Pink1 deficiency enhances neurological deficits and inflammatory responses after intracerebral hemorrhage in mice.

Pink1 (PTEN-induced putative kinase 1) is a protein associated with maintaining mitochondrial function and integrity and has been reported to mediate neurodegeneration and neuroinflammation. While the role of Pink1 in intracerebral hemorrhage (ICH)-related neurological deficits and inflammatory responses is not deciphered. Congenic blood was transfused into the left corpus striatum to construct the ICH model in C57/BL6 wild-type (WT) and Pink1-/- mice. The relative expression of Pink1, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-2, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, Cd86, nitric oxide synthase 2 (Nos2), Cd206, arginase 1 (Arg-1), and IL-10 was detected with qRT-PCR, Western blotting, or ELISA. Mouse neurological deficit scores (mNSS) and water content were detected, and an open-field test was performed to assay anxiety-like behavior. Remarkably decreased Pink1 expression and increased MIP-2, IL-1ß, MCP-1, and TNF-α expression were observed after 12 â€‹h, 24 â€‹h, 48 â€‹h, 72 â€‹h, and 7 â€‹d post-ICH induction in the ipsilateral injury hemispheres. Pink1 deficiency could further up-regulate mNSS scores, brain water content, MIP-2, MCP-1, IL-1ß, and TNF-α in the ipsilateral injury hemispheres. On the other hand, Pink1 deficiency could decrease the number of center cross, the velocity, and the total distance traveled in open field test. Pink1 deficiency could further up-regulate the mRNA levels of pro-inflammatory (M1) molecules (Cd86, Nos2), and down-regulate the relative expression of anti-inflammatory (M2) molecules (Cd206, Arg-1, and IL-10). Pink1 deficiency deteriorates neurological deficits and inflammatory responses after ICH, which can be considered as a treatment target.

Diagnostic Significance of Targeted Next-Generation Sequencing in Central Nervous System Infections in Neurosurgery of Pediatrics.

Background: Cerebrospinal fluid (CSF) pathogen culture suffers from the drawbacks of prolonged cycle time and a low positivity rate in diagnosing intracranial infections in children. This study aims to investigate the diagnostic potential of targeted next-generation sequencing (tNGS) in pediatric neurosurgery for central nervous system (CNS) infections. Methods: A retrospective study was conducted on children under 14 with suspected intracranial infections following craniocerebral trauma or surgery between November 2018 and August 2020. Routine, biochemical, smear, and pathogen culture tests were performed on CSF during treatment. The main parameters of CSF analysis encompassed white blood cells (WBC, ×106/L) count, percentage of multinucleated cells (%), protein levels (g/L), glucose concentration (GLU, mmol/L), chloride levels (mmol/L), and pressure (mmH2O). The outcomes of tNGS were assessed through the Receiver Operating Characteristic (ROC) curve and pertinent diagnostic parameters. Results: Among the 35 included pediatric patients, 22 were clinically diagnosed with CNS infection in neurosurgery, tNGS was confirmed in 18 cases. The sensitivity and specificity of tNGS were 81.8% and 76.9%, respectively, while the traditional method of CSF cultures and smears exhibited a sensitivity of 13.6% and a specificity of 100%. ROC curve analysis indicated an area under the curve (AUC) of 0.794 for tNGS and 0.568 for the CSF cultures and smears. CSF analysis indicated that the two groups exhibited statistically significant differences in terms of WBC count [330.0 (110.00-2639.75) vs 14.00 (4.50-26.50), P<0.001] and percentage of multinuclear cells (%) [87.50 (39.75-90.00) vs 0 (0-10.00), P<0.001]. However, the remaining parameters did not statistically significant differences between the groups (all P>0.05). Conclusion: tNGS demonstrates a high degree of diagnostic accuracy when detecting infections within the CNS of pediatric neurosurgery patients. tNGS can effectively establish for diagnosing CNS infections by detecting pathogenic microorganisms and their corresponding virulence and/or resistance genes within the test samples.

PINK1 antagonize intracerebral hemorrhage by promoting mitochondrial autophagy.

BACKGROUND: Intracerebral hemorrhage (ICH) causes neurotransmitter release, oligemia, membrane depolarization, mitochondrial dysfunction, and results in the high rate of mortality and functional disability. Here, we focus on PTEN-induced kinase 1 (PINK1), a mitochondrial-targeted protein kinase, and explore its role in ICH progression. METHODS: The qPCR and Western blot were performed to examine the expression of PINK1 in ICH patients and mouse model. PINK1 gain- and loss-of-function mice were used to evaluate their protective role on brain injury and behavioral disorders. Flow cytometry was carried out, mitochondrial membrane potential and reactive oxygen species production were detected to explore the distribution and neuroprotective function of PINK1. RESULTS: PINK1 mRNA was upregulated, however, its protein was downregulated in ICH patients. The reduction of PINK1 was mainly happened in microglial cells in ICH model. Overexpression of PINK1 is able to rescue ICH-induced behavioral disorders. PINK1 protects ICH-induced brain injury by promoting mitochondrial autophagy in microglia. CONCLUSION: PINK1 possesses a neuroprotective role and antagonizes ICH by promoting mitochondrial autophagy, which may be of value as a therapeutic target for ICH treatment.

Long Noncoding RNA LINC00958 Accelerates Gliomagenesis Through Regulating miR-203/CDK2.

Increasing evidence has indicated that long noncoding RNAs (lncRNAs) play crucial roles in various biological processes, including glioma. However, the underlying mechanism of lncRNAs in gliomagenesis is still ambiguous. In this study, we aim to investigate the role of long intergenic noncoding RNA 00958 (LINC00958) in the tumorigenesis of glioma. Results revealed that LINC00958 was significantly upregulated in glioma tissues and cell lines compared with that of adjacent normal brain tissues and normal human astrocytes. Moreover, the ectopic overexpression of LINC00958 was correlated with poor prognosis of glioma patients. Loss-of-function experiments indicated that LINC00958 knockdown suppressed glioma cell proliferation, invasion, and induced cycle arrest at G0/G1 phase in vitro, and inhibited tumor growth in vivo. Bioinformatics programs and luciferase reporter assay revealed that miR-203 shared complementary binding sites with both 3'-untranslated region of LINC00958 and CDK2. In summary, our study concludes that LINC00958 acts as an oncogenic gene in the gliomagenesis through miR-203-CDK2 regulation, providing a novel insight into glioma tumorigenesis.

Overexpression of SCUBE2 Inhibits Proliferation, Migration, and Invasion in Glioma Cells.

Signal peptide CUB EGF-like domain-containing protein 2 (SCUBE2), a member of the SCUBE family of proteins, was recently found to play an important role in cancer development. However, little is known regarding its biological function in glioma. In the present study, we investigated the effect of SCUBE2 on glioma and explored its relevant mechanisms. The study showed that SCUBE2 had a low expression in glioma tissue and cell lines. SCUBE2 overexpression inhibited glioma cell proliferation in vitro and in vivo as well as suppressed glioma cell migration and invasion in vitro. Furthermore, we found that the Sonic hedgehog (Shh) signaling pathway was involved in the inhibitory effect of SCUBE2 overexpression on glioma cells. In light of the results obtained from our study, SCUBE2 may be regarded as a potential therapeutic target for glioma.

Cytoplasmic polyadenylation element-binding protein 4 is highly expressed in human glioma.

Cytoplasmic polyadenylation element-binding protein 4 (CPEB4) is a highly conserved, sequence-specific RNA-binding protein that recruits translational repression or cytoplasmic polyadenylation machinery to target mRNAs. Recent studies have shown that CPEBs are expressed in somatic tissues and have essential functions supporting tumor growth, vascularization, and invasion. Overexpression of CPEB4 has been reported in pancreatic ductal adenocarcinoma and is associated with poor prognoses. However, whether CPEB4 plays a role in the tumorigenesis of gliomas is unknown. Here, we analyzed the expression of CPEB4 in gliomas. The expression profiles of CPEB4 mRNA and protein in nine normal brain tissues and 63 gliomas were detected using immunohistochemistry, real-time PCR, and western blotting. CPEB4-positive expression was significantly correlated with the pathological grade of glioma; abundant expression was observed in high-grade gliomas, whereas little or no expression was observed in normal astrocytes. Immunohistochemistry staining indicated that CPEB4 was mainly localized in the cytoplasm. In addition, CPEB4 was more highly expressed in U87 glioma cells than in U251 cells. CPEB4 expression significantly correlated with the grade in clinical gliomas. This study suggested that CPEB4 might play a role in the pathogenesis of glioma.

Knockdown of long noncoding RNA SPRY4-IT1 suppresses glioma cell proliferation, metastasis and epithelial-mesenchymal transition.

Long noncoding RNAs (lncRNAs), a class of ribonucleic molecules, participate in various cellular processes. They are highly expressed in several types of cancer and their expression was related to pathophysiological characteristics of tumor growth, therefore, they can be considered as a promising diagnostic tool and a convenient prognostic biomarker. SPRY4-IT1, belonging to a group of intron-retained lncRNAs, was reported to affect tumor development of many types of cancer. However, the expression and the role of SPRY4-IT1 in glioma are still unclear. Therefore, in this study, we examined for the first time the expression and role of SPRY4-IT1 in glioma cells. The results of our study showed that SPRY4-IT1 was up-regulated in human glioma tissues and cell lines. Knockdown of SPRY4-IT1 could inhibit glioma cell growth and migration. Moreover, knockdown of SPRY4-IT1 could inhibit epithelial-mesenchymal transition (EMT) phenotype in glioma cells. Based on these findings, SPRY4-IT1 may be used as a new target for diagnosis and treatment of glioma.

Over-expression of wild-type p53-induced phosphatase 1 confers poor prognosis of patients with gliomas.

Wild-type p53-induced phosphatase 1 (Wip1) is a member of the protein phosphatase 2C family, which is characterized by distinctive oncogenic properties. Overexpression of Wip1 is observed in certain types of human tumors that are associated with significantly poor prognosis. This study aimed to detect the expression of Wip1 in gliomas and to analyze its prognostic value in the patients. Wip1 mRNA and protein expression profiles in 81 gliomas and 15 normal brain tissues were detected using RT-PCR, Western blot and immunohistochemistry. The specimens were stained with proliferating cell nuclear antigen (PCNA) and p53 and evaluated using immunohistochemistry. Detailed clinical and demographic information of patients were retrospectively collected until 5years post-operation. Kaplan-Meier survival and Cox's regression analyses were performed to evaluate the prognosis of patients. Wip1-positive expression was observed in the majority of glioma tissues, whereas no Wip1 expression was detected in the normal brain tissues. Wip1-positive expression significantly correlated with glioma histological grade. The PCNA index was higher in the Wip1-positive group compared to that in the Wip1-negative group. A univariate analysis and log-rank test indicated that statistically significant association between Wip1 expression and the lower overall survival rate in the patients with glioma. A multivariate analysis also indicated a statistically significant association between increased Wip1 expression and lower overall survival rate. Our results suggest that Wip1 may be related to pathological diagnosis and prognosis evaluation for malignant gliomas.