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Detailed studies in the past two decades have shown that redox active metals like iron (Fe), copper (Cu), chromium (Cr), cobalt (Co) and other metals undergo redox cycling reactions and possess the ability to produce reactive radicals such as superoxide anion radical and nitric oxide in biological systems. Disruption of metal ion homeostasis may lead to oxidative stress, a state where increased formation of reactive oxygen species (ROS) overwhelms body antioxidant protection and subsequently induces DNA damage, lipid peroxidation, protein modification and other effects, all symptomatic for numerous diseases, involving cancer, cardiovascular disease, diabetes, atherosclerosis, neurological disorders (Alzheimer's disease, Parkinson's disease), chronic inflammation and others. The underlying mechanism of action for all these metals involves formation of the superoxide radical, hydroxyl radical (mainly via Fenton reaction) and other ROS, finally producing mutagenic and carcinogenic malondialdehyde (MDA), 4-hydroxynonenal (HNE) and other exocyclic DNA adducts. On the other hand, the redox inactive metals, such as cadmium (Cd), arsenic (As) and lead (Pb) show their toxic effects via bonding to sulphydryl groups of proteins and depletion of glutathione. Interestingly, for arsenic an alternative mechanism of action based on the formation of hydrogen peroxide under physiological conditions has been proposed. A special position among metals is occupied by the redox inert metal zinc (Zn). Zn is an essential component of numerous proteins involved in the defense against oxidative stress. It has been shown, that depletion of Zn may enhance DNA damage via impairments of DNA repair mechanisms. In addition, Zn has an impact on the immune system and possesses neuroprotective properties. The mechanism of metal-induced formation of free radicals is tightly influenced by the action of cellular antioxidants. Many low-molecular weight antioxidants (ascorbic acid (vitamin C), alpha-tocopherol (vitamin E), glutathione (GSH), carotenoids, flavonoids, and other antioxidants) are capable of chelating metal ions reducing thus their catalytic activity to form ROS. A novel therapeutic approach to suppress oxidative stress is based on the development of dual function antioxidants comprising not only chelating, but also scavenging components. Parodoxically, two major antioxidant enzymes, superoxide dismutase (SOD) and catalase contain as an integral part of their active sites metal ions to battle against toxic effects of metal-induced free radicals. The aim of this review is to provide an overview of redox and non-redox metal-induced formation of free radicals and the role of oxidative stress in toxic action of metals., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

The neurodegenerative diseases, Alzheimer's disease (AD) and Parkinson's disease (PD), are age-related disorders characterized by the deposition of abnormal forms of specific proteins in the brain. AD is characterized by the presence of extracellular amyloid plaques and intraneuronal neurofibrillary tangles in the brain. Biochemical analysis of amyloid plaques revealed that the main constituent is fibrillar aggregates of a 39-42 residue peptide referred to as the amyloid-β protein (Aβ). PD is associated with the degeneration of dopaminergic neurons in the substantia nigra pars compacta. One of the pathological hallmarks of PD is the presence of intracellular inclusions called Lewy bodies that consist of aggregates of the presynaptic soluble protein called α-synuclein. There are various factors influencing the pathological depositions, and in general, the cause of neuronal death in neurological disorders appears to be multifactorial. However, it is clear, that the underlying factor in the neurological disorders is increased oxidative stress substantiated by the findings that the protein side-chains are modified either directly by reactive oxygen species (ROS) or reactive nitrogen species (RNS), or indirectly, by the products of lipid peroxidation. The increased level of oxidative stress in AD brain is reflected by the increased brain content of iron (Fe) and copper (Cu) both capable of stimulating free radical formation (e.g. hydroxyl radicals via Fenton reaction), increased protein and DNA oxidation in the AD brain, enhanced lipid peroxidation, decreased level of cytochrome c oxidase and advanced glycation end products (AGEs), carbonyls, malondialdehyde (MDA), peroxynitrite, and heme oxygenase-1 (HO-1). AGEs, mainly through their interaction with receptors for advanced glycation end products (RAGEs), further activate signaling pathways, inducing formation of proinflammatory cytokines such as interleukin-6 (IL-6). The conjugated aromatic ring of tyrosine residues is a target for free-radical attack, and accumulation of dityrosine and 3-nitrotyrosine has also been reported in AD brain. The oxidative stress linked with PD is supported by both postmortem studies and by studies showing the increased level of oxidative stress in the substantia nigra pars compacta, demonstrating thus the capacity of oxidative stress to induce nigral cell degeneration. Markers of lipid peroxidation include 4-hydroxy-trans-2-nonenal (HNE), 4-oxo-trans-2-nonenal (4-ONE), acrolein, and 4-oxo-trans-2-hexenal, all of which are well recognized neurotoxic agents. In addition, other important factors, involving inflammation, toxic action of nitric oxide (NO·), defects in protein clearance, and mitochondrial dysfunction all contribute to the etiology of PD. It has been suggested that several individual antioxidants or their combinations can be neuroprotective and decrease the risk of AD or slow its progression. The aim of this review is to discuss the role of redox metals Fe and Cu and non-redox metal zinc (Zn) in oxidative stress-related etiology of AD and PD. Attention is focused on the metal-induced formation of free radicals and the protective role of antioxidants [glutathione (GSH), vitamin C (ascorbic acid)], vitamin E (α-Tocopherol), lipoic acid, flavonoids [catechins, epigallocatechin gallate (EGCG)], and curcumin. An alternate hypothesis topic in AD is also discussed.

The development of cancer in humans and animals is a multistep process. The complex series of cellular and molecular changes participating in cancer development are mediated by a diversity of endogenous and exogenous stimuli. One type of endogenous damage is that arising from intermediates of oxygen (dioxygen) reduction - oxygen-free radicals (OFR), which attacks not only the bases but also the deoxyribosyl backbone of DNA. Thanks to improvements in analytical techniques, a major achievement in the understanding of carcinogenesis in the past two decades has been the identification and quantification of various adducts of OFR with DNA. OFR are also known to attack other cellular components such as lipids, leaving behind reactive species that in turn can couple to DNA bases. Endogenous DNA lesions are genotoxic and induce mutations. The most extensively studied lesion is the formation of 8-OH-dG. This lesion is important because it is relatively easily formed and is mutagenic and therefore is a potential biomarker of carcinogenesis. Mutations that may arise from formation of 8-OH-dG involve GC --> TA transversions. In view of these findings, OFR are considered as an important class of carcinogens. The effect of OFR is balanced by the antioxidant action of non-enzymatic antioxidants as well as antioxidant enzymes. Non-enzymatic antioxidants involve vitamin C, vitamin E, carotenoids (CAR), selenium and others. However, under certain conditions, some antioxidants can also exhibit a pro-oxidant mechanism of action. For example, beta-carotene at high concentration and with increased partial pressure of dioxygen is known to behave as a pro-oxidant. Some concerns have also been raised over the potentially deleterious transition metal ion-mediated (iron, copper) pro-oxidant effect of vitamin C. Clinical studies mapping the effect of preventive antioxidants have shown surprisingly little or no effect on cancer incidence. The epidemiological trials together with in vitro experiments suggest that the optimal approach is to reduce endogenous and exogenous sources of oxidative stress, rather than increase intake of anti-oxidants. In this review, we highlight some major achievements in the study of DNA damage caused by OFR and the role in carcinogenesis played by oxidatively damaged DNA. The protective effect of antioxidants against free radicals is also discussed.