Vitamin D (VD) deficiency is associated with neuroinflammation and neurocognitive deficits in patients with traumatic brain injury (TBI). The present study was aimed at investigating the therapeutic effects of VD and the molecular mechanisms after TBI. After the intraperitoneal injection of VD (1 μg/kg), sensorimotor and cognitive function was assessed via a series of behavioral tests in TBI rats. Traumatic outcomes were investigated by brain edema, blood‐brain barrier (BBB) disruption, and morphologic staining. In vitro, cellular viability and cytotoxicity in primary hippocampal neurons were detected via the MTT method and LDH release. Hippocampal oxidative stress‐related enzymes and proinflammatory mediators and the serum concentration of VD were analyzed by ELISA. The expression of VDR, TLR4, MyD88, and NF‐κB p65 was measured by Western blot. Furthermore, the levels of M1/M2 microglial markers were quantified using real‐time PCR and Western blot. VD treatment significantly increased the serum level of VD and the hippocampal expression of VDR. VD not only effectively alleviated neurocognitive deficits, brain edema, and BBB disruption but also promoted hippocampal neuronal survival in vivo and in vitro. Moreover, VD therapy prevented excessive neuroinflammation and oxidative stress caused by TBI. Mechanically, the hippocampal expression of TLR4, MyD88, and nuclear NF‐κB p65 was elevated in the TBI group but robustly restrained by VD treatment. Taken together, VD provides an important neuroprotection through modulating hippocampal microglial M2 polarization and neuroinflammation via the TLR4/MyD88/NF‐κB pathway.

Background: Atherosclerosis occurs mainly at arterial branching points exposed to disturbed blood flow. How MST1 (mammalian sterile 20-like kinase 1), the primary kinase in the mechanosensitive Hippo pathway modulates disturbed flow induced endothelial cells (ECs) activation and atherosclerosis remains unclear. Methods: To assess the role of MST1 in vivo, mice with EC-specific Mst1 deficiency on ApoE ^−/− background ( Mst1 ^iECKO ApoE ^−/− ) were used in an atherosclerosis model generated by carotid artery ligation. Mass spectrometry, immunoprecipitation, proximity ligation assay, and dye uptake assay were used to identify the functional substrate of MST1. Human umbilical vein endothelial cells and human aortic endothelial cells were subjected to oscillatory shear stress that mimic disturbed flow in experiments conducted in vitro. Results: We found that the phosphorylation of endothelial MST1 was significantly inhibited in oscillatory shear stress-exposed regions of human and mouse arteries and ECs. Ectopic lenti-mediated overexpression of wild-type MST1, but not a kinase-deficient mutant of MST1, reversed disturbed flow-caused EC activation and atherosclerosis in EC-specific Mst1 deficiency on ApoE ^−/− background ( Mst1 ^iECKO ApoE ^−/− ). Inhibition of MST1 by oscillatory shear stress led to reduced phosphorylation of Cx43 (connexin 43) at Ser255, the Cx43 hemichannel open, EC activation, and atherosclerosis, which were blocked by TAT-GAP19, a Cx43 hemichannel inhibitory peptide. Mass spectrometry studies identified that Filamin B fueled the translocation of Cx43 to lipid rafts for further hemichannel open. Finally, lenti-mediated overexpression of the Cx43 ^S255 mutant into glutamate to mimic phosphorylation blunted disturbed flow-induced EC activation, thereby inhibiting the atherogenesis in both ApoE ^−/− and Mst1 ^iECKO ApoE ^−/− mice. Conclusions: Our study reveals that inhibition of the MST1-Cx43 axis is an essential driver of oscillatory shear stress-induced endothelial dysfunction and atherosclerosis, which provides a new therapeutic target for the treatment of atherosclerosis.

The enhancement of endogenous neurogenesis has been suggested in the treatment of traumatic brain injury (TBI); however, the factors that trigger the process of adult neurogenesis following TBI remain elusive. In the adult mammalian central nervous system, there are 2 neurogenic regions: the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ) of the lateral ventricles, both of which maintain relatively quiescent states in a stable microenvironment. However, once stimulated by intrinsic and extrinsic events, relevant signals are activated in these 2 regions. In this study, in order to explore the mechanisms behind endogenous neurogenesis following TBI, we investigated potential factors regulating this process. We observed that the expression of survivin, an anti-apoptotic protein, increased in a time-dependent manner in the hippocampus in a mouse model of TBI. In addition, the number of survivin (+) cells, as well as that of BrdU (+) cells increased in the SGZ of the dentate gyrus (DG) in the hippocampus following TBI, as shown by immunofluorescence double staining; the co-localization of survivin and BrdU was shown in the merged images. The expression of survivin was also significantly increased in the doublecortin (DCX) (+) immature neurons in the DG of the hippocampus soon after the induction of TBI. Taken together, these data confirm the connection between the expression of survivin and adult neurogenesis following TBI; our data also suggest the therapeutic potential of upregulating survivin expression as a novel strategy for the effective treatment of TBI.