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BACKGROUND: Favorable venous outflow (VO) has been recognized as an independent predictor of excellent clinical outcomes in acute ischemic stroke caused by anterior circulation large vessel occlusion (AIS-LVO) patients who received endovascular treatment (EVT). However, the reasons why VO affects clinical outcomes have not been fully explained. In this study, we aimed to identify the potential mediators of VO affecting prognosis. METHODS: We conducted a multicenter retrospective cohort study of consecutive patients with AIS-LVO who underwent EVT. Baseline computed tomographic angiography (CTA) was applied to assess VO by the Cortical Vein Opacification Score (COVES). The primary outcome was functional independence at 90 days (modified Rankin Scale (mRS) score of 0-2). Classifying subtypes of intracranial hemorrhage (ICH) to explore the relationship between ICH subtypes and VO. Multivariate logistic regression and causal mediation analyses were used to evaluate the relationship among VO, functional independence, and potential mediators. RESULTS: Among 860 AIS-LVO patients undergoing EVT, a total of 515 patients were included in the present study after strict screening. In multivariate logistic regression analysis, favorable VO profiles (defined as COVES 3-6) were significantly associated with a lower incidence of ICH (24.2% vs 46.9%, adjusted odds ratio (aOR) 0.48, 95% confidence interval (CI) 0.30 to 0.77, P=0.002) and a higher proportion of functional independence (58.9% vs 15.0%, aOR 4.07, 95% CI 2.41 to 6.88, P<0.001). Mediation analysis showed that favorable VO profiles significantly reduced the incidence of parencuymal hematoma (PH) 2 accounting for 8.0% (95% CI 0.9% to 19.0%) of its beneficial effect on functional independence. CONCLUSION: This study demonstrated the potential mediating effects of severe ICH for the beneficial effect of favorable VO on clinical prognosis among patients with AIS-LVO who underwent EVT.
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BACKGROUND: Kidney renal clear cell carcinoma (KIRC), with low survival rate, is the most frequent subtype of renal cell carcinoma. Recently, more and more studies indicate that cuproptosis-related genes (CRGs) and long non-coding RNAs (lncRNAs) play a vital role in the occurrence and development of many types of cancers. However, the roles of cuproptosis-related lncRNAs (CRlncRNAs) in the KIRC was uncertain. RESULTS: In our study, CRlncRNAs were obtained by coexpression between differentially expressed and prognostic CRGs and differentially expressed and prognostic lncRNAs, and an 8-CRlncRNAs (AC007743.1, AC022915.1, AP005136.4, APCDD1L-DT, HAGLR, LINC02027, MANCR and SMARCA5-AS1) risk model was established according to least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression. This risk model could differentiate immune cell infiltration, immune function and gene mutation. CONCLUSIONS: This 8-CRlncRNAs risk model may be promising for the clinical prediction of prognoses, tumor immune, immunotherapy response and chemotherapeutic response in KIRC patients.
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BACKGROUND: Epilepsy is the second most prevalent neurological disease. Although there are many antiseizure drugs, approximately 30% of cases are refractory to treatment. Temporal lobe epilepsy (TLE) is the most common epilepsy subtype, and previous studies have reported that hippocampal inflammation is an important mechanism associated with the occurrence and development of TLE. However, the inflammatory biomarkers associated with TLE are not well defined. METHODS: In our study, we merged human hippocampus datasets (GSE48350 and GSE63808) through batch correction and generally verified the diagnostic roles of inflammation-related genes (IRGs) and subtype classification according to IRGs in epilepsy through differential expression, random forest, support vector machine, nomogram, subtype classification, enrichment, proteinâprotein interaction, immune cell infiltration, and immune function analyses. Finally, we detected the location and expression of inhibitor of metalloproteinase-1 (TIMP1) in epileptic patients and kainic acid-induced epileptic mice. RESULTS: According to the bioinformatics analysis, we identified TIMP1 as the most significant IRG associated with TLE, and we found that TIMP1 was mainly located in cortical neurons and scantly expressed in cortical gliocytes by immunofluorescence staining. We detected decreased expression of TIMP1 by quantitative real-time polymerase chain reaction and western blotting. CONCLUSION: TIMP1, the most significant IRG associated with TLE, might be a novel and promising biomarker to study the mechanism of epilepsy and guide the discovery of new drugs for its treatment.
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Epilepsia del Lóbulo Temporal , Epilepsia , Humanos , Ratones , Animales , Epilepsia del Lóbulo Temporal/inducido químicamente , Epilepsia/metabolismo , Hipocampo/metabolismo , Inflamación/metabolismo , Biomarcadores/metabolismo , Inhibidor Tisular de Metaloproteinasa-1/genética , Inhibidor Tisular de Metaloproteinasa-1/metabolismoRESUMEN
Apoptosis is a major pathophysiological change following myocardial ischemia/reperfusion (I/R) injury. Glucagon-like peptide 1 (GLP-1) and its receptor GLP-1R are widely expressed in the cardiovascular system and GLP-1/GLP-1R activates the protein kinase G (PKG)-related signaling pathway. Therefore, this study tested whether semaglutide, a new GLP-1 analog, inhibits I/R injury-induced cardiomyocyte apoptosis by activating the PKG/PKCε/ERK1/2 pathway. We induced myocardial I/R injury in rats and hypoxia/reoxygenation (H/R) injury in H9C2 cells and detected the effects of semaglutide, a PKG analog (8-Br-cGMP), and a PKG inhibitor (KT-5823) on the PKG/PKCε/ERK1/2 pathway and cardiomyocyte apoptosis. We found that semaglutide upregulated GLP-1R levels, and both semaglutide and 8-Br-cGMP activated the PKG/PKCε/ERK1/2 pathway, inhibited myocardial infarction (MI), decreased hs-cTNT levels, increased NT-proBNP levels, and suppressed cardiomyocyte apoptosis in I/R rats and H/R H9C2 cells. However, KT-5823 exerted contrasting effects with semaglutide and 8-Br-cGMP, and KT-5823 weakened the cardioprotective effects of semaglutide. In conclusion, semaglutide inhibits I/R injury-induced cardiomyocyte apoptosis by activating the PKG/PKCε/ERK1/2 pathway. The beneficial effect of GLP-1/GLP-1R, involved in the activation of the PKG/PKCε/ERK1/2 pathway, may provide a novel treatment method for myocardial I/R injury.
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Infarto del Miocardio , Daño por Reperfusión Miocárdica , Ratas , Animales , Sistema de Señalización de MAP Quinasas , Miocitos Cardíacos/metabolismo , Proteínas Quinasas Dependientes de GMP Cíclico/metabolismo , Proteína Quinasa C-epsilon/metabolismo , Apoptosis , Infarto del Miocardio/metabolismo , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , ReperfusiónRESUMEN
Disruption of γ-aminobutyric acid type A receptors (GABAARs) synaptic clustering and a decrease number in the plasma membrane are thought to contribute to the alteration in the balance between excitatory and inhibitory neurotransmission in the epilepsy. Thus, it is important to elucidate the molecular mechanisms that regulate the stabilities of surface GABAARs populations as well as their concentrations at inhibitory synapses. However, the mechanism that delivers GABAARs to plasma membrane has not been conclusively determined. Our previous research indicated that huntingtin-associated protein 1 (HAP1), a major facilitator of pathological variations in membrane trafficking, modulates epileptic seizure by regulating GABAARs-mediated inhibitory synaptic transmission in pentylenetetrazole (PTZ)-induced epileptic rats. However, a detailed molecular interaction networks comprising GABAARs and HAP1 is necessary for studying and investigating new treatment targets for epilepsy. In this study, we indicate that HAP1 specifically interacts with 14-3-3, a protein that functions as a chaperone, forming a cargo adaptor complex to regulate surface GABAARs expression and the inhibitory post-synaptic current amplitudes. Disrupting the HAP1/14-3-3 complex decreases the strength of GABAARs-mediated inhibitory synaptic transmission in epilepsy. Taken together, HAP1/14-3-3 complex is linked to inhibitory synaptic transmission in evoking seizures, therefore, it is a possible drug target for epilepsy.
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Proteínas 14-3-3 , Epilepsia , Proteínas del Tejido Nervioso , Receptores de GABA-A , Transmisión Sináptica , Proteínas 14-3-3/metabolismo , Animales , Epilepsia/inducido químicamente , Proteínas del Tejido Nervioso/metabolismo , Pentilenotetrazol , Ratas , Receptores de GABA-A/metabolismo , Convulsiones/inducido químicamente , Ácido gamma-AminobutíricoRESUMEN
OBJECTIVE: This study was performed to assess the efficacy of a novel tool to assist transpedicular bone grafting in short-segment pedicle screw fixation combined with pedicle fixation at the level of the fractured vertebra (six-screw fixation). METHODS: We retrospectively analyzed 80 patients (40 in the control group and 40 in the tool-aided group) with single-level thoracolumbar fractures. Patients in the control group underwent traditional six-screw fixation combined with transpedicular bone grafting. In the tool-aided group, we introduced a novel vertebroplasty tool to assist transpedicular bone grafting. Basic information and related indicators were recorded. RESULTS: There were no significant differences in the patients' baseline characteristics or surgical outcomes between the control group and tool-aided group. Both traditional surgery and tool-aided surgery restored the height of the fractured vertebrae and decreased the Cobb angle, visual analog scale score, and Oswestry Disability Index. However, tool-aided surgery more effectively restored the height of the fractured vertebrae and reduced the visual analog scale score and Oswestry Disability Index than did traditional surgery. CONCLUSION: Vertebroplasty tool-aided surgery facilitated more precise and successful grafting of bone into damaged vertebrae than did traditional surgery and therefore might be recommended for treating single-level thoracolumbar fractures.
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Tornillos Pediculares , Fracturas de la Columna Vertebral , Vertebroplastia , Trasplante Óseo , Fijación Interna de Fracturas , Humanos , Vértebras Lumbares/diagnóstico por imagen , Vértebras Lumbares/lesiones , Vértebras Lumbares/cirugía , Estudios Retrospectivos , Fracturas de la Columna Vertebral/diagnóstico por imagen , Fracturas de la Columna Vertebral/cirugía , Vértebras Torácicas/diagnóstico por imagen , Vértebras Torácicas/cirugía , Resultado del TratamientoRESUMEN
Nucleoporin 37 kDa (NUP37), a member of the nucleoporin family, has been reported to regulate the proliferation and apoptosis of several tumor types. However, its role in the tumor immune microenvironment is unclear. Here, we evaluated the expression, methylation, copy number alteration, and prognostic significance of NUP37 using RNA-seq and clinical data from The Cancer Genome Atlas. We observed higher expression of NUP37 in 28 of 29 tumor types, and high NUP37 expression predicted worse survival status of patients in 15 tumors. Using data from the cBioportal database, we described the gene variation of NUP37 in glioma and pan-cancer. We further assessed the role of NUP37 in the tumor immune microenvironment using immune infiltration data. NUP37 expression was positively associated with the infiltration levels of immunosuppressive cells, such as nTregs, iTregs, and tumor-associated macrophages, and negatively correlated with immune killer cells, such as CD8+ T and NK cells across cancers. Furthermore, NUP37 expression was associated with immune checkpoints and immune regulation-related genes. The half-maximal inhibitory concentrations of anti-cancer drugs were obtained from the Genomics of Drug Sensitivity in the Cancer database. The correlation between half-maximal inhibitory concentration and NUP37 expression was evaluated. The patients with the evaluated expression of NUP37 were resistant to several anti-cancer drugs. These results suggest that NUP37 is a potential oncogene and prognostic biomarker in glioma and pan-cancer. Tumor tissues with high NUP37 expression exist in a relatively immunosuppressive microenvironment and are resistant to several anti-cancer drugs.
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Glioma , Proteínas de Complejo Poro Nuclear , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Glioma/genética , Humanos , Proteínas de Complejo Poro Nuclear/genética , Pronóstico , Microambiente Tumoral/genéticaRESUMEN
MicroRNA-25-3p (miR-25-3p) has been reported to be closely related with oxidative stress and apoptosis. Here, we aimed to detect the effects of miR-25-3p in the primarily cultured hippocampal neurons. Kainic acid (KA) was used to induce epileptic seizures in the rats. We predicted that oxidative stress responsive 1 (OXSR1) might be a potential target of miR-25-3p with TargetScan prediction and luciferase assays, and the primarily cultured hippocampal neurons were exposed to Mg2+-free solution for 3 h to induce spontaneous recurrent epileptiform discharges (SREDs). Then, the expression of miR-25-3p and OXSR1 in the rats hippocampi and primarily cultured hippocampal neurons were detected. Those SREDs neurons were treated with miR-25-3p mimic, miR-25-3p inhibitor or/and OXSR1 over-expression vector, and SREDs, oxidative stress and apoptosis were observed. We found down-regulation of miRNA-25-3p and up-regulation of OXSR1 in hippocampi of KA-treated rats and Mg2+-free-treated neurons. MiRNA-25-3p mimic could down-regulate OXSR1 expression, inhibit SREDs, reduce oxidative stress and decrease apoptosis. Additionally, over-expression of OXSR1 weakened those effects of miR-25-3p mimic. Those data indicated that miR-25-3p had anti-epileptic, anti-oxidant and anti-apoptosis effects on the primarily cultured neurons through targeting OXSR1, which provided a novel target for the treatment of epilepsy.
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Apoptosis/genética , Epilepsia/genética , MicroARNs/metabolismo , Neuronas/metabolismo , Estrés Oxidativo/genética , Proteínas/metabolismo , Animales , Secuencia de Bases , Células Cultivadas , Regulación hacia Abajo/genética , Hipocampo/metabolismo , Ácido Kaínico , Proteínas/genética , Ratas Sprague-Dawley , Regulación hacia Arriba/genéticaRESUMEN
Glucagon-like peptide-1 (GLP-1) and its receptor, GLP-1R, are valuable tools in the therapy of type 2 diabetes mellitus. Although GLP-1R stimulation is also potentially applicable to neurological disorders, few investigators have evaluated its beneficial effects in neurological disease models. Thus, we aimed to look into the antiepileptic effects of GLP-1R on epilepsy and its underlying mechanisms. The cerebral cortex of 22 patients with temporal lobe epilepsy (TLE) and 16 patients with trauma were collected to the epilepsy and control groups, respectively. Seizures were induced by pentylenetetrazole (PTZ) in rats. Liraglutide was used to up-regulate GLP-1R, and exendin fragment 9-39 (ex9-39) was used to down-regulate GLP-1R. The motor responses and scalp electroencephalograms of rats were recorded, and the interaction between GLP-1R and neuronal receptors (GABAARß2/3, GluA1-4, GluNR1, GluN2A and GluN2B) was evaluated by coimmunoprecipitation. GLP-1R expression was investigated by immunohistochemistry and immunofluorescence staining, and the levels of GLP-1R and neuronal receptors were evaluated by western blotting. The results indicated that GLP-1R was decreased in patients with TLE and in PTZ-treated rats and the administration of liraglutide decreased seizure severity, which indicates that liraglutide exerts antiepileptic effects. Moreover, liraglutide significantly up-regulated GLP-1R and GABAARß2/3 and down-regulated GluA1-4, GluNR1, GluN2A and GluN2B. In addition, ex9-39 exerted adverse effects and weakened the effects of liraglutide. Therefore, GLP-1R might suppress seizures by regulating the levels of neuronal receptors.
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Epilepsia/tratamiento farmacológico , Epilepsia/patología , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Hipoglucemiantes/uso terapéutico , Liraglutida/uso terapéutico , Animales , Anticonvulsivantes/uso terapéutico , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Epilepsia/metabolismo , Receptor del Péptido 1 Similar al Glucagón/análisis , Humanos , Masculino , Ratas Sprague-Dawley , Convulsiones/tratamiento farmacológico , Convulsiones/metabolismo , Convulsiones/patologíaRESUMEN
Mossy fiber sprouting (MFS) is a pathological phenomenon that is commonly observed in epilepsy, and plentiful data reveal that abnormal phosphorylated modification of tau protein plays a critical role in MSF by the regulation of microtubule dynamics and axonal transport. Ubiquitin C-terminal hydrolase L1 (UCH-L1), a proteasomal deubiquitinating enzyme, has been proved to be associated with tau aggregation through mediating degradation of ubiquitinated and hyperphosphorylated tau. Thus, this study aimed to determine the expression of UCH-L1 in the rat hippocampus during the pentylenetetrazole (PTZ)-induced process and to demonstrate the possible correlation with MFS in epileptogenesis. Seizures were established by intraperitoneal injection of PTZ and LDN-57444 was used to inhibit the hydrolase activity of UCH-L1. We used western blot, immunofluorescence, immunoprecipitation, and timm staining to detect phosphorylated modification of tau and MSF. The results presented that LDN-57444 induced the deteriorated severity of seizures, increased phosphorylation of tau and increased distribution of Timm granules in both the supragranular region of the dentate gyrus (DG) and the stratum pyramidale of CA3 subfield. Our results suggest that UCH-L1 may be associated with hippocampal MSF followed the epileptogenesis through mediating phosphorylation of tau. UCH-L1 may be a potential and novel therapeutic target to limit epileptogenesis.
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Excitación Neurológica/fisiología , Fibras Musgosas del Hipocampo/ultraestructura , Pentilenotetrazol/farmacología , Ubiquitina Tiolesterasa/antagonistas & inhibidores , Animales , Epilepsia/inducido químicamente , Fosforilación , Ratas , Proteínas tau/metabolismoRESUMEN
BACKGROUND: Repulsive guidance molecule A (RGMa) is implicated in focal cerebral ischemia-reperfusion (I/R) injury, but its mechanisms are still largely unknown. This work focused on the effects of RGMa on the blood-brain barrier (BBB) after focal cerebral I/R injury. METHODS: Sprague-Dawley (SD) rats were randomly divided into four groups: sham, middle cerebral artery occlusion (MCAO)/reperfusion (I/R), MCAO/reperfusion administered recombinant adenovirus expressing sh-con (I/Râ¯+â¯sh-con) and MCAO/reperfusion administered recombinant adenovirus expressing sh-RGMa (I/Râ¯+â¯sh-RGMa) groups. Infarct volume, brain edema and neurological scores were evaluated at 3 day after reperfusion. Evens blue leakage and transmission electron microscopy was performed. And the expression level of claudin-5 and ZO-1, CDC-42 and PAK-1, RGMa were detected by western blot. RESULTS: Compared with I/R or I/Râ¯+â¯sh-con groups, I/Râ¯+â¯sh-RGMa group showed smaller infarction volume, attenuated brain edema, improved neurological scores and better BBB integrity, such as reduced Evans blue leakage and ultra-structural change. We also observed improved BBB function followed by down-regulation of MMP-9 and up-regulation of claudin-5 and ZO-1 in the I/Râ¯+â¯sh-RGMa group. In addition, up-regulation of the CDC-42 and PAK-1 in the I/Râ¯+â¯sh-RGMa group was obtained. CONCLUSIONS: RGMa may be involved in I/R injury associated with BBB dysfunction via the CDC-42/PAK-1 signal pathway and may be a promising therapeutic target for I/R injury.
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Barrera Hematoencefálica , Terapia Genética , Infarto de la Arteria Cerebral Media/terapia , Proteínas de la Membrana/deficiencia , Proteínas del Tejido Nervioso/deficiencia , Daño por Reperfusión/terapia , Adenoviridae/genética , Animales , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Edema Encefálico/metabolismo , Edema Encefálico/patología , Edema Encefálico/terapia , Permeabilidad Capilar/fisiología , Proteínas Ligadas a GPI , Expresión Génica , Silenciador del Gen , Vectores Genéticos , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/patología , Masculino , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Distribución Aleatoria , Ratas Sprague-Dawley , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patologíaRESUMEN
BACKGROUND: Zinc-α2-glycoprotein (ZAG) is a 42-kDa protein reported as an anti-inflammatory adipocytokine. Evidences from clinical and experimental studies revealed that brain inflammation plays important roles in epileptogenesis and seizure. Interestingly, closely relationship between ZAG and many important inflammatory mediators has been proven. Our previous study identified ZAG in neurons and found that ZAG is decreased in epilepsy and interacts with TGFß and ERK. This study aimed to investigate the role of ZAG in seizure and explore its effect on seizure-related neuroinflammation. METHODS: We overexpressed AZGP1 in the hippocampus of rats via adeno-associated virus vector injection and observed their seizure behavior and EEG after pentylenetetrazol (PTZ) kindling. The level of typical inflammation mediators including TNFα, IL-6, TGFß, ERK, and ERK phosphorylation were determined. RESULTS: The overexpression of AZGP1 reduced the seizure severity, prolonged the latency of kindling, and alleviated epileptiform discharges in EEG changes induced by PTZ. Overexpression of AZGP1 also suppressed the expression of TNFα, IL-6, TGFß, and ERK phosphorylaton in PTZ-kindled rats. CONCLUSIONS: ZAG may inhibit TGFß-mediated ERK phosphorylation and inhibit neuroinflammation mediated by TNFα and IL-6, suggesting ZAG may suppress seizure via inhibiting neuroinflammation. ZAG may be a potential and novel therapeutic target for epilepsy.
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Proteínas Portadoras/metabolismo , Encefalitis , Regulación de la Expresión Génica/genética , Glicoproteínas/metabolismo , Convulsiones/complicaciones , Convulsiones/terapia , Adipoquinas , Animales , Ondas Encefálicas/efectos de los fármacos , Ondas Encefálicas/fisiología , Proteínas Portadoras/genética , Convulsivantes/toxicidad , Citocinas/metabolismo , Modelos Animales de Enfermedad , Electroencefalografía , Encefalitis/etiología , Encefalitis/metabolismo , Encefalitis/terapia , Glicoproteínas/genética , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Hipocampo , Excitación Neurológica/efectos de los fármacos , Masculino , Pentilenotetrazol/toxicidad , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Convulsiones/inducido químicamente , Convulsiones/patología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Factores de Tiempo , Transducción Genética , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , eIF-2 Quinasa/genética , eIF-2 Quinasa/metabolismoRESUMEN
FK506, a calcineurin inhibitor, shows neuroprotective effects and has been associated with neurodegenerative diseases. Calcineurin A (CaNA), a catalytic subunit of calcineurin, mediates the dephosphorylation of various proteins. N-methyl-D-aspartate receptor (GluN) is closely related to epileptogenesis, and various phosphorylation sites of GluN2B, a regulatory subunit of the GluN complex, have different functions. Thus, we hypothesized that one of the potential anti-epileptic mechanisms of FK506 is mediated by its ability to promote the phosphorylation of GluN2B and reduce the expression of GluN2B in membrane fraction by down-regulating CaNA. CaNA expression was increased in the cortex of patients with temporal lobe epilepsy and pentylenetetrazol (PTZ)-induced epileptic models. CaNA was shown to be expressed in neurons using immunofluorescence staining. According to our behavioral observations, epileptic rats exhibited less severe seizures and were less sensitive to PTZ after a systemic injection of FK506. The levels of phosphorylated GluN2B were decreased in epileptic rats but increased after the FK506 treatment. Moreover, there was no difference in the total GluN2B levels before and after FK506 treatment. However, the expression of GluN2B in membrane fraction was suppressed after FK506 treatment. Based on these results, FK506 may reduce the severity and frequency of seizures by reducing the expression of GluN2B in membrane fraction.
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Inhibidores de la Calcineurina/uso terapéutico , Membrana Celular/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/biosíntesis , Convulsiones/metabolismo , Tacrolimus/uso terapéutico , Adolescente , Adulto , Animales , Calcineurina/metabolismo , Inhibidores de la Calcineurina/farmacología , Membrana Celular/efectos de los fármacos , Membrana Celular/genética , Preescolar , Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Epilepsia del Lóbulo Temporal/genética , Epilepsia del Lóbulo Temporal/metabolismo , Femenino , Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/genética , Convulsiones/tratamiento farmacológico , Convulsiones/genética , Tacrolimus/farmacología , Adulto JovenRESUMEN
Gliomas are the most common and aggressive type of primary adult brain tumors. Although GGNBP2 has previously been considered to be a tumor suppressor gene, little is known about the association between GGNBP2 and glioma. In this study, we clearly demonstrated that GGNBP2 was downexpressed in glioma tissues, and its downexpression is related to the pathological grade and overall survival of patients with gliomas. Overexpression of GGNBP2 suppressed the proliferation, migration, and invasion of glioma cells. Mechanistically, we demonstrated that the PI3K/Akt and Wnt/ß-catenin signaling pathways were suppressed by GGNBP2 overexpression. In contrast, knockdown of GGNBP2 has precisely the opposite effect. Collectively, these data indicate that GGNBP2 shows tumor suppressive activity in human glioma cells and may stand out as a potential therapeutic target for glioma.
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Glioma/genética , Proteínas Supresoras de Tumor/genética , Proteínas Adaptadoras Transductoras de Señales , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular , Expresión Génica , Glioma/patología , Humanos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Vía de Señalización WntRESUMEN
OBJECTIVE: To investigate the effect of vildagliptin on pentamethazol (PTZ)-induced epilepsy in rats and explore the molecular mechanism. METHODS: Samples of temporal cortex from 23 patients with temporal lobe epilepsy were collected as epilepsy group and samples of temporal cortex from 14 patients with brain trauma were used as control group. Ninety male SD rats were randomly divided into control group (group A), PTZ-induced epilepsy group (group B), saline 2 mL/kg group (group C), vildagliptin 2.5 mg/kg group (group D), vildagliptin 5mg/kg group (group D) and vildagliptin 10 mg/kg group (group F). Use chronic model of epilepsy induced by PTZ (35 mg/kg) intraperitoneal injection for 3 consecutive weeks, and changes of behavior were observed. The expression of GLP-1R was detected by Western blotting and immunohistochemical (IHC) staining, and the expression of GLP-1 was detected by enzyme-linked immunosorbent assay (ELISA). The location of GLP-1R was detected by immunofluorescent staining. RESULTS: Immunofluorescent staining showed that the GLP-1R located in the neurons, and GLP-1R expression was obviously decreased both in patients with TLE and in rats with epilepsy. The latency time was prolonged and epilepsy attack time was decreased after vildagliptin treatment (P<0.05). GLP-1R expression was increased after vildagliptin treatment (P<0.05). ELISA showed the change of GLP-1 expression was the same as GLP-1R. CONCLUSION: Vildagliptin can suppress temporal lobe epilepsy in rats by up-regulating GLP-1 and GLP-1R expressions.
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Anticonvulsivantes/farmacología , Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Epilepsia del Lóbulo Temporal/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Hipoglucemiantes/farmacología , Regulación hacia Arriba/efectos de los fármacos , Vildagliptina/farmacología , Animales , Anticonvulsivantes/administración & dosificación , Estudios de Casos y Controles , Epilepsia del Lóbulo Temporal/inducido químicamente , Humanos , Hipoglucemiantes/administración & dosificación , Masculino , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Lóbulo Temporal/efectos de los fármacos , Lóbulo Temporal/metabolismo , Vildagliptina/administración & dosificaciónRESUMEN
E3 ubiquitin ligases are important protein-modifying enzymes involved in the pathogenesis of a variety of neurodegenerative diseases. F-box and leucine-rich repeat protein 20 (FBXL20), an E3 ubiquitin ligase widely expressed in the central nervous system, plays an important role in the ubiquitin-dependent degradation of regulating synaptic membrane exocytosis 1 (RIM1), which is an important factor in the release of synaptic vesicles. FBXL20 has been associated with a variety of neurodegenerative diseases; thus, we hypothesized that FBXL20 is involved in the development of epilepsy. Herein, we used immunofluorescence staining, immunohistochemistry and western blotting to determine the expression pattern of FBXL20 in temporal lobe epilepsy patients and pilocarpine-induced epilepsy animal models. We also injected SD rats with lentivirus-vector mediated overexpression of FBXL20. The results showed that FBXL20 is expressed in the membrane and the cytoplasm of cortical neurons, and overexpression of FBXL20 decreased the onset level of spontaneous seizure, the frequency and duration of seizures. Additionally, FBXL20 protein level was decreased but RIM1 protein level was increased in the epileptic group compared with the LV-FBXL20 and LV-GFP group. These findings in humans were consistent with the results from a pilocarpine-induced animal model of chronic epilepsy. Thus, abnormal expression of FBXL20 might play an important role in the development of epilepsy.