RESUMO
BACKGROUND: Despite the advances in glioblastoma (GBM) treatment, the average life span of patients is 14 months. Therefore, it is urgent to identity biomarkers of prognosis, treatment response, or development of novel treatment strategies. We previously described the association of high epidermal growth factor-like domain multiple 7 (EGFL7) expression and unfavorable outcome of pilocytic astrocytoma patients. The present study aims to analyze the prognostic potential of EGFL7 in GBM isocitrate dehydrogenase (IDH)-wildtype, using immunohistochemistry and in silico approaches. METHODS: Spearman's correlation analysis of The Cancer Genome Atlas RNA sequencing data was performed. The genes strongly correlated to EGFL7 expression were submitted to enrichment gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Additionally, EGFL7 expression was associated with patient overall survival. The expression of EGFL7 was analyzed through immunohistochemistry in 74 GBM IDH-wildtype patients' samples, and was associated with clinicopathological data and overall survival. RESULTS: In silico analysis found 78 genes strongly correlated to EGFL7 expression. These genes were enriched in 40 biological processes and eight KEGG pathways, including angiogenesis/vasculogenesis, cell adhesion, and phosphoinositide 3-kinase-Akt, Notch, and Rap1 signaling pathways. The immunostaining showed high EGFL7 expression in 39 cases (52.7%). High immunolabelling was significantly associated with low Karnofsky Performance Status and poor overall survival. Cox analysis showed that GBMs IDH-wildtype with high EGFL7 expression presented a higher risk of death compared to low expression (hazard ratio, 1.645; 95% confidence interval, 1.021 to 2.650; p = .041). CONCLUSIONS: This study gives insights regarding the genes that are correlated with EGFL7, as well as biological processes and signaling pathways, which should be further investigated in order to elucidate their role in glioblastoma biology.
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BACKGROUND: The consumption of a high-fat diet (HFD) during pregnancy and perinatal periods can lead to long-term effects in the offspring central nervous system, affecting pathways related to neurogenesis and behavior, and increasing predispositions to depressive and anxiety-like behaviors. Thus, this study aimed to investigate the effects of a maternal HFD on the hippocampi of adult offspring and behaviors related to anxiety and depression. METHODS: The protein and mRNA expression of the brain-derived neurotrophic factor (BDNF), Mash1, Notch1, Hes5, serotonin transporter (SERT), 5-HT1A serotonergic receptor (5-HT1A), tryptophan hydroxylase 2 (TPH2, key enzyme of serotonin synthesis), JNK and pJNK were analyzed in the hippocampi of male Swiss mice. Hippocampal serotonin levels were measured using ELISA. The lipid peroxidation, total oxidant status, total antioxidant status, and GSH/GSSG were evaluated as oxidative stress measures. For the behavioral analysis, the open field, elevated plus maze, and sucrose preference tests were used. RESULTS: Maternal HFD led to increased body weight in dams and their offspring, as well as altered body composition and LDL levels in the offspring. There were no alterations in oxidative stress or JNK phosphorylation. Hippocampal Mash1 and BDNF expression were altered in HFD offspring. The HFD offspring exhibited anhedonic behavior. CONCLUSION: These findings suggest that maternal HFD leads to long-term alterations in the offspring's neurotrophic systems, impairing their behavior.
Assuntos
Anedonia , Dieta Hiperlipídica/efeitos adversos , Ganho de Peso na Gestação , Hipocampo/metabolismo , Efeitos Tardios da Exposição Pré-Natal/psicologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/análise , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fator Neurotrófico Derivado do Encéfalo/análise , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismoRESUMO
Dowling-Degos disease (DDD) is a rare autosomal-dominant genodermatosis and it has been associated with hidradenitis suppurativa (HS). Deregulation of NOTCH pathway has been linked to the development of HS in DDD context (DDD-HS). However, molecular alterations in DDD-HS, including altered gene expression of NOTCH and downstream effectors that are involved in the follicular differentiation and inflammatory response, are poorly defined. We report two cases of patients diagnosed with DDD-HS, one of those, under Adalimumab treatment. Our results have shown downregulation of NOTCH1/NCSTN pathway, distinct molecular profiles of inflammatory cytokines (IL23A and TNF), and a novel aberrant upregulation of genes involved in the cornified envelope (CE) formation (SPRR1B, SPRR2D, SPRR3, and IVL) in paired HS lesions of two DDD patients.
Assuntos
Citocinas/metabolismo , Regulação da Expressão Gênica , Hidradenite Supurativa/patologia , Hiperpigmentação/patologia , Mediadores da Inflamação/metabolismo , Receptor Notch1/metabolismo , Dermatopatias Genéticas/patologia , Dermatopatias Papuloescamosas/patologia , Adulto , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Proteínas Ricas em Prolina do Estrato Córneo/genética , Proteínas Ricas em Prolina do Estrato Córneo/metabolismo , Feminino , Hidradenite Supurativa/complicações , Hidradenite Supurativa/genética , Hidradenite Supurativa/metabolismo , Humanos , Hiperpigmentação/complicações , Hiperpigmentação/genética , Hiperpigmentação/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Prognóstico , Receptor Notch1/genética , Dermatopatias Genéticas/complicações , Dermatopatias Genéticas/genética , Dermatopatias Genéticas/metabolismo , Dermatopatias Papuloescamosas/complicações , Dermatopatias Papuloescamosas/genética , Dermatopatias Papuloescamosas/metabolismoRESUMO
Several signaling molecules that govern development in higher animals have been identified in the parasite Schistosoma mansoni, including the transforming growth factor ß, protein tyrosine kinases, nuclear hormone receptors, among others. The Notch pathway is a highly conserved signaling mechanism which is involved in a wide variety of developmental processes including embryogenesis and oogenesis in worms and flies. Here we aimed to provide the molecular reconstitution of the Notch pathway in S. mansoni using the available transcriptome and genome databases. Our results also revealed the presence of the transcripts coded for SmNotch, SmSu(H), SmHes, and the gamma-secretase complex (SmNicastrin, SmAph-1, and SmPen-2), throughout all the life stages analyzed. Besides, it was observed that the viability and separation of adult worm pairs were not affected by treatment with N-[N(3,5)-difluorophenacetyl)-L-Alanyl]-S-phenylglycine t-butyl ester (DAPT), a Notch pathway inhibitor. Moreover, DAPT treatment decreased the production of phenotypically normal eggs and arrested their development in culture. Our results also showed a significant decrease in SmHes transcript levels in both adult worms and eggs treated with DAPT. These results provide, for the first time, functional validation of the Notch pathway in S. mansoni and suggest its involvement in parasite oogenesis and embryogenesis. Given the complexity of the Notch pathway, further experiments shall highlight the full repertoire of Notch-mediated cellular processes throughout the S. mansoni life cycle.
Assuntos
Genoma Helmíntico/genética , Receptores Notch/genética , Schistosoma mansoni/genética , Esquistossomose mansoni/parasitologia , Transdução de Sinais , Transcriptoma , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/genética , Animais , Biologia Computacional , Diaminas/farmacologia , Feminino , Proteínas de Helminto/genética , Proteínas de Helminto/metabolismo , Humanos , Estágios do Ciclo de Vida/efeitos dos fármacos , Masculino , Camundongos Endogâmicos BALB C , Óvulo/efeitos dos fármacos , Receptores Notch/metabolismo , Schistosoma mansoni/efeitos dos fármacos , Schistosoma mansoni/fisiologia , Caramujos , Tiazóis/farmacologiaRESUMO
La vía de señalización NOTCH es un mecanismo de señalización célula-célula conservado evolutivamente entre las especies, el cual es indispensable para un correcto desarrollo embrionario, mediando una variedad de procesos celulares como proliferación, diferenciación, apoptosis, transformación epitelio- mesénquimal, migración, angiogénesis, mantenimiento de células madre y definición de destino celular. Varios genes componentes de esta vía han sido implicados en el desarrollo de estructuras craneofaciales. El 80% de los pacientes con síndrome de Alagille, presentan mutaciones en el gen que codifica para el receptor Jagged1 (Jag1), acompañado de hipoplasia del tercio medio facial y de craneosinostosis esporádica. Ratones con mutaciones homocigotas en el gen Jagged2 (Jag2) presentan paladar hendido, como resultado de fusiones ectópicas entre la lengua y los procesos palatinos. Por otro lado, mutaciones inducidas en el gen Hes1 generan defectos en el desarrollo de estructuras craneofaciales, derivadas de las células de la cresta neural craneal (CCNC) que incluyen: paladar hendido, agenesia del hueso frontal, malformación de base craneal y disminución en el tamaño del maxilar superior e inferior. Recientes estudios han evidenciado alteraciones durante la morfogénesis dental de ratones mutantes Jagged2-/-, acompañada de defectos en la citodiferenciación de ameloblastos y deficiente deposición de matriz de esmalte. Estos estudios muestran cómo la vía de señalización NOTCH está implicada en el desarrollo de una variedad de estructuras craneofaciales como paladar, dientes, maxilares y cráneo. Por esta razón, el propósito del presente artículo es presentar una revisión de las diferentes funciones de la vía NOTCH durante el desarrollo de estas estructuras craneofaciales, y de las alteraciones resultantes cuando existen mutaciones en algunos genes componentes de la vía NOTCH, como Jagged2, Jagged1, Hes1, Notch1 y Notch2.