oa Editorial [Hot Topic: New Developments in Therapy for Oxidative Stress-Related Diseases: Pathophysiological and Clinical Consequences (Executive Guest Editor: Victor M. Victor)]

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....