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Increasing evidence has demonstrated that inflammatory response plays a crucial role in the pathogenesis of secondary injury following blast-induced traumatic brain injury (bTBI). Propofol, a lipid-soluble intravenous anesthetic, has been shown to possess therapeutic benefit during neuroinflammation on various brain injury models. Recent findings have proved that the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome involved in the process of the inflammatory response following brain trauma, may probably be a promising target in the treatment of bTBI. Rats were randomly divided into six groups (n = 8): normal group; bTBI-12 and 24 h group; bTBI-12 h and bTBI-24 h group treated with propofol; and bTBI treated with control dimethyl sulfoxide (DMSO) group. The effect of propofol on the expression and activation of NLRP3 inflammasome and the degree of oxidative stress and inflammatory cascades, as well as the brain trauma biomarkers were evaluated in rats suffering from bTBI. The enhanced expressions and activation of NLRP3 inflammasome in the cerebral cortex of bTBI rats were substantially suppressed by the administration of propofol, which was paralleled with the decreased oxidative stress, cytokines production, and the amelioration of cerebral cortex damage. Our results have, for the first time, revealed that over-activation of NLRP3 inflammasome in the cerebral cortex may be involved in the process of neuroinflammation during the secondary injury of bTBI in rats. Propofol might relieve the inflammatory response and attenuate brain injury by inhibiting ROS and reluctant depressing NLRP3 inflammasome activation and pro-inflammatory cytokines maturation.

We have previously demonstrated that infection by coxsackievirus B3 (CVB3), a positive-stranded RNA enterovirus, results in the accumulation of insoluble ubiquitin-protein aggregates, which resembles the common feature of neurodegenerative diseases. The importance of protein aggregation in viral pathogenesis has been recognized; however, the underlying regulatory mechanisms remain ill-defined. Transactive response DNA-binding protein-43 (TDP-43) is an RNA-binding protein that has an essential role in regulating RNA metabolism at multiple levels. Cleavage and cytoplasmic aggregation of TDP-43 serves as a major molecular marker for amyotrophic lateral sclerosis and frontotemporal lobar degeneration and contributes significantly to disease progression. In this study, we reported that TDP-43 is translocated from the nucleus to the cytoplasm during CVB3 infection through the activity of viral protease 2A, followed by the cleavage mediated by viral protease 3C. Cytoplasmic translocation of TDP-43 is accompanied by reduced solubility and increased formation of protein aggregates. The cleavage takes place at aminoacid 327 between glutamine and alanine, resulting in the generation of an N-and C-terminal cleavage fragment of~35 and~8 kDa, respectively. The C-terminal product of TDP-43 is unstable and quickly degraded through the proteasome degradation pathway, whereas the N-terminal truncation of TDP-43 acts as a dominant-negative mutant that inhibits the function of native TDP-43 in alternative RNA splicing. Lastly, we demonstrated that knockdown of TDP-43 results in an increase in viral titers, suggesting a protective role for TDP-43 in CVB3 infection. Taken together, our findings suggest a novel model by which cytoplasmic redistribution and cleavage of TDP-43 as a consequence of CVB3 infection disrupts the solubility and transcriptional activity of TDP-43. Our results also reveal a mechanism evolved by enteroviruses to support efficient viral infection. Coxsackievirus B3 (CVB3) is a small, positive-stranded RNA enterovirus. 1 The single open reading frame of CVB3 is translated into a viral polypeptide that is subsequently cleaved by two virus-encoded proteases 2A and 3C to generate structural and non-structural proteins. 2 In addition to processing viral polyprotein, 2A and 3C target host proteins important for maintenance of protein translation and transcription, antiviral activity, and cellular architecture and signaling, contributing to virus-induced pathogenesis. [3][4][5] Although enteroviral replication takes place exclusively in the cytoplasm, viral infection has been demonstrated to lead to cytoplasmic translocation of nuclear proteins. 6 For example, heterogeneous ribonucleoprotein D (hnRNP D) has been shown to translocate from the nucleus to the cytoplasm during enteroviral infection. 5,7,8 Moreover, hnRNP D is cleaved by 3C and has an antiviral function against enteroviral infection. 5,7,8 Cytoplasmic translocation after enteroviral infection has also been demonstrated for several other hnRNPs (A1, C, and K)...

Increasing evidence has demonstrated that reactive oxygen species (ROS) induces oxidative stress and plays a crucial role in the pathogenesis of acute pancreatitis (AP). Hydrogen-rich saline (HRS), a well-known ROS scavenger, has been shown to possess therapeutic benefit on AP in many animal experiments. Recent findings have indicated that the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome, an intracellular multiprotein complex required for the maturation of interleukin- (IL-) 1β, may probably be a potential target of HRS in the treatment of AP. Therefore, in this study, we evaluated the activation of NLRP3 inflammasome and meanwhile assessed the degree of oxidative stress and inflammatory cascades, as well as the histological alterations in mice suffering from cerulein-induced AP after the treatment of HRS. The results showed that the activation of NLRP3 inflammasome in AP mice was substantially inhibited following the administration of HRS, which was paralleled with the decreased NF-κB activity and cytokines production, attenuated oxidative stress and the amelioration of pancreatic tissue damage. In conclusion, our study has, for the first time, revealed that inhibition of the activation of NLRP3 inflammasome probably contributed to the therapeutic potential of HRS in AP.

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