It is now well established that reactive oxygen species (ROS) reactive

It is now well established that reactive oxygen species (ROS) reactive nitrogen LY2940680 species (RNS) and a basal level of oxidative stress are essential for cell survival. term this moderate level of oxidative stress as positive oxidative stress which usually involves imprinting molecular signatures on lipids and proteins via formation of lipid peroxidation by-products and protein oxidation LY2940680 adducts. As ROS/RNS are short-lived molecules these molecular signatures can thus execute the ultimate function of ROS/RNS. Representative examples of lipid peroxidation products and protein oxidation adducts are presented to illustrate the role of positive oxidative stress in a variety of pathological settings demonstrating that positive oxidative stress could be a valuable prophylactic and/or therapeutic approach targeting aging and aging-associated diseases. Keywords: Aging Reactive oxygen species Reactive nitrogen species Disease tolerance Positive oxidative stress Graphical abstract Introduction Production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) is part of normal aerobic cellular metabolism [1-5]. While RNS generally originate from nitric oxide synthases ROS can be generated by a variety of enzymes and metabolic pathways including mitochondrial complexes I-III [6-9] in the electron transport chain dihydrolipoamide dehydrogenase in the α-keto acid dehydrogenase complexes [10-14] NADPH oxidase [15 16 xanthine oxidase [17 18 monoamine oxidase [19] and cytochrome P450 proteins [20]. All of these systems may result in oxidative stress under appropriate conditions. Although basal levels of ROS/RNS are indispensible for redox signaling and cell survival [21 22 high levels of ROS/RNS would be detrimental to cells and have been thought to contribute to aging LY2940680 and the pathogenesis of numerous aging-related diseases [22 23 On the other hand a moderate level of oxidative stress reflected by a moderate level of ROS/RNS production could be induced and modulated to produce an adaptive cellular response that is beneficial for cell survival [22-27]. Oxidative stress is a situation whereby cellular levels of ROS or RNS overwhelm the cellular antioxidant capacities [20]. This condition when severe usually leads to extensive modifications or damage to macromolecules including DNA lipids and proteins [28 29 Collectively these damaged macromolecules when beyond the cell′s reparative and degradative activities can eventually induce cell death and tissue injury [22 25 Nonetheless increasing evidence has now established that many protein oxidation or lipid oxidation products can be beneficial for cell survival [29-32]. These oxidation products are usually caused by a moderate level of oxidative stress which is termed here as positive oxidative stress. This is the type of oxidative stress that can induce or is part of an adaptive response that protects cells against subsequent severe challenges that otherwise would trigger widespread oxidative damage and cell death [23 27 In order to create a positive oxidative stress condition it is necessary to stress cells with a stressor [22 27 Many stressors when used at appropriate dosages can elicit a moderate or non-lethal level of oxidative stress in the absence of cytotoxicity and LY2940680 cell death [27]. Nonetheless it should be pointed out that if used at higher dosages; LY2940680 almost all stressors will inevitably yield toxicity that leads to cell death. Gpr20 The best examples of positive oxidative stress would be ischemic tolerance including preconditioning and postconditioning which are clinically-relevant approaches applied in a variety of animal models for protection of tissues against ischemia-induced injuries [33-35]. It has been well-demonstrated that a variety of stressors such as mitochondrial electron transport chain inhibitors [36] hypoxia [37] hyperoxia [38 39 hyperthermia [40] and hypothermia [41] as well as short episodes of ischemia [42] can induce positive oxidative stress via a transiently increased ROS production that is involved in an adaptive response LY2940680 for prophylactic purposes (Table 1) [43-49]. Accordingly many studies have shown that antioxidants administered prior to or at the onset of preconditioning or postconditioning induction can abolish the preconditioning or postconditioning effect [34 35 50 51 thus demonstrating that ROS and oxidative stress are essential for preconditioning or postconditioning to take effect [52-54]. Interestingly the effects of preconditioning and postconditioning are only evident in severe pathological challenges such as.