BackgroundTraumatic brain injury (TBI) initiates a neuroinflammatory cascade that contributes to substantial neuronal damage and behavioral impairment, and Toll-like receptor 4 (TLR4) is an important mediator of thiscascade. In the current study, we tested the hypothesis that curcumin, a phytochemical compound with potent anti-inflammatory properties that is extracted from the rhizome Curcuma longa, alleviates acute inflammatory injury mediated by TLR4 following TBI.MethodsNeurological function, brain water content and cytokine levels were tested in TLR4-/- mice subjected to weight-drop contusion injury. Wild-type (WT) mice were injected intraperitoneally with different concentrations of curcumin or vehicle 15 minutes after TBI. At 24 hours post-injury, the activation of microglia/macrophages and TLR4 was detected by immunohistochemistry; neuronal apoptosis was measured by FJB and TUNEL staining; cytokines were assayed by ELISA; and TLR4, MyD88 and NF-κB levels were measured by Western blotting. In vitro, a co-culture system comprised of microglia and neurons was treated with curcumin following lipopolysaccharide (LPS) stimulation. TLR4 expression and morphological activation in microglia and morphological damage to neurons were detected by immunohistochemistry 24 hours post-stimulation.ResultsThe protein expression of TLR4 in pericontusional tissue reached a maximum at 24 hours post-TBI. Compared with WT mice, TLR4-/- mice showed attenuated functional impairment, brain edema and cytokine release post-TBI. In addition to improvement in the above aspects, 100 mg/kg curcumin treatment post-TBI significantly reduced the number of TLR4-positive microglia/macrophages as well as inflammatory mediator release and neuronal apoptosis in WT mice. Furthermore, Western blot analysis indicated that the levels of TLR4 and its known downstream effectors (MyD88, and NF-κB) were also decreased after curcumin treatment. Similar outcomes were observed in the microglia and neuron co-culture following treatment with curcumin after LPS stimulation. LPS increased TLR4 immunoreactivity and morphological activation in microglia and increased neuronal apoptosis, whereas curcumin normalized this upregulation. The increased protein levels of TLR4, MyD88 and NF-κB in microglia were attenuated by curcumin treatment.ConclusionsOur results suggest that post-injury, curcumin administration may improve patient outcome by reducing acute activation of microglia/macrophages and neuronal apoptosis through a mechanism involving the TLR4/MyD88/NF-κB signaling pathway in microglia/macrophages in TBI.

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Loss of the histone H3.3‐specific chaperone component ATRX or its partner DAXX frequently occurs in human cancers that employ alternative lengthening of telomeres (ALT) for chromosomal end protection, yet the underlying mechanism remains unclear. Here, we report that ATRX/DAXX does not serve as an immediate repressive switch for ALT. Instead, ATRX or DAXX depletion gradually induces telomere DNA replication dysfunction that activates not only homology‐directed DNA repair responses but also cell cycle checkpoint control. Mechanistically, we demonstrate that this process is contingent on ATRX/DAXX histone chaperone function, independently of telomere length. Combined ATAC‐seq and telomere chromatin immunoprecipitation studies reveal that ATRX loss provokes progressive telomere decondensation that culminates in the inception of persistent telomere replication dysfunction. We further show that endogenous telomerase activity cannot overcome telomere dysfunction induced by ATRX loss, leaving telomere repair‐based ALT as the only viable mechanism for telomere maintenance during immortalization. Together, these findings implicate ALT activation as an adaptive response to ATRX/DAXX loss‐induced telomere replication dysfunction.

Object A glial scar is thought to be responsible for halting neuroregeneration following spinal cord injury (SCI). However, little quantitative evidence has been provided to show the relationship of a glial scar and axonal regrowth after injury. Methods In this study performed in rats and dogs, a traumatic SCI model was made using a weight-drop injury device, and tissue sections were stained with H & E for immunohistochemical analysis. The function and behavior of model animals were tested using electrophysiological recording and the Basso-Beattie-Bresnahan Locomotor Rating Scale, respectively. The cavity in the spinal cord after SCI in dogs was observed using MR imaging. Results The morphological results showed that the formation of an astroglial scar was defined at 4 weeks after SCI. While regenerative axons reached the vicinity of the lesion site, the glial scar blocked the extension of regrown axons. In agreement with these findings, the electrophysiological, behavioral, and in vivo MR imaging tests showed that functional recovery reached a plateau at 4 weeks after SCI. The thickness of the glial scars in the injured rat spinal cords was also measured. The mean thickness of the glial scar rostral and caudal to the lesion cavity was 107.00 ± 20.12 μm; laterally it was 69.92 ± 15.12 μm. Conclusions These results provide comprehensive evidence indicating that the formation of a glial scar inhibits axonal regeneration at 4 weeks after SCI. This study reveals a critical time window of postinjury recovery and a detailed spatial orientation of glial scar, which would provide an important basis for the development of therapeutic strategy for glial scar ablation.

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Design and synthesis of new fluorophores with emission in the second near‐infrared window (NIR‐II, 1000–1700 nm) have fueled the advancement of in vivo fluorescence imaging. Organic NIR‐II probes particularly attract tremendous attention due to excellent stability and biocompatibility, which facilitate clinical translation. However, reported organic NIR‐II fluorescent agents often suffer from low quantum yield and complicated design. In this study, the acceptor unit of a known NIR‐I aggregation‐induced emission (AIE) luminogen (AIEgen) is molecularly engineered by varying a single atom from sulfur to selenium, leading to redshifted absorption and emission spectra. After formulation of the newly prepared AIEgen, the resultant AIE nanoparticles (referred as L897 NPs) have an emission tail extending to 1200 nm with a high quantum yield of 5.8%. Based on the L897 NPs, noninvasive vessel imaging and lymphatic imaging are achieved with high signal‐to‐background ratio and deep penetration. Furthermore, the L897 NPs can be used as good contrast agents for tumor imaging and image‐guided surgery due to the high tumor/normal tissue ratio, which peaks at 9.0 ± 0.6. This work suggests a simple strategy for designing and manufacturing NIR‐II AIEgens and demonstrates the potential of NIR‐II AIEgens in vessel, lymphatic, and tumor imaging.

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Gliomas are rare entities in the cerebellopontine angle (CPA) in adults. The authors present clinical, neuroradiological, serological, and neuropathological findings in a 60-year-old man with an extraaxial CPA glioblastoma arising from the proximal portion of cranial nerve VIII. The patient presented with progressive left-sided deafness and left-sided facial palsy lasting less than 2 months and progressive dysarthria and dysphagia lasting 2 weeks. Preoperative neuroimaging suggested the diagnosis of CPA meningioma with "dural-tail" sign and involvement of the internal auditory canal. Serological examination showed an increase in the malignant markers of ferritin and neuron-specific enolase, which suggested underlying malignancy. The tumor was subtotally removed, and it was confirmed to be completely separated from the brainstem and cerebellum. Cranial nerves VII and VIII were destroyed and sacrificed. Transient severe bradycardia occurred during surgery due to entrapment of the caudal cranial nerve complex by the tumor in such an infiltrative way. The neuropathological examination revealed a glioblastoma. The patient underwent no further treatment and died of cachexia 2 months postoperatively. To the authors' knowledge, this represents the first case of a primary glioblastoma in the CPA in an adult. A high index of suspicion along with reliance on clinical assessment, radiological findings, and serum detection of specific malignant markers is essential to diagnose such uncommon CPA lesions.