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2.
Int. microbiol ; 22(1): 7-17, mar. 2019. graf, tab
Artigo em Inglês | IBECS | ID: ibc-184809

RESUMO

The present study attempts to identify the novel inhibitors of shikimate dehydrogenase (SD), the enzyme that catalyzes the fourth reaction in the shikimate pathway, through virtual screening and toxicity studies. Crystal structure of SD was obtained from Protein Data Bank (PDB ID 4P4G, 1.7 Å) and subjected to energy minimization and structure optimization. A total of 13,803 compounds retrieved from two public databases and used for the virtual screening based on physicochemical properties (Lipinski rule of five) and molecular docking analyses. A total of 26 compounds with good AutoDock binding energies values ranging between −12.03 and −8.33 kcal/mol was selected and further filtered for absorption distribution metabolism excretion and toxicity analyses (ADMET). In this, eight compounds were selected, which satisfied all the ADME and toxicity analysis properties. Three compounds with better AutoDock binding energies values (ZINC12135132, −12.03 kcal/mol; ZINC08951370, −10.04 kcal/mol; and ZINC14733847, 9.82 kcal/mol) were considered for molecular dynamic (MD) simulation and molecular generalized born surface area (MM-GBSA) analyses. The results of the analyses revealed that the two ligands (ZINC12135132 and ZINC08951370) had better inhibitory activities within their complexes, after the 50-ns MD simulation, which suggested that the complexes formed stable conformation. It is noteworthy that compounds identified by docking, MD simulation, and MM-GBSA methods could be a drug for tuberculosis which required further experimental validation


No disponible


Assuntos
Oxirredutases/administração & dosagem , Tuberculose/tratamento farmacológico , Oxirredutases do Álcool/antagonistas & inibidores , Antituberculosos/isolamento & purificação , Biologia Computacional/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/isolamento & purificação , Tuberculose/microbiologia , Oxirredutases do Álcool/química , Antituberculosos/toxicidade , Inibidores Enzimáticos/toxicidade , Simulação de Acoplamento Molecular , Ligação Proteica , Conformação Proteica
3.
Int. microbiol ; 22(1): 69-80, mar. 2019. ilus, graf, tab
Artigo em Inglês | IBECS | ID: ibc-184815

RESUMO

Shikimate dehydrogenase (HpSDH) (EC 1.1.1.25) is a key enzyme in the shikimate pathway of Helicobacter pylori (H. pylori), which catalyzes the NADPH-dependent reversible reduction of 3-dehydroshikimate to shikimate. Targeting HpSDH has been recognized as an attractive therapeutic strategy against H. pylori infection. Here, the catalytic active site in the crystal structure of HpSDH in complex with its substrate NADPH and product shikimate was examined in detail; the site can be divided into three spatially separated subpockets that separately correspond to the binding regions of shikimate, NADPH dihydronicotinamide moiety, and NADPH adenine moiety. Subsequently, a cascading protocol that integrated virtual screening and antibacterial test was performed against a biogenic compound library to identify biologically active, subpocket-specific inhibitors. Consequently, five, eight, and six promising compounds for, respectively, subpockets 1, 2, and 3 were selected from the top-100 docking-ranked hits, from which 11 compounds were determined to have high or moderate antibacterial potencies against two reference H. pylori strains, with MIC range between 8 and 93 μg/mL. It is found that the HpSDH active site prefers to accommodate amphipathic and polar inhibitors that consist of an aromatic core as well as a number of oxygen-rich polar/charged substituents such as hydroxyl, carbonyl, and carboxyl groups. Subpockets 1- and 2-specific inhibitors exhibit a generally higher activity than subpocket 3-specific inhibitors. Molecular dynamics simulations revealed an intense nonbonded network of hydrogen bonds, π-π stacking, and van der Waals contacts at the tightly packed complex interfaces of active-site subpockets with their cognate inhibitors, conferring strong stability and specificity to these complex systems. Binding energetic analysis demonstrated that the identified potent inhibitors can target their cognate subpockets with an effective selectivity over noncognate ones


No disponible


Assuntos
Oxirredutases do Álcool/antagonistas & inibidores , Antibacterianos/isolamento & purificação , Biologia Computacional , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/isolamento & purificação , Helicobacter pylori/enzimologia , Antibacterianos/química , Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Domínio Catalítico , Cristalografia por Raios X , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Conformação Proteica
4.
Emergencias (Sant Vicenç dels Horts) ; 31(1): 39-42, feb. 2019. tab
Artigo em Espanhol | IBECS | ID: ibc-182435

RESUMO

Introducción: La intoxicación digitálica es un motivo frecuente de consulta en los servicios de urgencias hospitalarios (SUH). El objetivo de este estudio es conocer la mortalidad asociada a dicha intoxicación. Método: Estudio descriptivo y observacional de las intoxicaciones digitálicas atendidas en los SUH de 4 hospitales de Cataluña durante los años 2013-15. Se recogieron datos relativos a la intoxicación, la mortalidad inmediata y a los 30 días. Se analizó la existencia de posibles factores asociados a la mortalidad. Resultados: Se registraron 171 intoxicaciones digitálicas. Siete eran agudas (4,1%) y 164 (95,9%) crónicas. La mortalidad inmediata fue del 6,4% y a los 30 días fue del 13,4%. El análisis binario no identificó ningún factor relacionado con la mortalidad inmediata. En cuanto a la mortalidad a 30 días, los pacientes que fallecieron tenían con mayor frecuencia una intoxicación aguda (13% vs 2,7%; p= 0,05), había más intoxicaciones con intencionalidad suicida (8,7% vs 0,7%; p= 0,048), más afectación renal (21,7% vs 9,5%; p= 0,037), menos sintomatología neurológica (4,3% vs 17,8%; p= 0,005), mayor digoxinemia (4,7 mg/dl vs 3,7 mg/dl; p= 0,027) y menor puntuación en el índice de Barthel (IB) (49,1 (33,4) vs 70,3 (28,5); p= 0,006). El análisis de regresión logística identificó la digoxinemia como un factor independiente de mortalidad inmediata y la puntuación en el IB en la mortalidad a 30 días. Conclusiones: La digoxinemia se relaciona con la mortalidad inmediata y el IB se relaciona con la mortalidad a 30 días


Background and objective: Digoxin poisoning is a frequent reason for seeking emergency care. This study aimed to assess mortality related to digoxin poisoning. Methods: Descriptive observational study of digoxin poisonings attended in the emergency departments of 4 hospitals in Catalonia from 2013 through 2015. We gathered data relevant to the poisonings and recorded immediate and 30-day mortality. Factors possibly related to mortality were explored. Results: A total of 171 digoxin poisonings were attended. Seven (4.1%) were acute and 164 (95.9%) were chronic. The immediate and 30-day mortality rates were 6.4% and 13.4%, respectively. Bivariate analysis did not identify factors related to immediate mortality. However, the variables more often associated with 30-day mortality in this analysis were acute poisoning (after which 13% died vs 2.7% of those with chronic poisoning, P=.05), suicide attempts (8.7% of whom died vs 0.7%, P=.048), more compromised renal function (21.7% vs 9.5%, P=.037), fewer neurologic symptoms (4.3% vs 17.8% with more symptoms, P=.005), higher mean digoxin concentrations (4.7 mg/dL in those who died vs 3.7 mg/dL, P=.027), and a lower Barthel index (mean [SD] 49.1 [33.4] in those who died vs 70.3 [28.5]; P=.006). Logistic regression analysis identified serum digoxin concentration to be independently associated with immediate mortality. A lower Barthel index was associated with 30-day mortality. Conclusions: Immediate mortality is related to a high digoxin concentration in serum, and 30-day mortality to a low Barthel index


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Digoxina/envenenamento , Inibidores Enzimáticos/envenenamento , Envenenamento/mortalidade , Digoxina/sangue , Serviço Hospitalar de Emergência , Inibidores Enzimáticos/sangue , Envenenamento/sangue , Envenenamento/diagnóstico , Espanha/epidemiologia
5.
Rev. esp. quimioter ; 32(1): 1-5, feb. 2019. ilus
Artigo em Espanhol | IBECS | ID: ibc-182741

RESUMO

Baloxavir marboxil (ácido 5-hidroxi-4-piridona-3-carboxilo) es un nuevo fármaco antiviral con especial eficacia sobre los virus gripales que actúa inhibiendo la endonuclease cap-dependiente que precisan para su replicación. Es el primer representante de los denominados inhibidores de la proteína básica 2 (PB2) gripal. Ha mostrado eficacia frente a los virus gripales A y B y la mayoría de cepas de origen animal (gripe aviar). Los ensayos clínicos realizados en pacientes sanos de entre 12 y 64 años sin patologías y no hospitalizados (gripe leve) han mostrado una reducción de la duración de la sintomatología parecida a la obtenida por oseltamivir. Sin embargo baloxavir es un inhibidor de la replicación viral mucho más potente que este fármaco. Se ha mostrado como un fármaco seguro y bien tolerado. Se administra una sola dosis de 40-80 mg las primeras 48 horas del inicio de los síntomas. En estos ensayos se han detectado cepas con sensibilidad moderada (mutantes PA/I38T) en el 2,2% de la gripe A (H1N1)pdm09 y en el 9,7% de la gripe A (H3N2). A pesar de estos datos podría ser un buen fármaco para tratar la gripe leve o moderada, precisando de ensayos en gripe grave y pacientes con patologías crónicas para establecer su verdadera utilidad clínica


Baloxavir marboxil (5-hydroxy-4-pyridone-3-carboxyl acid) is a new antiviral drug with special efficacy on influenza viruses that acts by inhibiting the cap-dependent endonuclease required for its replication. It is the first representative of the so-called inhibitors of influenza-like PB2. It has shown efficacy against influenza viruses A and B and most strains of animal origin (avian flu). Clinical trials conducted in healthy patients between 12 and 64 years without pathologies and not hospitalized (mild flu) have shown a reduction in the duration of symptoms similar to that obtained by oseltamivir. However, baloxavir is a much more potent inhibitor of viral replication than this drug. It has been shown as a safe and well tolerated drug. A single dose of 40-80 mg is administered the first 48 hours after onset of symptoms. In these trials, strains with moderate sensitivity (PA / I38T mutants) were detected in 2.2% of influenza A (H1N1) pdm09 and in 9.7% of influenza A (H3N2). Although these data could be a good drug to treat mild or moderate influenza, requiring trials in severe influenza and patients with chronic diseases to establish their true clinical utility


Assuntos
Humanos , Endonucleases/antagonistas & inibidores , Influenza Humana/tratamento farmacológico , Antivirais/farmacocinética , Orthomyxoviridae/efeitos dos fármacos , Inibidores Enzimáticos/farmacocinética , Medicamentos Compostos contra Resfriado, Influenza e Alergia/farmacocinética , Resultado do Tratamento
6.
J. physiol. biochem ; 74(4): 623-633, nov. 2018. tab, graf
Artigo em Inglês | IBECS | ID: ibc-179040

RESUMO

Tyramine is found in foodstuffs, the richest being cheeses, sausages, and wines. Tyramine has been recognized to release catecholamines from nerve endings and to trigger hypertensive reaction. Thereby, tyramine-free diet is recommended for depressed patients treated with irreversible inhibitors of monoamine oxidases (MAO) to limit the risk of hypertension. Tyramine is a substrate of amine oxidases and also an agonist at trace amine-associated receptors. Our aim was to characterize the dose-dependent effects of tyramine on human adipocyte metabolic functions. Lipolytic activity was determined in adipocytes from human subcutaneous abdominal adipose tissue. Glycerol release was increased by a fourfold factor with classical lipolytic agents (1 μM isoprenaline, 1 mM isobutylmethylxanthine) while the amine was ineffective from 0.01 to 100 μM and hardly stimulatory at 1 mM. Tyramine exhibited a partial antilipolytic effect at 100 μM and 1 mM, which was similar to that of insulin but weaker than that obtained with agonists at purinergic A1 receptors, α2-adrenoceptors, or nicotinic acid receptors. Gi-protein blockade by Pertussis toxin abolished all these antilipolytic responses save that of tyramine. Indeed, tyramine antilipolytic effect was impaired by MAO-A inhibition. Tyramine inhibited protein tyrosine phosphatase activities in a manner sensitive to ascorbic acid and amine oxidase inhibitors. Thus, millimolar tyramine restrained lipolysis via the hydrogen peroxide it generates when oxidized by MAO. Since tyramine plasma levels have been reported to reach 0.2 μM after ingestion of 200 mg tyramine in healthy individuals, the direct effects we observed in vitro on adipocytes could be nutritionally relevant only when the MAO-dependent hepato-intestinal detoxifying system is overpassed


No disponible


Assuntos
Humanos , Feminino , Adulto , Inibidores da Captação Adrenérgica/efeitos adversos , Gordura Subcutânea/metabolismo , Tiramina/efeitos adversos , Toxina Adenilato Ciclase/farmacologia , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Inibidores da Captação Adrenérgica/química , Agonistas Adrenérgicos beta/farmacologia , Inibidores Enzimáticos/farmacologia , Glicerol/metabolismo , Gordura Subcutânea/citologia , Gordura Subcutânea , Tiramina/antagonistas & inibidores
7.
Nutr. hosp ; 35(4): 928-935, jul.-ago. 2018. graf
Artigo em Espanhol | IBECS | ID: ibc-179888

RESUMO

Introducción: los biopéptidos son secuencias aminoacídicas que pueden ejercer funciones biológicas sobre el metabolismo y la absorción de carbohidratos. Objetivo: la finalidad de este estudio fue evaluar el efecto inhibitorio de fracciones peptídicas derivadas de la hidrólisis de Salvia hispanica sobre las enzimas alfa-amilasa y alfa-glucosidasa, para comprobar su actividad en el metabolismo glucídico. Material y métodos: se obtuvo una fracción rica en proteína, la cual fue hidrolizada mediante dos sistemas enzimáticos: Alcalasa(R)-Flavourzima(R) y pepsina-pancreatina. A las muestras obtenidas se les determinó el grado de hidrólisis. El hidrolizado fue centrifugado y la porción soluble fue ultrafiltrada, utilizando diferentes membranas de corte. A cada fracción se le determinó el contenido de proteína. Se realizó un análisis in vitro midiendo el porcentaje de inhibición de las fracciones de Salvia hispanica sobre α-amilasa y α-glucosidasa. Resultados: el sistema enzimático que presentó el mayor grado de hidrólisis (63,53%) fue la pepsina-pancreatina. De la ultrafiltración se obtuvieron cinco fracciones peptídicas: > 10 kDa, 5-10 kDa, 3-5 kDa, 1-3 kDa y < 1 kDa. El mayor contenido de proteína lo presentaron las fracciones de > 10 kDa y 5-10 kDa (0,90 y 0,93 mg/ml, respectivamente) para pepsina-pancreatina. Los porcentajes de inhibición obtenidos fueron de 85,61% y 79,19% para las fracciones de > 10 kDa y 5-10 kDa, respectivamente para la enzima α-amilasa. Para la enzima alfa-glucosidasa, el mayor porcentaje de inhibición fue para la fracción de > 10 kDa, con 96,91%. Conclusión: los péptidos obtenidos de la chía podrían incrementar las fuentes naturales para la elaboración de alimentos funcionales importantes para la dieta de pacientes diabéticos


Introduction: biopeptides are amino acid sequences with biological functions about metabolism and carbohydrates absorption. Objective: the aim of this study was the evaluation of the inhibitory effect of peptide fractions derivatives of the hydrolysis of Salvia hispanica against alfa-amylase and α-glucosidase enzymes to know their activity on the carbohydrates metabolism. Material and methods: the fraction rich in protein was hydrolyzed by two enzymatic systems: Alcalase (R)-Flavourzyme(R) and pepsin-pancreatine. The grade of hydrolysis was determined for the samples. The hydrolyzed samples were centrifuged and the soluble portion was ultra-fi ltered using different cut membranes. The content of protein was determined for each fraction. An in vitro analysis was made, measuring the percentage of inhibition of the Salvia hispanica fractions against α-amylase and alfa-glucosidase. Results: the enzymatic system showing the highest grade of hydrolysis (63.53%) was pepsin-pancreatine. From the ultrafi ltration, fi ve peptide fractions were obtained: 10 kDa, 5-10 kDa, 3-5 kDa, 1-3 kDa and 1 kDa. The highest protein content was for these fractions: 10 kDa and 5-10 kDa, (0.90 and 0.93 mg/ml, respectively) for pepsin-pancreatine. The inhibition percentages obtained were 85.61% and 79.19% for the 10 kDa and 5-10 kDa fractions, respectively, for the alfa-amylase enzyme. With respect to the alfa-glucosidase enzyme, the highest inhibition was for the 10 kDa fraction, with 96.91%. Conclusion: the peptide fractions obtained from the chia may increase the natural sources for the preparation of functional foods important for the diabetic patient's diet


Assuntos
Humanos , Inibidores Enzimáticos/farmacologia , Peptídeos/farmacologia , Extratos Vegetais/farmacologia , Salvia/química , alfa-Amilases/antagonistas & inibidores , alfa-Glucosidases/metabolismo , Peptídeos/química , Extratos Vegetais/química , Proteínas de Plantas/química
8.
Rev. esp. med. prev. salud pública ; 23(1): 21-30, 2018. graf, tab
Artigo em Espanhol | IBECS | ID: ibc-175720

RESUMO

ntroducción: El objetivo es conocer la evolución de la prevalencia de infección nosocomial por microorga-nismos multirresistentes y el consumo hospitalario de antimicrobianos. Métodos: Análisis descriptivo de los datos del EPINE del Hospital Universitario de Salamanca periodo 2004-2015. Variables: tipo infección, consumo de antimicrobianos, cirugía, profilaxis quirúrgica y factores de riesgo. Resultados: La prevalencia de infección nosocomial por gérmenes multirresistentes se incrementó desde el año 2004, destaca el aumento de infecciones por Clostridium difficile. El consumo de antimicrobianos se mantiene estable pero se ha producido un cambio en las prevalencias individuales con disminución de amoxicilina e inhibidor enzimático (IE) y aumento de otros destacando a piperacilina e inhibidor enzimático. Conclusiones: El aumento de gérmenes multirresistentes y el cambio en el consumo de antimicrobianos hace que nos planteemos el desarrollo de nuevas estrategias y la necesidad de actualizar y evaluar de manera continua los protocolos de adecuación del uso de antimicrobianos


Introduction: The objective is to know the evolution of the prevalence of nosocomial infection by multiresistant microorganisms and the hospital consumption of antimicrobials. Methods: Descriptive analysis of EPINE data from Hospital Universitario de Salamanca period 2004-2015. Variables: infection type, antimicrobial consumption, surgery, surgical prophylaxis and risk factors. Results: The prevalence of nosocomial infection by multiresistant germs has increased since 2004, with the increase in Clostridium difficile infections. The consumption of antimicrobials remains stable but there has been a change in the individual prevalences with decrease of amoxicillin and enzyme inhibitor (IE) and increase of others emphasizing piperacillin and IE. Conclusions: The increase of multiresistant germs and the change in antimicrobial consumption makes us consider the development of new strategies and the need to continuously update and evaluate protocols for adequacy of antimicrobial use


Assuntos
Humanos , Infecção Hospitalar/epidemiologia , Anti-Infecciosos/administração & dosagem , Fatores de Risco , Resistência a Múltiplos Medicamentos , Infecção Hospitalar/microbiologia , Amoxicilina/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Piperacilina/administração & dosagem , Antibioticoprofilaxia
9.
J. physiol. biochem ; 73(4): 551-560, nov. 2017. graf
Artigo em Inglês | IBECS | ID: ibc-178905

RESUMO

A still growing body of evidence suggests the importance of epoxyeicosatrienoic acids (EETs) in the regulation of inflammatory response; therefore, drugs that stabilize their levels by targeting the soluble epoxide hydrolase (sEH), an enzyme responsible for their metabolism, are currently under investigation. The effect of sEH inhibitors on molecular components of fever mechanism, i.e., on synthesis of pro-inflammatory cytokines or prostaglandins, has been repeatedly proven; however, the hypothesis that sEH inhibitors affect febrile response has never been tested. The aim of this study was to examine if sEH inhibition affects core body temperature (Tb) as well as Tb changes during febrile response to infectious (lipopolysaccharide; LPS) or non-infectious (turpentine; TRP) stimuli. Male Wistar rats were implanted intra-abdominally with miniature biotelemeters to monitor Tb. A potent sEH inhibitor 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) was suspended in olive oil and administrated into animals in the intraperitoneal (i.p.) dose of 15 mg/kg, which, as we showed, has no significant influence on normal Tb. We have found that AUDA injected 3 h after LPS (50 μg/kg i.p.) significantly weakened febrile rise of Tb. Moreover, injection of sEH inhibitor 7 h after turpentine (administrated subcutaneously in a dose of 100 μL/rat) markedly reduced the peak period of aseptic fever. Obtained results provide first experimental evidence that sEH inhibitors possess anti-pyretic properties. Therefore, medicines targeting sEH enzymatic activity should be considered as a complement to the arsenal of topical medications used to treat fever especially in clinical situations when non-steroidal anti-inflammatory drugs are ineffective


No disponible


Assuntos
Animais , Masculino , Ratos , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Febre/induzido quimicamente , Lipopolissacarídeos/administração & dosagem , Terebintina/farmacologia , Ratos Wistar , Telemetria , Inflamação
10.
J. physiol. biochem ; 73(2): 175-185, mayo 2017. ilus, graf, tab
Artigo em Inglês | IBECS | ID: ibc-168474

RESUMO

We and others have demonstrated a protective role for pacing postconditioning (PPC) against ischemia/reperfusion (I/R) injury in the heart; however, the underlying mechanisms behind these protective effects are not completely understood. In this study, we wanted to further characterize PPC-mediated cardiac protection, specifically identify optimal pacing sites; examine the role of oxidative stress; and test the existence of a potential synergistic effect between PPC and adenosine. Isolated rat hearts were subjected to coronary occlusion followed by reperfusion. PPC involved three, 30 s, episodes of alternating left ventricular (LV) and right atrial (RA) pacing. Multiple pacing protocols with different pacing electrode locations were used. To test the involvement of oxidative stress, target-specific agonists or antagonists were infused at the beginning of reperfusion. Hemodynamic data were digitally recorded, and cardiac enzymes, oxidant, and antioxidant status were chemically measured. Pacing at the LV or RV but not at the heart apex or base significantly (P < 0.001) protected against ischemia-reperfusion injury. PPC-mediated protection was completely abrogated in the presence of reactive oxygen species (ROS) scavenger, ebselen; peroxynitrite (ONOO-) scavenger, uric acid; and nitric oxide synthase inhibitor, L-NAME. Nitric oxide (NO) donor, snap, however significantly (P < 0.05) protected the heart against I/R injury in the absence of PPC. The protective effects of PPC were significantly improved by adenosine. PPC-stimulated protection can be achieved by alternating LV and RA pacing applied at the beginning of reperfusion. NO, ROS, and the product of their interaction ONOO− play a significant role in PPC-induced cardiac protection. Finally, the protective effects of PPC can be synergized with adenosine (AU)


No disponible


Assuntos
Animais , Masculino , Ratos , Pós-Condicionamento Isquêmico/métodos , Cardiotônicos/uso terapêutico , Adenosina/uso terapêutico , Circulação Coronária , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Estresse Oxidativo , Ventrículos do Coração , Espécies Reativas de Oxigênio , Espécies Reativas de Nitrogênio , Óxido Nítrico Sintase , Terapia Combinada/efeitos adversos , Técnicas In Vitro , Antioxidantes , Doadores de Óxido Nítrico , Inibidores Enzimáticos , Depuradores de Radicais Livres
11.
J. physiol. biochem ; 72(3): 371-380, sept. 2016. tab, ilus
Artigo em Inglês | IBECS | ID: ibc-168281

RESUMO

Sirtuins are evolutionarily conserved nicotinamide adenine dinucleotide (NAD+)-dependent lysine deacylases or ADP-ribosyltransferases. These cellular enzymes are metabolic sensors sensitive to NAD+ levels that maintain physiological homeostasis in the animal and plant cells (AU)


No disponible


Assuntos
Humanos , Animais , Homeostase , Modelos Biológicos , Sirtuínas/fisiologia , Ativação Enzimática , Isoenzimas , Acetilação , DNA/metabolismo , Inibidores Enzimáticos/farmacologia , Especificidade da Espécie , Domínio Catalítico , Sequência Conservada , Proteínas de Plantas , Transporte Proteico , Especificidade por Substrato
12.
Clin. transl. oncol. (Print) ; 18(8): 848-858, ago. 2016. tab, graf
Artigo em Inglês | IBECS | ID: ibc-154061

RESUMO

BACKGROUND: We executed a comparative systematic review and meta-analysis of the efficacy and toxicity of doublet BRAF/MEK inhibition versus single-agent BRAF inhibitor in the management of BRAF-mutant advanced melanoma. METHODS: Eligible studies included prospective studies evaluating doublet regimens versus BRAF-inhibitor monotherapy for the management of BRAF-mutant advanced melanoma. RESULTS: Our search strategy yielded 200 potentially relevant citations from searched databases. After preclusion of ineligible studies, four studies were included in the final analysis. Efficacy analyses demonstrate that BRAF/MEK inhibition strategy is associated with a significant improvement in ORR [OR 1.35; 95 % CI (1.16, 1.58); P = 0.0002], PFS [HR 0.56; 95 % CI (0.49, 0.64); P < 0.00001] and OS [HR 0.70; 95 % CI (0.58, 0.84); P = 0.0001]. Moreover, this combination is associated with a higher RR for diarrhea [1.30; 95 % CI (1.30, 1.49); P = 0.0002], decreased ejection fraction [4.63; 95 % CI (2.56, 8.37); P = <0.00001], acneiform dermatitis [1.61; 95 % CI (1.03, 2.53); P = 0.04] and pyrexia [1.98; 95 % CI (1.72, 2.27); P < 0.00001]. CONCLUSIONS: Our meta-analysis has demonstrated that combination of MEK/BRAF inhibitors is associated with higher ORR, PFS and OS. However, this comes at the expense of a higher risk of selected toxicities


No disponible


Assuntos
Humanos , Melanoma/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Inibidores Enzimáticos/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , MAP Quinase Quinase Quinases/antagonistas & inibidores , Vemurafenib/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
13.
J. physiol. biochem ; 72(2): 133-144, jun. 2016. tab, graf
Artigo em Inglês | IBECS | ID: ibc-168261

RESUMO

Tacrolimus (TAC), a calcineurin inhibitor (CNI), is clinically used as an immunosuppressive agent in the transplant recipient; however, the use of TAC is greatly limited by its nephrotoxicity and hepatotoxicity. Mycophenolate mofetil (MMF), an inhibitor of the purine synthesis, has been used in combination with many immunosuppressive drugs such as TAC. The association TAC/MMF was used in organ transplantation to increase the efficiency and reduce acute rejection rates, but the effects of MMF on TAC-induced kidney and liver injuries are still not well investigated. The aims of this study are to explore whether MMF co-administration with TAC has a renoprotective and hepatoprotective effect against TAC-induced renal and hepatic injuries and to check the implication of oxidative stress in the MMF’s possible protective effect. Our results showed that MMF (at 50 mg kg−1 body weight (b.w.)) restored creatinine, in addition to increased AST and ALT levels by TAC (at 60 mg kg−1 b.w.). Furthermore, MMF decreased DNA damage induced by TAC in the kidney and liver of rats as assessed by comet assay. This renoprotective and hepatoprotective effect of MMF was associated with an antioxidant effect. In fact, MMF co-treatment with TAC decreased oxidative damage induced by TAC. It reduced malondialdehyde (MDA) and protein carbonyl (PC) levels as well as catalase and superoxide dismutase (SOD) activities. We conclude that the co-administration MMF with TAC protect liver and kidney against TAC toxicity via an antioxidant process (AU)


No disponible


Assuntos
Animais , Masculino , Insuficiência Renal/prevenção & controle , Substâncias Protetoras/uso terapêutico , Inibidores de Calcineurina/efeitos adversos , Ácido Micofenólico/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Biomarcadores/sangue , Ratos Wistar , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Estresse Oxidativo , Imunossupressores/farmacologia , Tacrolimo/farmacologia , Inibidores Enzimáticos/administração & dosagem , IMP Desidrogenase
14.
J. physiol. biochem ; 72(2): 245-253, jun. 2016. graf
Artigo em Inglês | IBECS | ID: ibc-168269

RESUMO

We previously observed that sarcoendoplasmic reticulum Ca2+ ATPase (SERCA) blockade by cyclopiazonic acid (CPA) significantly potentiates serotonin (5-hydroxytryptamine (5-HT))-induced vascular contractions. Furthermore, 5-HT receptor antagonist methysergide partially inhibited CPA-potentiated 5-HT contractions. In the present study, we further investigated whether SERCA inhibition potentiates 5-HT-induced Ca2+ responses along with attenuating the receptor antagonism by store-operated Ca2+ (SOC) entry and protein kinase C (PKC)-mediated mechanisms. The effects of dexamethasone that was previously shown to induce SOC entry and enhance 5-HT responses were also tested. For this purpose, intracellular Ca2+ levels were monitored in A7r5 embryonic rat vascular smooth muscle cells by spectrofluorometry using the fluorescent indicator fura-2. The results showed that CPA, although not dexamethasone, significantly potentiated 5-HT-induced Ca2+ elevations. Ketanserin partially decreased 5-HT-induced and CPA-potentiated Ca2+ elevations whereas both PKC inhibitor D-sphingosine and SOC entry blocker 2-aminoethoxydiphenyl borate (2-APB) abolished the remaining responses. The data suggests that diminished antagonistic effect on 5-HT-induced Ca2+ elevations in the presence of SERCA inhibition is induced by SOC entry and PKC activation (AU)


No disponible


Assuntos
Animais , Ratos , Sinalização do Cálcio , Inibidores Enzimáticos/farmacologia , Indóis/farmacologia , Músculo Liso Vascular , Agonistas do Receptor de Serotonina/farmacologia , Serotonina/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/antagonistas & inibidores , Anti-Inflamatórios , Bloqueadores dos Canais de Cálcio/farmacologia , Antagonistas da Serotonina/farmacologia , Vasoconstritores , Vasodilatadores , Proteína Quinase C , Linhagem Celular
16.
Clin. transl. oncol. (Print) ; 18(2): 212-219, feb. 2016. ilus, graf
Artigo em Inglês | IBECS | ID: ibc-148227

RESUMO

Objective. To investigate the role of the vascular endothelial growth factor receptor 2 (VEGFR2) in the proliferation, migration, invasion, and radiation-induced apoptosis of the non-small cell lung cancer (NSCLC) cell line Calu-1. Methods. VEGFR2 gene was silenced by RNA interference in Calu-1 cells, and the expression of VEGFR2 was measured by qRT-PCR and Western blot analysis. The cells were divided into control, VEGF-treated, VEGFR2 knockdown, and VEGFR2 knockdown and VEGF-treated groups. A CCK8 assay and Transwell assay were performed to assess cell proliferation, migration, and invasion, respectively, after VEGFR2 knockdown. Western blot assays were used to detect signaling proteins downstream of VEGFR2. Cells in the groups listed above were also subjected to radiation treatment, followed by apoptosis analysis. Results. (1) RNA interference of VEGFR2 in Calu-1 cells reduced VEGFR2 mRNA (P < 0.01) and protein levels (P < 0.01). (2) VEGFR2 knockdown inhibited proliferation (P < 0.05), migration (P < 0.05), and invasion (P < 0.05) in Calu-1 cells. (3) VEGFR2 knockdown blocked the phosphorylation of protein kinase B (Akt, also known as PKB), extracellular regulated kinase (ERK) 1/2, and p38 mitogen-activated protein kinase (p38 MAPK) to various extent (P < 0.05), but did not change their total protein expression. (4) Knockdown of VEGFR2 suppressed HIF-1α protein synthesis (P < 0.05), and exacerbated apoptosis induced by radiation (P < 0.05). Conclusion. VEGFR2 gene knockdown significantly suppressed a number of cellular activities in Calu-1 cells and increased radiation-induced cell death (AU)


No disponible


Assuntos
Humanos , Masculino , Feminino , Inibidores Enzimáticos/administração & dosagem , Proliferação de Células/genética , Fator 1 de Crescimento de Fibroblastos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Apoptose/genética , Carcinoma de Células Escamosas/metabolismo , Eletroforese/métodos , Inibidores Enzimáticos/metabolismo , Proliferação de Células/fisiologia , Fator 1 de Crescimento de Fibroblastos/provisão & distribução , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/terapia , Apoptose/fisiologia , Carcinoma de Células Escamosas/complicações , Eletroforese
17.
J. physiol. biochem ; 71(1): 89-98, mar. 2015.
Artigo em Inglês | IBECS | ID: ibc-133906

RESUMO

Type 2 diabetes (T2D) is a complicated systemic disease, and the exact pathogenetic molecular mechanism is unclear. Distinct histone modifications regulate gene expression in certain diseases, but little is known about histone epigenetics in diabetes. In the current study, C57BL/6 J mice were used to build T2D model, then treated with exendin-4 (10 μg/kg). Histone H3K9 and H3K23 acetylation, H3K4 monomethylation and H3K9 dimethylation were explored by Western blotting of liver histone extracts. Real-time polymerase chain reaction (PCR) was used to examine expression levels of diabetes-related genes, while chromatin immunoprecipitation (ChIP) was applied to analyze H3 and H3K9 acetylation, H3K4 monomethylation, and H3K9 dimethylation in the promoter of facilitated glucose transporter member 2 (Glut2) gene. The results showed that liver’s total H3K4 monomethylation and H3K9 dimethylation was increased in diabetic mice, which was abrogated with the treatment of exendin-4. In contrast, H3K9 and H3K23 acetylation were reduced in diabetic mice, while exendin-4 only alleviated the reduction of H3K9 acetylation. Our data indicated that the progression of type 2 diabetes mellitus (T2D) is associated with global liver histone H3K9 and H3K23 acetylation, H3K4 monomethylation, and H3K9 dimethylation. Exploiting exact histone modify enzyme inhibitors, which may represent a novel strategy to prevent T2D (AU)


Assuntos
Humanos , Histonas/fisiologia , Metilação , Acetilação , Diabetes Mellitus Tipo 2/fisiopatologia , Epigênese Genética , Membro 2 da Família 12 de Carreador de Soluto/fisiologia , Inibidores Enzimáticos/análise
18.
Reumatol. clín. (Barc.) ; 10(4): 210-217, jul.-ago. 2014. tab, ilus
Artigo em Espanhol | IBECS | ID: ibc-124008

RESUMO

Objetivo: Evaluar, desde la perspectiva del Sistema Nacional de Salud, la eficiencia de la combinación a dosis fija de naproxeno y esomeprazol (naproxeno/esomeprazol) en artrosis frente a otros AINE en monoterapia o combinados con un inhibidor de la bomba de protones (IBP). Métodos: Se empleó un modelo de Markov con estados de salud definidos por episodios gastrointestinales (GI): dispepsia, úlcera péptica sintomática o complicada; o cardiovasculares (CV): infarto agudo de miocardio, ictus o insuficiencia cardiaca. El modelo es semejante al utilizado por el NICE en su evaluación de AINE en artrosis publicada en 2008. Se estimaron, en un horizonte temporal de 1 año (ciclos de 3 meses), los costes totales (D , 2012), incluyendo coste farmacológico y de manejo de episodios, y los resultados en salud, expresados en años de vidaajustados por calidad (AVAC), en pacientes mayores de 65 años con riesgo GI aumentado, tras 6 meses de tratamiento con celecoxib (200 mg/día), celecoxib + IBP, diclofenaco (150 mg/día) + IBP, etoricoxib (60 mg/día), etoricoxib + IBP, ibuprofeno (1.800 mg/día) + IBP, naproxeno (1.000 mg/día) + IBP o naproxeno/ esomeprazol (naproxeno 1.000 mg/esomeprazol 40 mg/día). El IBP fue omeprazol (20 mg/día). Resultados: Naproxeno/esomeprazol resultó dominante (más efectivo y menor coste) respecto a celecoxib, etoricoxib y diclofenaco + IBP. Celecoxib + IBP y etoricoxib + IBP fueron más efectivos. Considerando un umbral de 30.000 D /AVAC adicional, naproxeno/esomeprazol resultó coste-efectivo respecto a ibuprofeno + IBP y naproxeno + IBP con valores de relación coste-efectividad incremental de 15.154D y 5.202 D /AVAC adicional, respectivamente. Conclusiones: La combinación a dosis fijas de naproxeno y esomeprazol en pacientes con artrosis y riesgo GI aumentado es una alternativa coste-efectiva e incluso dominante frente a otras opciones (AU)


Objective: To assess, from the perspective of the National Healthcare System, the efficiency of a fixed-dose combination of naproxen and esomeprazole (naproxen/esomeprazole) in the treatment of osteoarthritis (OA) compared to other NSAID, alone or in combination with a proton pump inhibitor (PPI). Methods: A Markov model was used; it included different health states defined by gastrointestinal (GI) events: dyspepsia, symptomatic or complicated ulcer; or cardiovascular (CV) events: myocardial infarction, stroke or heart failure. The model is similar to the one used by NICE in its NSAID evaluation of OA published in 2008 The total costs (D , 2012), including drug and event-related costs, and the health outcomes expressed in quality-adjusted life years (QALY) were estimated in patients with increased GI risk, aged 65 or over, for a 1-year time horizon and a 6-month treatment with celecoxib (200 mg/day), celecoxib + PPI, diclofenac (150 mg/day) + PPI, etoricoxib (60 mg/day), etoricoxib + PPI, ibuprofen (1,800 mg/day) + PPI, naproxen (1,000 mg/day) + PPI or naproxen/esomeprazole (naproxen 1,000 mg/esomeprazole 40 mg/day). The selected PPI was omeprazole (20 mg/day). Results: Naproxen/esomeprazole was a dominant strategy (more effective and less costly) compared to celecoxib, etoricoxib and diclofenac + PPI. Celecoxib + PPI and etoricoxib + PPI were more effective. Considering a cost-effectiveness threshold of D 30,000 per additional QALY, naproxen/esomeprazole was cost-effective compared to ibuprofen + PPI and naproxen + PPI with incremental cost-effectiveness ratios (ICER) of D15,154 and D 5,202 per additional QALY, respectively. Conclusions: A fixed-dose combination of naproxen and esomeprazole is a cost-effective, and even dominant, alternative compared to other options in OA patients with increased GI risk (AU)


Assuntos
Humanos , Naproxeno/uso terapêutico , Osteoartrite/tratamento farmacológico , Inibidores da Bomba de Prótons/uso terapêutico , Antirreumáticos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Combinação de Medicamentos
20.
Rev. neurol. (Ed. impr.) ; 55(supl.1): s3-s6, 31 dic., 2012.
Artigo em Espanhol | IBECS | ID: ibc-148648

RESUMO

En el momento actual, contamos con medicación antiparkinsoniana eficaz y potente, lo que permite una capacidad funcional aceptable durante los primeros años de la enfermedad de Parkinson. Sin embargo, con el paso del tiempo, existe un deterioro motor y funcional en parte por la presencia de complicaciones motoras y no motoras. La medicación convencional no es capaz de dar respuesta suficiente si las fluctuaciones motoras son superiores a 3-4 horas. En ese punto es razonable evaluar otras terapias; entre ellas hay que considerar, por su sencillez y eficacia, la apomorfina en inyección subcutánea y posteriormente la apomorfina en infusión. La apomorfina es un tratamiento muy efectivo y claramente infrautilizado en la enfermedad de Parkinson avanzada (AU)


At the present time, we have effective and potent antiparkinsonian drugs available which allow patients to have an acceptable functional capacity during the early years of Parkinson’s disease. Yet, as time goes by, motor and functional deterioration develop, partly due to the presence of motor and non-motor complications. The conventional medication is unable to provide an adequate response if the motor fluctuations are beyond 3-4 hours of duration. At this point, it is reasonable to consider other therapies; among them subcutaneous apomorphine injection must be taken into account due to its simplicity and efficacy and later on, subcutaneous apomorphine infusion. Apomorphine is a very effective and clearly underused drug in the treatment of advanced Parkinson’s disease (AU)


Assuntos
Humanos , Antiparkinsonianos/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Indanos/administração & dosagem , Indanos/uso terapêutico , Catecol O-Metiltransferase , Inibidores de Catecol O-Metiltransferase , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/uso terapêutico , Meia-Vida , Inibidores Enzimáticos/administração & dosagem , Administração Cutânea , Administração Oral , Antiparkinsonianos/administração & dosagem , Apomorfina/administração & dosagem , Apomorfina/uso terapêutico , Apomorfina/farmacocinética , Ensaios Clínicos como Assunto , Estudos Multicêntricos como Assunto , Metanálise como Assunto , Injeções Subcutâneas , Levodopa/uso terapêutico , Levodopa/administração & dosagem , Quimioterapia Combinada , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico
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