Digitalizado únicamente el v.1

Archivo en PDF (10.1 MB). Bogotá : Biblioteca Nacional de Colombia, 2010

NEW-GRAL

NEW-GRAL

Descripción física : [8], 208 p. :il. (grab., pleg.) ;20 cm.

Retrato de Antonio Vargas Reyes

This report compiles the results of a research project aimed at describing the current palliative care situation in eight Latin American countries. The project’s general objective—to raise awareness and influence public policy around the need to approach palliative care from a human rights perspective—was achieved through rapprochement among professionals from various fields in the region, which in and of itself is a key step forward in terms of bringing together communities that defend patients’ rights with communities that advocate a drug policy embracing a public health focus. We hope that this diagnostic report is useful for professional associations, health professionals, patients’ rights advocates, drug policy reform activists, and decision makers, who can rely on its findings to better integrate palliative care into general health services and to use human rights language to promote public policy reform and guarantee the human rights of those in the Americas who suffer from severe and chronic pain. Description tooked from: https://www.dejusticia.org/publication/palliative-care-a-human-rights-approach-to-health-care-2/ Consulte la versión en español en la siguiente URL: http://babel.banrepcultural.org/cdm/ref/collection/p17054coll31/id/30

Transcriptional activity of Forkhead box transcription factor class O (FOXO) proteins can result in a variety of cellular outcomes depending on cell type and activating stimulus. These transcription factors are negatively regulated by the phosphoinositol 3-kinase (PI3K)–protein kinase B (PKB) signaling pathway, which is thought to have a pivotal role in regulating survival of tumor cells in a variety of cancers. Recently, it has become clear that FOXO proteins can promote resistance to anti-cancer therapeutics, designed to inhibit PI3K–PKB activity, by inducing the expression of proteins that provide feedback at different levels of this pathway. We questioned whether such a feedback mechanism may also exist directly at the level of FOXO-induced transcription. To identify critical modulators of FOXO transcriptional output, we performed gene expression analyses after conditional activation of key components of the PI3K–PKB–FOXO signaling pathway and identified FOXP1 as a direct FOXO transcriptional target. Using chromatin immunoprecipitation followed by next-generation sequencing, we show that FOXP1 binds enhancers that are pre-occupied by FOXO3. By sequencing the transcriptomes of cells in which FOXO is specifically activated in the absence of FOXP1, we demonstrate that FOXP1 can modulate the expression of a specific subset of FOXO target genes, including inhibiting expression of the pro-apoptotic gene BIK. FOXO activation in FOXP1-knockdown cells resulted in increased cell death, demonstrating that FOXP1 prevents FOXO-induced apoptosis. We therefore propose that FOXP1 represents an important modulator of FOXO-induced transcription, promoting cellular survival.

Abstract: Bone remodeling is a continuous physiological process that requires constant generation of new osteoblasts from mesenchymal stem cells (MSCs). Differentiation of MSCs to osteoblast requires a metabolic switch from glycolysis to increased mitochondrial respiration to ensure the sufficient energy supply to complete this process. As a consequence of this increased mitochondrial metabolism, the levels of endogenous reactive oxygen species (ROS) rise. In the current study we analyzed the role of forkhead box O3 (FOXO3) in the control of ROS levels in human MSCs (hMSCs) during osteogenic differentiation. Treatment of hMSCs with H2O2 induced FOXO3 phosphorylation at Ser294 and nuclear translocation. This ROS-mediated activation of FOXO3 was dependent on mitogen-activated protein kinase 8 (MAPK8/JNK) activity. Upon FOXO3 downregulation, osteoblastic differentiation was impaired and hMSCs lost their ability to control elevated ROS levels. Our results also demonstrate that in response to elevated ROS levels, FOXO3 induces autophagy in hMSCs. In line with this, impairment of autophagy by autophagy-related 7 (ATG7) knockdown resulted in a reduced capacity of hMSCs to regulate elevated ROS levels, together with a reduced osteoblast differentiation. Taken together our findings are consistent with a model where in hMSCs, FOXO3 is required to induce autophagy and thereby reduce elevated ROS levels resulting from the increased mitochondrial respiration during osteoblast differentiation. These new molecular insights provide an important contribution to our better understanding of bone physiology. Resumen: La remodelación ósea es un proceso fisiológico continuo que demanda la generación constante de nuevos osteoblastos a partir de células madre mesenquimales (CMMs). La diferenciación de las CMMs a osteoblastos requiere un cambio de glicólisis a respiración mitocondrial para así asegurar la obtención de suficiente energía. Como consecuencia, los niveles endógenos de especies reactivas del oxígeno (ERO) se elevan siendo perjudiciales para la integridad celular. En el presente estudio hemos analizado el papel de FOXO3 en el control de ERO en las CMMs durante la diferenciación osteogénica. El tratamiento de las CMMs con H2O2 induce la fosforilacion de FOXO3 en la serina 294 resultando en la translocación de FOXO3 al núcleo. Dicha activación mediada por el aumento de ERO es dependiente de la actividad de JNK. Al disminuir los niveles de FOXO3, la diferenciación osteoblástica se deteriora y las CMMs pierden su capacidad para controlar los niveles de ERO. Adicionalmente, nuestros resultados demuestran que en presencia de ERO, FOXO3 induce la autofagia en CMMs. En este orden de ideas, la disminución en los niveles de ATG7 da lugar a una reducción de la capacidad de las CMMs para regular los niveles elevados de ERO, junto con una reducción de la diferenciación de osteoblastos. Tomados en conjunto, nuestros resultados son consistentes con un modelo en el que FOXO3 es necesario para inducir la autofagia y por lo tanto reducir los niveles elevados de ERO que resultan del aumento de la respiración mitocondrial durante la diferenciación de osteoblastos. Estos nuevos conocimientos moleculares son importantes para una mejor comprensión de la fisiología ósea.

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