Oxidants in asthma and in chronic obstructive pulmonary disease (COPD)

Experimental and clinical evidences suggest that oxidants play a role in the pathogenesis of respiratory disorders characterised by chronic airway inflammation such as asthma and chronic obstructive pulmonary disease (COPD). The respiratory system is chronically exposed to environmental pollutants, including oxidants. Exogenous sources of oxidants are particularly relevant to the pathogenesis of COPD, being cigarette smoke an extremely rich source of oxidants. In addition, the inflammatory cells recruited to the airways of patients with asthma and COPD, have an exceptional capacity to produce oxidants. Many decades of research have produced a significant amount of data indicating pro-oxidative molecular mechanisms putatively relevant in the pathogenesis of the oxidative stress which characterises these diseases, both locally and systemically. As a consequence, a drug therapy able to restore the redox imbalance in asthma and COPD would probably exert clinical and functional benefits. Indeed, currently available therapies for asthma and COPD can exert an inhibitory effect on oxidant production in the airways. However, it is unknown whether the efficacy of the treatment is somehow linked to the pharmacological modulation of the oxidant/antioxidant balance. So far, it appears that the potential role of antioxidant compounds in the treatment of asthma and COPD has not been fully explored.     

Bioactive effects of olive oil phenolic compounds in humans: reduction of heart disease factors and oxidative damage

Oxidative stress is defined as an imbalance between the oxidant and antioxidant systems of the body, in favour of the oxidants. Oxidative stress produced by free radicals has been linked to the development of several diseases such as cardiovascular, cancer, and neurodegenerative diseases. Olive oil is the main source of fat of the Mediterranean diet which has been shown to be effective against oxidative stress associated diseases and also with the ageing. Besides its richness in monounsaturated fatty acid, the oleic acid, olive oil contains minor components with antioxidant properties. Here, we update the state of the art, and degree of evidence, of the body of knowledge concerning the protective role on lipids and lipid oxidative damage in humans of the olive oil phenolic compounds.     

Antioxidant treatment for lung diseases

The lung is constantly exposed to endogenous (i.e., recruitment of inflammatory cells) as well exogenous sources of oxidative stress (i.e., oxygen, air pollution and tobacco smoke and particulate matter) and, therefore, is well-equipped with multiple antioxidant mechanisms. Increased pulmonary exposure to oxidative sources and/or reduced antioxidant defences may lead to an imbalance known as oxidative stress. The pulmonary effects of this oxidant–antioxidant imbalance can vary from progressive airway remodelling to overwhelming lung injury, depending on its severity and chronicity. This review will discuss the main sources for oxidation in the lung and how they relate to pulmonary antioxidant mechanisms, together with the mechanisms by which oxidative stress leads to an amplification of the inflammatory cascade, as well as the development of antioxidant mechanisms. This section will be followed by an in-depth discussion of each class of antioxidants, including current therapeutic uses and potential clinical applications related to lung diseases. Antioxidant treatment has had limited therapeutic success even for lung disorders, in which oxidative stress is known to play an important role. Potential reasons to explain antioxidant limitations will be discussed in the Expert opinion section of this review.     

Oxidative stress in allergic and irritant dermatitis: from basic research to clinical management

Allergic and irritant skin diseases may be the results of representative inflammatory response in the skin. It has been established that inflammatory response includes reactive oxygen species, reactive nitrogen species, and free radicals. Subsequently, an imbalance between the oxidant and antioxidant components occurs; this is so-called oxidative stress. As various important roles of oxidative stress in contact dermatitis have been reported, controlling oxidative stress in these diseases could be a supplementary and/or novel therapeutic approach. However, there is little convincing clinical evidence that modulation of oxidative stress can be used therapeutically to modulate inflammatory response in allergic and irritant skin diseases. The reason for this discrepancy may be partially due to an insufficient understanding of the dynamics of oxidative stress in allergic and irritant skin diseases. This review introduces the importance of oxidative stress in allergic and irritant skin diseases from basic research to clinical management aspects. This review also introduces recent patents for the methods and compositions for the treatment of skin diseases with antioxidants. These methods may be helpful in treating allergic and irritant skin diseases through topical application of antioxidants.     

The role of selenium,zinc and antioxidant vitamin supplementation in the treatment of bronchial asthma: adjuvant therapy or not?

In the last few years, nutrition has represented an important conditioning factor of many cardiovascular, gastrointestinal and pulmonary chronic diseases. Many published works have documented specific inflammatory abnormalities in the airways of subjects with mild-to-moderate persistent bronchial asthma in which the inflammation state is often associated with an increased generation of reactive oxygen species and free radical-mediated reactions. This evidence has stimulated many researchers to suppose that the oxidative stress could be an important pathogenetic determining factor in the progression of chronic diseases, and the decrease of oxidant insults to the lung can be modified with antioxidant supplementary therapy. There are many studies regarding dietary interventions that confirm the relationship to oxidative stress, bronchial inflammation, the development of asthmatic symptoms and the lowered cellular reducing capacity. Simple dietary and environmental supplementations significantly reduce the oxidant stress, minimise the development of asthmatic symptoms, and should prove to be an effective new approach to asthma management in addition to current pharmacological strategies. Many randomised controlled trials with antioxidant vitamins and trace element supplements have not confirmed the results shown in other clinical trials. The aim of this review is to focus the attention on published works discussing the relationship between asthma and nutritional supplements (some trace elements and vitamins) and the effectiveness of these supplements in the treatment of bronchial asthma.     

The role of selenium, zinc and antioxidant vitamin supplementation in the treatment of bronchial asthma: adjuvant therapy or not?

In the last few years, nutrition has represented an important conditioning factor of many cardiovascular, gastrointestinal and pulmonary chronic diseases. Many published works have documented specific inflammatory abnormalities in the airways of subjects with mild-to-moderate persistent bronchial asthma in which the inflammation state is often associated with an increased generation of reactive oxygen species and free radical-mediated reactions. This evidence has stimulated many researchers to suppose that the oxidative stress could be an important pathogenetic determining factor in the progression of chronic diseases, and the decrease of oxidant insults to the lung can be modified with antioxidant supplementary therapy. There are many studies regarding dietary interventions that confirm the relationship to oxidative stress, bronchial inflammation, the development of asthmatic symptoms and the lowered cellular reducing capacity. Simple dietary and environmental supplementations significantly reduce the oxidant stress, minimise the development of asthmatic symptoms, and should prove to be an effective new approach to asthma management in addition to current pharmacological strategies. Many randomised controlled trials with antioxidant vitamins and trace element supplements have not confirmed the results shown in other clinical trials. The aim of this review is to focus the attention on published works discussing the relationship between asthma and nutritional supplements (some trace elements and vitamins) and the effectiveness of these supplements in the treatment of bronchial asthma.     

Uric acid and oxidative stress

Uric acid is the final product of purine metabolism in humans. The final two reactions of its production catalyzing the conversion of hypoxanthine to xanthine and the latter to uric acid are catalysed by the enzyme xanthine oxidoreductase, which may attain two inter-convertible forms, namely xanthine dehydrogenase or xanthine oxidase. The latter uses molecular oxygen as electron acceptor and generates superoxide anion and other reactive oxygen products. The role of uric acid in conditions associated with oxidative stress is not entirely clear. Evidence mainly based on epidemiological studies suggests that increased serum levels of uric acid are a risk factor for cardiovascular disease where oxidative stress plays an important pathophysiological role. Also, allopurinol, a xanthine oxidoreductase inhibitor that lowers serum levels of uric acid exerts protective effects in situations associated with oxidative stress (e.g. ischaemia-reperfusion injury, cardiovascular disease). However, there is increasing experimental and clinical evidence showing that uric acid has an important role in vivo as an antioxidant. This review presents the current evidence regarding the antioxidant role of uric acid and suggests that it has an important role as an oxidative stress marker and a potential therapeutic role as an antioxidant. Further well designed clinical studies are needed to clarify the potential use of uric acid (or uric acid precursors) in diseases associated with oxidative stress.     

Oxidative stress in human diseases

Oxidative stress is an abnormal phenomenon occurring inside our cells or tissues when production of oxygen radicals exceeds their antioxidant capacity. Excess of free radicals damage essential macromolecules of the cell, leading to abnormal gene expression, disturbance in receptor activity, proliferation or cell dye, immunity perturbation, mutagenesis, protein or lipofushin deposition. Numerous human diseases involve during the pathological process such a stress, localized or general (in the same way as inflammation). In many serious diseases such as cancer, ocular degeneration (age related macular degeneration or cataract), neurodegenerative diseases (ataxia, amyotrophic lateral sclerosis, Alzheimer's disease) stress is the factor original. In familial amyotrophic lateral sclerosis the genetic abnormality occurred an abnormal coding for an antioxidant enzyme, copper-zinc super oxide dismutase. In various other diseases oxidative stress occur secondary to the initial disease but plays an important in role immune or vascular complications. This is the case in infectious disease such as AIDS or septic shock, Parkinson's disease or renal failure. So antioxidant treatment seems logical to be tested in these pathologies. But they have to be applied early in the process, before irreversible mechanisms. They need also to be prescribed at low doses as baseline free radical production have to be preserved to maintain useful activity that cannot be suppressed.     

Dual effects of antioxidants in neurodegeneration: direct neuroprotection against oxidative stress and indirect protection via suppression of glia-mediated inflammation

Oxidative stress, in which production of highly reactive oxygen species (ROS) and reactive nitrogen species (RNS) overwhelms antioxidant defenses, is a feature of many neurological diseases and neurodegeneration. ROS and RNS generated extracellularly and intracellularly by various processes initiate and promote neurodegeneration in CNS. ROS and RNS can directly oxidize and damage macromolecules such as DNA, proteins, and lipids, culminating in neurodegeneration in the CNS. Neurons are most susceptible to direct oxidative injury by ROS and RNS. ROS and RNS can also indirectly contribute to tissue damage by activating a number of cellular pathways resulting in the expression of stress-sensitive genes and proteins to cause oxidative injury. Moreover, oxidative stress also activates mechanisms that result in a glia-mediated inflammation that also causes secondary neuronal damage. Associated with neuronal injuries caused by many CNS insults is an activation of glial cells (particularly astrocytes and microglia) at the sites of injury. Activated glial cells are thus histopathological hallmarks of neurodegenerative diseases. Even though direct contact of activated glia with neurons per se may not necessarily be toxic, the immune mediators (e.g. nitric oxide and reactive oxygen species, pro-inflammatory cytokines and chemokines) released by activated glial cells are currently considered to be candidate neurotoxins. Therefore, study of the protective role of antioxidant compounds on inhibition of the inflammatory response and correcting the fundamental oxidant/antioxidant imbalance in patients suffering from neurodegenerative diseases are important vistas for further research. The purpose of this review is to summarize the current evidence in support of this critical role played by oxidative stress of neuronal and glial origin in neurodegenerative diseases. The mechanistic basis of the neuroprotective activity of antioxidants does not only rely on the general free radical trapping or antioxidant activity per se in neurons, but also the suppression of genes induced by pro-inflammatory cytokines and other mediators released by glial cells. We propose that combinations of agents which act at sequential steps in the neurodegenerative process can produce additive neuroprotective effects. A cocktail of multiple antioxidants with anti-inflammatory agents may be more beneficial in the prevention of neurodegenerative disease. A clearer appreciation of the potential therapeutic utility of antioxidants would emerge only when the complexity of their effects on mechanisms that interact to determine the extent of oxidative damage in vivo are more fully defined and understood.     

Nrf2-ARE信号通路功能与临床疾病及相关药物的研究新进展

Nrf2（NF-E2-related factor 2）核因子E2相关因子是一种机体抵抗内界和外界氧化或化学等刺激的中枢调节者。Nrf2-ARE则是近年来新发现的细胞氧化应激反应的关键传导通路,当其在体内被有毒有害物质激活后转位进入细胞核能与抗氧化反应元件（antioxidant response element,ARE）结合形成Nrf2-ARE信号通路,从而调控下游抗氧化蛋白、氧化酶和Ⅱ相解毒酶等。研究发现该通路在抗衰老、抗肿瘤、抗炎症、神经损伤、眼科等多方面均有重要作用。以Nrf2为靶点的药物有望用于肿瘤、糖尿病、神经退行性疾病等。本文综述了Nrf2-ARE信号通路功能及以其为靶点的药物研究的进展。     

Brain as a critical target of mercury in environmentally exposed fish (Dicentrarchus labrax)--bioaccumulation and oxidative stress profiles

Although mercury is recognized as a potent neurotoxicant, information regarding its threat to fish brain and underlying mechanisms is still scarce. In accordance, the objective of this work was to assess vulnerability of fish to mercury neurotoxicity by evaluating brain pro-oxidant status in wild European sea bass (Dicentrarchus labrax) captured in an estuarine area affected by chlor-alkali industry discharges (Laranjo Basin, Ria de Aveiro, Portugal). To achieve this goal, brain antioxidant responses such as catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST) activities and total glutathione (GSHt) content were measured. Additionally, damage was determined as lipid peroxidation. To ascertain the influence of seasonal variables on both mercury accumulation and oxidative stress profiles, surveys were conducted in contrasting conditions-warm and cold periods. In the warm period, brain of fish from mercury contaminated sites exhibited ambivalent antioxidant responses, viz. higher GR activity and lower CAT activity regarded, respectively, as possible signs of protective adaptation and increased susceptibility to oxidative stress challenge. Though the risk of an overwhelming ROS production cannot be excluded, brain appeared to possess compensatory mechanisms and was able to avoid lipid peroxidative damage. The warm period was the most critical for the appearance of oxidative damage as no inter-site alterations on oxidative stress endpoints were detected in the cold period. Since seasonal differences were found in oxidative stress responses and not in mercury bioaccumulation, environmental factors affected the former more than the latter. This work increases the knowledge on mercury neurotoxicity in feral fish, highlighting that the definition of critical tissue concentrations depends on environmental variables.     

Emerging role of polyphenolic compounds in the treatment of neurodegenerative diseases: a review of their intracellular targets

Aging is the major risk factor for neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. A large body of evidence indicates that oxidative stress is involved in the pathophysiology of these diseases. Oxidative stress can induce neuronal damages, modulate intracellular signaling, ultimately leading to neuronal death by apoptosis or necrosis. Thus antioxidants have been studied for their effectiveness in reducing these deleterious effects and neuronal death in many in vitro and in vivo studies. Increasing number of studies demonstrated the efficacy of polyphenolic antioxidants from fruits and vegetables to reduce or to block neuronal death occurring in the pathophysiology of these disorders. These studies revealed that other mechanisms than the antioxidant activities could be involved in the neuroprotective effect of these phenolic compounds. We will review some of these mechanisms and particular emphasis will be given to polyphenolic compounds from green tea, the Ginkgo biloba extract EGb 761, blueberries extracts, wine components and curcumin.     

Oxidative DNA damage protection and repair by polyphenolic compounds in PC12 cells

Biological systems are frequently exposed to excessive reactive oxygen species, causing a disturbance in the cells natural antioxidant defence systems and resulting in damage to all biomolecules, including nucleic acids. In fact, oxidative DNA damage is described as the type of damage most likely to occur in neuronal cells. In this study, three polyphenolic compounds, luteolin, quercetin and rosmarinic acid, were investigated for their protective effects against oxidative DNA damage induced in PC12 cells, a neuronal cell model. Although luteolin and quercetin prevented the formation of strand breaks to a greater extent than rosmarinic acid, this last one presented the highest capacity to repair strand breaks formation. In addition, rosmarinic acid was the only compound tested that increased the repair of oxidized nucleotidic bases induced with the photosensitizer compound [R]-1-[(10-chloro-4-oxo-3-phenyl-4H-benzo[a]quinolizin-1-yl) carbonyl]-2-pyrrolidine-methanol (Ro 19-8022). The activity of repair enzymes was indicated by the in vitro base excision repair assay, using a cell-free extract obtained from cells previously treated with the compounds to incise DNA. The protective effect of rosmarinic acid was further confirmed by the increased expression of OGG1 repair gene, observed through real time RT-PCR. The data obtained is indicative that rosmarinic acid seems to act on the intracellular mechanisms responsible for DNA repair, rather than by a direct effect on reactive oxygen species scavenging, as deducted from the effects observed for luteolin and quercetin. Therefore, these results suggest the importance of these polyphenols, and in particular rosmarinic acid, as protectors of oxidative stress-induced DNA damage that commonly occurs in several pathological conditions, such as neurodegenerative diseases.     

Protective effects of salidroside on hydrogen peroxide-induced apoptosis in SH-SY5Y human neuroblastoma cells

Oxidative stress plays an important role in Alzheimer's disease and other neurodegenerative disorders. Salidroside, a phenylpropanoid glycoside isolated from Rhodiola rosea L, shows potent antioxidant property. In this paper, the neuroprotective effects of salidroside on hydrogen peroxide (H2O2)-induced apoptosis in SH-SY5Y cells were investigated. Pretreatment with salidroside markedly attenuated H2O2-induced cell viability loss and apoptotic cell death in a dose-dependent manner. The mechanisms by which salidroside protected neuron cells from oxidative stress included the induction of several antioxidant enzymes, thioredoxin, heme oxygenase-1, and peroxiredoxin-I; the downregulation of pro-apoptotic gene Bax and the upregulation of anti-apoptotic genes Bcl-2 and Bcl-X(L). Furthermore, salidroside dose-dependently restored H2O2-induced loss of mitochondrial membrane potential as well as the elevation of intracellular calcium level. These results suggest that salidroside has protective effects against oxidative stress-induced cell apoptosis, which might be a potential therapeutic agent for treating or preventing neurodegenerative diseases implicated with oxidative stress.