Browsing by Author "Santos, Manuel J."

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    Bioethical aspects of basic research and medical applications of human stem cells
    (2012) Santos, Manuel J.; Ventura-Junca, Patricio
    The new discoveries, the extraordinary dynamism in human stem cell (SC) research, and the great expectations of the benefits in clinical treatment of many diseases are on the edge of unparalleled advances in both: 1) the understanding of basic mechanisms of cell differentiation and development and 2) the translation from basic research to new clinical therapies. Human stem cells are obtained from different sources, such as embryo, fetal, and adult tissues, in vitro induction (iPS cells) or transdifferentiation. The evidence that these cells are pluripotent (or multipotent), meaning they have the ability to differentiate into all body tissues or tissues of the same lineage, raises the possibility that they could regenerate diseased or damaged tissue in diseases that until now have had no effective treatments. Human stem cell research and therapy raise important bioethical considerations because of the human nature of these cells and their peculiar characteristics. Here we discuss the bioethical aspects of basic human SC research and the conditions necessary for the translation of basic preclinical research into clinical use of SC.
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    Peroxisome Proliferator-Activated Receptor (PPAR) γ and PPARα Agonists Modulate Mitochondrial Fusion-Fission Dynamics: Relevance to Reactive Oxygen Species (ROS)-Related Neurodegenerative Disorders?
    (2013) Zolezzi, Juan M.; Silva-Alvarez, Carmen; Ordenes, Daniela; Godoy, Juan A.; Carvajal, Francisco J.; Santos, Manuel J.; Inestrosa, Nibaldo C.
    Recent studies showed that the activation of the retinoid X receptor, which dimerizes with peroxisome proliferator-activated receptors (PPARs), leads to an enhanced clearance of A beta from the brain of transgenic mice model of Alzheimer's disease (AD), because an increased expression of apolipoprotein E and it main transporters. However, the effects observed must involve additional underlying mechanisms that have not been yet explored. Several studies conducted in our laboratory suggest that part of the effects observed for the PPARs agonist might involves mitochondrial function and, particularly, mitochondrial dynamics. In the present study we assessed the effects of oxidative stress challenge on mitochondrial morphology and mitochondrial dynamics-related proteins in hippocampal neurons. Using immunofluorescence, we evaluated the PPAR gamma co-activator 1 alpha (PGC-1 alpha), dynamin related protein 1 (DRP1), mitochondrial fission protein 1 (FIS1), and mitochondrial length, in order to determine if PPARs agonist pre-treatment is able to protect mitochondrial population from hippocampal neurons through modulation of the mitochondrial fusion-fission events. Our results suggest that both a PPAR gamma agonist (ciglitazone) and a PPAR alpha agonist (WY 14.643) are able to protect neurons by modulating mitochondrial fusion and fission, leading to a better response of neurons to oxidative stress, suggesting that a PPAR based therapy could acts simultaneously in different cellular components. Additionally, our results suggest that PGC-1 alpha and mitochondrial dynamics should be further studied in future therapy research oriented to ameliorate neurodegenerative disorders, such as AD.
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    Pex3p-Dependent Peroxisomal Biogenesis Initiates in the Endoplasmic Reticulum of Human Fibroblasts
    (WILEY-BLACKWELL, 2009) Toro, Andres A.; Araya, Claudia A.; Cordova, Gonzalo J.; Arredondo, Cristian A.; Cardenas, Hugo G.; Moreno, Regina E.; Venegas, Alejandro; Koenig, Cecilia S.; Cancino, Jorge; Gonzalez, Alfonso; Santos, Manuel J.
    The mechanisms of peroxisomal biogenesis remain incompletely understood, specially regarding the role of the endoplasmic reticulum (ER) in human cells, where genetic disorders of peroxisome biogenesis lead to Zellweger syndrome (ZS). The Pex3p peroxisomal membrane protein (PMP) required for early steps of peroxisome biogenesis has been detected in the ER in yeast but not in mammalian cells. Here, we show that Pex3p-GFP expressed in a new ZS cell line (MR), which lacks peroxisomes due to a mutation in the PEX3 gene, localizes first in the ER and subsequently in newly formed peroxisomes. Pex3p bearing an artificial N-glycosylation site shows an electrophoretic shift indicative of ER targeting while en route to preformed peroxisomes in normal fibroblast. A signal peptide that forces its entry into the ER does not eliminate its capability to drive peroxisome biogenesis in ZS cells. Thus, Pex3p is able to drive peroxisome biogenesis from the ER and its ER pathway is not privative of ZS cells. Cross-expression experiments of Pex3p in GM623 cells lacking Pex16p or Pex16p in MR cells lacking Pex3p, showed evidence that Pex3p requires Pex16p for ER location but: is dispensable for the ER location of Pex16p. These results indicate that Pex3p follows the ER-to-peroxisomal route in mammalian cells and provides new clues to understand its function. J. Cell. Biochem. 107: 10831096, 2009. (C) 2009 Wiley-Liss, Inc.