MicroRNA-26b/PTEN Signaling Pathway Mediates Glycine-Induced Neuroprotection in SAH Injury.

Subarachnoid hemorrhage (SAH) is a form of stroke associated with high mortality and morbidity. Despite advances in treatment for SAH, the prognosis remains poor. We have previously demonstrated that glycine, a non-essential amino acid is involved in neuroprotection following intracerebral hemorrhage via the Phosphatase and tensin homolog (PTEN)/protein kinase B (AKT) signaling pathway. However, whether it has a role in inducing neuroprotection in SAH is not known. The present study was designed to investigate the role of glycine in SAH. In this study, we show that glycine can reduce brain edema and protect neurons in SAH via a novel pathway. Following a hemorrhagic episode, there is evidence of downregulation of S473 phosphorylation of AKT (p-AKT), and this can be reversed with glycine treatment. We also found that administration of glycine can reduce neuronal cell death in SAH by activating the AKT pathway. Glycine was shown to upregulate miRNA-26b, which led to PTEN downregulation followed by AKT activation, resulting in inhibition of neuronal death. Inhibition of miRNA-26b, PTEN or AKT activation suppressed the neuroprotective effects of glycine. Glycine treatment also suppressed SAH-induced M1 microglial polarization and thereby inflammation. Taken together, we conclude that glycine has neuroprotective effects in SAH and is mediated by the miRNA-26b/PTEN/AKT signaling pathway, which may be a therapeutic target for treatment of SAH injury.

Pallidus Stimulation for Chorea-Acanthocytosis: A Systematic Review and Meta-Analysis of Individual Data.

A significant proportion of patients with chorea-acanthocytosis (ChAc) fail to respond to standard therapies. Recent evidence suggests that globus pallidus internus (GPi) deep brain stimulation (DBS) is a promising treatment option; however, reports are few and limited by sample sizes. We conducted a systematic literature review to evaluate the clinical outcome of GPi-DBS for ChAc. PubMed, Embase, and Cochrane Library databases were searched for relevant articles published before August 2021. The improvement of multiple motor and nonmotor symptoms was qualitatively presented. Improvements in the Unified Huntington's Disease Rating Scale motor score (UHDRS-MS) were also analyzed during different follow-up periods. A multivariate linear regression analysis was conducted to identify potential predictors of clinical outcomes. Twenty articles, including 27 patients, were eligible. Ninety-six percent of patients with oromandibular dystonia reported significant improvement. GPi-DBS significantly improved the UHDRS-motor score at < 6 months (p < 0.001) and ≥ 6 months (p < 0.001). The UHDRS-motor score improvement rate was over 25% in 75% (15/20 cases) of patients at long-term follow-up (≥ 6 months). The multiple linear regression analysis showed that sex, age at onset, course of disease, and preoperative movement score had no linear relationship with motor improvement at long-term follow-up (p > 0.05). GPi-DBS is an effective and safe treatment in most patients with ChAc, but no reliable predictor of efficacy has been found. Oromandibular dystonia-dominant patients might be the best candidates for GPi-DBS.

Bilateral Anterior Capsulotomy for the Treatment of Refractory Somatic Symptom Disorder: A Case Report.

Somatic symptom disorder (SSD) is a form of mental illness that causes one or more distressing somatic symptoms leading to a significant disruption to everyday life, characterized by excessive thoughts, feelings, or behaviors related to these symptoms. While SSD is characterized by significant discomfort in some parts of the body, these symptoms are not related to any known medical condition and therefore it cannot be diagnosed using any medical instrument examination. Currently available treatments for SSD, including drug therapy and psychotherapy (such as cognitive behavioral therapy), usually improve psychiatric symptoms, but the results are often disappointing. Furthermore, SSD is often comorbid with anxiety and depression (75.1 and 65.7%, respectively). Importantly, interventions targeting the anterior limb of the internal capsule (ALIC; e.g., deep brain stimulation and thermal ablation) can effectively treat various mental disorders, such as refractory obsessive-compulsive disorder, depression, and eating disorders, suggesting that it may also be effective for treating the depressive symptoms associated with SSD comorbidity. In this report, a 65-year-old woman diagnosed with SSD accompanied with depression and anxiety underwent bilateral anterior capsulotomy. The patient complained of nausea and vomiting, swelling of the hilum of the liver for 14 years, weakness of the limbs for 13 years, and burning pain in the esophagus for 1 year. Psychiatric and neuropsychological assessments were conducted to record the severity of the patients' symptoms and the progression of postoperative symptoms. The patient's somatization, depression, and anxiety symptoms as well as quality of life improved significantly and steadily; thus, anti-depressive and anti-anxiety medication were stopped. However, the patient developed new somatization symptoms, including dizziness, headache, and sternal pain, 10 months after the operation. Therefore, the patient resumed taking flupentixol and melitracen in order to control the new symptoms. This study shows that bilateral anterior capsulotomy appears to be a complementary treatment for refractory SSD with depressive and anxiety symptoms. Furthermore, postoperative use of anxiolytic and antidepressant medications may be useful for controlling future somatization symptoms.

Macrophage Polarization in Cerebral Aneurysm: Perspectives and Potential Targets.

Cerebral aneurysms (CAs) have become a health burden not only because their rupture is life threatening, but for a series of devastating complications left in survivors. It is well accepted that sustained chronic inflammation plays a crucial role in the pathology of cerebral aneurysms. In particular, macrophages have been identified as critical effector cells orchestrating inflammation in CAs. In recent years, dysregulated M1/M2 polarization has been proposed to participate in the progression of CAs. Although the pathological mechanisms of M1/M2 imbalance in CAs remain largely unknown, recent advances have been made in the understanding of the molecular basis and other immune cells involving in this sophisticated network. We provide a concise overview of the mechanisms associated with macrophage plasticity and the emerging molecular targets.

Daphnetin Protects against Cerebral Ischemia/Reperfusion Injury in Mice via Inhibition of TLR4/NF-κB Signaling Pathway.

Growing evidences indicate that immune-mediated mechanisms contribute to the development of cerebral ischemia/reperfusion (I/R) injury. Daphnetin (DAP) is a coumarin derivative extracted from Daphne odora var., which displays anti-inflammatory properties. However, the effect of DAP on cerebral I/R injury is not yet clear. Recent studies have demonstrated that TLR4/NF-κB signaling pathway takes part in the damaging inflammatory process of cerebral I/R injury. The present study aimed to investigate the effect of DAP on cerebral I/R injury in vivo and its possible mechanisms. DAP was administered before middle cerebral artery occlusion and reperfusion in mice. The neurological scores, cerebral infarct sizes, the levels of inflammatory cytokines, apoptotic neural cells, and the levels of TLR4, NF-κB p65, and IκBα were estimated. The results showed that an obvious improvement of neurological scores and infarct sizes was observed in DAP-treated mice after MCAO/R. DAP treatment decreased the overexpression of TNF-α, IL-1ß, and IL-6 and attenuated neural cells apoptosis. Moreover, DAP treatment decreased the TLR4 expression, IκB-α degradation, and nuclear translocation of NF-κB. Taken together, our results suggested that DAP exerted neuroprotective and anti-inflammatory effects on cerebral I/R injury. The potential mechanism was involved in the inhibition of TLR4/NF-κB mediated inflammatory signaling pathway.

Association between X-ray repair cross-complementing group 1 gene polymorphisms and glioma risk: a systematic review and meta-analysis based on 22 case-control studies.

OBJECTIVES: Glioma is the most common central nervous system tumor. This systematic review and meta-analysis is aimed to systematically assess the association of XRCC1 polymorphisms with the risk of glioma. METHODS: Such databases as EMbase, PubMed, The Cochrane Library, the China National Knowledge Infrastructure (CNKI) platforms, VIP and WanFang were searched up to April 2015 to collect case-control studies of association between XRCC1 polymorphisms and glioma. Data were extracted and meta-analysis was conducted by using Stata 12.0 softwares. RESULTS: A total of 22 studies were included in the meta-analysis, including 18503 glioma patients and 24367 controls. The overall data indicated that XRCC1 Arg194Trp (C>T) polymorphism significantly increased glioma risk (allele C versus T: OR=0.72, 95% CI=0.55-0.93, CC versus TT: OR=0.55, 95% CI=0.46-0.67; CC versus CT+TT: OR=0.64, 95% CI=0.45-0.91 and CC+CT vs. TT: OR=0.61, 95% CI=0.51-0.74), especially in Asia ethnicity. XRCC1 Arg280His (G>A) polymorphism has no association with glioma (allele G versus A: OR=1.01, 95% CI=0.83-1.22; GG versus AA: OR=1.07, 95% CI=0.66-1.75; GA versus AA: OR=1.01, 95% CI=0.77-1.32; GG versus GA+AA: OR=1.01, 95% CI=0.84-1.22 and GG+GT versus AA: OR=1.06, 95% CI=0.67-1.69). XRCC1 Arg399Gln (G>A) polymorphism will significantly increase glioma risk in Asian (allele G versus A: OR=0.78, 95% CI= 0.72-0.84; GG versus AA: OR=0.56, 95% CI=0.47-0.66; GA versus AA OR=0.71, 95% CI=0.59-0.84; GG versus GA+AA: OR=0.76, 95% CI=0.68-0.84 and GG+GA vs. AA: OR=0.62, 95% CI=0.53-0.73) but not Caucasian ethnicity. XRCC1 Pro161Leu (C>T), Leu387Leu (G>A), Pro602Thr (C>A), Ser593Arg (C>G) and Glu491Lys (G>A) polymorphisms increased glioma risk in different degrees. CONCLUSION: This meta-analysis suggested that XRCC1 Arg194Trp and XRCC1 Arg399Gln (G>A) polymorphisms led to susceptibility to glioma in Asian but not Caucasian population. XRCC1 Glu491Lys (G>A), Pro161Leu (C>T), Leu387Leu (G>A), Pro602Thr (C>A), Thr304Ala (A>G) and Ser593Arg (C>G) polymorphisms will increase glioma risk. However, XRCC1 Arg280His (G>A) is irrelevant to the increased or decreased glioma risk.

Puerarin inhibits proliferation and induces apoptosis in human glioblastoma cell lines.

Puerarin has been widely used in clinical treatment and experiment research and is considered to exert an anticancer effect recently. The present study investigated the anticancer activity of puerarin in U251 and U87 human glioblastoma cells. The cells were treated with puerarin at various concentrations for different times. Cell viability and cell proliferation were detected by cell counting kit-8 (CCK-8) assay and 5-ethynyl-2'-deoxyuridine (EdU) staining respectively. Cell cycle and apoptosis were measured separately with PI staining and Annexin V-FITC/PI double staining method by flow cytometry. DNA damage of glioblastoma cells caused by puerarin exposure was evaluated by γ-H2AX foci detection, and the expressions of p-AKT, caspase-3 and apoptosis-related proteins were detected by Western blotting after puerarin treatment. Cell viability and proliferation of glioblastoma cells treated with puerarin were significantly lower than that of the control group; the apoptosis rate increased obviously compared to the control group. Puerarin significantly decreased the proportion at G1 phase of cell cycling accompanied by increased populations at the S and G2/M phases in both cell lines. At the same time, DNA damage level of puerarin treated cells was significantly higher than that in the control cells. Moreover, puerarin treatment suppressed the expression of p-Akt and Bcl-2 and promoted the expression of Bax and cleaved caspase-3 in U251 cells. These findings indicate that puerarin exerts antitumor effects both in U251 and U87 cells.

LRIG1 enhances the radiosensitivity of radioresistant human glioblastoma U251 cells via attenuation of the EGFR/Akt signaling pathway.

The radiotherapy as a local and regional modality is widely applied in treatment of glioma, but most glioblastomas are commonly resistant to irradiation treatment. It remains challengeable to seek out efficient strategies to conquer the resistance of human glioblastoma cells to radiotherapy. Leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) is a newly discovered tumor suppressor which involved in regulation of chemosensitivity in various human cancer cells. In the present study, we established a radioresistant U251 cell line (U251R) to investigate the role of LRIG1 in regulation of radiosensitivity in human glioblastoma cells. Significantly decreased expression level of LRIG1 and enhanced expression of EGFR and phosphorylated Akt were detected in U251R cells compared with the parental U251 cells. U251R cells exhibited an advantage in colony formation ability, which accompanied by remarkably reduced X-ray-induced γ-H2AX foci formation and cell apoptosis. LRIG1 overexpression significantly inhibited the colony formation ability of U251R cells and obviously enhanced X-ray-inducedγ-H2AX foci formation and cell apoptosis. In addition, up-regulated expression of LRIG1 suppressed the expression level of EGFR and phosphorylated Akt protein. Our results demonstrated that LRIG1 expression was related to the radiosensitivity of human glioblastoma cells and may play an important role in the regulation of cellular radiosensitivity of human glioblastoma cells through the EGFR/Akt signaling pathway.

Risk association of meningiomas with MTHFR C677T and GSTs polymorphisms: a meta-analysis.

Previous studies have shown that the single nucleotide polymorphisms (SNPs) in Methylenetetrahydrofolate reductase (MTHFR) and Glutathione S-transferases (GSTs, including GSTM1, GSTT1) genes play an important role in determining the response of an individual to environmental pathogenesis and significantly relate to incidences of various human tumors, including brain tumors. However, these genes' polymorphisms on meningioma risk remains poorly understood. The relevant inferences from previous studies are hindered by their limited statistical power and conflicting results. The aim of this meta-analysis is to provide a relatively comprehensive account of the association between these polymorphisms and human meningioma risk. A literature search for eligible studies published before January 1, 2014 was conducted in PubMed, Embase, Web of Science, Cochrane Library, and CNKI databases. Pooled odds ratios (OR) with their corresponding 95% confidence intervals (95% CI) were used to evaluate the strength of the association under a fixed or random effect model according to heterogeneity test results. Heterogeneity and publication bias were evaluated. All statistical analyses were conducted by using the software of STATA 12.0 (STATA Corporation, College Station, TX, USA). For MTHFR C677T (dbSNP: rs1801133) (C T) polymorphism, 9 individual case-control studies from six publications with 1,615 cases and 1,909 controls were obtained. For GSTM1 null polymorphism, there were 4 studies with 417 cases and 1,735 controls. For GSTT1 null polymorphism, there were 4 studies with 405 cases and 1,622 controls. The combined results for the MTHFR C677T show that carriers of the CT genotype may be associated with a higher meningioma risk (OR = 1.20, 95% CI 1.05-1.38, P = 0.009). Stratified analyses show that Caucasians have significantly higher risk if they carry the CT genotype of MTHFR (OR = 1.31, 95% CI 1.05-1.63, P = 0.02). Risk of Caucasians carrying TT + CT genotype is also significantly higher (OR = 1.27, 95% CI 1.02-1.58, P = 0.03). Risk of Caucasians carrying TT genotype is not significantly different compared to control population (OR = 0.96, 95% CI 0.69-1.34, P = 0.82). All of the enrolled studies about GSTM1/GSTT1 are on Caucasians. The pooled ORGSTM1 and ORGSTT1 were not significant in Caucasian population. These results indicate SNPs of MTHFR C677T are related to meningioma risk with ethnic differences. Caucasians carrying CT genotype of MTHFR C677T have significantly higher meningioma susceptibility. SNPs of GSTM1/GSTT1 are not related to meningioma risk.

MicroRNA-19a promotes glioma cell growth by repressing LRIG1.

Growing evidence indicates that deregulation of miRNAs contributes to the development of glioma. In present study, we found that the level of miRNA-19a was significantly elevated in glioma tissues and cell lines. Moreover, down-regulation of miRNA-19a dramatically repressed glioma cell growth in vitro and in vivo. Meanwhile, the expression of LRIG1, a tumor suppressor in glioma, was increased following miRNA-19a knockdown. Furthermore, luciferase reporter assay confirmed that LRIG1 was a direct target of miRNA-19a. In addition, silencing of LRIG1 could reverse the suppressive effect of miRNA-19a inhibitor. Taken together, our results demonstrated that down-regulation of miRNA-19a could suppress the growth of glioma cells, at least in part, through up-regulating LRIG1.