Alterações da taxa metabólica por provimento de oxigênio advindo de alterações do sistema circulatório e respiratório e por substratos da cadeia de transporte de elétrons mitocondrial

Dissertação (mestrado)—Universidade de Brasília, Faculdade de Ceilândia, Pós-Graduação em Ciências e Tecnologias em Saúde, 2016.A taxa metabólica basal é o principal componente no gasto energético total dos seres humanos e demais animais na maioria das situações. Devido a isso, em muitas situações desfavoráveis energeticamente, ocorre alterações da taxa metabólica, permitindo o sistema manter a homestasia. Os seres humanos, durante restrição calórica, reduzem a taxa metabólica, situação conhecida como adaptação metabólica. Essa adaptação também ocorre em muitos animais na natureza, devido a estresses ambientais, dentre eles a falta de disponibilidade de nutrientes e de água, levando-os à depressão metabólica. É conhecido que esses animais sofrem maior estresse oxidativo, devido à redução e o aumento abrupto da atividade mitocondrial, decorrente das condições desfavoráveis e favoráveis, respectivamente. No caso dos seres humanos, a depressão metabólica advinda da restrição calórica dificulta a perda de peso e contribui para a obesidade.O presente trabalho avaliou: (1) as alterações de uma espécie tolerante à hipóxia sobre o nível de danos oxidativos; (2) a resistência à diminuição do provimento sistêmico de oxigênio advindo da desidratação em um animal aquático ao estresse da desidratação; (3) o controle da taxa metabólica pela disponibilidade de substratos da cadeia de transporte de elétrons mitocondrial por meio de dados da literatura; (4) uma teoria (manuscrito/artigo submetido) que relaciona a disponibilidade de nutrientes com a taxa metabólica e uma estratégia que utilize tal relação para o combate da obesidade e doenças relacionadas.Basal metabolic rate is the main component in total energy expenditure of humans and other animals in most situations. Because of this, in many energetically unfavorable situations occurs changes in metabolic rate, allowing the system to maintain homestasia. During caloric restriction, humans reduces metabolic rate, a condition known as metabolic adaptation. This adaptation also occurs in many animals in nature, due to environmental stresses, including the lack of availability of nutrients and water, causing them to metabolic depression. It is known that these animals show increased oxidative stress due to the reduction and the abrupt increase in mitochondrial activity, due to the unfavorable conditions and favorable, respectively. In the case of human beings, arising metabolic depression of calorie restriction hinders weight loss and contributes to obesidade.This study evaluated: (1) changes of a tolerant species to hypoxia on the level of oxidative damage; (2) resistance to reduced systemic provision of oxygen arising from dehydration in an aquatic animal to the stress of dehydration; (3) the control metabolic rate by the availability of substrates of the mitochondrial electron transport chain through the literature; (4) a theory (manuscript / submitted article) relating to nutrient availability to the metabolic rate and a strategy that uses such a relationship to combat the obesity and related diseases

Asistencia farmacéutica en la pandemia de Covid-19 : una investigación documental

Este artigo objetivou discutir as propostas de reorganização da assistência farmacêutica durante a pandemia da Coronavirus disease-19 (Covid-19) pelas secretarias de saúde dos estados brasileiros e do Distrito Federal. Para tanto, foi realizada uma pesquisa documental dos arquivos disponibilizados nos sites das secretarias. A interpretação dos dados revelou três categorias de discussão sobre a reorganização da assistência farmacêutica do Sistema Único de Saúde: garantia do acesso às tecnologias em saúde, telefarmácia e promoção do uso racional de medicamentos e segurança na dispensação. Além de oferecer um sistema de abastecimento de tecnologias indispensáveis para o funcionamento dos serviços de saúde, as ações de assistência farmacêutica foram citadas como estratégicas para a difusão de informações fundamentadas em evidências, colaborando para a integralidade, a resolubilidade e a eficiência das intervenções em saúde.This article aimed to discuss the proposals for reorganizing pharmaceutical assistance during the Coronavirus disease-19 (COVID-19) pandemic by the health departments of the Brazilian states and the Federal District. To this end, a documentary search of the files made available on the websites of the aforementioned departments was carried out. The interpretation of the data showed three categories of discussion on the reorganization of pharmaceutical assistance in the Unified Health System: ensuring access to health technologies, tele-pharmacy and promoting the rational use of medicines and safety in dispensing. In addition to offering a system of supply of essential technologies for the functioning of health services, pharmaceutical assistance actions were cited as strategic for the dissemination of evidence-based information, contributing to the completeness, resolvability and efficiency of health interventions

Paternal resistance training modulates calcaneal tendon proteome in the offspring exposed to high-fat diet

The increase in high-energy dietary intakes is a well-known risk factor for many diseases, and can also negatively impact the tendon. Ancestral lifestyle can mitigate the metabolic harmful effects of offspring exposed to high-fat diet (HF). However, the influence of paternal exercise on molecular pathways associated to offspring tendon remodeling remains to be determined. We investigated the effects of 8 weeks of paternal resistance training (RT) on offspring tendon proteome exposed to standard diet or HF diet. Wistar rats were randomly divided into two groups: sedentary fathers and trained fathers (8 weeks, three times per week, with 8–12 dynamic movements per climb in a stair climbing apparatus). The offspring were obtained by mating with sedentary females. Upon weaning, male offspring were divided into four groups (five animals per group): offspring from sedentary fathers were exposed either to control diet (SFO-C), or to high-fat diet (SFO-HF); offspring from trained fathers were exposed to control diet (TFO-C) or to a high-fat diet (TFO-HF). The Nano-LC-MS/MS analysis revealed 383 regulated proteins among offspring groups. HF diet induced a decrease of abundance in tendon proteins related to extracellular matrix organization, transport, immune response and translation. On the other hand, the changes in the offspring tendon proteome in response to paternal RT were more pronounced when the offspring were exposed to HF diet, resulting in positive regulation of proteins essential for the maintenance of tendon integrity. Most of the modulated proteins are associated to biological pathways related to tendon protection and damage recovery, such as extracellular matrix organization and transport. The present study demonstrated that the father’s lifestyle could be crucial for tendon homeostasis in the first generation. Our results provide important insights into the molecular mechanisms involved in paternal intergenerational effects and potential protective outcomes of paternal RT

Papel das etapas precoces de ativação da produção de EROs na indução das NETs

Tese (doutorado) — Universidade de Brasília, Faculdade de Medicina, Programa de Pós-Graduação em Patologia Molecular, 2021.Neutrófilos são células do sistema imune inato que se destacam por serem as células mais abundantes do sangue periférico. Eles são os primeiros a chegarem no local da infecção e, dentre os mecanismos de defesa, utilizam as armadilhas extracelulares (NETs), que permitem captura e morte extracelular de microrganismos, o que ocorre independente da fagocitose e morte intracelular. Apesar, de ser um mecanismo benéfico para a defesa imune do hospedeiro, as NETs têm sido associadas a diversas doenças, devido à liberação do DNA e proteínas que favorecem a formação de trombos, bem como constituem-se como autoantígenos. Dessa forma, a atuação regulada de NETs é importante para a defesa do hospedeiro, enquanto a resposta acentuada leva a danos. Uma das vias, conhecida como NETose suicida, é dependente de espécies reativas de oxigênio (EROs) e engatilha diversos mecanismos celulares levando à liberação do DNA nuclear. O objetivo do presente trabalho foi elucidar o envolvimento de proteínas e vias de sinalização durante o período inicial da formação de NETs (60 minutos) associadas ao burst respiratório, por meio da análise proteômica de neutrófilos ativados por PMA e inibidos por apocinina. A cinética da produção de EROs mostrou que a inibição da NADPH oxidase posterior ao estímulo possui uma menor influência comparada à inibição antes do estímulo. Essa produção observada nos primeiros 20 minutos foi suficiente para desencadear a formação das NETs e favorecer a morte dos microrganismos devido a um maior aprisionamento observado. Além disso, a produção de EROs nos primeiros minutos é capaz de desencadear alterações no proteoma, associadas a formação das NETs. As proteínas alteradas contribuem com a polimerização da actina (LIMS1, ADAM10 e AMBP) que se associaram com a migração celular. Curiosamente, a migração celular tardia (após 20 min) que não foi associada à formação de NETs, parece não ter a participação da polimerização da actina, mas da tubulina e vitronectina. Além disso, pela primeira vez, este estudo mostrou que neutrófilos podem liberar o componente C4 do sistema complemento, sugerindo o possível envolvimento da ativação do complemento na NETose.Neutrophils are the most abundant innate immune cell in the peripheral blood. They are the first to arrive at the infection site and among their defense mechanisms, they use extracellular traps (NETs) that promote extracellular capture and death of microorganisms and occur independently of phagocytosis and intracellular death. Despite being a beneficial mechanism for the immune defense of the host, NETs have been associated with several diseases, due to the release of DNA and proteins that favor the formation of thrombi, as well as being recognized as autoantigens. In this way, the regulated performance of NETs is important for the defense of the host, while an intense deregulated response leads to damage. One of the known pathways of NETs is suicidal NETosis. This formation of NETs is dependent on ROS produced by NADPH oxidase, which triggers several cellular mechanisms leading to the release of nuclear DNA. In order to elucidate the involvement of proteins and pathways during the initial period of NETosis (60 minutes) associated to the respiratory burst, we analyzed the proteomic changes of neutrophils induced by PMA and controlled by apocinin, to produce NETs. Kinetic analysis of ROS production showed that the NADPH oxidase inhibition after the PMA stimulus has less influence on ROS generation, compared to inhibition before stimulus. The production of ROS observed in the first 20min was enough to trigger the formation of NETs, favoring microorganisms’ death by entrapment. Furthermore, ROS production in the first minutes is able to initiate proteomic changes associated to NETs formation. Proteins related to actin polymerization (LIMS1, ADAM10 and AMBP) were associated to cellular migration. Curiously, late cellular migration (after 20min.), that was not associated to NETs formation, seems not associated to actin polymerization, however, associated to tubulin and vitronectin. Moreover, this study showed the first time that neutrophils can release the C4 component of the complement system, suggesting the probable activation of complement pathway contributes to NETs extrusion

Neutrophil Activated by the Famous and Potent PMA (Phorbol Myristate Acetate)

This review will briefly outline the major signaling pathways in PMA-activated neutrophils. PMA is widely used to understand neutrophil pathways and formation of NETs. PMA activates PKC; however, we highlight some isoforms that contribute to specific functions. PKC α, β and δ contribute to ROS production while PKC βII and PKC ζ are involved in cytoskeleton remodeling. Actin polymerization is important for the chemotaxis of neutrophils and its remodeling is connected to ROS balance. We suggest that, although ROS and production of NETs are usually observed together in PMA-activated neutrophils, there might be a regulatory mechanism balancing both. Interestingly, we suggest that serine proteases might determine the PAD4 action. PAD4 could be responsible for the activation of the NF-κB pathway that leads to IL-1β release, triggering the cleavage of gasdermin D by serine proteases such as elastase, leading to pore formation contributing to release of NETs. On the other hand, when serine proteases are inhibited, NETs are formed by citrullination through the PAD4 pathway. This review puts together results from the last 31 years of research on the effects of PMA on the neutrophil and proposes new insights on their interpretation