Protection of blood-brain barrier by endothelial DAPK1 deletion after stroke.

Death-associated protein kinase (DAPK) 1 is a critical mediator for neuronal cell death in cerebral ischemia, but its role in blood-brain barrier (BBB) disruption is incompletely understood. Here, we found that endothelial-specific deletion of Dapk1 using Tie2 Cre protected the brain of Dapk1fl/fl mice against middle cerebral artery occlusion (MCAO), characterized by mitigated Evans blue dye (EBD) extravasation, reduced infarct size and improved behavior. In vitro experiments also indicated that DAPK1 deletion inhibited oxygen-glucose deprivation (OGD)-induced tight junction alteration between cerebral endothelial cells (CECs). Mechanistically, we revealed that DAPK1-DAPK3 interaction activated cytosolic phospholipase A2 (cPLA2) in OGD-stimulated CECs. Our results thus suggest that inhibition of endothelial DAPK1 specifically prevents BBB damage after stroke.

Nrf2 activation by neferine mitigates microglial neuroinflammation after subarachnoid hemorrhage through inhibiting TAK1-NF-κB signaling.

Oxidative stress and neuroinflammation are two major causes leading to early brain injury after subarachnoid hemorrhage (SAH). Nuclear factor E2-related factor 2 (Nrf2) is a critical transcription factor that contributes to antioxidant responses. Additionally, Nrf2 could inhibit transforming growth factor beta-activated kinase 1 (TAK1), which plays a vital role in microglial activation-mediated neuroinflammation. Neferine (NE) exhibits considerable protective effects in diverse disease models. However, the detailed effect and mechanism of NE on SAH remain unknown. Our data showed that NE treatment significantly reduced behavior and cognitive impairment, and brain edema in the early period after SAH. In addition, NE mitigated SAH-induced oxidative damage, neuroinflammation, and neural death. Moreover, NE inhibited M1 microglial polarization and enhanced M2 phenotype microglia both in vivo and in vitro. Further investigations revealed that NE enhanced the Nrf2-antioxidant response element (ARE) signaling pathway and suppressed TAK1-NF-κB signaling. In contrast, depletion of Nrf2 by ML385 suppressed Nrf2-ARE signaling, induced TAK1-NF-κB activation, and further promoted M1 microglial polarization. Additionally, ML385 abated the neuroprotective effects of NE against SAH. Notably, LPS also aggravated TAK1-NF-κB activation and reversed the beneficial effects of NE after SAH. In summary, NE provides protection after SAH by inhibiting oxidative stress and modulating microglial polarization through Nrf2 activation and TAK1-NF-κB suppression.

The Prognosis of Pineal Parenchymal Tumors: Development and Validation of a Nomogram Based on Surveillance, Epidemiology and End Results.

BACKGROUND: Pineal parenchymal tumors are exceedingly rare, and optimal disease management has yet to be defined. In this study, we aimed to identify prognostic factors and establish a predictive model for the prognosis of patients with pineal parenchymal tumors. METHODS: All patients with pineal parenchymal tumors in the Surveillance, Epidemiology and End Results database between 1975 and 2019 were reviewed. Data were summarized, and survival was modeled with Cox regression analyses. In addition, a nomogram predicting 5- and 10-year survival probability for pineal parenchymal tumors was developed and validated. RESULTS: We found 691 pineal parenchymal and 1961 pineal region neoplasms during 1975 and 2019 resulting in an incidence of 35%. In total, 441 patients were excluded due to incomplete data. The final cohort was subdivided into groups based on tumor histology: pineocytomas, pineoblastomas, and pineal parenchymal tumors of intermediate differentiation. Multivariate Cox analysis identified age and beam radiation as prognostic factors in pineoblastomas. Age, histology, tumor size, extent of resection, radiation, and chemotherapy were selected to build a clinical nomogram. The C-index for the nomogram was 0.795 (95% confidence interval 0.738-0.852). The calibration curves of the 5- and 10-year survival rates showed good agreement between the nomogram predictions and actual observations. CONCLUSIONS: This nomogram is a convenient and precise tool for clinicians to evaluate prognosis of pineal parenchymal tumors.