RESUMEN
Glioblastoma (GBM) is a WHO grade 4 tumor and is the most malignant form of glioma. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), a mitochondrial enzyme involved in folate metabolism, has been reported to be highly expressed in several human tumors. However, little is known about the role of MTHFD2 in GBM. In this study, we aimed to explore the biological functions of MTHFD2 in GBM and identify the associated mechanisms. We performed experiments such as immunohistochemistry, Western blot, and transwell assays and found that MTHFD2 expression was lower in high-grade glioma than in low-grade glioma. Furthermore, a high expression of MTHFD2 was associated with a favorable prognosis, and MTHFD2 levels showed good prognostic accuracy for glioma patients. The overexpression of MTHFD2 could inhibit the migration, invasion, and proliferation of GBM cells, whereas its knockdown induced the opposite effect. Mechanistically, our findings revealed that MTHFD2 suppressed GBM progression independent of its enzymatic activity, likely by inducing cytoskeletal remodeling through the regulation of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, thereby influencing GBM malignance. Collectively, these findings uncover a potential tumor-suppressor role of MTHFD2 in GBM cells. MTHFD2 may act as a promising diagnostic and therapeutic target for GBM treatment.
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Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Glioblastoma/genética , Sistema de Señalización de MAP Quinasas , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , FosforilaciónRESUMEN
BACKGROUND The extent of glioma resection influences the overall survival (OS) and progression-free survival (PFS). Ferroptosis is a newly recognized type of cell death, which may be associated with low-grade glioma border detection and OS. This study is assessed an optimized ferroptosis gene panel for glioma treatment. MATERIAL AND METHODS We obtained 45 reports on ferroptosis-related proteins in PubMed and conducted a statistical test of the patients' overall survival (OS) in the TCGA GBMLGG and CGGA databases. The statistically significant genes were screened for an optimal panel, followed by GO and KEGG analysis and evaluated its correlation with known prognostic factors of glioma, including IDH1 mutation, methylated MGMT, tumor purity, 1p/19q LOH, and methionine cycle. RESULTS Eight genes panel (ALOX5, CISD1, FTL, CD44, FANCD2, NFE2L2, SLC1A5, and GOT1) were highly related to OS (P<0.001) and PFS (P<0.001) of low-grade glioma (LGG) patients, out of which 6 genes (ALOX5, CISD1, CD44, FTL, FANCD2, and SLC1A5) were correlated with IDH1_p.R132H (P<0.001) and 5 genes (ALOX5, CD44, FTL, NFE2L2, SLC1A5) showed a correlation with tumor purity (P<0.001). Five genes (ALOX5, CD44, CISD1, FTL, and SLC1A5) were associated with methylated MGMT (P<0.001), out of which 6 genes (ALOX5, CD44, FANCD2, NFE2L2, SLC1A5, and GOT1) had significantly different expression in healthy brain tissue vs. glioma (P<0.001). CONCLUSIONS Our panel of 8 ferroptosis genes showed a significant correlation with the diagnostic and prognostic factors of low-grade glioma and can be applied in neuroradiology and surgery.
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Neoplasias Encefálicas/genética , Ferroptosis/genética , Glioma/genética , Adulto , Sistema de Transporte de Aminoácidos ASC/genética , Apoferritinas/genética , Araquidonato 5-Lipooxigenasa/genética , Aspartato Aminotransferasa Citoplasmática/genética , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Metilación de ADN , Bases de Datos Genéticas , Proteína del Grupo de Complementación D2 de la Anemia de Fanconi/genética , Femenino , Ferroptosis/fisiología , Glioma/diagnóstico , Glioma/mortalidad , Glioma/patología , Humanos , Receptores de Hialuranos/genética , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Antígenos de Histocompatibilidad Menor/genética , Proteínas Mitocondriales/genética , Mutación , Factor 2 Relacionado con NF-E2/genética , Pronóstico , Supervivencia sin Progresión , Regiones Promotoras GenéticasRESUMEN
Solitary fibrous tumor (SFT) is a benign mesenchymal neoplasm occurring anywhere in the body, such as the visceral pleura, while it is extremely rare in the central nervous system, especially within the spinal cord. Here, we present a case of recurrent spinal SFT in a 44-year-old woman who had the tumor resected 5 years before. This time, her magnetic resonance imaging revealed an intradural tumor at the level of C6-7. A secondary resection was performed completely, and the patient's neurological conditions recovered fully after resection. Histological and immunohistochemical findings revealed an SFT. Although rare, the preferred treatment for recurrent tumor in SFT is surgery, and postoperative follow-up is necessary for early detection of tumor progression.
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Recurrencia Local de Neoplasia/patología , Tumores Fibrosos Solitarios/patología , Neoplasias de la Médula Espinal/patología , Adulto , Femenino , Humanos , Tumores Fibrosos Solitarios/cirugía , Neoplasias de la Médula Espinal/cirugíaRESUMEN
Endovascular treatment (EVT) is safe and effective for acute ischemic stroke (AIS) caused by large artery occlusion in the anterior circulation. However, some patients require decompressive craniectomy (DC), despite having undergone a timely EVT. This study aimed to evaluate the risk factors for subsequent DC after EVT. This retrospective cohort study comprised 138 patients who received EVT between April 2015 and June 2019 at our center. The need for subsequent DC was defined as cerebral edema or/and hemorrhagic transformation caused by large ischemic infarction, with a ≥ 5-mm midline shift and clinical deterioration after EVT. The relationship between risk factors and DC after EVT was assessed via univariate and multivariable logistic regression. Thirty (21.7%) patients required DC. These patients tended to have atrial fibrillation (P = 0.037), sedation (P = 0.049), mechanical ventilation (P = 0.008), poorer collateral circulation (P = 0.003), a higher baseline National Institutes of Health Stroke Scale (NIHSS) score (P < 0.001), heavier thrombus burden (P < 0.001), a lower baseline Alberta Stroke Program Early Computed Tomography Score (ASPECTS) (P < 0.001), and unsuccessful recanalization (P < 0.001). In the multivariate analysis, higher baseline NIHSS score [odds ratio (OR), 1.17; 95% confidence interval (CI), 1.03-1.32], heavier thrombus burden [OR, 1.35; 95% CI, 1.02-1.79], baseline ASPECTS ≤ 8 [OR, 7.41; 95% CI, 2.43-22.66], and unsuccessful recanalization [OR, 7.49; 95% CI, 2.13-26.36] were independent risk factors for DC after EVT. DC remains an essential treatment for some AIS patients after EVT, especially those with higher baseline NIHSS scores, heavier thrombus burden, baseline ASPECTS ≤ 8, and unsuccessful recanalization.
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Craniectomía Descompresiva/estadística & datos numéricos , Procedimientos Endovasculares/métodos , Accidente Cerebrovascular Isquémico/cirugía , Procedimientos Neuroquirúrgicos/métodos , Complicaciones Posoperatorias/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Infarto de la Arteria Cerebral Media/cirugía , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/cirugía , Curva ROC , Factores de Riesgo , Trombosis/epidemiología , Resultado del TratamientoRESUMEN
BACKGROUND Epithelial-mesenchymal transition (EMT) is responsible for metastasis of cancers, and NF-κB can promote tumor progression. Ezrin is an important molecule participating in EMT. However, whether Ezrin mediates NF-κB in EGF-induced osteosarcoma is unknown. MATERIAL AND METHODS Ezrin phosphorylation, NF-κB activation, and EGF-induced EMT were studied in MG63 and U20S cells with NF-κB inhibition, silencing, or over-expressing Ezrin. Cell morphology, proliferation, migration, and motility were analyzed. An osteosarcoma model was established in mice by injecting MG63 and U20S and reducing Ezrin. RESULTS With EGF induction in vitro, Ezrin Tyr353 and Thr567 were phosphorylated, and EMT, proliferation, migration, and motility of osteosarcoma cells were promoted. Silencing Ezrin suppressed and over-expressing Ezrin promoted the nuclear translocation of p65 and phosphorylated IκBα (p-IκBα) in EGF-induced osteosarcoma cells. NF-κB inhibitor blocked EGF-induced EMT in both cell types, as well as reserving cell morphology and suppressing proliferation, migration, and motility. In vivo, reducing Ezrin significantly suppressed metastasis of osteosarcoma xenografts, increased liver and lung weights, and activated NF-κB, which were both induced by EGF. CONCLUSIONS Ezrin/NF-κB regulated EGF-induced EMT, as well as progression and metastasis of osteosarcoma in vivo and in vitro. Ezrin/NF-κB may be a new therapeutic target to prevent osteosarcoma from deterioration.
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Neoplasias Óseas/metabolismo , Proteínas del Citoesqueleto/metabolismo , Factor de Crecimiento Epidérmico/farmacología , FN-kappa B/metabolismo , Osteosarcoma/metabolismo , Animales , Neoplasias Óseas/inducido químicamente , Neoplasias Óseas/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal/efectos de los fármacos , Xenoinjertos , Masculino , Ratones , Ratones Endogámicos BALB C , Inhibidor NF-kappaB alfa/metabolismo , Metástasis de la Neoplasia , Osteosarcoma/inducido químicamente , Osteosarcoma/patología , Fosforilación , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND Osteosarcoma and fibrosarcoma are malignant tumors with poor prognosis. Peroxiredoxin 1 (PRDX1) is considered to prevent tumors in many malignances. However, few studies have focused on the functions of PRDX1 in osteosarcoma and fibrosarcoma. MATERIAL AND METHODS PRDX1 mRNA in tumors and adjacent tissues of 32 osteosarcoma patients and 16 fibrosarcoma patients was extracted and measured. Proliferation and invasion of MG63 and HT1080 cell lines after silencing or overexpressing PRDX1 were used to detect the role of PRDX1 in metastasis of osteosarcoma and fibrosarcoma. RESULTS PRDX1 mRNA level was lower in tumor tissues than in adjacent tissues of osteosarcoma (F=50.105) and fibrosarcoma (F=28.472) patients, both significantly (P<0.05). Silencing PRDX1 promoted proliferation of MG63 and HT1080 cells, while overexpressing PRDX1 suppressed proliferation after 24 h, 48 h, and 72 h, compared to the control group, both significantly (P<0.05). Silencing PRDX1 increased invasive cells of MG63 (F=246.218) and HT1080 (F=245.602), while overexpressing PRDX1 decreased invasive cells of both, compared to the control, and the difference was significant (P<0.05). CONCLUSIONS PRDX1 expression is low in osteosarcoma and fibrosarcoma tumors. PRDX1 suppressed the progression and metastasis of osteosarcoma and fibrosarcoma cells.
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Neoplasias Óseas/genética , Fibrosarcoma/genética , Osteosarcoma/genética , Peroxirredoxinas/genética , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Línea Celular Tumoral , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Progresión de la Enfermedad , Femenino , Fibrosarcoma/metabolismo , Fibrosarcoma/patología , Humanos , Masculino , Invasividad Neoplásica , Metástasis de la Neoplasia , Osteosarcoma/metabolismo , Osteosarcoma/patología , Peroxirredoxinas/biosíntesis , Peroxirredoxinas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
The aim of the study was to determine whether the area of Tanggu, Tianjin Binhai New Economic Developing Area, China, is subject to similar effects of ambient particulate matter less than 10 micrometres in aerodynamic diameter (PM10) similar to other areas of China. This study was designed to investigate cause-specific mortality risks associated with air pollution in this geographical region. The present study used a time-series analysis to explore the relationship between PM10 and the cause-specific mortalities for non-accidental, cardiovascular, and cardiopulmonary mortality from 1 January 2006 to 31 December 2010. A 10 µg/m(3) increment of PM10 was associated with a 1.02% (95% confidence interval (CI): 0.48, 1.56) increase in cardiovascular mortality, and a 0.88% (95% CI: 0.36, 1.39) increase in cardiopulmonary mortality. In addition, the effects from PM10 appear to be consistent with multi-pollutant models. The results show that there are strong associations between daily cardiovascular and cardiopulmonary mortality and ambient PM10 exposure.
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Contaminantes Atmosféricos/análisis , Contaminación del Aire/análisis , Material Particulado/análisis , Contaminantes Atmosféricos/toxicidad , Contaminación del Aire/efectos adversos , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/mortalidad , China/epidemiología , Monitoreo del Ambiente/métodos , Humanos , Enfermedades Pulmonares/epidemiología , Enfermedades Pulmonares/mortalidad , Mortalidad/tendencias , Tamaño de la Partícula , Material Particulado/toxicidad , Riesgo , Factores de TiempoRESUMEN
BACKGROUND: Mounting evidence indicates that stem cell-derived exosomal miRNAs have therapeutic effects on traumatic brain injury (TBI). This research is focused on exploring the molecular processes of miR-124-3p obtained from bone marrow stromal cells-derived exosomes (BMSCs-Exos) in attenuating posttraumatic glutamate-mediated excitotoxicity. METHODS: We created a TBI rat model and analyzed the expression profile of miRNA through miRNA microarray. The miR-124-3p and p38 MAPK levels were analyzed utilizing RT-qPCR and western blotting. Dual-luciferase reporter (DLR) assay showed the targeting relationship between miR-124-3p and p38 MAPK. We subsequently conducted a TUNEL assay and flow cytometry to evaluate the neuronal apoptotic rate in an in vitro glutamate-mediated excitotoxicity model treated with BMSCs-Exos enriched with miR-124-3p (BMSCs-ExosmiR-124-3p). Moreover, the levels of p38 MAPK and glutamate transporter-1 (GLT-1) were measured by western blotting. Furthermore, BMSCs-ExosmiR-124-3p were administered to the TBI rats, and their neuroprotective effects were observed using western blotting, immunohistochemistry, histological staining, magnetic resonance imaging (MRI), and Morris water maze (MWM). RESULTS: The results revealed that the brains of TBI rats exhibited lowered miR-124-3p and enhanced p38 MAPK levels. DLR assay demonstrated miR-124-3p's role in targeting p38 MAPK and negatively regulating its expression. In vitro and in vivo studies confirmed that BMSCs-ExosmiR-124-3p attenuated glutamate-mediated excitotoxicity by downregulating p38 MAPK and upregulating GLT-1 expressions via transferring exosomal miR-124-3p. Moreover, histopathological evaluation and MRI results showed that BMSCs-ExosmiR-124-3p remarkably alleviated neuronal cell death and minimized the lesion volumes post-TBI. MWM outcomes illustrated that BMSCs-ExosmiR-124-3p treatment could substantially improve neurological function post-TBI. Furthermore, the effects of treatment with p38 MAPK inhibitor SB203580 were similar to BMSCs-ExosmiR-124-3p. CONCLUSION: Overall, the outcomes of the current report highlighted that BMSCs-ExosmiR-124-3p can lead to the upregulation of GLT-1 in TBI rat models by inhibiting the p38 MAPK signaling pathway, hence alleviating glutamate-mediated excitotoxicity and attenuating neurological damage post-TBI.
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Lesiones Traumáticas del Encéfalo , Exosomas , Células Madre Mesenquimatosas , MicroARNs , Ratas , Animales , Exosomas/metabolismo , MicroARNs/metabolismo , Células Madre Mesenquimatosas/metabolismo , Lesiones Traumáticas del Encéfalo/patología , Glutamatos/metabolismoRESUMEN
Glioblastoma (GBM) is a malignant tumor characterized by poor prognosis and low overall survival (OS) rate. Identification of novel biological markers for the diagnosis and treatment of GBM is crucial to developing interventions to improve patient survival. GNA13, a member of the G12 family, has been reported to play important roles in a variety of biological processes involved in tumorigenesis and development. However, its role in GBM is currently unknown. Here, we explored the expression patterns and functions of GNA13 in GBM, as wells its impact on metastasis process. Results showed that GNA13 was downregulated in GBM tissues and correlated with poor prognosis of GBM. Downregulation of GNA13 promoted the migration, invasion and proliferation of GBM cells; whereas its overexpression abolished these effects. Western blots revealed that GNA13 knockdown and overexpression upregulated and inhibited the phosphorylation of ERKs, respectively. Moreover, GNA13 was the upstream of ERKs signaling to regulating ERKs phosphorylation level. Furthermore, U0126 alleviated the metastasis effect induced by GNA13 knockdown. Bioinformatics analyses and qRT-PCR experiments demonstrated that GNA13 could regulate FOXO3, a downstream signaling molecule of ERKs pathway. Overall, our results demonstrate that GNA13 expression is negatively correlated with GBM and can suppress tumor metastasis by inhibiting the ERKs signaling pathway and upregulating FOXO3 expression.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/metabolismo , Línea Celular Tumoral , Proliferación Celular , Transducción de Señal , Sistema de Señalización de MAP Quinasas , Regulación Neoplásica de la Expresión Génica , Neoplasias Encefálicas/metabolismo , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismoRESUMEN
Importance: High-grade gliomas (HGGs) constitute the most common and aggressive primary brain tumor, with 5-year survival rates of 30.9% for grade 3 gliomas and 6.6% for grade 4 gliomas. The add-on efficacy of interferon alfa is unclear for the treatment of HGG. Objectives: To compare the therapeutic efficacy and toxic effects of the combination of temozolomide and interferon alfa and temozolomide alone in patients with newly diagnosed HGG. Design, Setting, and Participants: This multicenter, randomized, phase 3 clinical trial enrolled 199 patients with newly diagnosed HGG from May 1, 2012, to March 30, 2016, at 15 Chinese medical centers. Follow-up was completed July 31, 2021, and data were analyzed from September 13 to November 24, 2021. Eligible patients were aged 18 to 75 years with newly diagnosed and histologically confirmed HGG and had received no prior chemotherapy, radiotherapy, or immunotherapy for their HGG. Interventions: All patients received standard radiotherapy concurrent with temozolomide. After a 4-week break, patients in the temozolomide with interferon alfa group received standard temozolomide combined with interferon alfa every 28 days. Patients in the temozolomide group received standard temozolomide. Main Outcomes and Measures: The primary end point was 2-year overall survival (OS). Secondary end points were 2-year progression-free survival (PFS) and treatment tolerability. Results: A total of 199 patients with HGG were enrolled, with a median follow-up time of 66.0 (95% CI, 59.1-72.9) months. Seventy-nine patients (39.7%) were women and 120 (60.3%) were men, with ages ranging from 18 to 75 years and a median age of 46.9 (95% CI, 45.3-48.7) years. The median OS of patients in the temozolomide plus interferon alfa group (26.7 [95% CI, 21.6-31.7] months) was significantly longer than that in the standard group (18.8 [95% CI, 16.9-20.7] months; hazard ratio [HR], 0.64 [95% CI, 0.47-0.88]; P = .005). Temozolomide plus interferon alfa also significantly improved median OS in patients with O6-methylguanine-DNA methyltransferase (MGMT) unmethylation (24.7 [95% CI, 20.5-28.8] months) compared with temozolomide (17.4 [95% CI, 14.1-20.7] months; HR, 0.57 [95% CI, 0.37-0.87]; P = .008). Seizure and influenzalike symptoms were more common in the temozolomide plus interferon alfa group, with 2 of 100 (2.0%) and 5 of 100 (5.0%) patients with grades 1 and 2 toxic effects, respectively (P = .02). Finally, results suggested that methylation level at the IFNAR1/2 promoter was a marker of sensitivity to temozolomide plus interferon alfa. Conclusions and Relevance: Compared with the standard regimen, temozolomide plus interferon alfa treatment could prolong the survival time of patients with HGG, especially the MGMT promoter unmethylation variant, and the toxic effects remained tolerable. Trial Registration: ClinicalTrials.gov Identifier: NCT01765088.
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Neoplasias Encefálicas , Glioma , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antineoplásicos Alquilantes/uso terapéutico , Antineoplásicos Alquilantes/efectos adversos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Dacarbazina/uso terapéutico , Glioma/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Temozolomida/uso terapéutico , Adolescente , Adulto Joven , Adulto , AncianoRESUMEN
Background: Insulin resistance (IR) is involved in the pathogenesis of atherosclerosis. As a new indicator, the triglyceride-glucose (TyG) index has greater operability for the evaluation of insulin resistance. Previous studies have shown inconsistent results in evaluating the association between the TyG index and stroke incidence in people without stroke at baseline. Therefore, this study aimed to systematically assess this association through a meta-analysis. Methods: Cohort studies with the multivariate-adjusted hazard ratio (HR) association between the TyG index and stroke were obtained by searching the PubMed, Cochrane Library, and EMBASE databases before 16 December 2021. We pooled the adjusted HR along with 95% CI using a random-effects model. The primary outcome was stroke including ischemic and hemorrhagic stroke. We conducted subgroup analyses stratified by study design, ethnicity, characteristics of participants, weight of studies, and length of follow-up duration. Review Manager 5.3 and Stata 17 were used to perform the meta-analysis. Results: Eight cohort studies with 5,804,215 participants were included. The results showed that participants with the highest TyG index category at baseline compared to those with the lowest TyG index category were independently associated with a higher risk of stroke (HR: 1.26, 95% CI: 1.24-1.29, I2 = 0%, P < 0.001). This finding was consistent with the results of the meta-analysis with the TyG index analyzed as a continuous variable (HR per each-unit increment of the TyG index: 1.13, 95% CI 1.09-1.18, I2 = 0%, P < 0.001). Subgroup analysis had no significant effects (for subgroup analysis, all P > 0.05). No significant heterogeneity was observed among the included cohort studies. Conclusion: A higher TyG index may be independently associated with a higher risk of stroke in individuals without stroke at baseline. The aforementioned findings need to be verified by a large-scale prospective cohort study to further clarify the underlying pathophysiological mechanism between the TyG index and stroke.
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BACKGROUND: Traumatic brain injury (TBI) is one of the major contributors to disability and death worldwide. Glutamate-mediated excitotoxicity, one of the secondary injuries occurring after TBI, leads to extreme neuronal apoptosis, and can be a potential target for intervention. Bone marrow mesenchymal stem cells-derived exosomes (BMSCs-Exos) have demonstrated neuroprotective effects on TBI. However, their precise role and the underlying mechanism by which they regulate glutamate-mediated excitotoxicity have not yet been determined. Therefore, this study aimed to determine whether BMSCs-Exos alleviate glutamate excitotoxicity post-TBI and their associated mechanism. METHODS: BMSCs-Exos were extracted from the BMSCs incubation medium and identified by transmission electron microscopy, nanoparticle trafficking analysis, and western blotting. The neuroprotective effects of BMSCs-Exos on glutamate excitotoxicity were investigated in the glutamate-mediated excitotoxicity neuronal cell model and the TBI rat model (TBI induced by controlled cortical impact) using western blotting and TUNEL assay. Cortical lesion samples were collected post-TBI on day-1 and day-14 to study histology. In addition, cortical lesion volume on days 1, 3 and 7 following TBI was determined using T2-weighted magnetic resonance imaging (MRI), and cognitive function was assessed at 4 weeks following TBI using the Morris water maze (MWM) test. RESULTS: BMSCs-Exos were observed to be spherical with a mean diameter of 109.9 nm, and expressed exosomal markers CD9, CD81 and TSG101. BMSCs-Exos were efficiently endocytosed by astrocytes after co-incubation for 24 h. In vitro studies revealed that 125 µM of glutamate significantly induced neuronal apoptosis, which was attenuated by BMSCs-Exos in astrocyte-neuron co-cultures. This attenuation was mediated by the upregulation of glutamate transporter-1 (GLT-1) level and the downregulation of p-p38 MAPK level in astrocytes. Similar results were obtained in vivo, wherein we verified that PKH67-labeled BMSCs-Exos administered intravenously could reach the perilesional cortex crossing the blood-brain barrier and significantly reduce glutamate levels in the perilesional cortex of the TBI rat, accompanied by increased GLT-1 level and downregulation in p-p38 MAPK level. Additionally, western blotting and TUNEL staining also revealed that BMSCs-Exos significantly downregulated the expression of pro-apoptosis markers, including cleaved caspase-3 and cleaved caspase-9, and attenuated neuronal apoptosis following TBI. Immunohistochemical analysis and Nissl staining showed that BMSCs-Exos significantly increased GLT-1-positive cells, and the number of apoptotic neurons decreased in the perilesional cortex. Moreover, MRI and MWM results revealed that BMSCs-Exos significantly minimized cortical lesion volume and ameliorated cognitive function after TBI. The underlying neuroprotective mechanism of BMSCs-Exos may be due to an increase in GLT-1 level in astrocytes by blocking the p38 MAPK signaling pathway. CONCLUSION: Taken together, our findings demonstrate that the implementation of BMSCs-Exos may be an effective prospective therapy for attenuating post-TBI neurological damage.
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Lesiones Traumáticas del Encéfalo , Exosomas , Células Madre Mesenquimatosas , Fármacos Neuroprotectores , Animales , Lesiones Traumáticas del Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/terapia , Exosomas/metabolismo , Ácido Glutámico/metabolismo , Células Madre Mesenquimatosas/metabolismo , Fármacos Neuroprotectores/metabolismo , Ratas , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Recently, neutrophil gelatinase-associated lipocalin (NGAL) and its cell surface receptor, NGALR, have been shown to have critical roles in the biology of various tumors. Therefore, we investigated the expression of NGAL and NGALR in tumor sections obtained from patients with gliomas, and compared these results with the clinical characteristics of the patients. Using immunohistochemical assays, the expression levels of NGAL and NGALR were found to be up-regulated in tumor tissues, and to be related to tumor grade (p < 0.001). A positive correlation between expression of the two markers was also observed in these assays (r = 0.849; p < 0.001). Overexpression of NGAL and NGALR in glioma tissues was also confirmed in western blot analysis and real-time quantitative RT-PCR assays. Furthermore, overexpression of NGAL and NGALR was found to be significantly associated with poor prognosis (p < 0.001 in each case). Multivariate analysis identified patient age, tumor grade, and expression levels of NGAL and NGALR to be independent prognostic factors. In particular, NGAL(2+)/NGALR(2+) tissues were associated with lower rates of survival (risk ratio, 1.378; 95% CI, 1.102-1.724; p = 0.005). These findings suggest that NGAL and NGALR expression are frequently up-regulated in gliomas, and are closely associated with poor clinical outcome.
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Proteínas de Fase Aguda/metabolismo , Neoplasias Encefálicas/metabolismo , Regulación Neoplásica de la Expresión Génica/fisiología , Glioma/metabolismo , Lipocalinas/metabolismo , Proteínas de Transporte de Catión Orgánico/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas de Fase Aguda/genética , Adolescente , Adulto , Anciano , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/mortalidad , Niño , Preescolar , Femenino , Glioma/diagnóstico , Glioma/mortalidad , Humanos , Estimación de Kaplan-Meier , Lipocalina 2 , Lipocalinas/genética , Masculino , Persona de Mediana Edad , Proteínas de Transporte de Catión Orgánico/genética , Pronóstico , Proteínas Proto-Oncogénicas/genética , Índice de Severidad de la Enfermedad , Estadística como Asunto , Adulto JovenRESUMEN
BACKGROUND: The aim of the present study was to explore the clinical effect and to predict the prognosis of severe craniocerebral injury patients with decompressive craniectomy by combining transcranial Doppler (TCD) and invasive intracranial pressure (ICP). METHODS: A total of 60 severe craniocerebral injury patients with decompressive craniectomy, who were admitted to Shantou Central Hospital from June 2017 to March 2019, were enrolled in this retrospective study. Of these, 25 patients who had a Glasgow Coma Scale (GCS) score no greater 8 and no less than 6 underwent transcranial Doppler (TCD) before decompressive craniectomy, as well as ICP, after removing the skull and suturing the dura mater. The 60 patients were divided into 2 groups according to the following standards: (I) GCS score ≥8 on the 7th day postoperatively; (II) ICP continuously lower than 25 mmHg for the entire 7-day duration postoperatively; and (III) brain tissue consistently offset from the skull surface by 5 mm. The clinical outcome was determined based on the Glasgow Outcome Scale (GOS) 1, 3, and 6 months postoperatively. The TCD value, ICP, and prognosis were compared between the 2 groups. RESULTS: The average postoperative ICP <19 mmHg in the first 24 h, mean blood flow velocity >56.33 cm/s, end-diastolic blood flow velocity >40.28 cm/s, and resistance index <0.57 were statistically significant indicators to predict good prognosis . CONCLUSIONS: The use of TCD can predict the prognosis of severe craniocerebral injury patients.
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Traumatismos Craneocerebrales , Craniectomía Descompresiva , Traumatismos Craneocerebrales/diagnóstico por imagen , Traumatismos Craneocerebrales/cirugía , Humanos , Presión Intracraneal , Estudios Retrospectivos , Cráneo , Resultado del TratamientoRESUMEN
Temozolomide (TMZ), one of the few effective drugs used during adjuvant therapy, could effectively prolong the overall survival (OS) of glioma patients. In our previous study, the mRNA level of G Protein Subunit Alpha 13 (GNA13) was found to be inversely correlated with OS and was therefore identified as a potential biomarker for the prognosis of glioma. Henceforth, this study aims to identify the molecular mechanism of GNA13 in enhancing TMZ sensitization through bioinformatic analyses of GSE80729 and GSE43452 and other experiments. In glioma, overexpression of GNA13 downregulated PRKACA, which is a subunit of PKA, hence reducing phosphorylated RELA and MGMT. Since p-RELA and MGMT were proven to be closely associated with TMZ resistance, we therefore investigated whether thetwo signaling pathways, "GNA13/PRKACA/p-RELA", and "GNA13/PRKACA/MGMT", were involved in the molecular mechanism of GNA13 in TMZ sensitization. Our conclusion was that, GNA13 overexpression in glioma cells were more sensitive in TMZ treatment.
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Background: Glioma is the most common malignant tumor of the central nervous system, and often displays invasive growth. Recently, circular RNA (circRNA), which is a novel non-coding type of RNA, has been shown to play a vital role in glioma tumorigenesis. However, the functions and mechanism of lipocalin-2 (Lcn2)-derived circular RNA (hsa_circ_0088732) in glioma progression remain unclear. Methods: We evaluated hsa_circ_0088732 expression by fluorescence in situ hybridization (FISH), Sanger sequencing, and PCR assays. Cell apoptosis was evaluated by flow cytometry and Hoechst 33258 staining. Transwell migration and invasion assays were performed to measure cell metastasis and viability. In addition, the target miRNA of hsa_circ_0088732 and the target gene of miR-661 were predicted by a bioinformatics analysis, and the interactions were verified by dual-luciferase reporter assays. RAB3D expression was analyzed by an immunochemistry assay, and E-cadherin, N-cadherin, and vimentin protein expression were examined by western blot assays. A mouse xenograft model was developed and used to analyze the effects of hsa_circ_0088732 on glioma growth in vivo. Results: We verified that hsa_circ_0088732 is circular and highly expressed in glioma tissues. Knockdown of hsa_circ_0088732 induced glioma cell apoptosis and inhibited glioma cell migration, invasion, and epithelial-mesenchymal transition (EMT). We found that hsa_circ_0088732 negatively regulated miR-661 by targeting miR-661, and RAB3D was a target gene of miR-661. In addition, inhibition of miR-661 promoted glioma cell metastasis and suppressed cell apoptosis. Knockdown of RAB3D induced cell apoptosis and suppressed cell metastasis. Moreover, hsa_circ_0088732 accelerated glioma progression through its effects on the miR-661/RAB3D axis. Finally, results from a mouse xenograft model confirmed that knockdown of hsa_circ_0088732 induced miR-661 expression, resulting in suppression of RAB3D expression and inhibition of tumor growth in vivo. Conclusion: We demonstrated that hsa_circ_0088732 facilitated glioma progression by sponging miR-661 to increase RAB3D expression. This study provides a theoretical basis for understanding the development and occurrence of glioma, as well as for the development of targeted drugs.
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Glioma is the most common malignant tumor in the central nervous system. This study aims to explore the potential mechanism and identify gene signatures of glioma. The glioma gene expression profile GSE4290 was analyzed for differentially expressed genes (DEGs). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were applied for the enriched pathways. A protein-protein interaction (PPI) network was constructed to find the hub genes. Survival analysis was conducted to screen and validate critical genes. In this study, 775 downregulated DEGs were identified. GO analysis demonstrated that the DEGs were enriched in cellular protein modification, regulation of cell communication, and regulation of signaling. KEGG analysis indicated that the DEGs were enriched in the MAPK signaling pathway, endocytosis, oxytocin signaling, and calcium signaling. PPI network and module analysis found 12 hub genes, which were enriched in synaptic vesicle cycling rheumatoid arthritis and collecting duct acid secretion. The four key genes CDK17, GNA13, PHF21A, and MTHFD2 were identified in both generation (GSE4412) and validation (GSE4271) dataset, respectively. Regression analysis showed that CDK13, PHF21A, and MTHFD2 were independent predictors. The results suggested that CDK17, GNA13, PHF21A, and MTHFD2 might play important roles and potentially be valuable in the prognosis and treatment of glioma.
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Aminohidrolasas/genética , Glioma/genética , Histona Desacetilasas/genética , Metilenotetrahidrofolato Deshidrogenasa (NADP)/genética , Enzimas Multifuncionales/genética , Calcio/metabolismo , Biología Computacional , Quinasas Ciclina-Dependientes/genética , Endocitosis/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Ontología de Genes , Redes Reguladoras de Genes/genética , Glioma/diagnóstico , Humanos , Oxitocina/metabolismo , Pronóstico , Mapas de Interacción de Proteínas , Transducción de SeñalRESUMEN
Matrix metalloproteinase-9/neutrophil gelatinase-associated lipocalin (MMP-9/NGAL) complex activity is elevated in brain tumors and may serve as a molecular marker for brain tumors. However, the relationship between MMP-9/NGAL activity in brain tumors and patient prognosis and treatment response remains unclear. Here, we compared the clinical characteristics of glioma patients with the MMP-9/NGAL activity measured in their respective tumor and urine samples. Using gelatin zymography assays, we found that MMP-9/NGAL activity was significantly increased in tumor tissues (TT) and preoperative urine samples (Preop-1d urine). Activity was reduced by seven days after surgery (Postop-1w urine) and elevated again in cases of tumor recurrence. The MMP-9/NGAL status correlated well with MRI-based tumor assessments. These findings suggest that MMP-9/NGAL activity could be a novel marker to detect gliomas and predict the clinical outcome of patients.
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Proteínas de Fase Aguda/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/diagnóstico , Glioma/diagnóstico , Lipocalinas/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas de Fase Aguda/genética , Proteínas de Fase Aguda/orina , Adolescente , Adulto , Anciano , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/orina , Estudios de Casos y Controles , Niño , Femenino , Humanos , Lipocalina 2 , Lipocalinas/genética , Lipocalinas/orina , Masculino , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/orina , Persona de Mediana Edad , Pronóstico , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/orinaRESUMEN
BACKGROUND: Sentinel surveillance of Keshan disease (KD) is limited by unable to give the prevalence rates and their estimates. This study was to find the national KD prevalence and the estimated patient numbers to provide evidence toward modifying the policy of KD prevention and control. METHOD: Using a probability proportional to population size, randomized, multistage, and cluster sampling, we surveyed 101,127, measured grain selenium levels; and surveyed household income with pre-designed questionnaires. RESULTS: The national prevalence rates of KD, chronic KD and latent KD were 2.21%, 0.50%, and 1.71% respectively. Chronic KD patients are mainly in the provinces where KD had been seriously epidemic. The KD prevalence rate was higher in females (2.20%) than in males (1.98%). These were also higher in older age groups. The cases younger than 30 years accounted for 13.6%, indicating the possibility that KD is still occurring. Nationally, the estimated numbers of KD and chronic KD patients are 1,675,500 (95% CI, 1,608,500-1,747,300) and 379,800 (95% CI, 346,700-412,800) respectively. Multiple logistic regression analysis indicated that family income was a significant dependent variable (OR: -0.258, 95% CI: -0.332 to -0.185, p<0.001). More than 2000 chronic KD patients found in the study were treated in 2009-2011. The limitation of this study was that sampling size was determined at national level. CONCLUSION: KD is still a public health issue among the people of the historically severe endemic areas. Selenium supplementation, self-management program for chronic KD patients and translation epidemiology of KD surveillance should be strengthened.
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Cardiomiopatías/diagnóstico , Cardiomiopatías/epidemiología , Infecciones por Enterovirus/diagnóstico , Infecciones por Enterovirus/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , China/epidemiología , Análisis por Conglomerados , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Encuestas y Cuestionarios , Adulto JovenRESUMEN
MicroRNAs (miRNAs) are small, noncoding RNAs which regulate gene expression at the post-transcriptional level. Abnormal expression of miRNAs occurs frequently in tumors. Although the two miRNAs miR243p and miR27a3p come from two duplicated gene clusters of miR23a~27a~242 and miR23b~27b~241 which are found to be deregulated in a variety of cancers, the role of cooperation of the two clusters and the function of the two miRNAs in tumors have not been completely characterized. Here, we show that overexpression of miR243p and miR27a3p could promote cell proliferation using the MTT assay. By integrated bioinformatic analysis and experimental confirmation, we identified MXI1, which has been found to act as a tumor suppressor gene by affecting cMyc, as a direct target of miR243p and miR27a3p. While targeting the MXI1 3' untranslated region by miR243p or miR27a3p, luciferase activity was attenuated. The two miRNAs promote glioma cell proliferation via targeting MXI1 and the experiment was confirmed by the rescue experiments. Furthermore, our results show that two clusters of miR-23a~27a~24-2 and miR23b~27b~241 regulate MXI1 synergistically. These findings reveal, for the first time, the novel functions of cooperation of miR243p and miR27a3p from two clusters in promoting cell proliferation through MXI1. Additionally, we observed that miR27a3p is upregulated in glioma tissues.