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1.
Hematol., Transfus. Cell Ther. (Impr.) ; 43(4): 430-436, Oct.-Dec. 2021. graf, ilus
Artigo em Inglês | LILACS | ID: biblio-1350823

RESUMO

ABSTRACT Background: In Philadelphia chromosome-negative myeloproliferative neoplasm (MPN) models, reactive oxygen species (ROS) are elevated and have been implicated in genomic instability, JAK2/STAT signaling amplification, and disease progression. Although the potential effects of ROS on the MPN phenotype, the effects of ruxolitinib treatment on ROS regulation have been poorly explored. Herein, we have reported the impact of ruxolitinib on redox signaling transcriptional network, and the effects of diphenyleneiodonium (DPI), a pan NOX inhibitor, in JAK2V617F-driven cellular models. Method: Redox signaling-related genes were investigated in SET2 cells upon ruxolitinib treatment by RNA-seq (GEO accession GSE69827). SET2 and HEL cells, which represent JAK2V617F-positive MPN cellular models with distinct sensitivity to apoptosis induced by ruxolitinib, were used. Cell viability was evaluated by MTT, apoptosis by annexin V/PI and flow cytometry, and cell signaling by quantitative PCR and Western blot. Main results: Ruxolitinib impacted on a network composed of redox signaling-related genes, and DUOX1 and DUOX2 were identified as potential modulators of ruxolitinib response. In SET2 and HEL cells, DPI reduced cell viability and, at low doses, it significantly potentiated ruxolitinib-induced apoptosis. In the molecular scenario, DPI inhibited STAT3, STAT5 and S6 ribosomal protein phosphorylation and induced PARP1 cleavage in JAK2V617F-positive cells. DPI combined with ruxolitinib increased PARP1 cleavage in SET2 cells and potentiated ruxolitinib-reduced STAT3, STAT5 and S6 ribosomal protein in HEL cells. Conclusion: Our study reveals a potential adaptation mechanism for resistance against ruxolitinib by transcriptionally reprogramming redox signaling in JAK2V617F cells and exposes redox vulnerabilities with therapeutic value in MPN cellular models.


Assuntos
Janus Quinase 2 , Doenças Mieloproliferativas-Mielodisplásicas/tratamento farmacológico , Oxirredução , NADPH Oxidases , Oxidases Duais , Transtornos Mieloproliferativos
2.
Braz. j. biol ; 80(4): 948-956, Oct.-Dec. 2020. graf
Artigo em Inglês | LILACS | ID: biblio-1142528

RESUMO

Abstract Mucosal epithelial cells act as the first immunologic barrier of organisms, and contact directly with pathogens. Therefore, hosts must have differential strategies to combat pathogens efficiently. Reactive oxygen species (ROS), as a kind of oxidizing agents, participates in the early stage of killing pathogens quickly. Recent reports have revealed that dual oxidase (DUOX) plays a key role in mucosal immunity. And the DUOX is a transmembrane protein which produces ROS as their primary enzymatic products. This process is an important pattern for eliminating pathogens. In this review, we highlight the DUOX immunologic functions in the respiratory and digestive tract of vertebrates.


Resumo As células epiteliais da mucosa atuam como a primeira barreira imunológica dos organismos e entram em contato direto com os patógenos. Portanto, os hospedeiros devem ter estratégias diferenciadas para combater os patógenos de forma eficiente. Trabalhos recentes revelaram que a oxidase dupla (DUOX) desempenha um papel fundamental para a imunidade da mucosa. A DUOX é uma proteína transmembrana geradora de espécies reativas de oxigênio (EROs) como seus principais produtos enzimáticos. Nesta revisão, apresentaremos as funções imunológicas da DUOX no trato respiratório e digestivo dos vertebrados.


Assuntos
Animais , Vertebrados , NADPH Oxidases , Espécies Reativas de Oxigênio , Oxidases Duais
3.
Acta cir. bras ; 33(8): 703-712, Aug. 2018. tab, graf
Artigo em Inglês | LILACS | ID: biblio-949375

RESUMO

Abstract Purpose: To assess the action of vitamin C on the expression of 84 oxidative stress related-genes in cultured skin fibroblasts from burn patients. Methods: Skin samples were obtained from ten burn patients. Human primary fibroblasts were isolated and cultured to be distributed into 2 groups: TF (n = 10, fibroblasts treated with vitamin C) and UF (n = 10, untreated fibroblasts). Gene expression analysis using quantitative polymerase chain reaction array was performed for comparisons between groups. Results: The comparison revealed 10 upregulated genes as follows: arachidonate 12-lipoxygenase (ALOX12), 24-dehydrocholesterol reductase (DHCR24), dual oxidase 1 (DUOX1), glutathione peroxidase 2 (GPX2), glutathione peroxidase 5 (GPX5), microsomal glutathione S-transferase 3 (MGST3), peroxiredoxin 4 (PRDX4), phosphatidylinositol-3,4,5-trisphosphate dependent Rac exchange factor 1 (P-REX1), prostaglandin-endoperoxide synthase 1 (PTGS1), and ring finger protein 7 (RNF7). Conclusion: Cultured fibroblasts obtained from burn patients and treated with vitamin C resulted in 10 differentially expressed genes, all overexpressed, with DUOX1, GPX5, GPX2 and PTGS1 being of most interest.


Assuntos
Humanos , Masculino , Feminino , Adulto , Adulto Jovem , Ácido Ascórbico/farmacologia , Queimaduras/patologia , Expressão Gênica/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Valores de Referência , Pele/patologia , Araquidonato 12-Lipoxigenase/análise , Araquidonato 12-Lipoxigenase/efeitos dos fármacos , Queimaduras/tratamento farmacológico , Células Cultivadas , Estudos Transversais , Estatísticas não Paramétricas , Ubiquitina-Proteína Ligases/análise , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/análise , Ciclo-Oxigenase 1/análise , Ciclo-Oxigenase 1/efeitos dos fármacos , Peroxirredoxinas/análise , Reação em Cadeia da Polimerase em Tempo Real , Oxidases Duais/análise , Oxidases Duais/efeitos dos fármacos , Glutationa Peroxidase/análise , Glutationa Peroxidase/efeitos dos fármacos
4.
Arch. argent. pediatr ; 115(3): 162-165, jun. 2017. ilus
Artigo em Espanhol | LILACS, BINACIS | ID: biblio-887328

RESUMO

El hipotiroidismo congénito afecta a 1:2000-3000 recién nacidos detectados por pesquisa neonatal. Las oxidasas duales, DUOX1 y 2, generan agua oxigenada, lo que constituye un paso crítico en la síntesis hormonal. Se han comunicado mutaciones en el gen DUOX2 en casos de hipotiroidismo congénito transitorio y permanente. Se describen dos hermanos con hipotiroidismo congénito detectados por pesquisa neonatal, con glándula tiroides eutópica y tiroglobulina elevada. Recibieron levotiroxina hasta su reevaluación en la infancia con suspensión del tratamiento. Su función tiroidea fue normal y se consideró el cuadro como transitorio por un posible defecto de organificación. Ambos pacientes eran heterocigotos compuestos para una mutación en el exón 9 del alelo paterno (c.1057_1058delTT, p.F353PfsX36 o p.F353fsX388) y otra en el exón 11 del alelo materno (c.1271T>G, p.Y425X) del gen DUOX2. Nuestro hallazgo confirma que la magnitud del defecto de DUOX2 no se relaciona con el número de alelos afectados, lo que sugiere mecanismos compensadores en la generación de peróxido.


Congenital hypothyroidism affects 1:2000-3000 newborns detected by neonatal screening programs. Dual oxidases, DUOX1 and 2, generate hydrogen peroxide needed for the thyroid hormone synthesis. Mutations in the DUOX2 gene have been described in transient and permanent congenital hypothyroidism. Two brothers with congenital hypothyroidism detected by neonatal screening with eutopic gland and elevated thyroglobulin are described. They were treated with levothyroxine until it could be suspended in both during childhood, assuming the picture as transient. Organification disorder was confirmed. Both patients were compounds heterozygous for a mutation in exon 9 of the paternal allele (c.1057_1058delTT, p.F353PfsX36 or p.F353fsX388) and in exon 11 of the maternal allele (c.1271T > G, p.Y425X) of DUOX2 gene. Our finding confirms that the magnitude of the defect of DUOX2 is not related to the number of inactivated alleles, suggesting compensatory mechanisms in the peroxide supply


Assuntos
Humanos , Masculino , Feminino , Recém-Nascido , Hipotireoidismo Congênito/genética , Oxidases Duais/genética , Mutação , Linhagem
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