RESUMEN
Synaptic dysfunction plays a crucial role in the pathogenesis of Alzheimer's disease (AD). α/ß-hydrolase domain-containing 6 (ABHD6) contributes to synaptic dysfunctions, and ABHD6 inhibition has shown potential therapeutic value in neurological disorders. However, the role of ABHD6 in AD has not been fully defined. In this study, we demonstrated that adeno-associated virus (AAV) mediated shRNA targeting ABHD6 in hippocampal neurons attenuated synaptic dysfunction and memory impairment of APPswe/PS1dE9 (APP/PS1) mice, while it didn't affect the amyloid-beta (Aß) levels and neuroinflammation in the brains. In addition, intraperitoneal injection of wwl70, a specific inhibitor of ABHD6, improved synaptic plasticity and memory function in APP/PS1 mice, which might attribute to the activation of endogenous cannabinoid signaling. Furthermore, wwl70 significantly decreased the Aß levels and neuroinflammation in the hippocampus of AD mice, and enhanced Aß phagocytized by microglia. In conclusion, for the first time our data have shown that ABHD6 inhibition might be a promising strategy for AD treatment, and wwl70 is a potential candidate for AD drug development pipeline.
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Enfermedad de Alzheimer , Hidrolasas , Animales , Ratones , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides , Precursor de Proteína beta-Amiloide , Modelos Animales de Enfermedad , Trastornos de la Memoria/tratamiento farmacológico , Ratones Transgénicos , Monoacilglicerol Lipasas , Enfermedades NeuroinflamatoriasRESUMEN
Glioma is one of the most common malignancies. De novo serine synthesis promotes glioma progression and therapeutic resistance. Therefore, clarifying the regulatory mechanism of serine synthesis is of great significance for glioma therapy. In this study, we found that the expression of TFCP2 was upregulated in glioma and that TFCP2 promoted glioma cell growth and sphere formation. Knockdown of TFCP2 expression inhibited glioma cell growth, sphere formation and tumorigenicity in nude mice. In terms of its molecular mechanism, TFCP2 was found to interact with ATF3 to cooperatively regulate the de novo synthesis of serine. Knockdown of TFCP2 expression significantly inhibited the binding of ATF3 to the promoter of PHGDH (a rate-limiting enzyme in the serine synthesis process). In conclusion, our studies proved that TFCP2 jointly regulates the de novo synthesis of serine through interaction with ATF3, thus promoting glioma progression. This study suggests that TFCP2 is a potential target for glioma therapy.
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Glioma , Serina , Animales , Proteínas Portadoras , Línea Celular Tumoral , Proteínas de Unión al ADN , Glioma/genética , Ratones , Ratones Desnudos , Serina/metabolismo , Factores de Transcripción/metabolismoRESUMEN
ABSTRACT: Chordoid glioma is a rare low-grade tumor that originates almost exclusively in the anterior part of the third ventricle. The diagnosis and treatment of the tumor remain controversial. In this article, the authors present a novel case of chordoid glioma of the third ventricle. The patient was treated with less invasive microsurgery followed by low-dose gamma knife radiosurgery. Magnetic resonance imaging revealed a decrease in tumor size and necrosis in the central region of the tumor, without significant complications at follow-up 14 months later. Based on these findings, the authors suggest that less invasive microsurgical resection followed by low-dose gamma knife radiosurgery is safe and effective for the treatment of chordoid glioma of the third ventricle.
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Neoplasias del Ventrículo Cerebral , Glioma , Radiocirugia , Tercer Ventrículo , Neoplasias del Ventrículo Cerebral/diagnóstico por imagen , Neoplasias del Ventrículo Cerebral/cirugía , Glioma/diagnóstico por imagen , Glioma/cirugía , Humanos , Imagen por Resonancia Magnética , Tercer Ventrículo/diagnóstico por imagen , Tercer Ventrículo/cirugíaRESUMEN
Increasing evidence has validated the essential regulation of long non-coding RNAs (lncRNAs) in the biological process of tumours. LncRNA PXN-AS1 has been discovered to be as a tumour suppressor in pancreatic cancer; however, its function and mechanism remain greatly unknown in glioblastoma (GBM). Our present study indicated that PXN-AS1 was highly expressed in GBM tissues and cells. Besides, the knock-down of PXN-AS1 was closely associated with the inhibitory proliferation and inducing apoptosis of GBM cells. PXN-AS1 inhibition was also found to restrain GBM tumour growth. Importantly, SOX9 functioned as a transcription factor and activated PXN-AS1 expression, and overexpressed PXN-AS1 rescued the inhibitory role of down-regulated SOX9 in GBM cell growth. Subsequently, it was discovered that PXN-AS1 activated Wnt/ß-catenin pathway. DKK1 was widely known as an inhibitor gene of Wnt/ß-catenin pathway, and its expression was negatively associated with PXN-AS1 and SOX9. Interestingly, we found that PXN-AS1 could recruit EZH2 to mediate the H3K27me3 level of DKK1 promoter. Restoration experiments manifested that DKK1 knock-down counteracted PXN-AS1 depletion-mediated repression in GBM cell growth. All facts pointed out that PXN-AS1 might be of importance in exploring the therapeutic strategies of GBM.
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Neoplasias Encefálicas/genética , Carcinogénesis/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Glioblastoma/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , ARN Largo no Codificante/metabolismo , Factor de Transcripción SOX9/metabolismo , Animales , Apoptosis/genética , Secuencia de Bases , Neoplasias Encefálicas/patología , Carcinogénesis/patología , Línea Celular Tumoral , Proliferación Celular/genética , Progresión de la Enfermedad , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Glioblastoma/patología , Humanos , Masculino , Metilación , Ratones Endogámicos BALB C , Regiones Promotoras Genéticas/genética , ARN Largo no Codificante/genética , Vía de Señalización Wnt/genéticaRESUMEN
Aberrant PDGF-PDGFR signaling and its effects on downstream effectors have been implicated in glioma development. A crucial AKT regulator, ACK1 (TNK2) has been shown to be a downstream mediator of PDGF signaling; however, the exact underlying mechanisms in gliomas remain elusive. Here, we report that in glioma cells, PDGFR-ß activation enhanced the interaction between ACK1 and AKT, resulting in AKT activation. PDGF treatment consistently promoted the formation of complexes containing PDGFR-ß and ACK1. Mutational analysis suggested that Y635 of ACK1 is a PDGFR-ß phosphorylation site and that the ACK1 Y635F mutant abrogated the sequential activation of AKT. Moreover, PDK1 interacted with ACK1 during PDGF stimulation, which is required for the binding of ACK1 to PDGFR-ß. Further mutational analysis showed that T325 of ACK1 was crucial for the ACK1 and PDK1 interaction. ACK1 Y635F or T325A mutants abolished PDGFR-ß-induced AKT activation, the subsequent nuclear translocation of ß-catenin and the expression of cyclin D1. Glioma cell cycle progression, proliferation and tumorigenesis were accordingly blocked by ACK1 Y635F or T325A. In glioblastoma multiforme samples from 51 patients, increased ACK1 tyrosine phosphorylation correlated with upregulated PDGFR-ß activity and AKT activation. Taken together, our data demonstrate that ACK1 plays a pivotal role in PDGF-PDGFR-induced AKT signaling in glioma tumorigenesis. This knowledge contributes to our understanding of glioma progression and may facilitate the identification of novel therapeutic targets for future glioma treatment.
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Carcinogénesis/genética , Glioblastoma/genética , Glioblastoma/patología , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Transducción de Señal/genética , Carcinogénesis/patología , Ciclo Celular/genética , Línea Celular , Línea Celular Tumoral , Proliferación Celular/genética , Ciclina D1/genética , Ciclina D1/metabolismo , Glioblastoma/metabolismo , Células HEK293 , Humanos , Fosforilación/genética , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Regulación hacia Arriba/genética , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
Glioblastoma multiforme (GBM) is notoriously resistant to radiation, and consequently, new radiosensitizers are urgently needed. MicroRNAs are a class of endogenous gene modulators with emerging roles in DNA repair. We found that overexpression of miR-26a can enhance radiosensitivity and reduce the DNA repair ability of U87 cells. However, knockdown miR-26a in U87 cells could act the converse manner. Mechanistically, this effect is mediated by direct targeting of miR-26a to the 3'UTR of ATM, which leads to reduced ATM levels and consequent inhibition of the homologous recombination repair pathway. These results suggest that miR-26a may act as a new radiosensitizer of GBM.
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Proteínas de la Ataxia Telangiectasia Mutada/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Glioblastoma/genética , Glioblastoma/radioterapia , MicroARNs/fisiología , Tolerancia a Radiación/genética , Animales , Reparación del ADN/genética , Reparación del ADN/efectos de la radiación , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Marcación de Gen , Humanos , Ratones , Ratones Desnudos , MicroARNs/antagonistas & inhibidores , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cerebral venous sinus thrombosis (CVST) rarely induces cerebral hemorrhage, and CVST with cerebral hemorrhage during early pregnancy is extremely rare. Upon literature review, we are able to find only one case of CVST with cerebral hemorrhage in early pregnancy. In this paper, we report another case of a 27-year-old patient who developed CVST with cerebral hemorrhage in her fifth week of pregnancy. Although the optimal treatment for this infrequent condition remains controversial, we adopted anticoagulation as the first choice of treatment and obtained favorable results.
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Anticoagulantes/uso terapéutico , Encéfalo/irrigación sanguínea , Hemorragia Cerebral/tratamiento farmacológico , Complicaciones del Embarazo/tratamiento farmacológico , Trombosis de los Senos Intracraneales/tratamiento farmacológico , Adulto , Hemorragia Cerebral/complicaciones , Hemorragia Cerebral/diagnóstico , Femenino , Humanos , Embarazo , Trombosis de los Senos Intracraneales/complicaciones , Trombosis de los Senos Intracraneales/diagnóstico , Tomografía Computarizada por Rayos X/métodos , Resultado del TratamientoRESUMEN
Intracranial dolichoectasia is an angiopathy characterized by dilation, elongation, and tortuosity of the cerebral arteries. It most frequently involves the vertebrobasilar arteries and carotid arteries, whereas a more peripheral location involving the anterior and the middle cerebral arteries (MCAs) is less frequent. We present a male patient with MCA dolichoectasia with radiologic follow-up for 3 years, and no ischemia or intracranial bleeding occurred after the antiplatelet therapy. From the reported case series of MCA dolichoectasia, we suggest that surgical procedure should not be adopted unless accompanied by aneurysm located at dolichoectatic MCA. Moreover, anticoagulation or antiplatelet therapy could be a good treatment of option to prevent ischemic events.
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Enfermedades Arteriales Cerebrales/diagnóstico por imagen , Arteria Cerebral Media/diagnóstico por imagen , Adulto , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Angiografía Cerebral/métodos , Dilatación Patológica/diagnóstico por imagen , Estudios de Seguimiento , Humanos , Masculino , Arteria Cerebral Media/patologíaRESUMEN
Bromocriptine has been the most widely used and effective agent to treat macroprolactinoma, and chiasmal herniation in a macroprolactinoma patient following the treatment with bromocriptine is a well-recognized complication. However, herniation of the inferior mesial frontal lobe into the sella has been rarely reported. The present clinical report is the second radiographic demonstration of herniation of the inferior mesial frontal lobe into the sella. After the treatment with transsphenoidal endoscopic chiasmopexy, the patient's visual disturbance improved dramatically. We suggest that transsphenoidal endoscopic chiasmopexy is an effective treatment option for the prolactinoma patient with brain and chiasmal herniations following the treatment with bromocriptine.
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Hernia/etiología , Herniorrafia/métodos , Procedimientos Neuroquirúrgicos/métodos , Quiasma Óptico/cirugía , Prolactinoma/tratamiento farmacológico , Silla Turca , Bromocriptina/efectos adversos , Agonistas de Dopamina/efectos adversos , Endoscopía/métodos , Femenino , Humanos , Neoplasias Hipofisarias/cirugía , Hueso Esfenoides/cirugía , Resultado del Tratamiento , Adulto JovenRESUMEN
This paper presents three methods aimed at enhancing the flashover voltage of the supporting insulator in a Tesla transformer. These methods include optimizing the maximum electric field on the insulator surface, adjusting the overall structure of the insulator, and changing the surface structure of the insulator. Ten insulator samples with different structures were designed based on electric field simulation. Subsequent experiments were conducted to validate the effectiveness of these methods in improving flashover voltage. On this basis, the supporting insulator of the Tesla transformer was redesigned, leading to an increased output voltage. The results are summarized in the following. First, optimization of the shielding rings of the cathode and anode reduces the electric field at the triple junction, which significantly increases the flashover voltage. Second, extending the inclination starting position of insulators with the same inclination angle effectively reduces the surface electric field intensity and increases the flashover voltage. Third, increasing the inclination angle within a certain range while keeping the inclination starting position constant extends the creepage distance and enhances the flashover voltage. However, excessively large inclination angles may lead to a decrease in flashover voltage due to excessive normal electric field. Fourth, grooving on the insulator surface at appropriate locations can inhibit the development of the streamer and improve flashover voltage. Finally, the supporting insulator of the Tesla transformer was redesigned based on these results, elevating the output voltage from 750 kV to over 1 MV.
RESUMEN
Glioma remains one of the most challenging primary brain malignancies to treat. Long noncoding RNAs (lncRNAs) and mRNAs (mRNAs) are implicated in regulating the malignant phenotypes of cancers including glioma. This study aimed to elucidate the functions and mechanisms of lncRNA LINC00265 and mRNA IFI30 in the pathogenesis of glioma. Quantitative real-time polymerase chain reaction (RT-qPCR) analysis revealed the upregulated expression of LINC00265 and IFI30 in glioma cells compared to normal human astrocytes. Western blot (WB) quantified the associated proteins. Glioma stemness and epithelial-to-mesenchymal transition (EMT) were assessed by aldehyde dehydrogenase 1 (ALDH1) activity, sphere formation, and WB. Mechanistic and rescue assays evaluated the LINC00265/miR-let-7d-5p/IFI30/ZNF384/IGF2BP2 axis. The results demonstrated that LINC00265 and IFI30 were highly expressed in glioma cells, promoting stemness and EMT. ZNF384 was identified as a transcription factor that upregulates IFI30. Moreover, LINC00265 elevated ZNF384 by sponging miR-let-7d-5p and recruiting IGF2BP2. In conclusion, LINC00265 and IFI30 act as oncogenes in glioma by driving stemness and EMT, underscoring their potential as therapeutic targets.
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Neoplasias Encefálicas , Glioma , MicroARNs , Humanos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Glioma/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Transactivadores/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , ARN no Traducido/genéticaRESUMEN
AIMS: Excessive neuroinflammation mediated mainly by microglia plays a crucial role in ischemic stroke. AZD1390, an ataxia telangiectasia mutated (ATM) specific inhibitor, has been shown to promote radio-sensitization and survival in central nervous system malignancies, while the role of AZD1390 in ischemic stroke remains unknown. METHODS: Real-time PCR, western blot, immunofluorescence staining, flow cytometry and enzyme-linked immunosorbent assays were used to assess the activation of microglia and the release of inflammatory cytokines. Behavioral tests were performed to measure neurological deficits. 2,3,5-Triphenyltetrazolium chloride staining was conducted to assess the infarct volume. The activation of NF-κB signaling pathway was explored through immunofluorescence staining, western blot, co-immunoprecipitation and proximity ligation assay. RESULTS: The level of pro-inflammation cytokines and activation of NF-κB signaling pathway was suppressed by AZD1390 in vitro and in vivo. The behavior deficits and infarct size were partially restored with AZD1390 treatment in experimental stroke. AZD1390 restrict ubiquitylation and sumoylation of the essential regulatory subunit of NF-κB (NEMO) in an ATM-dependent and ATM-independent way respectively, which reduced the activation of the NF-κB pathway. CONCLUSION: AZD1390 suppressed NF-κB signaling pathway to alleviate ischemic brain injury in experimental stroke, and attenuated microglia activation and neuroinflammation, which indicated that AZD1390 might be an attractive agent for the treatment of ischemic stroke.
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Microglía , Enfermedades Neuroinflamatorias , Piridinas , Quinolonas , Animales , Microglía/efectos de los fármacos , Microglía/metabolismo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , FN-kappa B/metabolismo , FN-kappa B/antagonistas & inhibidores , Citocinas/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
The c-Myc oncogene is amplified in many tumor types. It is an important regulator of cell proliferation and has been linked to altered miRNA expression, suggesting that c-Myc-regulated miRNAs might contribute to tumor progression. Although miR-26a has been reported to be upregulated in glioblastoma multiforme (GBM), the mechanism has not been established. We have shown that ectopic expression of miR-26a influenced cell proliferation by targeting PTEN, a tumor suppressor gene that is inactivated in many common malignancies, including GBM. Our findings suggest that c-Myc modulates genes associated with oncogenesis in GBM through deregulation of miRNAs via the c-Myc-miR-26a-PTEN signaling pathway. This may be of clinical relevance.
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Neoplasias Encefálicas/genética , Glioblastoma/genética , MicroARNs/genética , Fosfohidrolasa PTEN/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Regulación hacia Arriba/genética , Regiones no Traducidas 3'/genética , Secuencia de Bases , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Glioblastoma/patología , Humanos , MicroARNs/metabolismo , Datos de Secuencia Molecular , Fosfohidrolasa PTEN/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/genéticaRESUMEN
Glioma is one of the most common solid tumors, and the molecular mechanism for this disease is poorly understood. EphB4 tyrosine kinase receptor has been involved in various physiologic and pathologic processes, and the role of EphB4 in tumorigenesis has recently attracted much interest. However, its function in glioma remains largely unknown. In this study, we explored the function of EphB4 in glioma. We found that the expression of EphB4 was significantly upregulated in clinical glioma samples. Overexpression of EphB4 in glioma cell lines accelerated cell growth and tumorigenesis. In contrast, downregulation of EphB4 inhibited cell growth. Furthermore, we showed that EphB4 promoted cell growth by promoting EGFR signaling. Taken together, our findings suggest that EphB4 plays an important role in the progression of glioma by stimulating cell growth and EphB4 might be a potential therapeutic target for glioma.
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Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Glioma/metabolismo , Glioma/patología , Receptor EphB4/metabolismo , Neoplasias Encefálicas/genética , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Receptores ErbB/metabolismo , Regulación Neoplásica de la Expresión Génica , Glioma/genética , Humanos , Interferencia de ARN , ARN Interferente Pequeño , Receptor EphB4/biosíntesis , Transducción de Señal , Regulación hacia ArribaRESUMEN
Experience is an important point in the effectiveness of the surgical procedure and in the reduction of complications in pituitary surgery. Endoscopic pituitary surgery differs from microscopic surgery because it requires a steep learning curve for endoscopic skills. In this study, we investigated the learning curve of endoscopic transsphenoidal pituitary surgery in our department. Endoscopic transsphenoidal operations were performed on 80 patients, who were retrospectively examined and grouped as the early and late experience groups to evaluate the learning curve. The patients' characteristics, gross total resection, endocrinological cure, visual field improvement, duration of surgery, postoperative hospital stay, and complications were noted. After examining our patients of the 2 groups of period, our experience showed that as the effectiveness of endoscopic surgery increases, the duration of surgery and postoperative hospital stay decrease. In this study, we identified a learning curve in endoscopic pituitary surgery.
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Adenoma/cirugía , Endoscopía/educación , Curva de Aprendizaje , Neurocirugia/educación , Neoplasias Hipofisarias/cirugía , Seno Esfenoidal/cirugía , Adulto , Anciano , Femenino , Humanos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
As a sustainable, clean, and friendly technology with a minimal carbon footprint when treating seawater or wastewater, interfacial solar vapor generation (ISVG) technology is a great alternative to traditional desalination and water purification methods (e.g., reverse osmosis and ultrafiltration). So far, it presents tremendous potential for applications in realizing desalination of seawater or brine, wastewater treatment, and so forth. However, the precipitated salt particles during conventional ISVG inevitably block the evaporator surface, resulting in the degradation of photothermal conversion and decrease of evaporation rate. Herein, a multi-functional non-contact Janus hollow evaporator based on copper foam was prepared, which was assembled by a hydrophobic light-to-heat conversion layer and a hydrophilic interfacial water evaporation layer as two separate parts. Accordingly, the precipitated salt in the ISVG system does not block the photothermal interface, increasing the stability of solar capture and reusability of the evaporator. Notably, the hollow structure of the evaporator has a local interfacial heating effect, endowing the evaporation system with a high seawater evaporation rate of 2.249 kg m-2 h-1. The evaporator is capable of stable operation for 10 h under 1 sun illumination even when evaporating concentrated brine (15 wt %). Moreover, the evaporation rate of water under one sun irradiation reached 2.284 kg m-2 h-1 and the solar-to-vapor efficiency reached 96.6%. Not only that, the evaporator was able to successfully purify wastewater containing dyes and heavy metal ions. The multi-functional Janus hollow interfacial solar evaporator will provide inspiration for upcoming research on the production of safety water.
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AIMS: Oxygen therapy plays a vital role in the development of bronchopulmonary dysplasia (BPD), which is the independent risk factor for neurodevelopment deficits in premature infants. However, the effect of hippocampal cyclin-dependent kinase 5 (CDK5) on BPD-associated neurodevelopment deficits is not fully understood. METHODS: Mice were placed in a hyperoxia chamber from postnatal Day 1 to Day 7. Hematoxylin and eosin staining was used to evaluate the lung histomorphological characteristics. Learning and memory functions of mice were detected by Morris water maze. TUNEL staining was applied to measure the number of apoptotic cells. The expression of CDK5, apoptosis-related protein, and neuroplasticity-related proteins were analyzed by Western blot. Golgi staining was used to assess the structure of dendritic spines. RESULTS: Hyperoxia-induced BPD mice showed a long-term learning and memory dysfunction, more severe neuronal apoptosis, and a decline of synaptic plasticity. Inhibition of CDK5 overactivation ameliorated cognitive deficits, neuronal apoptosis, and synaptic plasticity disorders in BPD mice. CONCLUSIONS: This study first found a vital role of CDK5 in BPD-associated neurodevelopmental disorders. Inhibition of CDK5 overexpression could effectively improve cognitive dysfunctions in BPD mice, which indicated that hippocampal CDK5 may be a new target for prevention and treatment in learning and memory dysfunction of BPD.
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Displasia Broncopulmonar , Quinasa 5 Dependiente de la Ciclina , Hiperoxia , Animales , Ratones , Displasia Broncopulmonar/tratamiento farmacológico , Displasia Broncopulmonar/complicaciones , Quinasa 5 Dependiente de la Ciclina/metabolismo , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Hiperoxia/complicaciones , Hiperoxia/metabolismo , Aprendizaje , Trastornos de la MemoriaRESUMEN
Synaptic plasticity impairment plays a critical role in the pathogenesis of Alzheimer's disease (AD), and emerging evidence has shown that microRNAs (miRs) are alternative biomarkers and therapeutic targets for synaptic dysfunctions in AD. In this study, we found that the level of miR-431 was downregulated in the plasma of patients with amnestic mild cognitive impairment and AD. In addition, it was decreased in the hippocampus and plasma of APPswe/PS1dE9 (APP/PS1) mice. Lentivirus-mediated miR-431 overexpression in the hippocampus CA1 ameliorated synaptic plasticity and memory deficits of APP/PS1 mice, while it did not affect amyloid-ß levels. Smad4 was identified as a target of miR-431, and Smad4 knockdown modulated the expression of synaptic proteins, including SAP102, and protected against synaptic plasticity and memory dysfunctions in APP/PS1 mice. Furthermore, Smad4 overexpression reversed the protective effects of miR-431, indicating that miR-431 attenuated synaptic impairment at least partially by Smad4 inhibition. Thus, these results indicated that miR-431/Smad4 might be a potential therapeutic target for AD treatment.
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Enfermedad de Alzheimer , MicroARNs , Ratones , Animales , Ratones Transgénicos , Enfermedad de Alzheimer/tratamiento farmacológico , MicroARNs/metabolismo , Plasticidad Neuronal/genética , Trastornos de la Memoria/genéticaRESUMEN
Oxygen and nutrient deprivation are common features of solid tumors. Although abnormal alternative splicing (AS) has been found to be an important driving force in tumor pathogenesis and progression, the regulatory mechanisms of AS that underly the adaptation of cancer cells to harsh microenvironments remain unclear. Here, we found that hypoxia- and nutrient deprivation-induced asparagine endopeptidase (AEP) specifically cleaved DDX3X in a HIF1A-dependent manner. This cleavage yields truncated carboxyl-terminal DDX3X (tDDX3X-C), which translocates and aggregates in the nucleus. Unlike intact DDX3X, nuclear tDDX3X-C complexes with an array of splicing factors and induces AS events of many pre-mRNAs; for example, enhanced exon skipping (ES) in exon 2 of the classic tumor suppressor PRDM2 leads to a frameshift mutation of PRDM2. Intriguingly, the isoform ARRB1-Δexon 13 binds to glycolytic enzymes and regulates glycolysis. By utilizing in vitro assays, glioblastoma organoids, and animal models, we revealed that AEP/tDDX3X-C promoted tumor malignancy via these isoforms. More importantly, high AEP/tDDX3X-C/ARRB1-Δexon 13 in cancerous tissues was tightly associated with poor patient prognosis. Overall, our discovery of the effect of AEP-cleaved DDX3X switching on alternative RNA splicing events identifies a mechanism in which cancer cells adapt to oxygen and nutrient shortages and provides potential diagnostic and/or therapeutic targets.
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Empalme Alternativo , Glioblastoma , Animales , Humanos , ARN Helicasas DEAD-box/genética , ARN Helicasas DEAD-box/metabolismo , Glioblastoma/patología , Oxígeno/metabolismo , Isoformas de Proteínas/metabolismo , Empalme del ARN , Factores de Empalme de ARN/metabolismo , Microambiente TumoralRESUMEN
The Notch signaling pathway has been implicated in both developmental processes and tumorigenesis. Aberrant Notch signaling has been repeatedly demonstrated to facilitate the proliferation and survival of glioma cells by regulating downstream effectors or other signaling pathways. In glioblastoma multiforme specimens from 59 patients, Notch1 was highly expressed in tumor tissues compared with normal brain tissues, and this expression was correlated with elevated AKT phosphorylation and Snail expression. Increased nuclear localization of ß-catenin and p50 as well as enhanced IKKα/AKT interaction were also observed in glioma tissues. In U87MG cells, the activation of Notch1 by DLL4 stimulation or by the overexpression of Notch intracellular domain (NICD) resulted in AKT activation and thereby promoted ß-catenin activity and NF-κB signaling. Inhibition of EGFR partially blocked the ß-catenin and NF-κB signaling stimulated by Notch1 activation. Furthermore, NICD overexpression in U87MG cells led to the upregulated expression of several metastasis-associated molecules, which could be abrogated by the knockdown of either ß-catenin or p50. In U87MG and U251 cells, DLL4-induced cellular migration and invasion could be inhibited by either ß-catenin or a p50 inhibitor. Collectively, these results indicate that Notch activation could stimulate ß-catenin and NF-κB signaling through AKT activation in glioma cells. Thus, Notch activation-stimulated ß-catenin and NF-κB signaling synergistically promote the migratory and invasive properties of glioma cells.