Efeito dos macrocíclos na regulação de funções vasculares

As células do músculo liso (SMC) vascular são fundamentais para a regulação do tónus vascular e têm capacidade de responder a diversos estímulos hormonais e hemodinâmicos. São células altamente especializadas que podem contribuir para o estudo de vários processos de sinalização envolvidos no controlo do tónus vascular, tais como o metabolismo do cálcio e diferentes vias envolvidas na modulação da reatividade vascular. A regulação do fluxo de Ca2+ é fundamental para a contração e a sua desregulação pode estar envolvida na patofisiologia de diversas doenças cardiovasculares. A entrada de cálcio nas células do músculo liso vascular através de canais de Ca2+ tipo L (LTCC) pode ser desencadeada pela ativação de recetores presentes na membrana plasmática ou por despolarização da membrana. A formação do complexo Ca2+-calmodulina leva à ativação da cadeia leve de miosina (MLC), e é o estado de fosforilação desta que determina a atividade contráctil do músculo liso. Os compostos macrocíclicos são macromoléculas cíclicas que podem ser usadas como transportadores moleculares, uma vez que, para além de terem a capacidade de atravessar a membrana celular sem alterar a sua integridade, não são tóxicos nas concentrações usadas e podem transportar outras moléculas. Os macrocíclos são considerados como importantes hospedeiros seletivos em algumas aplicações biológicas, nomeadamente em solubilizadores e estabilizadores de fármacos e agentes anticancerígenos, formando complexos estáveis e específicos. O principal objetivo deste trabalho é analisar se os macrocíclos têm atividade biológica. Assim, foi estudado o efeito de diferentes compostos macrocíclicos (MaC) sobre a atividade dos canais de Ca2+ tipo L e sobre a contractilidade das células A7r5. Utilizou-se a técnica Patch Clamp na configuração whole cell para medir a atividade dos LTCC nas células A7r5. O efeito de quatro macrocíclos (Me2[28]py2N6, [16]phenN2, [32]phen2N4, [30]phen2N6) foi analisado a diferentes concentrações (0,01μM, 0,1μM, 1μM e 10μM) sobre a corrente basal de Ca2+ e estimulada por Bay K (Bay K8644 – ativador específico dos LTCC). Foi também analisado o efeito destes MaC, nas mesmas concentrações, sobre a contractilidade das SMC vasculares através da técnica de PCSA (Planar Cell Surface Area), usando um microscópio de fluorescência. Este efeito foi analisado após contração das células com serotonina e noradrenalina. Pelos resultados obtidos através do Patch clamp e do PCSA pode-se observar que, nas concentrações mais baixas, o [32]phen2N4 inibe ligeiramente os LTCC, tanto a corrente basal como a corrente estimulada por Bay K. Relativamente à contractilidade, este composto não tem qualquer efeito sobre a contração induzida por serotonina ou por noradrenalina. No que diz respeito ao [16]phenN2 e ao [30]phen2N6, verifica-se que estes MaC não ativam nem inibem os LTCC mas, por outro lado, induzem redução da área celular. No caso do Me2[28]py2N6, este ativa os LTCC, de forma não significativa, mas este efeito parece não estar concordante com o efeito a nível da contractilidade, pois este MaC não tem efeito significativo sobre a redução da área celular. Assim, dos macrocíclos estudados, o [32]phen2N4 na concentração mais baixa (0,01μM) pode ser considerado como um bom transportador de fármacos, uma vez que não apresenta um efeito prejudicial sobre o sistema cardiovascular.The vascular smooth muscle cells (SMC) are crucial for the vascular tone regulation and have the ability to respond to various hormonal and hemodynamic stimuli. These are highly specialized cells that can contribute to the study of several signaling processes involved in the control of vascular tone, such as calcium metabolism and different pathways involved in the modulation of vascular reactivity. The regulation of Ca2+ flux is pivotal and important for contraction and its deregulation can be involved in the pathophysiology of some cardiovascular diseases. The entry of calcium into vascular smooth muscle cells through Ltype calcium channels (LTCC) can be triggered by the activation of receptors present on plasma membrane or by membrane depolarization. The Ca2+ -calmodulin complex formation leads to the activation of the myosin light chain (MLC), and it is its phosphorylation state that determines the contractile activity in smooth muscle. The macrocyclic compounds are cyclic macromolecules that can be used as molecular carriers, because besides having the ability to cross the cell membrane without altering its integrity, they are nontoxic in the concentrations used. Macrocyclic ligands are considered as important selective hosts in some biological applications, in particular drug solubilizers and stabilizers and anticancer agents, forming stable and specific complexes. The aim of this work is to analyze whether the macrocycles have biological activity. Therefor, it was studied the effect of different macrocyclic compounds (MaC) on the activity of the L-type calcium channels and contractility in A7r5 cells. These studies are the first step before trying to use the MaC as carriers for phosphodiesterases inhibitors. The whole cell configuration of Patch Clamp technique was used to measure the LTCC activity in A7r5 cells. The effect of four MaC (Me2[28]py2N6, [16]phenN2, [32]phen2N4, [30]phen2N6) was analyzed at different concentrations (0,01µM, 0,1µM, 1µM and 10µM) on basal and stimulated (Bay K8644 - a specific stimulator of the LTCC) activity of LTCC. It was also analyzed the effect of the related MaC in the same concentrations (0,01µM, 0,1µM, 1µM and 10µM) on vascular SMC contractility by PCSA (Planar Cell Surface Area) technique, using a fluorescence microscope. This effect was analysed after contracting the cells with serotonin and norepinephrine. From the results obtained by Patch Clamp and PCSA techniques, it is observed that at the lowest concentrations the [32]phen2N4 slightly inhibits LTCC, both basal and Bay K8644 stimulated activity. Regarding contractility, this compound has no effect on the contraction induced by serotonin or noradrenaline. It appears that [16]phenN2 and [30]phen2N6 do not activate or inhibit LTCC but, on the other hand, these MaC induce reduction in cell area. In the case of Me2[28]py2N6, this activates the LTCC but this effect does not seem consistent in terms of contractility, since this MaC does not have no significant effect on reducing cell area. Thus, from the macrocycles studied, [32]phen2N4 at the lowest concentration (0,01μM) can be considered as a good drug carrier, since it does not display a damaging effect on the cardiovascular system

Process mapping in a prototype development case

Process mapping in indirect areas is a powerful tool to increase company awareness of the complete process and it allows to identify problems and improve opportunities leading to the reduction of lead time and waste as well as improving productivity and competitiveness. In this article a team of students carried out a project in a company aiming to reduce the lead time in the prototype development using a process mapping tool called VSDia (Value Stream Design in Indirect Areas). This tool allowed the identification of several improvement opportunities leading to a reduction of the lead time from 27 to 17 days as well as gains in productivity. This activity also created in the personnel a new awareness of the whole process, the particularities of the process steps and the impact of each process step in other steps of the process.This work has been partially supported by projects COMPETE-POCI-01-0145-FEDER-007043 and FCT-UID-CEC-00319-2013, from Portugal

Vascular Pathways of Testosterone: Clinical Implications

Cardiovascular diseases (CVD) are one of the leading causes of death worldwide. Testosterone (T) is an important sex hormone that triggers several genomic and non-genomic pathways, leading to improvements of several cardiovascular risk factors and quality of life in men. At the vascular level, the key effect of T is the vasorelaxation. This review discusses the molecular pathways and clinical implications of T in the vascular system. Firstly, the mechanisms involved in the T vasodilator effect will be presented. Then, it will be discussed the association of T with the main risks for CVD, namely metabolic syndrome, type 2 diabetes mellitus, obesity, atherosclerosis, dyslipidaemia and hypertension. Several studies have shown a correlation between low T levels and an increased prevalence of several CVD. These observations suggest that T has beneficial effects on the cardiovascular system and that testosterone replacement therapy may become a therapeutic reality for some of these disorders.UBI-Santander Totta (BID/FCS/2018)info:eu-repo/semantics/publishedVersio

Kangaroo method: perceptions of mothers who experience the second stage

Objective: Understanding the perceptions of mothers of newborn preterm and/or low birth weight about the second stage of Kangaroo method. Method: This is a descriptive exploratory research of a qualitative approach performed at a teaching hospital in Southern Brazil, through semi-structured interviews and observation with five mothers who were in the neonatal unit accompanying their children. For data analysis there was used the content analysis. Results: Three categories emerged: "The importance of early", "Dilemmas and difficulties in carrying out the Method" and the "Kangaroo method facilitating the care of your child". Conclusions: The experience of the second stage allows overcoming the negative feelings that surfaced with preterm birth and promotes the empowerment of mothers in relation to caring for their children. However, it is necessary that the nursing staff develop different skills to the Kangaroo Method be effectively implemented in practice

Fortalecimiento integral de la organización juvenil para incidir y prevenir el fenómeno de la trata de personas y otras violencias en contextos educativos de la Comuna Cuba de la ciudad de Pereira: Institución Educativa Rodrígo Arenas Betancurt

CD-T 362.708 69 A98; 70 pLa presente investigación se refiere al tema de fortalecimiento de las organizaciones juveniles para incidir y prevenir el fenómeno de la trata de personas y otras violencias educativas en la institución educativa Rodrigo Arenas Betancurt, reconociendo que el contexto de Cuba es una comunidad de alto riesgo frente al fenómeno, teniendo entonces como interés principal formar y empoderar a los jóvenes que ya hacen parte de alguna organización para que tengan la capacidad de prevenir riesgos y realizar incidencia en prevención de la misma, como también otras violencias escolares; para de que de esta manera también crezca cada día más la red juvenil contra la trata de personas.Universidad Libre Seccional Pereir

Injusticia ambiental y marginación: la falta de acceso al agua en la Zona Metropolitana del Valle de México

En este artículo se analiza cómo influye la marginación territorial en la distribución de los recursos hídricos en el caso de la Zona Metropolitana del Valle de México. La obtención de recursos hídricos se ha basado en la sobreexplotación de los mantos acuíferos del Valle de México causando daños irreversibles. Se plantea que se ha priorizado la centralización de los recursos hídricos para la capital, más que en su distribución equitativa con la periferia, a pesar de que esta última también presenta un crecimiento de población exponencial que se traduce en escasez y conflictos socioambientales. El objetivo es describir, mediante fuentes documen­tales primarias, la influencia del territorio en la situación actual, así como analizar los factores gubernamentales y de participación ciudadana que han intervenido en el problema. Finalmente, se concluye con propuestas que podrían redireccionar la situación actual hacia la sostenibilidad y la justicia ambiental

Campaña de lanzamiento para la marca Flying Tiger Copenhagen

Para el presente trabajo, se realizó una propuesta de campaña de lanzamiento para la marca Flying Tiger Copenhagen y su próxima apertura de tiendas en Perú. El principal objetivo es posicionar la marca Flying Tiger Copenhagen en el mercado peruano, dando énfasis en sus principales ventajas diferenciales sin dejar de lado su cultura corporativa. Para ello, en primer lugar, se realizó un análisis a profundidad de la marca, una investigación de mercado y sus principales competidores. Se identificó el segmento al cual el proyecto está dirigido, sus principales insights, hábitos de compra y principales gustos y preferencias. En segundo lugar, con toda la información obtenida, se realizó la propuesta de campaña publicitaria de lanzamiento, para la cual se realizaron dos validaciones: la primera, se consideró importante recolectar información de primera mano con una trabajadora de la tienda Flying Tiger Copenhagen en España, Ana Rodríguez Fernández, quien dio los inputs de la marca para tener un mayor conocimiento de su cultura corporativa; por otro lado, la segunda experta, una ejecutiva de cuentas de la agencia MediaLab, Alexandra Correa, quien con sus conocimientos en lanzamientos de marca y desarrollo de campañas creativas, validó la propuesta alineada al objetivo.For this work, a launching campaign proposal was made for the brand Flying Tiger Copenhagen and its next store opening in Peru. The main objective is to position the Flying Tiger Copenhagen brand in the Peruvian market, emphasizing its main differential advantages without neglecting its corporate culture. To do this, first, an indepth analysis of the brand, market research and its main competitors was carried out. We identified the segment at which the project is aimed, its main insights, buying habits and main tastes and preferences. Secondly, with all the information obtained, the proposal for the launching advertising campaign was made, for which two validations were carried out: first, it was considered important to collect first-hand information with an employee of the Flying Tiger Copenhagen store in Spain, Ana Rodriguez Fernandez, who gave the inputs of the brand to have a better understanding of its corporate culture; on the other hand, the second expert, an account executive of the agency MediaLab, Alexandra Correa, who with her knowledge in brand launches and development of creative campaigns, validated the proposal aligned to the objective