氧化应激在阿尔茨海默病中的作用及相关药物研究进展

阿尔茨海默病(Alzheimer’s disease，AD)是以进行性认知功能障碍和记忆力损害为主的中枢神经系统的退行性疾病，其发病机制十分复杂。氧化应激可损伤细胞内多种生物大分子。在AD患者脑中，脂质、蛋白质、DNA、RNA和糖类都存在过氧化形式。氧化应激也参与了形成老年斑、神经原纤维缠结以及神经元细胞凋亡。此外，氧化应激还与AD发病机制的神经炎症和线粒体功能异常有关联，与其共同加剧了AD的发生。具有强抗氧化活性的生物活性分子（如褪黑素和吡咯喹啉醌）有望成为很有前途的以氧化应激为靶点的抗AD治疗药物。     

氧化应激在阿尔茨海默病中的作用及相关药物研究进展

阿尔茨海默病(Alzheimer’s disease，AD)是以进行性认知功能障碍和记忆力损害为主的中枢神经系统的退行性疾病，其发病机制十分复杂。氧化应激可损伤细胞内多种生物大分子。在AD患者脑中，脂质、蛋白质、DNA、RNA和糖类都存在过氧化形式。氧化应激也参与了形成老年斑、神经原纤维缠结以及神经元细胞凋亡。此外，氧化应激还与AD发病机制的神经炎症和线粒体功能异常有关联，与其共同加剧了AD的发生。具有强抗氧化活性的生物活性分子（如褪黑素和吡咯喹啉醌）有望成为很有前途的以氧化应激为靶点的抗AD治疗药物。     

氧化应激在阿尔茨海默病中的作用及相关药物研究进展

阿尔茨海默病(Alzheimer’s disease，AD)是以进行性认知功能障碍和记忆力损害为主的中枢神经系统的退行性疾病，其发病机制十分复杂。氧化应激可损伤细胞内多种生物大分子。在AD患者脑中，脂质、蛋白质、DNA、RNA和糖类都存在过氧化形式。氧化应激也参与了形成老年斑、神经原纤维缠结以及神经元细胞凋亡。此外，氧化应激还与AD发病机制的神经炎症和线粒体功能异常有关联，与其共同加剧了AD的发生。具有强抗氧化活性的生物活性分子（如褪黑素和吡咯喹啉醌）有望成为很有前途的以氧化应激为靶点的抗AD治疗药物。     

多糖类化合物抗氧化作用及其机制的研究进展

肌体的氧化应激损伤与多种疾病,如肿瘤、动脉粥样硬化、糖尿病、神经退行性疾病以及炎症等的发生和发展有着密切的关系;因此,抗氧化作用机制从细胞水平大致可以分为清除自由基、上调抗氧化酶活性、减少脂质代谢产物、保护细胞重要的细胞器和调控细胞信号转导通路抑制细胞凋亡.随着对天然药物的进一步研究,发现其中的多糖类化合物对疾病起着一定的治疗和缓解作用,其作用机制多与其抗氧化作用有关.本文根据多糖类化合物抗氧化作用特点、结合抗氧化的作用机制和原理进行归纳和总结.     

水飞蓟素在慢性疾病中的抗氧化作用研究概述

水飞蓟素(silymarin)作为护肝药物被广泛应用于各类肝病,其护肝作用与水飞蓟素强大的抗氧化、抗炎和抗脂质沉积等作用有关。越来越多研究表明水飞蓟素在氧化应激引发的如心血管疾病、代谢综合征、神经退行性疾病、癌症和并发症等慢性疾病都具有良好治疗效果。本篇列举了近五年水飞蓟素治疗慢性病的通路研究,重点阐述慢性疾病与氧化应激的损伤机制和水飞蓟素的抗氧化能力在其中发挥的关键作用,以期为水飞蓟素的临床使用提供用药思路。     

生活中的氧化应激与抗氧化

公益节目中经常宣传，“平衡膳食的同时多吃富含维生素的蔬菜水果可以延缓衰老”、某些营养保健品就以此标榜自己的产品具有抗氧化抗衰老的作用来吸引消费者；化妆品广告宣称某某“神奇水”有抗氧化、延缓衰老、永葆青春作用之类的广告语更是铺天盖地，令人心动不已。确实，生活中氧化应激、氧化损伤可谓无处不在，环境污染、吸烟、饮酒、疾病、肥胖、强烈的紫外线以及不良的饮食生活习惯等，都会引起身体的氧化应激而造成各器官组织的损伤、衰老，引起疾病的发生。     

线粒体靶向抗氧化剂研究进展

线粒体是细胞呼吸的主要场所,在细胞的生命周期中扮演重要角色,三羧酸循环和氧化磷酸化都是在线粒体中进行。线粒体功能障碍可导致一系列疾病,如缺血-再灌注损伤、败血症和糖尿病等。线粒体是神经退行性病变的治疗靶点,也是药物转运策略研究的引人注目的靶位。虽然线粒体所介导的疾病进程的分子机制尚未完全阐明,但氧化应激是关键的环节。开发线粒体靶向的抗氧化应激保护药物具有诱人的前景。线粒体靶向抗氧化剂是指以线粒体为作用靶位的具有抗氧化作用的药物。该文介绍了现有的线粒体靶向抗氧化剂的概念、分类及其疾病治疗研究进展。     

铁死亡在肝脏疾病中的作用及治疗策略

调节性细胞死亡的发现使人类在疾病治疗领域取得了新的突破。作为近十年来新发现的一种调节性细胞死亡,铁死亡的显著特点是细胞内铁离子的异常升高和细胞膜脂质的过氧化破损,形态学特征为线粒体体积缩小、线粒体膜密度增高和线粒体减少或消失。铁死亡的发生机制主要与铁代谢紊乱、脂质代谢异常、氨基酸抗氧化系统失衡和氧化应激等因素相关。由于人体内储存铁离子的主要器官为肝脏,因此深度剖析铁死亡在肝脏疾病中的作用机制非常必要。相关研究表明,铁死亡在不同的肝脏疾病背景下扮演不同的角色,与肝脏疾病的发生过程密切相关,在药物性肝损伤、酒精性脂肪肝、非酒精性脂肪肝、病毒性肝炎、肝纤维化和肝细胞癌等病变过程中都发挥着重要调控作用。本文以铁代谢紊乱、细胞膜脂质过氧化物积累、氨基酸抗氧化系统失衡、线粒体膜电位超极化及其脂质过氧化物积累和氧化应激相关转录因子等方面为切入点,对铁死亡的调控机制、研究现状及其在肝脏相关疾病中的作用进行综述,为铁死亡的深入研究和肝脏疾病的治疗提供新的理论基础和研究思路。     

硝酸酯类的生物转化及其耐受机制的研究进展

硝酸酯类的生物转化涉及谷胱甘肽转移酶、细胞色素P450代谢酶、黄嘌呤氧化酶和线粒体醛脱氢酶等多种酶,其中线粒体醛脱氢酶的作用引人注目;硝酸酯类耐受的机制包括巯基耗竭学说、神经激素激活学说和氧化应激学说等,其中氧化应激学说比较流行;对于硝酸酯类耐受的防治除补充巯基供体等传统方法外,一些具有抗氧化特性的药物如肼屈嗪和硫辛酸等具有良好的抗硝酸酯耐受作用,其机制与恢复被抑制的线粒体醛脱氢酶活性有关。因此,抗氧化治疗特别是寻找和开发针对恢复线粒体醛脱氢酶活性的抗氧化药物成为目前防治硝酸酯类耐受的新策略。     

氧化应激在阿尔茨海默病中的作用及相关药物研究进展

阿尔茨海默病(Alzheimer’s disease,AD)是以进行性认知功能障碍和记忆力损害为主的中枢神经系统的退行性疾病,其发病机制十分复杂。氧化应激可损伤细胞内多种生物大分子。在AD患者脑中,脂质、蛋白质、DNA、RNA和糖类都存在过氧化形式。氧化应激也参与了形成老年斑、神经原纤维缠结以及神经元细胞凋亡。此外,氧化应激还与AD发病机制的神经炎症和线粒体功能异常有关联,与其共同加剧了AD的发生。具有强抗氧化活性的生物活性分子（如褪黑素和吡咯喹啉醌）有望成为很有前途的以氧化应激为靶点的抗AD治疗药物。     

New concepts to fight oxidative stress: nanosized three-dimensional supramolecular antioxidant assemblies

Introduction: Misregulation of reactive oxygen species and reactive nitrogen species by the body’s antioxidant system results in oxidative stress, which is known to be associated with aging, and involved in various pathologies including cancer, neurodegenerative and cardiovascular diseases. A large variety of low-molecular-weight (LMW) antioxidant compounds and antioxidant enzymes have been proposed to alleviate oxidative stress, but their therapeutic efficacy is limited by their solubility, stability or bioavailability. In this respect, nanoscience-based systems are expected to provide more efficient mitigation of oxidative stress.

Areas covered: The main nanoscience-based three-dimensional (3D) supramolecular assemblies, decorated with, or entrapping antioxidant compounds, or which possess intrinsic antioxidant activity are discussed and illustrated with recent examples. Assemblies with different architectures and sizes in the nanometer range serve: i) to deliver LMW antioxidant compounds or enzymes; ii) as antioxidant systems due to their intrinsic activity; and recently iii) to provide a confined space where catalytic antioxidant reactions take place in situ (nanoreactors and artificial organelles). A few insights into the role of antioxidants in mitigating oxidative stress caused by therapeutic compounds or drug carriers are also discussed.

Expert opinion: Several challenges must still be overcome in the development of 3D supramolecular assemblies to efficiently fight oxidative stress. First, an improvement of the assemblies’ properties and stability in biological conditions has to be addressed. Second, new systems based on the combination of biomolecules or mimics in supramolecular assemblies should provide multifunctionality, stimuli-responsiveness and targeting properties for a more efficient therapeutic effect. Third, comparative studies are necessary to evaluate these systems in a standardized manner both in vitro and in vivo.     

Oxidative stress induced mitochondrial DNA deletion as a hallmark for the drug development in the context of the cerebrovascular diseases

Oxidative stress in the cardiovascular system, including brain microvessels and/or parenchymal cells results in an accumulation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) compounds thus promoting leukocyte adhesion and increasing endothelial permeability. The resulting chronic injury stimulus results in progressive cellular hypometabolism. We propose that hypometabolism, coupled with oxidative stressors, is responsible for most Alzheimer disease (AD) and cerebrovascular accidents (CVAs) and appears to be a central initiating factor for vascular abnormalities, mitochondrial damage and an imbalance in the activity of vasoactive substances, such as different isoforms of nitric oxide synthase (NOS), endothelin-1 (ET-1), oxidative stress markers, mtDNA and mitochondrial enzymes in the vascular wall and in brain parenchymal cells. At higher concentrations, ROS induces cell injury and death, which occurs during the aging process, where accelerated generation of ROS and a gradual decline in cellular antioxidant defense mechanisms, especially in the mitochondria. Vascular endothelial and neuronal mitochondria are especially vulnerable to oxidative stress due to their role in energy supply and use, which can cause a cascade of debilitating factors such as the production of giant and/or vulnerable young mitochondrion who's DNA has been compromised. Therefore, mitochondrial DNA abnormalities such as overproliferation and or deletion can be used as a key marker for diseases differentiation and effectiveness of the treatment. We speculate that specific antioxidants such as acetyl-L-carnitine and R-alpha lipoic acid seem to be potential treatments for AD. They target the factors that damage mitochondria and reverse its effect, thus eliminating the imbalance seen in energy production and restore the normal cellular function, making these antioxidants very powerful alternate strategies for the treatment of cardiovascular cerebrovascular as well as neurodegenerative diseases including AD. Future potential exploration using mtDNA markers can be considered more accurate hallmarks for diagnosis and monitoring treatment of human diseases. The present article discusses some of the patents regarding the oxidative stress.     

Mitochondria targeting drugs for neurodegenerative diseases—Design,mechanism and application

Neurodegenerative diseases (NDDs) such as Alzheimer''s disease (AD) and Parkinson''s disease (PD) are a heterogeneous group of disorders characterized by progressive degeneration of neurons. NDDs threaten the lives of millions of people worldwide and regretfully remain incurable. It is well accepted that dysfunction of mitochondria underlies the pathogenesis of NDDs. Dysfunction of mitochondria results in energy depletion, oxidative stress, calcium overloading, caspases activation, which dominates the neuronal death of NDDs. Therefore, mitochondria are the preferred target for intervention of NDDs. So far various mitochondria-targeting drugs have been developed and delightfully some of them demonstrate promising outcome, though there are still some obstacles such as targeting specificity, delivery capacity hindering the drugs development. In present review, we will elaborately address 1) the strategy to design mitochondria targeting drugs, 2) the rescue mechanism of respective mitochondria targeting drugs, 3) how to evaluate the therapeutic effect. Hopefully this review will provide comprehensive knowledge for understanding how to develop more effective drugs for the treatment of NDDs.KEY WORDS: Neurodegenerative diseases, Mitochondria, Targeting drug, Apoptosis, Reactive oxygen species, Adenosine triphosphate, Mitochondrial membrane potential, Evaluation     

Neuroprotection by Spirulina platensis protean extract and phycocyanin against iron-induced toxicity in SH-SY5Y neuroblastoma cells.

We investigated the effect of Spirulina platensis protean extract and the biliprotein phycocyanin isolated from this microalga, on the activities of the antioxidant enzymes SOD, CAT, GPx, and GR, lipid peroxidation inhibitory activity and glutathione levels after the iron induced oxidative stress in SH-SY5Y neuroblastoma cells. Iron is one of the most important agents that produce oxidative stress and decline of neuronal functions. S. platensis protean extract and phycocyanin exert the antioxidant activity by protecting the activity of the cellular antioxidant enzymes total GPx, GPx-Se and GR and by increasing reduced glutathione in cells against oxidative stress induced by iron. These results suggested that S. platensis protean extract is a powerful antioxidant through a mechanism related to antioxidant activity, capable of interfering with radical-mediated cell death. S. platensis may be useful in diseases known to be aggravated by reactive oxygen species and in the development of novel treatments for neurodegenerative disorders as long as iron has been implicated in the neuropathology of several neurodegenerative disorders such as Alzheimer's or Parkinson diseases.     

Mitochondria-targeted peptide antioxidants: Novel neuroprotective agents

Increasing evidence suggests that mitochondrial dysfunction and oxidative stress play a crucial role in the majority of neurodegenerative diseases. Mitochondria are a major source of intracellular reactive oxygen species (ROS) and are particularly vulnerable to oxidative stress. Oxidative damage to mitochondria has been shown to impair mitochondrial function and lead to cell death via apoptosis and necrosis. Because dysfunctional mitochondria will produce more ROS, a feed-forward loop is set up whereby ROS-mediated oxidative damage to mitochondria favors more ROS generation, resulting in a vicious cycle. It is now appreciated that reduction of mitochondrial oxidative stress may prevent or slow down the progression of these neurodegenerative disorders. However, if mitochondria are the major source of intracellular ROS and mitochondria are most vulnerable to oxidative damage, then it would be ideal to deliver the antioxidant therapy to mitochondria. This review will summarize the development of a novel class of mitochondria-targeted antioxidants that can protect mitochondria against oxidative stress and prevent neuronal cell death in animal models of stroke, Parkinson's disease, and amyotrophic lateral sclerosis.     

Vitamin C protects rat cerebellum and encephalon from oxidative stress following exposure to radiofrequency wave generated by a BTS antenna model

Radio frequency wave (RFW) generated by base transceiver station has been reported to produce deleterious effects on the central nervous system function, possibly through oxidative stress. This study was conducted to evaluate the effect of RFW-induced oxidative stress in the cerebellum and encephalon and the prophylactic effect of vitamin C on theses tissues by measuring the antioxidant enzymes activity, including: glutathione peroxidase, superoxide dismutase, catalase, and malondialdehyde (MDA). Thirty-two adult male Sprague-Dawley rats were randomly divided into four equal groups. The control group; the control-vitamin C group received L-ascorbic acid (200?mg/kg of body weight/day by gavage) for 45 days. The RFW group was exposed to RFW and the RFW+ vitamin C group was exposed to RFW and received vitamin C. At the end of the experiment, all groups were killed and encephalon and cerebellum of all rats were removed and stored at ?70?°C for measurement of antioxidant enzymes activity and MDA. The results indicate that exposure to RFW in the test group decreased antioxidant enzymes activity and increased MDA compared with the control groups (p?p?相似文献   

Antioxidant strategies in protection against neurodegenerative disorders

The most common neurodegenerative diseases include Alzheimer’s disease, Parkinson’s disease and stroke; they are devastating clinical problems which lack effective treatments. Although the aetiology of these diseases is not fully understood, oxidative stress is believed to be a contributing causative factor. In addition to conventional therapies, antioxidant strategies in protection against neurodegenerative conditions have been increasingly addressed, as evidenced by an increasing number of animal studies, clinical reports and patents regarding these processes in recent years. The effectiveness of antioxidants in protecting against neurodegenerative disorders lies mainly in their ability to cross the blood–brain barrier, their potential in terms of subcellular distribution occurring in membranes, in the cytoplasm and especially in mitochondria, and their multifunctional capacity as well as their synergistic actions. The naturally occurring antioxidants with different properties collaborate as an array to defend against oxidative stress. Single antioxidant supplementation would not then be expected to have a remarkable influence on neurodegenerative diseases, which may involve free radicals. Thus, using combinations of antioxidants with different subcellular distributions and different properties for prophylaxis or treatment would probably improve therapeutic outcomes. Based on their multifactoral aetiology, the development of novel antioxidants with anti-inflammatory and metal-chelating properties and the ability to improve metabolism, for example by increasing ATP production rate or a new formulation of antioxidants with other agents, which have different functions, will become the new strategies in protecting against neurodegenerative disorders.     

Acetyl-L-Carnitine selectively prevents post-ischemic LTP via a possible action on mitochondrial energy metabolism

It has been hypothesized that Acetyl-L-Carnitine (ALC) contributes to mitochondrial ATP production through maintenance of key mitochondrial proteins and protects mitochondria against oxidative stress. We have investigated the role of ALC on the expression of two forms of synaptic plasticity in the striatum: (i) the physiological long-term potentiation (LTP) and (ii) the ischemic long-term potentiation (i-LTP), an aberrant form of synaptic plasticity occurring after in vitro ischemia. The application in vitro of ALC did not alter the induction or the maintenance of physiological activity-dependent LTP, while it prevented i-LTP in a dose-dependent manner. The ability of ALC to prevent i-LTP was not affected by previous application of scopolamine, a non-selective muscarinic receptors antagonist. Given the susceptibility of mitochondrial complex IV to ischemic oxidative insult, we investigated the role of this complex as possible target of ALC action. Thus, the application of a low dose of the mitochondrial toxin sodium azide, conventionally used as a model of hypoxia due to its capability to inhibit mitochondrial complex IV, induced a pathological synaptic potentiation that was fully prevented by ALC application. In the presence of a very low dose of the mitochondrial uncoupler FCCP, ALC no longer prevented i-LTP suggesting that neuroprotective effects of ALC require a compensatory activity of mitochondrial energy metabolism. Our data demonstrate that ALC exerts neuroprotective effects by preventing the expression of pathological synaptic plasticity induced by ischemia. These effects crucially depend on the ability on ALC to affect mitochondrial processes.