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1.
Acta Neurochir Suppl ; 127: 47-54, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31407062

RESUMO

BACKGROUND: Previously studies have shown that Nox2 and Nox4, as members of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase, Nox), participate in brain damage caused by ischemia-reperfusion (I/R). The aim of this study is to investigate the effects of specific chemical inhibitors of Nox2 and Nox4 on cerebral I/R-induced brain injury in rats. METHODS: At 0.5 h before MCAO surgery, the rats were pretreated with vehicle, Nox2 inhibitor (gp91ds-tat), and Nox4 inhibitor (GKT137831), respectively. After reperfusion for 24 h, the infarct sizes of brain tissues in rats in various groups are determined. The penumbra (ischemic) tissues are collected to measure ROS levels, neuronal apoptosis, and degeneration, as well as the integrity of the blood-brain barrier (BBB) in brain tissues of rats. RESULTS: gp91ds-tat and GKT137831 pretreatment significantly reduced the infarct sizes in brain tissues of rats, effectively suppressed I/R-induced increase in ROS levels, neuronal apoptosis and degeneration, and obviously alleviated BBB damage. CONCLUSION: Under cerebral I/R conditions, Nox2 inhibitor (gp91ds-tat) and Nox4 inhibitor (GKT137831) can effectively play a protective role in the brain tissues of rats.


Assuntos
Lesões Encefálicas , Isquemia Encefálica , NADPH Oxidase 2 , NADPH Oxidase 4 , Traumatismo por Reperfusão , Animais , Apoptose/efeitos dos fármacos , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/metabolismo , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , NADPH Oxidase 2/antagonistas & inibidores , NADPH Oxidase 2/metabolismo , NADPH Oxidase 4/antagonistas & inibidores , NADPH Oxidase 4/metabolismo , NADPH Oxidases , Ratos , Espécies Reativas de Oxigênio , Traumatismo por Reperfusão/metabolismo
2.
Biosci Biotechnol Biochem ; 84(1): 134-142, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31490096

RESUMO

Plumbagin (PLB), an alkaloid obtained from the roots of the plants of Plumbago genus, is an inhibitor of NADPH oxidase 4 (NOX4). This study aimed to investigate the beneficial effect of PLB against oxygen-glucose deprivation/reoxygenation (OGDR)-induced neuroinjury in human SH-SY5Y neuronal cultures. Our results showed that OGD/R stimulated NOX4 protein expression and reactive oxygen species (ROS) production in SH-SY5Y cells, whereas increased 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) production, resulting in the activation of the NLRP3 inflammasome. And PLB pretreatment reduced the ROS production by regulating the expression of NOX4 and downregulated NF-κB signaling which was induced by OGDR. Furthermore, PLB inhibited OGDR induced NLRP3 inflammasome activation but not PARP1. Overall, PLB improved OGDR induced neuroinjury by inhibiting NOX4-derived ROS-activated NLRP3 inflammasome.


Assuntos
Hipóxia Celular/efeitos dos fármacos , Glucose/deficiência , Inflamassomos/metabolismo , NADPH Oxidase 4/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Naftoquinonas/farmacologia , Neurônios/metabolismo , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Isquemia Encefálica/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Raízes de Plantas/química , Plumbaginaceae/química
3.
Oxid Med Cell Longev ; 2019: 3264858, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31178956

RESUMO

The family of NADPH oxidases represents an important source of reactive oxygen species (ROS) within the cell. Nox4 is a special member of this family as it constitutively produces H2O2 and its loss promotes inflammation. A major cellular component of inflammation is the macrophage population, which can be divided into several subpopulations depending on their phenotype, with proinflammatory M(LPS+IFNγ) and wound-healing M(IL4+IL13) macrophages being extremes of the functional spectrum. Whether Nox4 is expressed in macrophages is discussed controversially. Here, we show that macrophages besides a high level of Nox2 indeed express Nox4. As Nox4 contributes to differentiation of many cells, we hypothesize that Nox4 plays a role in determining the polarization and the phenotype of macrophages. In bone marrow-derived monocytes, ex vivo treatment with LPS/IFNγ or IL4/IL13 results in polarization of the cells into M(LPS+IFNγ) or M(IL4+IL13) macrophages, respectively. In this ex vivo setting, Nox4 deficiency reduces M(IL4+IL13) polarization and forces M(LPS+IFNγ). Nox4-/- M(LPS+IFNγ)-polarized macrophages express more Nox2 and produce more superoxide anions than wild type M(LPS+IFNγ)-polarized macrophages. Mechanistically, Nox4 deficiency reduces STAT6 activation and promotes NFκB activity, with the latter being responsible for the higher level of Nox2 in Nox4-deficient M(LPS+IFNγ)-polarized macrophages. According to those findings, in vivo, in a murine inflammation-driven fibrosarcoma model, Nox4 deficiency forces the expression of proinflammatory genes and cytokines, accompanied by an increase in the number of proinflammatory Ly6C+ macrophages in the tumors. Collectively, the data obtained in this study suggest an anti-inflammatory role for Nox4 in macrophages. Nox4 deficiency results in less M(IL4+IL13) polarization and suppression of NFκB activity in monocytes.


Assuntos
Macrófagos/metabolismo , NADPH Oxidase 4/metabolismo , NF-kappa B/metabolismo , Animais , Polaridade Celular/fisiologia , Fibrossarcoma/enzimologia , Fibrossarcoma/patologia , Humanos , Interferon gama/farmacologia , Interleucinas/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Camundongos , Camundongos Endogâmicos C57BL , NADPH Oxidase 4/antagonistas & inibidores , NADPH Oxidase 4/deficiência , Espécies Reativas de Oxigênio/metabolismo
4.
Eur J Pharmacol ; 859: 172490, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31229536

RESUMO

Doxorubicin (DOX) is a classic anti-tumor chemotherapeutic used to treat a wide range of tumors. One major downfall of DOX treatment is it can induce fatal cardiotoxicity. Astragaloside IV (AS-IV) is one of the primary active ingredients that can be isolated from the traditional Chinese herbal medicine, Astragalus membranaceus. This study uses both in vitro and in vivo tools to investigate whether AS-IV alleviates DOX induced cardiomyopathy. We found that AS-IV supplementation alleviates body weight loss, myocardial injury, apoptosis of cardiomyocytes, cardiac fibrosis and cardiac dysfunction in DOX-treated mice. Also, DOX-induced cardiomyocyte injury and apoptosis were effectively improved by AS-IV treatment in vitro. NADPH oxidase (NOX) plays an important role in the progress of the oxidative signal transduction and DOX-induced cardiomyopathy. In this study, we found that AS-IV treatment relieves DOX-induced NOX2 and NOX4 expression and oxidative stress in cardiomyocytes. In conclusion, AS-IV, an antioxidant, attenuates DOX-induced cardiomyopathy through the suppression of NOX2 and NOX4.


Assuntos
Cardiomiopatias/induzido quimicamente , Cardiomiopatias/tratamento farmacológico , Doxorrubicina/efeitos adversos , NADPH Oxidase 2/antagonistas & inibidores , NADPH Oxidase 4/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Saponinas/farmacologia , Triterpenos/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Tamanho Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , NADPH Oxidase 2/metabolismo , NADPH Oxidase 4/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Ratos , Saponinas/uso terapêutico , Triterpenos/uso terapêutico
5.
Mol Med Rep ; 19(1): 382-390, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30431085

RESUMO

To investigate the function of progranulin on the retina under hypoxic conditions, 8­week­old C57BL/6 mice were divided into normal condition and hypoxic condition groups (n=24 mice/group). The hypoxia model was established through intravitreal injection of 9 mM cobalt chloride. Subsequently, 10 mM progranulin and an equal amount of PBS were injected into the right and left eyes, respectively. Photoreceptor function was examined using electroretinogram (ERG) analysis. Morphological alterations were examined using immunofluorescence co­localization, retinal vascular inflammation was examined using the leukostasis assay, and signaling pathways were screened using immunoblotting. The results revealed that ERG amplitude was significantly lower under hypoxic conditions compared with under normal conditions. Furthermore, the amplitude was significantly reduced in the PBS­injected eyes compared with in the progranulin­injected eyes. Morphological examination demonstrated that the number of rods in the PBS­injected eyes was decreased compared with in the progranulin­injected eyes under hypoxic conditions. In addition, the arrangement of the cones was sparse and the morphology of the outer segments was short and small. Although the number of adherent leukocytes in the progranulin­injected eyes was higher in the hypoxic mice compared with in those under normal conditions, the number was only 52.31% of the number detected in the PBS­injected eyes. Analysis of the signaling pathways demonstrated that the protective effects of progranulin on retinas under hypoxic conditions were regulated by the Toll­like receptor 4 (TLR4)­NADPH oxidase 4 (NOX4) pathway, instead of the caspase and Wnt/ß­catenin pathways. In conclusion, progranulin exerted protective effects on the function and morphology of photoreceptors in a hypoxic environment, and could reduce retinal vascular inflammation, through inhibition of the TLR4­NOX4 pathway.


Assuntos
Hipóxia , NADPH Oxidase 4/antagonistas & inibidores , Progranulinas/farmacologia , Substâncias Protetoras/farmacologia , Retina/citologia , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Células Cultivadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NADPH Oxidase 4/genética , NADPH Oxidase 4/metabolismo , Retina/efeitos dos fármacos , Retina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
6.
Inflammation ; 42(1): 64-80, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30315526

RESUMO

Hyperhomocysteinemia (HHCY) has been recognized as an independent risk factor for atherosclerosis and plays a vital role in the development of atherosclerosis. Catalpol, an iridoid glucoside extracted from the root of Rehmannia glutinosa, can produce anti-inflammatory, anti-oxidant, anti-tumor, and dopaminergic neurons protecting effects. This study aimed to determine the protecting effects of catalpol against homocysteine (HCY)-induced injuries in human aortic endothelial cells (HAECs) and uncover the underlying mechanisms: 1. HAECs were cultured with different concentrations of HCY (3 mM) and catalpol (7.5 µΜ, 15 µΜ, 30 µΜ) for 24 h. (1) The level of MDA and GSH as well as LDH release was measured with colorimetric assay. (2) Reactive oxygen species (ROS) were detected by flow cytometry analysis. (3) Western blotting analysis was performed to detect the expression of Nox4, p22phox, ICAM-1, MCP-1, VCAM-1, IκB, nucleus p65, p65 phosphorylation, caspase-3, -9, bax, bcl-2, and ER stress-related proteins. (4) The expressions of CHOP, ATF4 were measured by qRT-PCR. (5) Mitochondrial membrane potential in HCY-treated HAECs was measured by rhodamine 123 staining, and the samples were observed by confocal laser scanning microscopy. 2. DPI, PDTC, and TUDCA were used to determine the interaction among Nox4/ROS, NF-κB, and endoplasmic reticulum stress. 3. TUDCA or Nox4 siRNA were used to investigate whether the effect of catalpol inhibiting the over-production of ROS were associated with inhibiting ER stress and Nox4 expression. Catalpol significantly suppressed LDH release, MDA level, and the reduction of GSH. Catalpol reduced HCY-stimulated ROS over-generation, inhibited the NF-κB transcriptional activation as well as the protein over-expressions of Nox4, ICAM-1, VCAM-1, and MCP-1. Catalpol elevated bcl-2 protein expression and reduced bax, caspase-3, -9 protein expressions in the HCY-treated HAECs. Simultaneously, catalpol could also inhibit the activation of ER stress-associated sensors GRP78, IRE1α, ATF6, P-PERK, P-eIF2α, CHOP, and ATF4 induced by HCY. In addition, the extent of catalpol inhibiting ROS over-generation and NF-κB signaling pathway was reduced after inhibiting Nox4 or ER stress with DPI or TUDCA. The inhibitor of NF-κB PDTC also reduced the effects of catalpol inhibiting the expressions of Nox4 and GRP78. Furthermore, the effect of catalpol inhibiting the over-generation of ROS was reduced by Nox4 siRNA. Catalpol could ameliorate HCY-induced oxidation, cells apoptosis and inflammation in HAECs possibly by inhibiting Nox4/NF-κB and ER stress.


Assuntos
Aorta/citologia , Células Endoteliais/metabolismo , Homocisteína/efeitos adversos , Inflamação/prevenção & controle , Glucosídeos Iridoides/farmacologia , NADPH Oxidase 4/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Proteínas de Choque Térmico/antagonistas & inibidores , Proteínas de Choque Térmico/metabolismo , Humanos , Inflamação/induzido quimicamente , Glucosídeos Iridoides/uso terapêutico , NADPH Oxidase 4/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , eIF-2 Quinase/antagonistas & inibidores , eIF-2 Quinase/metabolismo
7.
Biomed Pharmacother ; 109: 1907-1914, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30551445

RESUMO

NADPH oxidases (Noxs) 1/4 dual inhibitor GKT137831 prevents hypertensive cardiac remodelling in angiotensin II-infused transgenic mice with cardiomyocyte-specific human Nox4 (c-hNo x 4 Tg); however, further research is still required to determine the beneficial role of GKT137831 in hypertensive cardiac remodelling in other types of hypertensive models because this hypertensive model is insufficient to mimic the complicated pathological mechanisms of hypertension. A disintegrin and metalloprotease 17 (ADAM17) promotes the shedding of tumour necrosis factor α (TNF-α), TNF-α receptor, interleukin 1 receptor-II and interleukin 6 (IL-6) receptor from cells, thereby mediating the signalling pathways induced by corresponding proinflammatory cytokines. This study aimed to determine whether GKT137831 prevents hypertensive cardiac remodelling and its mechanisms of action in the rats with abdominal artery coarctation (AAC). The rats subjected to AAC were orally given GKT137831 for a consecutive period of 28 days. Echocardiography and histological analysis were performed to evaluate cardiac remodelling; and immunohistochemistry and real-time PCR were used to detect the expression of proinflammatory cytokines. GKT137831 significantly suppressed hypertensive cardiac remodelling in AAC-induced hypertensive rats. Concurrently, Nox1/4 dual inhibitor GKT137831 reduced the protein and mRNA levels of proinflammatory cytokines interleukin 1ß (IL-1ß), IL-6, and TNF-α in the left ventricle of AAC-induced hypertensive rats. Moreover, the treatment with GKT137831 markedly diminished the protein and mRNA levels of ADAM17 in the left ventricle of AAC-induced hypertensive rats. In summary, Nox1/4 dual inhibitor GKT137831 protects against hypertensive cardiac remodelling in AAC-induced hypertensive rats, and the inhibition of ADAM17-dependent proinflammatory cytokines-induced signalling pathways are related to its beneficial effect on hypertensive cardiac remodelling.


Assuntos
Artérias/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , NADPH Oxidase 1/antagonistas & inibidores , NADPH Oxidase 4/antagonistas & inibidores , Pirazóis/farmacologia , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteína ADAM17 , Animais , Artérias/metabolismo , Constrição , Citocinas/metabolismo , Hipertensão/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Miócitos Cardíacos/metabolismo , Ratos , Ratos Sprague-Dawley
8.
Nephrol Dial Transplant ; 34(4): 567-576, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29931336

RESUMO

The main function of NADPH oxidases is to catalyse the formation of reactive oxygen species (ROS). NADPH oxidase 4 (NOX4) is expressed at high levels in kidney tubular cells, and at lower levels in endothelial cells, cardiomyocytes and other cell types under physiological conditions. NOX4 is constitutively active producing hydrogen peroxide (H2O2) as the prevalent ROS detected, whereas other NOX isoforms present in the renal and cardiovascular systems (i.e. NOX1, NOX2 and NOX5) generate superoxide radical anions as main products. Pharmacological inhibition of NOX4 has received enormous attention for its potential therapeutic benefit in fibrotic disease and nephropathologies. Ongoing clinical trials are testing this approach in humans. Diabetes elevates NOX4 expression in podocytes and mesangial cells, which was shown to damage glomeruli leading to podocyte loss, mesangial cell hypertrophy and matrix accumulation. Consequently, NOX4 represents an interesting therapeutic target in diabetic nephropathy. On the contrary, experiments using NOX4-deficient mice have shown that NOX4 is cytoprotective in tubular cells, cardiomyocytes, endothelial cells and vascular smooth muscle cells, and has a metabolism-regulating role when these cells are subjected to injury. Mice with systemic NOX4 deletion are more susceptible to acute and chronic tubular injury, heart failure and atherosclerosis. Overall, the current literature suggests a detrimental role of increased NOX4 expression in mesangial cells and podocytes during diabetic nephropathy, but a cytoprotective role of this enzyme in other cellular types where it is expressed endogenously. We review here the recent evidence on the role of NOX4 in the kidneys and cardiovascular system. With the emergence of pharmacological NOX4 inhibitors in clinical trials, caution should be taken in identifying potential side effects in patients prone to acute kidney injury and cardiovascular disease.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , NADPH Oxidase 4/antagonistas & inibidores , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/patologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Humanos , NADPH Oxidase 4/metabolismo , Prognóstico
9.
PLoS One ; 13(12): e0209444, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30571757

RESUMO

Lung ischemia and reperfusion injury (LIRI) were mediated by several processes including over-production of reactive oxygen species (ROS) and inflammatory activation. ROS generated by nicotinamide adenine dinucletide phosphate (NADPH) oxidase (Nox) may play a pivotal role in pathophysiological changes in a range of disease. However, it was poorly understood in LIRI. Thus, the purpose of our study was to explore whether GKT137831, as a special dual inhibitor of Nox1 and 4, could alleviate LIRI in mice model and explore the minimal dose. According to the protocol, this study was divided into two parts. The first part was to determine the minimal dose of Nox1/4 inhibitor in attenuating LIRI via histopathology and apoptosis analysis. Eighteen C57BL/6J male wild-type mice were randomly divided in to sham, 2.5Nox+sham, 5.0Nox+sham, IR, 2.5Nox+IR and 5.0Nox+IR groups. According to the different group, mice were pretreated with corresponding dose of Nox1/4 inhibitors or normal saline. After LIRI, the results showed 5.0mg/kg Nox1/4 inhibitor could be considered as the minimal dose to alleviate injury by decreasing of lung injury score and the number of TUNEL-positive cells. The second part was to further verify the benefit of 5.0mg/kg Nox1/4 inhibitor in lung protective effects. Thirty-seven C57BL/6J male wild-type mice were divided in to sham, IR and 5.0Nox+IR groups randomly. The results showed that expressions of inflammatory, autophagy cytokines were markedly elevated and PH value was declined after LIRI. However, 5.0 mg/kg Nox1/4 inhibitor significantly attenuated cytokine production as reflected by immunohistochemistry, western blotting and Q-PCR analysis. In conclusion, our findings suggested that 5.0mg/kg Nox1/4 inhibitor contributed to protect lung tissue damage after LIRI via the suppression of inflammatory and autophagy activation.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Pulmão/efeitos dos fármacos , Pirazóis/farmacologia , Piridinas/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Autofagia/imunologia , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/uso terapêutico , Humanos , Pulmão/irrigação sanguínea , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NADPH Oxidase 1/antagonistas & inibidores , NADPH Oxidase 1/metabolismo , NADPH Oxidase 4/antagonistas & inibidores , NADPH Oxidase 4/metabolismo , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/patologia
10.
Biomed Pharmacother ; 108: 1640-1650, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30372866

RESUMO

Diabetic cardiomyopathy (DCM) is one of the most severe cardiovascular complications in diabetes. Caffeic acid para-nitro phenethyl ester (CAPE-pNO2) could ameliorate diabetic nephropathy in the diabetic mice in our previous study. This paper was aimed to investigate the effect of CAPE-pNO2 on DCM and its potential mechanism. The DCM mice were established by intraperitoneal injection with streptozotocin (STZ, 50 mg/kg) for 5 days. When the fasting blood glucose level remains above 11.1 mmol/L, treated the mice with CAPE and CAPE-pNO2 for 8 weeks, then the mice were executed, and the samples of blood and heart tissue were collected for the subsequent experiments. The results showed that CAPE-pNO2 can alleviate CK, LDH, TC and TG levels, as well as depress the activity of ROS by down-regulating the expression of NOX4 and improving SOD activity in the serum of STZ-induced DCM mice. Meanwhile, it can also reduce the content of MDA and inhibit lipid accumulation. Besides, CAPE-pNO2 could repress the expression of TNF-α, IL-1ß and IL-6 IL - 6 via the NOX4/NF-κB pathway to improve the development of inflammation. Furthermore, it can suppress the expression of collagen and fibronectin to inhibit myocardial fibrosis through the TGF-ß1/Smad pathway, and inhibit ECM deposition by regulating TGF-ß1 directly, as shown in cardiac tissue section. Importantly, the above results showed that CAPE-pNO2 had better effects of reversing pathological changes than CAPE in a significant difference of p < 0.05. In brief, CAPE-pNO2 can prevent the heart injury of DCM mice via the NOX4/NF-κB pathway, and shows the improvement effects of anti-fibrosis, anti-oxidative and anti-inflammatory.


Assuntos
Ácidos Cafeicos/uso terapêutico , Diabetes Mellitus Experimental/prevenção & controle , Cardiomiopatias Diabéticas/prevenção & controle , NADPH Oxidase 4/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Álcool Feniletílico/análogos & derivados , Transdução de Sinais/efeitos dos fármacos , Animais , Ácidos Cafeicos/farmacologia , Citotoxinas/farmacologia , Citotoxinas/uso terapêutico , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Cardiomiopatias Diabéticas/induzido quimicamente , Cardiomiopatias Diabéticas/metabolismo , Relação Dose-Resposta a Droga , Masculino , Camundongos , NADPH Oxidase 4/metabolismo , NF-kappa B/metabolismo , Nitrofenóis/farmacologia , Nitrofenóis/uso terapêutico , Álcool Feniletílico/farmacologia , Álcool Feniletílico/uso terapêutico , Transdução de Sinais/fisiologia , Estreptozocina/toxicidade
11.
Sci Rep ; 8(1): 15897, 2018 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-30367082

RESUMO

The function of the NAD(P)H oxidases (NOXs) family member NOX4 is to generate reactive oxygen species (ROS), however, the molecular function of NOX4 has not been fully studied and waiting to be clarified. To elucidate the function of endogenous Nox4 in human thyroid carcinomas, papillomatosis thyroid cancer cells were used to study the cell growth by knocking down the expression of NOX4 and knocking out its functional partner p22phox/CYBA. As a result, the increasement of mitochondrial ROS(mROS) was abolished due to both knockdown of NOX4 and p22phox knockout in hypoxia, which destabilized HIF1α decreasing glycolysis and retarded cell growth. These data suggests that Nox4 is potent oncotarget due to its role in regulating glycolysis through mROS-HIF1α pathway, thereby mediating proliferation in thyroid carcinomas.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Mitocôndrias/metabolismo , NADPH Oxidase 4/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Hipóxia Celular , Linhagem Celular Tumoral , Proliferação de Células , Edição de Genes , Glicólise , Humanos , Peróxido de Hidrogênio/metabolismo , NADPH Oxidase 4/antagonistas & inibidores , NADPH Oxidase 4/genética , NADPH Oxidases/deficiência , NADPH Oxidases/genética , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia
12.
PLoS One ; 13(9): e0204271, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30265686

RESUMO

It has been proposed that pancreatic beta-cell dysfunction in type 2 diabetes is promoted by oxidative stress caused by NADPH oxidase (Nox) over-activity. The aim of the present study was to evaluate the efficacy of novel Nox inhibitors as protective agents against cytokine- or high glucose + palmitate-induced human beta-cell death. The Nox2 protein was present mainly in the cytoplasm and was induced by cytokines. Nox4 protein immunoreactivity, with some nuclear accumulation, was observed in human islet cells, and was not affected by islet culture in the presence of cytokines or high glucose + palmitate. Nox inhibitors with partial or no isoform selectivity (DPI, dapsone, GLX351322, and GLX481372) all reduced ROS production of human islet cells exposed to high glucose + palmitate. This was paralleled by improved viability and reduced caspase 3 activation. The Nox1 selective inhibitor ML171 failed to reduce human islet cell death in response to both cytokines and high glucose + palmitate. The selective Nox2 inhibitor Phox-I2 also failed to protect against cytokines, but protected partially against high glucose + palmitate-induced cellular death. The highly selective Nox4 inhibitor GLX7013114 protected islet cells against both cytokines and high glucose + palmitate. However, as no osmotic control for high glucose was used, we cannot exclude the possibility that the high glucose effect was due to osmosis. It is concluded that Nox4 may participate in stress-induced islet cell death in human islets in vitro. We propose that Nox4 mediates pro-apoptotic effects in intact islets under stressful conditions and that selective Nox4-inhibition may be a therapeutic strategy in type 2 diabetes.


Assuntos
Morte Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/efeitos dos fármacos , NADPH Oxidase 4/antagonistas & inibidores , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Glucose/farmacologia , Células HEK293 , Humanos , Ilhotas Pancreáticas/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , NADPH Oxidase 2/metabolismo , NADPH Oxidase 4/metabolismo , Ácido Palmítico/farmacologia , Superóxidos/metabolismo
13.
Biochem Biophys Res Commun ; 505(2): 339-345, 2018 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-30245133

RESUMO

Podocyte injury plays crucial roles in the pathogenesis of diabetic nephropathy (DN). Aberrant microRNAs (miRNAs) have been suggested to contribute to podocyte injury. However, whether miR-423-5p could alleviate high glucose (HG)-mediated podocyte injury and the underlying mechanisms remains unclear. In this study, we found that patients with DN have reduced miR-423-5p and elevated Nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) expressions in clinical renal tissues, and HG induced Nox4 but suppressed miR-423-5p expressions in cultured podocytes in a time-dependent manner. Moreover, overexpression of miR-423-5p antagonized HG-stimulated podocyte injury by enhancing cell viability, inhibiting reactive oxygen species (ROS) production, suppressing cell apoptosis, reducing inflammatory activity, and repressing cytoskeleton damage accompanied with alternations of podocyte specific proteins. Furthermore, functional assays substantiated that Nox4 was a direct target and negatively regulated by miR-423-5p. Additionally, restoration of Nox4 impeded the protective effect of miR-423-5p on podocyte injury via activation of p38 MAPK pathway. Therefore, this study manifested that miR-423-5p overexpression protected HG-induced podocyte damage by inhibiting ROS generation via targeting Nox4, providing a potential therapeutic strategy against DN.


Assuntos
Glucose/farmacologia , MicroRNAs/farmacologia , NADPH Oxidase 4/antagonistas & inibidores , Podócitos/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Humanos , Rim/metabolismo , Rim/patologia , MicroRNAs/metabolismo , NADPH Oxidase 4/metabolismo , Podócitos/patologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
14.
J Dig Dis ; 19(10): 578-585, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30058122

RESUMO

Oxidative stress has been implicated as an important factor in tumorigenesis and tumor progression. The nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit 4 (NOX4), a substrate of NADPH that can generate H2 O2 reactive oxygen species, has been reported to be highly expressed in gastrointestinal tumors. In this review we summarize the available evidence on the biological function of NOX4 in digestive system tumors by focusing on its correlation with classical cell signaling pathways, including VEGF, MAPK and PI3K/AKT, and with biochemical mediators, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), activator protein (AP)-1 and transforming growth factor (TGF)-ß. According to the clinical and database studies on tumors of the digestive system, such as colorectal, gastric and pancreatic cancer, there are significant associations between NOX4 expression and tumor prognosis as well as patient's survival. Animal studies using NOX4 inhibitors such as diphenylene iodonium and GKT137831, which selectively block NOX4, indicate their potential as therapeutic agents for targeting cancer cells.


Assuntos
Neoplasias do Sistema Digestório/etiologia , NADPH Oxidase 4/fisiologia , Animais , Neoplasias do Sistema Digestório/tratamento farmacológico , Neoplasias do Sistema Digestório/metabolismo , Humanos , NADPH Oxidase 4/antagonistas & inibidores , NADPH Oxidase 4/genética , NF-kappa B/fisiologia , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/fisiologia
15.
Drug Discov Ther ; 12(2): 58-67, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29760339

RESUMO

Liver fibrosis results from chronic inflammation that precipitates excessive accumulation of extracellular matrix. Oxidative stress is involved in its pathogenesis. This study aimed to elucidate the potential antifibrotic effect of the NADPH oxidase (NOX) inhibitor, apocynin against concanavalin A (ConA)-induced immunological model of liver fibrosis, and to investigate the ability of the antioxidant, alpha-lipoic acid (α-LA) to potentiate this effect. Rats were treated with apocynin and/or α-LA for six weeks. Hepatotoxicity indices, oxidative stress, insulin, NOXs, inflammatory and liver fibrosis markers were assessed. Treatment of animals with apocynin and α-LA significantly ameliorated the changes in liver functions and histopathological architecture induced by ConA. Liver fibrosis induced by ConA was evident where alpha-smooth muscle actin and transforming growth factor- beta1 were elevated, which was further confirmed by Masson's trichrome stain and increased hydroxyproline. Co-treatment with apocynin and α-LA significantly reduced their expression. Besides, apocynin and α-LA significantly ameliorated oxidative stress injury evoked by ConA, as evidenced by enhancing reduced glutathione content, antioxidant enzymes activities and decreasing lipid peroxides. ConA induced a significant elevation in serum insulin level and inflammatory markers; tumor necrosis factor-alpha, interleukin-6 and nuclear factor kappa b. Furthermore, the mRNA tissue expression of NOXs 1 and 4 was found to be elevated in the ConA group. All these elevations were significantly reduced by apocynin and α-LA co-treatment. These findings indicate that using apocynin and α-LA in combination possess marked antifibrotic effects, and that NOX enzymes are partially involved in the pathogenesis of ConA-induced liver fibrosis.


Assuntos
Acetofenonas/administração & dosagem , Concanavalina A/efeitos adversos , Cirrose Hepática/tratamento farmacológico , NADPH Oxidase 1/genética , NADPH Oxidase 4/genética , Ácido Tióctico/administração & dosagem , Acetofenonas/farmacologia , Animais , Modelos Animais de Doenças , Sinergismo Farmacológico , Quimioterapia Combinada , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Fígado/fisiopatologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/enzimologia , Testes de Função Hepática , Masculino , NADPH Oxidase 1/antagonistas & inibidores , NADPH Oxidase 4/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ácido Tióctico/farmacologia
16.
Am J Physiol Renal Physiol ; 315(3): F583-F594, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29846114

RESUMO

Maternal undernutrition (MUN) during pregnancy leads to low-birth weight (LBW) neonates that have a reduced kidney nephron endowment and higher morbidity as adults. Using a severe combined caloric and protein-restricted mouse model of MUN to generate LBW mice, we examined the progression of renal insufficiency in LBW adults. Through 6 mo of age, LBW males experienced greater albuminuria (ELISA analysis), a more rapid onset of glomerular hypertrophy, and a worse survival rate than LBW females. In contrast, both sexes experienced a comparable progressive decline in renal vascular density (immunofluorescence analysis), renal blood flow (Laser-Doppler flowmetry analysis), glomerular filtration rate (FITC-sinistrin clearance analysis), and a progressive increase in systemic blood pressure (measured via tail-cuff method). Isolated aortas from both LBW sexes demonstrated reduced vasodilation in response to ACh, indicative of reduced nitric oxide bioavailability and endothelial dysfunction. ELISA and immunofluorescence analysis revealed a significant increase of circulating reactive oxygen species and NADPH oxidase type 4 (NOX4) expression in both LBW sexes, although these increases were more pronounced in males. Although more effective in males, chronic tempol treatment did improve all observed pathologies in both sexes of LBW mice. Chronic NOX4 inhibition with GKT137831 was more effective than tempol in preventing pathologies in LBW males. In conclusion, despite some minor differences, LBW female and male adults have a reduced nephron endowment comparable with progressive renal and vascular dysfunction, which is associated with increased oxidative stress and subsequent endothelial dysfunction. Tempol treatment and/or NOX4 inhibition attenuates renal and vascular dysfunction in LBW adults.


Assuntos
Peso ao Nascer , Taxa de Filtração Glomerular , Nefropatias/fisiopatologia , Rim/fisiopatologia , Desnutrição/fisiopatologia , Estresse Oxidativo , Efeitos Tardios da Exposição Pré-Natal , Fatores Etários , Fenômenos Fisiológicos da Nutrição Animal , Animais , Animais Recém-Nascidos , Antioxidantes/farmacologia , Restrição Calórica , Óxidos N-Cíclicos/farmacologia , Dieta com Restrição de Proteínas , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Hemodinâmica , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Nefropatias/metabolismo , Nefropatias/patologia , Nefropatias/prevenção & controle , Masculino , Desnutrição/metabolismo , Fenômenos Fisiológicos da Nutrição Materna , Camundongos , NADPH Oxidase 4/antagonistas & inibidores , NADPH Oxidase 4/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Gravidez , Pirazóis/farmacologia , Piridinas/farmacologia , Circulação Renal , Marcadores de Spin
17.
Cell Physiol Biochem ; 47(2): 458-474, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29794432

RESUMO

BACKGROUND/AIMS: Sepsis is a severe and complicated syndrome that is characterized by dysregulation of host inflammatory responses and organ failure. Cystathionine-γ-lyase (CSE)/ hydrogen sulfide (H2S) has potential anti-inflammatory activities in a variety of inflammatory diseases. NADPH oxidase 4 (Nox4), a member of the NADPH oxidases, is the major source of reactive oxygen species (ROS) and its expression is increased in sepsis, but its function in CSE-mediated anti-inflammatory activities remains unknown. METHODS: Macrophages were either transfected with CSE, Nox4 siRNA or transduced with lentiviral vector encoding CSE or Nox4, and then stimulated with lipopolysaccharide (LPS). The expression of inflammatory mediators and signaling pathway activation were measured by quantitative PCR (qPCR), ELISA, and immunoblotting. LPS-induced shock severity in WT, Nox4 knockdown and CSE knockout (CSE-/-) mice was assessed. RESULTS: Here we showed that CSE and Nox4 were upregulated in macrophage and mouse in response to LPS. After LPS stimulation, the inflammatory responses were significantly ameliorated by lentiviral Nox4 shRNA knockdown, but were exacerbated by lentiviral overexpressing Nox4. Furthermore, Nox4 mediated inflammation through PI3K/Akt and p-p38 mitogen-activated protein kinase signal pathway. Notably, CSE knockout served to amplify the inflammatory cascade by increasing Nox4-ROS signaling activation in septic mice and macrophage. Similarly, the enhanced production of inflammatory mediators by macrophages was reduced by CSE overexpression. CONCLUSION: Thus, we demonstrated that CSE/H2S attenuated LPS-induced sepsis against oxidative stress and inflammation damage probably largely through mediated Nox4 pathway.


Assuntos
Sulfeto de Hidrogênio/farmacologia , Lipopolissacarídeos/farmacologia , NADPH Oxidase 4/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Cistationina gama-Liase/deficiência , Cistationina gama-Liase/genética , Citocinas/análise , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidase 4/antagonistas & inibidores , NADPH Oxidase 4/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células RAW 264.7 , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
18.
Acta Pharmacol Sin ; 39(9): 1439-1452, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29671417

RESUMO

Cyanidin is polyphenolic pigment found in plants. We have previously demonstrated that cyanidin protects nerve cells against Aß25-35-induced toxicity by decreasing oxidative stress and attenuating apoptosis mediated by both the mitochondrial apoptotic pathway and the ER stress pathway. To further elucidate the molecular mechanisms underlying the neuroprotective effects of cyanidin, we investigated the effects of cyanidin on neuroinflammation mediated by the TLR4/NOX4 pathway in Aß25-35-treated human neuroblastoma cell line (SK-N-SH). SK-N-SH cells were exposed to Aß25-35 (10 µmol/L) for 24 h. Pretreatment with cyanidin (20 µmol/L) or NAC (20 µmol/L) strongly inhibited the NF-κB signaling pathway in the cells evidenced by suppressing the degradation of IκBα, translocation of the p65 subunit of NF-κB from the cytoplasm to the nucleus, and thereby reducing the expression of iNOS protein and the production of NO. Furthermore, pretreatment with cyanidin greatly promoted the translocation of the Nrf2 protein from the cytoplasm to the nucleus; upregulating cytoprotective enzymes, including HO-1, NQO-1 and GCLC; and increased the activity of SOD enzymes. Pretreatment with cyanidin also decreased the expression of TLR4, directly improved intracellular ROS levels and regulated the activity of inflammation-related downstream pathways including NO production and SOD activity through TLR4/NOX4 signaling. These results demonstrate that TLR4 is a primary receptor in SK-N-SH cells, by which Aß25-35 triggers neuroinflammation, and cyanidin attenuates Aß-induced inflammation and ROS production mediated by the TLR4/NOX4 pathway, suggesting that inhibition of TLR4 by cyanidin could be beneficial in preventing neuronal cell death in the process of Alzheimer's disease.


Assuntos
Antocianinas/farmacologia , Inflamação/metabolismo , NF-kappa B/metabolismo , Neuroblastoma/metabolismo , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais/efeitos dos fármacos , Acetilcisteína/farmacologia , Peptídeos beta-Amiloides , Anti-Inflamatórios não Esteroides/farmacologia , Linhagem Celular Tumoral , Humanos , Inflamação/induzido quimicamente , NADPH Oxidase 4/antagonistas & inibidores , NADPH Oxidase 4/metabolismo , Fragmentos de Peptídeos , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/metabolismo
19.
Redox Biol ; 17: 99-111, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29684820

RESUMO

PARP inhibitors have been widely tested in clinical trials, especially for the treatment of breast cancer and ovarian cancer, and were shown to be highly successful. Because PARP primarily functions in sensing and repairing DNA strand breaks, the therapeutic effect of PARP inhibition is generally believed to be attributed to impaired DNA repair. We here report that oxidative stress is also increased by PARP inhibition and mediates the antitumor effect. We showed that PARP1 is highly expressed in specimens of high grade serous ovarian carcinoma and its activity is required for unperturbed proliferation of ovarian cancer cells. Inhibition or depletion of PARP leads to not only an increase in DNA damage, but also an elevation in the levels of reactive oxygen species (ROS). Importantly, antioxidant N-acetylcysteine (NAC) significantly attenuated the induction of DNA damage and the perturbation of proliferation by PARP inhibition or depletion. We further showed that NADPH oxidases 1 and 4 were significantly upregulated by PARP inhibition and were partially responsible for the induction of oxidative stress. Depletion of NOX1 and NOX4 partially rescued the growth inhibition of PARP1-deficient tumor xenografts. Our findings suggest that in addition to compromising the repair of DNA damage, PARP inhibition or depletion may exert extra antitumor effect by elevating oxidative stress in ovarian cancer cells.


Assuntos
NADPH Oxidase 1/genética , NADPH Oxidase 4/genética , Neoplasias Ovarianas/tratamento farmacológico , Poli(ADP-Ribose) Polimerase-1/genética , Animais , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , NADPH Oxidase 1/antagonistas & inibidores , NADPH Oxidase 4/antagonistas & inibidores , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Estresse Oxidativo/efeitos dos fármacos , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Espécies Reativas de Oxigênio/metabolismo , Análise Serial de Tecidos , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Cell Physiol Biochem ; 46(2): 781-792, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29621765

RESUMO

BACKGROUND/AIMS: Nuclear erythroid 2-related factor-2 (Nrf2) is a major stress-response transcription factor that has been implicated in regulating ischemic angiogenesis. We investigated the effects of Nrf2 in regulating revascularization and modulating acute lung injury. METHODS: The expression of Nrf2 and sirtuin1 (Sirt1) was assessed in lung tissue by western blotting and immunofluorescence staining after intestinal ischemia/reperfusion (IIR) in Nrf2-/- and wild-type (WT) mice. The involvement of Nrf2 in angiogenesis, cell viability, and migration was investigated in human pulmonary microvascular endothelial cells (PMVECs). Additionally, the influence of Nrf2 expression on NOX pathway activation was measured in PMVECs after oxygen-glucose deprivation/reoxygenation. RESULTS: We found activation and nuclear accumulation of Nrf2 in lung tissue after IIR. Compared to IIR in WT mice, IIR in Nrf2-/- mice significantly enhanced leukocyte infiltration and collagen deposit, and inhibited endothelial cell marker CD31 expression. Nrf2 upregulation and translocation into the nucleus stimulated by Sirt1 overexpression exhibited remission of histopathologic changes and enhanced CD31 expression. Nrf2 knockdown repressed non-phagocytic cell oxidase 4 (NOX4), hypoxia-inducible factor (HIF-1α) and vascular endothelial growth factor (VEGF) expression after IIR. Nrf2 upregulation by Sirt1 enhances NOX4, HIF-1α and VEGF expression after IIR in WT mice. Furthermore, Nrf2 knockdown suppressed cell viability, capillary tube formation and cell migration in PMVECs after oxygen-glucose deprivation/reoxygenation and also inhibited NOX4, HIF-1 and VEGF expression. Moreover, NOX4 knockdown in PMVECs decreased the levels of VEGF, HIF-1α and angiogenesis. CONCLUSION: Nrf2 stimulation by Sirt1 plays an important role in sustaining angiogenic potential through NOX4-mediated gene regulation.


Assuntos
Lesão Pulmonar Aguda/patologia , NADPH Oxidase 4/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Traumatismo por Reperfusão/patologia , Sirtuína 1/metabolismo , Lesão Pulmonar Aguda/complicações , Lesão Pulmonar Aguda/metabolismo , Animais , Hipóxia Celular , Células Cultivadas , Colágeno/metabolismo , Regulação para Baixo , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Leucócitos/citologia , Leucócitos/imunologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidase 4/antagonistas & inibidores , NADPH Oxidase 4/genética , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/genética , Neovascularização Fisiológica , Traumatismo por Reperfusão/complicações , Sirtuína 1/genética , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/metabolismo
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