16 A very important source of reactive species during exercise is the electron transport chain reactions in the mitochondria. It has been established that oxygen uptake is increased about 20-fold whereas oxygen levels in muscle fibers are increased up to 100-fold (Ji 1999). Thus, the number of electrons leaking during exercise is much higher compared with those leaking at rest. Xanthine oxidase is one of the major contributors of reactive species during exercise. Xanthine oxidoreductase is an enzyme catalyzing the oxidation of hypoxanthine to xanthine to uric acid in the pathway of purine degradation and exists in two forms. At rest, xanthine oxidoreductase exists as xanthine dehydrogenase, which uses NAD as electron acceptor and does not generate reactive species. However, during exercise, xanthine oxidoreductase is converted to xanthine oxidase, which uses molecular oxygen as the electron acceptor, thereby resulting in O2⋅− and H2O2 production (McCord and Fridovich 1968). Xanthine oxidase also generates reactive species through ischemia–reperfusion, which is usually induced by anaero- bic exercise or aerobic exercise of high intensity. During ischemia, oxygen uptake in tissues is reduced and ATP is converted to AMP. Xanthine oxidase is produced by the ischemia-triggered proteolytic conversion of xanthine de- hydrogenase, oxidizing AMP to hypoxanthine (Nishino et al. 2008). When blood flows again in tissues (reperfusion), hypoxanthine is oxidized to xanthine to uric acid by xanthine oxidase and reactive species are produced (McBride and Kraemer 1999). The role of xanthine oxidase inhibition during exercise has not yet been elucidated as the outcome is dual. It results not only in the inhibition of reactive species generation but also in the inhibition of the production of uric acid, a very potent antioxidant molecule of plasma. It has been previously demonstrated that xanthine oxidase inhibition by allopurinol leads to an increase in antioxidant defense (Gomez-Cabrera et al. 2005), but it has also been shown that allopurinol induces oxidative stress and reduces exercise performance in rats (Veskoukis et al. 2008). A very common mechanism of reactive species genera- tion during muscle-damaging exercise (e.g., eccentric) is inflammatory response. Polymorphoneutrophils participate in tissue defense via the excretion of lysozyme, Ο2⋅−, and other reactive species produced by enzymes present in cellular membranes (NADPH oxidase and lipoxygenase; Leeuwenburgh and Heinecke 2001). Furthermore, hemo- globin is oxidized to methemoglobin, leading to Ο2⋅− production (Misra and Fridovich 1972), and myoglobin is oxidized, resulting in the formation of peroxyl radicals (Giulivi and Cadenas 1998). During the last three decades, there have been numerous studies indicating that exercise of sufficient intensity and duration increases the formation of reactive species and that A.S. Veskoukis et al. antioxidant mechanisms cannot scavenge them, thus result- ing in oxidative stress. Furthermore, it has been demon- strated that free radical generation is greater when the intensity and duration of exercise increases (Finaud et al. 2006; Bloomer 2008). Therefore, exhaustive exercise (aerobic swimming and treadmill running) has been associated with increased oxidative stress (Veskoukis et al. 2008; Michailidis et al. 2007; Nikolaidis et al. 2006). There are various studies demonstrating that different kinds of exercise such as exhaustive treadmill running, ultra- and half-marathon running, downhill running, exhaustive swim- ming, mountain cycling, and cycling on ergometer induce oxidative stress in humans (Davies et al. 1982; Lovlin et al. 1987; Alessio 1993; Child et al. 1998; Mastaloudis et al. 2001; Palmer et al. 2003; Aguilo et al. 2005; Goldfarb et al. 2005; Tauler et al. 2006; Bloomer et al. 2007; Powers and Jackson 2008; Powers et al. 2011) and animals (Brady et al. 1979; Jenkins et al. 1993; Venditti and Di Meo 1996; Radak et al. 1995, 2002; You et al. 2005; Gomez-Cabrera et al. 2005; Veskoukis et al. 2008; Saborido et al. 2011). Apart from the commonly used markers of oxidative stress, albumin has also been proposed to be an index of tissue oxidative damage. More specifically, it has been found that strenuous exercise increases the oxidized form of albumin (albumin dimmers) in human serum (Imai et al. 2002) and rat skeletal muscle (Veskoukis et al. 2010) and that the oxidative modification of albumin is intensity-dependent (Lamprecht et al. 2008, 2009). These findings indicate that albumin could possibly serve as a new oxidative stress marker. The field of exercise biology, apart from human studies, is rich in experiments using animal models. The reasons are obvious, but the extrapolation of the results from animals to humans is not easy. Most of the studies use rats or mice which have similarities in their physiology with human subjects. Such experiments are necessary as they help in investigating the mechanisms of in vivo oxidative stress induction and antioxidant action. However, the translation of these results from animals to humans is a rather complicated task. It is noteworthy that rodents (rats and mice) used for laboratory experiments seem to be more sensitive to the effects of dietary antioxidants than humans. Therefore, it is more likely to enhance antioxidant defense or to reduce oxidative damage after dietary antioxidant administration (Halliwell and Gutteridge 2007; Lehr et al. 1999; Loke et al. 2010). Furthermore, rodent models of human diseases in which reactive species are important for their pathology, namely, atherosclerosis, stroke, and amyo- trophic lateral sclerosis, appear to be more responsive to plant antioxidant administration than humans. Thus, al- though the results of relative experiments in rodent models are promising, it is possible that there is no comparable outcome in humans (Halliwell 2001b, 2011). One of the