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1.
J Agric Food Chem ; 67(40): 11230-11235, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31523955

RESUMO

Ochratoxin A (OTA) is a mycotoxin which could cause strong immunosuppressive toxicological effects in animals and humans. Heterophil extracellular traps (HETs) as a novel defense of chicken heterophils play an important role against pathogen infection. It has been reported that OTA can weaken the phagocytosis function of neutrophils. However, whether or not OTA shows immunosuppressive effects on HET release remains unclear. In the present study, we aim to first investigate the effects of OTA on HET release and then try to clarify the mechanisms in this process. OTA-induced HET structures were observed and analyzed by fluorescence confocal microscopy. The quantitative determination of OTA-induced HETs was measured by PicoGreen and a fluorescence microplate. The results clearly showed that OTA obviously induced the release of HET-like structures in heterophils, and these extracellular networks were composed by chromatin decorated with histones and neutrophil elastase. Reactive oxygen species (ROS) production was also increased in the process of OTA-induced HET formation. Furthermore, the inhibitors of NADPH oxidase, ERK [Formula: see text], and p38 MAPK signaling pathways significantly decreased OTA-induced HET formation. The abovementioned results suggest that OTA-induced HET formation is related to ROS production dependent on the activation of NADPH oxidase, ERK [Formula: see text], and p38 MAPK signaling pathways. Taken together, this study first shows that OTA possesses the ability to trigger HET formation, which provides our understanding of the host that continuously suffered OTA exposure leading to the hyporeactivity of the immune system against infection.


Assuntos
Galinhas/imunologia , MAP Quinases Reguladas por Sinal Extracelular/imunologia , Armadilhas Extracelulares/imunologia , NADPH Oxidases/imunologia , Neutrófilos/efeitos dos fármacos , Ocratoxinas/toxicidade , Espécies Reativas de Oxigênio/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia , Animais , Galinhas/genética , MAP Quinases Reguladas por Sinal Extracelular/genética , Armadilhas Extracelulares/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , NADPH Oxidases/genética , Neutrófilos/enzimologia , Neutrófilos/imunologia , Fagocitose , Proteínas Quinases p38 Ativadas por Mitógeno/genética
2.
Nat Commun ; 10(1): 3081, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300673

RESUMO

Dimethyl fumarate (DMF) is a first-line-treatment for relapsing-remitting multiple sclerosis (RRMS). The redox master regulator Nrf2, essential for redox balance, is a target of DMF, but its precise therapeutic mechanisms of action remain elusive. Here we show impact of DMF on circulating monocytes and T cells in a prospective longitudinal RRMS patient cohort. DMF increases the level of oxidized isoprostanes in peripheral blood. Other observed changes, including methylome and transcriptome profiles, occur in monocytes prior to T cells. Importantly, monocyte counts and monocytic ROS increase following DMF and distinguish patients with beneficial treatment-response from non-responders. A single nucleotide polymorphism in the ROS-generating NOX3 gene is associated with beneficial DMF treatment-response. Our data implicate monocyte-derived oxidative processes in autoimmune diseases and their treatment, and identify NOX3 genetic variant, monocyte counts and redox state as parameters potentially useful to inform clinical decisions on DMF therapy of RRMS.


Assuntos
Fumarato de Dimetilo/uso terapêutico , Imunossupressores/uso terapêutico , Monócitos/imunologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , NADPH Oxidases/genética , Adulto , Metilação de DNA/efeitos dos fármacos , Fumarato de Dimetilo/farmacologia , Epigênese Genética/efeitos dos fármacos , Feminino , Humanos , Imunossupressores/farmacologia , Contagem de Leucócitos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/imunologia , NADPH Oxidases/metabolismo , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/metabolismo , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
3.
Mol Plant Microbe Interact ; 32(11): 1508-1516, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31230563

RESUMO

During interactions, both plants and pathogens produce reactive oxygen species (ROS). Plants generate ROS for defense induction, while pathogens synthesize ROS for growth, sporulation, and virulence. NADPH oxidase (NOX) complex in the plasma membrane represents a main protein complex for ROS production in pathogens. Although NOX plays a crucial role in pathogenicity of pathogens, the underlying molecular mechanisms of NOX, especially the proteins regulated by NOX, remain largely unknown. Here, we applied an iodoacetyl tandem mass tag-based redox proteomic assay to investigate the protein redox dynamics in deletion mutant of bcnoxR, which encodes a regulatory subunit of NOX in the fungal pathogen Botrytis cinerea. In total, 214 unique peptidyl cysteine (Cys) thiols from 168 proteins were identified and quantified in both the wild type and ∆bcnoxR mutant. The Cys thiols in the ∆bcnoxR mutant were generally more oxidized than those in the wild type, suggesting that BcNoxR is essential for maintaining the equilibrium of the redox state in B. cinerea. Site-specific thiol oxidation analysis indicated that 142 peptides containing the oxidized thiols changed abundance significantly in the ∆bcnoxR mutant. Proteins containing these differential peptides are classified into various functional categories. Functional analysis revealed that one of these proteins, 6-phosphate dehydrogenase, played roles in oxidative stress response and pathogenesis of B. cinerea. These results provide insight into the potential target proteins and the ROS signal transduction pathway regulated by NOX.


Assuntos
Botrytis , Homeostase , NADPH Oxidases , Botrytis/enzimologia , Botrytis/genética , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Homeostase/genética , Mutação , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Oxirredução , Proteômica , Espécies Reativas de Oxigênio , Transdução de Sinais
4.
Int J Mol Sci ; 20(11)2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31167403

RESUMO

The respiratory burst oxidase homolog D (RbohD) acts as a central driving force of reactive oxygen species signaling in plant cells by integrating many different signal transduction pathways in plants, including incompatible interactions with pathogens. This study demonstrated the localization and distribution of RbohD in two types of potato-potato virus Y (PVY) interactions: Compatible and incompatible (resistant). The results indicated a statistically significant induction of the RbohD antigen signal in both interaction types. In the hypersensitive response (resistant reaction) of potato with a high level of resistance to the potato tuber necrotic strain of PVY (PVYNTN), RbohD localization followed by hydrogen peroxide (H2O2) detection was concentrated in the apoplast. In contrast, in the hypersensitive response of potato with a low resistance level to PVYNTN, the distribution of RbohD was concentrated more in the plant cell organelles than in the apoplast, resulting in the virus particles being present outside the inoculation area. Moreover, when compared to mock-inoculated plants and to the hypersensitive response, the PVYNTN-compatible potato interaction triggered high induction in the RbohD distribution, which was associated with necrotization. Our findings indicated that RbohD and hydrogen peroxide deposition was associated with the hypersensitive response, and both were detected in the vascular tissues and chloroplasts. These results suggest that the RbohD distribution is actively dependent on different types of PVY NTN-potato plant interactions. Additionally, the RbohD may be involved in the PVYNTN tissue limitation during the hypersensitive response, and it could be an active component of the systemic signal transduction in the susceptible host reaction.


Assuntos
Interações Hospedeiro-Patógeno , NADPH Oxidases/genética , Doenças das Plantas/genética , Doenças das Plantas/virologia , Proteínas de Plantas/genética , Potyvirus/fisiologia , Biomarcadores , Suscetibilidade a Doenças , Imunofluorescência , Peróxido de Hidrogênio , NADPH Oxidases/metabolismo , Proteínas de Plantas/metabolismo , Transporte Proteico , Explosão Respiratória , Vírion/ultraestrutura
5.
Iran J Allergy Asthma Immunol ; 18(2): 131-142, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31066249

RESUMO

The Chronic granulomatous disease (CGD) is a primary immunodeficiency that characterized by mutations in phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, resulting in deficient antimicrobial activity of phagocytic cells and recurrent childhood infections. Hematopoietic stem cell transplantation (HSCT) is a curative option for patients with human leukocyte antigen (HLA) matched donor, when conventional cares and therapies fail. However, in many cases when the patients have not an HLA-matched donor, they need to a method to recapitulate the function of the affected gene within the patient's own cells. Gene therapy is a promising approach for CGD. While, the success of retroviral or lentiviral vectors in gene therapy for CGD has been hampered by random integration and insertional activation of proto-oncogenes. These serious adverse events led to improvement and generations of viral vectors with increased safety characteristics. Gene therapy continues to progress and the advent of new technologies, such as engineered endonucleases that have shown a great promise for the treatment of genetic disease. This review focuses on the application of gene therapy for the CGD, the limitations encountered in current clinical trials, advantages and disadvantages of endonucleases in gene correction and modeling with CRISPR/Cas9 approach.


Assuntos
Terapia Genética , Doença Granulomatosa Crônica/terapia , Infecção/terapia , Mutação/genética , NADPH Oxidases/genética , Animais , Sistemas CRISPR-Cas , Ensaios Clínicos como Assunto , Vetores Genéticos , Doença Granulomatosa Crônica/genética , Transplante de Células-Tronco Hematopoéticas , Humanos , Infecção/genética , Fagocitose/genética
6.
J Agric Food Chem ; 67(28): 7968-7976, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31062982

RESUMO

Curcumin exhibits efficient antimicrobial activity; nevertheless, its effect on the postharvest decay of fruit has not been examined. Here, effects of curcumin on the fruit gray mold of kiwifruit infected by Botrytis cinerea were analyzed. Results demonstrated that curcumin induced reactive oxygen species (ROS) production and triggered apoptosis in B. cinerea hyphae. Use of N-acetylcysteine, a ROS scavenger, partially ameliorated the inhibition of curcumin on B. cinerea. The NADPH oxidase inhibitor, diphenyleneiodonium chlorine, abrogated the ROS production induced by curcumin, suggesting that curcumin induces oxidative stress in B. cinerea via a NADPH-oxidase-dependent mechanism. Disease severity of gray mold in curcumin-treated kiwifruit was significantly reduced. The malondialdehyde content decreased while the antioxidant enzyme activity increased in kiwifruit with the application of increasing concentrations of curcumin. Collectively, these results indicate that curcumin can be used to control gray mold and elevate antioxidant activity in kiwifruit.


Assuntos
Actinidia/microbiologia , Botrytis/efeitos dos fármacos , Curcumina/farmacologia , Fungicidas Industriais/farmacologia , Doenças das Plantas/microbiologia , Botrytis/metabolismo , Frutas/microbiologia , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
7.
Mol Med Rep ; 19(6): 5115-5122, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059037

RESUMO

3,3'­Diindolylmethane (DIM) is a naturally derived indole compound found in the Brassica family of vegetables. DIM has several beneficial effects, including anti­cancer, anti­inflammatory and anti­angiogenic functions. However, the effects of DIM on acute kidney injury (AKI) stimulated by lipopolysaccharide (LPS) are poorly studied. In this present study, male BALB/c mouse models of AKI were established using intraperitoneal injections of 10 mg/kg LPS. DIM (40 mg/kg) was administered intraperitoneally 24 and 2 h before LPS exposure. The results indicated that DIM significantly mitigated histopathological changes in the kidneys and improved the levels of blood urea nitrogen and serum creatinine. DIM also suppressed the LPS­induced production of reactive oxygen species and cell apoptosis. Furthermore, DIM treatment significantly decreased the expression of NADPH oxidase 2 (NOX2) and NOX4 in LPS­treated mice. Therefore, DIM may exert its renoprotective actions by inhibiting NOX­mediated oxidative stress and the apoptosis of renal tubular epithelial cells.


Assuntos
Lesão Renal Aguda/prevenção & controle , Apoptose/efeitos dos fármacos , Indóis/farmacologia , Lipopolissacarídeos/toxicidade , NADPH Oxidases/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/patologia , Animais , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Regulação para Baixo/efeitos dos fármacos , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Glutationa/metabolismo , Rim/patologia , Túbulos Renais/citologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NADPH Oxidases/genética , Espécies Reativas de Oxigênio/metabolismo
8.
Int J Mol Sci ; 20(9)2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31067654

RESUMO

As a gaseous biological signaling molecule, nitric oxide (NO) regulates many physiological processes in plants. Over the last decades, this low molecular weight compound has been identified as a key signaling molecule to regulate plant stress responses, and also plays an important role in plant development. However, elucidation of the molecular mechanisms for NO in leaf development has so far been limited due to a lack of mutant resources. Here, we employed the NO-deficient mutant nia1nia2 to examine the role of NO in leaf development. We have found that nia1nia2 mutant plants displayed very different leaf phenotypes as compared to wild type Col-0. Further studies have shown that reactive oxygen species (ROS) levels are higher in nia1nia2 mutant plants. Interestingly, ROS-related enzymes ascorbate peroxidase (APX), catalases (CAT), and peroxidases (POD) have shown decreases in their activities. Our transcriptome data have revealed that the ROS synthesis gene RBOHD was enhanced in nia1nia2 mutants and the photosynthesis-related pathway was impaired, which suggests that NO is required for chloroplast development and leaf development. Together, these results imply that NO plays a significant role in plant leaf development by regulating ROS homeostasis.


Assuntos
Arabidopsis/metabolismo , Homeostase , Óxido Nítrico/metabolismo , Folhas de Planta/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Arabidopsis/crescimento & desenvolvimento , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Nitrato Redutase/genética , Nitrato Redutase/metabolismo , Fotossíntese , Folhas de Planta/crescimento & desenvolvimento
9.
Virology ; 531: 269-279, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30974383

RESUMO

The study evaluated the effects of nucleoprotein viral and the infectious virus in SHK-1 cells. The results show a strong respiratory burst activation and the induction of p47phox, SOD, GLURED, and apoptotic genes. Additionally, the cells alter the profile of SUMOylated proteins by the effect of transfection and infection experiments. In silico analyses show a set of structural motifs in NP susceptible of post-translational modification by the SUMO protein. Interestingly, the inhibition of the NADPH oxidase complex blocked the production of reactive oxygen species and the high level of cellular ROS due to the nucleoprotein and the ISAv. At the same time, the blocking of the p38MAPK signaling pathway and the use of Aristotelia chilensis, decreased viral progeny production. These results suggest that the NP triggers a strong production of ROS and modifying the post-translational profile mediated by SUMO-2/3, a phenomenon that favors the production of new virions.


Assuntos
Doenças dos Peixes/metabolismo , Proteínas de Peixes/metabolismo , Isavirus/metabolismo , NADPH Oxidases/metabolismo , Nucleoproteínas/metabolismo , Infecções por Orthomyxoviridae/veterinária , Estresse Oxidativo , Proteínas Virais/metabolismo , Animais , Doenças dos Peixes/genética , Doenças dos Peixes/virologia , Proteínas de Peixes/genética , Interações Hospedeiro-Patógeno , Isavirus/genética , NADPH Oxidases/genética , Nucleoproteínas/genética , Infecções por Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/metabolismo , Infecções por Orthomyxoviridae/virologia , Espécies Reativas de Oxigênio/metabolismo , Explosão Respiratória , Salmão , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/genética , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Sumoilação , Proteínas Virais/genética , Vírion/genética , Vírion/metabolismo
10.
Scand J Immunol ; 90(1): e12767, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30963593

RESUMO

One of the components of NADPH oxidase is p47-phox, encoded by NCF1 gene. This study aims to find new genetic changes and clinical features in 38 Iranian patients with autosomal recessive chronic granulomatous disease (AR-CGD) caused by NCF1 gene defect. Patients who had abnormal NBT and DHR-1,2,3 assay with loss of p47-phox in Western blotting were included in this study. After recording demographic and clinical data, PCR amplification was performed followed by direct sequencing for all exons and exon-intron boundaries. The most common form of CGD in Iran was AR-CGD due to consanguinity marriages. Among patients with AR-CGD, NCF1 deficiency was found to be more common than other forms. Cutaneous involvements (53%), pulmonary infections (50%) and lymphadenopathy (29%) were more prevalent than other clinical manifestations of CGD. Mutation analysis of NCF1 gene identified five different mutations. Homozygous delta GT deletion (c.75_76delGT) was the most frequent mutation and was detected in more than 63% of families. Six families had a nonsense mutation in exon 7 (c.579G > A). Two novel mutations were found in exon 4 in two families, including a missense mutation (c.328C > T) and a nine-nucleotide deletion (c.331_339delTGTCCCCAC). Genetic detection of these mutations may result in early diagnosis and prevention of possible complications of the disease. This could be useful for timely decision-making for haematopoietic stem cell transplantation and for carrier detection as well as prenatal diagnosis of next children in the affected families. Our findings might help to predict outcomes, raise awareness and help effective treatment in these patients.


Assuntos
Doença Granulomatosa Crônica/genética , Linfonodos/patologia , Mutação/genética , NADPH Oxidases/genética , Infecções Respiratórias/genética , Pele/patologia , Adolescente , Adulto , Criança , Análise Mutacional de DNA , Diagnóstico Precoce , Feminino , Humanos , Irã (Geográfico) , Masculino , Reação em Cadeia da Polimerase , Adulto Jovem
11.
Int Arch Allergy Immunol ; 179(1): 62-73, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30904913

RESUMO

Recurrent severe bacterial and fungal infections are characteristic features of the rare genetic immunodeficiency disorder chronic granulomatous disease (CGD). The disease usually manifests within the first years of life with an incidence of 1 in approximately 200,000 live births. The incidence is higher in Iran and Morocco where it reaches 1.5 per 100,000 live births. Mutations have been described in the 5 subunits of NADPH oxidase, mostly in gp91phox and p47phox, with fewer mutations reported in p67phox, p22phox, and p40phox. These mutations cause loss of superoxide production in phagocytic cells. CYBB, the gene encoding the large gp91phox subunit of the transmembrane component cytochrome b558 of the NADPH oxidase complex, is localized on the X-chromosome. Genetic defects in CYBB are responsible for the disease in the majority of male CGD patients. CGD is associated with the development of granulomatous reactions in the skin, lungs, bones, and lymph nodes, and chronic infections may be seen in the liver, gastrointestinal tract, brain, and eyes. There is usually a history of repeated infections, including inflammation of the lymph glands, skin infections, and pneumonia. There may also be a persistent runny nose, inflammation of the skin, and inflammation of the mucous membranes of the mouth. Gastrointestinal problems can also occur, including diarrhea, abdominal pain, and perianal abscesses. Infection of the bones, brain abscesses, obstruction of the genitourinary tract and/or gastrointestinal tract due to the formation of granulomatous tissue, and delayed growth are also symptomatic of CGD. The prevention of infectious complications in patients with CGD involves targeted prophylaxis against opportunistic microorganisms such as Staphylococcus aureus, Klebsiella spp., Salmonella spp. and Aspergillus spp. In this review, we provide an update on organ involvement and the association with specific isolated microorganisms in CGD patients.


Assuntos
Infecções Bacterianas/etiologia , Doença Granulomatosa Crônica/complicações , Micoses/etiologia , Autoimunidade , Criança , Pré-Escolar , Feminino , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/imunologia , Humanos , Lactente , Abscesso Hepático/etiologia , Pneumopatias/etiologia , Masculino , NADPH Oxidases/genética , Dermatopatias/etiologia
12.
Int J Mol Sci ; 20(3)2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30717240

RESUMO

Three kinds of new water-soluble polysaccharides (FA, FB and FC) were isolated from wild mushroom Agaricus bitorquis (Quél.) Sacc. Chaidam by the classical method "water extraction and alcohol precipitation" and purified by column chromatography. The Mw of FA, FB and FC ranged from 5690 Da to 38,340 Da. The three polysaccharide fractions in the fruiting body were mainly composed of 4 kinds of monosaccharides, including glucose, galactose, mannose, and arabinose, among which glucose and galactose were the major monosaccharides. The FTIR and NMR spectroscopy indicated that the skeleton of three fractions composed of a (1→4)-α-D-glycosidic backbone containing α-D-mannopyranose. In vitro anti-hypoxia activity data showed that three polysaccharide fractions possessed a significant effect on inhibiting PASM cells apoptosis under hypoxia. Among them, FC at the concentration of 200 µg/mL revealed a significant anti-hypoxia effect. These results revealed that the intracellular polysaccharides possessed potent anti-hypoxic activity, which might be related to inhibiting LDH and NADPH oxidase expression and promoting the formation of 5-hydroxytryptamine, dopamine, endothelins, acetylcholine. More importantly, FC showed good performance inducing KV1.5 expression and prohibiting KIR6.2 formation at protein level.


Assuntos
Agaricus/química , Polissacarídeos Fúngicos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Arabinose/química , Sequência de Carboidratos , Hipóxia Celular , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Fracionamento Químico/métodos , Carpóforos/química , Polissacarídeos Fúngicos/química , Polissacarídeos Fúngicos/isolamento & purificação , Galactose/química , Glucose/química , Humanos , Canal de Potássio Kv1.5/agonistas , Canal de Potássio Kv1.5/genética , Canal de Potássio Kv1.5/metabolismo , L-Lactato Desidrogenase/antagonistas & inibidores , L-Lactato Desidrogenase/genética , L-Lactato Desidrogenase/metabolismo , Manose/química , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , NADPH Oxidases/antagonistas & inibidores , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Oxigênio/farmacologia , Canais de Potássio Corretores do Fluxo de Internalização/antagonistas & inibidores , Canais de Potássio Corretores do Fluxo de Internalização/genética , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Substâncias Protetoras/química , Substâncias Protetoras/isolamento & purificação , Artéria Pulmonar/citologia , Artéria Pulmonar/metabolismo
13.
Pediatr Allergy Immunol ; 30(3): 378-386, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30716179

RESUMO

BACKGROUND: Chronic granulomatous disease (CGD) is a rare disease in China, and very little large-scale studies have been conducted to date. We aimed to investigate the clinical and genetic features of CGD in Chinese pediatric patients. METHODS: Pediatric patients with CGD from Beijing Children's Hospital, Capital Medical University, China, were enrolled from January 2006 to December 2016. RESULTS: A total of 159 pediatric patients with CGD were enrolled. The median age of clinical onset was 1.4 months, and 73% (116/159) had clinical onset symptoms before the 1 year of age. The most common site of invasion was the lungs. The lymph nodes, liver, and skin were more frequently invaded in X-linked (XL) CGD patients than in autosomal recessive (AR) CGD patients (P < 0.05). Approximately 64% (92/144) of the pediatric patients suffered from abnormal response to BCG vaccination. The most frequent pathogens were Aspergillus and Mycobacterium tuberculosis. Gene analysis indicated that 132 cases (89%, 132/147) harbored CYBB pathogenic variants, 7 (5%, 7/147) carried CYBA pathogenic variants, 4 (3%, 4/147) had NCF1 pathogenic variants, and 4 (3%, 4/147) had NCF2 pathogenic variants. The overall mortality rate in this study was 43%, particularly the patients were males, with CYBB mutant and did not receive HSCT treatment. CONCLUSIONS: Chronic granulomatous disease is a rare disease affecting Chinese children; however, it is often diagnosed at a later age, and thus, the mortality rate is relatively high. The prevalence and the severity of disease in XL-CGD are higher than AR-CGD.


Assuntos
Doença Granulomatosa Crônica/diagnóstico , NADPH Oxidases/genética , Adolescente , Anti-Infecciosos/uso terapêutico , Grupo com Ancestrais do Continente Asiático/genética , Criança , Pré-Escolar , China , Feminino , Testes Genéticos/métodos , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/mortalidade , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Estudos Retrospectivos
15.
Int J Mol Sci ; 19(12)2018 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-30558263

RESUMO

It has long been observed that females are more susceptible to thyroid diseases than males. Epidemiological and experimental data show that actions of hormonal factors-especially estrogens-may explain such disparity. However, the exact cause and mechanisms of this sexual dimorphism remain so far unknown. Therefore, we aimed at evaluating the effect of 17ß-estradiol on the redox balance in thyroids of male and female rats. Expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, i.e., dual oxidase 1 (DUOX1), dual oxidase 2 (DUOX2) and NADPH oxidase 4 (NOX4), and hydrogen peroxide (H2O2) levels were evaluated in the primary cell cultures derived from thyroid glands of adult male or female Wistar rats. The measurement was made before and after treatment with 17ß-estradiol alone or with addition of one of its receptor antagonists. We found that under basal conditions female thyroid cells are exposed to higher concentrations of H2O2, most likely due to NOX/DUOX enzymes activity. Additionally, exogenous 17ß-estradiol stimulated NOX/DUOX expression as well as H2O2 production, and this effect was mainly mediated through ERα. In conclusion, oxidative processes may constitute mechanisms responsible for sexual dimorphism of thyroid diseases. Exogenous 17ß-estradiol may play a crucial pathogenic role in thyroid diseases via oxidative mechanisms, however without any gender differences.


Assuntos
Estradiol/metabolismo , Peróxido de Hidrogênio/metabolismo , NADPH Oxidases/metabolismo , Ratos/fisiologia , Caracteres Sexuais , Glândula Tireoide/citologia , Animais , Células Cultivadas , Feminino , Regulação da Expressão Gênica , Masculino , NADPH Oxidases/genética , RNA Mensageiro/genética , Ratos/genética , Ratos Wistar/genética , Ratos Wistar/fisiologia , Glândula Tireoide/metabolismo
16.
J Toxicol Sci ; 43(10): 611-621, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30298849

RESUMO

Mineralocorticoid receptor (MR)/NADPH oxidase (NOX) signaling is involved in the development of obesity, insulin resistance, and renal diseases; however, the role of this signaling on steatotic preneoplastic liver lesions is not fully elucidated. We determined the effects of the MR antagonist potassium canrenoate (PC) on MR/NOX signaling in hepatic steatosis and preneoplastic glutathione S-transferase placental form (GST-P)-positive liver foci. Rats were subjected to a two-stage hepatocarcinogenesis model and fed with basal diet or high fat diet (HFD) that was co-administered with PC alone or in combination with the antioxidant alpha-glycosyl isoquercitrin (AGIQ). PC reduced obesity and renal changes (basophilic tubules that expressed MR and p22phox) but did not affect blood glucose tolerance and non-alcoholic fatty liver disease activity score (NAS) in HFD-fed rats. However, the drug increased the area of GST-P-positive liver foci that expressed MR and p22phox as well as increased expression of NOX genes (p22phox, Poldip2, and NOX4). PC in combination with AGIQ had the potential of inhibiting the effects of PC on the area of GST-P-positive liver foci and the effects were associated with increasing expression of an anti-oxidative enzyme (Catalase). The results suggested that MR/NOX signaling might be involved in development of preneoplastic liver foci and renal basophilic changes in HFD-fed rats; however, the impacts of PC were different in each organ.


Assuntos
Ácido Canrenoico/farmacologia , Dieta Hiperlipídica/efeitos adversos , Rim/patologia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/patologia , Fígado/patologia , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Ácido Canrenoico/administração & dosagem , Catalase/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Glutationa S-Transferase pi/metabolismo , Rim/metabolismo , Fígado/metabolismo , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , NADPH Oxidases/fisiologia , Especificidade de Órgãos , Quercetina/administração & dosagem , Quercetina/análogos & derivados , Quercetina/farmacologia , Receptores de Mineralocorticoides/metabolismo , Receptores de Mineralocorticoides/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
17.
J Agric Food Chem ; 66(36): 9399-9408, 2018 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-30133277

RESUMO

Both NAC transcription factors (TFs) and reactive oxygen species (ROS) are known to be involved in leaf senescence. However, how NAC TFs modulate ROS metabolism associated with leaf senescence remains largely uncharacterized, especially during leaf senescence of postharvest economically leafy vegetables such as Chinese flowering cabbage. Here, we found that expression levels of two genes BrRbohB and BrRbohC-like encoding ROS-producing enzymes respiratory burst oxidase homologues (RBOHs) were increased consistently with the progression of postharvest leaf senescence, exhibiting a good correlation with ROS accumulation and chlorophyll degradation, as well as expressions of two chlorophyll catabolic genes ( CCGs), BrNYC1 and BrNYE1. Significantly, a novel, nuclear-localized transcriptional activator BrNAC055 was identified, and observed to show a similar expression pattern with BrRbohB, BrRbohC-like, BrNYC1 and BrNYE1. Further gel mobility shift and dual luciferase reporter assays confirmed that BrNAC055 bound directly to the NAC binding sequence (NACBS) in BrRbohB, BrRbohC-like, BrNYC1, and BrNYE1 promoters, and activated their activities. Moreover, transient overexpression of BrNAC055 in tobacco leaves made an increased ROS level and accelerated chlorophyll degradation via the up-regulation of NbRbohA and NbSGR1, resulting in the promoted leaf senescence. On the basis of these findings, we conclude that BrNAC055 acts as a transcriptional activator of ROS production and chlorophyll degradation by activating the transcriptions of RBOHs and CCGs and thereby accelerates leaf senescence in Chinese flowering cabbage.


Assuntos
Brassica/metabolismo , Clorofila/metabolismo , Regulação da Expressão Gênica de Plantas , NADPH Oxidases/metabolismo , Folhas de Planta/crescimento & desenvolvimento , Proteínas de Plantas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição/metabolismo , Brassica/genética , Brassica/crescimento & desenvolvimento , NADPH Oxidases/genética , Folhas de Planta/genética , Folhas de Planta/metabolismo , Proteínas de Plantas/genética , Regiões Promotoras Genéticas , Fatores de Transcrição/genética
18.
BMC Complement Altern Med ; 18(1): 211, 2018 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-29986680

RESUMO

BACKGROUND: Exposure to carbon black nanoparticles (CBNPs), a well-known industrial production, promotes pulmonary toxicity through inflammation and oxidative stress. Recent studies show that some polyphenols exert their antioxidant properties through regulation of protein kinase C-α (PKC-α) and NADPH oxidase (Nox) signaling. Resveratrol, a dietary polyphenol in fruits, possesses various health beneficial effects including anti-inflammatory and antioxidative properties. In this study, we aimed to elucidate the involvement of PKC-α and Nox in CBNPs-induced inflammation and oxidative stress, and to investigate the protective effects of resveratrol on CBNP-induced inflammation and oxidative stress in human lung epithelial A549 cells. METHODS: The production of reactive oxygen species (ROS) and the change of mitochondrial membrane potential (ΔΨm) were measured by flow cytometry. Nitric oxide (NO) was measured using the Griess reagent, and prostaglandin E2 (PGE2) production was detected by ELISA, while protein expressions were measured by Western blotting analysis. RESULTS: In lung epithelial A549 cells, CBNPs significantly enhanced oxidative stress by upregulation of Nox2 and membrane expression of p67phox accompanied with increase of ROS production. CBNPs also increased inflammatory factors, including iNOS, COX-2, NO and PGE2. However, resveratrol attenuated the above effects induced by CBNPs in A549 cells; additionally, CBNPs-induced activation of PKC-α was observed. We found that PKC-α inhibitor (Gö6976) could attenuate CBNPs-induced inflammation by down-regulation of ROS, NO and PGE2 production in A549 cells, suggesting PKC-α might be involved in CBNPs-induced oxidative stress and inflammation. Our results also found resveratrol was able to inhibit protein expression of PKC-α induced by CBNPs. Moreover, ROS scavenger (NAC) and Nox inhibitor (DPI) attenuated CBNPs-induced expressions of iNOS and COX-2. DPI could also attenuate CBNPs-induced ROS, NO and PGE2 production. CONCLUSIONS: Resveratrol attenuated CBNPs-induced oxidative and inflammatory factors in lung epithelial A549 cells, at least in part via inhibiting PKC-α- and Nox-related signaling.


Assuntos
Inflamação/imunologia , Inflamação/prevenção & controle , NADPH Oxidases/imunologia , Nanopartículas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Proteína Quinase C-alfa/imunologia , Fuligem/toxicidade , Estilbenos/farmacologia , Células A549 , Regulação para Baixo/efeitos dos fármacos , Humanos , Inflamação/genética , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Pulmão/imunologia , NADPH Oxidases/genética , Proteína Quinase C-alfa/genética , Espécies Reativas de Oxigênio/imunologia , Resveratrol
19.
Proc Natl Acad Sci U S A ; 115(26): E6085-E6094, 2018 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-29891679

RESUMO

Abiotic stresses in plants are often transient, and the recovery phase following stress removal is critical. Flooding, a major abiotic stress that negatively impacts plant biodiversity and agriculture, is a sequential stress where tolerance is strongly dependent on viability underwater and during the postflooding period. Here we show that in Arabidopsis thaliana accessions (Bay-0 and Lp2-6), different rates of submergence recovery correlate with submergence tolerance and fecundity. A genome-wide assessment of ribosome-associated transcripts in Bay-0 and Lp2-6 revealed a signaling network regulating recovery processes. Differential recovery between the accessions was related to the activity of three genes: RESPIRATORY BURST OXIDASE HOMOLOG D, SENESCENCE-ASSOCIATED GENE113, and ORESARA1, which function in a regulatory network involving a reactive oxygen species (ROS) burst upon desubmergence and the hormones abscisic acid and ethylene. This regulatory module controls ROS homeostasis, stomatal aperture, and chlorophyll degradation during submergence recovery. This work uncovers a signaling network that regulates recovery processes following flooding to hasten the return to prestress homeostasis.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , NADPH Oxidases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Estresse Fisiológico , Ácido Abscísico/genética , Ácido Abscísico/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Etilenos/metabolismo , NADPH Oxidases/genética
20.
Genet Test Mol Biomarkers ; 22(7): 413-419, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29924645

RESUMO

AIMS: The aim of our study was to investigate possible associations between three SNPs: rs4673 in the CYBA gene; rs1041740 in the SOD1 gene; and rs1001179 in the CAT gene, and type 1 diabetes (T1D) or diabetic peripheral neuropathy (DPN) in T1D patients. MATERIALS AND METHODS: Allelic variants of the selected SNPs were determined by allelic discrimination assays in 114 T1D patients enrolled in the study group and in 90 healthy individuals from a control group. Associations between each of the three SNPs were tested in subgroups of T1D patients divided according to the presence of DPN. RESULTS: The TT genotype of rs4673 in the CYBA gene was associated with DPN in T1D patients (OR 4.997, 95% CI 1.403-19.083, p = 0.016). Weak significance was observed for a protective effect of the TT genotype of rs1041740 in the SOD1 gene relative to T1D development (OR 0.318, 95% CI 0.092-0.959, p = 0.056). There was no significant association between the CAT gene SNP rs1001179 and T1D or DPN. CONCLUSION: We showed a strong association of the CYBA polymorphism rs4673 with DPN in Slovak children and adolescents with T1D. Further studies are necessary to assess the relationship between rs1041740 and T1D or DPN.


Assuntos
Catalase/genética , Diabetes Mellitus Tipo 1/genética , Neuropatias Diabéticas/genética , NADPH Oxidases/genética , Superóxido Dismutase-1/genética , Adolescente , Alelos , Criança , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Eslováquia , Adulto Jovem
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