RESUMO
OBJECTIVE: Glioma is one of the most prevalently diagnosed types of primary malignant brain tumors. Glioma stem cells (GSCs) are crucial in glioma recurrence. This study aims to elucidate the mechanism by which extracellular vehicles (EVs) derived from GSCs modulate glycometabolic reprogramming in glioma. METHODS: Xenograft mouse models and cell models of glioma were established and treated with GSC-EVs. Additionally, levels and activities of PFK1, LDHA, and FASN were assessed to evaluate the effect of GSC-EVs on glycometabolic reprogramming in glioma. Glioma cell proliferation, invasion, and migration were evaluated using MTT, EdU, Colony formation, and Transwell assays. miR-10b-5p expression was determined, with its target gene PTEN and downstream pathway PI3K/Akt evaluated. The involvement of miR-10b-5p and the PI3K/Akt pathway in the effect of GSC-EVs on glycometabolic reprogramming was tested through joint experiments. RESULTS: GSC-EVs facilitated glycometabolic reprogramming in glioma mice, along with enhancing glucose uptake, lactate level, and adenosine monophosphate-to-adenosine triphosphate ratio. Moreover, GSC-EV treatment potentiated glioma cell proliferation, invasion, and migration, reinforced cell resistance to temozolomide, and raised levels and activities of PFK1, LDHA, and FASN. miR-10b-5p was highly-expressed in GSC-EV-treated glioma cells while being carried into glioma cells by GSC-EVs. miR-10b-5p targeted PTEN and activated the PI3K/Akt pathway, hence stimulating glycometabolic reprogramming. CONCLUSION: GSC-EVs target PTEN and activate the PI3K/Akt pathway through carrying miR-10b-5p, subsequently accelerating glycometabolic reprogramming in glioma, which might provide new insights into glioma treatment.
Assuntos
Vesículas Extracelulares , Glioma , MicroRNAs , Animais , Humanos , Camundongos , Vesículas Extracelulares/metabolismo , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Glioma/metabolismo , Glioma/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Transdução de SinaisRESUMO
BACKGROUND The aim of this study was to determine the efficacy of sublingual administration of Dermatophagoides farinae drops for the treatment of allergic rhinitis (AR) accompanied by adenoid hypertrophy and the effect on immune function in children. MATERIAL AND METHODS Eosinophil counts in peripheral blood before and after treatment were determined; serum levels of immunoglobulin E (IgE), total IgE (T-IgE), immunoglobulin G4 (IgG4), interleukin-2 (IL-2), and interleukin-6 (IL-6) before and after treatment were detected by enzyme-linked immunosorbent assay. RESULTS The total effective rate in the study group was significantly higher than that in the control group (P<0.05). In both the study and control groups, symptom scores, medication scores, eosinophil counts in the peripheral blood, and serum levels of IgE, T-IgE, and IL-6 were significantly lower than those before treatment (P<0.05), while the serum levels of IgG4 and IL-2 were significantly higher than those before treatment (P<0.05). After treatment, symptom scores, medication scores, eosinophil counts in the peripheral blood, and serum levels of IgE, T-IgE, and IL-6 in the study group were significantly lower than those in the control group (P<0.05), while the serum levels of IgG4 and IL-2 were significantly higher in the study group than those in the control group (P<0.05). CONCLUSIONS Sublingual administration of D. farinae drops improved the clinical symptoms of pediatric AR caused by Dermatophagoides mites and improved the immune functions in children.
Assuntos
Dermatophagoides farinae/imunologia , Dessensibilização Imunológica/métodos , Rinite Alérgica/terapia , Tonsila Faríngea/efeitos dos fármacos , Tonsila Faríngea/fisiopatologia , Administração Sublingual , Animais , Asma/imunologia , Criança , Pré-Escolar , Eosinófilos/efeitos dos fármacos , Feminino , Humanos , Imunoglobulina E/análise , Imunoglobulina E/sangue , Imunoglobulina G/análise , Imunoglobulina G/sangue , Interleucina-2/análise , Interleucina-2/sangue , Interleucina-6/análise , Interleucina-6/sangue , Masculino , Estudos Retrospectivos , Imunoterapia Sublingual/métodos , Resultado do TratamentoRESUMO
Histone deacetylase 1 (HDAC1) plays a crucial role in cancer progression and development. This enzyme has been confirmed to be a key regulator of tumor biology functions, such as tumor cell proliferation, migration and invasion. However, HDAC1 expression in glioma remains controversial, and its specific function and molecular mechanism in glioblastoma is poorly understood. In this study, our findings demonstrated that protein and mRNA levels of HDAC1 were increased in glioma cell lines and glioma tissues compared to normal glial cell lines and non-neoplastic brain tissues, respectively. Furthermore, HDAC1 knockdown cells displayed decreased proliferation and invasion capabilities, whereas HDAC1 overexpressing glioblastoma cells displayed more proliferation and invasion capabilities in vitro. These novel outcomes suggested that knockdown of HDAC1 possibly suppressed the expression of phosphorylated AKT (p-AKT) and phosphorylated ERK (p-ERK) proteins, while overexpression of HDAC1 significantly increased p-AKT and p-ERK protein in glioblastoma cells. In addition, knockdown of HDAC1 repressed subcutaneous tumor growth in vivo, and led to down-regulation of p-AKT and p-ERK protein in U87 MG xenograft tumors. For the first time, we have demonstrated that HDAC1 promotes proliferation and invasion in glioblastoma cells by activating PI3K/AKT and MEK/ERK signaling pathways in vitro and in vivo. These results suggest that HDAC1 may be a novel biomarker and potential therapeutic target in glioblastoma.
Assuntos
Neoplasias Encefálicas/patologia , Proliferação de Células/fisiologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Glioblastoma/patologia , Histona Desacetilase 1/metabolismo , Transdução de Sinais/fisiologia , Adolescente , Adulto , Idoso , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Histona Desacetilase 1/genética , Humanos , Antígeno Ki-67/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Invasividade Neoplásica , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transfecção , Adulto JovemRESUMO
BACKGROUND: Glioblastoma (GBM), the most common primary brain tumor, is the most aggressive malignancy in humans. Its rapid proliferation is a major obstacle to successful treatment. Patients with GBM often suffer from psychological disturbances associated with poor prognosis and physical discomfort. Diazepam is one of the most frequently used benzodiazepines (BZs) in cancer patients for its desirable psychotropic effects. The central effects of BZs are mediated by the activation of central BZ receptors. This study investigates whether diazepam has inhibitory effect on proliferation of GBM cell line T98G and explores its possible mechanism. METHODS: Cell viability and proliferation were respectively determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay and 5-bromo-2'-deoxyuridine (BrdU) incorporation assay. Cell cycle distribution was examined by flow cytometry. Western blot with specific protein antibodies was used to detect regulatory proteins involved in cell cycle regulation. RESULTS: Diazepam significantly decreased the proliferation of T98G cells in a dose-dependent and time-dependent manner. This effect was not reversed by the central BZ receptor antagonist flumazenil or the peripheral BZ receptor antagonist PK11195, indicating that it was not mediated by BZ receptors. Flow cytometry indicated that diazepam caused a cell accumulation in G0/G1 phase, thereby contributing to cell proliferation inhibition. Furthermore, our findings showed that lessened phosphorylation of Rb accounted for diazepam-induced G0/G1 phase arrest. CONCLUSIONS: Diazepam inhibits the proliferation of human GBM T98G cells by inducing G0/G1 phase arrest. Diazepam has potential to be a lead for new drugs in GBM therapy because of its antitumor activity.
Assuntos
Neoplasias Encefálicas/patologia , Proliferação de Células/efeitos dos fármacos , Diazepam/farmacologia , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Moduladores GABAérgicos/farmacologia , Glioblastoma/patologia , Antimetabólitos , Benzimidazóis , Western Blotting , Bromodesoxiuridina , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Corantes , Corantes Fluorescentes , Fase G1/efeitos dos fármacos , Humanos , L-Lactato Desidrogenase/metabolismo , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Fase S/efeitos dos fármacos , Sais de Tetrazólio , TiazóisRESUMO
More and more cancer patients receive surgery and chronic pain control. Cell-mediated immunosuppression from surgical stress renders perioperative period a vulnerable period for tumor metastasis. Retrospective studies suggest that regional anesthesia reduces the risk of tumor metastasis and recurrence. This benefit may be due to the attenuation of immunosuppression by regional anesthesia. On the other hand, accumulating evidence points to a direct role of anesthetics in tumor progression. A variety of malignancies exhibit increased activity of voltage-gated sodium channels. Blockade of these channels by local anesthetics may help inhibit tumor progression. Opioids promote angiogenesis, cancer cell proliferation and metastasis. It will be interesting to examine the therapeutic potential of peripheral opioid antagonists against malignancy. Volatile anesthetics are organ-protective against hypoxia, however; this very protective mechanism may lead to tumor growth and poor prognosis. In this review, we examine the direct effects of anesthetics in tumor progression in hope that a thorough understanding will help to select the optimal anesthetic regimens for better outcomes in cancer patients.