Peroxymonocarbonate and Carbonate Radical Displace the Hydroxyl-like Oxidant in the Sod1 Peroxidase Activity under Physiological Conditions

Despite being one of the most important antioxidant defenses, Cu,Zn-superoxide dismutase (Sod1) has been frequently associated with harmful effects, including neurotoxicity. This toxicity has been attributed to immature forms of Sod1 and extraneous catalytic activities. Among these, the ability of Sod1 to function as a peroxidase may be particularly relevant because it is increased in bicarbonate buffer and produces the reactive carbonate radical. Despite many studies, how this radical forms remains unknown. To address this question, we systematically studied hSod1 peroxidase activity in the presence of nitrite, formate, and bicarbonate-carbon dioxide. Kinetic analyses of hydrogen peroxide consumption and of nitrite, formate, and bicarbonate-carbon dioxide oxidation showed that the Sod1-bound hydroxyl-like oxidant functions in the presence of nitrite and formate. In the presence of bicarbonate-carbon dioxide, this oxidant is replaced by peroxymonocarbonate, which is then reduced to the carbonate radical. Peroxymonocarbonate intermediacy was evidenced by (13)C NMR experiments showing line broadening of its peak in the presence of Zn,ZnSod1. In agreement, peroxymonocarbonate was docked into the hSod1 active site, where it interacted with the conserved Arg(143). Also, a reaction between peroxymonocarbonate and Cu(I)Sod1 was demonstrated by stopped-flow experiments. Kinetic simulations indicated that peroxymonocarbonate is produced during Sod1 turnover and not in bulk solution. In the presence of bicarbonate-carbon dioxide, sustained hSod1-mediated oxidations occurred with low steady-state concentrations of hydrogen peroxide (4-10 mu M). Thus, carbonate radical formation through peroxymonocarbonate may be a key event in Sod1-induced toxicity.

A novel physiological property of snake bradykinin-potentiating peptides-Reversion of MK-801 inhibition of nicotinic acetylcholine receptors

The first naturally occurring angiotensin-converting enzyme (ACE) inhibitors described are pyroglutamyl proline-rich oligopeptides, found in the venom of the viper Bothrops jararaca, and named as bradykinin-potentiating peptides (BPPs). Biochemical and pharmacological properties of these peptides were essential for the development of Captopril, the first active site-directed inhibitor of ACE, currently used for the treatment of human hypertension. However, a number of data have suggested that the pharmacological activity of BPPs could not only be explained by their inhibitory action on enzymatic activity of somatic ACE. In fact, we showed recently that the strong and long-lasting anti-hypertensive effect of BPP-10c [

Physiological demands of competitive elite cross-country skiing

Introduction Researchers have, for decades, contributed to an increased collective understanding of the physiological demands in cross-country skiing; however, almost all of these studies have used either non-elite subjects and/or performances that emulate cross-country skiing. To establish the physiological demands of cross-country skiing, it is important to relate the investigated physiological variables to the competitive performance of elite skiers. The overall aim of this doctoral thesis was, therefore, to investigate the external validity of physiological test variables to determine the physiological demands in competitive elite cross-country skiing. Methods The subjects in Study I – IV were elite male (I – III) and female (III – IV) cross-country skiers. In all studies, the relationship between test variables (general and ski-specific) and competitive performances (i.e. the results from competitions or the overall ski-ranking points of the International Ski Federation (FIS) for sprint (FISsprint) and distance (FISdist) races) were analysed. Test variables reflecting the subject’s general strength, upper-body and whole-body oxygen uptake, oxygen uptake and work intensity at the lactate threshold, mean upper-body power, lean mass, and maximal double-poling speed were investigated. Results The ability to maintain a high work rate without accumulating lactate is an indicator of distance performance, independent of sex (I, IV). Independent of sex, high oxygen uptake in whole-body and upper-body exercise was important for both sprint (II, IV) and distance (I, IV) performance. The maximal double-poling speed and 60-s double-poling mean power output were indicators of sprint (IV) and distance performance (I), respectively. Lean mass was correlated with distance performance for women (III), whereas correlations were found between lean mass and sprint performance among both male and female skiers (III). Moreover, no correlations between distance performance and test variables were derived from tests of knee-extension peak torque, vertical jumps, or double poling on a ski-ergometer with 20-s and 360-s durations (I), whereas gross efficiency while treadmill roller skiing showed no correlation with either distance or sprint performance in cross-country skiing (IV). Conclusion The results in this thesis show that, depending on discipline and sex, maximal and peak oxygen uptake, work intensity at the lactate threshold, lean mass, double-poling mean power output, and double-poling maximal speed are all externally valid physiological test variables for evaluation of performance capability among elite cross-country skiers; however, to optimally indicate performance capability different test-variable expressions should be used; in general, the absolute expression appears to be a better indicator of competitive sprint performance whereas the influence of body mass should be considered when evaluating competitive distance performance capability of elite cross-country skiers.