Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.254
Filtrar
1.
Molecules ; 27(7)2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35408682

RESUMO

A new dicoumarin, jusan coumarin, (1), has been isolated from Artemisia glauca aerial parts. The chemical structure of jusan coumarin was estimated, by 1D, 2D NMR as well as HR-Ms spectroscopic methods, to be 7-hydroxy-6-methoxy-3-[(2-oxo-2H-chromen-6-yl)oxy]-2H-chromen-2-one. As the first time to be introduced in nature, its potential against SARS-CoV-2 has been estimated using various in silico methods. Molecular similarity and fingerprints experiments have been utilized for 1 against nine co-crystallized ligands of COVID-19 vital proteins. The results declared a great similarity between Jusan Coumarin and X77, the ligand of COVID-19 main protease (PDB ID: 6W63), Mpro. To authenticate the obtained outputs, a DFT experiment was achieved to confirm the similarity of X77 and 1. Consequently, 1 was docked against Mpro. The results clarified that 1 bonded in a correct way inside Mpro active site, with a binding energy of -18.45 kcal/mol. Furthermore, the ADMET and toxicity profiles of 1 were evaluated and showed the safety of 1 and its likeness to be a drug. Finally, to confirm the binding and understand the thermodynamic characters between 1 and Mpro, several molecular dynamics (MD) simulations studies have been administered. Additionally, the known coumarin derivative, 7-isopentenyloxycoumarin (2), has been isolated as well as ß-sitosterol (3).


Assuntos
Artemisia , Proteases 3C de Coronavírus , Cumarínicos , Inibidores de Proteases , SARS-CoV-2 , Artemisia/química , Proteases 3C de Coronavírus/antagonistas & inibidores , Cumarínicos/química , Cumarínicos/farmacologia , Dicumarol/química , Dicumarol/farmacologia , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia
2.
Nature ; 599(7883): 120-124, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34646011

RESUMO

Antibiotics are used to fight pathogens but also target commensal bacteria, disturbing the composition of gut microbiota and causing dysbiosis and disease1. Despite this well-known collateral damage, the activity spectrum of different antibiotic classes on gut bacteria remains poorly characterized. Here we characterize further 144 antibiotics from a previous screen of more than 1,000 drugs on 38 representative human gut microbiome species2. Antibiotic classes exhibited distinct inhibition spectra, including generation dependence for quinolones and phylogeny independence for ß-lactams. Macrolides and tetracyclines, both prototypic bacteriostatic protein synthesis inhibitors, inhibited nearly all commensals tested but also killed several species. Killed bacteria were more readily eliminated from in vitro communities than those inhibited. This species-specific killing activity challenges the long-standing distinction between bactericidal and bacteriostatic antibiotic classes and provides a possible explanation for the strong effect of macrolides on animal3-5 and human6,7 gut microbiomes. To mitigate this collateral damage of macrolides and tetracyclines, we screened for drugs that specifically antagonized the antibiotic activity against abundant Bacteroides species but not against relevant pathogens. Such antidotes selectively protected Bacteroides species from erythromycin treatment in human-stool-derived communities and gnotobiotic mice. These findings illluminate the activity spectra of antibiotics in commensal bacteria and suggest strategies to circumvent their adverse effects on the gut microbiota.


Assuntos
Antibacterianos/efeitos adversos , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Antibacterianos/classificação , Bactérias/classificação , Bactérias Anaeróbias/efeitos dos fármacos , Bacteroides/efeitos dos fármacos , Clostridioides difficile/efeitos dos fármacos , Dicumarol/farmacologia , Eritromicina/farmacologia , Fezes/microbiologia , Feminino , Vida Livre de Germes , Humanos , Macrolídeos/farmacologia , Masculino , Camundongos , Microbiota/efeitos dos fármacos , Simbiose/efeitos dos fármacos , Tetraciclinas/farmacologia
3.
Neurochem Res ; 46(1): 88-99, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31902045

RESUMO

The reduction of water-soluble tetrazolium salts (WSTs) is frequently used to determine the metabolic integrity and the viability of cultured cells. Recently, we have reported that the electron cycler menadione can efficiently connect intracellular oxidation reactions in cultured astrocytes with the extracellular reduction of WST1 and that this menadione cycling reaction involves an enzyme. The enzymatic reaction involved in the menadione-dependent WST1 reduction was found strongly enriched in the cytosolic fraction of cultured astrocytes and is able to efficiently use both NADH and NADPH as electron donors. In addition, the reaction was highly sensitive towards dicoumarol with Kic values in the low nanomolar range, suggesting that the NAD(P)H:quinone oxidoreductase 1 (NQO1) catalyzes the menadione-dependent WST1 reduction in astrocytes. Also, in intact astrocytes, dicoumarol inhibited the menadione-dependent WST1 reduction in a concentration-dependent manner with half-maximal inhibition observed at around 50 nM. Moreover, the menadione-dependent WST1 reduction by viable astrocytes was strongly affected by the availability of glucose. In the absence of glucose only residual WST1 reduction was observed, while a concentration-dependent increase in WST1 reduction was found during a 30 min incubation with maximal WST1 reduction already determined in the presence of 0.5 mM glucose. Mannose could fully replace glucose as substrate for astrocytic WST1 reduction, while other hexoses, lactate and the mitochondrial substrate ß-hydroxybutyrate failed to provide electrons for the cell-dependent WST1 reduction. These results demonstrate that the menadione-mediated WST1 reduction involves cytosolic NQO1 activity and that this process is strongly affected by the availability of glucose as metabolic substrate.


Assuntos
Astrócitos/metabolismo , Glucose/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , Sais de Tetrazólio/metabolismo , Vitamina K 3/metabolismo , Animais , Animais Recém-Nascidos , Células Cultivadas , Dicumarol/farmacologia , Inibidores Enzimáticos/farmacologia , NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores , Oxirredução , Ratos Wistar , Sais de Tetrazólio/química
4.
J Hepatol ; 74(3): 522-534, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32987030

RESUMO

BACKGROUND & AIMS: Current antiviral therapies help keep HBV under control, but they are not curative, as they are unable to eliminate the intracellular viral replication intermediate termed covalently closed circular DNA (cccDNA). Therefore, there remains an urgent need to develop strategies to cure CHB. Functional silencing of cccDNA is a crucial curative strategy that may be achieved by targeting the viral protein HBx. METHODS: We screened 2,000 small-molecule compounds for their ability to inhibit HiBiT-tagged HBx (HiBiT-HBx) expression by using a HiBiT lytic detection system. The antiviral activity of a candidate compound and underlying mechanism of its effect on cccDNA transcription were evaluated in HBV-infected cells and a humanised liver mouse model. RESULTS: Dicoumarol, an inhibitor of NAD(P)H:quinone oxidoreductase 1 (NQO1), significantly reduced HBx expression. Moreover, dicoumarol showed potent antiviral activity against HBV RNAs, HBV DNA, HBsAg and HBc protein in HBV-infected cells and a humanised liver mouse model. Mechanistic studies demonstrated that endogenous NQO1 binds to and protects HBx protein from 20S proteasome-mediated degradation. NQO1 knockdown or dicoumarol treatment significantly reduced the recruitment of HBx to cccDNA and inhibited the transcriptional activity of cccDNA, which was associated with the establishment of a repressive chromatin state. The absence of HBx markedly blocked the antiviral effect induced by NQO1 knockdown or dicoumarol treatment in HBV-infected cells. CONCLUSIONS: Herein, we report on a novel small molecule that targets HBx to combat chronic HBV infection; we also reveal that NQO1 has a role in HBV replication through the regulation of HBx protein stability. LAY SUMMARY: Current antiviral therapies for hepatitis B are not curative because of their inability to eliminate covalently closed circular DNA (cccDNA), which persists in the nuclei of infected cells. HBV X (HBx) protein has an important role in regulating cccDNA transcription. Thus, targeting HBx to silence cccDNA transcription could be an important curative strategy. We identified that the small molecule dicoumarol could block cccDNA transcription by promoting HBx degradation; this is a promising therapeutic strategy for the treatment of chronic hepatitis B.


Assuntos
Antivirais/administração & dosagem , DNA Circular/metabolismo , Dicumarol/administração & dosagem , Vírus da Hepatite B/metabolismo , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/metabolismo , NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores , NAD(P)H Desidrogenase (Quinona)/metabolismo , Proteólise/efeitos dos fármacos , Transativadores/metabolismo , Transcrição Genética/efeitos dos fármacos , Proteínas Virais Reguladoras e Acessórias/metabolismo , Animais , DNA Circular/isolamento & purificação , Modelos Animais de Doenças , Células Hep G2 , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/virologia , Hepatócitos/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , NAD(P)H Desidrogenase (Quinona)/genética , Transfecção , Resultado do Tratamento , Replicação Viral/efeitos dos fármacos , Replicação Viral/genética
5.
Int J Mol Sci ; 21(22)2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33228195

RESUMO

Derivatives of tirapazamine and other heteroaromatic N-oxides (ArN→O) exhibit tumoricidal, antibacterial, and antiprotozoal activities, which are typically attributed to bioreductive activation and free radical generation. In this work, we aimed to clarify the role of NAD(P)H:quinone oxidoreductase (NQO1) in ArN→O aerobic cytotoxicity. We synthesized 9 representatives of ArN→O with uncharacterized redox properties and examined their single-electron reduction by rat NADPH:cytochrome P-450 reductase (P-450R) and Plasmodium falciparum ferredoxin:NADP+ oxidoreductase (PfFNR), and by rat NQO1. NQO1 catalyzed both redox cycling and the formation of stable reduction products of ArN→O. The reactivity of ArN→O in NQO1-catalyzed reactions did not correlate with the geometric average of their activity towards P-450R- and PfFNR, which was taken for the parameter of their redox cycling efficacy. The cytotoxicity of compounds in murine hepatoma MH22a cells was decreased by antioxidants and the inhibitor of NQO1, dicoumarol. The multiparameter regression analysis of the data of this and a previous study (DOI: 10.3390/ijms20184602) shows that the cytotoxicity of ArN→O (n = 18) in MH22a and human colon carcinoma HCT-116 cells increases with the geometric average of their reactivity towards P-450R and PfFNR, and with their reactivity towards NQO1. These data demonstrate that NQO1 is a potentially important target of action of heteroaromatic N-oxides.


Assuntos
Antibacterianos/farmacologia , Antioxidantes/farmacologia , Antiprotozoários/farmacologia , Óxidos N-Cíclicos/farmacologia , Ferredoxina-NADP Redutase/antagonistas & inibidores , NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores , NADPH-Ferri-Hemoproteína Redutase/antagonistas & inibidores , Aerobiose , Animais , Antibacterianos/síntese química , Antioxidantes/síntese química , Antiprotozoários/síntese química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Óxidos N-Cíclicos/síntese química , Dicumarol/farmacologia , Ensaios Enzimáticos , Inibidores Enzimáticos/farmacologia , Ferredoxina-NADP Redutase/química , Ferredoxina-NADP Redutase/metabolismo , Células HCT116 , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Hepatócitos/patologia , Humanos , Cinética , Camundongos , NAD(P)H Desidrogenase (Quinona)/química , NAD(P)H Desidrogenase (Quinona)/metabolismo , NADPH-Ferri-Hemoproteína Redutase/química , NADPH-Ferri-Hemoproteína Redutase/metabolismo , Oxirredução , Plasmodium falciparum/química , Plasmodium falciparum/enzimologia , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/química , Proteínas de Protozoários/metabolismo , Ratos , Tirapazamina/química , Tirapazamina/farmacologia
6.
Pharmacol Res ; 160: 105193, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32911072

RESUMO

Dicoumarol is an oral anticoagulant agent prescribed in clinical for decades. It is a natural hydroxycoumarin discovered from the spoilage of Melilotus officinalis (L.) Pall and is originally discovered as a rodenticide. Due to its structural similarity to that of vitamin K, it significantly inhibits vitamin K epoxide reductase and acts as a vitamin K antagonist. Dicoumarol is mainly used as an anticoagulant to prevent thrombogenesis and to cure vascular thrombosis. Other biological activities besides anticoagulants such as anticancer, antimicrobial, antiviral, etc., have also been documented. The side effects of dicoumarol raise safety concerns for clinical application. In this review, the physicochemical property, the pharmacological activities, the side effects, and the pharmacokinetics of dicoumarol were summarized, aiming to provide a whole picture of the "old" anticoagulant.


Assuntos
Anticoagulantes/farmacologia , Dicumarol/farmacologia , Animais , Anticoagulantes/uso terapêutico , Dicumarol/química , Dicumarol/uso terapêutico , Humanos , Melilotus/química , Vitamina K/antagonistas & inibidores , Vitamina K Epóxido Redutases/antagonistas & inibidores
7.
Toxicol Appl Pharmacol ; 404: 115180, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32739527

RESUMO

Numerous studies conducted in the past have reported deaths in the human population due to cardiovascular diseases (CVD) on exposure to air particulate matter (APM). BP-1,6-quinone (BP-1,6-Q) is one of the significant components of APM. However, the mechanism(s) by which it can exert its toxicity in endothelial cells is not yet completely understood. NAD(P)H: quinone oxidoreductase-1 (NQO1) is expressed highly in myocardium and vasculature tissues of the heart and plays a vital role in maintaining vascular homeostasis. This study, demonstrated that BP-1,6-Q diminishes NQO1 enzyme activity in a dose-dependent manner in human EA.hy926 endothelial cells. The decrease in the NQO1 enzyme causes potentiation in BP-1,6-Q-mediated toxicity in EA.hy926 endothelial cells. The enhancement of NQO1 in endothelial cells showed cytoprotection against BP-1,6-Q-induced cellular toxicity, lipid, and protein damage suggesting an essential role of NQO1 in cytoprotection against BP-1,6-Q toxicity. Using various biochemical assays and genetic approaches, results from this study further demonstrated that NQO1 also plays a crucial role in BP-1,6-Q-induced production of reactive oxygen species (ROS). These findings will contribute to elucidating BP-1,6-Q mediated toxicity and its role in the development of atherosclerosis.


Assuntos
Benzopirenos/toxicidade , Células Endoteliais/efeitos dos fármacos , NAD(P)H Desidrogenase (Quinona)/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Benzopirenos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Dicumarol/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/metabolismo , Estrutura Molecular , NAD(P)H Desidrogenase (Quinona)/genética
8.
Neurochem Res ; 45(10): 2442-2455, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32789798

RESUMO

ß-lapachone (ß-lap) is reduced in tumor cells by the enzyme NAD(P)H: quinone acceptor oxidoreductase 1 (NQO1) to a labile hydroquinone which spontaneously reoxidises to ß-lap, thereby generating reactive oxygen species (ROS) and oxidative stress. To test for the consequences of an acute exposure of brain cells to ß-lap, cultured primary rat astrocytes were incubated with ß-lap for up to 4 h. The presence of ß-lap in concentrations of up to 10 µM had no detectable adverse consequences, while higher concentrations of ß-lap compromised the cell viability and the metabolism of astrocytes in a concentration- and time-dependent manner with half-maximal effects observed for around 15 µM ß-lap after a 4 h incubation. Exposure of astrocytes to ß-lap caused already within 5 min a severe increase in the cellular production of ROS as well as a rapid oxidation of glutathione (GSH) to glutathione disulfide (GSSG). The transient cellular accumulation of GSSG was followed by GSSG export. The ß-lap-induced ROS production and GSSG accumulation were completely prevented in the presence of the NQO1 inhibitor dicoumarol. In addition, application of dicoumarol to ß-lap-exposed astrocytes caused rapid regeneration of the normal high cellular GSH to GSSG ratio. These results demonstrate that application of ß-lap to cultured astrocytes causes acute oxidative stress that depends on the activity of NQO1. The sequential application of ß-lap and dicoumarol to rapidly induce and terminate oxidative stress, respectively, is a suitable experimental paradigm to study consequences of a defined period of acute oxidative stress in NQO1-expressing cells.


Assuntos
Astrócitos/efeitos dos fármacos , Dicumarol/farmacologia , Inibidores Enzimáticos/farmacologia , Naftoquinonas/efeitos adversos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Glutationa/química , Glutationa/metabolismo , NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores , Oxirredução , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
10.
Int J Oncol ; 57(3): 733-742, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32705170

RESUMO

The Warburg effect is a unique metabolic feature of the majority of tumor cells and is closely related to chemotherapeutic resistance. Pyruvate dehydrogenase kinase 1 (PDK1) is considered a 'switch' that controls the fate of pyruvate in glucose metabolism. However, to date, to the best of our knowledge, there are only a few studies to available which had studied the reduction of chemotherapeutic resistance via the metabolic reprogramming of tumor cells with PDK1 as a target. In the present study, it was found dicoumarol (DIC) reduced the phosphorylation of pyruvate dehydrogenase (PDH) by inhibiting the activity of PDK1, which converted the metabolism of human hepatocellular carcinoma (HCC) cells to oxidative phosphorylation, leading to an increase in mitochondrial reactive oxygen species ROS (mtROS) and a decrease in mitochondrial membrane potential (MMP), thereby increasing the apoptosis induced by oxaliplatin (OXA). Furthermore, the present study elucidated that the targeting of PDK1 may be a potential strategy for targeting metabolism in the chemotherapy of HCC. In addition, DIC as an 'old drug' exhibits novel efficacy, bringing new hope for antitumor therapy.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Dicumarol/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Piruvato Desidrogenase Quinase de Transferência de Acetil/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dicumarol/uso terapêutico , Humanos , Neoplasias Hepáticas/patologia , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Fosforilação Oxidativa/efeitos dos fármacos , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Efeito Warburg em Oncologia/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Angew Chem Int Ed Engl ; 59(47): 21143-21150, 2020 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-32729980

RESUMO

Unpredictable in vivo therapeutic feedback of hydroxyl radical (. OH) efficiency is the major bottleneck of chemodynamic therapy. Herein, we describe novel Fenton-based nanotheranostics NQ-Cy@Fe&GOD for spatio-temporally reporting intratumor . OH-mediated treatment, which innovatively unites dual-channel near-infrared (NIR) fluorescence and magnetic resonance imaging (MRI) signals. Specifically, MRI signal traces the dose distribution of Fenton-based iron oxide nanoparticles (IONPs) with high-spatial resolution, meanwhile timely fluorescence signal quantifies . OH-mediated therapeutic response with high spatio-temporal resolution. NQ-Cy@Fe&GOD can successfully monitor the intracellular release of IONPs and . OH-induced NQO1 enzyme in living cells and tumor-bearing mice, which makes a breakthrough in conquering the inherent unpredictable obstacles on spatio-temporally reporting chemodynamic therapy, so as to manipulate dose-dependent therapeutic process.


Assuntos
Antineoplásicos/farmacologia , Peróxido de Hidrogênio/farmacologia , Radical Hidroxila/farmacologia , Ferro/farmacologia , Nanopartículas Magnéticas de Óxido de Ferro/química , Imageamento por Ressonância Magnética , Imagem Óptica , Células A549 , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dicumarol/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Peróxido de Hidrogênio/síntese química , Peróxido de Hidrogênio/química , Radical Hidroxila/química , Raios Infravermelhos , Ferro/química , Camundongos , Camundongos Nus , Estrutura Molecular , NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores , NAD(P)H Desidrogenase (Quinona)/metabolismo , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo
12.
Eur J Clin Invest ; 50(11): e13317, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32535903

RESUMO

BACKGROUND: Limited data are available on the clinical course of patients with history of atrial fibrillation (AF) when admitted in an intensive care environment. We aimed to describe the occurrence of major adverse events in AF patients admitted to a stepdown care unit (SDU) and to analyse clinical factors associated with outcomes, impact of dicumarolic oral anticoagulant (OAC) therapy impact and performance of clinical risk scores in this setting. MATERIALS AND METHODS: Single-centre, observational retrospective analysis on a population of subjects with AF history admitted to a SDU. Therapeutic failure (composite of transfer to ICU or death) was considered the main study outcome. Occurrence of stroke and major bleeding (MH) was considered as secondary outcomes. The performance of clinical risk scores was evaluated. RESULTS: A total of 1430 consecutive patients were enrolled. 194 (13.6%) reported the main outcome. Using multivariate logistic regression, age (odds ratio [OR]: 1.03, 95% confidence interval [CI]: 1.01-1.05), acute coronary syndrome (OR:3.10, 95% CI: 1.88-5.12), cardiogenic shock (OR:10.06, 95% CI: 5.37-18.84), septic shock (OR:5.19,95%CI:3.29-18.84), acute respiratory failure (OR:2.49, 95% CI: 1.67-3.64) and OAC use (OR: 1.61, 95% CI: 1.02-2.55) were independently associated with main outcome. OAC prescription was associated with stroke risk reduction and to both MH and main outcome risk increase. CHA2 DS2 -VASc (c-index: 0.545, P = .117 for stroke) and HAS-BLED (c-index:0.503, P = .900 for MH) did not significantly predict events occurrence. CONCLUSIONS: In critically ill AF patients admitted to a SDU, adverse outcomes are highly prevalent. OAC use is associated to an increased risk of therapeutic failure, clinical scores seem unhelpful in predicting stroke and MH, suggesting a highly individualized approach in AF management in this setting.


Assuntos
Síndrome Coronariana Aguda/terapia , Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Dicumarol/uso terapêutico , Mortalidade Hospitalar , Insuficiência Respiratória/terapia , Choque Cardiogênico/terapia , Choque Séptico/terapia , Síndrome Coronariana Aguda/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/complicações , Comorbidade , Estado Terminal , Feminino , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Unidades Hospitalares , Humanos , Unidades de Terapia Intensiva , Modelos Logísticos , Masculino , Análise Multivariada , Transferência de Pacientes/estatística & dados numéricos , Insuficiência Respiratória/epidemiologia , Estudos Retrospectivos , Choque Cardiogênico/epidemiologia , Choque Séptico/epidemiologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle
13.
Biochem Biophys Res Commun ; 524(4): 1003-1009, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32063361

RESUMO

Colon cancer is one of the leading causes of cancer-related deaths and its five-year survival rate remains low in locally advanced or metastatic stages of colon cancer. Overexpression of high mobility group protein AT-hook2 (HMGA2) is associated with cancer progression, metastasis, and poor prognosis in many malignancies. Oxidative stress regulates cellular mechanisms and provides an environment that favors the cancer cells to survive and progress, yet, at the same time, oxidative stress can also be utilized as a cancer-damaging strategy. The molecular regulatory roles of HMGA2 in oxidative stress and their involvement in cancer progression are largely unknown. In this study, we investigated the involvement of HMGA2 in regulation of oxidative stress responses by luciferase reporter assays. Moreover, we utilized dicoumarol (DIC), a derivative of coumarin which has been suggested to be involved in oxidation regulation with anticancer effects, and demonstrated that DIC could induce apoptosis and inhibit cell migration of HMGA2 overexpressing colon cancer cells. Further investigation also evidenced that DIC can enhance the cancer inhibition effect of 5-FU in colony formation assays. Taken together, our data revealed novel insights into the molecular mechanisms underlying HMGA2 and highlighted the possibility of targeting the cellular antioxidant system for treating patients and preventing from cancer progression in HMGA2 overexpressing colon cancer cells.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Dicumarol/farmacologia , Proteína HMGA2/metabolismo , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Inibidores Enzimáticos/farmacologia , Fluoruracila/farmacologia , Humanos , Estresse Oxidativo/efeitos dos fármacos
14.
Medicina (Kaunas) ; 55(8)2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31366186

RESUMO

Background and objectives: Medical devices such as catheters are used on a large scale to treat heart and cardiovascular diseases. Unfortunately, they present some important drawbacks (structure failure, calcifications, infections, thrombosis, etc.), with the main side effects occurring due to adhesion and proliferation of bacteria and living cells on the surface of the implanted devices. The aim of this work is to modify the surface of polyvinyl chloride (PVC), an affordable biocompatible material, in order to reduce these aforementioned side effects. Materials and Methods: The surface of PVC was modified by depositing a thin layer also of PVC that incorporates an active substance, dicoumarol (a well-known anticoagulant), by spin coating process. The modified surfaces were analyzed by Fourier-transform infrared (FT-IR) microscopy, Fourier-transform infrared (FT-IR) spectroscopy, Ultraviolet-visible spectroscopy (UV-VIS), and Scanning electron microscopy (SEM) in order to determine the surface morphology and behavior. The samples were tested for Gram-positive (S. aureus ATCC 25923) and Gram-negative (P. aeruginosa ATCC 27853) standard strains from American Type Culture Collection (ATCC). Results: The material obtained had a smooth surface with a uniform distribution of dicoumarol, which is released depending on the deposition parameters. The concentration of dicoumarol at the surface of the material and also the release rate is important for the applications for which the surface modification was designed. PVC modified using the proposed method showed a good ability to prevent salt deposition and decreased the protein adhesion, and the resistance to bacterial adherence was improved compared with standard PVC.


Assuntos
Dicumarol/uso terapêutico , Cloreto de Polivinila/efeitos adversos , Materiais Biocompatíveis , Cateteres/efeitos adversos , Cateteres/microbiologia , Cateteres/normas , Dicumarol/normas , Desenho de Equipamento/métodos , Desenho de Equipamento/normas , Humanos , Cloreto de Polivinila/normas , Cloreto de Polivinila/uso terapêutico
15.
Biosci Rep ; 39(9)2019 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-31431515

RESUMO

Human NAD(P)H quinone oxidoreductase (DT-diaphorase, NQO1) exhibits negative cooperativity towards its potent inhibitor, dicoumarol. Here, we addressed the hypothesis that the effects of the two cancer-associated polymorphisms (p.R139W and p.P187S) may be partly mediated by their effects on inhibitor binding and negative cooperativity. Dicoumarol stabilized both variants and bound with much higher affinity for p.R139W than p.P187S. Both variants exhibited negative cooperativity towards dicoumarol; in both cases, the Hill coefficient (h) was approximately 0.5 and similar to that observed with the wild-type protein. NQO1 was also inhibited by resveratrol and by nicotinamide. Inhibition of NQO1 by resveratrol was approximately 10,000-fold less strong than that observed with the structurally similar enzyme, NRH quinine oxidoreductase 2 (NQO2). The enzyme exhibited non-cooperative behaviour towards nicotinamide, whereas resveratrol induced modest negative cooperativity (h = 0.85). Nicotinamide stabilized wild-type NQO1 and p.R139W towards thermal denaturation but had no detectable effect on p.P187S. Resveratrol destabilized the wild-type enzyme and both cancer-associated variants. Our data suggest that neither polymorphism exerts its effect by changing the enzyme's ability to exhibit negative cooperativity towards inhibitors. However, it does demonstrate that resveratrol can inhibit NQO1 in addition to this compound's well-documented effects on NQO2. The implications of these findings for molecular pathology are discussed.


Assuntos
Estabilidade Enzimática/efeitos dos fármacos , NAD(P)H Desidrogenase (Quinona)/genética , Neoplasias/genética , Quinona Redutases/genética , Dicumarol/química , Dicumarol/farmacologia , Humanos , Cinética , NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores , NAD(P)H Desidrogenase (Quinona)/química , Neoplasias/química , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Niacinamida/química , Niacinamida/farmacologia , Polimorfismo Genético , Ligação Proteica , Quinona Redutases/antagonistas & inibidores , Quinona Redutases/química
16.
Chembiochem ; 20(22): 2841-2849, 2019 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-31165578

RESUMO

NAD(P)H quinone oxidoreductase-1 (NQO1) is a homodimeric protein that acts as a detoxifying enzyme or as a chaperone protein. Dicourmarol interacts with NQO1 at the NAD(P)H binding site and can both inhibit enzyme activity and modulate the interaction of NQO1 with other proteins. We show that the binding of dicoumarol and related compounds to NQO1 generates negative cooperativity between the monomers. This does not occur in the presence of the reducing cofactor, NAD(P)H, alone. Alteration of Gly150 (but not Gly149 or Gly174) abolished the dicoumarol-induced negative cooperativity. Analysis of the dynamics of NQO1 with the Gaussian network model indicates a high degree of collective motion by monomers and domains within NQO1. Ligand binding is predicted to alter NQO1 dynamics both proximal to the ligand binding site and remotely, close to the second binding site. Thus, drug-induced modulation of protein motion might contribute to the biological effects of putative inhibitors of NQO1.


Assuntos
Regulação Alostérica/efeitos dos fármacos , Dicumarol/farmacologia , Inibidores Enzimáticos/farmacologia , NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores , Substituição de Aminoácidos , Domínio Catalítico , Linhagem Celular Tumoral , Dicumarol/metabolismo , Inibidores Enzimáticos/metabolismo , Humanos , Ligantes , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Ligação Proteica , Proteína Supressora de Tumor p53/metabolismo
17.
Chem Commun (Camb) ; 55(27): 3951-3954, 2019 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-30874262

RESUMO

A far-red fluorescent probe has been developed for sensing fungal laccase. The probe was used to determine that Rhizopus oryzae had a high level endogenous laccase amongst 24 fungal strains. The Rhizopus oryzae was then used as a biocatalyst for the preparation of dicoumarin resulting in significant inhibition of Mycobacterium tuberculosis H37Ra.


Assuntos
Antituberculosos/farmacologia , Biocatálise , Dicumarol/farmacologia , Corantes Fluorescentes/química , Lacase/análise , Lacase/metabolismo , Mycobacterium tuberculosis/efeitos dos fármacos , Rhizopus/enzimologia , Antituberculosos/química , Antituberculosos/metabolismo , Dicumarol/química , Dicumarol/metabolismo , Testes de Sensibilidade Microbiana , Microscopia Confocal , Estrutura Molecular , Imagem Óptica
18.
Bioorg Med Chem Lett ; 29(10): 1236-1240, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30898405

RESUMO

Lipase RMIM was firstly used as a promiscuous biocatalyst to catalyze the Knoevenagel-Michael cascade reactions of 4-hydroxycoumarin with aromatic, heterocyclic or aliphatic aldehydes to synthesize dicoumarol derivatives in water. Results showed that the adopted methodology could offer many advantages, such as mild reaction conditions, pure aqueous reaction system, wide substrate applicability, recyclable catalyst, excellent yields (81-98%), operational simplicity, and environmentally friendly reactions.


Assuntos
Dicumarol/síntese química , Lipase/química , Rhizomucor/enzimologia , Aldeídos/química , Catálise , Dicumarol/análogos & derivados , Química Verde/métodos , Estrutura Molecular , Temperatura , Fatores de Tempo , Água/química
19.
PLoS One ; 14(2): e0212233, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30779774

RESUMO

Currently, there is no available therapy to eradicate hepatitis B virus (HBV) in chronically infected individuals. This is due to the difficulty in eliminating viral covalently closed circular (ccc) DNA, which is central to the gene expression and replication of HBV. We developed an assay system for nuclear circular DNA using an integration-deficient lentiviral vector. This vector produced non-integrated circular DNA in nuclei of infected cells. We engineered this vector to encode firefly luciferase to monitor the lentiviral episome DNA. We screened 3,840 chemicals by this assay for luciferase-reducing activity and identified dicumarol, which is known to have anticoagulation activity. We confirmed that dicumarol reduced lentiviral episome DNA. Furthermore, dicumarol inhibited HBV replication in cell culture using NTCP-expressing HepG2 and primary human hepatocytes. Dicumarol reduced intracellular HBV RNA, DNA, supernatant HBV antigens and DNA. We also found that dicumarol reduced the cccDNA level in HBV infected cells, but did not affect HBV adsorption/entry. This is a novel assay system for screening inhibitors targeting nuclear cccDNA and is useful for finding new antiviral substances for HBV.


Assuntos
Antivirais/farmacologia , Núcleo Celular/metabolismo , DNA Viral/metabolismo , Dicumarol/farmacologia , Vírus da Hepatite B/metabolismo , Plasmídeos/metabolismo , Núcleo Celular/genética , Núcleo Celular/virologia , DNA Viral/genética , Avaliação Pré-Clínica de Medicamentos , Vetores Genéticos , Células HEK293 , Células Hep G2 , Vírus da Hepatite B/genética , Humanos , Lentivirus , Plasmídeos/genética , RNA Viral/genética , RNA Viral/metabolismo
20.
Neurochem Res ; 44(2): 333-346, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30443714

RESUMO

Dicoumarol is frequently used as inhibitor of the detoxifying enzyme NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1). In order to test whether dicoumarol may also affect the cellular glutathione (GSH) metabolism, we have exposed cultured primary astrocytes to dicoumarol and investigated potential effects of this compound on the cell viability as well as on the cellular and extracellular contents of GSH and its metabolites. Incubation of astrocytes with dicoumarol in concentrations of up to 100 µM did not acutely compromise cell viability nor was any GSH consumption or GSH oxidation to glutathione disulfide (GSSG) observed. However, unexpectedly dicoumarol inhibited the cellular multidrug resistance protein (Mrp) 1-dependent export of GSH in a time- and concentration-dependent manner with half-maximal effects observed at low micromolar concentrations of dicoumarol. Inhibition of GSH export by dicoumarol was not additive to that observed for the known Mrp1 inhibitor MK571. In addition, dicoumarol inhibited also the Mrp1-mediated export of GSSG during menadione-induced oxidative stress and the export of the GSH-bimane-conjugate (GS-B) that had been generated in the cells after exposure to monochlorobimane. Half-maximal inhibition of the export of Mrp1 substrates was observed at dicoumarol concentrations of around 4 µM (GSH and GSSG) and 30 µM (GS-B). These data demonstrate that dicoumarol strongly affects the GSH metabolism of viable cultured astrocytes by inhibiting Mrp1-mediated export processes and identifies for the first time Mrp1 as additional cellular target of dicoumarol.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dicumarol/farmacologia , Propionatos/farmacologia , Quinolinas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Astrócitos/metabolismo , Células Cultivadas , Glutationa/metabolismo , Peróxido de Hidrogênio/metabolismo , Ratos Wistar
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...