Here, we investigated whether plasmin-mediated cleavage regulates MCP1-induced BBB breakdown. We have previously shown that mouse MCP1 can be cleaved by plasmin at K104, and the truncated MCP1 is more potent than the full-length MCP1 in inducing microglial migration ( Sheehan et al., 2007 Yao and Tsirka, 2010) through its receptor CCR2.īesides chemotaxis, MCP1 is also involved in blood–brain barrier (BBB) compromise ( Dimitrijevic et al., 2006 Stamatovic et al., 2006 Stamatovic et al., 2003 Stamatovic et al., 2005). The rodent MCP1 differs from the human protein at the C-terminus, with the rodent protein having a longer highly glycosylated C-terminus. Monocyte chemoattractant protein-1 (MCP1 officially known as C-C motif chemokine 2, CCL2) is one of the most highly and transiently expressed chemokines in many central nervous system (CNS) injuries, including ischemia, hemorrhage and excitotoxic injury ( Capoccia et al., 2008 Dimitrijevic et al., 2006 Frangogiannis et al., 2007 Hanisch, 2002 Kim et al., 2008 Morimoto et al., 2008 Sheehan et al., 2007 Yan et al., 2007). By binding to their specific G-protein-coupled receptors, chemokines induce cell-specific migration and activation of immune cells ( Glabinski et al., 1996 Hulkower et al., 1993 Lahrtz et al., 1998 Miller and Meucci, 1999). These findings identify plasmin as a key signaling molecule in the regulation of BBB integrity and suggest that plasmin inhibitors might be used to modulate diseases accompanied by BBB compromise.Ĭhemokines are a superfamily of structurally related small proteins with strong chemotactic activity. Finally, we show that the redistribution of ZO-1 is mediated by phosphorylation of ezrin-radixin-moesin (ERM) proteins. Furthermore, we show that the mechanisms underlying MCP1-induced BBB disruption involve redistribution of tight junction proteins (occludin and ZO-1) and reorganization of the actin cytoskeleton. K104Stop-MCP1 increases the permeability of BBB in both wild-type mice and mice deficient for tissue plasminogen activator (tPA), which converts plasminogen into active plasmin, suggesting that plasmin-mediated truncation of MCP1 plays an important role in BBB compromise. Here, we show that K104Stop-MCP1, truncated at the K104 where plasmin would normally cleave, is more efficient than the full-length protein (FL-MCP1) in compromising the integrity of the BBB in in vitro and in vivo models. Accumulating evidence reveals that MCP1 also disrupts the integrity of the blood–brain barrier (BBB). His mission complete, Bond sets course for home.Previous studies have shown that plasmin cleaves monocyte chemoattractant protein 1 (MCP1 officially known as C-C motif chemokine 2, CCL2) at K104, and this cleavage enhances its chemotactic potency significantly. Steering with his knees, Bond evades a pair of air-to-air missiles and maneuvers his aircraft below the enemy jet ejecting his unwelcome passenger into, and ultimately destroying, the terrorist L-39. Pursued by the second L-39, the terrorist co-pilot behind 007 regains consciousness and begins garroting him. With several minutes until impact, James Bond rushes to steal the plane - along with its deadly cargo - and narrowly escapes. After the British order a cruise missile strike on the location it is revealed that one of the aircraft is carrying two Soviet SB-5 nuclear torpedos. Following the dissolution of the Soviet Union and the formation of the Russian Air Force in 1991, the newly formed service found itself with hundreds of L-39 aircraft, the majority of which were surplus to their training requirements.ĭuring the pre-title sequence of Tomorrow Never Dies, a pair of armed L-39s were among the stolen equipment for sale at a terrorist arms bazaar somewhere on the Russian border. It was the first trainer aircraft to be equipped with a turbofan powerplant and was exported to a wide range of countries as a military trainer. The L-39 Albatros was designed during the 1960s as a replacement for the Aero L-29 Delfín as a cost-effective jet-powered trainer aircraft, which was also capable of performing ground attack missions.
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