　探讨天麻在大鼠肾缺血再灌注损伤中的抗氧化作用 .方法　通过建立大鼠急性肾缺血再灌注损伤模型 ,测定天麻对肾缺血再灌注后肾组织SOD活力与MDA含量的变化 .结果　与对照组相比 ,使用天麻后 ,在再灌注 6h、12h和 2 4h后肾组织SOD活力明显升高 (p值分别 <0 .0 1,0 .0 5 ,0 .0 1) ,MDA含量明显降低 (p值分别 <0 .0 5 ,0 .0 1,0 .0 5 ) .结论　天麻在大鼠肾缺血再灌注损伤模型中 ,有抗自由基损伤和减轻脂质过氧化的作用 .     

右美托咪定抗缺血再灌注损伤的信号通路

背景：右旋美托咪定具有抗缺血再灌注损伤的作用，但对其信号通路全面、系统的综述较少。目的：重点对右旋美托咪定在抗氧化应激、抑制炎症、抗凋亡、自噬等机制方面的信号通路进行综述。方法：计算机检索PubMed数据库、中国知网、万方数据库及维普数据库的相关文章，英文检索词为“ischemia-reperfusion injury,dexmedetomidine,signal path,oxidative stress,inflammation,apoptosis”；中文检索词为“缺血再灌注损伤，右旋美托咪定，信号通路，氧化应激，炎症，凋亡”。排除重复性研究及部分相关性较低的基础类文章，最终纳入57篇文献进行评价。结果与结论：(1)右旋美托咪定主要通过抗氧化应激损伤、抗炎、抗细胞凋亡和自噬等多种机制发挥器官保护作用，这其中又涉及众多通路，主要包括Nrf2及其下游蛋白抗氧化应激通路、Toll样受体4家族和核因子κB相关抗炎通路、JAK2/STAT3相关抗炎通路、胆碱能抗炎通路，而且胆碱能通路是众多核因子κB信号通路的上游机制；(2)PI3K/Akt通路依据其激活的下游信号不同发挥不同的作用，抑制NL...     

血红素加氧酶-1在心血管疾病中的作用研究新进展

血红素加氧酶-1是一种应激蛋白, 除了促进血红素代谢, 还具有抗炎、抗凋亡、抗增生和抗氧化应激等许多重要生物学作用。这一功能广泛的氧化酶系统参与心血管系统的病理生理过程,它的作用涉及血压的调控、抗动脉粥样硬化的发生发展、预防缺血/再灌注损伤和冠状动脉介入治疗后再狭窄的发生。     

钙及活性氧在大鼠肾缺血再灌流损伤中的作用

目的和方法 :应用电镜细胞化学方法 ,对缺血 -再灌流损伤过程中活性氧的产生及细胞内钙变化情况进行研究。结果 :缺血期 ,细胞内钙明显增多 ,而此时尚无H2 O2 产生 ;缺血后再灌流早期H2 O2 大量产生 ,细胞内钙与缺血期类似 ;再灌流晚期H2 O2 产生有所减少 ,而细胞内钙持续增高。结论 :钙及活性氧都参与缺血再灌流损伤 ,但其参与时机及作用并不相同。     

Free radicals and lipid peroxidation in cell biology: physiopathologic prospects

Oxygen derived free radicals (OFR) arise in the course of normal cellular life, especially during cellular respiration. They are formed when molecular oxygen is reduced to water. These highly reactive species are controlled by a protective system both enzymatic and non enzymatic which helps to prevent the accumulation of peroxidative damage to the cell. Lipid peroxides result from the reaction of oxygen derived free radicals with polyinsatured fatty acids of membranes phospholipids and can be formed both non enzymatically and enzymatically (eicosanoids). Oxygen derived free radicals attack over-running beyond the protective system leads to oxidative stress. The cells involved in inflammation (polymorphonuclear, leucocytes, monocytes, platelets, endothelial cells) release oxygen derived free radicals and lipid peroxides and inflammatory diseases of infectious or non infectious origin can be considered as oxidative stress. Intracellular oxidative stress can lead to cellular death or trigger a strong inflammatory reaction. This occurs during ischemia reperfusion injury and hyperoxia. Exposure to ionizing radiation results in overproduction of oxygen derived free radicals both extra and intracellular. Oxidative stress may be involved in atheroma (where oxidised LDL are described), ageing and cancer.     

Biochemical mechanisms of oxidative liver cell injury

The toxicological implications of the formation of active oxygen species have attracted growing interest in recent years. Under aerobic conditions, oxygen radicals are normal cellular metabolites. However, the production of oxygen radicals may be greatly stimulated in the presence of various redox active compounds. Eventually, the stimulation of oxygen radical production may be so great as to overwhelm the cellular defence systems, create an oxidative stress and bring about toxicity. Recent studies in this laboratory indicate that glutathione and protein thiol depletion play a critical role in the development of oxidative cell injury. This depletion of cellular thiols can result in a disturbance of intracellular calcium ion homeostasis, which seems to be directly related to cell killing.     

Mechanisms of oxidant-induced changes in erythrocytes

There is an increasing body of experimental studies demonstrating the toxic effects of oxygen-derived free radicals. Evidence supports an important role for free radicals in ischemic injuries, inflammation, and chemical-induced tissue injury. Free radicals are involved in normal biochemical processes like oxidative reduction and cellular metabolism; however, they also mediate disease processes. The participation of oxygen free radicals in lysis of red cells is important in some situations of intravascular hemolysis. This article will review neutrophil-derived oxygen free radicals, emphasizing: (1) their effects on the erythrocyte and (2) how these effects may be attenuated.Supported in part by NIH Grants HL-31963, GM-28499, and GM-29507.     

Cardiac toxicity of singlet oxygen: implication in reperfusion injury

Oxygen-derived free radicals (O2.-, H2O2, and .OH) that are produced during postischemic reperfusion are currently suspected to be involved in the pathogenesis of tissue injury. Another reactive oxygen species, the electronically excited molecular oxygen (1O2), is of increasing interest in the area of experimental research in cardiology. In this review are discussed the main potential sources of singlet oxygen in the organism, particularly in the myocardium, the various cardiovascular cytotoxic effects induced by this reactive oxygen intermediate, and the growing evidence of its involvement in ischemia/reperfusion injury.     

Role of nitric oxide in the pathogenesis of chronic pulmonary hypertension

Chronic pulmonary hypertension is a serious complication of a number of chronic lung and heart diseases. In addition to vasoconstriction, its pathogenesis includes injury to the peripheral pulmonary arteries leading to their structural remodeling. Increased pulmonary vascular synthesis of an endogenous vasodilator, nitric oxide (NO), opposes excessive increases of intravascular pressure during acute pulmonary vasoconstriction and chronic pulmonary hypertension, although evidence for reduced NO activity in pulmonary hypertension has also been presented. NO can modulate the degree of vascular injury and subsequent fibroproduction, which both underlie the development of chronic pulmonary hypertension. On one hand, NO can interrupt vascular wall injury by oxygen radicals produced in increased amounts in pulmonary hypertension. NO can also inhibit pulmonary vascular smooth muscle and fibroblast proliferative response to the injury. On the other hand, NO may combine with oxygen radicals to yield peroxynitrite and other related, highly reactive compounds. The oxidants formed in this manner may exert cytotoxic and collagenolytic effects and, therefore, promote the process of reparative vascular remodeling. The balance between the protective and adverse effects of NO is determined by the relative amounts of NO and reactive oxygen species. We speculate that this balance may be shifted toward more severe injury especially during exacerbations of chronic diseases associated with pulmonary hypertension. Targeting these adverse effects of NO-derived radicals on vascular structure represents a potential novel therapeutic approach to pulmonary hypertension in chronic lung diseases.     

Evaluation of the role of oxygen radicals in polymorphonuclear leukocyte aggregation

Oxygen radicals have been shown to alter granulocyte function by injury to the cell membrane or cytoskeleton. We have investigated the effect of such injury on the aggregation of granulocytes upon C5a or PMA stimulation. Granulocyte aggregation was not altered in the presence of the oxygen radical scavengers SOD, catalase, mannitol, or benzoate. To test whether oxygen radicals were required for aggregation, we evaluated three patients with chronic granulomatous disease of childhood. The response of PMNs from these patients was no different from controls. Hydrocortisone, an inhibitor of both granulocyte aggregation and oxygen radical generation, was then studied to decide whether its impairment of radical production contributed to its effect on aggregation. Five times the concentration of hydrocortisone needed to inhibit radical generation was required to impair aggregation by 50%. In addition, hydrocortisone was able to impair the aggregation of the PMNs of a patient with chronic granulomatous disease. These data suggest that oxidative injury to the cell membrane or cytoskeleton does not significantly contribute to the aggregation of granulocytes. In addition, inhibitors of aggregation, such as hydrocortisone, work through mechanisms other than by scavenging radicals.     

Chronic oxidative stress after irradiation: An unproven hypothesis

Injury and organ failure after irradiation of late-responding tissues is a substantial problem in radiation oncology and a major threat after accidental or belligerent exposures. The mechanisms of injury may include death of clonogens, vascular injury, activation of cytokine networks, and/or chronic oxidative stress. Knowledge of mechanisms may guide optimal use of mitigators. The hypothesis of chronic oxidative stress as a mechanism for late radiation injury has received much attention. We review herein the published evidence for chronic oxidative stress in vivo, and for use of antioxidants as mitigators of normal tissue radiation injury. We conclude that there is only indirect evidence for chronic oxidative stress after irradiation, and there are only limited published reports of mitigation by antioxidants. We did not find a differentiation of persistent markers of oxidative stress from an ongoing production of oxygen radicals. It is thus unproven that chronic oxidative stress plays a major role in causing radiation injury and organ failure in late-responding tissues. Further investigation is justified, to identify chronic oxidative stress and to identify optimal mitigators of radiation injury.     

3-Aminopropanal is a lysosomotropic aldehyde that causes oxidative stress and apoptosis by rupturing lysosomes

During cerebral ischemia and following trauma, potent cytotoxic polyamine-derived aminoaldehydes form, diffuse, and damage adjacent tissues not directly subjected to the initial insult. One such aldehyde is 3-aminopropanal (3-AP). The mechanisms by which such a small aldehydic compound is excessively cytotoxic have been unclear until recently when we showed that 3-AP, having the structure of a weak lysosomotropic base, concentrates within the acidic vacuolar compartment and causes lysosomal rupture that, in turn, induces caspase activation and apoptotic cell death. Here, using cultured J774 cells and 3-AP as a way to selectively burst lysosomes, we show that moderate lysosomal rupture induces a transient wave of oxidative stress. The start of this oxidative stress period is concomitant with a short period of enhanced mitochondrial membrane potential that later fades and is replaced by a decreased potential before the oxidative stress diminishes. The result of the study suggests that oxidative stress, which has often been described during apoptosis induced by agonists other than oxidative stress per se, may be a consequence of lysosomal rupture with direct and/or indirect effects on mitochondrial respiration and electron transport causing a period of passing enhanced formation of reactive oxygen species.     

Effects of oxygen concentrations on human fibroblasts treated with Fe(3+)-NTA

Free radicals derived from the reaction of iron and oxygen are thought to be one of the causes of tissue injury. In order to identify whether oxygen concentrations are an important factor in iron-mediated damage to cells, cytotoxic effects of Fe(3+)-NTA on human fibroblasts (KMST-6 line) were studied under the conditions of 1% and 20% oxygen concentrations in an incubator. A comparison of the effects of Fe(3+)-NTA on cells cultured in 1% and 20% oxygen environments showed that the following features were more prominent under the usual culture concentrations of 20% oxygen: i) cytotoxicity, ii) increase in intracellular reactive oxygen species, iii) increase in H(2)O(2) production in the cells, and iv) formation of 8-hydroxydeoxyguanosine. To elucidate the roles of endogenous antioxidants, the levels of manganese superoxide dismutase (MnSOD) and catalase were measured by Western blotting. The increase in MnSOD in the presence of Fe(3+)-NTA was greater under the condition of 20% O(2) than under the condition of 1% O(2). The expression of catalase was significantly up-regulated at 20% O(2). However, when the cells were treated with Fe(3+)-NTA, the expression of catalase was markedly down-regulated under the condition of 20% O(2). Hydroxyl radical scavengers such as vitamin E, dimethyl-sulfoxide (DMSO) and mannitol reduced endogenous ROS generation and alleviated the cytotoxic effects of iron. On the other hand, superoxide dismutase (SOD), vitamin C and catalase did not show any protective effects against Fe(3+)-NTA. These findings suggest that enhanced cytotoxic effects of Fe(3+)-NTA at 20% O(2 )are due to endogenously produced hydroxyl radicals.