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Mounting evidence supports the role of neuroinflammation in radiation-induced brain injury (RIBI), a chronic disease characterized by delayed and progressive neurological impairment. Asparagine endopeptidase (AEP), also known as legumain (LGMN), participates in multiple malignancies and neurodegenerative diseases and may potentially be involved in RIBI. Here, we found AEP expression was substantially elevated in the cortex and hippocampus of wild-type (Lgmn+/+) mice following whole-brain irradiation. Lgmn knockout (Lgmn-/-) alleviated neurological impairment caused by whole-brain irradiation by suppressing neuronal senescence. Bulk RNA and metabolomic sequencing revealed AEP's involvement in the antigen processing and presentation pathway and neuroinflammation. This was further confirmed by co-culturing Lgmn+/+ primary neurons with the conditioned media derived from irradiated Lgmn+/+ or Lgmn-/- primary microglia. Furthermore, esomeprazole inhibited the enzymatic activity of AEP and RIBI. These findings identified AEP as a critical factor of neuroinflammation in RIBI, highlighting the prospect of targeting AEP as a therapeutic approach.
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INTRODUCTION: To explore and evaluate the performance of MRI-based brain tumor super-resolution generative adversarial network (MRBT-SR-GAN) for improving the MRI image resolution in brain tumors. METHODS: A total of 237 patients from December 2018 and April 2020 with T2-fluid attenuated inversion recovery (FLAIR) MR images (one image per patient) were included in the present research to form the super-resolution MR dataset. The MRBT-SR-GAN was modified from the enhanced super-resolution generative adversarial networks (ESRGAN) architecture, which could effectively recover high-resolution MRI images while retaining the quality of the images. The T2-FLAIR images from the brain tumor segmentation (BRATS) dataset were used to evaluate the performance of MRBT-SR-GAN contributed to the BRATS task. RESULTS: The super-resolution T2-FLAIR images yielded a 0.062 dice ratio improvement from 0.724 to 0.786 compared with the original low-resolution T2-FLAIR images, indicating the robustness of MRBT-SR-GAN in providing more substantial supervision for intensity consistency and texture recovery of the MRI images. The MRBT-SR-GAN was also modified and generalized to perform slice interpolation and other tasks. CONCLUSIONS: MRBT-SR-GAN exhibited great potential in the early detection and accurate evaluation of the recurrence and prognosis of brain tumors, which could be employed in brain tumor surgery planning and navigation. In addition, this technique renders precise radiotherapy possible. The design paradigm of the MRBT-SR-GAN neural network may be applied for medical image super-resolution in other diseases with different modalities as well.
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Neoplasias Encefálicas , Aprendizaje Profundo , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética/métodos , Redes Neurales de la Computación , Neoplasias Encefálicas/diagnóstico por imagenRESUMEN
LncRNA PVT1 has been implicated in numerous pathophysiological processes and diseases, especially cancers. However, the role and mechanism of PVT1 in the tumorigenesis of glioblastoma remain unclear. We investigated the alteration of PVT1 and its key functions in glioblastoma. PVT1 was upregulated and associated with poor prognosis in glioblastoma. We demonstrated that PVT1 silencing suppressed cell proliferation, colony formation, and orthotopic xenograft tumor growth. Mechanistic investigations found that PVT1 interacted with TRIM24 directly and increased its protein stability. PVT1 recruited COPS5 to deubiquitinate TRIM24; reciprocally, PVT1 depletion impaired the interaction between COPS5 and TRIM24, resulting in decreased expression of TRIM24. PVT1, TRIM24, and COPS5 coordinately contributed to the activation of STAT3 signaling and malignant phenotype of glioblastoma. Collectively, this study elucidates the essential role of PVT1 in the tumorigenesis of glioblastoma, which provides candidacy therapeutic target for glioblastoma treatment.
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Live stream services have emerged as a highly profitable Internet application in recent years with rapidly growing audiences for this form of instant and interactive Internet media. This study applies media richness theory along with uses and gratifications theory to predict user loyalty to live stream services. The proposed model is empirically evaluated using survey data collected from 295 users responding about their perception of such services. Empirical results show that perceived media richness and gratifications such as entertainment and sociability are antecedents of loyalty, while immediate feedback is the most salient facet of perceived media richness. The results provide further useful insights for service providers and streamers to build loyal user bases.
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Medios de Comunicación , Comportamiento del Consumidor , Internet , HumanosRESUMEN
BACKGROUND: Circular RNAs (circRNAs) are widely expressed non-coding RNAs in eukaryotic cells, involved in regulating tumorigenesis of several types of cancers. However, the expression profiles and the precise functional role in glioblastoma remain unclear. RESULTS: Circ-EPB41L5 was downregulated in glioblastoma tissues and cell lines compared to the normal brain tissues and cell lines. Low circ-EPB41L5 expression was correlated to the poor prognosis of glioblastoma patients, while the overexpression inhibited proliferation, clone formation, migration, and invasion abilities of glioma cells, and the suppression had counter effects. Furthermore, RNA-seq results determined that the host gene was the target gene of circ-EPB41L5, which served as a sponge against miR-19a and inhibited miR-19a activity from upregulating the expression of EPB41L5. Finally, we found that circ-EPB41L5 regulated the RhoC expression and phosphorylation of AKT through EPB41L5. CONCLUSION: The current study highlights a novel suppressive function of circ-EPB41L5 and reveals that circ-EPB41L5/miR-19a/EPB41L5/p-AKT regulatory axis plays a striking role in the progression of glioblastoma, which provides a novel insight into the mechanisms underlying glioblastoma. METHODS: The expression profiles of circRNAs in glioblastoma were determined by Illumina HiSeq from six glioblastoma tissues and six normal brain tissues. Then, the correlation between circ-EPB41L5 expression and clinical features and the survival time of 45 glioblastoma patients was detected. The interaction between circ-EPB41L5, miR-19a, and EPB41L5 was assessed by luciferase reporter and RNA pull-down assays. The effects of expression of the ectopic intervention of circ-EPB41L5 or EPB41L5 on proliferation, clone formation, migration, and invasion in vitro and tumorigenesis in vivo were observed to evaluate the function of circ-EPB41L5 or EPB41L5.
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Transformación Celular Neoplásica/genética , Regulación Neoplásica de la Expresión Génica , Glioblastoma/genética , Proteínas de la Membrana/genética , MicroARNs/genética , ARN Circular , Anciano , Anciano de 80 o más Años , Apoptosis/genética , Línea Celular Tumoral , Movimiento Celular , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Modelos Biológicos , Interferencia de ARN , Carga TumoralRESUMEN
BACKGROUND: Isocitrate dehydrogenase wild-type (WT) glioblastoma (GBM) accounts for 90% of all GBMs, yet only 27% of isocitrate dehydrogenase WT-GBMs have p53 mutations. However, the tumor surveillance function of WT-p53 in GBM is subverted by mechanisms that are not fully understood. METHODS: We investigated the proteolytic inactivation of WT-p53 by asparaginyl endopeptidase (AEP) and its effects on GBM progression in cancer cells, murine models, and patients' specimens using biochemical and functional assays. The sera of healthy donors (n = 48) and GBM patients (n = 20) were examined by enzyme-linked immunosorbent assay. Furthermore, effects of AEP inhibitors on GBM progression were evaluated in murine models (n = 6-8 per group). The statistical significance between groups was determined using two-tailed Student t tests. RESULTS: We demonstrate that AEP binds to and directly cleaves WT-p53, resulting in the inhibition of WT-p53-mediated tumor suppressor function in both tumor cells and stromal cells via extracellular vesicle communication. High expression of uncleavable p53-N311A-mutant rescue AEP-induced tumorigenesis, proliferation, and anti-apoptotic abilities. Knock down or pharmacological inhibition of AEP reduced tumorigenesis and prolonged survival in murine models. However, overexpression of AEP promoted tumorigenesis and shortened the survival time. Moreover, high AEP levels in GBM tissues were associated with a poor prognosis of GBM patients (n = 83; hazard ratio = 3.94, 95% confidence interval = 1.87 to 8.28; P < .001). A correlation was found between high plasma AEP levels and a larger tumor size in GBM patients (r = 0.6, P = .03), which decreased dramatically after surgery. CONCLUSIONS: Our results indicate that AEP promotes GBM progression via inactivation of WT-p53 and may serve as a prognostic and therapeutic target for GBM.
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Cisteína Endopeptidasas/metabolismo , Glioblastoma/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Línea Celular Tumoral , Inhibidores de Cisteína Proteinasa/farmacología , Progresión de la Enfermedad , Glioblastoma/enzimología , Glioblastoma/patología , Xenoinjertos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ratones , Ratones Transgénicos , Células del Estroma/enzimología , Células del Estroma/metabolismo , Células del Estroma/patologíaRESUMEN
BACKGROUND: Malignant glioma is one of the essentially incurable tumors with chemoresistance and tumor recurrence. As a histone methyltransferase, SUV39H2 can trimethylate H3K9. SUV39H2 is highly expressed in many types of human tumors, while the function of SUV39H2 in the development and progression of glioma has never been elucidated. METHODS: RT-qPCR and IHC were used to test SUV39H2 levels in glioma tissues and paired normal tissues. The clinical relevance of SUV39H2 in glioma was analyzed in a public database. Colony formation assays, CCK-8 assays, and flow cytometry were conducted to explore the role of SUV39H2 in the growth of glioma cells in vitro. A cell line-derived xenograft model was applied to explore SUV39H2's role in U251 cell proliferation in vivo. Sphere formation assays, RT-qPCR, flow cytometry, and IF were conducted to illustrate the role of SUV39H2 in the stemness and chemosensitivity of glioma. Luciferase reporter assays and WB were applied to determine the function of SUV39H2 in Hh signaling. RESULTS: SUV39H2 was highly expressed in glioma tissues relative to normal tissues. SUV39H2 knockdown inhibited cell proliferation and stemness and promoted the chemosensitivity of glioma cells in vitro. In addition, SUV39H2 knockdown also significantly inhibited glioma cell growth in vivo. Moreover, we further uncovered that SUV39H2 regulated hedgehog signaling by repressing HHIP expression. CONCLUSIONS: Our findings delineate the role of SUV39H2 in glioma cell growth and chemosensitivity as a pivotal regulator of the hedgehog signaling pathway and may support SUV39H2 as a potential target for diagnosis and therapy in glioma management.
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BACKGROUND: Circular RNAs (circRNAs), a newly discovered type of endogenous noncoding RNA, have been proposed to mediate the progression of diverse types of tumors. Systematic studies of circRNAs have just begun, and the physiological roles of circRNAs remain largely unknown. Here, we focused on elucidating the potential role and molecular mechanism of circular forkhead box O3 (circFOXO3) in glioblastoma (GBM) progression. METHODS: First, we analyzed circFOXO3 alterations in GBM and noncancerous tissues through real-time quantitative reverse transcription PCR (qRT-PCR). Next, we used loss- and gain-of-function approaches to evaluate the effect of circFOXO3 on GBM cell proliferation and invasion. Mechanistically, fluorescent in situ hybridization, RNA pull-down, dual luciferase reporter, and RNA immunoprecipitation assays were performed to confirm the interaction between circFOXO3 and miR-138-5p/miR-432-5p in GBM. An animal model was used to verify the in vitro experimental findings. RESULTS: CircFOXO3 expression was significantly higher in GBM tissues than in noncancerous tissues. GBM cell proliferation and invasion were reduced by circFOXO3 knockdown and enhanced by circFOXO3 overexpression. Further biochemical analysis showed that circFOXO3 exerted its pro-tumorigenic activity by acting as a competing endogenous RNA (ceRNA) to increase expression of nuclear factor of activated T cells 5 (NFAT5) via sponging both miR-138-5p and miR-432-5p. Notably, tumor inhibition by circFOXO3 downregulation could be reversed by miR-138-5p/miR-432-5p inhibitors in GBM cells. Moreover, GBM cells with lower circFOXO3 expression developed less aggressive tumors in vivo. CONCLUSIONS: Our data demonstrate that circFOXO3 can exert regulatory functions in GBM and that ceRNA-mediated microRNA sequestration might be a potential strategy for GBM therapy.
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Neoplasias Encefálicas/patología , Proteína Forkhead Box O3/genética , Regulación Neoplásica de la Expresión Génica/genética , Glioblastoma/patología , Factores de Transcripción/genética , Animales , Neoplasias Encefálicas/genética , ADN Circular/genética , Progresión de la Enfermedad , Glioblastoma/genética , Xenoinjertos , Humanos , Ratones , Ratones Desnudos , MicroARNs/genética , Factores de Transcripción/metabolismoRESUMEN
The current study used a rat middle cerebral artery occlusion (MCAO) model with the aim to explore the effects of compound porcine cerebroside and ganglioside injection (CPCGI) on brain ischemia/reperfusion injury in rats. Improvement in the infarctside microcirculation and the overall recovery of neurological function were detected by triphenyltetrazolium chloride staining, laser speckle blood flow monitoring, latex perfusion, immunofluorescence and immunoblotting. The results revealed that administration of CPCGI for 7 consecutive days following ischemic stroke contributed to the recovery of neurological function and the reduction of cerebral infarct volume in rats. Blood flow monitoring results demonstrated that the administration of CPCGI effectively promoted cerebral blood flow following stroke, and contributed to the protection of the ischemic side blood vessels. In addition, CPCGI treatment increased the numbers of new blood vessels in the peripheral ischemic region, and upregulated the expression levels of vascular endothelial growth factor, angiopoietin 1 and its receptor TEK receptor tyrosine kinase, fibroblast growth factor and Wnt signaling pathwayassociated proteins. Taken together, the present results indicated that CPCGI improved the blood circulation and neurological function following cerebral ischemia/reperfusion in rats.
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Cerebrósidos/uso terapéutico , Gangliósidos/uso terapéutico , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Daño por Reperfusión/tratamiento farmacológico , Animales , Encéfalo/irrigación sanguínea , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Cerebrósidos/administración & dosificación , Gangliósidos/administración & dosificación , Infarto de la Arteria Cerebral Media/fisiopatología , Inyecciones , Masculino , Fármacos Neuroprotectores/administración & dosificación , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/fisiopatologíaRESUMEN
The study reported a case of an intrasellar arachnoid cyst with visual disturbances as the main symptom. Arachnoid cyst is a common intracranial benign space-occupying lesion, but rarely seen in intrasellar region with less than 100 cases reported available in English language literature. Therefore, it is still controversial about the diagnosis and treatment of such patients. This article reviewed previous literature and discussed the differential diagnosis and surgical strategies of intrasellar arachnoid cyst in combination with our own case.
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Quistes Aracnoideos/diagnóstico , Diagnóstico Diferencial , Adulto , Quistes Aracnoideos/cirugía , Femenino , Humanos , Silla Turca/patologíaRESUMEN
Drug resistance induced by increasing intracellular levels of detoxifying agents for conventional platinum(II) drugs such as metallothioneins (MTs) and glutathione (GSH) are the major obstacles for widely used platinum-based chemotherapeutic cancer treatment. Here, we developed trans-geometry platinum (II) drugs with sterically hindered bulky ligands PyPt which is able to hind the GSH attack of platinum drug to overcome cisplatin resistance. Moreover, the PyPt can self-assemble with biodegradable copolymer mPEG-PGA into uniform nanoparticles with PyPt drugs in the polymeric core and PEG as the shell, further protecting PyPt from GSH detoxification to further slow the reaction rate with GSH in vivo. This strategy was developed to bring benefit of not only increasing the solubility of sterically hindered platinum drugs but also combating cisplatin resistance. The M(PyPt) exhibited environment controlled releasing of Pt in tumor micro-environment which prohibited the division of cancer cells. Furthermore, due to the increasing solubility of nanoparticle encapsulated PyPt, the cellular uptake and cytotoxicity of M(PyPt) against both cancer resistance cells was enhanced compared to the cisplatin and PyPt through evaluating with flow cytometry and MTT, respectively. Thus, it was concluded that the M(PyPt) was capable to successfully overcome the cisplatin resistance in the drug-resistant cell line, indicating its potential application in the treatment of clinical cancers with strong cisplatin resistance. Hence the M(PyPt) strategy may represent a promising novel drug delivery system for the local treatment of drug resistance cancer.
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Cisplatino , Sistemas de Liberación de Medicamentos/métodos , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Línea Celular , Cisplatino/química , Cisplatino/farmacocinética , Cisplatino/farmacología , Humanos , Neoplasias/metabolismo , Neoplasias/patologíaRESUMEN
Glioblastoma multiforme (GBM) has the highest mortality rate among patients with brain tumors, and radiotherapy forms an important part of its treatment. Thus, there is an urgent requirement to elucidate the mechanisms conferring GBM progression and radioresistance. In the present study, it was identified that antisense transcript of hypoxiainducible factor1α (AHIF) was significantly upregulated in GBM cancerous tissues, as well as in radioresistant GBM cells. The expression of AHIF was also upregulated in response to radiation. Knockdown of AHIF in GBM cells decreased viability and invasive capacities, and increased the proportion of apoptotic cells. By contrast, overexpression of AHIF in GBM cells increased viability and invasive capacities, and decreased the proportion of apoptotic cells. Furthermore, exosomes derived from AHIFknockdown GBM cells inhibited viability, invasion and radioresistance, whereas exosomes derived from AHIFoverexpressing GBM cells promoted viability, invasion and radioresistance. Further biochemical analysis identified that AHIF regulates factors associated with migration and angiogenesis in exosomes. To the best of our knowledge, the present study is the first to establish that AHIF promotes glioblastoma progression and radioresistance via exosomes, which suggests that AHIF is a potential therapeutic target for GBM.
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Neoplasias Encefálicas/metabolismo , Exosomas/genética , Glioblastoma/metabolismo , ARN Largo no Codificante/genética , Tolerancia a Radiación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Línea Celular Tumoral , Supervivencia Celular , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Glioblastoma/genética , Glioblastoma/radioterapia , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Regulación hacia Arriba , Adulto JovenRESUMEN
Circular RNAs (circRNAs) have been demonstrated to be involved in various biological processes. Nevertheless, the function of circRNAs in medulloblastoma (MB) is still unknown. The present study aimed to investigate the expression profiles of circRNAs and related mechanisms for regulating the proliferation and growth of tumor cells in MB. The expression profiles of circRNAs were screened from four normal cerebellum and four MB samples using a HiSeq Sequencer. Bioinformatic analysis was employed to predict the interaction between circRNAs and mRNAs in MB. Subsequently, the expression levels of eight differential circRNAs [circ-SKA3 (hsa_circ_0029696), circ-DTL (hsa_circ_0000179), circ-CRTAM, circ-MAP3K5 (hsa_circ_0006856), circ-RIMS1-1 (hsa_circ_0132250), circ-RIMS1-2 (hsa_circ_0076967), circ-FLT3-1 (hsa_circ_0100165), and circ-FLT3-2 (hsa_circ_0100168)] were validated using quantitative reverse transcription-polymerase chain reaction. Moreover, circ-SKA3 and circ-DTL were silenced using small interfering RNAs and their host genes were overexpressed to investigate their role in the pathogenesis of MB. A total of 33 circRNAs were found to be differentially expressed in MB tissues (fold change ≥ 2.0, FDR <0.05), of which three were upregulated and 30 were downregulated; six circRNAs were experimentally validated successfully. Upregulated circ-SKA3 and circ-DTL promoted the proliferation migration and invasion in vitro by regulating the expression of host genes. This novel study exploited the profiling of circRNAs in MB and demonstrated that circ-SKA3 and circ-DTL were crucial in the tumorigenesis and development of MB and might be considered as novel and potential biomarkers for the diagnosis and new targets for the intervention of MB.
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Neoplasias Cerebelosas/genética , Meduloblastoma/genética , ARN , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Neoplasias Cerebelosas/patología , Cerebelo/metabolismo , Regulación hacia Abajo , Humanos , Meduloblastoma/patología , ARN Circular , ARN Mensajero , Regulación hacia ArribaRESUMEN
Xenon (Xe), a noble gas, has promising neuroprotective properties with no proven adverse side-effects. We evaluated neuroprotective effects of Xe delivered by Xe-containing echogenic liposomes (Xe-ELIP) via ultrasound-controlled cerebral drug release on early brain injury following subarachnoid hemorrhage (SAH). The Xe-ELIP structure was evaluated by ultrasound imaging, electron microscopy and gas chromatography-mass spectroscopy. Animals were randomly divided into five groups: Sham, SAH, SAH treated with Xe-ELIP, empty ELIP, or Xe-saturated saline. Treatments were administrated intravenously in combination with ultrasound application over the common carotid artery to trigger Xe release from circulating Xe-ELIP. Hematoma development was graded by SAH scaling and quantitated by a colorimetric method. Neurological evaluation and motor behavioral tests were conducted for three days following SAH injury. Ultrasound imaging and electron microscopy demonstrated that Xe-ELIP have a unique two-compartment structure, which allows a two-stage Xe release profile. Xe-ELIP treatment effectively reduced bleeding, improved general neurological function, and alleviated motor function damage in association with reduced apoptotic neuronal death and decreased mortality. Xe-ELIP alleviated early SAH brain injury by inhibiting neuronal death and bleeding. This novel approach provides a noninvasive strategy of therapeutic gas delivery for SAH treatment.
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Lesiones Encefálicas/tratamiento farmacológico , Fármacos Neuroprotectores/administración & dosificación , Hemorragia Subaracnoidea/tratamiento farmacológico , Xenón/administración & dosificación , Administración Intravenosa , Animales , Lesiones Encefálicas/diagnóstico por imagen , Lesiones Encefálicas/etiología , Modelos Animales de Enfermedad , Liberación de Fármacos , Liposomas/administración & dosificación , Liposomas/química , Microscopía Electrónica de Transmisión , Fármacos Neuroprotectores/farmacocinética , Distribución Aleatoria , Ratas , Hemorragia Subaracnoidea/complicaciones , Hemorragia Subaracnoidea/diagnóstico por imagen , Ultrasonografía , Xenón/farmacocinéticaRESUMEN
Granulomatosis with polyangiitis (GPA) is a necrotizing granulomatous vasculitis occasionally affecting central nervous system (CNS), and GPA patients with initial CNS symptoms are even rarer, whose diagnosis is further confused by an absence of positive antineutrophil cytoplasmic antibody. The authors described the characteristics of antineutrophil cytoplasmic antibody -negative GPA with CNS onset in a patient and discussed on its management, which may contribute to future diagnosis and treatment of patients with similar conditions.
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Enfermedades del Sistema Nervioso Central , Granulomatosis con Poliangitis , Anticuerpos Anticitoplasma de Neutrófilos , HumanosRESUMEN
Hemorrhagerelated neurologic injury is a primary cause of disability and mortality following subarachnoid hemorrhage (SAH). The aim of the present study was to investigate the potential neuroprotective effect and the possible role of autophagy in limb remote ischemic postconditioning (RIPostC) using an endovascular puncture rat model of SAH. RIPostC was induced by three cycles of occlusion (10 min) and release (10 min) in the bilateral femoral artery using an aneurysm clip. Early RIPostC began immediately following SAH, delayed RIPostC began following a 30 min delay and the repeated RIPostC group underwent the protocol every day for 3 days. Brain water content, SAH grading, terminal deoxynucleotidyl transferase dUTP nick end labelingDAPI staining, transmission electron microscopy, and neurological and behavioral tests were conducted three days following surgery. Long term outcomes of behavior and memory were assessed using a rotarod test and Morris water maze test 1 month subsequently. Biomarkers of autophagy, including Beclin1 and light chain 3 (LC3), were assessed using western blotting. The results of the present study demonstrated that, compared with other groups, repeated RIPostC was able to alleviate brain edema, prevent neuronal apoptosis, and improve short term and long term neurological function and memory. Beclin1 and LC3 in the cortex were upregulated following treatment with repeated RIPostC. Autolysosomes increased 3 days following SAH and were maintained for 1 month in the repeated RIPostC group. Therefore, the present study indicated that the optimized repeated RIPostC may provide a noninvasive strategy to induce neuroprotection, and improve the short and long term outcomes of SAHrelated cerebral injury, possibly involving the autophagy pathway.
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Extremidades/irrigación sanguínea , Poscondicionamiento Isquémico , Hemorragia Subaracnoidea/patología , Hemorragia Subaracnoidea/rehabilitación , Animales , Apoptosis , Autofagia , Biomarcadores , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/ultraestructura , Edema Encefálico/metabolismo , Edema Encefálico/patología , Modelos Animales de Enfermedad , Poscondicionamiento Isquémico/métodos , Masculino , Actividad Motora , Neuroprotección , Ratas , Hemorragia Subaracnoidea/etiologíaRESUMEN
Early brain injury (EBI) following subarachnoid hemorrhage (SAH) is the main cause to poor outcomes of SAH patients, and early inflammation plays an important role in the acute pathophysiological events. It has been demonstrated that ethyl pyruvate (EP) has anti-inflammatory and neuroprotective effects in various critical diseases, however, the role of EP on EBI following SAH remains to be elucidated. Our study aimed to evaluate the effects of EP on EBI following SAH in the endovascular perforation rabbit model. All rabbits were randomly divided into three groups: sham, SAH + Vehicle (equal volume) and SAH + EP (30 mg/kg/day). MRI was performed to estimate the reliability of the EBI at 24 and 72 h after SAH. Neurological scores were recorded to evaluate the neurological deficit, ELISA kit was used to measure the level of tumor necrosis factor-α (TNF-α), and western blot was used to detect the expression of TNF-α, tJNK, pJNK, bax and bcl-2 at 24 and 72 h after SAH. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and Fluoro-jade B (FJB) staining were used to detect neuronal apoptosis and neurodegeneration respectively, meanwhile hematoxylin and eosin (H&E) staining was used to assess the degree of vasospasm. Our results demonstrated that EP alleviated brain tissue injury (characterized by diffusion weighted imaging and T2 sequence in MRI scan), and significantly improved neurological scores at 72 h after SAH. EP decreased the level of TNF-α and downregulated pJNK/tJNK and bax/bcl-2 in cerebral cortex and hippocampus effectively both at 24 and 72 h after SAH. Furthermore, EP reduced TUNEL and FJB positive cells significantly. In conclusion, the present study supported that EP afforded neuroprotective effects possibly via reducing TNF-α expression and inhibition of the JNK signaling pathway. Therefore, EP may be a potent therapeutic agent to attenuate EBI following SAH.
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Antiinflamatorios/uso terapéutico , Lesiones Encefálicas/prevención & control , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Piruvatos/uso terapéutico , Hemorragia Subaracnoidea/tratamiento farmacológico , Animales , Antiinflamatorios/farmacología , Lesiones Encefálicas/diagnóstico por imagen , Lesiones Encefálicas/metabolismo , Procedimientos Endovasculares/efectos adversos , Sistema de Señalización de MAP Quinasas/fisiología , Imagen por Resonancia Magnética/métodos , Masculino , Piruvatos/farmacología , Conejos , Distribución Aleatoria , Hemorragia Subaracnoidea/diagnóstico por imagen , Hemorragia Subaracnoidea/metabolismoRESUMEN
Ischemic postconditioning, including early and delayed ischemic postconditioning, has been recognized as a simple and promising strategy in the treatment of stroke. However, the effects of the combination of early and delayed ischemic postconditioning, and the mechanisms underlying these effects, remain unclear. The aim of the present study was to determine whether the combination of early and delayed ischemic postconditioning offers greater protection against stroke, and enhances the production of brainderived neurotrophic factor (BDNF). A combination of early and delayed ischemic postconditioning was established by repeated, transient occlusion and reperfusion of the ipsilateral common carotid artery in a rat model of middle cerebral artery occlusion. Infarct size, motor function, cerebral blood flow and brain edema were then evaluated, in order to confirm the effects of combinative ischemic postconditioning. TUNEL staining was used to analyze the rate of apoptosis of cells in the penumbral area. BDNF, extracellular signalregulated kinases 1/2 (ERK1/2) and cAMP response elementbinding protein (CREB) expression was detected using immunofluorescence staining and western blot analysis. The results of the present study indicated that the combination of early and delayed ischemic postconditioning further reduced the infarct volume, stabilized cerebral blood disturbance and attenuated neuronal apoptosis, compared with either alone. However, combinative postconditioning exerted the same effect on neurological function and brain edema, compared with early or delayed ischemic postconditioning alone. Further investigation indicated that combinative ischemic postconditioning increased the expression of BDNF, and a significantly higher number of BDNFpositive cells was observed in neurons and astrocytes from the combined group than in the early or delayed groups. Combinative ischemic postconditioning also induced the phosphorylation of ERK1/2 and CREB in the cortex, following focal ischemia. The results of the present study suggest that the combination of early and delayed ischemic postconditioning may further reduce brain ischemic reperfusion injury following focal ischemia, compared with either treatment alone. In addition, it induces the production of BDNF in neurons and astrocytes. Furthermore, the effects of combinative ischemic postconditioning may be mediated by the activation of ERK1/2 and CREB.
Asunto(s)
Edema Encefálico/genética , Isquemia Encefálica/genética , Factor Neurotrófico Derivado del Encéfalo/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/genética , Accidente Cerebrovascular/genética , Animales , Apoptosis , Astrocitos/metabolismo , Astrocitos/patología , Edema Encefálico/etiología , Edema Encefálico/patología , Edema Encefálico/terapia , Isquemia Encefálica/etiología , Isquemia Encefálica/patología , Isquemia Encefálica/terapia , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Regulación de la Expresión Génica , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/cirugía , Poscondicionamiento Isquémico/métodos , Sistema de Señalización de MAP Quinasas , Masculino , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Neuronas/metabolismo , Neuronas/patología , Ratas , Ratas Sprague-Dawley , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/terapia , Factores de TiempoRESUMEN
AIM: Human pituitary adenomas account for 10% of intracranial tumours and occur in about 20% of the population. They cause hypopituitarism or the compression of adjacent regional structures. However, little is known about the molecular pathogenesis that contributes to the development of these tumours. MATERIAL AND METHODS: In this study, we investigated the relationship between the expression level of folate receptor alpha and some clinical factors (endocrine, age, gender, repeated operation or not, mean diameter of tumour and invasiveness) of pituitary adenomas. Realtime fluorescent quantitative reverse transcriptase polymerase chain reaction was used to determine the expression of folate receptor alpha mRNA in pituitary adenomas and normal pituitaries. Folate receptor alpha protein levels were quantified using Western blot analysis and Immunohistochemistry. RESULTS: We found folate receptor alpha mRNA and protein were significantly upregulated in clinically nonfunctional pituitary adenomas compared to functional tumours. For nonfunctional tumours, folate receptor alpha expression was much higher in the invasive group than in non-invasive group. CONCLUSION: These results suggest that the overexpression of folate receptor alpha mRNA and protein by nonfunctional pituitary adenomas may facilitate the growth of these tumours. Potentially, this finding could be exploited to develop innovative molecular targeted diagnosis and treatment for human nonfunctional pituitary adenomas.
Asunto(s)
Adenoma/metabolismo , Biomarcadores de Tumor/biosíntesis , Receptor 1 de Folato/biosíntesis , Regulación Neoplásica de la Expresión Génica , Neoplasias Hipofisarias/metabolismo , ARN Mensajero/biosíntesis , Adenoma/patología , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Hipófisis/metabolismo , Neoplasias Hipofisarias/patologíaRESUMEN
Hypothermia treatment is a promising therapeutic strategy for brain injury. We previously demonstrated that 5'-adenosine monophosphate (5'-AMP), a ribonucleic acid nucleotide, produces reversible deep hypothermia in rats when the ambient temperature is appropriately controlled. Thus, we hypothesized that 5'-AMP-induced hypothermia (AIH) may attenuate brain ischemia/reperfusion injury. Transient cerebral ischemia was induced by using the middle cerebral artery occlusion (MCAO) model in rats. Rats that underwent AIH treatment exhibited a significant reduction in neutrophil elastase infiltration into neuronal cells and matrix metalloproteinase 9 (MMP-9), interleukin-1 receptor (IL-1R), tumor necrosis factor receptor (TNFR), and Toll-like receptor (TLR) protein expression in the infarcted area compared to euthermic controls. AIH treatment also decreased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling- (TUNEL-) positive neuronal cells. The overall infarct volume was significantly smaller in AIH-treated rats, and neurological function was improved. By contrast, rats with ischemic brain injury that were administered 5'-AMP without inducing hypothermia had ischemia/reperfusion injuries similar to those in euthermic controls. Thus, the neuroprotective effects of AIH were primarily related to hypothermia.