Plos One
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Neutrophil extracellular traps (NETs) represent extracellular microbial trapping and killing. Recently, it has been implicated in thrombogenesis, autoimmune disease, and cancer progression. The aim of this study was to characterize NETs in various organs of a murine sepsis model in vivo and to investigate their associations with platelets, leukocytes, or vascular endothelium. ⋯ Microvessel occlusions which may be caused by platelet aggregates or leukocyte-platelet aggregates and heterogeneously decreased blood flow were also observed in septic mice. NETs appeared to be associated with the formation of platelet aggregates or leukocyte-platelet aggregates. These observational findings may suggest the adverse effect of intravascular NETs on the host during a sepsis.
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Cyclin-dependent kinase 5 (Cdk5) has been shown to play an important role in mediating inflammation-induced heat hyperalgesia. However, the underlying mechanism remains unclear. The aim of this study was to determine whether roscovitine, an inhibitor of Cdk5, could reverse the heat hyperalgesia induced by peripheral injection of complete Freund's adjuvant (CFA) via the brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) signaling pathway in the dorsal horn of the spinal cord in rats. ⋯ Our data suggested that the BDNF-TrkB signaling pathway was involved in CFA-induced heat hyperalgesia mediated by Cdk5. Roscovitine reversed the heat hyperalgesia induced by peripheral injection of CFA by blocking BDNF/TrkB signaling pathway, suggesting that severing the close crosstalk between Cdk5 and the BDNF/TrkB signaling cascade may present a potential target for anti-inflammatory pain.
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Psychometric assessment of the Rat Grimace Scale and development of an analgesic intervention score.
Our limited ability to assess spontaneous pain in rodent models of painful human conditions may be associated with a translational failure of promising analgesic compounds in to clinical use. If measurement of spontaneous pain behaviours can be used to generate an analgesic intervention score their use could expand to guide the use of analgesics, as mandated by regulatory bodies and ethical and welfare obligations. One such measure of spontaneous pain, the Rat Grimace Scale (RGS), has recently been described and shown to exhibit reliability. ⋯ The RGS scores showed very good inter- and intra-rater reliability (0.85 [0.78-0.90 95% CI] and 0.83 [0.76-0.89], respectively). An analgesic intervention threshold of greater than 0.67 was determined. These data demonstrate that the RGS is a useful tool which can be successfully employed in a heterogenous setting, and has the potential to guide analgesic intervention.
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miRNA155 has been implicated in normal T cell function and their differentiations into the Th1 subtype. We have shown that acute alcohol (ethanol) intoxication combined with burn injury suppresses T cell IFN-γ release. Herein, we examined whether the decrease in IFN-γ is resulted from altered expression of miRNA155 and transcription factors--NFAT, Tbx21, Jun and Fos--in T cells following ethanol and burn injury. ⋯ It did not prevent the decrease in IFN-γ, Tbx21, Jun, Fos and miRNA155. Finally, results obtained in miRNA155-/- mice did not show any change in T cell release of IFN-γ or expression of nuclear factors compared to wildtype mice. Together, these findings suggest that while ethanol and burn injury decreases the expression of miRNA155, it may not be involved in decreased IFN-γ under those conditions.
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Microtubules depolymerization caused by the CK1 inhibitor IC261 may be not mediated by CK1 blockage.
The ubiquitously expressed serine/threonine specific casein kinase 1 (CK1) family plays important roles in the regulation of various physiological processes. Small-molecule inhibitors, such as the CK1δ/ε selectively inhibitor IC261, have been used to antagonize CK1 phosphorylation events in cells in many studies. Here we present data to show that, similarly to the microtubule destabilizing agent nocodazole, IC261 depolymerizes microtubules in interphase cells. ⋯ In addition, FACS analysis revealed that IC261 could induce apoptosis independent of cell cycle arrest. In summary this study provides additional and valuable information about various IC261-induced effects that could be caused by microtubule depolymerization rather than by inhibition of CK1. Data from studies that have used IC261 as an inhibitor of CK1 should be interpreted in light of these observations.