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1.
Br J Neurosurg ; 37(5): 1074-1077, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33307833

RESUMO

OBJECTIVE: To evaluate the value of texture analysis of routine MRI image in peritumoral edema of differentiating diagnosis between glioblastoma (GBM) and primary brain lymphoma (PBL). METHODS: The MRI imaging data of 22 patients with glioblastoma and 21 patients with PBL who were hospitalized in our hospital from January 2010 to October 2018 were selected. All the patients were pathologically diagnosed as glioblastoma or PBL, and MRI plain scan and enhanced examination were performed before operation. FireVoxel software was used to delineate the region of interest (ROI) on the most obvious level of peritumoral edema based on T1WI enhancement. Texture parameters were extracted and compared between glioblastoma and PBL. RESULTS: In the glioblastoma group, the inhomogeneity, kurtosis and entropy texture parameters were statistically different from those in the PBL group. The entropy parameter area under the curve (AUC) (0.903) was significantly better than the kurtosis parameter AUC (0.859) and the inhomogeneity parameter AUC (0.729). When the entropy parameter Cut-off point = 3.883, the sensitivity, specificity and accuracy of glioblastoma and PBL were 85.7, 86.4 and 86.0%, respectively, by differential diagnosis. CONCLUSION: Texture analysis of tumor peritumoral edema provided quantifiable information, which might be a new method for differentiating glioblastoma from PBL.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Linfoma , Humanos , Glioblastoma/diagnóstico por imagem , Glioblastoma/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Linfoma/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Diagnóstico Diferencial , Edema/diagnóstico , Encéfalo/patologia , Estudos Retrospectivos
2.
J Cell Mol Med ; 24(8): 4494-4509, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32125767

RESUMO

RIOK2 is a member of RIO (right open reading frame) kinase family. Recent studies have revealed the involvement of RIO kinases in glioma cell growth and expansion. However, the role and mechanism of RIOK2 in glioma cell migration and invasion remain unclear. Wound healing assay, Transwell assay and real-time quantitative PCR (qRT-PCR) detection of matrix metalloproteinases (MMPs) were used to evaluate the migration/invasion of glioma cells. Western blot and qRT-PCR were employed to measure the expression of epithelial-mesenchymal transition (EMT) markers. Dual luciferase reporter assay was performed to determine the binding between RIOK2 and miR-4744. In addition, RIOK2 and miR-4744 levels were quantified by qRT-PCR and/or immunohistochemistry in glioma tissues. Transfection of RIOK2 siRNAs significantly inhibited glioma cell migration and invasion and down-regulated the expression of MMPs (MMP2 and MMP9) and mesenchymal markers (N-cadherin, ß-catenin, Twist1, fibronectin, ZEB-1) in glioma cells. Overexpression of RIOK2 showed the opposite effects. MiR-4744 directly bound to the 3'-untranslated region of RIOK2 and negatively regulated the expression of RIOK2. Up-regulation of miR-4744 inhibited the migration and invasion of glioma cells. Overexpression of RIOK2 could reverse the effects of miR-4744 up-regulation on the migration, invasion and EMT process in glioma cells. Moreover, RIOK2 was high, while miR-4744 was low in glioma tissues, and a negative correlation was found between them. These results suggest that RIOK2 is post-transcriptionally targeted by miR-4744, the low miR-4744 and high RIOK2 levels in glioma may contribute to tumour cell infiltration through promoting the EMT.


Assuntos
Proliferação de Células/genética , Glioma/genética , MicroRNAs/genética , Proteínas Serina-Treonina Quinases/genética , Adulto , Idoso , Caderinas/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Proteína 1 Relacionada a Twist/genética
3.
J Cell Mol Med ; 24(13): 7550-7562, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32452133

RESUMO

Glioblastoma multiforme (GBM) is the most common malignant tumour in the adult brain and hard to treat. Nuclear factor κB (NF-κB) signalling has a crucial role in the tumorigenesis of GBM. EGFR signalling is an important driver of NF-κB activation in GBM; however, the correlation between EGFR and the NF-κB pathway remains unclear. In this study, we investigated the role of mucosa-associated lymphoma antigen 1 (MALT1) in glioma progression and evaluated the anti-tumour activity and effectiveness of MI-2, a MALT1 inhibitor in a pre-clinical GBM model. We identified a paracaspase MALT1 that is involved in EGFR-induced NF-kB activation in GBM. MALT1 deficiency or inhibition significantly affected the proliferation, survival, migration and invasion of GBM cells both in vitro and in vivo. Moreover, MALT1 inhibition caused G1 cell cycle arrest by regulating multiple cell cycle-associated proteins. Mechanistically, MALTI inhibition blocks the degradation of IκBα and prevents the nuclear accumulation of the NF-κB p65 subunit in GBM cells. This study found that MALT1, a key signal transduction cascade, can mediate EGFR-induced NF-kB activation in GBM and may be potentially used as a novel therapeutic target for GBM.


Assuntos
Receptores ErbB/metabolismo , Glioblastoma/metabolismo , Terapia de Alvo Molecular , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , NF-kappa B/metabolismo , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Fator de Crescimento Epidérmico/farmacologia , Glioblastoma/patologia , Humanos , Camundongos Knockout , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/antagonistas & inibidores , Invasividade Neoplásica , Ensaio Tumoral de Célula-Tronco
4.
Cancer Cell Int ; 20: 97, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32256206

RESUMO

BACKGROUND: Activation of nuclear factor-kappa B (NF-κΒ) through DNA damage is one of the causes of tumor cell resistance to radiotherapy. Chromosome region 1 (CRM1) regulates tumor cell proliferation, drug resistance, and radiation resistance by regulating the nuclear-cytoplasmic translocation of important tumor suppressor proteins or proto-oncoproteins. A large number of studies have reported that inhibition of CRM1 suppresses the activation of NF-κΒ. Thus, we hypothesize that the reversible CRM1 inhibitor S109 may induce radiosensitivity in glioblastoma (GBM) by regulating the NF-κΒ signaling pathway. METHODS: This study utilized the cell counting kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), and colony formation assay to evaluate the effect of S109 combined with radiotherapy on the proliferation and survival of GBM cells. The therapeutic efficacy of S109 combined with radiotherapy was evaluated in vivo to explore the therapeutic mechanism of S109-induced GBM radiosensitization. RESULTS: We found that S109 combined with radiotherapy significantly inhibited GBM cell proliferation and colony formation. By regulating the levels of multiple cell cycle- and apoptosis-related proteins, the combination therapy induced G1 cell cycle arrest in GBM cells. In vivo studies showed that S109 combined with radiotherapy significantly inhibited the growth of intracranial GBM and prolonged survival. Importantly, we found that S109 combined with radiotherapy promoted the nuclear accumulation of IκΒα, and inhibited phosphorylation of p65 and the transcriptional activation of NF-κΒ. CONCLUSION: Our findings provide a new therapeutic regimen for improving GBM radiosensitivity as well as a scientific basis for further clinical trials to evaluate this combination therapy.

5.
Cereb Cortex ; 29(9): 3752-3765, 2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-30307500

RESUMO

Aberrant regulation and activity of synaptic proteins may cause synaptic pathology in the prefrontal cortex (PFC) of mood disorder patients. Carboxy-terminal PDZ ligand of NOS1 (CAPON) is a critical scaffold protein linked to synaptic proteins like nitric oxide synthase 1, synapsins. We hypothesized that CAPON is altered together with its interacting synaptic proteins in the PFC in mood disorder patients and may contribute to depression-like behaviors in mice subjected to chronic unpredictable mild stress (CUMS). Here, we found that CAPON-immunoreactivity (ir) was significantly increased in the dorsolateral PFC (DLPFC) and anterior cingulate cortex in major depressive disorder (MDD), which was accompanied by an upregulation of spinophilin-ir and a downregulation of synapsin-ir. The increases in CAPON and spinophilin and the decrease in synapsin in the DLPFC of MDD patients were also seen in the PFC of CUMS mice. CAPON-ir positively correlated with spinophilin-ir (but not with synapsin-ir) in mood disorder patients. CAPON colocalized with spinophilin in the DLPFC of MDD patients and interacted with spinophilin in human brain. Viral-mediated CAPON downregulation in the medial PFC notably reversed the depression-like behaviors in the CUMS mice. These data suggest that CAPON may contribute to aspects of depressive behavior, possibly as an interacting protein for spinophilin in the PFC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Encéfalo/metabolismo , Depressão/metabolismo , Transtorno Depressivo Maior/metabolismo , Neurônios/metabolismo , Córtex Pré-Frontal/metabolismo , Sinapses/metabolismo , Animais , Modelos Animais de Doenças , Giro do Cíngulo/metabolismo , Humanos , Proteínas dos Microfilamentos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Sinapsinas/metabolismo
6.
Korean J Physiol Pharmacol ; 24(3): 193-201, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32392910

RESUMO

Chromosomal region maintenance 1 (CRM1) is associated with an adverse prognosis in glioma. We previously reported that CRM1 inhibition suppressed glioma cell proliferation both in vitro and in vivo. In this study, we investigated the role of CRM1 in the migration and invasion of glioma cells. S109, a novel reversible selective inhibitor of CRM1, was used to treat Human glioma U87 and U251 cells. Cell migration and invasion were evaluated by wound-healing and transwell invasion assays. The results showed that S109 significantly inhibited the migration and invasion of U87 and U251 cells. However, mutation of Cys528 in CRM1 abolished the inhibitory activity of S109 in glioma cells. Furthermore, we found that S109 treatment decreased the expression level and activity of MMP2 and reduced the level of phosphorylated STAT3 but not total STAT3. Therefore, the inhibition of migration and invasion induced by S109 may be associated with the downregulation of MMP2 activity and expression, and inactivation of the STAT3 signaling pathway. These results support our previous conclusion that inhibition of CRM1 is an attractive strategy for the treatment of glioma.

8.
Int J Med Sci ; 16(4): 614-622, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31171914

RESUMO

Background: CAPON has two isoforms in human brain: long form of CAPON (CAPON-L) and short form of CAPON (CAPON-S). Recent studies have indicated the involvement of CAPON in tumor cell growth. We aimed to reveal the role of the two CAPON isoforms in the proliferation of glioma cells in this study. Materials and Methods: Lentivirus-mediated stable cell lines with CAPON-L or CAPON-S overexpression were established in U87 and U251 glioma cells. Cell counting kit-8 and colony formation assays were used to evaluate cell proliferation. Western blot analysis of cell cycle-related proteins and flow cytometry were performed to analyze cell cycle progression. Some important molecules of the AKT/mTOR pathway and P53 were also measured by Western blot analysis. Results: Overexpression of CAPON-L showed a significantly inhibitory role in U251 cells, while it exhibited a promoting role in U87 cells. Consistently, overexpressing CAPON-L impeded the cell cycle progression and down-regulated the expression levels of Cyclin D1, CDK4 and CDK6 in U251 cells, whereas it up-regulated the CDK6 level in U87 cells. The overexpression of CAPON-L significantly decreased the phosphorylation and/or total levels of AKT, mTOR and S6 in U251 cells, while it did not affect these signaling molecules in U87 cells, except for a significant increase in the phosphorylation of AKT at Thr-308 site. Transfecting constitutively active AKT (myr-AKT) partially reversed the decreased phosphorylation of AKT and S6 in the CAPON-L-overexpressing U251 cells. In addition, we found a significant decrease in the wild-type P53 level in the CAPON-L-overexpressing U87 cells. The overexpression of CAPON-S also inhibited cell proliferation, blocked cell cycle progression, and decreased the AKT/mTOR pathway activity in U251 cells. Conclusion: The effects of CAPON-L overexpression on glioma cell proliferation are dependent on the AKT/mTOR/P53 activity. The overexpression of CAPON inhibits U251 cell proliferation through the AKT/mTOR signaling pathway, while overexpressing CAPON-L promoted U87 cell proliferation, possibly through down-regulating the P53 level.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Glioma/genética , Proteína Oncogênica v-akt/genética , Serina-Treonina Quinases TOR/genética , Proteína Supressora de Tumor p53/genética , Apoptose/genética , Autofagia/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Glioma/patologia , Humanos , Fosfatidilinositol 3-Quinases/genética , Transdução de Sinais/genética
9.
J Cell Mol Med ; 22(7): 3595-3604, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29667783

RESUMO

PHAP1 (Putative HLA-DR-associated protein 1), also termed acidic leucine-rich nuclear phosphoprotein 32A (ANP32A), Phosphoprotein 32 (pp32) or protein phosphatase 2A inhibitor (I1PP2A), is a multifunctional protein aberrantly expressed in multiple types of human cancers. However, its expression pattern and clinical relevance in human glioma remain unknown. In this study, Western blotting and immunohistochemistry analysis demonstrated PHAP1 protein was highly expressed in glioma patients, especially in those with high-grade disease. Publicly available data also revealed high levels of PHAP1 were associated with poor prognosis in glioma patients. The functional studies showed that knock-down of PHAP1 suppressed the proliferation of glioma cells, while overexpression of PHAP1 facilitated it. The iTRAQ proteomic analysis suggested that stathmin might be a potential downstream target of PHAP1. Consistently, PHAP1 knock-down significantly decreased the expression of stathmin, while overexpression of PHAP1 increased it. Also, the upstream negative regulator, p27, expression levels increased upon PHAP1 knock-down and decreased when PHAP1 was overexpressed. As a result, the phosphorylated Akt (S473), an upstream regulator of p27, expression levels decreased upon silencing of PHAP1, but elevated after PHAP1 overexpression. Importantly, we demonstrate the p27 down-regulation, stathmin up-regulation and cell proliferation acceleration induced by PHAP1 overexpression were dependent on Akt activation. In conclusion, the above results suggest that PHAP1 expression is elevated in glioma patients, which may accelerate the proliferation of glioma cells by regulating the Akt/p27/stathmin pathway.


Assuntos
Neoplasias Encefálicas/patologia , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Glioma/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas de Ligação a RNA/metabolismo , Estatmina/metabolismo , Western Blotting , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Glioma/metabolismo , Glioma/mortalidade , Humanos , Imuno-Histoquímica , Proteínas Nucleares , Prognóstico , Proteômica/métodos , Proteínas de Ligação a RNA/genética
10.
Tumour Biol ; 2016 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-27718125

RESUMO

Dysregulation of Hippo/YAP signaling leads to aberrant cell growth and neoplasia. Although the roles and regulation of Hippo/YAP signaling were extensively studied in cancer biology recently, study systematically checking the expression pattern of core components of this pathway at the tumor tissue level remains lacking. In this study, we thoroughly examined the profile of core components of Hippo/YAP signaling in patient specimens both at the mRNA and at protein levels. We found that the mRNA level of YAP1/TAZ and their target genes, CRY61, CTGF, and BIRC5, was remarkably amplified in glioma tissues. Consistently, the protein level of YAP1/TAZ increased and meanwhile those of p-YAP1/p-TAZ and LATS1/2 decreased in gliomas. Unexpectedly, both the mRNA and protein levels of MST1/2 increased in the glioma tissues, inconsistent with its presumed tumor suppressor identity. In addition, over-expression of LATS2 decreased, while over-expression of YPA1 increased the cell proliferation ability. Furthermore, based on the data from the free public database, YAP1/TAZ and BIRC5 were positively associated with the prognosis of glioma patients, while LATS1/2 exhibited negative correlation with the glioma patient prognosis. Collectively, we deduce that, in glioma tissue context, MST1/2 may not be the essential component of the hippo/YAP pathway. Moreover, our findings uncover a new evidence supporting that YAP1/TAZ-BIRC5 might be abnormally activated due to LATS1/2 down-regulation, which in turn promote the occurrence and development of gliomas, paving the way to identify the potential therapeutic molecular target for gliomas.

11.
Int J Mol Sci ; 17(11)2016 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-27869735

RESUMO

CAPON is an adapter protein for nitric oxide synthase 1 (NOS1). CAPON has two isoforms in the human brain: CAPON-L (long form of CAPON) and CAPON-S (short form of CAPON). Recent studies have indicated the involvement of CAPON in tumorigenesis beyond its classical role in NOS1 activity regulation. In this study, we found that the protein levels of CAPON-S, but not than CAPON-L, were significantly decreased in glioma tissues. Therefore, we established lentivirus-mediated stable cell lines with CAPON-S overexpression or down-regulation, and investigated the role of CAPON-S in the proliferation of glioma cells by using CCK8, EdU, and flow cytometry assays. Overexpression of CAPON-S reduced the cell variability and the percentage of EdU-positive cells, and arrested the cells in the G1 phase in glioma cells. Silencing of CAPON by short-hairpin RNA showed the opposite effects. Furthermore, an intracellular signaling array revealed that overexpression of CAPON-S resulted in a remarkable reduction in the phosphorylation of Akt and S6 ribosomal protein in glioma cells, which was further confirmed by Western blot. These findings suggest that CAPON may function as a tumor suppressor in human brain glioma and that the inactivation of the Akt signaling pathway caused by CAPON-S overexpression may provide insight into the underlying mechanism of CAPON in glioma cell proliferation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proliferação de Células , Glioma/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Western Blotting , Linhagem Celular Tumoral , Sobrevivência Celular , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Glioma/patologia , Células HEK293 , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto Jovem
12.
Hippocampus ; 25(3): 373-84, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25330763

RESUMO

Geranylgeranyltransferase I (GGT), a protein prenyltransferase, is responsible for the posttranslational lipidation of Rho GTPases, such as Rac, Rho and Cdc42, all of which play an important role in neuronal synaptogenesis. We previously demonstrated that GGT promotes dendritic morphogenesis in cultured hippocampal neurons and cerebellar slices. We report here that inhibiting GGT activity decreases basal- and activity-dependent changes in spine density as well as in learning and memory ability of mice in vivo. We found that KCl- or bicuculline-induced dendritic spine density increases was abolished by specific GGT inhibitor GGTi-2147 treatment in cultured hippocampal neurons. GGTi-2147 lateral ventricular injection reduced GGT activity and membrane association of Rac and decreased the density of dendritic spines in the mouse hippocampus, frontal cortex and cerebellum. GGTi-2147 administration also impaired learning and memory ability of mice. More importantly, mice exposed to environmental enrichment (EE) showed increased spine density and learning and memory ability, which were significantly reversed by GGTi-2147 administration. These data demonstrate that inhibiting GGT activity prevents both basal- and activity-dependent changes in spine density in central nervous system both in vitro and in vivo. Manipulating GGT activity may be a promising strategy for the therapies of neurodevelopmental disorders, such as autism, depression, and schizophrenia.


Assuntos
Alquil e Aril Transferases/metabolismo , Sistema Nervoso Central/citologia , Sistema Nervoso Central/enzimologia , Espinhas Dendríticas/patologia , Animais , Bicuculina/farmacologia , Células Cultivadas , Sistema Nervoso Central/efeitos dos fármacos , Espinhas Dendríticas/efeitos dos fármacos , Embrião de Mamíferos , Inibidores Enzimáticos/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Hipocampo/citologia , Imidazóis/farmacologia , Aprendizagem/efeitos dos fármacos , Leucina/análogos & derivados , Leucina/farmacologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/ultraestrutura , Cloreto de Potássio/farmacologia , Ratos , Ratos Sprague-Dawley , Proteínas rac de Ligação ao GTP/metabolismo
13.
J Neurooncol ; 121(3): 469-77, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25528634

RESUMO

Plumbagin, a natural quinonoid constituent isolated from the root of medicinal plant Plumbago zeylanica L, has exhibited anti-tumor and anti-proliferative activities in various tumor cell lines as well as in animal tumor models. However, its anticancer effects and the mechanisms underlying its suppression of glioma cell growth have not been elucidated. Oncogenic transcription factor Forkhead Box M1 (FOXM1) has garnered particular interest in recent years as a potential target for the prevention and/or therapeutic intervention in glioma, nevertheless, less information is currently available regarding FOXM1 inhibitor. Here, we reported that plumbagin could effectively inhibit cell proliferation, migration and invasion and induce apoptosis of glioma cells. Cell cycle assay showed that plumbagin induced G2/M arrest. Interestingly, we found that plumbagin decreased the expression of FOXM1 both at mRNA level and protein level. Plumbagin also inhibited the transactivation ability of FOXM1, resulting in down-regulating the expression of FOXM1 downstream target genes, such as cyclin D1, Cdc25B, survivin, and increasing the expression of p21(CIP1) and p27(KIP1). Most importantly, down-regulation of FOXM1 by siFOXM1 transfection enhanced plumbagin-induced change in viability. On the contrary, over-expression of FOXM1 by cDNA transfection reduced plumbagin-induced glioma cell growth inhibition. These results suggest that plumbagin exhibits its anticancer activity partially by inactivation of FOXM1 signaling pathway in glioma cells. Our findings indicate that plumbagin may be considered as a potential natural FOXM1 inhibitor, which could contribute to the development of new anticancer agent for therapy of gliomas.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Fatores de Transcrição Forkhead/biossíntese , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/metabolismo , Naftoquinonas/farmacologia , Apoptose/efeitos dos fármacos , Western Blotting , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Regulação para Baixo , Proteína Forkhead Box M1 , Humanos , RNA Interferente Pequeno , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transfecção
14.
J Pharmacol Sci ; 128(3): 131-6, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26154848

RESUMO

Plumbagin is a natural compound that is isolated from the root of the medicinal plant Plumbago zeylanica L. Based on a previous in vitro study performed by our group, which demonstrated the effectiveness of plumbagin against glioma cells, we further ascertained whether plumbagin exhibits the same effectiveness against glioma cell xenografts in nude mice. Our results revealed that tumor volume was reduced by 54.48% in the plumbagin-treated group compared with the controls. Furthermore, there were no obvious signs of toxicity as assessed by the organ sizes and cell morphologies of the mice that were treated with plumbagin. Immunofluorescence assays further revealed that plumbagin significantly inhibited glioma cell proliferation and induced cell apoptosis. Importantly, we also determined that the expressions of FOXM1 and its downstream target effectors, including cyclin D1 and Cdc25B, were down-regulated in the treated group, while the expressions of p21 and p27 were increased; the latter findings corroborate the results of our previous in vitro study. Taken together, these findings indicate that plumbagin may be a natural downregulator of FOXM1 with potential therapeutic effectiveness for the treatment of gliomas.


Assuntos
Antineoplásicos Fitogênicos , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Expressão Gênica/efeitos dos fármacos , Glioma/genética , Glioma/patologia , Terapia de Alvo Molecular , Naftoquinonas/farmacologia , Naftoquinonas/uso terapêutico , Fitoterapia , Plumbaginaceae/química , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Proteína Forkhead Box M1 , Expressão Gênica/genética , Glioma/tratamento farmacológico , Humanos , Camundongos Nus , Naftoquinonas/isolamento & purificação , Transplante de Neoplasias
15.
BMC Cancer ; 14: 63, 2014 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-24495453

RESUMO

BACKGROUND: The goal of this study was to compare treatment outcomes for Federation of Gynecology and Obstetrics (FIGO) stage IIB cervical carcinoma patients receiving radical surgery followed by adjuvant postoperative radiotherapy versus radical radiotherapy. METHODS: Medical records of FIGO stage IIB cervical cancer patients treated between July 2008 and December 2011 were retrospectively reviewed. A total of 148 patients underwent radical hysterectomy with pelvic lymph node dissection followed by adjuvant radiotherapy (surgery-based group). These patients were compared with 290 patients that received radical radiotherapy alone (RT-based group). Recurrence rates, progression-free survival (PFS), overall survival (OS), local control rates, and treatment-related complications were compared for these two groups. RESULTS: Similar rates of recurrence (16.89% vs. 12.41%, p = 0.200), PFS (log-rank, p = 0.211), OS (log-rank, p = 0.347), and local control rates (log-rank, p = 0.668) were observed for the surgery-based group and the RT-based group, respectively. Moreover, the incidence of acute grade 3-4 gastrointestinal reactions and late grade 3-4 lower limb lymphedema were significantly higher for the surgery-based group versus the RT-based group. Cox multivariate analyses found no significant difference in survival outcome between the two groups, and tumor diameter and histopathology were identified as significant prognostic factors for OS. CONCLUSIONS: Radical radiotherapy was associated with fewer treatment-related complications and achieved comparable survival outcomes for patients with FIGO stage IIB cervical cancer compared to radical hysterectomy followed by postoperative radiotherapy.


Assuntos
Histerectomia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/radioterapia , Neoplasias do Colo do Útero/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Intervalo Livre de Doença , Feminino , Humanos , Histerectomia/efeitos adversos , Histerectomia/mortalidade , Estimativa de Kaplan-Meier , Excisão de Linfonodo , Pessoa de Meia-Idade , Análise Multivariada , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Radioterapia Adjuvante , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Carga Tumoral , Neoplasias do Colo do Útero/mortalidade , Adulto Jovem
16.
Cereb Cortex ; 23(12): 2956-64, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22989585

RESUMO

Decreased function of the anterior cingulate cortex (ACC) is crucially involved in the pathogenesis of depression. A key role of nitric oxide (NO) has also been proposed. We aimed to determine the NO content in the cerebrospinal fluid (CSF) and the expression of NO synthase (NOS) isoforms, that is, NOS1, NOS2, and NOS3 in the ACC in depression. In depressive patients, CSF-NOx levels (the levels of the NO metabolites nitrite and nitrate) were significantly decreased (P = 0.007), indicating a more general decrease of NO production in this disorder. This agreed with a trend toward lower NOS1-mRNA levels (P = 0.083) and a significant decrease of NOS1-immunoreactivity (ir) (P = 0.043) in ACC. In controls, there was a significant positive correlation between ACC-NOS1-ir cell densities and their CSF-NOx levels. Furthermore, both localization of NOS1 in pyramidal neurons that are known to be glutamatergic and co-localization between NOS1 and GABAergic neurons were observed in human ACC. The diminished ACC-NOS1 expression and decreased CSF-NOx levels may be involved in the alterations of ACC activity in depression, possibly by affecting glutamatergic and GABAergic neurotransmission.


Assuntos
Transtorno Depressivo Maior/enzimologia , Giro do Cíngulo/enzimologia , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico/líquido cefalorraquidiano , Transtorno Depressivo Maior/líquido cefalorraquidiano , Transtorno Depressivo Maior/genética , Feminino , Neurônios GABAérgicos/enzimologia , Humanos , Masculino , Óxido Nítrico Sintase Tipo I/genética , Células Piramidais/enzimologia
17.
Cancer Lett ; 598: 217114, 2024 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-38992488

RESUMO

Gender plays a crucial role in the occurrence and development of cancer, as well as in the metabolism of nutrients and energy. Men and women display significant differences in the incidence, prognosis, and treatment response across various types of cancer, including certain sex-specific tumors. It has been observed that male glioma patients have a higher incidence and worse prognosis than female patients, but there is currently a limited systematic evaluation of sex differences in gliomas. The purpose of this study is to provide an overview of the association between fluctuations in sex hormone levels and changes in their receptor expression with the incidence, progression, treatment, and prognosis of gliomas. Estrogen may have a protective effect on glioma patients, while exposure to androgens increases the risk of glioma. We also discussed the specific genetic and molecular differences between genders in terms of the malignant nature and prognosis of gliomas. Factors such as TP53, MGMT methylation status may play a crucial role. Therefore, it is essential to consider the gender of patients while treating glioma, particularly the differences at the hormonal and molecular levels. This approach can help in the adoption of an individualized treatment strategy.


Assuntos
Neoplasias Encefálicas , Glioma , Hormônios Esteroides Gonadais , Humanos , Glioma/epidemiologia , Glioma/genética , Glioma/patologia , Glioma/metabolismo , Feminino , Masculino , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Fatores Sexuais , Hormônios Esteroides Gonadais/metabolismo , Prognóstico , Incidência , Fatores de Risco , Metilação de DNA , Metilases de Modificação do DNA/genética , Metilases de Modificação do DNA/metabolismo
18.
Explor Target Antitumor Ther ; 4(1): 139-156, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36937322

RESUMO

Medulloblastoma (MB) is the commonest primary malignant brain cancer. The current treatment of MB is usually surgical resection combined with radiotherapy or chemotherapy. Although great progress has been made in the clinical management of MB, tumor metastasis and recurrence are still the main cause of death. Therefore, definitive and timely diagnosis is of great importance for improving therapeutic effects on MB. In 2016, the World Health Organization (WHO) divided MB into four subtypes: wingless-type mouse mammary tumor virus integration site (WNT), sonic hedgehog (SHH), non-WNT/non-SHH group 3, and group 4. Each subtype of MB has a unique profile in copy number variation, DNA alteration, gene transcription, or post-transcriptional/translational modification, all of which are associated with different biological manifestations, clinical features, and prognosis. This article reviewed the research progress of different molecular pathology markers in MB and summarized some targeted drugs against these molecular markers, hoping to stimulate the clinical application of these molecular markers in the classification, diagnosis, and treatment of MB.

19.
Front Mol Neurosci ; 16: 1304224, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38115820

RESUMO

Background: Synaptic transmission between neurons and glioma cells can promote glioma progression. The soluble N-ethylmaleimide-sensitive fusion factor attachment protein receptors (SNARE) play a key role in synaptic functions. We aimed to construct and validate a novel model based on the SNARE proteins to predict the prognosis and immune microenvironment of glioma. Methods: Differential expression analysis and COX regression analysis were used to identify key SRGs in glioma datasets, and we constructed a prognostic risk model based on the key SRGs. The prognostic value and predictive performance of the model were assessed in The Cancer Genome Atlas (TCGA) and Chinese glioma Genome Atlas (CGGA) datasets. Functional enrichment analysis and immune-related evaluation were employed to reveal the association of risk scores with tumor progression and microenvironment. A prognostic nomogram containing the risk score was established and assessed by calibration curves and time-dependent receiver operating characteristic curves. We verified the changes of the key SRGs in glioma specimens and cells by real-time quantitative PCR and Western blot analyses. Results: Vesicle-associated membrane protein 2 (VAMP2) and vesicle-associated membrane protein 5 (VAMP5) were identified as two SRGs affecting the prognoses of glioma patients. High-risk patients characterized by higher VAMP5 and lower VAMP2 expression had a worse prognosis. Higher risk scores were associated with older age, higher tumor grades, IDH wild-type, and 1p19q non-codeletion. The SRGs risk model showed an excellent predictive performance in predicting the prognosis in TCGA and CGGA datasets. Differentially expressed genes between low- and high-risk groups were mainly enriched in the pathways related to immune infiltration, tumor metastasis, and neuronal activity. Immune score, stromal score, estimate score, tumor mutational burden, and expression of checkpoint genes were positively correlated with risk scores. The nomogram containing the risk score showed good performance in predicting the prognosis of glioma. Low VAMP2 and high VAMP5 were found in different grades of glioma specimens and cell lines. Conclusion: We constructed and validated a novel risk model based on the expression of VAMP2 and VAMP5 by bioinformatics analysis and experimental confirmation. This model might be helpful for clinically predicting the prognosis and response to immunotherapy of glioma patients.

20.
Biomed Pharmacother ; 162: 114555, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36966667

RESUMO

The standard regimen treatment has improved GBM outcomes, but the survival rate of patients is still unsatisfactory. Temozolomide (TMZ) resistance is one of main reasons limiting the therapeutic efficacy of GBM. However, there are currently no TMZ-sensitizing drugs available in the clinic. Here we aimed to study whether the antidiabetic drug Sitagliptin can inhibit the survival, stemness and autophagy of GBM cells, and thus enhance TMZ cytotoxicity. We used CCK-8, EdU, colony formation, TUNEL and flow cytometry assays to assess cell proliferation and apoptosis; sphere formation and limiting dilution assays to measure self-renewal and stemness of glioma stem cells (GSCs); Western blot, qRT-PCR or immunohistochemical analysis to measure the expression of proliferation or stem cell markers; Western blot/fluorescent analysis of LC3 and other molecules to evaluate autophagy formation and degradation in glioma cells. We found that Sitagliptin inhibited proliferation and induced apoptosis in GBM cells and suppressed self-renewal and stemness of GSCs. The in vitro findings were further confirmed in glioma intracranial xenograft models. Sitagliptin administration prolonged the survival time of tumor-bearing mice. Sitagliptin could inhibit TMZ-induced protective autophagy and enhance the cytotoxicity of TMZ in glioma cells. In addition, Sitagliptin acted as a dipeptidyl peptidase 4 inhibitor in glioma as well as in diabetes, but it did not affect the blood glucose level and body weight of mice. These findings suggest that Sitagliptin with established pharmacologic and safety profiles could be repurposed as an antiglioma drug to overcome TMZ resistance, providing a new option for GBM therapy.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Animais , Camundongos , Temozolomida , Fosfato de Sitagliptina/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Glioma/tratamento farmacológico , Apoptose , Autofagia , Glioblastoma/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Antineoplásicos Alquilantes/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
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