Dibutyltin Disrupts Glucocorticoid Receptor Function and Impairs Glucocorticoid-Induced Suppression of Cytokine Production

BACKGROUND: Organotins are highly toxic and widely distributed environmental chemicals. Dibutyltin (DBT) is used as stabilizer in the production of polyvinyl chloride plastics, and it is also the major metabolite formed from tributyltin (TBT) in vivo. DBT is immunotoxic, however, the responsible targets remain to be defined. Due to the importance of glucocorticoids in immune-modulation, we investigated whether DBT could interfere with glucocorticoid receptor (GR) function. METHODOLOGY: We used HEK-293 cells transiently transfected with human GR as well as rat H4IIE hepatoma cells and native human macrophages and human THP-1 macrophages expressing endogenous receptor to study organotin effects on GR function. Docking of organotins was used to investigate the binding mechanism. PRINCIPAL FINDINGS: We found that nanomolar concentrations of DBT, but not other organotins tested, inhibit ligand binding to GR and its transcriptional activity. Docking analysis indicated that DBT inhibits GR activation allosterically by inserting into a site close to the steroid-binding pocket, which disrupts a key interaction between the A-ring of the glucocorticoid and the GR. DBT inhibited glucocorticoid-induced expression of phosphoenolpyruvate carboxykinase (PEPCK) and tyrosine-aminotransferase (TAT) and abolished the glucocorticoid-mediated transrepression of TNF-alpha-induced NF-kappaB activity. Moreover, DBT abrogated the glucocorticoid-mediated suppression of interleukin-6 (IL-6) and TNF-alpha production in lipopolysaccharide (LPS)-stimulated native human macrophages and human THP-1 macrophages. CONCLUSIONS: DBT inhibits ligand binding to GR and subsequent activation of the receptor. By blocking GR activation, DBT may disturb metabolic functions and modulation of the immune system, providing an explanation for some of the toxic effects of this organotin

Le traitement conservateur dans les traumatismes graves du rein: A propos de deux cas

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Post-Arab Spring: The Arab World Between the Dilemma of the Nation-State and the Rise of Identity Conflicts

The Arab world is one of the most volatile regions in the world suffering from identity conflicts. These conflicts, which revolve around religious, sectarian, ethnic, and tribal issues, represent the other side of the crisis of nation-state building in the Arab world in the postindependence era. Although identity conflicts are not new to the region, they have intensified after the US invasion of Iraq in 2003 and the revolutions of the so-called Arab Spring. These two events revealed the deep crisis of the nation-state, thereby highlighting the failure of the postindependence ruling elites to establish nation states that can maintain a position of legitimacy and effectiveness. Being both legitimate and effective enables a state to include religious, sectarian, ethnic, and tribal pluralism within the framework of its national identity, based on the foundations and principles of citizenship, rule of law, respect for human rights, minority rights, and social justice.Additionally, identity conflicts are linked to two other factors that escalated after the US invasion of Iraq and the events of the “Arab spring.” First, was the increased politicization of religious, sectarian, and tribal affiliations, which was used to serve political ends, either by ruling regimes, political parties, or non-state actors. Second, is the current expansion of the political polarization between the forces of political Islam which rose rapidly after the “Arab spring” on one hand and the liberal, leftist, and national civil forces on the other hand. This polarization reflects the deep gap between the advocates of the “religious state” and the advocates of the “civil state.” The purpose of this chapter is to analyze and interpret the dimensions of the relationship between the deep crisis of the nation–state and identity conflicts in the post-Arab spring era