Plos One
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Nebivolol is known to have beta-1 blocker activity, but it was also suggested that it elicits relaxation of the peripheral arteries in part via release of nitric oxide (NO). However, the effect of nebivolol on the vasomotor tone of cerebral arteries is still unclear. ⋯ Nebivolol seems to have an important dilator effect in cerebral arteries, which is mediated via several vasomotor mechanisms, converging on the reduction of smooth muscle Ca2+ levels. As such, nebivolol may be effective to improve cerebral circulation in various diseased conditions, such as hemorrhage.
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Anti-platelet drugs are the mainstay of pharmacotherapy for heart attack and stroke prevention, yet improvements are continually sought. Thrombin is the most potent activator of platelets and targeting platelet thrombin receptors (protease-activated receptors; PARs) is an emerging anti-thrombotic approach. Humans express two PARs on their platelets-PAR1 and PAR4. ⋯ Platelets from hPAR1-KI mice did display significantly diminished responsiveness to thrombin stimulation in both assays, consistent with a Par3-/- phenotype. In contrast to the observations in hPAR1-KI mouse platelets, the PAR1 construct used here was successfully expressed in HEK293T cells. Together, these data suggest ectopic PAR1 expression is not tolerated in mouse platelets and indicate a different approach is required to develop a small animal model for the purpose of any future preclinical testing of PAR antagonists as anti-platelet drugs.
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Mechanical ventilation is a life-saving procedure for patients with acute respiratory failure, although it may cause pulmonary vascular inflammation and leakage, leading to ventilator-induced lung injury (VILI). Ly6C+high monocytes are involved in the pathogenesis of VILI. In this study, we investigated whether pulmonary infiltrated Ly6C+high monocytes produce vascular endothelial growth factor (VEGF) and contribute to VILI. ⋯ VEGF produced by pulmonary infiltrated Ly6C+high monocytes regulates vasculature permeability in a two-hit model of HTV-induced lung injury. Ly6C+high monocytes play an important role in the pathogenesis of VILI.
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Conserved protein antigens among serotypes of group A Streptococcus pyogenes (GAS) have been focused for vaccine development because of the diversity of GAS serotypes and risks of autoimmunity post-GAS infection. Precise delineation of protective immune response to each of GAS antigens is critical for vaccine efficacy and safety. We recently reported that immunization with SrtA of GAS provides Th17-dependent clearance of heterologous serotypes of GAS in NALT. ⋯ The co-immunization induced Th17 and robust SCPA antibody responses, accompanied by a rapid influx of neutrophils and high myeloperoxidase activity in NALT, suggesting that simultaneous induction of mucosal Th17 and neutralizing antibody responses offers more effective GAS elimination through rapid infiltration and activation of neutrophils. Moreover, Th17 response was strongly induced in mice that experienced repeated GAS-infection and maintained at a high level even after the bacteria were cleared; whereas, it was moderately induced and promptly returned to baseline following bacterial elimination in SrtA/SCPA co-immunized mice. Additional results showed that the survival rate of systemic challenge was significantly higher in infection experienced than in co-immunized mice, indicating that more immune elements are required for protection against systemic than mucosal GAS infection.
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The pathophysiological mechanisms underlying mild traumatic brain injury (mTBI) are not well understood, but likely involve neuroinflammation. Here the controlled cortical impact model of mTBI in rats was used to test this hypothesis. Mild TBI caused a rapid (within 6 h post-mTBI) upregulation of synthesis of TNF-α and IL-1β in the cerebral cortex and hippocampus, followed by an increase in production of neutrophil (CXCL1-3) and monocyte (CCL2) chemoattractants. ⋯ The monocyte influx was not observed until 24 h post-mTBI, and these inflammatory cells predominantly entered the ipsilateral SAS and CVI, with a limited invasion of brain parenchyma. These observations indicate that the endothelium of pial microvessels responds to injury differently than that of intraparenchymal microvessels, which may be associated with the lack of astrocytic ensheathment of cerebrovascular endothelium in pial microvessels. These findings also suggest that neuroinflammation represents the potential therapeutic target in mTBI.