Assuntos
Evolução Clonal , Proteínas de Ligação a DNA/genética , Células Dendríticas/patologia , Dioxigenases/genética , Neoplasias Hematológicas/patologia , Leucemia Mielomonocítica Crônica/patologia , Mutação , Idoso , Neoplasias Hematológicas/genética , Humanos , Leucemia Mielomonocítica Crônica/genética , Masculino , PrognósticoRESUMO
Currently, we are experiencing a true pandemic of a communicable disease by the virus SARS-CoV-2 holding the whole world firmly in its grasp. Amazingly and unfortunately, this virus uses a metabolic and endocrine pathway via ACE2 to enter our cells causing damage and disease. Our international research training programme funded by the German Research Foundation has a clear mission to train the best students wherever they may come from to learn to tackle the enormous challenges of diabetes and its complications for our society. A modern training programme in diabetes and metabolism does not only involve a thorough understanding of classical physiology, biology and clinical diabetology but has to bring together an interdisciplinary team. With the arrival of the coronavirus pandemic, this prestigious and unique metabolic training programme is facing new challenges but also new opportunities. The consortium of the training programme has recognized early on the need for a guidance and for practical recommendations to cope with the COVID-19 pandemic for the community of patients with metabolic disease, obesity and diabetes. This involves the optimal management from surgical obesity programmes to medications and insulin replacement. We also established a global registry analyzing the dimension and role of metabolic disease including new onset diabetes potentially triggered by the virus. We have involved experts of infectious disease and virology to our faculty with this metabolic training programme to offer the full breadth and scope of expertise needed to meet these scientific challenges. We have all learned that this pandemic does not respect or heed any national borders and that we have to work together as a global community. We believe that this transCampus metabolic training programme provides a prime example how an international team of established experts in the field of metabolism can work together with students from all over the world to address a new pandemic.
Assuntos
COVID-19 , Diabetes Mellitus , Educação Médica Continuada , Obesidade , Pandemias , SARS-CoV-2 , COVID-19/epidemiologia , COVID-19/terapia , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/terapia , Humanos , Obesidade/epidemiologia , Obesidade/terapiaRESUMO
Inhibition of complex I (CI) of the mitochondrial respiratory chain by BAY 87-2243 ('BAY') triggers death of BRAFV600E melanoma cell lines and inhibits in vivo tumor growth. Here we studied the mechanism by which this inhibition induces melanoma cell death. BAY treatment depolarized the mitochondrial membrane potential (Δψ), increased cellular ROS levels, stimulated lipid peroxidation and reduced glutathione levels. These effects were paralleled by increased opening of the mitochondrial permeability transition pore (mPTP) and stimulation of autophagosome formation and mitophagy. BAY-induced cell death was not due to glucose shortage and inhibited by the antioxidant α-tocopherol and the mPTP inhibitor cyclosporin A. Tumor necrosis factor receptor-associated protein 1 (TRAP1) overexpression in BAY-treated cells lowered ROS levels and inhibited mPTP opening and cell death, whereas the latter was potentiated by TRAP1 knockdown. Knockdown of autophagy-related 5 (ATG5) inhibited the BAY-stimulated autophagosome formation, cellular ROS increase and cell death. Knockdown of phosphatase and tensin homolog-induced putative kinase 1 (PINK1) inhibited the BAY-induced Δψ depolarization, mitophagy stimulation, ROS increase and cell death. Dynamin-related protein 1 (Drp1) knockdown induced mitochondrial filamentation and inhibited BAY-induced cell death. The latter was insensitive to the pancaspase inhibitor z-VAD-FMK, but reduced by necroptosis inhibitors (necrostatin-1, necrostatin-1s)) and knockdown of key necroptosis proteins (receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and mixed lineage kinase domain-like (MLKL)). BAY-induced cell death was also reduced by the ferroptosis inhibitor ferrostatin-1 and overexpression of the ferroptosis-inhibiting protein glutathione peroxidase 4 (GPX4). This overexpression also inhibited the BAY-induced ROS increase and lipid peroxidation. Conversely, GPX4 knockdown potentiated BAY-induced cell death. We propose a chain of events in which: (i) CI inhibition induces mPTP opening and Δψ depolarization, that (ii) stimulate autophagosome formation, mitophagy and an associated ROS increase, leading to (iii) activation of combined necroptotic/ferroptotic cell death.
Assuntos
Complexo I de Transporte de Elétrons/metabolismo , Melanoma/enzimologia , Mitofagia , Espécies Reativas de Oxigênio/metabolismo , Proteína 5 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/metabolismo , Linhagem Celular Tumoral , Dinaminas , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Complexo I de Transporte de Elétrons/genética , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/genética , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Poro de Transição de Permeabilidade Mitocondrial , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Oxidiazóis/farmacologia , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Pirazóis/farmacologiaRESUMO
Os autores estudaram em uma maternidade de Florianopolis, SC, num periodo de seis meses, todas as pacientes que foram internadas para tratamento de complicacoes decorrentes de aborto provocado. Identidicaram que 70% das cinquenta mulheres entrevistadas eram solteiras e 86,0% tinha idades compreendidas entre 17 e 20 anos. Destas mulheres 46,0% tinham renda familiar menor que 1 salario minimo e 40,0% de 1 a 2 salarios mininos. Entre os metodos abortivos apontados pelas mesmas, houve maior predominancia dos agressivos, como: sondas, aparelhos, instrumentos, agressoes fisicas, agulhas de trico, que representam em conjunto 60,0% dos metodos alegados, seguindo-se de chas, beberagens e outros de uso consagrado na medicina de folk. Entre os motivos citados como determinantes do aborto identificaram maior proporcao para os de ordem economica
