RESUMO
Background: Tetralogy of Fallot is one of the most frequent cyanotic heart diseases in our country, occupying the second place reported by the national health program 2007- 2012 and its prevalence is around 11%. Patients undergoing correction for tetralogy of Fallot are considered patients with a prolonged ischemic time and a high risk of presenting low cardiac output syndrome. Objective: To compare levosimendan with milrinone to prevent low cardiac output syndrome in patients undergoing tetralogy of Fallot correction. Material and methods: Randomized controlled open, prospective, longitudinal and comparative clinical trial. The sample size consisted of 19 patients, with a 95% confidence level. Group 1: levosimendan 0.1 mcg/kg/min from anesthetic induction. Group 2: conventional management with milrinone 0.5 mcg/kg/min. Results: When comparing the final measurements, it can be observed that the mean arterial pressure of the intervention group (levosimendan) was statistically significant (p = 0.04), both in the intraoperative measurement and in the final measurement. When comparing uresis, we found that the intervention group had a greater amount of uresis (p = 0.03). Regarding lactate, both in the intraoperative measurement (p = 0.002) and in the final measurement (p = 0.02), a lower amount was found in the intervention group. Conclusions: The results in favor of the use of levosimendan were reported, demonstrating the prevention of low cardiac output syndrome.
Introducción: la tetralogía de Fallot es una de las cardiopatías cianóticas más frecuentes de nuestro país, pues ocupa el segundo lugar reportado por el Programa Nacional de Salud 2007-2012 y su prevalencia se sitúa aproximadamente en 11%. Los pacientes sometidos a corrección de tetralogía de Fallot se consideran pacientes con un tiempo de isquemia prolongado y con riesgo alto de presentar síndrome de bajo gasto cardiaco. Objetivo: comparar levosimendán con milrinona para prevenir el síndrome de bajo gasto cardiaco en pacientes operados de corrección de tetralogía de Fallot. Material y métodos: ensayo clínico aleatorizado, controlado, abierto, prospectivo, longitudinal y comparativo. El tamaño de la muestra se estimó en 19 pacientes, con un nivel de confianza del 95%. En el grupo 1 se empleó 0.1 mcg/kg/min de levosimendán desde la inducción anestésica; en el grupo 2 se usó el manejo convencional con milrinona de 0.5 mcg/kg/min. Resultados: al comparar las mediciones finales se pudo observar que la presión arterial media del grupo de intervención (levosimendán) fue estadísticamente significativa (p = 0.04), tanto en la medición transoperatoria como en la medición final. Al comparar la uresis encontramos que el grupo con intervención tuvo mayor cantidad de uresis (p = 0.03). En cuanto al lactato, tanto en la medición transoperatoria (p = 0.002) como en la medición final (p = 0.02) se encontró una menor cantidad en el grupo de intervención. Conclusiones: se reportaron los resultados a favor del uso del levosimendán, pues se demostró que previene el síndrome de bajo gasto cardiaco.
Assuntos
Baixo Débito Cardíaco/prevenção & controle , Cardiotônicos , Piridazinas , Tetralogia de Fallot , Baixo Débito Cardíaco/tratamento farmacológico , Baixo Débito Cardíaco/etiologia , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Criança , Humanos , Hidrazonas/farmacologia , Hidrazonas/uso terapêutico , Estudos Longitudinais , Milrinona/farmacologia , Milrinona/uso terapêutico , Estudos Prospectivos , Piridazinas/farmacologia , Piridazinas/uso terapêutico , Simendana/uso terapêutico , Síndrome , Tetralogia de Fallot/complicações , Tetralogia de Fallot/cirurgiaRESUMO
The expression of several hippocampal genes implicated in learning and memory processes requires that Ca2+ signals generated in dendritic spines, dendrites, or the soma in response to neuronal stimulation reach the nucleus. The diffusion of Ca2+ in the cytoplasm is highly restricted, so neurons must use other mechanisms to propagate Ca2+ signals to the nucleus. Here, we present evidence showing that Ca2+ release mediated by the ryanodine receptor (RyR) channel type-2 isoform (RyR2) contributes to the generation of nuclear Ca2+ signals induced by gabazine (GBZ) addition, glutamate uncaging in the dendrites, or high-frequency field stimulation of primary hippocampal neurons. Additionally, GBZ treatment significantly increased cyclic adenosine monophosphate response element binding protein (CREB) phosphorylation-a key event in synaptic plasticity and hippocampal memory-and enhanced the expression of Neuronal Per Arnt Sim domain protein 4 (Npas4) and RyR2, two central regulators of these processes. Suppression of RyR-mediated Ca2+ release with ryanodine significantly reduced the increase in CREB phosphorylation and the enhanced Npas4 and RyR2 expression induced by GBZ. We propose that RyR-mediated Ca2+ release induced by neuronal activity, through its contribution to the sequential generation of nuclear Ca2+ signals, CREB phosphorylation, Npas4, and RyR2 up-regulation, plays a central role in hippocampal synaptic plasticity and memory processes.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Cálcio/metabolismo , Hipocampo/citologia , Neurônios/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Técnicas de Cultura de Células , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Antagonistas GABAérgicos/farmacologia , Ácido Glutâmico/farmacologia , Piridazinas/farmacologia , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Sinapses/fisiologia , Técnicas de Cultura de TecidosRESUMO
Gastric cancer is one of the most common and deadly types of cancer in the world, and poor prognosis with treatment failure is widely reported in the literature. In this context, kinases have been considered a relevant choice for targeted therapy in gastric cancer. Here, we explore the antiproliferative and antimigratory effects of the AURKA inhibitor and the prognostic and therapeutic value as a biomarker of gastric cancer. A total of 145 kinase inhibitors were screened to evaluate the cytotoxic or cytostatic effects in the gastric cancer cell line. Using the Alamar Blue assay, flow cytometry, quantitative polymerase chain reaction, and observation of caspase 3/7 activity and cell migration, we investigated the antiproliferative, proapoptotic, and antimigratory effects of the AURKA inhibitor. Moreover, AURKA overexpression was evaluated in the gastric cell lines and the gastric tumor tissue. Out of the 145 inhibitors, two presented the highest antiproliferative effect. Both molecules can induce apoptosis by the caspases 3/7 pathway in addition to inhibiting cancer cell migration, mainly the AURKA inhibitor. Moreover, molecular docking analysis revealed that GW779439X interacts in the active site of the AURKA enzyme with similar energy as a well-described inhibitor. Our study identified AURKA overexpression in the gastric cancer cell line and gastric tumor tissue, revealing that its overexpression in patients with cancer is correlated with low survival. Therefore, it is feasible to suggest AURKA as a potential marker of gastric cancer, besides providing robust information for diagnosis and estimated survival of patients. AURKA can be considered a new molecular target used in the prognosis and therapy of gastric cancer.
Assuntos
Aurora Quinase A/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Piridazinas/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Apoptose , Aurora Quinase A/metabolismo , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Ensaios de Triagem em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Simulação de Acoplamento Molecular , Prognóstico , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/patologia , Taxa de SobrevidaRESUMO
Stearoyl-CoA desaturase (SCD) is a central lipogenic enzyme for the synthesis of monounsaturated fatty acids (MUFA). SCD1 overexpression is associated with a genetic predisposition to hepatocarcinogenesis in mice and rats. This work hypothesized possible roles of SCD1 to genomic stability, lipogenesis, cell proliferation, and survival that contribute to the malignant transformation of non-tumorigenic liver cells. Therefore, HepG2 tumor cells were treated with the SCD1 inhibitor (CAY10566) to ensure a decrease in proliferation/survival, as confirmed by a lipidomic analysis that detected an efficient decrease in the concentration of MUFA. According to that, we switched to a model of normal hepatocytes, the HepaRG cell line, where we: (i) overexpressed SCD1 (HepaRG-SCD1 clones), (ii) inhibited the endogenous SCD1 activity with CAY10566, or (iii) treated with two monounsaturated (oleic OA and/or palmitoleic PA) fatty acids. SCD1 overexpression or MUFA stimulation increased cell proliferation, survival, and the levels of AKT, phospho-AKT(Ser473), and proliferating cell nuclear antigen (PCNA) proteins. By contrast, opposite molecular and cellular responses were observed in HepaRG cells treated with CAY10566. To assess genomic stability, HepaRG-SCD1 clones were treated with ionizing radiation (IR) and presented reduced levels of DNA damage and higher survival at doses of 5 Gy and 10 Gy compared to parental cells. In sum, this work suggests that modulation of SCD1 activity not only plays a role in cell proliferation and survival, but also in maintaining genomic stability, and therefore, contributes to a better understanding of this enzyme in molecular mechanisms of hepatocarcinogenesis projecting SCD1 as a potential translational target.
Assuntos
Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Ácidos Oleicos/farmacologia , Oxidiazóis/farmacologia , Piridazinas/farmacologia , Estearoil-CoA Dessaturase/metabolismo , Apoptose , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Ciclo Celular , Proliferação de Células , Instabilidade Genômica , Hepatócitos/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Estearoil-CoA Dessaturase/genética , Células Tumorais CultivadasRESUMO
Paracoccidioidomycosis is an endemic mycosis in Latin America for which there is a high mortality rate and limited treatment options. There are no specific drugs to treat the systemic disease. Thus, there is a need for further studies focused on the development of specific drugs. In this work we synthesized new hybrids pyrimido[4,5-d]pyridazinone-N-acylhydrazone (5a-p) by simple methodologies with good yields. The antifungal activity of compounds was evaluated against P. brasiliensis (Pb18) and Candida spp. Compounds 5a, 5f, 5i, 5 k, 5m and 5n showed significant inhibition against Pb18 with MIC of 0.125 to 64 µg mL-1. Compound 5a is the most promising, showing potent fungicidal profile with MFC of 0.5 µg mL-1, synergic effect with amphotericin B, besides showing no toxicity against HeLa and Vero cells.
Assuntos
Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Hidrazonas/farmacologia , Paracoccidioides/efeitos dos fármacos , Piridazinas/farmacologia , Animais , Antifúngicos/síntese química , Antifúngicos/química , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piridazinas/síntese química , Piridazinas/química , Relação Estrutura-Atividade , Células VeroRESUMO
PIM kinases are a family of serine/threonine protein kinases that potentiate the progression of the cell cycle and inhibit apoptosis. Because of this, they are considered to be proto-oncogenes, and they represent an interesting target for the development of anticancer drugs. In mammals, three PIM kinases exist (PIM-1, PIM-2 and PIM-3), and different inhibitors have been developed to block their activity. In addition to their involvement in cancer, some publications have reported that the PIM kinases have pro-viral activity, and different mechanisms where PIM kinases favour viral infections have been proposed. Zebrafish possess more than 300 Pim kinase members in their genome, and by using RNA-Seq analysis, we found a high number of Pim kinase genes that were significantly induced after infection with spring viraemia of carp virus (SVCV). Moreover, analysis of the miRNAs modulated by this infection revealed that some of them could be involved in the post-transcriptional regulation of Pim kinase abundance. To elucidate the potential role of the 16 overexpressed Pim kinases in the infectivity of SVCV, we used three different pan-PIM kinase inhibitors (SGI-1776, INCB053914 and AZD1208), and different experiments were conducted both in vitro and in vivo. We observed that the PIM kinase inhibitors had a protective effect against SVCV, indicating that, similar to what is observed in mammals, PIM kinases are beneficial for the virus in zebrafish. Moreover, zebrafish Pim kinases seem to facilitate viral entry into the host cells because when ZF4 cells were pre-incubated with the virus and then were treated with the inhibitors, the protective effect of the inhibitors was abrogated. Although more investigation is necessary, these results show that pan-PIM kinase inhibitors could serve as a useful treatment for preventing the spread of viral diseases.
Assuntos
Rim/enzimologia , Proteínas Proto-Oncogênicas c-pim-1/genética , Infecções por Rhabdoviridae/veterinária , Internalização do Vírus/efeitos dos fármacos , Peixe-Zebra/virologia , Animais , Apoptose , Compostos de Bifenilo/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Imidazóis/farmacologia , Rim/virologia , Poli I-C/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Piridazinas/farmacologia , RNA-Seq , Rhabdoviridae , Tiazolidinas/farmacologia , Peixe-Zebra/anatomia & histologiaAssuntos
Fármacos Anti-HIV/farmacologia , Farmacorresistência Viral , Soropositividade para HIV/tratamento farmacológico , Piridazinas/farmacologia , Argentina/epidemiologia , Farmacorresistência Viral/genética , Feminino , Soropositividade para HIV/epidemiologia , Soropositividade para HIV/genética , Humanos , Mutação , Nitrilas , Fenótipo , Gravidez , Pirimidinas , Falha de TratamentoRESUMO
Mutations in the connection subdomain (CN) and RNase H domain (RH) of HIV-1 reverse transcriptase (RT) from subtype B-infected patients enhance nucleoside and nonnucleoside RT inhibitor (NRTI and NNRTI) resistance by affecting the balance between polymerization and RNase H activity. To determine whether CN mutations in subtype C influence drug sensitivity, single genome sequencing was performed on Brazilian subtype C-infected patients failing RTI therapy. CN mutations identified were similar to subtype B, including A376S, A400T, Q334D, G335D, N348I, and A371V, and increased AZT resistance in the presence of thymidine analog mutations. CN mutations also enhanced NNRTI resistance in the presence of classical NNRTI mutations: etravirine resistance was enhanced 6- to 11-fold in the presence of L100I/K103N/Y181C. These results indicate that selection of CN mutations in treatment-experienced patients also occurs in subtype-C-infected patients and are likely to provide valuable information in predicting clinical RTI resistance.
Assuntos
Fármacos Anti-HIV/farmacologia , Farmacorresistência Viral/genética , Transcriptase Reversa do HIV/química , Transcriptase Reversa do HIV/genética , HIV-1/efeitos dos fármacos , Mutação , Inibidores da Transcriptase Reversa/farmacologia , Sequência de Aminoácidos , Brasil , Linhagem Celular , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/genética , Humanos , Dados de Sequência Molecular , Nitrilas , Estrutura Terciária de Proteína/genética , Piridazinas/farmacologia , Pirimidinas , Zidovudina/farmacologiaRESUMO
The objective of this study was to evaluate the effect of short-term levosimendan exposure on oxidant/antioxidant status and trace element levels in the testes of rats under physiological conditions. Twenty male Wistar albino rats were randomly divided into two groups of 10 animals each. Group 1 was not exposed to levosimendan and served as control. Levosimendan (12 µg/kg) diluted in 10 mL 0.9% NaCl was administered intraperitoneally to group 2. Animals of both groups were sacrificed after 3 days and their testes were harvested for the determination of changes in tissue oxidant/antioxidant status and trace element levels. Tissue malondialdehyde (MDA) was significantly lower in the levosimendan group (P < 0.001) than in the untreated control group and superoxide dismutase and glutathione peroxidase (GSH-Px) levels were significantly higher in the levosimendan group (P < 0.001). Carbonic anhydrase, catalase and GSH levels were not significantly different from controls. Mg and Zn levels of testes were significantly higher (P < 0.001) and Co, Pb, Cd, Mn, and Cu were significantly lower (P < 0.001) in group 2 compared to group 1. Fe levels were similar for the two groups (P = 0.94). These results suggest that 3-day exposure to levosimendan induced a significant decrease in tissue MDA level, which is a lipid peroxidation product and an indicator of oxidative stress, and a significant increase in the activity of an important number of the enzymes that protect against oxidative stress in rat testes.