Effects of training on iron status in cross-country skiers

Haematological changes were studied in cross-country skiers during a 33-week training season (7 h a week). The daily amounts of training were calculated from the duration and the intensity of the exercise and then used to estimate training responses associated with a first order transfer function. The profile of system training responses (STR) was determined by convolution between the amounts of training and a first-order transfer function. Linear regressions were used to determine correlation coefficients between STR and iron status indices. Among the values for the time constants of decay, the one giving the best fit between STR and iron status indices was chosen. A relationship was noted between on the one hand STR and changes in serum ferritin concentration ([FERR]) and on the other hand STR and change in mean cell volume (MCV). The [FERR] was decreased and MCV was increased by training. It is suggested that a decrease in [FERR] could have been related to a decrease in total body iron stores. However, large and rapid changes in [FERR] could not have been a reflection of changes in total body iron stores. Equilibrium between [FERR] and total body iron stores could have been temporarily altered by the effects of training. Moreover, iron stores did not seem to have been sufficiently depleted to restrict erythropoiesis. The MCV increased slightly in response to intense training suggesting that training enhances the proportion of young erythrocytes.     

Gout. Mechanisms of inflammation in gout

An acute attack of gout is a paradigm of acute sterile inflammation, as opposed to pyogenic inflammation. Recent studies suggest that the triggering of IL-1β release from leucocytes lies at the heart of a cascade of processes that involves multiple cytokines and mediators. The NLRP3 inflammasome appears to have a specific role in this regard, but the biochemical events leading to its activation are still not well understood. We review the known mechanisms that underlie the inflammatory process triggered by urate crystals and suggest areas that require further research.     

Hormonal adaptations and modelled responses in elite weightlifters during 6 weeks of training

The concentrations of serum testosterone, sex-hormone-binding-globulin (SHBG) and luteinizing hormone (LH) were examined throughout 1-year of training in six elite weightlifters. A systems model, providing an estimation of fatigue and fitness, was applied to records of training volume and performance levels in clean and jerk. The analysis focused on a 6-week training period during which blood samples were taken at 2-week intervals. A 4-week period of intensive training (period I) could be distinguished from the following 2-week period of reduced training (period II). During period I, decreases in serum testosterone (P less than 0.05) and increases in serum LH concentrations (P less than 0.01) were observed; a significant correlation (r = 0.90, P less than 0.05) was also observed between the changes in serum LH concentration and in estimated fitness. The magnitude of LH response was not related to the change in serum androgens. On the other hand, the change in testosterone:SHBG ratio during period II was significantly correlated (r = 0.97, P less than 0.01) to the LH variations during period I. These finding suggested that the LH response indicated that the decrease in testosterone concentration was not primarily due to a dysfunction of the hypothalamic-pituitary system control, and that the fatigue/fitness status of an athlete could have influenced the LH response to the decreased testosterone concentration. The negative effect of training on hormonal balance could have been amplified by its influence on the hypothalamic-pituitary axis. A decrease in physiological stress would thus have been necessary for the completion of the effect of LH release on androgenic activity.     

Anticandidal activity of synthetic peptides: Mechanism of action revealed by scanning electron and fluorescence microscopies and synergism effect with nystatin

Candida albicans has emerged as a major public health problem in recent decades. The most important contributing factor is the rapid increase in resistance to conventional drugs worldwide. Synthetic antimicrobial peptides (SAMPs) have attracted substantial attention as alternatives and/or adjuvants in therapeutic treatments due to their strong activity at low concentrations without apparent toxicity. Here, two SAMPs, named Mo‐CBP₃‐PepI (CPAIQRCC) and Mo‐CBP₃‐PepII (NIQPPCRCC), are described, bioinspired by Mo‐CBP₃, which is an antifungal chitin‐binding protein from Moringa oleifera seeds. Furthermore, the mechanism of anticandidal activity was evaluated as well as their synergistic effects with nystatin. Both peptides induced the production of reactive oxygen species (ROS), cell wall degradation, and large pores in the C. albicans cell membrane. In addition, the peptides exhibited high potential as adjuvants because of their synergistic effects, by increasing almost 50‐fold the anticandidal activity of the conventional antifungal drug nystatin. These peptides have excellent potential as new drugs and/or adjuvants to conventional drugs for treatment of clinical infections caused by C. albicans.     

Ubiquitination of human AP-endonuclease 1 (APE1) enhanced by T233E substitution and by CDK5

Apurinic/apyrimidinic endonuclease-1 (APE1) is a multifunctional DNA repair/gene regulatory protein in mammalian cells, and was recently reported to be phosphorylated at Thr233 by CDK5. We here report that ubiquitination of T233E APE1, a mimicry of phospho-T233 APE1, was markedly increased in multiple cell lines. Expression of CDK5 enhanced monoubiquitination of endogenous APE1. Polyubiquitinated APE1 was decreased when K48R ubiquitin was expressed, suggesting that polyubiquitination was mediated mainly through Lys48 of ubiquitin. The ubiquitination activity of MDM2, consistent in its role for APE1 ubiquitination, was increased for T233E APE1 compared to the wild-type APE1. In mouse embryonic fibroblasts lacking the MDM2 gene, ubiquitination of T233E APE1 was still observed probably because of the decreased degradation activity for monoubiquitinated APE1 and because of backup E3 ligases in the cells. Monoubiquitinated APE1 was present in the nucleus, and analyzing global gene expression profiles with or without induction of a ubiquitin-APE1 fusion gene suggested that monoubiquitination enhanced the gene suppression activity of APE1. These data reveal a delicate balance of ubiquitination and phosphorylation activities that alter the gene regulatory function of APE1.     

Role of the mitogen-activated protein kinase pathway in the differential response of bovine monocytes to Mycobacterium avium subsp. paratuberculosis and Mycobacterium avium subsp. avium

We compared the kinetics of activation and antimicrobial activities of MAPK-p38 and MAPK-ERK in bovine monocytes infected with Mycobacterium avium subsp. paratuberculosis (MAP) and Mycobacterium avium subsp. avium (Maa). Monocytes were incubated with MAP or Maa organisms with or without a specific inhibitor of the MAPK-p38 pathway (SB203580), and MAPK phosphorylation and antimicrobial functions of monocytes were evaluated. At early time points MAPK-p38 phosphorylation was greater in MAP-infected bovine monocytes than in Maa-infected monocytes. At later time points MAPK-p38 phosphorylation by both organisms was similar. MAPKp38 phosphorylation in MAP-infected monocytes was similar to negative control cells, whereas in Maa-infected this activation remained greater than negative control cells. Increase phosphorylation MAPK-ERK was similar at all time points for both organisms. Bovine monocytes had minimal capacity to kill MAP organisms, to acidify MAP-containing phagosomes, or to form phagolysosome. Alternatively, bovine monocytes were able to kill Maa organisms. Addition of SB203580 to monocyte cultures increased phagosome acidification, phagolysosome formation, and killing of MAP and Maa organisms. Taken together these data indicate that early transient activation of MAPK-p38 in bovine mononuclear phagocytes by MAP organisms may be a key mechanism involved in the capacity of MAP to survive in bovine monocytes.     

Over-expression of COQ10 in Saccharomyces cerevisiae inhibits mitochondrial respiration

COQ10 deletion in Saccharomyces cerevisiae elicits a defect in mitochondrial respiration correctable by addition of coenzyme Q₂. Rescue of respiration by Q₂ is a characteristic of mutants blocked in coenzyme Q₆ synthesis. Unlike Q₆ deficient mutants, mitochondria of the coq10 null mutant have wild-type concentrations of Q₆. The physiological significance of earlier observations that purified Coq10p contains bound Q₆ was examined in the present study by testing the in vivo effect of over-expression of Coq10p on respiration. Mitochondria with elevated levels of Coq10p display reduced respiration in the bc1 span of the electron transport chain, which can be restored with exogenous Q₂. This suggests that in vivo binding of Q₆ by excess Coq10p reduces the pool of this redox carrier available for its normal function in providing electrons to the bc1 complex. This is confirmed by observing that extra Coq8p relieves the inhibitory effect of excess Coq10p. Coq8p is a putative kinase, and a high-copy suppressor of the coq10 null mutant. As shown here, when over-produced in coq mutants, Coq8p counteracts turnover of Coq3p and Coq4p subunits of the Q-biosynthetic complex. This can account for the observed rescue by COQ8 of the respiratory defect in strains over-producing Coq10p.     

Plasminogen activators and their inhibitors in a human mammary cell line (HBL-100). Modulation by glucocorticoids

Culture of human mammary HBL-100 cells in the presence of dexamethasone, a synthetic glucocorticoid, resulted in opposite effects on the production of the two plasminogen activators (PAs): a decrease in urokinase-type PA (u-PA) and a concomitant increase in tissue-type PA (t-PA). Two PA-specific inhibitors, one related to that produced by bovine aortic endothelial cells, and the other related to that isolated from human placenta, were also produced by these cells; dexamethasone did not affect the production of either of these inhibitors. The glucocorticoid effects observed on PA enzymatic activities were associated with changes in PA mRNA levels. Experiments using inhibitors of RNA and protein synthesis suggested that the glucocorticoid-induced decrease in u-PA mRNA was a secondary event, requiring synthesis of new regulatory proteins; in contrast, the increase in t-PA mRNA appeared to be a direct effect on t-PA gene expression.