Considerable evidence implicates oxidative stress in the pathophysiology of many complications of human pregnancy, and this topic has now become a major focus of both clinical and basic science research. Oxidative stress arises when the production of reactive oxygen species overwhelms the intrinsic anti-oxidant defences. Reactive oxygen species play important roles as second messengers in many intracellular signalling cascades aimed at maintaining the cell in homeostasis with its immediate environment. At higher levels, they can cause indiscriminate damage to biological molecules, leading to loss of function and even cell death. In this chapter, we will review how reactive oxygen species are generated and detoxified in the human placenta, and what roles they may play at homeostatic concentrations. We will then consider their involvement in normal placental development, and in complications ranging from miscarriage to pre-eclampsia and premature rupture of the membranes.
The pathophysiologies of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and Alzheimer’s disease (AD), are far from being fully explained. Oxidative stress (OS) has been proposed as one factor that plays a potential role in the pathogenesis of neurodegenerative disorders. Clinical and preclinical studies indicate that neurodegenerative diseases are characterized by higher levels of OS biomarkers and by lower levels of antioxidant defense biomarkers in the brain and peripheral tissues. In this article, we review the current knowledge regarding the involvement of OS in neurodegenerative diseases, based on clinical trials and animal studies. In addition, we analyze the effects of the drug-induced modulation of oxidative balance, and we explore pharmacotherapeutic strategies for OS reduction.
Oxidative stress is often defined as an imbalance of pro-oxidants and antioxidants, which can be quantified in humans as the redox state of plasma GSH/GSSG. Plasma GSH redox in humans becomes oxidized with age, in response to oxidative stress (chemotherapy, smoking), and in common diseases (type 2 diabetes, cardiovascular disease). However, data also show that redox of plasma GSH/GSSG is not equilibrated with the larger plasma cysteine/cystine (Cys/CySS) pool, indicating that the "balance" of pro-oxidants and antioxidants cannot be defined by a single entity. The major cellular thiol/disulfide systems, including GSH/GSSG, thioredoxin- 1 (-SH 2 /-SS-), and Cys/CySS, are not in redox equilibrium and respond differently to chemical toxicants and physiologic stimuli. Individual signaling and control events occur through discrete redox pathways rather than through mechanisms that are directly responsive to a global thiol/disulfide balance such as that conceptualized in the common definition of oxidative stress. Thus, from a mechanistic standpoint, oxidative stress may be better defined as a disruption of redox signaling and control. Adoption of such a definition could redirect research to identify key perturbations of redox signaling and control and lead to new treatments for oxidative stress-related disease processes.
There is increasing awareness of the ubiquitous role of oxidative stress in neurodegenerative disease states. A continuing challenge is to be able to distinguish between oxidative changes that occur early in the disease from those that are secondary manifestations of neuronal degeneration. This perspective highlights the role of oxidative stress in Alzheimer’s, Parkinson’s, and Huntington’s diseases, amyotrophic lateral sclerosis, and multiple sclerosis, neurodegenerative and neuroinflammatory disorders where there is evidence for a primary contribution of oxidative stress in neuronal death, as opposed to other diseases where oxidative stress more likely plays a secondary or by-stander role. We begin with a brief review of the biochemistry of oxidative stress as it relates to mechanisms that lead to cell death, and why the central nervous system is particularly susceptible to such mechanisms. Following a review of oxidative stress involvement in individual disease states, some conclusions are provided as to what further research should hope to accomplish in the field.
The ataxia-telangiectasia mutated (ATM) protein kinase is activated by DNA double-strand breaks (DSBs) through the Mre11-Rad50-Nbs1 (MRN) DNA repair complex and orchestrates signaling cascades that initiate the DNA damage response. Cells lacking ATM are also hypersensitive to insults other than DSBs, particularly oxidative stress. We show that oxidation of ATM directly induces ATM activation in the absence of DNA DSBs and the MRN complex. The oxidized form of ATM is a disulfide—cross-linked dimer, and mutation of a critical cysteine residue involved in disulfide bond formation specifically blocked activation through the oxidation pathway. Identification of this pathway explains observations of ATM activation under conditions of oxidative stress and shows that ATM is an important sensor of reactive oxygen species in human cells.
Abstract Mitochondria are involved in ATP supply to cells through oxidative phosphorylation (OXPHOS), synthesis of key molecules and response to oxidative stress, as well as in apoptosis. They contain many redox enzymes and naturally occurring inefficiencies of oxidative phosphorylation generate reactive oxygen species (ROS). CNS functions depend heavily on efficient mitochondrial function, since brain tissue has a high energy demand. Mutations in mitochondrial DNA (mtDNA), generation and presence of ROS and environmental factors may contribute to energy failure and lead to neurodegenerative diseases. Many rare metabolic disorders have been associated with mitochondrial dysfunction. More than 300 pathogenic mtDNA mutations involve proteins that regulate OXPHOS and mitochondrial structural integrity, and have also been described in neurodegenerative diseases with autosomal inheritance. Mitochondria may have an important role in ageing-related neurodegenerative disorders like Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). In primary mitochondrial and neurodegenerative disorders, there is strong evidence that mitochondrial dysfunction occurs early and has a primary role in pathogenesis. In the present review, we discuss several mitochondrial diseases as models of neurodegeneration.
Reactive oxygen and nitrogen species (RONS) are produced by several endogenous and exogenous processes, and their negative effects are neutralized by antioxidant defenses. Oxidative stress occurs from the imbalance between RONS production and these antioxidant defenses. Aging is a process characterized by the progressive loss of tissue and organ function. The oxidative stress theory of aging is based on the hypothesis that age-associated functional losses are due to the accumulation of RONS-induced damages. At the same time, oxidative stress is involved in several age-related conditions (ie, cardiovascular diseases [CVDs], chronic obstructive pulmonary disease, chronic kidney disease, neurodegenerative diseases, and cancer), including sarcopenia and frailty. Different types of oxidative stress biomarkers have been identified and may provide important information about the efficacy of the treatment, guiding the selection of the most effective drugs/dose regimens for patients and, if particularly relevant from a pathophysiological point of view, acting on a specific therapeutic target. Given the important role of oxidative stress in the pathogenesis of many clinical conditions and aging, antioxidant therapy could positively affect the natural history of several diseases, but further investigation is needed to evaluate the real efficacy of these therapeutic interventions. The purpose of this paper is to provide a review of literature on this complex topic of ever increasing interest.
Parkinson disease (PD) is a chronic, progressive neurological disease that is associated with a loss of dopaminergic neurons in the substantia nigra pars compacta of the brain. The molecular mechanisms underlying the loss of these neurons still remain elusive. Oxidative stress is thought to play an important role in dopaminergic neurotoxicity. Complex I deficiencies of the respiratory chain account for the majority of unfavorable neuronal degeneration in PD. Environmental factors, such as neurotoxins, pesticides, insecticides, dopamine (DA) itself, and genetic mutations in PD-associated proteins contribute to mitochondrial dysfunction which precedes reactive oxygen species formation. In this mini review, we give an update of the classical pathways involving these mechanisms of neurodegeneration, the biochemical and molecular events that mediate or regulate DA neuronal vulnerability, and the role of PD-related gene products in modulating cellular responses to oxidative stress in the course of the neurodegenerative process.
The discovery of the colocalization of catalase with H O -generating oxidases in peroxisomes was the first indication of their involvement in the metabolism of oxygen metabolites. In past decades it has been revealed that peroxisomes participate not only in the generation of reactive oxygen species (ROS) with grave consequences for cell fate such as malignant degeneration but also in cell rescue from the damaging effects of such radicals. In this review the role of peroxisomes in a variety of physiological and pathological processes involving ROS mainly in animal cells is presented. At the outset the enzymes generating and scavenging H O and other oxygen metabolites are reviewed. The exposure of cultured cells to UV light and different oxidizing agents induces peroxisome proliferation with formation of tubular peroxisomes and apparent upregulation of PEX genes. Significant reduction of peroxisomal volume density and several of their enzymes is observed in inflammatory processes such as infections, ischemia–reperfusion injury and hepatic allograft rejection. The latter response is related to the suppressive effects of TNFα on peroxisomal function and on PPARα. Their massive proliferation induced by a variety of xenobiotics and the subsequent tumor formation in rodents is evidently due to an imbalance in the formation and scavenging of ROS, and is mediated by PPARα. In PEX5 mice with the absence of functional peroxisomes severe abnormalities of mitochondria in different organs are observed which resemble closely those in respiratory chain disorders associated with oxidative stress. Interestingly, no evidence of oxidative damage to proteins or lipids, nor of increased peroxide production has been found in that mouse model. In this respect the role of PPARα, which is highly activated in those mice, in prevention of oxidative stress deserves further investigation.
Much has been learnt about oxidative stress from studies of . Key regulators of the adaptive responses in this organism are the SoxRS and OxyR transcription factors, which induce the expression of antioxidant activities in response to O - and H O stress, respectively. Recently, a variety of biochemical assays together with the characterization of strains carrying mutations affecting the antioxidant activities and the regulators have given general insights into the sources of oxidative stress, the damage caused by oxidative stress, defenses against the oxidative stress, and the mechanisms by which the stress is perceived. These studies have also shown that the oxidative stress responses are intimately coupled to other regulatory networks in the cell.