An update on the role of free radicals and antioxidant defense in human disease

Mounting clinical and experimental evidence indicates that free radicals play important roles in many physiological and pathological conditions. The wider application of free radical measurement has increased awareness of functional implications of radical-induced impairment of the oxidative/antioxidative balance. In the following review, the role of oxygen free radicals in some human and experimental pathological conditions is described, with particular emphasis on the mechanisms by which they produce oxidative damage to lipids, proteins, and nucleic bases. The role of free radicals and the activation of the antioxidant systems in arteriosclerosis and ageing, diabetes, ischemia/reperfusion injury, ethanol intoxication, and liver steatosis is discussed. Therapeutic approaches to the use of antioxidants have been described and prospects for clinical use have been considered.     

The ultrastructural and biochemical evidences of the beneficial effects of chronic caffeic acid phenethyl ester and melatonin administration on brain and cerebellum of aged rats

Nervous system is highly vulnerable to the deleterious effects of age‐related oxidative stress. A large body of researches has consistently confirmed the implication of free radicals both in normal cerebral ageing and ageing‐related pathologies. In the present study, in addition to the light and electron microscopic pictures of brain and cerebellum of young, old and antioxidant administered old Sprague–Dawley rats, pro‐oxidant status was evaluated in terms of measurements of total glutathione, lipid peroxidation (malondialdehyde) and activities of superoxide dismutase, catalase and glutathione peroxidase. Taking the results together, we suggest that supplemental administration of caffeic acid phenethyl ester and melatonin is beneficial in delaying age‐related cellular damage in nervous system.     

Oxygen-derived free radicals and postischemic myocardial reperfusion: therapeutic implications

Oxygen-derived free radicals have been implicated in the pathogenesis of various disease states, including myocardial ischemia and reperfusion. In this article, we review 1) the evidence linking free radical production and myocardial injury during myocardial ischemia and reperfusion and 2) results of studies of the effects of the pharmacological therapies available potentially to prevent free radical-mediated injury. Free radicals can be produced during ischemia and reperfusion by several different biochemical pathways. Of these, the xanthine oxidase reaction and the output of free radicals by neutrophils that have accumulated in damaged tissue have been studied extensively. When produced, free radicals can potentially damage myocytes or endothelial cells through peroxidation of membrane lipids or damage to proteins or nucleic acids. Using electron spin resonance spectroscopy, several studies have shown a 'burst' of oxygen free radicals immediately after reperfusion. Moreover, exogenous generation of intravascular free radicals has been shown to produce marked vascular and myocyte damage, as well as contractile dysfunction. 'Anti-free radical' interventions, such as xanthine oxidase inhibitors and free radical scavengers have been reported to prevent contractile dysfunction and reperfusion-induced arrhythmias after an episode of reversible ischemic injury. However, after more severe episodes of ischemia, such interventions have had conflicting effects on myocardial infarct size. 'Anti-free radical' interventions could be of potential use in situations where reversible ischemic injury occurs. In situations where reperfusion is achieved after irreversible ischemic injury has occurred, the potential beneficial effect of these treatments on infarct size is more doubtful.     

A review of free radicals and antioxidants for critical care nurses.

In the critical care setting, nurses frequently care for patients with acute and chronic diseases that affect multiple body systems. Many of these medical conditions have been associated with an imbalance between oxidizing chemicals called free radicals and antioxidants. Free radical damage is now assumed to be a contributing factor in all major diseases. In order to provide the most current and comprehensive care, critical care nurses need to be well informed about how free radicals cause damage and the antioxidant compounds that neutralize their destructive effects. This article provides an overview of oxygen free radicals and antioxidants and how they impact different clinical illnesses familiar to critical care nurses.     

Oxidative stress in critically ill patients.

Oxygen-derived free radicals play an important role in the development of disease in critically ill patients. Normally, oxygen free radicals are neutralized by antioxidants such as vitamin E or enzymes such as superoxide dismutase. However, in patients who require intensive care, oxygen free radicals become a problem when either a decrease in the removal or an overproduction of the radicals occurs. This oxidative stress and the damage due to it have been implicated in many diseases in critically ill patients. Many drugs and treatments now being investigated are directed toward preventing the damage from oxidative stress. The formation of reactive oxygen species, the damage caused by them, and the body's defense system against them are reviewed. New interventions are described that may be used in critically ill patients to prevent or treat oxidative damage.     

Free radicals, antioxidants and ageing.

Multiple mechanisms underlie the human ageing process but interest continues in the role that free radicals and antioxidants may play. Tissue levels of lipofuscin (a mixture of proteins, peroxidised lipids, pigments and metal ions) increase with age as do plasma levels of lipid peroxides. There does not appear to be a progressive increase in free radical-induced DNA damage with age. The evidence that there is a reproducible alteration in intra- or extra-cellular antioxidant mechanisms with age is far from conclusive. Differences in geographical location, the populations studied, methodology and inadequate attention to confounding factors such as gender, alcohol consumption, smoking and disease all contribute to this lack of consensus amongst workers. It is clear, however, that elderly people suffering from chronic and acute illness have reduced protective antioxidant mechanisms. Although this may not initiate an increase in free radical-mediated cell damage it may contribute to this group being less able to deal with increased free radical activity and consequent increased lipid peroxidation. The beneficial role of antioxidant supplementation to healthy individuals remains controversial, but needs to be evaluated in the sick elderly.     

Biologic theories of aging

Many theories have been proposed to explain aging. Currently, the most important theories include genetic control, deterioration of the immune system, somatic mutation, accumulated damage by free radicals, cross-linkage of macromolecules, and metabolic causes. While no single theory accounts for all of the observations about aging, recent research suggests that the primary process is under genetic control, with contributions from environmental factors.     

自由基对线粒体DNA的氧化损伤与衰老

自由基是一类氧化剂,对生物具有多种损害作用,衰老的自由基学说是有关衰老机理的诸多学说之一,线粒体DNA组成结构特殊,易受自然基攻击;目前认为,线粒体DNA的氧化损害是由自由基引起衰老的分子基础。     

Neuroinflammation and ageing: current theories and an overview of the data

The increase in the average lifespan and the consequent proportional growth of the elderly segment of society has furthered the interest in studying ageing processes. Ageing may be considered a multifactorial process derived from the interaction between genetic and environmental factors including lifestyle. There is ample evidence in many species that the maximum age attainable (maximum lifespan potential, MLSP) is genetically determined and several mitochondrial DNA polymorphisms are associated with longevity. This review will address the current understanding of the relationship between ageing and several factors both genetics and life style related. Firstly we focused on the most reliable and commonly shared theories which attempt to explain the phenomenon of ageing as the genetic, cellular, neuroendocrine, immunological and free-radicals related theories. Many studies have shown that most of the phenotypic characteristics observed in the aging process are the result of the occurrence, with age, of a low grade chronic pro-inflammatory status called "inflammaging", partially under genetic control. The term indicate that aging is accompanied by a low degree of chronic inflammatory, an up-regulation of inflammatory response and that inflammatory changes are common to many age-related diseases. In this review special attention was dedicated to diseases related to age as atherosclerosis, cancer and Alzheimer disease. Despite the fact that in recent years many theories about ageing have been developed, we are still far from a full understanding of the mechanisms underlying the ageing process.     

Mitochondria as sources and targets of damage in cellular aging

Mitochondria are considered as the most important cellular sources and targets of free radicals. They are also a source of signalling molecules that regulate cell cycle, proliferation, and apoptosis. Denham Harman postulated the free radical theory of aging in 1956. Previously Rebecca Gershman showed that radiation toxicity could be attributed to free radical damage. Subsequently, Jaime Miquel formulated the mitochondrial free radical theory of aging. We have shown that mitochondrial size, membrane potential, inner membrane mass and peroxide production is altered inside cells in old animals. These result in an increase in the oxidative damage to mitochondrial DNA with aging that can be prevented by antioxidant supplementation. Aging is also associated with a lower renewal of mitochondria. This is mainly due to the lack of reactivity of proliferator-activated receptor-γ (PPAR-γ) coactivator 1α (PGC-1α) in old animals. PGC-1α acts as a master regulator of energy metabolism and mitochondrial biogenesis and recent evidence shows that it interacts with p53 and telomerase. The promotion of mitochondriogenesis is critical to prevent aging. In skeletal muscle it has relevance to prevent sarcopenia and frailty.     

Iron regulation by hepatocytes and free radicals

Iron is an essential metallic microelement for life. However, iron overload is toxic. The liver serves an important role as a storehouse for iron in the body. About 20–25 mg of iron is required each day for hemoglobin synthesis. To maintain iron homeostasis, transferrin and transferrin receptors are primarily involved in the uptake of iron into hepatocytes, ferritin in its storage, and ferroportin in its export. Moreover, hepcidin controls ferroportin and plays a central role in the iron metabolism. Excess “free” reactive iron produces damaging free radicals via Fenton or Harber-Weiss reactions. Produced free radicals attack cellular proteins, lipids and nucleic acid. Several detoxification system and anti-oxidant defense mechanisms exist to prevent cellular damage by free radicals. Excessive free radicals can lead to hepatocellular damage, liver fibrosis, and hepatocarcinogenesis.     

Recombinant superoxide dismutase reduces oxygen free radical concentrations in reperfused myocardium.

It has been proposed that oxygen free radicals mediate damage that occurs during postischemic reperfusion. Recombinant human superoxide dismutase (r-h-SOD) has been shown to be effective at reducing reperfusion injury, but it is not known if this infused enzyme actually reduces oxygen free radical concentrations in the myocardial tissue. Electron paramagnetic resonance spectroscopy was used to directly measure the effect of r-h-SOD on free radical concentrations in the postischemic heart. Hearts were freeze clamped at 77 degrees K after 10 min of normothermic global ischemia followed by 10 s of reflow with control perfusate (n = 7) or perfusate containing 60,000 U r-h-SOD (n = 7). The spectra of these hearts exhibited three different signals: signal A isotropic, g = 2.004, identical to the carbon-centered ubiquinone free radical; signal B anisotropic with axial symmetry, g parallel = 2.033, g perpendicular = 2.005, identical to the oxygen-centered alkyl peroxyl free radical; and the signal C an isotropic triplet, g parallel = 2.000, an = 24 G, similar to a nitrogen-centered free radical such as a peroxyl amine. With r-h-SOD administration the concentration of the oxygen free radical, signal B, was reduced 49% from 6.8 +/- 0.3 microM to 3.5 +/- 0.3 microM (P less than 0.01) and the concentration of the nitrogen free radical, signal C, was reduced 38% from 3.4 +/- 0.3 to 2.1 +/- 0.3 microM (P less than 0.01). The concentration of the carbon-centered free radical, signal A, however, was increased 51% from 3.3 +/- 0.2 to 5.0 +/- 0.2 microM (P less than 0.01). Identical reperfusion with peroxide-inactivated r-h-SOD did not alter the concentrations of free radicals indicating that the specific enzymatic activity of r-h-SOD is required to decrease the concentrations of reactive oxygen free radicals. Additional measurements performed varying the duration of reflow demonstrate a burst of oxygen free radical generation peaking at 10 s of reperfusion. r-h-SOD entirely abolished this burst. These studies demonstrate that superoxide-derived free radicals are generated during postischemic reperfusion and suggest that the beneficial effect of r-h-SOD is due to its specific enzymatic scavenging of superoxide free radicals.     

自由基损害与红细胞免疫功能状态对急性脑血管病预后的影响

Background: Recent studies show free radicals play an important role in pathogenesis of brain infarction. Over formation of free radicals damage neurons primarily and secondly. A series of free radical reaction accounts from the most part during generation and necrosis due to brain ischemia and reperfusion. Changes in free radicals and immunological state of red cells will affect prognosis in patients with cerebral infarction.     

Collagen, ageing and nutrition.

The relationship between ageing and nutrition is considered with collagen as the intermediate target. Some data showed that diet restriction resulted in decreased collagen accumulation and collagen ageing. Conversely, being overweight reduced the lifespan and increased collagen ageing. Collagen ageing, which includes low turnover and glycoxidation, involves an increase in both stiffness and weakness. Their consequences concern all tissues including those with vital importance such as cartilage, heart ventricle or arterial wall.     

紫外线照射充氧自血回输疗法对家兔脊髓损伤后自由基的影响

目的研究紫外线照射充氧自血回输疗法(UBIO)对脊髓损伤后自由基的影响。方法18只家兔随机分为对照组、损伤组和治疗组,造成不完全性脊髓损伤,用电子顺磁共振法直接测定脊髓组织中自由基信号的相对强度。结果损伤组脊髓组织自由基信号(7.014±0.914)mm／100mg与对照组(1.938±0.430)mm／100mg比较显著增强(H＝18.93,P＜0.01)。治疗组采用UBIO治疗后,脊髓组织自由基信号(4.215±0.914)mm／100mg与损伤组比较显著减弱(H＝13.71,P＜0.01)。结论紫外线照射充氧自血回输疗法可以减轻脊髓组织自由基损害。     

创伤性骨关节炎软骨细胞损坏与修复机制

背景：目前骨关节炎的发病机制在宏观及微观层次上虽然得到了很大的确证,但是仍然不甚清楚,甚至自相矛盾、顾此失彼、没能形成更加系统、全面、科学的理论体系。目的：对国内外创伤性骨关节炎软骨细胞损坏与修复机制的现状及新进展作一综述。方法：应用计算机检索CNKI和Pubmed数据库中1994年1月至2011年10月关于创伤性骨关节炎软骨细胞损坏与修复机制的文章,在标题和摘要中以＂骨关节炎;细胞凋亡;基质金属蛋白酶;自由基＂或＂osteoarthritis,apoptosis,metalloprotease free radical＂为检索词进行检索。选择文章内容与创伤性骨关节发病机制有关者,同一领域文献则选择近期发表或发表在权威杂志文章。初检得到140篇文献,根据纳入标准选择关于牙周局部缓释剂的31文献进行综述。结果与结论：创伤性骨关节炎的发生是在宏观生物力学改变的基础上,启动了细胞通讯系统中的细胞转导通路机制,激发了程序化的＂破坏与修复＂机制,其中软骨细胞凋亡、分解代谢酶、自由基以及相关细胞因子的免疫应答有可能就是其发病的＂轴心＂机制。     

Caffeic acid phenethyl ester improves oxidative erythrocyte damage in a rat model of thermal injury

Oxygen-derived free radicals impair cell membrane functions and induce circulatory disturbances, and free radicals, such as superoxide anion, hydrogen peroxide, hydroxyl radicals, and peroxynitrite, have been suggested to play important roles in the pathogenesis of major burn injuries. The present study investigated the effects of thermal injury on erythrocyte lipid peroxidation and antioxidant status and investigated the effects of caffeic acid phenethyl ester (CAPE), a new antioxidant and anti-inflammatory agent, in rats subjected to thermal injury. Burn injury caused a remarkable increase in erythrocyte lipid peroxidation, levels of nitric oxide (NO), and activities of antioxidant enzymes and xanthine oxidase (XO). The treatment with CAPE decreased both activity of burn-induced XO activity and levels of NO in the erythrocytes. In conclusion, CAPE treatment resulted in decreased erythrocyte lipid peroxidation in thermal injury and helped to prevent oxidative damage by decreasing activity of XO and levels of NO.     

Antioxidant measurements

Chemical reactions, including oxidation and reduction of molecules, occur in every cell. These reactions can lead to the production of free radicals. Free radicals react with organic substrates such as lipids, proteins, and DNA. Through oxidation free radicals cause damage to these molecules, disturbing their normal function, and may therefore contribute to a variety of diseases. The anti-oxidation system, which consists of enzymatic antioxidants and non-enzymatic antioxidants, defends against oxidative stress. The aim of this review is to summarize general aspects of methods to measure the antioxidant defence system all in one (total antioxidant capacity) and discuss a number of methods which are currently used for detection of antioxidant properties.     

自由基与白血病关系的研究进展

自由基是一类带电荷的原子、分子或离子，具有很强的生物活性，在肿瘤和其它许多疾病的发生过程中起重要作用。自由基在人体内通过一系列级联反应产生或，它可以激活癌基因，在细胞内参与肿瘤细胞凋亡、生存、增殖相关的信号传导，修饰关键酶或蛋白并改变其功能，从而导致肿瘤的发生，同时对组织、器官造成损伤，产生多种病理变化。自由基还是许多抗白血病药物发挥药理作用的中间产物或功能物质。