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One of the prevailing perceptions regarding the ageing of cells and organisms is the intracellular gradual accumulation of oxidatively damaged macromolecules, leading to the decline of cell and organ function (free radical theory of ageing). This chemically undefined material known as “lipofuscin,” “ceroid,” or “age pigment” is mainly formed through unregulated and nonspecific oxidative modifications of cellular macromolecules that are induced by highly reactive free radicals. A necessary precondition for reactive free radical generation and lipofuscin formation is the intracellular availability of ferrous iron (Fe2+) (“labile iron”), catalyzing the conversion of weak oxidants such as peroxides, to extremely reactive ones like hydroxyl (HO•) or alcoxyl (RO•) radicals. If the oxidized materials remain unrepaired for extended periods of time, they can be further oxidized to generate ultimate over-oxidized products that are unable to be repaired, degraded, or exocytosed by the relevant cellular systems. Additionally, over-oxidized materials might inactivate cellular protection and repair mechanisms, thus allowing for futile cycles of increasingly rapid lipofuscin accumulation. In this review paper, we present evidence that the modulation of the labile iron pool distribution by nutritional or pharmacological means represents a hitherto unappreciated target for hampering lipofuscin accumulation and cellular ageing.

Apart from triglycerides, olive oil contains low quantities of polar compounds, such as polyphenols, which are believed to be relevant for maintaining human health. In this presentation, we will discuss potential molecular mechanisms by which specific phenolic compounds present in olive oil can exert cytoprotective and cell signal modulating effects, through chelation of intracellular labile (redox-active) iron. Iron chelation by specific polyphenols can prevent or relocalize the interaction of iron with hydroperoxides produced in the cells and the formation of extremely reactive species. The latter are able, either to induce uncontrolled oxidation of basic cell components or to modulate redox signaling. It is proposed that olive oil–contained polyphenols can influence the outcome of cell responses in conditions of increased oxidative stress mainly by this way.

The human thymus is a primary lymphoepithelial organ which supports the production of self-tolerant T cells with competent and regulatory functions. Paradoxically, despite the crucial role that it exerts in T cell-mediated immunity and prevention of systemic autoimmunity, the thymus is the first organ of the body that exhibits age-associated degeneration/regression, termed “thymic involution.” A hallmark of this early phenomenon is a progressive decline of thymic mass as well as a decreased output of naïve T cells, thus resulting in impaired immune response. Importantly, thymic involution has been recently linked with cellular senescence which is a stress response induced by various stimuli. Accumulation of senescent cells in tissues has been implicated in aging and a plethora of age-related diseases. In addition, several lines of evidence indicate that oxidative stress, a well-established trigger of senescence, is also involved in thymic involution, thus highlighting a possible interplay between oxidative stress, senescence, and thymic involution.

Iron is a transition metal and essential constituent of almost all living cells and organisms. As component of various metalloproteins it is involved in critical biochemical processes such as transport of oxygen in tissues, electron transfer reactions during respiration in mitochondria, synthesis and repair of DNA, metabolism of xenobiotics, etc. However, when present in excess within cells and tissues, iron disrupts redox homeostasis and catalyzes the propagation of reactive oxygen species (ROS), leading to oxidative stress. ROS are critical for physiological signaling pathways, but oxidative stress is associated with tissue injury and disease. At the cellular level, oxidative stress may lead to ferroptosis, an iron-dependent form of cell death. In this review, we focus on the intimate relationship between iron metabolism and oxidative stress in health and disease. We discuss aspects of redox- and iron-mediated signaling, toxicity, ferroptotic cell death, homeostatic pathways and pathophysiological implications.

Naturally occurring cinnamic acid derivatives are ubiquitously distributed in the plant kingdom, and it has been proposed that their consumption contributes to the maintenance of human health. However, the molecular mechanisms underlying their health keeping effects remain unknown. In the present investigation, we evaluated the capacity of several cinnamic acid derivatives (trans-cinnamic, p-coumaric, caffeic and ferulic acids, as well as caffeic acid-methyl and -propyl esters) to protect cells from oxidative stress-induced DNA damage. It was observed that effective protection was based on the ability of each compound to (i) reach the intracellular space and (ii) chelate intracellular "labile" iron. These results support the notion that numerous lipophilic iron chelating compounds, present abundantly in plant-derived diet components, may protect cells in conditions of oxidative stress and in this way be important contributors toward maintenance of human health.

Jurkat cells in culture were exposed to oxidative stress in the form of continuously generated hydrogen peroxide, obtained by the addition of glucose oxidase to the medium. This treatment induced a rapid, dose-dependent increase in the ICIP (intracellular calcein-chelatable iron pool). Early destabilization of lysosomal membranes and subsequent nuclear DNA strand breaks were also observed, as evaluated by the Acridine Orange relocation test and the comet assay respectively. Somewhat later, these effects were followed by a lowered mitochondrial membrane potential, with release of cytochrome c and apoptosis-inducing factor. These events were all prevented if cells were pretreated with the potent iron chelator DFO (desferrioxamine) for a period of time (2–3 h) long enough to allow the drug to reach the lysosomal compartment following fluid-phase endocytosis. The hydrophilic calcein, a cleavage product of calcein acetoxymethyl ester following the action of cytosolic esterases, obviously does not penetrate intact lysosomal membranes, thus explaining why ICIP increased dramatically following lysosomal rupture. The rapid decrease in ICIP after addition of DFO to the medium suggests draining of cytosolic iron to the medium, rather than penetration of DFO through the plasma membrane. Most importantly, these observations directly connect oxidative stress and resultant DNA damage with lysosomal rupture and the release of redox-active iron into the cytosol and, apparently, the nucleus.

Data regarding sources of oxidative stress in the failing myocardium are sparse. Leukocytes actively participate in the oxidative damage observed in human heart failure (HF). The intracellular labile iron pool (LIP) represents a source of toxic reactive oxygen species.We studied patients with chronic systolic HF who had a left ventricular ejection fraction (LVEF) 45%. We examined the LIP status in different populations of leukocytes in HF patients and we investigated its association with clinical and laboratory parameters, including conventional inflammatory markers.Sixty patients were finally included in the analysis (mean age: 67 ± 11 years, 54 men, 42 with ischemic cardiomyopathy). The multivariate logistic regression analysis showed that only LIP in granulocytes (OR: 0.73; 95% CI: 0.55-0.98; p=0.039) and right ventricular systolic pressure (RVSP) (OR: 0.95; 95% CI: 0.92-0.99; p=0.027) were independently associated with severe LV systolic dysfunction (LVEF30%). The correlation analysis revealed that LVEF was inversely associated with LIP in granulocytes (Spearman's rho: -0.39, p=0.002), LIP in monocytes (Spearman's rho: -0.35, p=0.007), and RVSP (Spearman's rho: -0.43, p=0.003). No significant correlation between LVEF and inflammatory indexes was noted.LIP in granulocytes is independently associated with the severity of LV dysfunction in patients with systolic HF. Intracellular redox active iron may represent a source of leukocyte reactive oxygen species in this setting.

Strong experimental data support the notion that excessive generation of reactive free radicals takes place in the ischemic area following a stroke episode and that these radicals are responsible for a substantial part of brain injury. However, the exact biochemical mechanisms underlying brain cell damage remain elusive, thus hindering the attempts for development of effective therapeutic strategies. In this presentation, the molecular mechanisms of tissue damage in relation to temporal and spatial generation of “reactive oxygen species” are considered. The mechanisms of oxidant-mediated brain damage are discussed and the role of “labile iron” in this process is evaluated. Although oxygen based oxidants are generated during all phases, their sources and intensities as well as their temporal and spatial generation differ considerably among different phases in stroke. Based on the above ­considerations, it is proposed that administration of appropriate “labile iron” chelating agents, preferentially prior to reperfusion, might improve the efficacy of any therapeutic strategy.

Publisher Summary Reactive oxygen species (ROS) are continuously generated and removed in all kinds of aerobic cells, thus creating an intracellular dynamic equilibrium that varies among different types of cells or even in the same cell type under different conditions. Increased rates of generation or decreased capacity to remove ROS leads to elevated steady-state levels of these species, a phenomenon usually assigned as “oxidative stress.” Depending on the intensity of the oxidative stress applied, basic cellular functions such as cell proliferation and differentiation are modulated, while higher levels of oxidative stress can induce transient or permanent cell arrest or even cell death either by apoptosis or necrosis. Consequently, oxidative stress has been implicated in pathogenic molecular mechanisms of a variety of diseases, including cardiovascular disease, ischemia–reperfusion syndrome, neurodegenerative diseases, cancer, and the physiological process of normal aging. Intensive research work has been performed in order to elucidate these mechanisms and to discover agents able to prevent or modulate the deleterious effects of oxidative stress that contribute to the development of these pathological complications. An unlimited number of potentially protective agents are believed to be present in diet and especially in the so-called “Mediterranean diet,” which has been shown to be able to prevent or impede the development of diseases associated with oxidative stress. This chapter provides evidence that natural phenolic compounds present ubiquitously in the Mediterranean diet and in olive oil exert their cytoprotective action mainly through chelation of intracellular redox-active iron, thus preventing the catalysis of the formation of deleterious free radicals near basic cell components, like DNA, proteins, and lipids.

Background/Aims: Oxidative damage has been reported to be involved in the pathophysiology of chronic kidney disease (CKD) as well as in the pathogenesis of cardiovascular complications of CKD patients. The aim of the present investigation was to evaluate the levels of plasma carbonyl formation, a sensitive marker of enhanced oxidative stress in predialysis, hemodialysis (HD) and peritoneal dialysis (PD) patients. Methods: Plasma samples from 20 apparently healthy control individuals and 127 CKD (stages 2, 3, 4, HD and PD) patients were evaluated by Western blot analysis for the estimation of the levels of protein carbonyl formation. Results: Albumin represented the main plasma carbonylated protein. Increasing carbonylation of albumin was detected along with the severity of CKD, reaching significance at stages 3 and 4 (p < 0.01, compared to healthy controls). The carbonylation of albumin was even higher in the plasma of HD patients (p < 0.001), while in PD patients it was not statistically significant compared to controls (p = 0.224). Conclusions: The data presented in this work indicate that oxidative stress in CKD patients gradually increased during the development of the disease. This stress is probably intensified during HD, but not in PD subjects.

Reactive oxygen species (ROS) were viewed for a long time as unavoidable by-products of normal cell catabolism. This view has recently changed and it is now apparent that ROS generation is a tightly regulated process that plays a central role in cell signaling. Thus, it is known that regulated changes in intracellular ROS levels can induce biochemical signaling processes that control basic cellular functions, such as proliferation and apoptosis which are prevalent in the development of cancer. In this short review, we will try to provide a background to this emerging field by summarizing the biochemistry of ROS-mediated cell signaling and its relation to carcinogenesis. Special emphasis will be focused on the emerging role of the so called "labile" iron (the redox-active form of iron) in ROS-mediated signaling in relation to cancer development. It is tempting to speculate that elucidation of the exact molecular mechanisms that govern ROS-mediated regulation of cell signaling will provide the basis for development of new therapeutic strategies for cancer prevention and treatment. Cancer Lett

Ischemia-reperfusion (IR) injury is a multifactorial process triggered when the liver or other organs are transiently subjected to reduced blood supply followed by reperfusion. It has been shown that "reactive oxygen species" (ROS) are generated during ischemia and reperfusion and may represent pivotal mediators of the ensuing pathological complications. In some cases, however, moderate production of ROS may exert protective effects, a phenomenon presumably related to "ischemic preconditioning". This review will focus mainly on: a) describing the sources and the biochemical mechanisms of ROS generation during ischemia and reperfusion, b) discussing current developments in understanding the biochemical pathways by which ROS may induce toxic or protective effects, c) critically evaluating the results of previous attempts to counteract the toxic effects of ROS by using a variety of antioxidant and transition metal-chelating agents, and d) if feasible, proposing potential new pharmaceutical agents aimed at ameliorating ROS-inducing deleterious effects during reperfusion. It is concluded that ROS are generated from different sources, at different periods during IR, and may act by a variety of not well understood biochemical mechanisms which ultimately lead to cell damage and tissue failure. Curr Pharm Des

● Background: A growing body of evidence suggesting that oxidative stress might be one of the most important complications occurring during hemodialysis (HD) has accumulated. However, although the role of reactive oxygen species has been investigated extensively, little is known about the involvement of reactive nitrogen species. In the present investigation, levels of protein modifications in the form of tyrosine nitration in patients undergoing long-term HD therapy were evaluated. Methods: Tyrosine nitration of plasma proteins was detected by means of Western blotting using a specific nitrotyrosine-recognizing monoclonal antibody, and band intensity was evaluated by using image analysis software. Immunoprecipitation of plasma proteins by antinitrotyrosine-agarose‐ conjugated antibodies, followed by Western blotting, was used in an attempt to identify the nitrated proteins. Results: Although several proteins with nitrated tyrosine residues were observed in plasma of healthy individuals, increased nitration levels were observed in some specific proteins in all patients tested (n 25) compared with controls (n 6). At least 6 apparent bands appeared to be more nitrated than their counterparts in plasma from controls. Ceruloplasmin was identified as 1 of the proteins with significantly increased nitration in patients. Conclusion: Results of the present investigation show that specific plasma proteins of HD patients are posttranslationally modified by nitration of their tyrosine residues. The nature of these proteins, as well as the exact molecular mechanisms and consequences of these modifications, warrant additional investigation. Am J Kidney Dis 44:286-292. © 2004 by the National Kidney Foundation, Inc.