RESUMO
Voltage dependent anion channels (VDAC) in the outer mitochondrial membrane regulate the influx of metabolites that sustain mitochondrial metabolism and the efflux of ATP to the cytosol. Free tubulin and NADH close VDAC. The VDAC-binding small molecules X1 and SC18 modulate mitochondrial metabolism. X1 antagonizes the inhibitory effect of tubulin on VDAC. SC18 occupies an NADH-binding pocket in the inner wall of all VDAC isoforms. Here, we hypothesized that X1 and SC18 have a synergistic effect with sorafenib, regorafenib or lenvatinib to arrest proliferation and induce death in hepatocarcinoma cells. We used colony formation assays to determine cell proliferation, and a combination of calcein/propidium iodide, and trypan blue exclusion to assess cell death in the well differentiated Huh7 and the poorly differentiated SNU-449 cells. Synergism was assessed using the Chou-Talalay method. The inhibitory effect of X1, SC18, sorafenib, regorafenib and lenvatinib was concentration and time dependent. IC50s calculated from the inhibition of clonogenic capacity were lower than those determined from cell survival. At IC50s that inhibited cell proliferation, SC18 arrested cells in G0/G1. SC18 at 0.25-2 IC50s had a synergistic effect with sorafenib on clonogenic inhibition in Huh7 and SNU-449 cells, and with regorafenib or lenvatinib in SNU-449 cells. X1 or SC18 also had synergistic effects with sorafenib on promoting cell death at 0.5-2 IC50s for SC18 in Huh7 and SNU-449 cells. These results suggest that small molecules targeting VDAC represent a potential new class of drugs to treat liver cancer.
Assuntos
Carcinoma Hepatocelular , NAD , Humanos , Sorafenibe/farmacologia , Tubulina (Proteína) , Carcinoma Hepatocelular/tratamento farmacológico , Proliferação de Células , Canais de Ânion Dependentes de VoltagemRESUMO
Many COVID-19 vaccines are proving to be highly effective to prevent severe disease and to diminish infections. Their uneven geographical distribution favors the appearance of new variants of concern, as the highly transmissible Delta variant, affecting particularly non-vaccinated people. It is important to device reliable models to analyze the spread of the different variants. A key factor is to consider the effects of vaccination as well as other measures used to contain the pandemic like social behaviour. The stochastic geographical model presented here, fulfills these requirements. It is based on an extended compartmental model that includes various strains and vaccination strategies, allowing to study the emergence and dynamics of the new COVID-19 variants. The model conveniently separates the parameters related to the disease from the ones related to social behavior and mobility restrictions. We applied the model to the United Kingdom by using available data to fit the recurrence of the currently prevalent variants. Our computer simulations allow to describe the appearance of periodic waves and the features that determine the prevalence of certain variants. They also provide useful predictions to help planning future vaccination boosters. We stress that the model could be applied to any other country of interest.
Assuntos
COVID-19 , SARS-CoV-2 , COVID-19/epidemiologia , Vacinas contra COVID-19 , Humanos , SARS-CoV-2/genética , VacinaçãoRESUMO
In a world being hit by waves of COVID-19, vaccination is a light on the horizon. However, the roll-out of vaccination strategies and their influence on the pandemic are still open questions. In order to compare the effect of various strategies proposed by the World Health Organization and other authorities, a previously developed SEIRS stochastic model of geographical spreading of the virus is extended by adding a compartment for vaccinated people. The parameters of the model were fitted to describe the pandemic evolution in Argentina, Mexico and Spain to analyze the effect of the proposed vaccination strategies. The mobility parameters allow to simulate different social behaviors (e.g. lock-down interventions). Schemes in which vaccines are applied homogeneously in all the country, or limited to the most densely-populated areas, are simulated and compared. The second strategy is found to be more effective. Moreover, under the current global shortage of vaccines, it should be remarked that immunization is enhanced when mobility is reduced. Additionally, repetition of vaccination campaigns should be timed considering the immunity lapse of the vaccinated (and recovered) people. Finally, the model is extended to include the effect of isolation of detected positive cases, shown to be important to reduce infections.
Assuntos
Vacinas contra COVID-19/uso terapêutico , COVID-19/prevenção & controle , Acessibilidade aos Serviços de Saúde , Programas de Imunização/métodos , Modelos Estatísticos , Pandemias/prevenção & controle , SARS-CoV-2/imunologia , Vacinação/métodos , Argentina/epidemiologia , COVID-19/epidemiologia , COVID-19/transmissão , COVID-19/virologia , Humanos , México , Comportamento Social , Espanha , Processos Estocásticos , ViagemRESUMO
Organophosphorus chlorpyrifos (CPF) is currently considered an endocrine disruptor (ED), as it can imitate hormone actions both in vitro and in vivo. We recently reported that CPF induces migration and invasion in 2D cultures and changes the expression of key molecular markers involved in epithelial mesenchymal transition in MCF-7 and MDA-MB-231 cell lines. In this study, we investigated whether CPF could behave as a predisposing factor for tumors to become more metastatic and aggressive using 3D culture models. In MCF-7 cells, 0.05 µM CPF induced an increase in the number and size of mammospheres via estrogen receptor alpha (ERα) and c-SRC. Furthermore, 0.05 µM CPF increased the area of spheroids generated from MCF-7 cells, induced invasion using both Matrigel® and type 1 collagen matrices, and increased cell migration capacity via ERα in this 3D model. In turn, 50 µM CPF increased cell migration capacity and invasion using type 1 collagen matrix. In monolayers, CPF increased the phosphorylation and membrane translocation of c-SRC at both concentrations assayed. CPF at 0.05 µM boosted p-AKT, p-GSK-3ß and p-P38. While p-AKT rose in a ERα-dependent way, p-GSK-3ß was dependent on ERα- and c-SRC, and p-P38 was only dependent on c-SRC. On the other hand, the increase in p-AKT and p-P38 induced by 50 µM CPF was dependent on the c-SRC pathway. We also observed that 0.05 µM CPF increased IGF-1R and IRS-1 expression and that 50 µM CPF induced IGF-1Rß phosphorylation. In the MDA-MB-231 cell line, 0.05 and 50 µM CPF increased p-c-SRC. Finally, p-AKT and p-GSK-3ß were also induced by CPF at 0.05 and 50 µM, and an increase in p-P38 was observed at 50 µM. Taken together, these data provide support for the notion that CPF may represent a risk factor for breast cancer development and progression.
Assuntos
Neoplasias da Mama , Clorpirifos , Disruptores Endócrinos , Linhagem Celular Tumoral , Proliferação de Células , Clorpirifos/toxicidade , Disruptores Endócrinos/toxicidade , Feminino , Glicogênio Sintase Quinase 3 beta , Humanos , Fenótipo , FosforilaçãoRESUMO
Chlorpyrifos (CPF) is one of the most frequently used pesticide in extensive agriculture around the world and can be incorporated by humans and animals with possible consequences on health. The effects of this pesticide on carcinogenesis are not clear and there is no consensus concerning the risks of this compound. In previous work, we demonstrated that CPF induces proliferation of breast cancer cells both in vivo and in vitro. In this work we investigate whether CPF promotes the epithelial-mesenchymal transition (EMT) in breast cancer cells. Herein, we demonstrate that 50 µM CFP induces invasion in MCF-7 and MDA-MB-231 cells. In addition, 0.05 and 50 µM CPF increases migration in both cell lines. In MCF-7 cells, 0.05 and 50 µM CPF increase the metalloprotease MMP2 expression and decrease E-Cadherin and ß-Catenin expression diminishing their membrane location. Furthermore, 50 µM CPF induces Vimentin expression and Slug nuclear translocation in MCF-7 cells. 0.05 and 50 µM CPF increase MMP2 gelatinolytic activity and expression, decrease ß-Catenin expression and increase Vimentin expression in MDA-MB-231 cells. Inhibition of the oncoprotein c-Src reverses all the effects induced by CPF in MDA-MB-231 but not in MCF-7 indicating that c-Src is a kinase with a crucial role in the cells which grow in an estrogen-independent way. In MCF-7 cells both c-Src and estrogen receptor alpha must be blocked to completly inhibit the CPF-mediated effects. Our results show for the first time that the exposure to subthreshold concentrations of CPF promotes the modulation of EMT-molecular markers and pathways. These results, together with the ubiquitous distribution of the pesticide CPF, make it of utmost importance to take measures to minimize the risk of exposure to this compound.
Assuntos
Movimento Celular/efeitos dos fármacos , Clorpirifos/toxicidade , Disruptores Endócrinos/toxicidade , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Praguicidas/toxicidade , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteína Tirosina Quinase CSK/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Relação Dose-Resposta a Droga , Transição Epitelial-Mesenquimal/genética , Receptor alfa de Estrogênio/genética , Feminino , Humanos , Células MCF-7 , Metaloproteinase 2 da Matriz/genética , Transdução de SinaisRESUMO
Resumen: Objetivo: El propósito de este estudio fue describir las percepciones de docentes de enfermería de habla hispana en América Latina, sobre las competencias relacionadas a la salud global que deben mostrar los estudiantes de enfermería del pregrado. Métodos: Este estudio descriptivo fue basado en una muestra de docentes de escuelas de enfermería miembros de la Asociación Latinoamericana de Escuelas y Facultades de Enfermería (ALADEFE) y de la Asociación de Escuelas de la Zona Centro Sur de México, las cuales recibieron un correo electrónico con una liga para responder una encuesta electrónica por Survey Monkey©. La encuesta incluyó una lista de 30 competencias en salud global dividida en seis dimensiones. Los docentes indicaron en una escala Likert de 4 puntos la relevancia de cada competencia para la educación de enfermería en el nivel de pregrado (1 = Completamente en desacuerdo; 2 = En desacuerdo; 3 = De acuerdo; 4 = Completamente de acuerdo). Resultados: En total, 110 profesores de nueve países respondieron a la encuesta. El promedio de cada ítem fue entre 3.0 - 4.0, esto indica que los profesores estuvieron de acuerdo en que todas las competencias son relevantes para la formación de estudiantes de enfermería a nivel de pregrado. Conclusiones: Los resultados de este estudio sugirieron que estas competencias deben ser incluidas en los currículos de enfermería a nivel de pregrado, para formar a los estudiantes en su labor como enfermeras y enfermeros en un mundo globalizado y prepararlos para contribuir a la Cobertura y el Acceso Universal a la Salud (Salud Universal).
Abstract: Objective: To describe the perceptions of Spanish-speaking nursing teachers in Latin America on the global health competences which, undergraduate nursing students should demonstrate. Methods: This descriptive study was based on a sample of teachers of nursing schools belonging to the Latin American Association of Nursing Schools and Faculties, and the Association of Schools of the Center-South Zone in Mexico. These institutions received an invitation via e-mail to respond to a survey through the Survey Monkey© platform. The survey included a list of 30 Global Health competencies grouped in 6 dimensions. Teachers indicated through a 4-point Likert scale their perception on the relevance to undergraduate nursing education of each of these competencies (1 = total disagreement, 2 = disagreement, 3 = agreement, 4 = total agreement). Results: In total, 110 professors of 9 countries responded to the survey. The average score per item was 3.0 - 4.0 suggesting that the teachers agreed that all competencies are relevant to the formation of undergraduate nursing students. Conclusions: These results suggested that these competencies should be part of the objectives of undergraduate nursing curricula in order to prepare the students to contribute to the Coverage and Access to Universal Health agenda.
Resumo: Objetivo: O propósito deste estudo foi descrever as percepções de docentes de enfermagem de fala hispana na América Latina, sobre as competências relacionadas à saúde global que devem mostrar os estudantes de enfermagem de graduação. Métodos: Este estudo descritivo foi baseado em uma amostra de docentes de escolas de enfermagem membros da Associação Latino-americana de Escolas e Faculdades de Enfermagem (ALADEFE) e da Associação de Escolas da Zona Centro Sul do México, as quais receberam um e-mail electrónico com um link para responder uma enquete electrónica por Survey Monkey©. A enquete incluiu uma lista de 30 competências em saúde global dividida em seis dimensões. Os docentes indicaram em uma escala Likert de 4 pontos a relevância de cada competência para a educação de enfermagem no nível de graduação (1 = Completamente em discordância; 2 = Em discordância; 3 = Em concordância; 4 = Completamente em concordância). Resultados: Em total, 110 professores de nove países responderam à enquete. A média de cada item foi entre 3.0-4.0, isto indica que os professores concordaram em que todas as competências são relevantes para a formação de estudantes de enfermagem a nível de graduação. Conclusões: Os resultados deste estudo sugeriram que estas competências devem ser incluídas nos currículos de enfermagem a nível de graduação, para formar aos estudantes em seu labor como enfermeiras e enfermeiros em um mundo globalizado e prepará-los para contribuir à Cobertura e o Acesso Universal à Saúde (Saúde Universal).
Assuntos
Humanos , Masculino , FemininoRESUMO
Zika virus (ZIKV) disease outbreak, which was declared by the end of 2015 in Brazil, has become the largest one to date. Being reported in the Americas and in certain islands of the Pacific, it has the potential to spread worldwide. Although ZIKV infections are mostly self-limiting and/or asymptomatic in the healthy adult, they are responsible for devastating congenital neurologic malformations ZIKV (mainly microcephaly) when contracted during the first months of pregnancy. Ocular manifestations during the acute adult infection include conjunctivitis and more rarely ocular inflammation. Congenital infection is associated with chorioretinal atrophy pigment mottling of the retina retinal vasculature abnormalities and optic nerve atrophy. Therefore, complete ophthalmological evaluation is recommended for suspected congenital infections.
Assuntos
Infecções Oculares Virais/diagnóstico , Infecções Oculares Virais/terapia , Infecção por Zika virus/diagnóstico , Infecção por Zika virus/terapia , Brasil/epidemiologia , Surtos de Doenças , Epidemias , Infecções Oculares Virais/congênito , Infecções Oculares Virais/epidemiologia , Feminino , Humanos , Recém-Nascido , Doenças do Recém-Nascido/diagnóstico , Doenças do Recém-Nascido/epidemiologia , Doenças do Recém-Nascido/terapia , Transmissão Vertical de Doenças Infecciosas/estatística & dados numéricos , Triagem Neonatal/métodos , Gravidez , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/epidemiologia , Complicações Infecciosas na Gravidez/terapia , Infecção por Zika virus/congênito , Infecção por Zika virus/epidemiologiaRESUMO
Hexachlorobenzene (HCB) is an organochlorine pollutant widely distributed in the environment around the entire world. Previous reports from our group and others have demonstrated that this compound is as an endocrine disruptor. We have also reported that HCB presents a co-carcinogenic effect in N-Nitroso-N-methyl-urea-induced mammary tumours in rats. In this work, we studied the effects of HCB on cell cycle progression and cell cycle regulating protein expression in the estrogen-sensitive breast cancer cell line, MCF-7. Here, we show that HCB alters cell cycle in a concentration-dependent way. The lowest assessed concentration (0.005µM) promotes the cell cycle progression, enhances cyclin D1 expression, and reduces the nuclear localization of p27 accompanied by an increased interaction between p27 and c-Src kinase. On the other hand, 5µM HCB delays the cell cycle progression and promotes the formation of the cyclin E-CDK2-p27 protein complex. Our results show that HCB stimulates cell proliferation through cell cycle modulation and c-Src involvement in MCF-7 cells. Here, we report for the first time that differential mechanisms of action of HCB on mammary cell cycle progression are triggered at different concentrations of this pollutant.
Assuntos
Ciclo Celular/efeitos dos fármacos , Ciclina E/metabolismo , Quinase 2 Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Hexaclorobenzeno/toxicidade , Proteínas Oncogênicas/metabolismo , Quinases da Família src/metabolismo , Proteína Tirosina Quinase CSK , Divisão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ciclina D1/genética , Ciclina D1/metabolismo , Ciclina E/genética , Quinase 2 Dependente de Ciclina/genética , Inibidor de Quinase Dependente de Ciclina p27/genética , Humanos , Células MCF-7 , Proteínas Oncogênicas/genética , Fosforilação , Quinases da Família src/genéticaRESUMO
ABSTRACT Seeds of Acacia farnesiana are commonly sold in the local markets of northeastern Brazil as a therapeutic agent. The present work aimed to evaluate the anti-inflammatory and analgesic activities of proteins obtained from A. farnesiana seeds. Five different protein fractions (albumin, globulin, prolamin, acidic and basic glutelins) were obtained and investigated for the protein pattern, the presence of hemagglutinating and proteolytic activities. The globulin fraction (GLB) was also evaluated for anti-inflammatory and analgesic activities. Globulins reduced the paw edema induced by carrageenan in a dose-dependent manner, which was accompanied by a reduction of myeloperoxidase activity (p < 0.05). Additionally, GLB reduced the neutrophil peritoneal migration induced by carrageenan. However, GLB was not able to inhibit the edema triggered by dextran. Pre-treatment with globulins reduced the abdominal constrictions induced by acetic acid as well as the paw licking time induced by formalin (69.1% at first phase). However, it did not produce a significant antinociceptive effect in the hot plate test (55-56 °C). Treating the GLB with heat (at 100 °C for 30 min) abolished its anti-edematogenic and hemagglutinating activities. Our results showed that seeds from A. farnesiana are a source of proteins with anti-inflammatory and analgesic properties.
RESUMO Sementes de Acacia farnesiana são comumente vendidas em feiras locais no nordeste do Brasil como agente terapêutico. O presente trabalho objetivou avaliar as atividades antiinflamatória e antinociceptiva de proteínas obtidas de sementes de A. farnesiana. Cinco frações protéicas distintas (albuminas, globulinas, prolaminas, glutelinas ácidas e básicas) foram obtidas e investigadas quanto o perfil de proteínas, presença de atividade hemaglutinante e proteolítica. A fração globulina (GLB) também foi avaliada quanto a presença de atividade antiinflamatória e analgésica. Globulinas reduziram o edema de pata induzido por carragenina de modo dependente da dose que foi acompanhada da redução da atividade da mieloperoxidase (p < 0,05). Em adição, GLB reduziu a migração de neutrófilos para cavidade peritoneal induzida por carragenina. Entretanto, GLB não foi capaz de inibir o edema induzido por dextrana. O pré-tratamento com globulinas reduziu as contorções abdominais induzidas por ácido acético, bem como o tempo de lambedura da pata induzida por formalina (69.1% na primeira fase). Por outro lado, GLB não produziu um efeito antinociceptivo significante no teste de placa quente (55-56 °C). O pré-tratamento de GLB com calor (100 °C por 30 min) aboliu sua atividade anti-edematogênica e hemaglutinante. Nossos resultados mostraram que sementes de A. farnesiana são fonte de proteínas com propriedades antiinflamatórias e analgésicas.
Assuntos
Acacia/classificação , Analgésicos/classificação , Anti-Inflamatórios/classificação , Nociceptividade/classificação , Lectinas/análiseRESUMO
BACKGROUND: Angola is one of the largest African countries with continuing levels of insecurity, considerable weakness in terms of respect for human rights, destroyed infrastructure and low transparency and social accountability levels. The health system displays gaps and nursing represents the main contingent among human resources in health. AIM: This research aims to understand the healthcare context in Angola from the perspective of Brazilian nurses who were involved in helping their Angolan colleagues. This general view of health services is followed by a description of nursing workforce particularities at a tertiary health service in the province of Luanda. METHODS: Data were extracted from the database of the Global Network of World Health Organization Collaborating Centres for Nursing and Midwifery Development, constructed based on technical visits to Angola in 2009. Information related to health service characteristics was used, focusing on nursing human resource activities at two tertiary, one secondary and one primary health institutions located in the province of Luanda. The study data were analysed through descriptive statistics. FINDINGS: Among the problems the nursing workforce faces, the lack of human, material and financial resources stands out, as well as insufficient professional qualification, excessive work journeys, low remunerations, non-valuation of professionals, leading to unsatisfactory work environments and discouraged human resources. CONCLUSIONS: Nursing in Angola is conquering its professional space. Therefore, regulatory policies are fundamental, defining the rights and obligations of all categories involved, with a view to determining nurses' function in the health team, including respect for and acknowledgement of their role in the community.