氧化应激与阿尔采末病

阿尔采末病(Alzheimer’s disease,AD)是一种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退行性疾病。对AD的发病机制存在多种假说,其中氧化应激假说目前越来越受到重视。该文从自由基来源、AD病理特征与氧化应激的关系、相关的动物和临床相关研究、常用抗氧化剂和磷酸二酯酶抑制剂在抗氧化应激方面对AD的治疗作用等,对近年来国内外氧化应激与AD关系的研究进行简要综述。     

阿尔茨海默病的氧应激与阿魏酸的抗氧化作用

阿尔茨海默病(Alzheimer’s disease,AD)是一种神经系统退行性疾病,自由基损伤在发病机理中起重要作用。本文综述AD自由基的产生机制,以及AD与氧应激的关系。探讨阿魏酸与金属螯合剂的抗氧化作用,为治疗AD提供一种新思路。     

抗氧化剂在防治阿尔茨海默病中的效果和安全性评价

阿尔茨海默病（Alzheimer＇s disease,AD）属于常见的神经退行性疾病,以进行性认知功能减退为主要特征,至今病因未明,也没有治愈AD的有效方法.抗氧化剂可以清除体内自由基,有助于预防和治疗与氧化应激相关的疾病,现已在抗衰老以及肿瘤、心血管疾病的防治中广泛使用.近年来,国内外学者尝试用抗氧化剂防治AD,但其使用剂量不同于在防治其他疾病时的用量,可能会带来潜在的危险.抗氧化剂在防治AD中的疗效和安全性究竟怎样？近年来出现了越来越多的负面结果和讨论,因此有必要客观评价该类药物在AD中的临床效果和安全性.     

自由基和抗氧化剂生物效应的双相性理论模型及核化生损伤医学防护的应用研究

目的:提出自由基和抗氧化剂双相性理论模型,建立统一的自由基和抗氧化剂生物效应理论模型,定性和定量描述自由基、抗氧化剂生物效应的双相性,研究完善Hormesis理论,并应用核化生损伤的医学防护等研究。方法:总结自由基生物医学最新成果的基础上,提出有关自由基和抗氧化剂的10个基本原理,建立了自由基和抗氧化剂双相性理论模型。结果:提出自由基和抗氧化剂双相性理论模型,建立了3个自由基和抗氧化剂双相性理论模型方程,定性和定量解释自由基和抗氧化剂生物效应的双相性,发现一类新的Hormesis效应,提出了两类Hormesis,提出双自由基致癌和抗癌理论模型,提出核化生损伤的统一的氧化还原应激损伤机理和防护措施,提出生态网络系统氧化剂药物的设计原理。结论:建立自由基和抗氧化剂双相性理论模型,定性和定量描述自由基和抗氧化剂生物效应的双相性;研究和完善了Hormesis效应理论,建立双自由基致癌和抗癌理论模型,提出生态网络系统氧化剂药物的设计原理,提出了核化生损伤统一氧化还原应激损伤机理和防护策略。     

依达拉奉对脑缺血再灌注损伤的保护机制

依达拉奉是一种合成的新型自由基清除剂和抗氧化剂,对缺血再灌注损伤具有神经保护作用,可通过消除自由基、抑制脂质过氧化减轻氧化应激损伤;通过调控凋亡相关基因的表达,抑制神经细胞的凋亡;并通过减少炎症因子的产生从而减轻脑缺血及脑缺血引起的水肿和组织损伤。本文主要综述依达拉奉在脑缺血再灌注损伤中保护作用机制的研究进展,为临床应用提供理论依据。     

生物活性多糖在防治阿尔茨海默病中的作用

阿尔茨海默病(AD)主要表现为认知功能障碍和记忆障碍,是一种中枢神经系统退化性疾病,发病机制复杂,目前临床尚未有能彻底治愈的有效药物。AD的病理学特征主要为脑细胞外β-淀粉样蛋白(Aβ)沉积形成的老年斑(SP),脑细胞内高度磷酸化的tau蛋白形成神经元纤维缠结(NFT)。AD病因及分子机制十分复杂,至今尚不明确,其中Aβ级联假说、自由基学说和Tau蛋白异常磷酸化学说占主要地位。目前临床上治疗AD主要以西药为主,但具有毒性大、易耐药等局限性。研究发现,中药及其有效成分如多糖具有改善学习记忆能力、抗Aβ沉积、抗NO诱导的神经毒性、抗氧化应激、抗自由基损伤、抗炎症和抑制神经细胞凋亡等多方面的作用,使其可以从多靶点的角度来对AD进行防治。多糖具有广泛的生物活性,越来越多的研究证据显示,多糖对AD的防治也具有一定的积极作用。本文详细综述了微生物多糖、植物多糖和动物多糖防治AD方面的药理作用及其机制研究进展。微生物多糖:保护神经细胞和突触,AD早期海马和内嗅皮质区域会出现神经元和突触的缺失,因此保护神经细胞和突触对于AD的治疗具有重要作用。灵芝多糖高、中剂量组能明显提高AD大鼠学习记忆能力,其提高大鼠记忆能力的作用可能是通过升高AD大鼠海马内降低的突触素/突触来实现的。植物多糖:(1)清除自由基、抗氧化,在AD发生发展过程中Aβ与氧化应激关系密切,Aβ可通过多种途径产生过氧化物和自由基,从而加剧过氧化作用对神经细胞的损伤。例如肉苁蓉多糖能明显升高AD大鼠脑组织超氧化物歧化酶(SOD)活性,降低脑内丙二醛含量,使脑内的氧自由基减少,所以肉苁蓉多糖提高AD大鼠的学习记忆能力,可能是通过减少氧自由基的损伤、加速体内自由基的清除以及抑制海马神经元的凋亡来实现的。(2)改善tau蛋白过度磷酸化,tau蛋白过度磷酸化导致NFT形成的主要原因之一,也是痴呆发病的重要机制之一。例如山茱萸多糖可通过抑制p-tau(Ser422)和p-tau(Ser396)生成,改善AD大鼠学习记忆能力。(3)抑制细胞凋亡,细胞凋亡与AD的发生、发展关系密切,AD患者大脑皮质和海马区的神经元丢失与神经细胞凋亡密切相关。所以通过抑制神经细胞凋亡延缓AD的病程进展。(4)改善能量代谢,脑组织神经细胞能量代谢障碍如葡萄糖代谢降低是AD患者的一个重要病理特征,因此改善脑组织的能量代谢障碍是目前抗痴呆的一个策略。宁夏枸杞多糖可通过缓解脑内葡萄糖代谢障碍从而改善衰老状态。动物多糖:改善中枢胆碱能系统,乙酰胆碱(ACh)是脑组织内重要的神经递质,脑内细胞外液中ACh的变化与认知功能的改变具有密切关系。综上所述,多糖具有防治阿尔茨海默病的作用,在抗AD药物开发方面有良好的应用前景。     

缺血性脑血管疾病治疗的抗氧化应激策略

自由基是细胞呼吸及正常代谢过程中产生的高活性分子 ,氧化应激 (OS)是细胞内自由基生成和清除能力失衡 ,是缺血性脑血管疾病重要病理反应过程。缺血性脑损伤后 ,活性氧自由基 (ROS)增加 ,以不同的细胞分子机制引起组织损伤。自由基可以损伤细胞内脂质、蛋白质、核酸等重要物质 ,继而通过坏死或凋亡的方式引起细胞死亡。抗氧化剂可防止脑组织损伤 ,改善神经细胞存活率及功能。本文就治疗缺血性脑血管疾病的抗氧化剂作一综述 ,并分析动物与临床试验结果不一致的原因 ,提出缺血性脑血管疾病治疗的抗氧化应激策略。     

抗氧化维生素在心肌缺血再灌注中的应用

心肌缺血再灌注（ischemia／reperfusion，I／R）损伤可以导致心律失常、心肌顿抑，改变已受损伤心肌细胞的坏死进程。心肌I／R过程中自由基对心肌的损伤是I／R损伤最重要的病理基础。应用抗氧化剂对抗I／R产生的自由基对心肌的损伤，有可能成为冠心病的一种新的治疗方向。笔者对维生素E、维生素C和辅酶Q（CoQ）在心肌I／R中作用的研究成果进行综述。以利今后的研究。     

栀子苷治疗阿尔采末病及神经保护的分子机制研究进展

阿尔采末病(AD)是一种中枢神经退行性疾病,以学习记忆和认知功能障碍为主要表现。Aβ毒性级联损伤是其核心病理之一。栀子苷是栀子的主要有效成分,其苷元为京尼平。实验研究表明,栀子苷和京尼平具有抗Aβ毒性损伤、抗氧化应激,抗内质网应激、抗炎症反应及促进神经生长作用。从分子作用机制角度综述近年来栀子苷及京尼平治疗AD和神经保护作用的有关文献,以期为栀子治疗AD提供借鉴。     

抗氧化剂与胃肠黏膜屏障损伤

<正>1 氧自由基及损伤作用含有一个不成对电子的分子或原子团称自由基。部分氧分子为活性氧簇(reactive oxygen spe- cies,ROS),包括过氧化氢、超氧阴离子自由基、羟自由基、一氧化氮黄嘌呤氧化酶(XO)自由基等。体内自由基的产生和清除应是平衡的,人体才能保持健康。如果自由基产生过多或清除自由基的能力下降,体内就会有多余的自由基(特别是氧自由基),会损伤细胞成分,导致疾病和衰老的发生。 ROS是许多疾病的特征。自由基和多种疾病有关, 包括与胃肠黏膜屏障损伤密切相关。各器官均有防御ROS形成即清除氧自由基的机制,从而可快速修复氧自由基造成的损伤。体内自由基清除体系主要包括抗氧化酶和抗氧化剂两类。自由基也涉及信号传导通路,如XO既参与传导,同时也是自由基清除剂。     

Dual effects of curcumin on neuronal oxidative stress in the presence of Cu(II)

Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders. Elevated copper (Cu) ions are thought to link AD pathology. Curcumin is suggested to treat AD because of its high anti-oxidative activity and coordination to transitional metal ions. In this study, the protective effect of curcumin against the Cu(II)-induced oxidative damage was investigated in primary rat cortical neurons. The neuronal damage was assessed by morphological observation, cell viability, and oxidative stress level. The results showed that curcumin at low dosage protected primary cultured neurons from the 20 μM Cu(II)-induced damage. Low dosage of curcumin depressed oxidative stress levels exacerbated by Cu(II). However, high dosage of curcumin failed to decrease the Cu(II)-induced oxidative stress. When Cu(II) was presented in primary neurons, curcumin at high dosage resulted in chromosomal aberration and cell damage. These results suggest that curcumin, in a concentration-dependent manner, plays both anti-oxidative and pro-oxidative roles in primary neurons treated with Cu(II).     

Oxidative stress in cardiovascular disease: a new avenue toward future therapeutic approaches

Oxidative stress is a common denominator in many aspects of the pathogenesis of atherosclerosis and cardiovascular diseases. Some drugs, such as vitamin C, vitamin E, and a free radical scavenger, edaravone, are prescribed with oxidative stress as their main target. Furthermore, of the drugs in current clinical use, such as anti-hypertension reagents including angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB), and anti-hyperlipidemic reagents like statins, protect various organs, e.g., vessel, brain, heart, and kidney, via anti-oxidative stress effects in addition to their original pharmacological properties. While results of clinical trials of anti-oxidative stress reagents in patients with cardiovascular disease are contradictory to date, this may be explained by a variety of reasons such as an inadequate study design. More competent anti-oxidative reagents are awaited, and superoxide dismutase mimetics, thiols, xanthine oxidase and NAD(P)H oxidase inhibitors, which regulate intracellular redox reaction and subsequently inhibit oxidative stress, are among promising candidates of future drug developments currently receiving much interest. In this review, the current advances will be highlighted in development of novel anti-oxidative therapeutic approaches against cardiovascular diseases.     

Review article: the role of oxidative stress in pathogenesis and treatment of inflammatory bowel diseases

In this review, we focus on the role of oxidative stress in the aetiology of inflammatory bowel diseases (IBD) and colitis-associated colorectal cancer and discuss free radicals and free radical-stimulated pathways as pharmacological targets for anti-IBD drugs. We also suggest novel anti-oxidative agents, which may become effective and less-toxic alternatives in IBD and colitis-associated colorectal cancer treatment. A Medline search was performed to identify relevant bibliography using search terms including: ‘free radicals,’ ‘antioxidants,’ ‘oxidative stress,’ ‘colon cancer,’ ‘ulcerative colitis,’ ‘Crohn’s disease,’ ‘inflammatory bowel disease.’ Several therapeutics commonly used in IBD treatment, among which are immunosuppressants, corticosteroids and anti-TNF-α antibodies, could also affect the IBD progression by interfering with cellular oxidative stress and cytokine production. Experimental data shows that these drugs may effectively scavenge free radicals, increase anti-oxidative capacity of cells, influence multiple signalling pathways, e.g. MAPK and NF-kB, and inhibit pro-oxidative enzyme and cytokine concentration. However, their anti-oxidative and anti-inflammatory effectiveness still needs further investigation. A highly specific antioxidative activity may be important for the clinical treatment and relapse of IBD. In the future, a combination of currently used pharmaceutics, together with natural and synthetic anti-oxidative compounds, like lipoic acid or curcumine, could be taken into account in the design of novel anti-IBD therapies.     

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。     

Intranasal administration of dauricine loaded on graphene oxide: multi-target therapy for Alzheimer's disease

Alzheimer''s disease (AD) is a degenerative disease of the central nervous system characterized by progressive cognitive and memory-related impairment. However, current therapeutic treatments have not proved sufficiently effective, mainly due to the complicated pathogenesis of the disease. In this study, a nano-formulation of graphene oxide (GO) loaded with dauricine (Dau) was investigated in terms of the combined anti-inflammatory and anti-oxidative stress effects of Dau and the inhibition of misfolding and aggregation of the amyloid-β (Aβ) protein by GO. Both in vivo and in vitro models were induced using Aβ_1-42, and the formulation was administered nasally in mice. The results showed that GO loaded with Dau greatly reduced oxidative stress through increasing superoxide dismutase levels and decreasing reactive oxygen species and malondialdehyde levels in vitro; it also alleviated the cognitive memory deficits and brain glial cell activation in mice with Aβ_1-42-induced AD. This proved that GO loaded with Dau could protect against Aβ_1-42-induced oxidative damage and apoptosis in both in vitro and in vivo AD models; therefore, GO loaded with Dau has the potential to be an effective and agent for the rapid treatment of AD.     

Antioxidant pathways in Alzheimer's disease: possibilities of intervention

Alzheimer's disease (AD) is closely related to the occurrence of oxidative stress. It was claimed that all pathophysiological mechanisms involved in the onset and progression of AD are related to oxidative stress. Thus, it is important to evaluate if there is oxidative stress as well as the mechanism by which this happens in AD patients as well as in animal models of AD. Extracellular plaques of amyloid b peptides (Aβ), a hallmark of the disease, have been postulated to be more protective than damaging in terms of oxidative stress because they may be chemical sinks in which heavy metals are placed. More than a decade ago we reasoned that damage due to Ab might be caused not by extracellular, but rather intracellular Ab peptide interacting with normal cell metabolism. Ab binds to mitochondrial membranes, interacts with heme and thus interferes with the normal electron flow through the respiratory chain. This results in a faulty mitochondrial energy metabolism and in an increased production of reactive oxygen species (ROS). The low mitochondrial energy metabolism may important to explain the hypo metabolism observed in AD patients in vivo (measured by positron emission tomography) and in isolated neurons incubated in the presence of Ab peptide. The increased ROS production results in oxidative stress. The occurrence of such stress provides the basis for a putative treatment of AD with antioxidants. Major efforts have been made to determine whether antioxidant supplementation could be a means of preventing, or even treating AD, but this idea is far from being well- established. We found that even though there is oxidative stress in AD, the administration of antioxidant vitamins, particularly vitamin E, is not effective in preventing the progression of the disease in all patients. We termed this the vitamin E paradox in AD. The paradox is the fact that for some patients, vitamin E could even be detrimental whereas for others vitamin E treatment partially prevents the loss memory associated with the progression of the disease. It is clear, however, that increasing the intake of fruits and vegetables rich in antioxidant vitamins, prevents or retards the onset of AD. Thus, the issue of whether antioxidant treatment is of use in AD is not settled and more research is warranted to clarify this point.     

Glutathione-related factors and oxidative stress in autism, a review

Autism spectrum disorders are complex neuro-developmental disorders whose neurobiology is proposed to be associated with oxidative stress which is induced by reactive oxygen species. The process of oxidative stress can be a target for therapeutic interventions. In this study, we aimed to review the role of oxidative stress, plasma glutathione (GSH), and related factors as the potential sources of damage to the brain as well as the possible related factors which reduce the oxidative stress. Methylation capacity, sulfates level, and the total glutathione level are decreased in autism. On the other hand, both oxidized glutathione and the ratio of oxidized to reduced glutathione are increased in autism. In addition, the activity of glutathione peroxidase, superoxide dismutase, and catalase, as a part of the antioxidative stress system are decreased. The current literature suggests an imbalance of oxidative and anti-oxidative stress systems in autism. Glutathione is involved in neuro-protection against oxidative stress and neuro-inflammation in autism by improving the anti-oxidative stress system. Decreasing the oxidative stress might be a potential treatment for autism.     

Alzheimer's disease and oxygen radicals: new insights

Alzheimer's disease (AD) is the most common form of neurodegenerative disease, with dementia, in the elderly. In addition to the presence of senile plaques and neurofibrillary tangles, the AD brain exhibits evidence for oxygen radical-mediated damage, a situation commonly known as oxidative stress. However, the ability to directly implicate this mechanism in AD has been a difficult task for several reasons. First, most of the analytical approaches used to investigate oxidative stress turned out to be unreliable. Second, the majority of the published studies have been performed in post-mortem tissues with advanced disease, leaving open the question as to whether oxidative stress is an early event or a common final step secondary to the degenerative process. The discovery of the isoprostanes, recent studies performed in living patients, and the development of transgenic animal models of AD-amyloidosis are three important factors that are helping us to better understand and define the role that oxygen radicals might play in AD pathogenesis. Here we review some of the most recent works that have supported the importance of oxygen radical-mediated damage in AD. The accumulated information points toward an earlier involvement than previously thought of oxidative stress in the pathogenesis of the disease, making this a potential target for therapeutic intervention, especially in subjects at high risk for developing AD.     

The role of statins in oxidative stress and cardiovascular disease

Statins have emerged as a highly efficacious class of drugs in the prevention of cardiovascular events. The primary mechanism of its cardioprotective effect is likely through its effectiveness in lowering serum lipids, particularly the low density lipoprotein (LDL) fractions. Recent studies suggest that statins also confer direct beneficial effects on the vascular cells in the attenuation of the atherogenic process through a variety of mechanisms. It remains the current dogma that oxidative modification of the LDL particles in the vessel wall plays a critical role for these lipoprotein particles to initiate the atherogenic cascade. The current failure of a number of antioxidants, which includes vitamin E, to favorably impact on the cardiovascular outcome in large scale clinical trials attests to the complexity of the oxidation processes in biological systems. In this review, we will highlight the current advances in a number of endogenous pro-oxidative and anti-oxidative systems in how they contribute to the net oxidative stress and how statin drugs may modulate this complex array of pro- and anti-oxidative processes.