Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 12 de 12
Filtrar
1.
Lipids Health Dis ; 17(1): 26, 2018 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-29426338

RESUMO

BACKGROUND: Arachidonic acid (AA) has potent pro-apoptotic effects on cancer cells at a low concentration and on macrophages at a very high concentration. However, the effects of AA on the macrophage cell cycle and related signaling pathways have not been fully investigated. Herein we aim to observe the effect of AA on macrophages cell cycle. RESULTS: AA exposure reduced the viability and number of macrophages in a dose- and time-dependent manner. The reduction in RAW264.7 cell viability was not caused by apoptosis, as indicated by caspase-3 and activated caspase-3 detection. Further research illustrated that AA exposure induced RAW264.7 cell cycle arrested at S phase, and some cell cycle-regulated proteins were altered accordingly. Moreover, JNK signaling was stimulated by AA, and the stimulation was partially reversed by a JNK signaling inhibitor in accordance with cell cycle-related factors. In addition, nuclear and total Foxo1/3a and phosphorylated Foxo1/3a were elevated by AA in a dose- and time-dependent manner, and this elevation was suppressed by the JNK signaling inhibitor. CONCLUSION: Our study demonstrated that AA inhibits macrophage viability by inducing S phase cell cycle arrest. The JNK signaling pathway and the downstream FoxO transcription factors are involved in AA-induced RAW264.7 cell cycle arrest.


Assuntos
Ácido Araquidônico/administração & dosagem , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteína Forkhead Box O1/genética , Macrófagos/efeitos dos fármacos , Animais , Caspase 3/genética , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , MAP Quinase Quinase 4/genética , Camundongos , Fosforilação , Células RAW 264.7 , Fase S/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
2.
Appl Microbiol Biotechnol ; 101(17): 6697-6703, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28710557

RESUMO

α-Toxin, one of the best known pore-forming proteins produced by Staphylococcus aureus (S. aureus), is a critical virulence factor in multiple infections. The necessity of α-toxin for S. aureus pathogenicity suggests that this toxin is an important target for the development of a potential treatment strategy. In this study, we showed that lysionotin, a natural compound, can inhibit the hemolytic activity of culture supernatants by S. aureus by reducing α-toxin expression. Using real-time PCR analysis, we showed that transcription of hla (the gene encoding α-toxin) and agr (the locus regulating hla) was significantly inhibited by lysionotin. Lactate dehydrogenase and live/dead assays indicated that lysionotin effectively protected human alveolar epithelial cells against S. aureus, and in vivo studies also demonstrated that lysionotin can protect mice from pneumonia caused by S. aureus. These findings suggest that lysionotin is an efficient inhibitor of α-toxin expression and shows significant protection against S. aureus in vitro and in vivo. This study supports a potential strategy for the treatment of S. aureus infection by inhibiting the expression of virulence factors and indicates that lysionotin may be a potential treatment for S. aureus pneumonia.


Assuntos
Antibacterianos/farmacologia , Toxinas Bacterianas/antagonistas & inibidores , Toxinas Bacterianas/genética , Flavonoides/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/patogenicidade , Animais , Proteínas de Bactérias/efeitos dos fármacos , Proteínas de Bactérias/genética , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/microbiologia , Proteínas Hemolisinas/efeitos dos fármacos , Proteínas Hemolisinas/genética , Hemólise/efeitos dos fármacos , Humanos , Camundongos , Pneumonia/microbiologia , Pneumonia/prevenção & controle , Reação em Cadeia da Polimerase em Tempo Real , Staphylococcus aureus/genética , Transativadores/efeitos dos fármacos , Transativadores/genética , Fatores de Virulência/genética
3.
Ren Fail ; 38(2): 294-304, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26643903

RESUMO

Diabetic nephropathy (DN) is one of the most common chronic complications of diabetes, which is associated with an increased oxidative stress induced by hyperglycemia and alterations in DJ-1/NF-E2-related factor-2 (Nrf2) pathway. In the present study, we investigated the role and the proper time nodes of DJ-1/Nrf2 pathway in the pathogenesis of DN. Diabetes mellitus (DM) model of rats was induced by intraperitoneal injection of streptozotocin (STZ) on male Sprague-Dawley (SD) rats. Then, the diabetic rats were divided into 4, 8 and 12 weeks groups. As early at 4 weeks of diabetes, renal histologic evaluation score, cystatin C (Cys C), ß2-microglobulin (ß2-MG) and malondialdehyde (MDA) levels were increased, and total antioxidative capacity (T-AOC) level was decreased as compared with that in the control group. The protein expressions of DJ-1, NF-E2-related factor-2 (Nrf2) and heme oxygenase-1 (HO-1) were upregulated compared with the control group from 4 weeks and further increased with the progression of DM. The protein expressions of DJ-1, Nrf2 and HO-1 in renal tissues have good line correlations with renal histologic evaluation score, respectively. Taken together, these results suggested that the activation of DJ-1/Nrf2 pathway was involved in the pathogenesis of diabetic nephropathy in rats.


Assuntos
Nefropatias Diabéticas/etiologia , Fator 2 Relacionado a NF-E2/fisiologia , Proteína Desglicase DJ-1/fisiologia , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
4.
J Mol Biol ; 435(4): 167935, 2023 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-36586462

RESUMO

Golgi-Associated plant Pathogenesis Related protein 1 (GAPR-1) acts as a negative regulator of autophagy by interacting with Beclin 1 at Golgi membranes in mammalian cells. The molecular mechanism of this interaction is largely unknown. We recently showed that human GAPR-1 (hGAPR-1) has amyloidogenic properties resulting in the formation of protein condensates upon overexpression in Saccharomyces cerevisiae. Here we show that human Beclin 1 (hBeclin 1) has several predicted amyloidogenic regions and that overexpression of hBeclin 1-mCherry in yeast also results in the formation of fluorescent protein condensates. Surprisingly, co-expression of hGAPR-1-GFP and hBeclin 1-mCherry results in a strong reduction of hBeclin 1 condensates. Mutations of the known interaction site on the hGAPR-1 and hBeclin 1 surface abolished the effect on condensate formation during co-expression without affecting the condensate formation properties of the individual proteins. Similarly, a hBeclin 1-derived B18 peptide that is known to bind hGAPR-1 and to interfere with the interaction between hGAPR-1 and hBeclin 1, abolished the reduction of hBeclin 1 condensates by co-expression of hGAPR-1. These results indicate that the same type of protein-protein interactions interfere with condensate formation during co-expression of hGAPR-1 and hBeclin 1 as previously described for their interaction at Golgi membranes. The amyloidogenic properties of the B18 peptide were, however, important for the interaction with hGAPR-1, as mutant peptides with reduced amyloidogenic properties also showed reduced interaction with hGAPR-1 and reduced interference with hGAPR-1/hBeclin 1 condensate formation. We propose that amyloidogenic interactions take place between hGAPR-1 and hBeclin 1 prior to condensate formation.


Assuntos
Proteínas Amiloidogênicas , Proteína Beclina-1 , Proteínas de Membrana , Mapeamento de Interação de Proteínas , Animais , Humanos , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Saccharomyces cerevisiae , Mutação , Proteínas Amiloidogênicas/genética , Proteínas Amiloidogênicas/metabolismo , Multimerização Proteica , Domínios e Motivos de Interação entre Proteínas
5.
Neuroreport ; 33(6): 252-258, 2022 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-35275882

RESUMO

OBJECTIVE: Prenatal sevoflurane exposure may pose neurotoxicity to embryonic brain development and lead to cognitive dysfunction in offspring, but the underlying mechanism is still unclear. We aimed to investigate whether sevoflurane could cause neurogenesis abnormality and ferroptosis in embryonic prefrontal cortex (PFC) and to identify the role of nuclear factor-erythroid 2-related factor 2 (Nrf2) in the sevoflurane-related neurotoxicity. METHODS: We used the rodents and primary neural stem cells to examine whether sevoflurane impacted proliferation, differentiation, ferroptosis and apoptosis in the neural stem cells of embryonic PFC. In addition, the expression of Nrf2 and the intensity of reactive oxygen species (ROS) were also assessed to explore the underlying molecular mechanism. RESULTS: Our results showed that sevoflurane exposure in third trimester could lead to neurogenesis inhibition and ferroptosis in-vivo embryonic PFC, with little influence on apoptosis. Moreover, a significant decrease in the expression of Nrf2 as well as an increase in ROS accumulation were also found in neural stem cells after sevoflurane anesthesia. CONCLUSION: We conclude that Nrf2-related neurogenesis inhibition and ferroptosis are a central mechanism contributing to sevoflurane-induced neurotoxicity in embryonic brain. The results of the present study are the first to demonstrate that ferroptosis and the expression of Nrf2 are involved in sevoflurane-related neurotoxicity in embryonic brain, which provides new vision for consideration in anesthesia-associated neurological abnormalities.


Assuntos
Ferroptose , Fator 2 Relacionado a NF-E2 , Feminino , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Neurogênese , Córtex Pré-Frontal/metabolismo , Gravidez , Sevoflurano/toxicidade
6.
J Cardiothorac Surg ; 17(1): 242, 2022 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-36175925

RESUMO

BACKGROUND: Hyperbilirubinemia (HB) is a serious complication in aortic arch surgery, which is associated with acute kidney injury (AKI). The association between HB and chronic kidney disease (CKD) is unknown. The aim of this study was to investigate the impact of HB associated AKI on CKD after aortic arch surgery. METHODS: We reviewed 284 patients who underwent aortic arch surgery from 2016 to 2020 in our hospital. AKI was defined as a 50% increase in sCr from baseline value within the first 7 postoperative days. HB was defined as total bilirubin > 51.3 µmol/L. Patients were divided into 3 groups based on AKI and HB: HB associated AKI (HB-AKI) group (AKI patients suffered HB within the first 7 postoperative days); AKI without HB group and Non-AKI group. RESULTS: Follow-up for 204 patients ranged from 3 to 12 months. Kaplan-Meier analysis showed that the 1-year cumulative incidence of CKD was highest in HB-AKI (32.6%) than AKI without HB (17.8%) and Non-AKI (7.4%, log-rank test, p < 0.001), and the incidence of CKD was higher in HB group than that in Non-HB group (26.7% vs. 13.9%, log-rank test, p = 0.015). Preoperative sCr (HR 1.010, 95% CI 1.004-1.016, p = 0.001), AKI without HB (HR 2.887, 95% CI 1.133-7.354, p = 0.026) and HB-AKI (HR 4.490, 95% CI 1.59-12.933, p = 0.005) were associated with CKD during 1-year follow-up. CONCLUSIONS: Patients suffering HB associated AKI were at more increased odds of CKD than patients suffering AKI without HB after aortic arch surgery.


Assuntos
Injúria Renal Aguda , Insuficiência Renal Crônica , Injúria Renal Aguda/complicações , Injúria Renal Aguda/etiologia , Aorta Torácica/cirurgia , Bilirrubina , Seguimentos , Humanos , Hiperbilirrubinemia/complicações , Insuficiência Renal Crônica/complicações , Estudos Retrospectivos , Fatores de Risco
7.
Artigo em Inglês | MEDLINE | ID: mdl-31157174

RESUMO

α-toxin, an essential virulence factor secreted by Staphylococcus aureus (S. aureus), is a critical exotoxin in multiple infections. In this study, we found that aloe-emodin (AE), a natural compound lacking anti-S. aureus activity, could inhibit the hemolytic activity of α-toxin. Oligomerization assays, molecular dynamics simulations, and fluorescence-quenching analyses were used to determine the mechanism of this inhibition. The oligomerization of α-toxin was restricted by the engagement of AE with K110, T112, and M113 of the toxin, which eventually resulted in inhibition of the hemolytic activity. Lactate dehydrogenase and live/dead assays demonstrated that AE decreased the injury of human lung epithelial cells (A549) and mouse lung macrophages (MH-S) mediated by S. aureus. Furthermore, treatment with AE showed robust protective effects in mice infected by S. aureus. These findings suggest that AE effectively inhibited the pore-forming activity of α-toxin and showed a protective effect against S. aureus virulence in vitro and in vivo, which may provide a new strategy and new antibacterial agent for clinical treatment of S. aureus infections.


Assuntos
Aloe/química , Antraquinonas/farmacologia , Toxinas Bacterianas/antagonistas & inibidores , Proteínas Hemolisinas/antagonistas & inibidores , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Células A549 , Animais , Antraquinonas/química , Antibacterianos/farmacologia , Toxinas Bacterianas/química , Modelos Animais de Doenças , Farmacorresistência Bacteriana/efeitos dos fármacos , Feminino , Proteínas Hemolisinas/química , Hemólise/efeitos dos fármacos , Humanos , Ligantes , Pulmão , Camundongos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Modelos Moleculares , Simulação de Dinâmica Molecular , Pneumonia/tratamento farmacológico , Pneumonia/microbiologia , Infecções Estafilocócicas/patologia , Virulência/efeitos dos fármacos , Fatores de Virulência
8.
Front Physiol ; 9: 939, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30174607

RESUMO

Andrographolide sulfonate (Andro-S), a sulfonation derivative of andrographolide, is known to be effective in treating inflammation-related diseases, while the underlying mechanisms and global protein alterations in response to Andro-S remain unknown. This study aimed to investigate the pharmacological effects and potential targets of Andro-S in a murine model of acute lung injury (ALI). ALI was induced by aerosolized lipopolysaccharide (LPS) exposure before treatment with Andro-S. Inflammatory state of each treatment group was determined by histological analysis and quantification of inflammatory markers. Differentially expressed proteins in lung tissues were identified by an iTRAQ-based quantitative proteomic approach and further confirmed by immunohistochemistry analysis. Administration of Andro-S alleviated LPS-induced histological changes in the lung and reduced the expression of inflammatory markers in serum, bronchoalveolar fluid and lung tissues. Proteomic analysis identified 31 differentially expressed proteins from a total of 2,234 quantified proteins in the lung. According to bioinformatics analysis, neutrophil elastase (ELANE), cathepsin G (CTSG) and myeloperoxidase (MPO), three neutrophil-derived proteases related to immune system process and defense responses to fungi were chosen as potential targets of Andro-S. Further immunohistochemistry analysis confirmed the inhibitory effects of Andro-S on LPS-induced ELANE, CTSG and MPO up-regulation. These results indicate that Andro-S suppressed the severity of LPS-induced ALI, possibly by attenuating the expression of and neutrophil-derived proteases.

9.
Exp Ther Med ; 14(5): 4201-4207, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29104636

RESUMO

The objective of the present study was to investigate acute kidney injury (AKI) induced by myocardial ischemia/reperfusion (MIR) in diabetic rats and elucidate its underlying mechanism. A rat model of MIR was established by left anterior descending coronary artery occlusion for 30 min, followed by reperfusion for 2 h. Rats were randomly divided into four groups: i) Sham group, ii) sham + MIR group, iii) diabetic group and iv) diabetes + MIR group. Myocardial injury was detected by plasma creatine kinase isoenzyme MB and lactate dehydrogenase assays. AKI induced by MIR in diabetic rats was characterized by increases in cystatin C and ß2-microglobulin levels. Oxidative stress injury was accompanied by an increase of malondialdehyde levels and a decrease of total antioxidative capacity in the renal tissues. Immunohistochemistry and western blot analysis demonstrated that the expression of DJ-1 and nuclear factor erythroid 2-related factor 2 (Nrf2) were significantly increased in the diabetes + MIR group compared with that in the sham + MIR and diabetic groups. Taken together, these results suggested that AKI induced by MIR in diabetic rats may be associated with activation of the DJ-1/Nrf2 pathway.

10.
Mol Nutr Food Res ; 61(10)2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28608449

RESUMO

SCOPE: Resveratrol is a naturally occurring polyphenolic compound with known cardioprotective, anti-inflammatory, and antioxidant properties. Lipoprotein-associated phospholipase A2 (Lp-PLA2 ) is associated with the risk of cardiovascular disease. Here, we investigated the effects of resveratrol on Lp-PLA2 expression in vitro and in vivo and explored the underlying mechanisms. METHODS AND RESULTS: Human monocytic cells (THP-1) were induced to differentiate into macrophages for an in vitro experimental model. Resveratrol suppressed Lp-PLA2 expression and reduced inflammation; lipopolysaccharide (LPS, 1 µg/mL), tumor necrosis factor-α (TNF-α, 10 ng/mL) and reactive oxygen species (ROS) were employed to stimulate an increase in Lp-PLA2 expression and ROS levels, and the stimulation was inhibited by resveratrol (50 µM) and other antioxidants. The inhibition of resveratrol was inversed partially by sirtuin 1 (SIRT1) inhibitors (Nicotinamide, 1-10 mM) (p<0.05). Next, a chronic inflammation mouse model induced by a HFD (high fat diet) supplemented with resveratrol 100 mg/kg/day orally for 12 weeks, resulted in resveratrol-induced decreases in the Lp-PLA2 levels in the plasma and liver and increases in the superoxide dismutase 2 (SOD2) expression in the liver (p<0.05). CONCLUSION: Based on our results, the protective effects of resveratrol on cardiovascular events may be related to its ability to suppress Lp-PLA2 expression.


Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Macrófagos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fosfolipases/metabolismo , Estilbenos/farmacologia , 1-Alquil-2-acetilglicerofosfocolina Esterase/sangue , Animais , Sobrevivência Celular/efeitos dos fármacos , Dieta Hiperlipídica , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Regulação para Baixo , Humanos , Inflamação/tratamento farmacológico , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Niacinamida/farmacologia , Fosfolipases/antagonistas & inibidores , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Resveratrol , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/genética , Sirtuína 1/metabolismo , Superóxido Dismutase/sangue , Superóxido Dismutase/genética , Células THP-1 , Fator de Necrose Tumoral alfa/metabolismo
11.
Int J Mol Med ; 38(3): 729-36, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27430285

RESUMO

Patients with diabetes are more vulnerable to renal ischemia/reperfusion (I/R) injury, which is implicated in hyperglycemia-induced oxidative stress. We previously reported that the hyperglycemia-induced inhibition of DJ-1, a novel oncogene that exhibits potent antioxidant activity, is implicated in the severity of myocardial I/R injury. In the present study, we aimed to explore the role of DJ-1 in hypoxia/reoxygenation (H/R) injury in renal cells exposed to high glucose (HG). For this purpose, NRK-52E cells were exposed to HG (30 mM) for 48 h and then exposed to hypoxia for 4 h and reoxygenation for 2 h, which significantly decreased cell viability and superoxide dismutase (SOD) activity, and increased the malondialdehyde (MDA) content, accompanied by a decrease in DJ­1 protein expression. The overexpression of DJ­1 by transfection with a DJ­1 overexpression plasmid exerted protective effects against HG-induced H/R injury, as evidenced by increased CCK-8 levels and SOD activity, the decreased release of lactate dehydrogenase (LDH) and the decreased MDA content, and increased nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1 (HO­1) expression. Similar effects were observed following treatment with the antioxidant, N-acetylcysteine. These results suggest that the overexpression of DJ­1 reduces oxidative stress and attenuates H/R injury in NRK-52E cells exposed to HG.


Assuntos
Células Epiteliais/efeitos dos fármacos , Glucose/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Proteína Desglicase DJ-1/metabolismo , Animais , Antioxidantes/farmacologia , Western Blotting , Hipóxia Celular , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cistina/análogos & derivados , Cistina/farmacologia , Relação Dose-Resposta a Droga , Células Epiteliais/metabolismo , Heme Oxigenase-1/metabolismo , Túbulos Renais Proximais/citologia , Malondialdeído/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Oxigênio/farmacologia , Proteína Desglicase DJ-1/genética , Ratos , Superóxido Dismutase/metabolismo , Fatores de Tempo , Transfecção
12.
Org Lett ; 15(19): 5068-71, 2013 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-24059675

RESUMO

A new class of highly oxygenated Schisandra nortriterpenoids, lancolides A-D (1-4), from Schisandra lancifolia, represents the first example of natural products that possess a tricyclo[6.3.0.0(2,11)]undecane-bridged system. Their structures were elucidated by NMR spectra, X-ray diffraction, and quantum chemical calculations. Lancolides A (1) and D (4) had specific antiplatelet aggregation induced by platelet-activating factor (PAF).


Assuntos
Alcanos/química , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologia , Schisandra/química , Triterpenos/química , Alcanos/farmacologia , Espectroscopia de Ressonância Magnética , Fator de Ativação de Plaquetas/química , Teoria Quântica , Triterpenos/isolamento & purificação , Triterpenos/farmacologia , Difração de Raios X
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA