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1.
J Cell Biochem ; 120(6): 9324-9336, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30520141

RESUMEN

Glioma is the most aggressive malignant tumor in the adult central nervous system. Abnormal long noncoding RNA (lncRNA) FOXD2-AS1 expression was associated with tumor development. However, the possible role of FOXD2-AS1 in the progression of glioma is not known. In the present study, we used in vitro and in vivo assays to investigate the effect of abnormal expression of FOXD2-AS1 on glioma progression and to explore the mechanisms. FOXD2-AS1 was upregulated in glioma tissue, cells, and sphere subpopulation. Upregulation of FOXD2-AS1 was correlated with poor prognosis of glioma. Downregulation of FOXD2-AS1 decreased cell proliferation, migration, invasion, stemness, and epithelial-mesenchymal transition (EMT) in glioma cells and inhibited tumor growth in transplanted tumor. We also revealed that FOXD2-AS1 was mainly located in cytoplasm and microRNA (miR)-185-5p both targeted FOXD2-AS1 and CCND2 messenger RNA (mRNA) 3'-untranslated region (3'-UTR). miR-185-5p was downregulated in glioma tissue, cells, and sphere subpopulation. Downregulation of miR-185-5p was closely correlated with poor prognosis of glioma patients. In addition, miR-185-5p mimics decreased cell proliferation, migration, invasion, stemness, and EMT in glioma cells. CCND2 was upregulated in glioma tissue, cells, and sphere subpopulation. Upregulation of CCND2 was closely correlated with poor prognosis of glioma patients. CCND2 knockdown decreased cell proliferation, migration, invasion, and EMT in glioma cells. In glioma tissues, CCND2 expression was negatively associated with miR-185-5p, but positively correlated with FOXD2-AS1. FOXD2-AS1 knockdown and miR-185-5p mimics decreased CCND2 expression. Inhibition of miR-185-5p suppressed FOXD2-AS1 knockdown-induced decrease of CCND2 expression. Overexpression of CCND2 suppressed FOXD2-AS1 knockdown-induced inhibition of glioma malignancy. Taken together, our findings highlight the FOXD2-AS1/miR-185-5p/CCND2 axis in the glioma development.


Asunto(s)
Ciclina D2/genética , Glioma/genética , MicroARNs/genética , ARN Largo no Codificante/genética , Apoptosis/genética , Carcinogénesis/genética , Proliferación Celular/genética , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Glioma/patología , Xenoinjertos , Humanos , Masculino , Transducción de Señal/genética
2.
Tumour Biol ; 35(8): 7451-7, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24782032

RESUMEN

We conducted a case-control study to assess the role of three single-nucleotide polymorphisms (SNPs) in excision repair cross-complementation group 1 (ERCC1) and two SNPs in excision repair cross-complementation group 2 (ERCC2) on the glioma risk in a Chinese population, and investigate the gene-environmental interaction for the cancer risk. A 1:2 matched case-control study was conducted. Logistic regression analysis revealed that individuals carrying ERCC1 rs2298881 CC genotype were associated with risk of glioma when compared with AA genotype carriers. The significant associations of ERCC1 rs2298881 polymorphism with glioma susceptibility were observed in both the dominant and the recessive models. In a stratification analysis, we found that ERCC1 rs2298881 variants showed an increased association with the risk of glioma in males, ever smokers, and high-grade glioma cases. In conclusion, our study suggests that ERCC1 rs2298881 polymorphism is associated with risk of glioma in codominant, dominant, and recessive models, especially in males, smokers, and high-grade glioma cases. This finding could be useful in revealing the genetic characteristics of glioma and suggests more effective strategies for prevention and treatment.


Asunto(s)
Neoplasias Encefálicas/genética , Proteínas de Unión al ADN/genética , Endonucleasas/genética , Predisposición Genética a la Enfermedad , Glioma/genética , Polimorfismo de Nucleótido Simple , Proteína de la Xerodermia Pigmentosa del Grupo D/genética , Adulto , Anciano , Neoplasias Encefálicas/etiología , Estudios de Casos y Controles , Reparación del ADN , Femenino , Genotipo , Glioma/etiología , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad
3.
Eur J Med Res ; 29(1): 13, 2024 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-38173030

RESUMEN

BACKGROUND: The WD40 repeat (WDR) domain provides scaffolds for numerous protein-protein interactions in multiple biological processes. WDR domain 76 (WDR76) has complex functionality owing to its diversified interactions; however, its mechanism in LGG has not yet been reported. METHODS: Transcriptomic data from public databases were multifariously analyzed to explore the role of WDR76 in LGG pathology and tumor immunity. Laboratory experiments were conducted to confirm these results. RESULTS: The results first confirmed that high expression of WDR76 in LGG was not only positively associated with clinical and molecular features of malignant LGG, but also served as an independent prognostic factor that predicted shorter survival in patients with LGG. Furthermore, high expression of WDR76 resulted in the upregulation of oncogenes, such as PRC1 and NUSAP1, and the activation of oncogenic mechanisms, such as the cell cycle and Notch signaling pathway. Finally, WDR76 was shown to be involved in LGG tumor immunity by promoting the infiltration of immune cells, such as M2 macrophages, and the expression of immune checkpoints, such as PDCD1 (encoding PD-1). CONCLUSIONS: This study shows for the first time the diagnostic and prognostic value of WDR76 in LGG and provides a novel personalized biomarker for future targeted therapy and immunotherapy. Thus, WDR76 may significantly improve the prognosis of patients with LGG.


Asunto(s)
Glioma , Repeticiones WD40 , Humanos , Inmunoterapia , Ciclo Celular , Perfilación de la Expresión Génica , Glioma/genética , Glioma/terapia , Pronóstico , Proteínas de Unión al ADN , Proteínas de Ciclo Celular
4.
Aging (Albany NY) ; 16(7): 6188-6211, 2024 03 28.
Artículo en Inglés | MEDLINE | ID: mdl-38552216

RESUMEN

BACKGROUND: REEP4 is involved in the regulation of the biological process of mitosis. Lower grade glioma (LGG), as a malignant tumor, is accompanied by abnormalities in mitosis, but there have been no reports of REEP4 so far. METHODS: We collected transcriptome data, DNA methylation data and the clinical characteristics of thousands of patients with LGG. Various big data analysis methods and molecular biology experiments were employed to reveal the impact of REEP4 on the pathological process of LGG. RESULTS: It was found that the expression of REEP4 was significantly elevated and negatively regulated by its methylation site. Therefore, both the high expression of REEP4 and low methylation state of cg16311504 showed that the patients are correlated with lower patient survival rate. In addition, high REEP4 expression participates in the regulation of various cancer-related cellular signaling pathways, such as the cell cycle, MAPK signaling pathway, NOD-like receptor signaling pathway, etc. More importantly, the level of immune cell infiltration significantly increased in the high expression group of REEP4 in the LGG tumor microenvironment and REEP4 has a high positive correlation with PD-L1 and other immune checkpoints. CONCLUSIONS: In brief, this study is the first to introduce REEP4 in malignant tumors, which can be used as an independent risk factor that participates in the malignant process of LGG. More importantly, REEP4 has the potential to become a new star in the field of anti-tumor treatment.


Asunto(s)
Neoplasias Encefálicas , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Glioma , Humanos , Glioma/genética , Glioma/metabolismo , Glioma/patología , Glioma/mortalidad , Pronóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/mortalidad , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Microambiente Tumoral/genética , Clasificación del Tumor , Transcriptoma , Femenino
5.
J Neurol ; 269(10): 5262-5271, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-35776193

RESUMEN

BACKGROUND: At present, studies regarding the efficacy and safety of tenecteplase for the treatment of patients with acute ischemic stroke (AIS) are still limited and inconsistent. The purpose of this systematic review and meta-analysis is to compare the efficacy and safety of tenecteplase with alteplase for the treatment of AIS patients. METHODS: Literature search was conducted in PubMed, Embase, and Cochrane Library up to May 10, 2022. Primary outcomes of this study included 90-day good outcome (defined as an mRS score of 0-2) and 90-day excellent outcome (defined as an mRS score of 0-1). Risk ratios (RRs) with 95% confidence intervals (95% CIs) were calculated using a random-effect model for each outcome. RESULTS: Fourteen studies with a total of 3537 patients were finally included in this meta-analysis. There was no statistical difference between patients receiving tenecteplase and those receiving alteplase in the rates of 90-day good outcome (RR 1.01; 95% CI 0.91-1.13; P = 0.79) and 90-day excellent outcome (RR 1.04; 95% CI 0.92-1.19; P = 0.50). Patients receiving tenecteplase might associated with higher incidence of early neurologic improvement compared with those receiving alteplase (RR 1.29; 95% CI 1.04-1.61; P = 0.02). In addition, no statistical difference was observed between the two groups in other outcomes. CONCLUSION: This meta-analysis indicated that tenecteplase in AIS patients is as safe and effective as alteplase and might provide more benefit than alteplase. However, due to several inherent limitations of this study, more prospective studies should be conducted to confirm the above results.


Asunto(s)
Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Isquemia Encefálica/tratamiento farmacológico , Fibrinolíticos/uso terapéutico , Humanos , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Estudios Prospectivos , Accidente Cerebrovascular/inducido químicamente , Accidente Cerebrovascular/tratamiento farmacológico , Tenecteplasa/uso terapéutico , Activador de Tejido Plasminógeno/efectos adversos , Resultado del Tratamiento
6.
Mol Med Rep ; 25(5)2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35244195

RESUMEN

Autism spectrum disorder (ASD) is a lifelong neurodevelopmental condition characterized by impaired social interaction, compromised communication, and restrictive or stereotyped behaviours and interests. Due to the complex pathophysiology of ASD, there are currently no available medical therapies for improving the associated social deficits. Consequently, the present study investigated the effects of STX209, a selective γ­aminobutyric acid type B receptor (GABABR2) agonist, on an environmental rodent model of autism. The mouse model of autism induced by prenatal exposure to valproic acid (VPA) was used to assess the therapeutic potential of STX209 on autism­like behaviour in the present study. This study investigated the effects of STX209 on VPA model mice via behavioral testing and revealed a significant reversal of core/associated autism­like behavior, including sociability and preference for social novelty, novelty recognition, locomotion and exploration activity and marble­burying deficit. This may be associated with STX209 correcting dendritic arborization, spine density and GABABR2 expression in hippocampus of VPA model mice. However, expression of glutamic acid decarboxylase 65/67 in the hippocampus were not altered by STX209. The present results demonstrated that STX209 administration ameliorated autism­like symptoms in mice exposed to VPA prenatally, suggesting that autism­like symptoms in children with a history of prenatal VPA exposure may also benefit from treatment with the GABABR2 agonist STX209.


Asunto(s)
Trastorno del Espectro Autista , Trastorno Autístico , Efectos Tardíos de la Exposición Prenatal , Animales , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/etiología , Trastorno Autístico/inducido químicamente , Trastorno Autístico/tratamiento farmacológico , Conducta Animal , Modelos Animales de Enfermedad , Femenino , Agonistas de Receptores GABA-B/efectos adversos , Ratones , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/tratamiento farmacológico , Conducta Social , Ácido Valproico/efectos adversos
7.
Front Pharmacol ; 12: 694476, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34349653

RESUMEN

Exendin-4 (Ex4), a long-lasting glucagon-like peptide-1 analog, was reported to exert favourable actions on inhibiting cocaine-associated rewarding and reinforcing effects of drug in animal models of addiction. However, the therapeutic potential of different dose of GLP-1 receptor agonist Ex4 in different behavioral paradigms and the underlying pharmacological mechanisms of action are incompletely understood. Herein, we firstly investigated the effects of Ex4 on cocaine-induced condition place preference (CPP) as well as extinction and reinstatement in male C57BL/6J mice. Additionally, we sought to elucidate the underlying pharmacological mechanism of these actions of Ex4. The paradigm of cocaine-induced CPP was established using 20 mg/kg cocaine or saline alternately during conditioning, while the reinstatement paradigm was modeled using 10 mg/kg cocaine on the reinstatement day. Different dose of Ex4 was administrated intraperitoneally either during conditioning or during extinction state or only on the test day. To elucidate the molecular mechanism underlying the potential effects of Ex4 on maladaptive behaviors of cocaine, the TLR4-related inflammation within the hippocampus was observed by immunofluorescence staining, and the expression levels of toll-like receptor 4 (TLR4), tumor necrosis factor (TNF)-α, and interleukin (IL)-1ß were detected by Western blotting. As a consequence, systemic administration of different dose of Ex4 was sufficient to inhibit the acquisition and expression of cocaine-induced CPP, facilitate the extinction of cocaine-associated reward and attenuate reinstatement of cocaine-induced behavior. Furthermore, Ex4 treatment diminished expression levels of TLR4, TNF-α, and IL-1ß, which were up-regulated by cocaine exposure. Altogether, our results indicated that Ex4 effectively ameliorated cocaine-induced behaviors likely through neurobiological mechanisms partly attributable to the inhibition of TLR4, TNF-α and IL-1ß in mice. Consequently, our findings improved our understanding of the efficacy of Ex4 for the amelioration of cocaine-induced behavior and suggested that Ex4 may be applied as a drug candidate for cocaine addiction.

8.
Front Psychiatry ; 11: 577155, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33173522

RESUMEN

Deep brain stimulation (DBS) modulates the neuronal activity in specific brain circuits and has been recently considered as a promising intervention for refractory addiction. The insula cortex is the hub of interoception and is known to be involved in different aspects of substance use disorder. In the present study, we investigate the effects of continuous high frequency DBS in the anterior insula (AI) on drug-seeking behaviors and examined the molecular mechanisms of DBS action in morphine-addicted rats. Sprague-Dawley rats were trained to the morphine-conditioned place preference (CPP, day 1-8) followed by bilaterally implanted with DBS electrodes in the AI (Day 10) and recovery (Day 10-15). Continuous high-frequency (HF) -DBS (130 Hz, 150 µA, 90 µs) was applied during withdrawal (Day 16-30) or extinction sessions. CPP tests were conducted on days 16, 30, 40 during withdrawal session and several rats were used for proteomic analysis on day 30. Following the complete extinction, morphine-CPP was reinstated by a priming dose of morphine infusion (2 mg/kg). The open field and novel objective recognition tests were also performed to evaluate the DBS side effect on the locomotion and recognition memory. Continuous HF-DBS in the AI attenuated the expression of morphine-CPP post-withdrawal (Day 30), but morphine addictive behavior relapsed 10 days after the cessation of DBS (Day 40). Continuous HF-DBS reduced the period to full extinction of morphine-CPP and blocked morphine priming-induced recurrence of morphine addiction. HF-DBS in the AI had no obvious effect on the locomotor activity and novel objective recognition and did not cause anxiety-like behavior. In addition, our proteomic analysis identified eight morphine-regulated proteins in the AI and their expression levels were reversely changed by HF-DBS. Continuous HF-DBS in the bilateral anterior insula prevents the relapse of morphine place preference after withdrawal, facilitates its extinction, blocks the reinstatement induced by morphine priming and reverses the expression of morphine-regulated proteins. Our findings suggest that manipulation of insular activity by DBS could be a potential intervention to treat substance use disorder, although future research is warranted.

9.
Neuroscience ; 438: 116-136, 2020 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-32418750

RESUMEN

Mutations in γ-aminobutyric acid A receptor (GABAA) subunits and sodium channel genes, especially GABRG2 and SCN1A, have been reported to be associated with febrile seizures (FS) and genetic epilepsy with febrile seizures plus (GEFS+). GEFS+ is a well-known family of epileptic syndrome with autosomal dominant inheritance in children. Its most common phenotypes are febrile seizures often with accessory afebrile generalized tonic-clonic seizures, febrile seizures plus (FS+), severe epileptic encephalopathy, as well as other types of generalized or localization-related seizures. However, the pathogenesis of febrile seizures remains largely unknown. Here, we generated a GABRG2 gene knockout cell line (HT22GABRG2KO) by applying the CRISPR/Cas9-mediated genomic deletion in HT-22 mouse hippocampal neuronal cell line to explore the function of GABRG2 in vitro. With mRNA-seq, we found significant changes in the expression profiles of several epilepsy-related genes when GABRG2 was knockout, some of them showing temperature-induced changes as well. Kyoto Encyclopedia Gene and Genomic (KEGG) analysis revealed a significant alteration in the MAPK and PI3K-Akt signaling pathways. We also observed an up-regulation of the matrix metalloproteinases (MMPs) family after GABRG2 knockout. Furthermore, the significant decrease in expression of GABRA1 and CACNA1A (but not others) with an increase in temperature is a novel finding. In summary, mutations in the GABAA receptor can lead to a decrease in numbers of receptors, which may cause the impairment of GABAergic pathway signaling. This data has been the first time to reveal that GABRG2 mutations would affect the function of other genes, and based on this finding we hope this work would also provide a new direction for the research of GABRG2 in GEFS+. It also may provide a molecular basis for the severity of epilepsy, and guide the clinical medication for the treatment of the epilepsy focused on the function on GABAA receptors, which, might be a new strategy for genetic diagnosis and targeted treatment of epilepsy.


Asunto(s)
Epilepsia Generalizada , Convulsiones Febriles , Humanos , Mutación , Canal de Sodio Activado por Voltaje NAV1.1 , Fosfatidilinositol 3-Quinasas , Receptores de GABA-A/genética , Convulsiones Febriles/genética , Temperatura
10.
Front Pharmacol ; 11: 743, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32508658

RESUMEN

Environmental cues associated with drug abuse are powerful mediators of drug craving and relapse in substance-abuse disorders. Consequently, attenuating the strength of cue-drug memories could reduce the number of factors that cause drug craving and relapse. Interestingly, impairing cue-drug memory reconsolidation is a generally accepted strategy aimed at reducing the intensity of cues that trigger drug-seeking and drug-taking behaviors. In addition, the agranular insular cortex (AI) is an important component of the neural circuits underlying drug-related memory reconsolidation. GABAB receptors (GABABRs) are potential targets for the treatment of addiction, and baclofen (BLF) is the only prototypical GABAB agonist available for application in clinical addiction treatment. Furthermore, ΔFosB is considered a biomarker for the evaluation of potential therapeutic interventions for addiction. Here, we used the morphine-induced conditioned place preference (CPP) paradigm to investigate whether postretrieval microinjections of BLF into the AI could affect reconsolidation of drug-reward memory, reinstatement of CPP, and the level of ΔFosB in mice. Our results showed that BLF infused into the AI immediately following morphine CPP memory retrieval, but not 6 h postretrieval or following nonretrieval, could eliminate the expression of a morphine CPP memory. This effect persisted in a morphine-priming-induced reinstatement test, suggesting that BLF in the AI was capable of preventing the reconsolidation of the morphine CPP memory. Our results also showed that the elimination of morphine CPP memory was associated with reduced morphine-associated ΔFosB expression in the longer term. Taken together, the results of our research provide evidence to support that GABABRs in the AI have an important role in drug-cue memory reconsolidation and further our understanding of the role of the AI in drug-related learning and memory.

11.
World Neurosurg ; 87: 607-12, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26546997

RESUMEN

OBJECTIVE: This prospective cohort-designed study was performed to verify whether higher levels of serum lipoprotein(a) (Lp(a)) could be a risk factor for deep vein thrombosis (DVT) in Chinese patients with spinal cord injuries (SCI). METHODS: During 2013-2014, consecutive patients with first-ever SCI were recruited and assessed for DVT using color Doppler ultrasonography for 15 days after injury and whenever clinically requested. Using logistic regression models, multivariate analyses were performed. Receiver operating characteristic curves tested the overall predicted accuracy of Lp(a) and other markers. RESULTS: In this study, 358 patients were screened in the analysis, and 279 patients with SCI were included and completed the 15-day follow-up. Fifty-five patients (19.7%) were diagnosed with DVT. Patients with SCI with DVT had significantly higher Lp(a) levels on admission (554 mg/L [interquartile range, 416-790 mg/L] vs. 158 mg/L [interquartile range, 72-252 mg/L]; P < 0.0001). Adjusted for common risk factors, multivariate analyses showed that serum Lp(a) ≥ 300 mg/L could be used independently to predict DVT (odds ratio, 10.35; 95% confidence interval [CI], 2.37-45.35; P < 0.0001). With an area under the curve (AUC) of 0.91 (95% CI, 0.86-0.94), Lp(a) showed a significantly greater discriminatory ability in predicting DVT compared with high-sensitivity C-reactive protein (AUC, 0.81; 95% CI, 0.74-0.88; P < 0.01), homocysteine (AUC, 0.78; 95% CI, 0.71-0.84; P < 0.01) and age (AUC, 0.66; 95% CI, 0.59-0.73; P < 0.001). CONCLUSIONS: Increased serum Lp(a) levels were independent predictors of DVT in patients with SCI in China, suggesting a possible role of Lp(a) in the pathogenesis of DVT.


Asunto(s)
Lipoproteína(a)/sangre , Traumatismos de la Médula Espinal/complicaciones , Trombosis de la Vena/sangre , Trombosis de la Vena/etiología , Adulto , Pueblo Asiatico , Biomarcadores , Proteína C-Reactiva/análisis , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Homocisteína/sangre , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Ultrasonografía Doppler en Color , Trombosis de la Vena/diagnóstico por imagen
12.
Int J Clin Exp Pathol ; 8(10): 12577-82, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26722447

RESUMEN

OBJECTIVE: To investigate the effect of isoliquiritigenin on the activity of DNA topoisomerase (TOP I) and its inhibitory effect on the growth of U87 glioma cells. METHODS: This study investigated the inhibitory effect of isoliquiritigenin on the growth of U87 glioma cells and its cytotoxicity by MTT method and determined the effect of isoliquiritigenin on TOP I activity by agarose gel electrophoresis. On this basis, we studied the interaction between isoliquiritigenin and TOP I and DNA. Finally, we further discussed the effect of isoliquiritigenin on the activity of Caspase 3, the apoptosis protein of U87 glioma cells. RESULTS: Isoliquiritigenin could inhibit the growth of U87 glioma cells (half inhibitory concentration IC50: 0.221 mM) and is of low cytotoxicity to normal cells. Agarose gel electrophoresis showed that isoliquiritigenin had significant inhibitory effect on TOP I activity. Molecular simulation results indicated that isoliquiritigenin took priority of binding to the active center of TOP I, and formed hydrogen bonds with the catalytic site Try723. Finally, Caspase 3 activity detection results suggested that isoliquiritigenin could significantly increase the activity of Caspase 3 (P < 0.05). CONCLUSION: Isoliquiritigenin had a reversible inhibitory effect on TOP I activity, reduced the rate of single strand DNA unwinding in tumor cells, and thus played an important role in inducing the apoptosis of U87 glioma cells.


Asunto(s)
Neoplasias Encefálicas/patología , Proliferación Celular/efectos de los fármacos , Chalconas/farmacología , Glioma/patología , Inhibidores de Topoisomerasa/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Electroforesis en Gel de Agar , Humanos , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular
13.
J Mol Neurosci ; 57(4): 546-53, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26254912

RESUMEN

Asymmetric dimethylarginine (ADMA) is emerging as a key contributor to endothelial dysfunction. The drug probucol was reported to have an anti-lipid peroxidation effect and improve endothelial dilation function. But little is known about the protective effect of probucol on ADMA-induced human brain microvascular endothelial cell (HBMEC) injury and its underlying mechanisms. Therefore, in this study, we investigated the effect of probucol on ADMA-induced HBMEC injury and its potential mechanisms. Results showed that probucol protected against ADMA-induced HBMEC injury in a dose-dependent manner; probucol pretreatment also significantly reduced the level of reactive oxygen species (ROS) and malondialdehyde (MDA), downregulated the expression of pro-apoptotic gene Bax and caspase-3 activity, as well as increased the brain-derived neurotrophic factor (BDNF) release and promoted anti-apoptotic gene Bcl-2 and eNOS expression in the cultured HBMECs. Furthermore, we found that ADMA significantly increased the phosphorylation of c-Jun NH2-terminal kinase (JNK) and p38, while probucol pretreatment effectively inhibited ADMA-induced JNK and p38 phosphorylation in HBMECs. In conclusion, our present results demonstrated that probucol protected against ADMA-induced HBMEC injury and suppressed oxidative stress through the JNK/p38 MAPK pathway, which was the potential underlying mechanism of HBMEC injury in ischemic cerebrovascular disease.


Asunto(s)
Antioxidantes/farmacología , Apoptosis , Células Endoteliales/efectos de los fármacos , Probucol/farmacología , Arginina/análogos & derivados , Arginina/toxicidad , Encéfalo/irrigación sanguínea , Células Cultivadas , Células Endoteliales/metabolismo , Endotelio Vascular/citología , Humanos , MAP Quinasa Quinasa 4/metabolismo , Microvasos/citología , Estrés Oxidativo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
14.
Int J Clin Exp Med ; 8(12): 22045-52, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26885179

RESUMEN

OBJECTIVE: To prepare transferrin modified artesunate nanoliposomes (Tf-ART-LPs) and study their glioma U87 cells-targeting treatment in-vitro and in-vivo. METHODS: Ammonium sulfate transmembrane gradient method was used to prepare Tf-ART-LPs, whose size and stability was detected by a Nanosizer. Besides, the encapsulation efficiency and release rate of artesunate (ART) were tested by a ultraviolet spectrophotometer. Further, isothiocyanate (FITC) was used to label nanoliposomes and the cell-targeting property of Tf-ART-LP in-vitro was observed under a fluorescence microscope. In addition, CCK-8 method was used to detect the effect of single nanoliposomes and Tf-ART-LPs on the viability of glioma U87 cells. At last, a subcutaneously implanted tumor model in nude mouse was established for studying the in-vivo anti-tumor effect of Tf-ART-LPs by caudal vein injection. The tumor volume and mice weight were monitored and pathological sections of their major organs were analyzed. RESULTS: Tf-ART-LPs were spherical with an average diameter of 94.2 nm. They showed no aggregation after being stored in a refrigerator for 14 days at 4°C. The encapsulation efficiency and highest releasing rate (48 hours after being placed in normal saline under 37°C) of ART was 85.9% and 58.7±2.9%, respectively. The uptake rate of U87 cells was 59.8±3.8% for Tf-ART-LPs and only 18.7±4.5% for ART-LPs. While single liposomes almost showed no toxicity, Tf-ART-LP had a concentration-dependent killing effect on U87 cells. Within 32 days of treatment, the growth of U87 cells was well inhibited by Tf-ART-LPs without significant toxicity. CONCLUSION: In this study, transferrin modified artesunate liposomes we prepared have a good targeting property to glioma U87 cells and good effect on glioma both in-vitro and in-vivo.

15.
Exp Ther Med ; 7(6): 1683-1686, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24926366

RESUMEN

The aim of the present study was to investigate the effects of ulinastatin on cerebral oxygen metabolism and C-reactive protein (CRP) levels in patients with severe traumatic brain injury (sTBI). A total of 92 patients with sTBI, admitted to the First Affiliated Hospital of Xinxiang Medical University (Xinxiang, China), were randomly divided into control and observation groups. The control group received conventional therapy plus a placebo (0.9% sodium chloride), while the observation group were administered conventional therapy plus 200,000 units ulinastatin via intravenous injection twice a day for seven days. Arterial and jugular venous blood was collected for blood gas analysis. The jugular venous blood lactate (JVBL), jugular venous bulb oxygen saturation (SjvO2), arteriovenous oxygen content difference (AVDO2) and cerebral extraction of oxygen (CEO2) levels were measured on day 1, 3, 5 and 7, as well as the level of CRP in the peripheral blood. In the control group, the level of JVBL decreased as compared with the level at day 1, however, no statistically significant differences were observed (P>0.05). By contrast, the observation group exhibited a significant reduction in the level of JVBL (P<0.05), which was also significantly lower compared with the control group (P<0.05). Statistically significant differences were observed between the two groups with regard to SjvO2, AVDO2 and CEO2 on day 3, 5 and 7. The CRP levels in the two groups increased and peaked on day 3. However, the CRP level in the observation group significantly decreased on day 5 (35.27±15.18 mg/l) and day 7 (22.65±10.48 mg/l), which was lower compared with the control group (56.19±13.24 mg/l and 47.36±15.73 mg/l, respectively); statistically significant differences were observed (P<0.05). Therefore, ulinastatin effectively improved cerebral oxygen metabolism and reduced the CRP level in patients with sTBI.

16.
Neural Regen Res ; 9(5): 519-25, 2014 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-25206849

RESUMEN

Previous studies show that transient axonal glycoprotein-1, a ligand of amyloid precursor protein, increases the secretion of amyloid precursor protein intracellular domain and is involved in apoptosis in Alzheimer's disease. In this study, we examined the effects of transient axonal glycoprotein-1 on U251 glioma cells. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that transient axonal glycoprotein-1 did not inhibit the proliferation of U251 cells, but promoted cell viability. The terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed that transient axonal glycoprotein-1 did not induce U251 cell apoptosis. Real-time PCR revealed that transient axonal glycoprotein-1 substantially upregulated levels of amyloid precursor protein intracellular C-terminal domain, and p53 and epidermal growth factor receptor mRNA expression. Thus, transient axonal glycoprotein-1 increased apoptosis-related gene expression in U251 cells without inducing apoptosis. Instead, transient axonal glycoprotein-1 promoted the proliferation of these glioma cells.

17.
Neurol Res ; 33(6): 563-71, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21708064

RESUMEN

OBJECTIVE: Functional neuroimaging techniques act as the navigator to assess changes in brain activity induced by repetitive transcranial magnetic stimulation (rTMS) in rTMS studies. The aim of this study was to investigate the feasibility of using manganese-enhanced magnetic resonance imaging (MEMRI) to measure the brain activity in rTMS studies. METHODS: Eighteen Wistar rats were randomized into three groups (n = 6) including a high rTMS group, a low rTMS group and a sham stimulation group (controls). They were given rTMS of 10 Hz, 1 Hz or sham stimulation for 5 hours separately. MEMRI was used to assess the changes of brain activity. RESULTS: Compared with the controls, image intensity was enhanced differently in various brain regions on T1-weighted images after rTMS with different frequencies, higher intensity and wider enhancement occurred in the high frequency rTMS group as compared with that in the low frequency rTMS group. CONCLUSION: MEMRI can be used to reveal the changes of brain activity in live rats following rTMS. SIGNIFICANCE: The current experiment might provide a new functional neuroimaging technique for the study of rTMS.


Asunto(s)
Encéfalo/fisiología , Medios de Contraste , Imagen por Resonancia Magnética/métodos , Manganeso , Actividad Motora/fisiología , Estimulación Magnética Transcraneal/métodos , Animales , Mapeo Encefálico/métodos , Medios de Contraste/análisis , Masculino , Manganeso/análisis , Ratas , Ratas Wistar
18.
Brain Imaging Behav ; 5(3): 181-8, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21637990

RESUMEN

This study further investigates the influence of temporarily disrupting the blood-brain barrier (BBB) on the level of manganese used in AIM fMRI other than the recognized function of allowing that substance to enter into the activated brain regions more effectively during the BBB opening. We injected manganese into Wistar rats through ICA following the disruption of BBB with mannitol in a functional MRI test of the visual cortex. Through comparing MRI signal intensity and manganese contents in the visual cortex of rats received visual stimuli of unequal degree after the restoration of BBB, we found that the signal in the visual cortex could be further enhanced on T1WI given visual stimulation after the restoration of BBB. Temporary BBB disruption has an additional advantage in allowing Mn(2+) to enter the CSF or brain for later transference to the activated brain area. So the dosage of manganese in AIM fMRI could be minimized by extending the stimulus.


Asunto(s)
Barrera Hematoencefálica/fisiología , Imagen por Resonancia Magnética/métodos , Manganeso/fisiología , Animales , Interpretación Estadística de Datos , Diuréticos/farmacología , Aumento de la Imagen , Procesamiento de Imagen Asistido por Computador , Masculino , Manganeso/líquido cefalorraquídeo , Manganeso/metabolismo , Manitol/farmacología , Estimulación Luminosa , Ratas , Ratas Wistar , Corteza Visual/fisiología , Campos Visuales
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