Current Pharmaceutical Design - Volume 17, Issue 36, 2011

Oxidative stress seems to play an important role in mitochondria-mediated disease processes, though the exact molecular mechanisms underlying its involvement remain elusive. Reactive oxygen species (ROS) are generally necessary for the proper functioning of the cell, but excessive ROS production can be harmful, which makes antioxidant defenses essential. Cellular targets attacked by ROS include DNA, proteins, membrane lipids and mitochondria. The review articles included in this issue of Current Pharmaceutical Design summarize recent information in the fields of physiology and pharmacology. The first review [1] describes diabetes as a chronic disease which, as a consequence of the overproduction of ROS, is related with oxidative stress. There are different sources of ROS, of which mitochondria is the most important. In this sense, oxidative stress seems to play an important role in mitochondria-mediated disease processes, though the exact molecular mechanisms responsible are still unclear. Furthermore, there is evidence to support the idea that impaired mitochondrial function is a cause of the insulin insensitivity that arises in different cell types as a result of an insufficient supply of energy or defects in the insulin signalling pathway. In this article, the authors consider the process of diabetes from a mitochondrial perspective and describe the role of autophagy in the development of diabetes. They also discuss the possible beneficial effects of selectively targeting antioxidants to mitochondria as a strategy for modulating mitochondrial function in diabetes. The outstanding work by Vina et al. [2] focuses on the role of oxidative stress and differences between females and males in ageing. It describes how females live longer than males and how mitochondrial oxidative stress is higher in males than females. The fact that higher levels of oestrogens protect females against ageing by up-regulating the expression of antioxidant longevity-related genes is also discussed. The authors demonstrate that physiological concentrations of oestrogens activate oestrogen receptors and the MAPK and NFκB pathways, and that activation of NFκB by oestrogens subsequently activates the expression of Mn-SOD and GPx. They also discuss how genistein reproduces the antioxidant effect of estradiol at nutritionally relevant concentrations by the same mechanism in both healthy aging individuals and Alzheimer's disease patients. The authors conclude that oestrogens and phytoestrogens up-regulate the expression of antioxidant enzymes via oestrogen receptor and MAPK activation, which in turn activates the NFκB signalling pathway, resulting in the up-regulation of the expression of longevity-related genes. The review by De la Fuente et al. [3] describes how the aging process is accompanied by an impairment of physiological systems, including the immune system, which is an excellent indicator of health. They also demonstrate that several of the functions of immune cells are good markers of biological age and predictors of longevity. In accordance with the oxidation-inflammation theory, they propose that the chronic oxidative stress that appears with age affects all cells, especially those of the regulatory systems (nervous, endocrine and immune systems) and the communication between them. This prevents an adequate homeostasis and, therefore, undermines the preservation of health. The authors point to an involvement of the immune system in the aging process of the organism, specifically in the rate of aging, since there is a relation between the redox state and functional capacity of the immune cells of an individual and his/her longevity. The importance of the role of the immune system in oxi-inflamm-aging is evident if we consider that several lifestyle strategies, such as the consumption of adequate amounts of antioxidants, physical exercise, physical and mental activity through environmental enrichment, and hormetic interventions, improve the functioning of immune cells, thereby decreasing their oxidative stress and consequently increasing longevity. The advantages and disadvantages of interventions for achieving a healthy aging and longevity are discussed. New insights into redox-modulated cell signaling are discussed by Leonarduzzi et al. [4]. The authors focus on the complex system of molecular communications underlying cell biochemistry and function and involving numerous components including kinases, phosphatases and transcription factors, which are known to be sensitive to cellular and tissue redox changes. They describe how ROS, whose constitutive generation in cells and tissues is amplified under pro-oxidant conditions, are now unanimously recognized to be important triggers and modulators of cell signalling and, consequently, cell behavior. They consider the major signalling pathways that mediate gene regulation in response to ROS. The review by Kastle et al. [5] outlines the relation between ageing, oxidative stress and protein oxidation and the influence of the ubiquitin proteasomal system in several associated diseases. The authors describe how lipids, nucleic acids and, in particular, proteins are extremely susceptible to oxidative modifications, which are manifested in alterations of single amino acids (formation of protein carbonyls and methionine sulfoxide) or aggregation of whole proteins. Due to the ongoing accumulation of protein aggregates during the ageing process, the cellular protein quality control system becomes increasingly overwhelmed. One of the most important aspects of the protein quality control machinery is the ubiquitin proteasomal system, which also plays a crucial part in the ageing process. Although there is no drastic loss of proteasomal subunits during the ageing process, there is a functional decline of proteasome activity in ageing organisms. The authors conclude that impairment of the ubiquitin proteasome system leads to increasing protein aggregation and cellular death. The review by Blanchet et al. [6] describes how mitochondrial dysfunction has been implicated in many human diseases and debates offtarget drug effects. They discuss how isolated deficiency of mitochondrial complex I (CI) can arise from mutations in nuclear DNA (nDNA)- encoded subunits. In humans, these mutations are generally associated with neurodegenerative disorders such as Leigh or Leigh-like syndrome, with onset in early childhood. No cure or mitigative treatment is currently available for these diseases. This review discusses how to obtain a multivariate dataset and in what ways explorative data analysis (EDA) techniques can be used for pattern analysis. The data offered highlight a connection between CI deficiency, ROS and mitochondrial morphology/function. This information not only contributes to our understanding of the pathophysiological mechanism of CI and mitochondrial deficiency but also suggests possible targets for cellular intervention strategies. The review by Gogvadge [7] describes the role of mitochondria in tumour cells and how targeting of mitochondria can be a useful tool for fighting cancer. In fact, in recent years, there have been a number of reports that confirm the involvement of mitochondria in the pathogenesis of a variety of disorders, including cancer and neurodegenerative diseases. Alteration of vital mitochondrial functions - production of ATP, calcium buffering capacity, abnormal production of ROS - could also be implicated in the aforementioned illnesses. The authors demonstrate that the involvement of mitochondria in various types of cell death makes them attractive targets for tumour cell elimination....

Diabetes is a chronic disease and, as a consequence of the overproduction of reactive oxygen species (ROS), is related with oxidative stress. There are different sources of ROS, of which mitochondria is the main one. Oxidative stress seems to play an important role in mitochondria- mediated disease processes, though the exact molecular mechanisms responsible remain elusive. There are evidences which supports the idea that impaired mitochondrial function is a cause of the insulin insensitivity in different type of cells that arised as a result of an insufficient supply of energy or defects in the insulin signaling pathway. ROS are generally necessary for the proper functioning of the cell, but excessive ROS production can be harmful, which makes antioxidant defenses essential. Moreover, some substances with antioxidant properties, such as vitamin C or vitamin E, erradicate the oxidative stress associated with diabetes. The results of clinical trials employing anti-oxidative stress reagents in patients with diabetes are contradictory, which may be a result of inadequate study design or selected targets. This review considers the process of diabetes from a mitochondrial perspective, and describes the role of autophagy in the development of diabetes. Furthermore, we discuss the possible beneficial effects of selectively targeting antioxidants to mitochondria as a strategy for modulating mitochondrial function in diabetes.

One of the most significant achievements of the twentieth century is the increase in human lifespan. In any period studied, females live longer than males. We showed that mitochondrial oxidative stress is higher in males than females and that the higher levels of estrogens in females protect them against ageing, by up-regulating the expression of antioxidant, longevity-related genes. The chemical structure of estradiol confers antioxidant properties to the molecule. However, the low concentration of estrogens in females makes it unlikely that they exhibit significant antioxidant capacity in the organism. Therefore we studied the mechanisms enabling estradiol to be antioxidant at physiological levels. Our results show that physiological concentrations of estrogens activate estrogen receptors and the MAPK and NFKB pathway. Activation of NFkB by estrogens subsequently activates the expression of Mn-SOD and GPx. Moreover, we have demonstrated that genistein, the most abundant phytoestrogen in soya, reproduces the antioxidant effect of estradiol at nutritionally relevant concentrations by the same mechanism, both in healthy ageing and in Alzheimer's disease We conclude that estrogens and phytoestrogens up-regulate expression of antioxidant enzymes via the estrogen receptor and MAPK activation, which in turn activate the NFkB signalling pathway, resulting in the up-regulation of the expression of longevity-related genes.

The aging process is accompanied by an impairment of the physiological systems including the immune system. This system is an excellent indicator of health. We have also observed that several functions of the immune cells are good markers of biological age and predictors of longevity. In agreement with the oxidation-inflammation theory that we have proposed, 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 an 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. A confirmation of the central role of the immune system in oxi-inflamm-aging is that several lifestyle strategies such as the administration of adequate amounts of antioxidants in the diet, physical exercise, physical and mental activity through environmental enrichment and hormetic interventions improve functions of immune cells, decreasing their oxidative stress, and consequently increasing the longevity of individuals. Recent results in mice of investigations on the effects of a new environmental enrichment (bathing in waters) as well as a hormetic intervention with slight infections (caused by injection of E.coli lipopolysaccharide, LPS), on several functions and redox parameters are shown. The advantages and possible problems of the use of those interventions to achieve a healthy aging and longevity are discussed.

The complex system of molecular communications underlying cell biochemistry and function involves numerous components including kinases, phosphatases and transcription factors, which are known to be sensitive to cellular and tissue redox changes. Reactive oxygen species (ROS), whose constitutive generation in cells and tissues is amplified under pro-oxidant conditions, are now unanimously recognized to be important triggers and modulators of cell signaling, and consequently of cell behavior. This review considers the major signaling pathways that mediate gene regulation in response to ROS.

Living in an oxygen containing environment is automatically connected to oxidative stress. Beside lipids and nucleic acids, especially proteins are very susceptible for oxidative modifications. These oxidative modifications comprise alterations of single amino acids, like the formation of protein carbonyls and methionine sulfoxide, or the aggregation of whole proteins. Due to the ongoing accumulation of protein aggregates during the aging process, the cellular protein quality control system becomes more and more overwhelmed. One essential element of the protein quality control machinery is the ubiquitin proteasomal system which plays therefore a crucial part in the aging process, too. Ubiquitination of proteins is a three step mechanism to tag proteins with a polyubiquitin chain for the proteasome. The proteasome is a regulated, barrel-shaped multi-enzyme complex which is responsible for the degradation of proteins. Although there is no drastic loss of all proteasomal subunits during the aging process, there is a functional decline of the proteasome activity in aging organisms. Impairment of the ubiquitin proteasome system leads to increasing protein aggregation and cellular death. A lot of age related diseases are closely connected to an inhibition of the proteasome and the formation of large protein aggregates. Especially skin aging, atherosclerosis, age-dependent macula degeneration, cataract formation and several neurodegenerative diseases are directly connected to the decline of proteasome function. This review outlines the connections between aging, oxidative stress and protein oxidation, as well as the influence on the ubiquitin proteasomal system and several associated diseases.

Mitochondrial dysfunction has been implicated in many human diseases and off-target drug effects. Isolated deficiency of mitochondrial complex I (CI), the first complex of the oxidative phosphorylation (OXPHOS) system, can arise from mutations in nuclear DNA (nDNA)-encoded subunits. In humans, these mutations are generally associated with neurodegenerative disorders like Leigh or Leigh-like syndrome with onset in early childhood. Currently, no cure or mitigative treatment is available for these diseases. To aid the future design of rational treatment strategies, insight into the pathophysiology of CI mutations is required. To this end, we quantitatively compared various cell physiological readouts between fibroblasts from healthy individuals and patients with isolated CI deficiency. Here we review how this multivariate dataset was obtained and in which way explorative data analysis (EDA) techniques can be used for pattern analysis. Based upon 13 experimental parameters two patient groups were identified. These displayed a later (cluster I) or earlier (cluster II) age of disease onset and death. Relative to cluster I, cluster II patient cells displayed a larger reduction in CI activity, a larger increase in NADH/ROS levels, mitochondrial fragmentation and lower cellular levels of OXPHOS proteins. Our results highlight a connection between CI deficiency, ROS and mitochondrial morphology/function. This information not only contributes to our understanding of the pathophysiological mechanism of CI and mitochondrial deficiency but also suggests possible targets for cellular intervention strategies.

During the last years, there have been a number of reports that prove involvement of mitochondria in the pathogenesis of variety of disorders including cancer and neurodegenerative diseases. Alteration of vital mitochondrial functions - production of ATP, calcium buffering capacity, abnormal production of reactive oxygen species, can be potentially responsible for pathogenesis of cancer and neurodegenerative diseases. Involvement of mitochondria in various types of cell death makes them attractive targets for tumor cell elimination. This review describes the role of mitochondria in tumor cells and how targeting of mitochondria can be used as a tool in fighting cancer.

Mitochondria are crucial, multifunctional organelles which actively regulate cellular homeostasis. Their complex and diverse role includes maintenance of the cellular energetic balance through hosting several catabolic pathways which result in the process of oxidative phosphorylation, as well as enabling various fundamental anabolic processes and controlling Ca2+ distribution. Moreover, mitochondria are the main cellular generator of reactive oxygen species, which act as second messengers and when over-produced provoke a state of oxidative stress, a condition implicated in many pathologies. Importantly, mitochondria are directly involved in triggering different and complexly interconnected programs promoting cell survival or death. The aim of this review is to summarize the current understanding regarding mitochondrial implication in the main cellular pathways controlling cell “fate” such as apoptosis, autophagy (mitophagy), mitoptosis and necrosis with particular emphasis on the role that reactive oxygen species and oxidative stress may play in these phenomena. The literature extensively covers the topic of reactive oxygen species and apoptosis, fewer articles however deal with mitophagy or mitochondrial dynamics and very few mention the implication oxidative stress and redox modifications have for mitoptosis or necrosis. This review offers a global picture of the complex role of mitochondria in the regulation of cell “fate”, referring specifically to the interconnection and balance between different cellular pathways of death and survival. Current knowledge regarding the involvement of these processes in particular human pathologies, specifically with respect to the implication of reactive oxygen species and oxidative stress, is also discussed.

Phytosterols, which are structurally related to cholesterol, are found in all plant foods with highest concentration occurring in vegetable oils and nuts. Phytosterols are known to reduce serum low-density lipoprotein cholesterol level without changing high-density lipoprotein cholesterol or triglyceride levels. Daily consumption of phytosterols-enriched foods is widely used as a therapeutic option to lower plasma cholesterol and atherosclerotic disease risk. The cholesterol-lowering action of phytosterols is thought to occur, at least in part, through competitive replacement of dietary and biliary cholesterol in mixed micelles, which undermines the absorption of cholesterol. The aim of this review is to provide a general overview of available evidence regarding the effects of phytosterols on cholesterol metabolism and addressing issues related to efficacy as dose, length, frecuency of consumption, type of phytosterol (sterols versus stanols) or food matrix. Futhermore, we will explore the factors that influence the response of individuals to phytosterol therapy and evaluate their safety and the possibility that elevated plasma phytosterol concentrations contribute to the development of premature coronary artery disease.

Thirty years after the discovery of HIV infection, there are numerous antiretroviral drugs that control the disease when administered in a potent combination referred to as Highly Active Antiretroviral Therapy (HAART). This therapy reduces the viral load and improves immune system reconstitution, leading to a significant reduction of HIV-related morbidity and mortality. However, HAART does not completely eliminate HIV, so treatment must continue throughout the patient's life. Prolonged use of HAART has been related to long-term adverse events that can compromise patient health. These deleterious effects have been reported for the majority of antiretroviral drugs and are the most common causes for therapy discontinuation. In most of these adverse events, such as diabetes, cardiovascular diseases, neurological disorders and metabolic alterations, oxidative stress and mitochondrial impairment play important roles. This review covers the implication of antiretroviral drugs in the overproduction of reactive oxygen species and the reduction of antioxidant defences, and in the consequent mitochondrial dysfunction, focusing on the molecular mechanisms involved and the clinical implications for HIV-infected patients.