Rel revealed: cocrystal structures of the NF-kappa B p50 homodimer

24 model rabbits with femoral arterial thrombosis were divided into two groups: the treatment group consisting of 12 rabbits which received API0134, and the control group composed of another 12 rabbits. 2 hours after recanalization by urokinase thrombolysis, reocclusion occurred only in 1/12 vessel (8%) with incomplete occlusion in the treated group, but in 8/12 (67%) with complete occlusion in the control group as assessed by angiograsphy. Pathological examination of specimen taken 24 hours after thrombolysis showed that 6/12 (50%) of the treated group gave the evidence of thrombus occlusion, and milder intimal injury and less adhered blood cells than in the control group, 83% of which had thrombus occlusion. In comparision with the control group, the function of platelet in the treated group demonstrated lower platelet aggregation rate (PAgR) and plasma thromboxane A2 (TXA2) level, higher prostacyclin (PGI2) and plasminogen activator (PA) activity as well as lower plasminogen activator inhibitor (PAI) activity. From the above it may be concluded that the preventive effect of API0134 on reocclusion might be due to inhibition of platelets aggregation and promotion of fibrinolysis.     

Temporal and subunit-specific modulations of the Rel/NF-kappaB transcription factors through CD28 costimulation

Stimulation of highly purified primary T lymphocytes through CD2 and CD28 adhesion molecules induces a long-term proliferation, dependent on persistent autocrine secretion of interleukin 2 (IL-2), high and prolonged expression of inducible CD25/IL-2 receptor alpha chain (IL-2Ralpha), and secretion of growth factors such as the granulocyte-macrophage colony-stimulating factor (GM-CSF). CD28 costimulation appears to activate cytokine gene expression through conserved kappaB-related CD28 response (CD28RE) or cytokine 1 (CK-1) elements in addition to canonical NF-kappaB-binding sites. In this report, we assess: 1) the evolution of the expression, over an 8-day time period, of the Rel/NF-kappaB family of proteins in costimulated versus TcR/CD3-stimulated primary T cells; 2) the impact of changes on the in vitro occupancy of GM-CSF kappaB and CK-1, as well as IL-2Ralpha kappaB sites; and 3) the differential regulation of newly synthesized p65 and c-Rel by IkappaB proteins. We show that CD2+CD28 stimulation specifically induces, at maximal T cell proliferation phase, sustained nuclear overexpression of NFKB2 p52 and c-Rel subunits which might rely on long-lasting processing of p100 precursor for p52 and increased neosynthesis of c-Rel. This up-regulation correlates with sustained occupancy of GM-CSF kappaB and CK-1 elements by both proteins. Conversely, these subunits do not appear to bind to the IL-2Ralpha kappaB site. Costimulation, but not TcR/CD3 stimulation, appears supported by sustained down-regulation of both IkappaBalpha and -beta regulators. Furthermore, contrary to p65, c-Rel appears to display little affinity for p105, p100 and IkappaBalpha regulators.