O FAIR PLAY NA ATUALIDADE

Durante todo o século XX, a sociedade ocidental e o esporte passaram por inúmeras transformações. Foi nasociedade aristocrática que surgiu o conceito de “fair playg, difundido pelo Barão Pierre de Coubertin idealizador dosJogos Olímpicos da Era Moderna. O “fair play” defendido por Coubertin representa a honra e a lealdade, o respeitopelos outros e por si próprio. Estes valores refletem o pensamento da aristocracia inglesa do século XIX a respeito daspráticas esportivas. Este estudo propõe uma discussão do conceito de “fair play”, fundamentado nos valores e característicasda sociedade pós-moderna. A metodologia utilizada foi a de revisão de literatura onde foram relacionados osfundamentos do “fair play” e do pós-modernismo, correlacionando ambos para propor uma discussão analítica doespírito esportivo adaptado ao momento em que vive a sociedade e o esporte. Conclui-se, parcialmente, que a influênciado marketing e da mídia pressionando os atletas por melhores resultados gera na mente de treinadores e esportistas opensamento de vitória a qualquer preço, culminando na utilização de meios ilícitos, tais como o doping, a manipulaçãogenética, processos de naturalização, entre outros, quebrando assim, os princípios do jogo limpo

TLR4 activation alters labile heme levels to regulate BACH1 and heme oxygenase-1 expression in macrophages

International audienceHeme oxygenase (HO)-1, a stress-inducible enzyme that converts heme into carbon monoxide (CO), iron and biliverdin, exerts important anti-inflammatory effects in activated macrophages. HO-1 expression is mainly governed by a mutual interplay between the transcriptional factor NRF2 and the nuclear repressor BTB and CNC homology 1 (BACH1), a heme sensor protein. In the current study we hypothesized that alterations in the levels of intracellular labile heme in macrophages stimulated by lipopolysaccharide (LPS), a prototypical pro-inflammatory Toll-like receptor (TLR)4 agonist, are responsible for BACH1-dependent HO-1 expression. To this end, labile heme was determined in both mouse bone marrow-derived macrophages (mBMDMs) and human monocyte-derived macrophages (hMDMs) using an apo-horseradish peroxidase-based assay. We found that LPS raised the levels of labile heme, depressed BACH1 protein and up-regulated HO-1 in mBMDMs. In contrast, in hMDMs LPS decreased labile heme levels while increasing BACH1 expression and down-regulating HO-1. These effects were abolished by the TLR4 antagonist TAK-242, suggesting that TLR4 activation triggers the signaling cascade leading to changes in the labile heme pool. Studies using mBMDMs from BACH1-/- and NRF2-/- mice revealed that regulation of HO-1 and levels of labile heme after LPS stimulation are strictly dependent on BACH1, but not NRF2. A strong interplay between BACH1-mediated HO-1 expression and intracellular levels of labile heme was also confirmed in hMDMs with siRNA knockdown studies and following inhibition of de novo heme synthesis with succinylacetone. Finally, CORM-401, a compound that liberates CO, counteracted LPS-dependent down-regulation of HO-1 and restored levels of labile heme in hMDMs. In conclusion, alterations of labile heme levels in macrophages following TLR4 stimulation play a crucial role in BACH1-mediated regulation of HO-1 expression

Human and murine macrophages exhibit differential metabolic responses to lipopolysaccharide - A divergent role for glycolysis

International audienceMacrophages adopt different phenotypes in response to microenvironmental changes, which can be principally classified into inflammatory and anti-inflammatory states. Inflammatory activation of macrophages has been linked with metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis. In contrast to mouse macrophages, little information is available on the link between metabolism and inflammation in human macrophages. In the current report it is demonstrated that lipopolysaccharide (LPS)-activated human peripheral blood monocyte-derived macrophages (hMDMs) fail to undergo metabolic reprogramming towards glycolysis, but rely on oxidative phosphorylation for the generation of ATP. By contrast, activation by LPS led to an increased extracellular acidification rate (glycolysis) and decreased oxygen consumption rate (oxidative phosphorylation) in mouse bone marrow-derived macrophages (mBMDMs). Mitochondrial bioenergetics after LPS stimulation in human macrophages was unchanged, but was markedly impaired in mouse macrophages. Furthermore, treatment with 2-deoxyglucose, an inhibitor of glycolysis, led to cell death in mouse, but not in human macrophages. Finally, glycolysis appeared to be critical for LPS-mediated induction of the anti-inflammatory cytokine interleukin-10 in both human and mouse macrophages. In summary, these findings indicate that LPS-induced immunometabolism in human macrophages is different to that observed in mouse macrophages