Upregulation of neuronal oxidative stress is involved in the progression of secondary brain injury (SBI) following intracerebral hemorrhage (ICH). In this study, we investigated the potential effects and underlying mechanisms of luteolin on ICH-induced SBI. Autologous blood and oxyhemoglobin (OxyHb) were used to establish in vivo and in vitro models of ICH, respectively. Luteolin treatment effectively alleviated brain edema and ameliorated neurobehavioral dysfunction and memory loss in vivo. Also, in vivo, we found that luteolin promoted the activation of the sequestosome 1 (p62)/kelch-like enoyl-coenzyme A hydratase (ECH)-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway by enhancing autophagy and increasing the translocation of Nrf2 to the nucleus. Meanwhile, luteolin inhibited the ubiquitination of Nrf2 and increased the expression levels of downstream antioxidant proteins, such as heme oxygenase-1 (HO-1) and reduced nicotinamide adenine dinucleotide phosphate (NADPH): quinine oxidoreductase 1 (NQO1). This effect of luteolin was also confirmed in vitro, which was reversed by the autophagy inhibitor, chloroquine (CQ). Additionally, we found that luteolin inhibited the production of neuronal mitochondrial superoxides (MitoSOX) and alleviated neuronal mitochondrial injury in vitro, as indicated via tetrachloro-tetraethylbenzimidazol carbocyanine-iodide (JC-1) staining and MitoSOX staining. Taken together, our findings demonstrate that luteolin enhances autophagy and anti-oxidative processes in both in vivo and in vitro models of ICH, and that activation of the p62-Keap1-Nrf2 pathway, is involved in such luteolin-induced neuroprotection. Hence, luteolin may represent a promising candidate for the treatment of ICH-induced SBI.

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Objectives: Adamantinomatous craniopharyngiomas (adaCP) accounts for 5.6% to 15% of intracranial tumors. High expression of chemokine (C-X-C motif) ligand 12 (CXCL12, also known as stromal cell-derived factor 1 [SDF1]) and its receptor CXC receptor type 4 (CXCR4) are widespread in various malignancy via multiple signal transduction pathways. This study aims to investigate the mechanism of CXCL12/CXCR4 promoting proliferation, migration, and invasion of adaCP. Methods: Quantitative real-time polymerase chain reaction, Western blot analysis, and immunohistochemistry were used to evaluate the expression of CXCL12/CXCR4 mRNA and protein in 10 human adaCP tissues. Three successfully primary cell lines were obtained from native mainly solid tumor specimens, and confirmed by the means of inverted contrast microscope directly and following hematoxylin and eosin staining. Immunofluorescence was used to detect protein expression in vivo for the verification of primary cell line. Proliferation, migration, and invasion assays were performed to assess the biological functional role of CXCL12/CXCR4 in adaCP. The signal pathways involved in the action of CXCL12/CXCR4 in adaCP were also evaluated. Results: CXCL12 and CXCR4 were highly expressed in human adaCP samples.Primary adaCP cells were isolated and detected by the means of immunofluorescence for the detection of pan cytokeratin (pan-CK) and vimentin (VIM). Overexpression of CXCL12/CXCR4 significantly promoted the proliferation, migration, and invasion of primary adaCP cells. Moreover, cancer-promoting activity of CXCL12/CXCR4 is partially through its facilitation of PI3K/AKT signal pathway.Conclusions: Our data showed that CXCL12/CXCR4 promotes adaCP proliferation, migration, and invasion through PI3K/AKT signal pathway. These findings suggested that therapeutic strategies regulating CXCL12/CXCR4 expression may provide an effective treatment of adaCP. K E Y W O R D S adamantinomatous craniopharyngiomas, CXCL12/CXCR4, metastasis, PI3K/AKT, progression J Cell Biochem. 2019;120:9724-9736. wileyonlinelibrary.com/journal/jcb 9724 |

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Background:The aim of this study was to systematically evaluate the prognostic role of microvessel density (MVD) in patients with glioma through performing a meta-analysis.Methods:Web of Science, EMBASE, PubMed, Cochrane Library, and China National Knowledge Infrastructure were searched for potentially relevant literature. The study characteristics and relevant data were extracted. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled to estimate the prognostic role of MVD in patients with glioma.Results:Nine studies with 536 patients were included. The pooled HR of higher MVD for overall survival (OS) was 1.64 (95% CI, 1.07–2.50) in patients with glioma. Subgroup analyses were also performed. The pooled HRs of higher MVD in studies from East Asia studies examining high-grade gliomas and studies using anti-CD105 antibodies were 1.99 (95% CI, 1.04–3.80), 1.60 (95% CI, 1.09–2.34) and 2.99 (95% CI, 1.50–5.99), respectively. No significant publication bias was found (P = .592), but significant between-study heterogeneity was observed (I2 = 80.5%, P <.001) in the meta-analysis.Conclusion:Our results suggested that higher MVD was associated with worse OS in patients with glioma. The findings may assist future research on antiangiogenic therapy and help predict prognosis in glioma. However, due to the limited number of studies, more well-designed studies are warranted to further verify our results.

Surgical brain injury (SBI) triggers microglia to release numerous inflammatory factors, leading to brain edema and neurological dysfunction. Reducing neuroinflammation and protecting the blood-brain barrier (BBB) are key factors to improve the neurological function and prognosis after SBI. Na+-K+-Cl– cotransporter 1 (NKCC1) and nuclear factor κB (NF-κB) have been implicated in the secretion of inflammatory cytokines by microglia in brain injury. This study aimed to establish the role of NKCC1 in inducing inflammation in SBI, as well as to determine whether NKCC1 controls the release of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) via phosphorylation of NF-κB in microglia, thus affecting BBB permeability and neuronal cell apoptosis. Male Sprague-Dawley (SD) rats were used to establish an SBI model. This study revealed that compared with the sham group, the expression levels of p-NKCC1, p-p65-NF-κB, and related inflammatory factor proteins in SBI model group significantly increased. After p-NKCC1 was inhibited, p-p65-NF-κB, IL-6, IL-1β, and TNF-α were downregulated, and nerve cell apoptosis and BBB permeability were significantly reduced. These findings suggest that the SBI-induced increase in p-NKCC1 exacerbates neuroinflammation, brain edema, and nerve function injury, which may be mediated by regulating the activity of p65-NF-κB that in turn influences the release of inflammatory factors.