TrkB signaling regulates the cold-shock protein RBM3-mediated neuroprotection

Increasing levels of the cold-shock protein, RNA-binding motif 3 (RBM3), either through cooling or by ectopic over-expression, prevents synapse and neuronal loss in mouse models of neurodegeneration. To exploit this process therapeutically requires an understanding of mechanisms controlling cold-induced RBM3 expression. Here, we show that cooling increases RBM3 through activation of TrkB via PLCγ1 and pCREB signaling. RBM3, in turn, has a hitherto unrecognized negative feedback on TrkB-induced ERK activation through induction of its specific phosphatase, DUSP6. Thus, RBM3 mediates structural plasticity through a distinct, non-canonical activation of TrkB signaling, which is abolished in RBM3-null neurons. Both genetic reduction and pharmacological antagonism of TrkB and its downstream mediators abrogate cooling-induced RBM3 induction and prevent structural plasticity, whereas TrkB inhibition similarly prevents RBM3 induction and the neuroprotective effects of cooling in prion-diseased mice. Conversely, TrkB agonism induces RBM3 without cooling, preventing synapse loss and neurodegeneration. TrkB signaling is, therefore, necessary for the induction of RBM3 and related neuroprotective effects and provides a target by which RBM3-mediated synapse-regenerative therapies in neurodegenerative disorders can be used therapeutically without the need for inducing hypothermia.

Post-TTM Rebound Pyrexia after Ischemia-Reperfusion Injury Results in Sterile Inflammation and Apoptosis in Cardiomyocytes

Introduction. Fever is frequently observed after acute ischemic events and is associated with poor outcome and higher mortality. Targeted temperature management (TTM) is recommended for neuroprotection in comatose cardiac arrest survivors, but pyrexia after rewarming is proven to be detrimental in clinical trials. However, the cellular mechanisms and kinetics of post-TTM rebound pyrexia remain to be elucidated. Therefore, we investigated the effects of cooling and post-TTM pyrexia on the inflammatory response and apoptosis in a cardiomyocyte ischemia-reperfusion (IR) injury model. Methods. HL-1 cardiomyocytes were divided into the following groups to investigate the effect of oxygen-glucose deprivation/reperfusion (OGD/R), hypothermia (33.5°C), and pyrexia (40°C): normoxia controls maintained at 37°C and warmed to 40°C, OGD/R groups maintained at 37°C and cooled to 33.5°C for 24 h with rewarming to 37°C, and OGD/R pyrexia groups further warmed from 37 to 40°C. Caspase-3 and RBM3 were assessed by Western blot and TNF-α, IL-6, IL-1β, SOCS3, iNOS, and RBM3 transcriptions by RT-qPCR. Results. OGD-induced oxidative stress (iNOS) in cardiomyocytes was attenuated post-TTM by cooling. Cytokine transcriptions were suppressed by OGD, while reperfusion induced significant TNF-α transcription that was exacerbated by cooling. Significant inductions of TNF-α, IL-6, IL-1β, and SOCS3 were observed in noncooled, but not in cooled and rewarmed, OGD/R-injured cardiomyocytes. Further warming to pyrexia induced a sterile inflammatory response in OGD/R-injured groups that was attenuated by previous cooling, but no inflammation was observed in pyrexic normoxia groups. Moreover, cytoprotective RBM3 expression was induced by cooling but suppressed by pyrexia, correlating with apoptotic caspase-3 activation. Conclusion. Our findings show that maintaining a period of post-TTM “therapeutic normothermia” is effective in preventing secondary apoptosis-driven myocardial cell death, thus minimizing the infarct area and further release of mediators of the innate sterile inflammatory response after acute IR injury.

Correlation analysis of RBM3 expression in tumor stroma and prognosis of patients with non-small cell lung cancer

Objective: To investigate the correlation between the expression of RNA binding motif protein 3 (RBM3) in non-small cell lung cancer (NSCLC) pathological tissue and known risk factors. Methods: A retrospective analysis of the clinical and pathological features of 128 patients with NSCLC from August 1, 2014 to August 1, 2015 was performed. The expression of RBM3 and protein kinase B (AKT) in the tumor stroma was examined by immunohistochemistry and pathological enumeration, followed by analysis of its correlation with prognosis. The survival status of patients was followed up. The relationships between RBM3 and AKT protein expression in tumor stroma with overall survival (OS) and progression-free survival (PFS) were evaluated. Results: The expression of RBM3 was significantly correlated with tumor differentiation ( P =0.012), lymph node metastasis ( P =0.02), T staging ( P =0.041), and AKT expression ( P =0.021). Univariate Kaplan-Meier analysis showed that high expression of RBM3, lymph node metastasis, T staging, and high expression of AKT were prognostic factors in NSCLC ( P <0.05). Multivariate analysis of Cox proportional hazard model showed that high RBM3 expression, lymph node metastasis, and high AKT expression were independent risk factors for prognosis ( P <0.05). Conclusion: RBM3, AKT, and lymph node metastasis are independent prognostic factors for NSCLC, significantly affecting the prognosis of patients possibly through the classical signaling pathway AKT. RBM3 may be a prognostic marker for the overall survival rate of NSCLC and a candidate for the treatment of NSCLC, with potential therapeutic prospects.