Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.297
Filtrar
1.
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
2.
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
3.
Zhonghua Gan Zang Bing Za Zhi ; 27(9): 677-680, 2019 Sep 20.
Artigo em Chinês | MEDLINE | ID: mdl-31594091

RESUMO

Objective: To study the effect of benazepril on the expression of nuclear factor E2 related factor 2 (Nrf2), nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) and reactive oxygen species (ROS) concentration in rats with hepatic fibrosis and to explore the possible antifibrotic mechanism of benazepril. Methods: Twenty-two healthy male Sprague-Dawley rats were randomly divided into 3 groups: control group (6 rats), model group (8 rats) and benazepril treatment group (8 rats). Two rats died during modeling and treatment in the model group and the benazepril treatment group, and a model of hepatic fibrosis induced by carbon tetrachloride (CCL(4)) was established. The rats in benazepril group were given benazepril for 8 weeks by gastric gavage. The assessment of liver tissue damage in each group was measured using conventional hematoxylin-eosin and Masson staining. The mRNA level of Nrf2, NOX4 in liver tissue was detected by RT-PCR, and serum ROS concentration was determined by colorimetry. All data were expressed in mean ± standard deviations, and were analyzed using SPSS21.0 statistical software. The data were compared using one-way analysis of variance, and the LSD-t method was used for pairwise comparison between the two groups. The correlation analysis was performed by Spearman's correlation analysis. Results: In the liver of the model group, with the aggravation of liver fibrosis the expression of Nrf2mRNA, NOX4 mRNA and ROS concentration were higher than control group [(4.01 ± 3.40), (31.78 ± 3.96), (1.82 ± 0.46) µg/ ml vs. (0.12 ± 0.11), (2.03 ± 0.31), (1.56±0.84) µg/ml, P < 0.05]. After benazepril treatment, NOX4 mRNA expression and ROS concentration were decreased than the model group [(15.93 ± 5.01), (0.78 ± 0.44) µg/ml vs. (31.78 ± 3.96), (1.82 ± 0.46) µg /ml, P < 0.05], while Nrf2 mRNA expression was higher than the model group [(6.69 ± 4.86) vs. (4.01 ± 3.40), P < 0.05]. There was a positive correlation between Nrf2 and NOX4, Nrf2 and ROS, and NOX4 and ROS (r = 0.616, 0.411, 0.802, P < 0.05). Conclusion: Benazepril may exert an anti-hepatic fibrosis effect by activating Nrf2 expression, or may inhibit the ROS-mediated oxidative stress in response to NOX4.


Assuntos
Benzazepinas/farmacologia , Cirrose Hepática/tratamento farmacológico , NADPH Oxidase 4/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Cirrose Hepática/metabolismo , Masculino , Estresse Oxidativo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
4.
Zhonghua Nei Ke Za Zhi ; 58(10): 770-776, 2019 Oct 01.
Artigo em Chinês | MEDLINE | ID: mdl-31594176

RESUMO

Objective: To observe the levels of serum reactive oxygen species (ROS) and hydrogen sulfide(H(2)S) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD), and nicotinamide adenine dinucleotide phosphate-reduced (NADPH) oxidase 4 (NOX4) and cystathionine-γ-lyase (CSE) in lung tissue of patients with stable chronic obstructive pulmonary disease (COPD). Methods: (1) A total of 60 patients with AECOPD admitted to the Department of Respiratory Medicine at Ningxia Hui People's Hospital from November 2015 to December 2016 were recruited. According to the results of pulmonary function and echocardiography, the participants were divided into AECOPD-related pulmonary hypertension (PH) group(A) and AECOPD non-PH group (B).Other 30 healthy subjects were selected as the control group (C).Serum ROS and H(2)S of group A, B and C were detected by enzyme-linked immunosorbent assay (ELISA).(2)The lung tissues of patients undergoing lobectomy for lung cancer from November 2012 to April 2017 were collected, who were divided into COPD-related PH group (D), COPD non-PH group (E) and negative control (F). The expression of NOX4 and CSE protein in lung tissue was detected by immunohistochemistry and the thickness of pulmonary arteriole wall was measured. Results: (1)The serum ROS level in group A was higher than group B and C which were (613.52±69.66)IU/ml,(565.76±71.33)IU/ml, (294.63±60.39)IU/ml, respectively with that in group B higher than that in group C (P<0.05). Serum H(2)S level in group A was lower than group B and C, with that in group B lower than group C [(18.59±5.50) nmol/ml, (20.49±4.97) nmol/ml, (38.03±4.43) nmol/ml, respectively P<0.05]. ROS level was positively correlated with pulmonary systolic pressure (PASP) (r=0.59, P<0.05), H(2)S level was negatively correlated with PASP(r=-0.62, P<0.05).(2)The lung tissue expression of NOX4 in group D was higher than group E and F (P<0.05), which were 0.08±0.01,0.06±0.01,0.03±0.01, respectively,while the level of NOX4 in group E was higher than group F (P<0.05). The expression of CSE between group D, E and F were all significantly different (P<0.05),which were 0.03±0.01, 0.07±0.02,0.12±0.02, respectively.(3)Smooth muscle thickness of pulmonary arterioles as a percentage of vascular diameter (WT%) between group D, E and F was all different(P<0.05), which were (40.58±6.63)%,(36.87±5.60)%,(31.27±6.24)%, respectively; so was smooth muscle area of pulmonary arterioles as a percentage of total vascular area(WA%) with (32.33±6.27)%, (30.20±5.28)%, (25.20±4.31)%, respectively (P<0.05). (4)The expression of NOX4 was positively correlated with WT% and WA%, r was 0.81 and 0.66, respectively (P<0.05). The expression of CSE was negatively correlated with WT% and WA%, r was -0.55 and -0.39 respectively (P<0.05). Conclusions: NOX4/ROS and CSE/H(2)S signaling pathways may play an important role in the pathogenesis of COPD related PH.


Assuntos
Cistationina gama-Liase/metabolismo , Cistationina/metabolismo , Sulfeto de Hidrogênio/sangue , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , NADPH Oxidase 4/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Espécies Reativas de Oxigênio/sangue , Estudos de Casos e Controles , Humanos , Hipertensão Pulmonar/sangue , Oxirredutases , Doença Pulmonar Obstrutiva Crônica/sangue
5.
Invest Ophthalmol Vis Sci ; 60(13): 4215-4223, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31618425

RESUMO

Purpose: To elucidate the mechanism whereby miR-590-3p regulates pyroptosis in diabetic retinopathy (DR). Methods: Human retinal microvascular endothelial cells (HRMECs) incubated with high glucose (HG) were used to establish cell models, and the expression levels of miR-590-3p, caspase-1, IL-1ß, NLRP1, NOX4, TXNIP, NLRP3, and ROS were determined. Additionally, miR-590-3p was altered using a mimic or an inhibitor, and siRNAs targeting NLRP1 and NOX4 were applied to explore the regulatory mechanism of miR-590-3p in DR. The relationships between miR-590-3p and NLRP1/NOX4 also were investigated using a luciferase reporter assay. Furthermore, vitreous tissue samples were collected to confirm pyroptosis in clinical DR. Results: Downregulated miR-590-3p and upregulated NLRP1/NOX4 levels were observed in a cell culture model of DR. Inhibiting miR-590-3p upregulated NLRP1, the NOX4/ROS/TXNIP/NLRP3 pathway, and caspase-1. NLRP1 and NOX4 were confirmed as direct target genes of miR-590-3p. The overexpression of miR-590-3p or knockdown of NLRP1 and NOX4 increased cell activity and suppressed pyroptosis. Intriguingly, the upregulation of IL-1ß induced the downregulation of miR-590-3p by lowering the DNA promoter activity of pri-miR-590. Conclusions: HG induced pyroptosis in a cell culture model of DR, and the downregulation of miR-590-3p promoted pyroptotic death by targeting NLRP1 and activating the NOX4/ROS/TXNIP/NLRP3 pathway via an IL-1ß-mediated positive feedback loop.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Retinopatia Diabética/metabolismo , Células Endoteliais/metabolismo , MicroRNAs/fisiologia , NADPH Oxidase 4/metabolismo , Piroptose/fisiologia , Células Cultivadas , Humanos , MicroRNAs/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/fisiologia
6.
Molecules ; 24(18)2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31547324

RESUMO

Oxidative stress is one of the primary factors leading to endothelial dysfunction, a major underlying cause of vascular disorders. This study aims to understand the key signalling pathways regulated by sorghum (Shawaya short black 1 variety; characterised to be very high in its antioxidant activity) under oxidative stress in endothelial cells. Human umbilical vein endothelial cells (HUVECs) were pre-treated with non-cytotoxic concentrations of phenolic-rich black sorghum extract (BSE) prior to induction of oxidative stress using hydrogen peroxide (H2O2). Treatment with BSE upregulated the expression of heme oxygenase 1 (HO1) and endothelial nitric oxide synthase (eNOS) and downregulated the levels of NADPH oxidase 4 (NOX4). BSE treatment significantly reduced the expression of pro-inflammatory mediators such as monocyte chemoattractant protein 1 (MCP1) and intracellular adhesion molecule 1 (ICAM1). Results from this study suggest that phenolic-rich BSE may reduce oxidative stress by regulating pro- and antioxidant signalling pathways and the expression of inflammatory mediators linked to endothelial dysfunction under oxidative stress.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/genética , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Sorghum/química , Antioxidantes/metabolismo , Apirase/genética , Heme Oxigenase-1/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/tratamento farmacológico , Mediadores da Inflamação/metabolismo , Molécula 1 de Adesão Intercelular/genética , NADPH Oxidase 4/genética , Óxido Nítrico Sintase Tipo III/genética , Estresse Oxidativo/genética , Fenóis/química , Fenóis/farmacologia , Extratos Vegetais/química
7.
Chem Biol Interact ; 313: 108818, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31494106

RESUMO

Diabetic nephropathy (DN) is a common complication of diabetes that remains the major cause of end-stage renal disease (ESRD). Forkhead box P1 (FOXP1) is a member of FOX family involved in the progression of diabetes. However, the pathogenic role of FOXP1 in DN remains unclear. This study was aimed to explore the effects of FOXP1 on glomerular mesangial cells (MCs) in response to high glucose (HG) stimulation. We found that HG stimulation markedly inhibited the FOXP1 expression in MCs in dose-and time-dependent manner. CCK-8 assay proved that FOXP1 overexpression attenuated HG-induced cell proliferation in MCs. FOXP1 exhibited anti-oxidative activity in HG-induced MCs, as proved by the decreased production of ROS and expressions of ROS producing enzymes, NADPH oxidase (NOX) 2 and NOX4. Besides, FOXP1 suppressed the expression and secretion of extracellular matrix (ECM) proteins including collagen IV (Col IV) and fibronectin (FN). Furthermore, FOXP1 overexpression significantly prevented HG-induced activation of Akt/mTOR signaling in MCs, and Akt activator blocked FOXP1-mediated cell proliferation, ROS production and ECM accumulation in MCs. Collectively, FOXP1 prevented HG-induced proliferation, oxidative stress, and ECM accumulation in MCs via inhibiting the activation of Akt/mTOR signaling pathway. The findings suggested that FOXP1 might be a therapeutic target for the treatment of DN.


Assuntos
Matriz Extracelular/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Glucose/metabolismo , Células Mesangiais/metabolismo , Proteínas Repressoras/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Colágeno Tipo IV/metabolismo , Relação Dose-Resposta a Droga , Matriz Extracelular/efeitos dos fármacos , Fibronectinas/metabolismo , Fatores de Transcrição Forkhead/genética , Glucose/administração & dosagem , Glucose/farmacologia , Humanos , Células Mesangiais/efeitos dos fármacos , NADPH Oxidase 2/metabolismo , NADPH Oxidase 4/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Repressoras/genética , Serina-Treonina Quinases TOR/metabolismo
8.
Int J Mol Sci ; 20(17)2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31466336

RESUMO

Reactive oxygen species (ROS) which lead to oxidative stress affect ovarian function. Grape seed extract (GSE) could be proposed as an effective antioxidant, particularly due to its proanthocyanidin content. In this study, we investigated a dose effect (0, 0.01, 0.1, 1, 10, 50, and 100 µg/mL) of GSE and proanthocyanidin B2 (GSPB2) on the ROS content, cell proliferation, cell viability, and steroidogenesis in both primary luteinized granulosa cells (hGC) and the tumor granulosa cell line (KGN). The levels of ROS were measured using ROS-Glo assay. Cell proliferation and viability were evaluated by [3H]-thymidine incorporation and Cell Counting Kit-8 (CCK8) assay, respectively. Steroid secretion was evaluated by radioimmunoassay. We also analyzed the cell cycle component protein level and signaling pathways by immunoblot and the NOX4 mRNA expression by RTqPCR. From 0.1 to 1 µg/mL, GSE and GSBP2 reduced the ROS cell content and the NOX4 mRNA levels, whereas, GSE and GSBP2 increased the ROS cell content from 50 to 100 µM in both hGC and KGN. GSE and GSPB2 treatments at 50 and 100 µg/mL induced a delay in G1 to S phase cell cycle progression as determined by fluorescence-activated cell sorting. Consequently, they reduced cell growth, cyclin D2 amount, and Akt phosphorylation, and they increased protein levels of p21 and p27 cyclin-dependent kinase inhibitors. These data were also associated with an increase in cell death that could be due to a reduction in Bcl-2-associated death promoter (BAD) phosphorylation and an increase in the cleaved-caspase-3 level. All these negative effects were not observed at lower concentrations of GSE and GSPB2 (0.01 to 10 µg/mL). Interestingly, we found that GSE and GSPB2 treatments (0.1 to 100 µg/mL) improved progesterone and estradiol secretion and this was associated with a higher level of the cholesterol carriers, StAR (steroidogenic acute regulatory protein), CREB (Cyclic adenosine monophosphate Response Element-binding protein), and MAPK ERK1/2 (Mitogen-Activated Protein Kinases Extracellular signal-Regulated Kinases 1/2) phosphorylation in both hGC and KGN cells. Taken together, GSE and GSPB2 (0.1-10 µg/mL) in vitro treatments decrease oxidative stress and increase steroidogenesis without affecting cell proliferation and viability in human granulosa cells.


Assuntos
Antioxidantes/farmacologia , Tumor de Células da Granulosa/metabolismo , Células da Granulosa/efeitos dos fármacos , Extrato de Sementes de Uva/farmacologia , Proantocianidinas/farmacologia , Esteroides/metabolismo , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Ciclina D2/genética , Ciclina D2/metabolismo , Proteínas Inibidoras de Quinase Dependente de Ciclina/genética , Proteínas Inibidoras de Quinase Dependente de Ciclina/metabolismo , Feminino , Células da Granulosa/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases , NADPH Oxidase 4/genética , NADPH Oxidase 4/metabolismo , Estresse Oxidativo
9.
Biosci Biotechnol Biochem ; 83(11): 1992-1999, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31362597

RESUMO

The present study focused on the effect of paeonol, one of the main components of Guizhi Fuling Pill, on blood pressure, cerebral blood flow, and vascular endothelium injury in spontaneously hypertensive rats to provide theoretical basis for the treatment of hypertension. After treatment with paeonol, the mean arterial pressure (MAP) of LSHRT and HSHRT rats decreased gradually with the prolongation of treatment time. The systolic blood flow velocity (Vs), diastolic blood flow velocity (Vd) and mean blood flow velocity (Vm) were significantly increased after paeonol treatment (p < 0.05). Paeonol effectively improved the blood pressure and increased the cerebral blood flow velocity in spontaneously hypertensive rats. This may be related to the fact that paeonol reduced the blood viscosity and the oxidative stress and improved the antioxidant capacity. Moreover, paeonol protected vascular endothelial cells and reduced vascular endothelial injury in spontaneously hypertensive rats.


Assuntos
Acetofenonas/farmacologia , Endotélio Vascular/efeitos dos fármacos , Hipertensão/prevenção & controle , Animais , Pressão Sanguínea/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Hemorreologia/efeitos dos fármacos , Hipertensão/metabolismo , Hipertensão/patologia , Hipertensão/fisiopatologia , Masculino , NADPH Oxidase 4/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Molécula 1 de Adesão de Célula Vascular/metabolismo
10.
Am J Chin Med ; 47(5): 1113-1131, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31352786

RESUMO

Pulmonary fibrosis (PF) is characterized by myofibroblast activation, which can be triggered by oxidative stress. In this study, we investigated the antifibrotic effect of the ethyl acetate extract of Salvia miltiorrhiza (EASM) on PF and examined the underlying molecular mechanism. EASM suppressed myofibroblast activation with reduced extracellular matrix deposition in the lungs of mice subjected to bleomycin (BLM) challenge, demonstrating the inhibitory effects on PF. EASM positively alleviated oxidative stress by upregulating nuclear factor-erythroid 2-related factor 2 (Nrf2) and concomitantly downregulating NADPH oxidase 4 (Nox4) in the lungs of BLM-treated mice. This effect was also observed in an in vitro model of transforming growth factor beta 1 (TGF-ß1)-stimulated fibroblast activation. EASM reduced reactive oxygen species (ROS) generation in fibroblasts by stabilizing Nrf2 protein with promoting kelch-like ECH-associated protein 1 (Keap1) degradation. Nrf2 knockdown in the lungs of BLM-treated mice diminished the inhibitory effects of EASM on fibrosis, providing evidence in vivo to address the unique role of Nrf2. Additionally, EASM inhibited TGF-ß1/Smad3 signaling by downregulating protein kinase C delta (PKC-δ) and Smad3 phosphorylation (p-Smad3), which led to suppression of the TGF-ß1-induced fibrogenic response. These results indicate that EASM exhibits potent antifibrotic activity in vitro and in vivo, which might be associated with activation of Nrf2 pathway and inhibition of TGF-ß1/Smad3 pathway. Our findings support that EASM may act as an effective antifibrotic remedy for PF.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , NADPH Oxidase 4/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Salvia miltiorrhiza/química , Animais , Feminino , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , NADPH Oxidase 4/genética , Fator 2 Relacionado a NF-E2/genética , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo
11.
EMBO J ; 38(15): e100871, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31304984

RESUMO

Reactive oxygen species (ROS) are emerging as important regulators of cancer growth and metastatic spread. However, how cells integrate redox signals to affect cancer progression is not fully understood. Mitochondria are cellular redox hubs, which are highly regulated by interactions with neighboring organelles. Here, we investigated how ROS at the endoplasmic reticulum (ER)-mitochondria interface are generated and translated to affect melanoma outcome. We show that TMX1 and TMX3 oxidoreductases, which promote ER-mitochondria communication, are upregulated in melanoma cells and patient samples. TMX knockdown altered mitochondrial organization, enhanced bioenergetics, and elevated mitochondrial- and NOX4-derived ROS. The TMX-knockdown-induced oxidative stress suppressed melanoma proliferation, migration, and xenograft tumor growth by inhibiting NFAT1. Furthermore, we identified NFAT1-positive and NFAT1-negative melanoma subgroups, wherein NFAT1 expression correlates with melanoma stage and metastatic potential. Integrative bioinformatics revealed that genes coding for mitochondrial- and redox-related proteins are under NFAT1 control and indicated that TMX1, TMX3, and NFAT1 are associated with poor disease outcome. Our study unravels a novel redox-controlled ER-mitochondria-NFAT1 signaling loop that regulates melanoma pathobiology and provides biomarkers indicative of aggressive disease.


Assuntos
Melanoma/patologia , Proteínas de Membrana/metabolismo , Fatores de Transcrição NFATC/metabolismo , Oxirredução , Isomerases de Dissulfetos de Proteínas/metabolismo , Tiorredoxinas/metabolismo , Animais , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Progressão da Doença , Retículo Endoplasmático/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Melanoma/metabolismo , Proteínas de Membrana/genética , Camundongos , Mitocôndrias/metabolismo , NADPH Oxidase 4/metabolismo , Transplante de Neoplasias , Transporte Proteico , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Análise de Sobrevida , Tiorredoxinas/genética , Regulação para Cima
12.
Biomed Res Int ; 2019: 7284767, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281844

RESUMO

The potential of oxidized-LDL (Ox-LDL) to elicit inflammatory responses in macrophages leading to the atherosclerosis (AS) progression is well known. Since proprotein convertase subtilisin/Kexin-9 (PCSK-9), the posttranslational regulator of LDL-receptor, is associated with elevated LDL in the circulation, the present report was aimed to uncover the ameliorative effects of Ginkgolide B, a terpenic lactone from Ginkgo biloba, against Ox-LDL-induced alterations in cholesterol metabolism in HUVECs. Consequently, our results demonstrated that incubation with Ox-LDL significantly upregulated the PCSK-9 expression in HUVECs, which was significantly downregulated, both at mRNA and protein level, after Ginkgolide B treatment via subsequent suppression of sterol element binding protein (SREBP-2) expression. Moreover, Ginkgolide B-mediated inhibition of PCSK-9 activity was also validated by in silico methods which revealed that it interferes the PSCK-9 interaction with LDL-receptor (LDL-R). Interestingly, Ox-LDL-induced LDL-R expression was further enhanced by Ginkgolide B treatment in HUVECs. Moreover, Ginkgolide B treatment lead to downregulation of lectin-like Ox-LDL receptor (LOX-1) and NADPH oxidase (NOX-4) expression which was upregulated in Ox-LDL-treated HUVECs, along with the attenuation of mitochondrial ROS generation. Furthermore, Ginkgolide B significantly inhibited the augmented expression of intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) in Ox-LDL-activated HUVECs. Ginkgolide B also significantly ameliorated the inflammatory response in Ox-LDL-activated HUVECs by suppressing the expression of IL-1α, IL-1ß, IL-6, CXCL-1, CXCL-2, and monocyte chemotactic protein (MCP-1), at mRNA and protein level. Our in vitro and in silico study established that Ginkgolide B alleviated the Ox-LDL-induced inflammatory cascades and altered lipid metabolism in HUVECs by suppressing the PCSK-9 and, thus, could be established as a treasured alternative therapeutic candidate in the atherosclerosis management.


Assuntos
Ginkgolídeos/uso terapêutico , Células Endoteliais da Veia Umbilical Humana/metabolismo , Inflamação/tratamento farmacológico , Lactonas/uso terapêutico , Metabolismo dos Lipídeos , Pró-Proteína Convertase 9/metabolismo , Atorvastatina/farmacologia , Moléculas de Adesão Celular/metabolismo , Colesterol/metabolismo , Citocinas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Ginkgolídeos/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Lactonas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipoproteínas LDL/metabolismo , NADPH Oxidase 4/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de LDL/química , Receptores de LDL/metabolismo , Receptores Depuradores Classe E/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo
13.
Eur J Pharmacol ; 857: 172459, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31216444

RESUMO

Previous studies have demonstrated that NADPH oxidase (NOX)/vascular peroxidase (VPO1) pathway - mediated oxidative stress plays an important role in the pathogenesis of multiple cardiovascular diseases. This study aims to evaluate the correlation between NOX/VPO1 pathway and endothelial progenitor cells (EPCs) dysfunctions in hypoxia-induced pulmonary hypertension (PH). The rats were exposed to 10% hypoxia for 3 weeks to establish a PH model, which showed increases in right ventricle systolic pressure, right ventricular and pulmonary vascular remodeling, acceleration in apoptosis and impairment in functions of the peripheral blood derived - EPCs (the reduced abilities in adhesion, migration and tube formation), accompanied by up-regulation of NOX (NOX2 and NOX4) and VPO1. Next, normal EPCs were cultured under hypoxia to induce apoptosis in vitro. Consistent with the in vivo findings, hypoxia enhanced the apoptosis and dysfunctions of EPCs concomitant with an increase in NOX and VPO1 expression, hydrogen peroxide (H2O2) and hypochlorous acid (HOCl) production; these phenomena were attenuated by NOX2 or NOX4 siRNA. Knockdown of VPO1 showed similar results to that of NOX siRNA except no effect on NOX expression and H2O2 production. Based on these observations, we conclude that NOX/VPO1 pathway-derived reactive oxygen species promote the oxidative injury and dysfunctions of EPCs in PH, which may contribute to endothelial dysfunctions in PH.


Assuntos
Células Progenitoras Endoteliais/patologia , Hemeproteínas/metabolismo , Hipertensão Pulmonar/enzimologia , Hipertensão Pulmonar/patologia , NADPH Oxidase 2/metabolismo , NADPH Oxidase 4/metabolismo , Peroxidases/metabolismo , Animais , Apoptose , Hipóxia Celular , Técnicas de Silenciamento de Genes , Hemeproteínas/deficiência , Hemeproteínas/genética , Hipertensão Pulmonar/genética , Masculino , NADPH Oxidase 2/deficiência , NADPH Oxidase 2/genética , NADPH Oxidase 4/deficiência , NADPH Oxidase 4/genética , Peroxidases/deficiência , Peroxidases/genética , Fenótipo , RNA Interferente Pequeno/genética , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
14.
Biomed Pharmacother ; 116: 108923, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31154269

RESUMO

AIMS: The purpose of this study was to investigate plumbagin (PL) on liver fibrosis in vitro and in vivo and to explore the underlying mechanisms. METHODS: Carbon tetrachloride (CCl4) was used to establish a rat liver fibrosis model, primary hepatic stellate cells (HSCs) were isolated from the rat liver, and fibrosis-related indicators were detected. RESULTS: The results revealed that PL significantly prevented CCl4-induced liver fibrosis, as evidenced by the attenuation of histopathological changes, the decrease of MDA and the increase of SOD and GSH-P X . In addition, PL downregulated the mRNA levels of NOX4 and procollagen I; the protein expression levels of NOX4 and p-IκB; and the transcriptional activity of NF-κB in liver fibrosis rats. Moreover, PL significantly decreased ROS expression, protein expression of α-SMA and collagen III, and activation of NF-κB and inhibited the nuclear translocation of NF-κB p65 in IL-1ß-stimulated HSCs in vitro. CONCLUSION: The results of our study indicate that PL can mitigate liver fibrosis in vitro and in vivo, which may be related to the ROS-mediated NF-кB signaling pathway.


Assuntos
Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , NF-kappa B/metabolismo , Naftoquinonas/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Animais , Antioxidantes/metabolismo , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Colágeno Tipo I/metabolismo , Colágeno Tipo III/metabolismo , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Interleucina-1beta/metabolismo , Cirrose Hepática/patologia , Masculino , NADPH Oxidase 4/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , Naftoquinonas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Fator de Transcrição RelA/metabolismo
15.
Methods Mol Biol ; 1982: 447-458, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31172488

RESUMO

The stabilization and activation of NOX4 through its binding with p22phox are well documented; however little is known of the precise manner by which these two proteins interact. In recent years, the field of proteomics has undergone tremendous development with the introduction of many novel methods for the identification and characterization of protein-protein interactions (PPIs). To enhance our understanding of structural determinants leading to the association between NOX4 and p22phox, we developed a binary luciferase reporter assay (NanoBiT®) to quantitatively assess NOX4-p22phox heterodimerization. The complementation reporter quantitatively determines the accurate, reduced, or failed complex assembly, which can be confirmed and further interrogated by analyzing NOX4 catalytic activity (H2O2 release), protein expression, and dimer localization. This association-based PPI technique represents both a much-needed expansion of the NOX4 lead discovery tool box and a versatile method to probe the architecture of NOX and DUOX complexes in the future.


Assuntos
NADPH Oxidase 4/química , NADPH Oxidase 4/metabolismo , NADPH Oxidases/química , NADPH Oxidases/metabolismo , Mapeamento de Interação de Proteínas , Multimerização Proteica , Bioensaio , Linhagem Celular , Espaço Extracelular/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Oxirredução , Ligação Proteica , Mapeamento de Interação de Proteínas/métodos , Espécies Reativas de Oxigênio/metabolismo
16.
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
17.
J Diabetes Res ; 2019: 2981705, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31179339

RESUMO

Diabetic nephropathy (DN) is a serious kidney-related complication of type 1 and type 2 diabetes. The Chinese herbal formula Baoshenfang (BSF) shows therapeutic potential in attenuating oxidative stress and apoptosis in podocytes in DN. This study evaluated the effects of BSF on podocyte injury in vivo and in vitro and explored the possible involvement of the nicotinamide adenine dinucleotide phosphate-oxidase-4/reactive oxygen species- (NOX-4/ROS-) activated p38 pathway. In the identified compounds by mass spectrometry, some active constituents of BSF were reported to show antioxidative activity. In addition, we found that BSF significantly decreased 24-hour urinary protein, serum creatinine, and blood urea nitrogen in DN patients. BSF treatment increased the nephrin expression, alleviated oxidative cellular damage, and inhibited Bcl-2 family-associated podocyte apoptosis in high-glucose cultured podocytes and/or in diabetic rats. More importantly, BSF also decreased phospho-p38, while high glucose-mediated apoptosis was blocked by p38 mitogen-activated protein kinase inhibitor in cultured podocytes, indicating that the antiapoptotic effect of BSF is p38 pathway-dependent. High glucose-induced upexpression of NOX-4 was normalized by BSF, and NOX-4 siRNAs inhibited the phosphorylation of p38, suggesting that the activated p38 pathway is at least partially mediated by NOX-4. In conclusion, BSF can decrease proteinuria and protect podocytes from injury in DN, in part through inhibiting the NOX-4/ROS/p38 pathway.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , NADPH Oxidase 4/metabolismo , Podócitos/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Idoso , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Nefropatias Diabéticas/metabolismo , Feminino , Humanos , Rim/metabolismo , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Podócitos/citologia , Proteinúria/metabolismo , Ratos , Ratos Sprague-Dawley , Método Simples-Cego
18.
Int Immunopharmacol ; 74: 105649, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31185450

RESUMO

Rheumatoid arthritis is a common autoimmune disease primarily characterized by chronic inflammation, the formation of an invasive pannus, and destruction of the joints. In the present study, we employed real-time PCR and western blot analysis to investigate the role of dulaglutide in human fibroblast-like synoviocytes (FLS). The results of our study show that dulaglutide exerted a powerful protective effect by rescuing mitochondrial membrane potential, inhibiting the production of NOX-4, and abrogating TNF-α-induced downregulation of the antioxidant GSH. Our findings demonstrate that dulaglutide significantly ameliorated the expression of proinflammatory cytokines and chemokines including IL-1ß, IL-6, MCP-1, and HMGB-1. Matrix metalloproteinases mediate cartilage destruction, thereby aiding in pannus formation. Our findings indicate that dulaglutide treatment significantly downregulated the expression of MMP-3 and MMP-13, two crucial degradative enzymes. Importantly, the results of our study demonstrate that the beneficial effects of dulaglutide are mediated through the JNK/NF-κB signaling pathway, which has been suggested as a potential treatment target against RA. Taken together, the results of this study show that dulaglutide may exert significant protective effects against the progression of RA induced by TNF-α.


Assuntos
Anti-Inflamatórios/farmacologia , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Fragmentos Fc das Imunoglobulinas/farmacologia , Proteínas Recombinantes de Fusão/farmacologia , Sinoviócitos/efeitos dos fármacos , Citocinas/genética , Citocinas/metabolismo , Fibroblastos , Peptídeos Semelhantes ao Glucagon/farmacologia , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/fisiologia , NADPH Oxidase 4/genética , NADPH Oxidase 4/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Sinoviócitos/metabolismo
19.
Biomed Pharmacother ; 117: 109124, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31228798

RESUMO

AIM: Cardiovascular diseases, such as coronary heart disease and myocardial infarction (MI) are currently considered as the leading causes of death and disability. The aim of the present study is to investigate the effects of Xin-Ji-Er-Kang (XJEK) on kidney injury and renal oxidative stress. In addition, the associated mechanism involved in these processes was examined in an MI model, and particularly focused on the nuclear factor erythroid 2-related factor (NRF2)/heme oxygenase-1 (HO-1) pathway. MATERIALS AND METHODS: A total of 138 Sprague-Dawley rats were used in the present study. The control group was designated as 0 wk (n = 8). A total of 3 phases (2, 4, 6 wk) of administration were used in the sham-operated groups (sham, n = 10), MI groups (MI, n = 10), MI + XJEK groups (XJEK, n = 10) and MI + fosinopril groups (fosinopril, n = 10). Additional 10 rats were used to evaluate the infarct area. At 2, 4 or 6 wk post-MI, the hemodynamic parameters were monitored, the rats were sacrificed, then blood, heart and renal tissues were collected for furtherly analysis. RESULTS: The results indicated that XJEK administration continuously ameliorated renal hypertrophy index, blood urea nitrogen and cystatin C concentrations. XJEK further improved post-MI cardiac function by limiting scar formation and caused a downregulation in the hemodynamic parameters at the end of 2 and 4 wk. The hemodynamic parameters were upregulated after 6 wk treatment with XJEKcompared with those noted in the MI groups. Similarly, XJEK treatment for 2 wk potentiated Nrf2 nuclear translocation and HO-1 expression and inhibited the deficiency of nuclear Nrf2 and HO-1 at 6 wk post-MI compared with that of the MI groups, indicating the attenuation of the renal oxidative stress condition. The levels of malondialdehyde and angiotensin II (Ang II) in plasma and renal tissues, as well as the levels of aldosterone, 8-hydroxydeoxyguanosine, angiotensin II type 1 receptor and NADPH Oxidase-4 in the kidney tissue significantly decreased following XJEK treatment for 6 wk. In addition, the XJEK treatment groups revealed a significant upregulation in the activity of superoxide dismutase and in the total antioxidant capacity activity compared with those noted in the corresponding MI groups. CONCLUSION: These results demonstrated that progressive nephropathy in MI rats was associated with intrarenal activation of the renin-angiotensin-aldosterone system. Concomitantly, this process was associated with oxidative stress and impaired Nrf2 activation. The improvement in the severity of nephropathy by XJEK in this model may be associated with the reversal of these abnormalities.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Heme Oxigenase-1/metabolismo , Rim/lesões , Rim/patologia , Infarto do Miocárdio/complicações , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais , Angiotensina II/metabolismo , Animais , Nitrogênio da Ureia Sanguínea , Cistatina C/metabolismo , Dano ao DNA , Regulação para Baixo/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/fisiopatologia , Infarto do Miocárdio/sangue , Infarto do Miocárdio/fisiopatologia , NADPH Oxidase 4/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/metabolismo , Transdução de Sinais/efeitos dos fármacos
20.
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
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA