Current Pharmaceutical Design - Volume 15, Issue 26, 2009

When there is an imbalance between the production of free radicals (ROS) and the ability of the cell to scavenge them, they accumulate in the cytoplasm, leading to what is known as “oxidative stress”. This situation occurs as a host defence mechanism whose involvement in maintaining homeostasis and/or inducing disease has been widely investigated over the past decade. Cellular targets attacked by ROS include DNA, proteins, membrane lipids, and mitochondria. In particular, free radicals are byproducts of aerobic metabolism, and most cellular ROS are produced due to “leakage” of electrons from the mitochondrial respiratory chain, resulting in an incomplete reduction of molecular oxygen (O2) during oxidative phosphorylation and a production of hydrogen peroxide and the superoxide radical anion. It has been estimated that at O2 physiological levels, 1-3% of the reduced molecular O2 in mitochondria form superoxide. Approximately 85-90% of O2 is used by mitochondria, making the mitochondrion the major site of ROS production. The remaining 10-15% of O2 is used by other cellular oxidative enzymes, including xanthine oxidase in the cytoplasm, and by the cytochrome P450 system in the endoplasmic reticulum, which can also yield ROS. The review articles included in this issue of Current Pharmaceutical Design summarize recent evidence in the field of physiology and pharmacology. In the first article [1], the author discusses the role of oxidative processes in atherosclerosis and the cardiovascular diseases (CVD) that can arise as a result. Atherosclerosis represents a state of heightened oxidative stress characterized by lipid and protein oxidation in the vascular wall. As an expert in the field, the author describes an overproduction of ROS under pathophysiologic conditions, and these ROS form an integral part of the development of CVD, and in particular atherosclerosis. Endothelial dysfunction, characterized by a diminution of nitric oxide (NO) bioactivity, occurs early on in the development of atherosclerosis, and determines future vascular complications. Although the molecular mechanisms responsible for mitochondria-mediated disease processes are not clear, oxidative stress seems to play an important role. This review provides a summary of the cellular metabolism of ROS and its role in pathophysiological processes such as atherosclerosis. In addition, the author describes currently available antioxidants and possible reasons for their efficacy and inefficacy in ameliorating oxidative stress-mediated diseases. The outstanding review by De la Fuente et al. [2] focuses on the aging process as one of the best examples of the effects of deterioration of homeostasis, describing how aging is accompanied by an impairment of physiological systems such as the immune system. The authors propose an integrative theory of aging. In accordance with this oxidation-mitochondrial theory, they have observed that the age-related changes of immune functions are based on a situation of oxidative and inflammatory stress among whose intracellular mechanisms is the activation of the NFkB in the immune cells. The authors present a clear argument for why several functions of the immune cells are good markers of biological age and predictors of longevity. Based on the above, they propose a theory of oxidation-inflammation as the main cause of aging. Accordingly, the chronic oxidative stress that appears with age affects all cells, and especially those of the regulatory systems, such as the nervous, endocrine and immune systems, and the communication between them. This prevents an adequate homeostasis, and therefore is an obstacle to the preservation of health. The authors also propose a key involvement of the immune system in the aging process of the organism, specifically in the rate of aging, based on the relation between the redox state and functional capacity of the immune cells and the longevity of individuals. Finally, they affirm that adequate amounts of antioxidants in the diet improve immune functions, thereby decreasing oxidative stress, and consequently increasing the longevity of subjects.

This review focuses on the role of oxidative processes in atherosclerosis and the cardiovascular diseases (CVD) that can arise as a result. Atherosclerosis represents a state of heightened oxidative stress characterized by lipid and protein oxidation in the vascular wall. Overproduction of reactive oxygen species (ROS) under pathophysiologic conditions forms an integral part of the development of CVD, and in particular atherosclerosis. Endothelial dysfunction, characterized by a loss of nitric oxide (NO) bioactivity, occurs early on in the development of atherosclerosis, and determines future vascular complications. Although the molecular mechanisms responsible for mitochondria-mediated disease processes are not clear, oxidative stress seems to play an important role. In general, ROS are essential to the functions of cells, but adequate levels of antioxidant defenses are required in order to avoid the harmful effects of excessive ROS production. In this review, we will provide a summary of the cellular metabolism of reactive oxygen species (ROS) and its role in pathophysiological processes such as atherosclerosis; and currently available antioxidants and possible reasons for their efficacy and inefficacy in ameliorating oxidative stress-mediated diseases.

The aging process is one of the best examples of the effects of a deterioration of homeostasis, since aging is accompanied by an impairment of the physiological systems including the homeostatic systems such as the immune system. We propose an integrative theory of aging providing answers to the how (oxidation), where first (mitochondria of differentiated cells) and why (pleiotropic genes) this process occurs. In agreement with this oxidation-mitochondrial theory of aging, we have observed that the age-related changes of immune functions have as their basis an oxidative and inflammatory stress situation, which has among its intracellular mechanisms the activation of NFκB in immune cells. Moreover, we have also observed that several functions of immune cells are good markers of biological age and predictors of longevity. Based on the above we have proposed the theory of oxidation-inflammation as the main cause of aging. Accordingly, the chronic oxidative stress that appears with age affects all cells and especially those of the regulatory systems, such as the nervous, endocrine and immune systems and the communication between them. This fact prevents an adequate homeostasis and, therefore, the preservation of health. We have also proposed a key involvement of the immune system in the aging process of the organism, concretely in the rate of aging, since there is a relation between the redox state and functional capacity of the immune cells and the longevity of individuals. Moreover, the role of the immune system in senescence could be of universal application. A confirmation of the central role of the immune system in oxi-inflamm-aging is that the administration of adequate amounts of antioxidants in the diet, improves the immune functions, decreasing their oxidative stress, and consequently increases the longevity of the subjects.

Acute pancreatitis is an acute inflammatory process localized in the pancreatic gland that frequently involves peripancreatic tissues. It is still under investigation why an episode of acute pancreatitis remains mild affecting only the pancreas or progresses to a severe form leading to multiple organ failure and death. Proinflammatory cytokines and oxidative stress play a pivotal role in the early pathophysiological events of the disease. Cytokines such as interleukin 1beta and tumor necrosis factor alpha initiate and propagate almost all consequences of the systemic inflammatory response syndrome. On the other hand, depletion of pancreatic glutathione is an early hallmark of acute pancreatitis and reactive oxygen species are also associated with the inflammatory process. Changes in thiol homestasis and redox signaling decisively contribute to amplification of the inflammatory cascade through mitogen activated protein kinase (MAP kinase) pathways. This review focuses on the relationship between oxidative stress, pro-inflammatory cytokines and MAP kinase/protein phosphatase pathways as major modulators of the inflammatory response in acute pancreatitis. Redox sensitive signal transduction mediated by inactivation of protein phosphatases, particularly protein tyrosin phosphatases, is highlighted.

The production of reactive species causes oxidative modifications of proteins accompanied by a loss of protein function. By protein oxidation all cellular compartments and any amino acid are effected. This might result in a defect of cellular homeostasis. Therefore, the degradation of non-functional, oxidized proteins is an essential function of the proteolytic branch of the antioxidant defense machinery. The major proteolytic system responsible for the removal of oxidized proteins is the proteasomal system. Whereas moderately oxidized proteins are more sensitive to proteolytic attack, severely oxidized ones are often poor substrates and might, however, inhibit the proteasome. This paper reviews the data available on protein modifications following oxidative stress, the cellular responses and the role of proteasome in this process.

Mitochondria produce large amounts of free radicals and play an important role in the life and death of a cell, regulating the signalling, metabolism, and energy production needed for cellular function. In this way, mitochondrial oxidative damage and dysfunction contribute to a number of cell pathologies that are manifested through a range of conditions that include cardiovascular diseases (CVD). Although the molecular mechanisms responsible for mitochondriamediated disease processes are not yet completely understood, oxidative stress definitely seems to play an important role. When examined at the protein level, both expression levels and protein modifications are altered by oxidative stress. While these effects have been studied in the past by classic biochemical methods, recent developments in proteomics have allowed the oxidative stress response to be studied in more depth. The focus of this work is the mitochondrial proteome/ genome interplay that is currently believed to be implicated in a range of human diseases. Particular attention is given to the current knowledge of the role of mitochondria in the development of oxidative-stress-based diseases; e.g. CVD is highlighted together with the prospective proteomics perspective as an alternative prognostic and diagnostic tool for interpreting many mitochondria-related anomalies. Accordingly, strategies for the targeted delivery of antioxidants to mitochondria are being developed. The insight provided by recent proteomic research and the effects of mitochondrialantioxidants on possible interventions are also discussed.

Reactive oxygen species (ROS), as well as reactive nitrogen species (RNS) play either harmful or beneficial role in biological systems. Beneficial effects of ROS include physiological roles in cellular responses against infectious agents and in several cellular signalling pathways. Harmful effects are due to high concentrations of ROS, which can damage biomolecules, including lipids, proteins and nucleic acids. The harmful effects of ROS are counterbalanced by the antioxidant action of both antioxidant enzymes and non-enzymatic antioxidants; however, despite the presence of the cell's antioxidant system, oxidative damage accumulates during the life cycle and has been proposed to play a pivotal role in the development of age-dependent diseases such as atherosclerosis, arthritis, neurodegenerative disorders and cancer. Numerous epidemiological studies indicate that a reduced risk of various lifestyle diseases, mainly cardiovascular diseases and cancer, as well as other disorders, is associated to a diet rich in fruits, vegetables and their products. The drive to enhance the consumption of fruits and vegetables in the human diet is linked with positive effects of beneficial antioxidants impacting on health promotion. In this review we present an outline of main roles of ROS in biological processes and diseases and how natural bioactive compounds of fruits and vegetables determine their health-promoting properties.

The N, N' dimethyl-biguanide : Metformin is an antidiabetic drug that increases glucose utilization in insulinsensitive tissues. As Polycystic Ovary Syndrome (PCOS) and diabetes share some altered parameters-such as abnormal glucose: insulin ratio, altered lipidic metabolism and insulin-resistance syndrome- the use of metformin has become increasingly accepted and widespread in the treatment of PCOS. Currently, metformin is used to induce ovulation and during early pregnancy in PCOS patients, however, a complete knowledge of the metformin action has not been achieved yet. This review describes beyond the classical reproductive action of metformin and explores other benefits of the drug. In addition, the present work discusses the molecular mechanisms involved further than the classical pathway that involves the AMP-activated protein kinase.

Oxidative stress is involved in the pathogenesis of atherosclerosis. A variety of antioxidants has been used in clinical studies, during the past few years, for the prevention and treatment of atherosclerosis. In small clinical studies it was found that both vitamins C and E may improve endothelial function in high risk patients. However, interventional trials have been controversial, with some positive findings, many null findings, and some suggestion of harm in certain high-risk populations. Therefore, treatment with antioxidant vitamins C and E should not be recommended for the prevention or treatment of coronary atherosclerosis. New antioxidant strategies are needed to clarify the exact role of antioxidant treatment in coronary atherosclerosis.