Synaptic dysfunction and oxidative stress in Alzheimer's disease: emerging mechanisms

In this paper, we review experimental advances in molecular neurobiology of Alzheimer's disease (AD), with special emphasis on analysis of neural function of proteins involved in AD pathogenesis, their relation with several signaling pathways and with oxidative stress in neurons. Molecular genetic studies have found that mutations in APP, PS1 and PS2 genes and polymorphisms in APOE gene are implicated in AD pathogenesis. Recent studies show that these proteins, in addition to its role in beta-amyloid processing, are involved in several neuroplasticity-signaling pathways (NMDA-PKA-CREB-BDNF, reelin, wingless, notch, among others). Genomic and proteomic studies show early synaptic protein alterations in AD brains and animal models. DNA damage caused by oxidative stress is not completely repaired in neurons and is accumulated in the genes of synaptic proteins. Several functional SNPs in synaptic genes may be interesting candidates to explore in AD as genetic correlates of this synaptopathy in a "synaptogenomics" approach. Thus, experimental evidence shows that proteins implicated in AD pathogenesis have differential roles in several signaling pathways related to neuromodulation and neurotransmission in adult and developing brain. Genomic and proteomic studies support these results. We suggest that oxidative stress effects on DNA and inherited variations in synaptic genes may explain in part the synaptic dysfunction seen in AD.     

Oxidative stress in patients with cardiovascular disease and chronic renal failure

Abstract

Oxidative response regulates many physiological response in human health, but if not properly regulated it could also lead to a number of deleterious effects. The importance of oxidative stress injury depends on the molecular target, the severity of the stress, and the mechanism by which the oxidative stress is imposed: it has been implicated in several diseases including cancer, neurodegenerative diseases, malaria, rheumatoid arthritis and cardiovascular and kidney disease. Most of the common diseases, such as hypertension, atherosclerosis, heart failure, and renal dysfunction, are associated with vascular functional and structural alterations including endothelial dysfunction, altered contractility, and vascular remodeling. Common to these processes is increased bioavailability of reactive oxygen species (ROS), decreased nitric oxide (NO) levels, and reduced antioxidant capacity. Oxidative processes are up-regulated also in patients with chronic renal failure (CRF) and seem to be a cause of elevated risk of morbidity and mortality in these patients.

In this review, we highlight the role of oxidative stress in cardiovascular and renal disease.     

内质网应激与心血管疾病研究概述

内质网应激是继死亡受体信号途径和线粒体途径之后新近发现的一条细胞凋亡通路,适度的应激可通过未折叠蛋白反应(UPR)产生细胞保护作用,但当应激过强或长时间不缓解时则会触发CHOP、ASK1/JNK及Caspases等通路诱导细胞凋亡。近年来研究发现内质网应激参与多种心血管疾病的发生发展,通过对相关通路的干预可以产生心肌细胞的保护作用,这有望成为防治心脏疾病的新靶点。     

Gender differences in free radical homeostasis during aging: shorter-lived female C57BL6 mice have increased oxidative stress

Gender is a profound determinant of aging and lifespan, but little is known about gender differences in free radical homeostasis. Free radicals are proposed as key elements in the multifactorial process of aging and it is predicted that the longer-lived gender should have lower levels of oxidative stress. While the majority of studies on aging have included a single gender, recent studies in rats compared genders and found that females, the longer-lived sex, had lower oxidative stress and mitochondrial dysfunction than males. We explored the association between oxidative stress and gender-specific aging in C57BL6 mice, in which females are the shorter-lived gender. Reactive oxygen species (ROS) were measured in young and old mice by confocal imaging of dihydroethidium (DHE) oxidation in the brain, and by electron paramagnetic resonance (EPR) spectrometry of isolated brain mitochondria. Both genders exhibited significant age-dependent increases in ROS. However, females had a greater increase with age than males in DHE oxidation but not mitochondrial EPR. Superoxide dismutase 1 (Sod1) and glutathione peroxidase 1 (GPx1) protein levels were lower in old females. To determine whether enhancing antioxidant defenses would eliminate gender differences in lifespan, mice were treated chronically with a superoxide dismutase mimetic. Treatment blocked the age-dependent increase in ROS, with a greater effect in females on DHE oxidation, but not mitochondrial EPR. Treatment also increased lifespan to a greater degree in females. Our results indicate that differences in ROS homeostasis contribute to gender divergence in survival, but also suggest that mitochondrial superoxide production may not be primarily responsible for gender differences in lifespan.     

Relationship between oxidative stress and erectile function

The aim of this study was to investigate markers of inflammation and oxidative stress in the corpus cavernosum (CC) and to compare levels of inflammatory markers recorded in CC to venous blood from the arm to examine the potential impact of inflammatory parameters on erectile function and endothelial dysfunction in vitro. Ninety-seven patients with no complaint of erectile dysfunction (ED) at inclusion were prospectively included and completed the Erectile Function domain of the IIEF questionnaire. Several parameters, including lipids, MPO-dependent oxidised LDL (Mox-LDL), IL-8, IL-18, were measured. After RNA extraction, the expression of eNOS was analysed. A paired t-test was used for comparisons between arm and CC blood results. A two-way ANOVA was used to estimate the effects of IL-18 and IL-8 on the IIEF score. Mean patient age was 59?±?14.5 years. IL-18, Mox-LDL, and Mox-LDL/ApoB levels were significantly increased in CC compared to arm blood. The IIEF score was correlated with IL-18 levels in the venous blood (R?=??0.31, p?=?.003) and in the CC (R?=??0.37, p?=?.004) and with IL-8 (R?=??0.31, p?=?.009 and R?=??0.28, respectively, p?=?.02). There was a significant effect with the IL-18 on IIEF potentiated by high serum IL-8 concentrations. IL-18 and Mox-LDL significantly decreased eNOS mRNA expression in human aortic endothelial cell line (HAEC). These preliminary results address the importance of inflammation in the CC and highlight a difference in marker concentrations between venous and CC blood. However, they do not show any difference in terms of clinical erectile score predictivity. Involvement of inflammatory cytokines isolated in CC in the genesis of ED requires further studies.     

Pannexin hemichannels: A novel promising therapy target for oxidative stress related diseases

Pannexins, which contain three subtypes: pannexin‐1, ‐2, and ‐3, are vertebrate glycoproteins that form non‐junctional plasma membrane intracellular hemichannels via oligomerization. Oxidative stress refers to an imbalance of the generation and elimination of reactive oxygen species (ROS). Studies have shown that elevated ROS levels are pivotal in the development of a variety of diseases. Recent studies indicate that the occurrence of these oxidative stress related diseases is associated with pannexin hemichannels. It is also reported that pannexins regulate the production of ROS which in turn may increase the opening of pannexin hemichannels. In this paper, we review recent researches about the important role of pannexin hemichannels in oxidative stress related diseases. Thus, pannexin hemichannels, novel therapeutic targets, hold promise in managing oxidative stress related diseases such as the tumor, inflammatory bowel diseases (IBD), pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), cardiovascular disease, insulin resistance (IR), and neural degeneration diseases.

     

Telomere length and cardiovascular risk factors in a middle-aged population free of overt cardiovascular disease

Evidence assembled over the last decade shows that average telomere length (TL) acts as a biomarker for biological aging and cardiovascular disease (CVD) in particular. Although essential for a more profound understanding of the underlying mechanisms, little reference information is available on TL. We therefore sought to provide baseline TL information and assess the association of prevalent CVD risk factors with TL in subjects free of overt CVD within a small age range. We measured mean telomere restriction fragment length of peripheral blood leukocytes in a large, representative Asklepios study cohort of 2509 community-dwelling, Caucasian female and male volunteers aged approximately 35-55 years and free of overt CVD. We found a manifest age-dependent telomere attrition, at a significantly faster rate in men as compared to women. No significant associations were established with classical CVD risk factors such as cholesterol status and blood pressure, yet shorter TL was associated with increased levels of several inflammation and oxidative stress markers. Importantly, shorter telomere length was associated with an increasingly unhealthy lifestyle, particularly in men. All findings were age and gender adjusted where appropriate. With these cross-sectional results we show that TL of peripheral blood leukocytes primarily reflects the burden of increased oxidative stress and inflammation, whether or not determined by an increasingly unhealthy lifestyle, while the association with classical CVD risk factors is limited. This further clarifies the added value of TL as a biomarker for biological aging and might improve our understanding of how TL is associated with CVD.     

Transgenic plants: An insight into oxidative stress tolerance mechanisms

Environmental stresses considerably limit plant productivity. At the molecular level the negative effect of stress is often mediated by reactive oxygen species-initiated oxidative damage. Hence, it was hypothesised that increased tolerance to several environmental constraints could be achieved through enhanced tolerance to oxidative stress. In recent years much effort has been undertaken to improve oxidative stress tolerance by transforming plants with native or bacterial genes coding either for reactive oxygen species-scavenging enzymes or for enzymes modulating the cellular antioxidant capacity. This review deals with data on transgenic plants with altered antioxidant capacity and focuses on the new insight into the antioxidant defence mechanism given by this type of experimental model.     

Gender differences in oxidative stress in spinal cord of rats submitted to repeated restraint stress

Behavioral and neurochemical gender-specific effects have been observed following repeated stress. The aim of this study is to verify the effects of repeated restraint stress on free radical production (evaluated by DCF test), lipoperoxidation (evaluated by TBARS levels), and total antioxidant reactivity (TAR) in the spinal cord of male and female rats. Results demonstrate no effect on lipoperoxidation; chronic stress decreased TAR both in male and female spinal cord. In addition, gender differences were observed both in TAR and in the production of free radicals, both being increased in females. These results may be relevant to the gender-specific differences observed after exposure to repeated stress.     

ROS-challenged keratinocytes as a new model for oxidative stress-mediated skin diseases

In the current study, the effects of the reactive oxygen species (ROS) generator 2,2′-azobis(2-amidinopropane) dihydrochloride (AAPH) on extracellular and intracellular ROS production in human keratinocytes (HACAT) were studied. AAPH is a water-soluble compound able to generate ROS at known and constant rates at 37°C. The short treatment (2 h) with AAPH brought a significant dose-dependent increase in NADPH oxidase activity in intact keratinocytes. The long-term treatment (24 h) with AAPH led to a persistent increase in NADPH oxidase activity for up to 48 hour following the AAPH removal from cell incubation medium. ROS and nitric oxide levels, lipoperoxidation, intracellular calcium, mitochondrial superoxide production, and membrane potential were significantly modified in AAPH-treated HACAT. Superoxide dismutase (SOD) and/or catalase addition to HACAT revealed that untreated keratinocytes produce mostly superoxide anion (O ₂ ⁻), while AAPH-treated keratinocytes overproduce hydrogen peroxide (H ₂O ₂) in extracellular medium. H ₂O ₂ is particularly stable and plays important roles in several cell signaling pathways. Taken together, our findings suggest a cost-effective and easily reproducible in vitro model of stressed human keratinocytes releasing significantly elevated ROS amounts in extracellular medium with respect to control keratinocytes. The possible application of the proposed model for keratinocytes-melanocytes cross-talk studies is also suggested. The model of AAPH-stressed human keratinocytes described here can represent a useful tool for redox cross-talk studies between keratinocytes and other skin cell types, and applied for researches regarding skin pathologies associated with oxidative stress.     

Reducing oxidative/nitrosative stress: a newly-discovered genre for melatonin

The discovery of melatonin and its derivatives as antioxidants has stimulated a very large number of studies which have, virtually uniformly, documented the ability of these molecules to detoxify harmful reactants and reduce molecular damage. These observations have clear clinical implications given that numerous age-related diseases in humans have an important free radical component. Moreover, a major theory to explain the processes of aging invokes radicals and their derivatives as causative agents. These conditions, coupled with the loss of melatonin as organisms age, suggest that some diseases and some aspects of aging may be aggravated by the diminished melatonin levels in advanced age. Another corollary of this is that the administration of melatonin, which has an uncommonly low toxicity profile, could theoretically defer the progression of some diseases and possibly forestall signs of aging. Certainly, research in the next decade will help to define the role of melatonin in age-related diseases and in determining successful aging. While increasing life span will not necessarily be a goal of these investigative efforts, improving health and the quality of life in the aged should be an aim of this research.     

The role of endothelial dysfunction and oxidative stress in cerebrovascular diseases

Cerebrovascular diseases (CBD) are one of the most dangerous complications of atherosclerosis. The clinical consequences of CBD deeply impact quality of life and the prognosis of patients. Atherosclerosis is the main cause of CBD development. Hypertension, dyslipidemia, diabetes, smoking, obesity, and other risk factors explain the higher CBD incidence in the general population, as they are able to anticipate the clinical expression of atherosclerosis. These risk factors are effectively able to promote endothelial dysfunction which is the premise for the early, clinical expression of atherosclerosis. The mechanisms by which risk factors can influence the occurrence of CBD are different and not fully understood. The inflammatory background of atherosclerosis can explain a great part of it. In particular, the oxidative stress may promote the development of vascular lesions by negatively influencing biochemical cellular processes of the endothelium, thus predisposing the vascular tree to morphological and functional damages. The aim of this narrative review is to evaluate the role of endothelial dysfunction and oxidative stress in CBD development.     

Blood markers of oxidative stress in Alzheimer's disease

Alzheimer's disease (AD) represents a highly common form of dementia, but can be diagnosed in the earlier stages before dementia onset. Early diagnosis is crucial for successful therapeutic intervention. The introduction of new diagnostic biomarkers for AD is aimed at detecting underlying brain pathology. These biomarkers reflect structural or biochemical changes related to AD. Examination of cerebrospinal fluid has many drawbacks; therefore, the search for sensitive and specific blood markers is ongoing. Investigation is mainly focused on upstream processes, among which oxidative stress in the brain is of particular interest. Products of oxidative stress may diffuse into the blood and evaluating them can contribute to diagnosis of AD. However, results of blood oxidative stress markers are not consistent among various studies, as documented in this review. To find a specific biochemical marker for AD, we should concentrate on specific metabolic products formed in the brain. Specific fluorescent intermediates of brain lipid peroxidation may represent such candidates as the composition of brain phospholipids is unique. They are small lipophilic molecules and can diffuse into the blood stream, where they can then be detected. We propose that these fluorescent products are potential candidates for blood biomarkers of AD.     

Circular RNA: A new expectation for cardiovascular diseases

Circular RNA (circRNA) is a class of RNA with the 5' and 3' ends connected covalently to form a closed loop structure and characterized by high stability, conserved sequences and tissue specificity, which is caused by special reverse splicing methods. Currently, it has become a hot spot for research. With the discovery of its powerful regulatory functions and roles, the molecular mechanisms and future value of circRNA in participating in and regulating biological and pathological processes are becoming increasingly apparent. Among them is the increasing prevalence of cardiovascular diseases (CVDs). Many studies have elucidated that circRNA plays a crucial role in the development and progression of CVDs. Therefore, circRNA shows its advantages and brilliant expectations in the field of CVDs. In this review, we describe the biogenesis, bioinformatics detection and function of circRNA and discuss the role of circRNA and its effects on CVDs, including atherosclerosis, myocardial infarction, cardiac hypertrophy and heart failure, myocardial fibrosis, cardiac senescence, pulmonary hypertension, and diabetic cardiomyopathy by different mechanisms. That shows circRNA advantages and brilliant expectations in the field of CVDs.     

球孢白僵菌响应氧化胁迫的分子机制研究进展

球孢白僵菌作为模式丝状真菌,以分生孢子、菌丝体、虫菌体等多种形态存在,在真菌孢子发育、寄主与宿主互作的研究中具有重要意义。同时,球孢白僵菌又是一类广泛应用的真菌杀虫剂,对森林防护和农业生产具有实际应用价值。球孢白僵菌的相关基因被敲除后,突变体响应氧化胁迫,孢子发育和毒力会发生改变。本文综述了近年来球孢白僵菌在响应氧化胁迫方面的研究进展,为丝状真菌氧化胁迫信号途径的研究提供参考。     

Proteotoxic stress and circulating cell stress proteins in the cardiovascular diseases

The cardiovasculature is one of the major body systems and probably the one most exposed to stress. There is clear evidence that increasing levels of cell stress proteins within the heart is cardioprotective. In addition, there is rapidly emerging evidence that secreted cell stress proteins play a role in the function of the cardiovascular tissues. Those secreted proteins have three potential functions: (1) as normal homeostatic cardiovascular signals (e.g. protein disulphide isomerase); (2) as anti-inflammatory molecules, which are able to inhibit cardiovascular pathology (e.g. Hsp27); and (iii) as pro-inflammatory signals that can induce and promote cardiovascular pathology (e.g. Hsp60). As all of these various proteins may be released—at different rates—and in different cardiovascular diseases—we need to consider the cohort of potential secreted cell stress proteins as a dynamic system (network) that can aid and/or damage the equally dynamic cardiovascular system.     

Protective effects of a new metalloporphyrin on paraquat-induced oxidative stress and apoptosis in N27 cells

Paraquat （PQ, 1,1′-dimethyl-4,4′-bipyridinium）,awidely-used herbicide, has been suggested as a potential etiologic factor for the development of Parkinson＇s disease. In recent years, many studies have focused on the mechanism（s） of PQ neurotoxicity. In this study, we examined the neuroprotective effect of manganese （Ⅲ） meso-tetrakis （N,N′-diethylimi- dazolium） porphyrin （MnTDM）, a superoxide dismutase/ catalase mimetic, on PQ-induced oxidative stress and apoptosis in 1 RB3AN27 （N27） cells, a dopaminergic neuronal cell line. The results indicated that MnTDM significantly attenuated PQ-induced loss of cell viability, glutathione depletion, and reactive oxygen species production. MnTDM also ameliorated PQ-induced morphological nuclear changes of apoptosis and increased rates of apoptosis. In addition, our data provide direct evidence that MnTDM suppressed PQ- induced caspase-3 cleavage, possibly a key event of PQ neurotoxicity. These observations suggested that oxidative stress and apoptosis are implicated in PQ-induced neurotoxicity and this toxicity could be prevented by MnTDM. These findings also proposed a novel therapeutic approach for Parkinson＇s disease and other disorders associated with oxidative stress.     

Cell death and diseases related to oxidative stress:4-hydroxynonenal (HNE) in the balance

During the last three decades, 4-hydroxy-2-nonenal (HNE), a major α,β-unsaturated aldehyde product of n-6 fatty acid oxidation, has been shown to be involved in a great number of pathologies such as metabolic diseases, neurodegenerative diseases and cancers. These multiple pathologies can be explained by the fact that HNE is a potent modulator of numerous cell processes such as oxidative stress signaling, cell proliferation, transformation or cell death. The main objective of this review is to focus on the different aspects of HNE-induced cell death, with a particular emphasis on apoptosis. HNE is a special apoptotic inducer because of its abilities to form protein adducts and to propagate oxidative stress. It can stimulate intrinsic and extrinsic apoptotic pathways and interact with typical actors such as tumor protein 53, JNK, Fas or mitochondrial regulators. At the same time, due to its oxidant status, it can also induce some cellular defense mechanisms against oxidative stress, thus being involved in its own detoxification. These processes in turn limit the apoptotic potential of HNE. These dualities can imbalance cell fate, either toward cell death or toward survival, depending on the cell type, the metabolic state and the ability to detoxify.     

Evaluation of oxidative stress markers and cardiovascular risk factors in Fabry Disease patients

Fabry Disease, an X-linked inborn error of metabolism, is characterized by progressive renal insufficiency, with cardio and cerebrovascular involvement. Homocysteine (Hcy) is considered a risk factor for vascular diseases, but the mechanisms by which it produces cardiovascular damage are still poorly understood. Regarding the vascular involvement in FD patients, the analysis of factors related to thromboembolic events could be useful to improving our understanding of the disease. The aim of this study was to evaluate plasma Hcy and other parameters involved in the methionine cycle, as well as oxidative stress markers. The sample consisted of a group of 10 male FD patients and a control group of 8 healthy individuals, paired by age. Venous blood was collected for Hcy determination, molecular analysis, identification of thiobarbituric acid reactive substances, total glutathione and antioxidant enzymes activity, as well as vitamins quantification. Comparative analysis of FD patients versus the control group indicated hyperhomocysteinemia in 8 of the 10 FD patients, as well as a significant increase in overall glutathione levels and catalase activity. It is inferred that FD patients, apart from activation of the antioxidant system, present increased levels of plasma Hcy, although this is probably unrelated to common alterations in the methionine cycle.