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Search Results: 1 - 10 of 29499 matches for " Luis Sobrevia "
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Tumorogénesis y proteína mdm2
Flores P,Carlos; Sobrevia L,Luis;
Revista médica de Chile , 2000, DOI: 10.4067/S0034-98872000000500014
Abstract: tumorogenesis is associated with several events by which a normal cell transforms itself into a tumour cell with an increased proliferation rate. one of the most important research initiatives in this area is the characterization of the molecular mechanisms involved in tumorogenesis and cancer. oncogenes and tumour suppressor genes are directly involved in the cell cycle, differentiation, and apoptosis. the cellular oncogene mdm2 seems to be abnormally elevated in several human tumours, specially in sarcomas. the mdm2 gene product, mdm2 protein, ps3 and retinoblastoma (rb) proteins, play crucial roles in the control of the cell cycle. the molecular interactions between mdm2, ps3 and rb in cancer, are associated with a loss of control in the g1 phase of the cell cycle leading to uncontrolled cell proliferation. studies by gene amplification appear to show an incomplete picture of mdm2 protein levels in tumour cells. the simultaneous determination of mdm2 protein and mrna levels seems to give a more accurate interpretation of the abnormal function of the mdm2 protein. thus, in addition to gene amplification, different mechanisms by which mdm2 is overexpressed in cancer cells also play an important role in tumorogenesis. (rev méd chile 2000; 128: 539-46)
CONGRESO MUNDIAL DE LA FEDERACIóN INTERNACIONAL DE ASOCIACIONES DE PLACENTA, IFPA CHILE 2010
Luis Sobrevia L,Paola Casanello T
Revista Chilena de Obstetricia y Ginecología , 2009,
Abstract:
Tumorogénesis y proteína mdm2 Tumorogenesis and mdm2 protein
Carlos Flores P,Luis Sobrevia L
Revista médica de Chile , 2000,
Abstract: Tumorogenesis is associated with several events by which a normal cell transforms itself into a tumour cell with an increased proliferation rate. One of the most important research initiatives in this area is the characterization of the molecular mechanisms involved in tumorogenesis and cancer. Oncogenes and tumour suppressor genes are directly involved in the cell cycle, differentiation, and apoptosis. The cellular oncogene MDM2 seems to be abnormally elevated in several human tumours, specially in sarcomas. The MDM2 gene product, mdm2 protein, pS3 and retinoblastoma (Rb) proteins, play crucial roles in the control of the cell cycle. The molecular interactions between mdm2, pS3 and Rb in cancer, are associated with a loss of control in the G1 phase of the cell cycle leading to uncontrolled cell proliferation. Studies by gene amplification appear to show an incomplete picture of mdm2 protein levels in tumour cells. The simultaneous determination of mdm2 protein and mRNA levels seems to give a more accurate interpretation of the abnormal function of the mdm2 protein. Thus, in addition to gene amplification, different mechanisms by which mdm2 is overexpressed in cancer cells also play an important role in tumorogenesis. (Rev Méd Chile 2000; 128: 539-46)
Fetoplacental Vascular Endothelial Dysfunction as an Early Phenomenon in the Programming of Human Adult Diseases in Subjects Born from Gestational Diabetes Mellitus or Obesity in Pregnancy
Andrea Leiva,Fabián Pardo,Marco A. Ramírez,Marcelo Farías,Paola Casanello,Luis Sobrevia
Experimental Diabetes Research , 2011, DOI: 10.1155/2011/349286
Abstract: Gestational diabetes mellitus (GDM) and obesity in pregnancy (OP) are pathological conditions associated with placenta vascular dysfunction coursing with metabolic changes at the fetoplacental microvascular and macrovascular endothelium. These alterations are seen as abnormal expression and activity of the cationic amino acid transporters and endothelial nitric oxide synthase isoform, that is, the “endothelial L-arginine/nitric oxide signalling pathway.” Several studies suggest that the endogenous nucleoside adenosine along with insulin, and potentially arginases, are factors involved in GDM-, but much less information regards their role in OP-associated placental vascular alterations. There is convincing evidence that GDM and OP prone placental endothelium to an “altered metabolic state” leading to fetal programming evidenced at birth, a phenomenon associated with future development of chronic diseases. In this paper it is suggested that this pathological state could be considered as a metabolic marker that could predict occurrence of diseases in adulthood, such as cardiovascular disease, obesity, diabetes mellitus (including gestational diabetes), and metabolic syndrome.
Hypoxia-Induced Changes in the Bioactivity of Cytotrophoblast-Derived Exosomes
Carlos Salomon, Miharu Kobayashi, Keith Ashman, Luis Sobrevia, Murray D. Mitchell, Gregory E. Rice
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0079636
Abstract: Migration of extravillous trophoblasts (EVT) into decidua and myometrium is a critical process in the conversion of maternal spiral arterioles and establishing placenta perfusion. EVT migration is affected by cell-to-cell communication and oxygen tension. While the release of exosomes from placental cells has been identified as a significant pathway in materno-fetal communication, the role of placental-derived exosomes in placentation has yet to be established. The aim of this study was to establish the effect of oxygen tension on the release and bioactivity of cytotrophoblast (CT)-derived exosomes on EVT invasion and proliferation. CT were isolated from first trimester fetal tissue (n = 12) using a trypsin-deoxyribonuclease-dispase/Percol?lmethod. CT were cultured under 8%, 3% or 1% O2 for 48 h. Exosomes from CT-conditioned media were isolated by differential and buoyant density centrifugation. The effect of oxygen tension on exosome release (μg exosomal protein/106cells/48 h) and bioactivity were established. HTR-8/SVneo (EVT) were used as target cells to establish the effect (bioactivity) of exosomes on invasion and proliferation as assessed by real-time, live-cell imaging (Incucyte?). The release and bioactivity of CT-derived exosomes were inversely correlated with oxygen tension (p<0.001). Under low oxygen tensions (i.e. 1% O2), CT-derived exosomes promoted EVT invasion and proliferation. Proteomic analysis of exosomes identified oxygen-dependent changes in protein content. We propose that in response to changes in oxygen tension, CTs modify the bioactivity of exosomes, thereby, regulating EVT phenotype. Exosomal induction of EVT migration may represent a normal process of placentation and/or an adaptive response to placental hypoxia.
Exosomal Signaling during Hypoxia Mediates Microvascular Endothelial Cell Migration and Vasculogenesis
Carlos Salomon, Jennifer Ryan, Luis Sobrevia, Miharu Kobayashi, Keith Ashman, Murray Mitchell, Gregory E. Rice
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0068451
Abstract: Vasculogenesis and angiogenesis are critical processes in fetal circulation and placental vasculature development. Placental mesenchymal stem cells (pMSC) are known to release paracrine factors (some of which are contained within exosomes) that promote angiogenesis and cell migration. The aims of this study were: to determine the effects of oxygen tension on the release of exosomes from pMSC; and to establish the effects of pMSC-derived exosomes on the migration and angiogenic tube formation of placental microvascular endothelial cells (hPMEC). pMSC were isolated from placental villi (8–12 weeks of gestation, n = 6) and cultured under an atmosphere of 1%, 3% or 8% O2. Cell-conditioned media were collected and exosomes (exo-pMSC) isolated by differential and buoyant density centrifugation. The dose effect (5–20 μg exosomal protein/ml) of pMSC-derived exosomes on hPMEC migration and tube formation were established using a real-time, live-cell imaging system (Incucyte?). The exosome pellet was resuspended in PBS and protein content was established by mass spectrometry (MS). Protein function and canonical pathways were identified using the PANTHER program and Ingenuity Pathway Analysis, respectively. Exo-pMSC were identified, by electron microscopy, as spherical vesicles, with a typical cup-shape and diameters around of 100 nm and positive for exosome markers: CD63, CD9 and CD81. Under hypoxic conditions (1% and 3% O2) exo-pMSC released increased by 3.3 and 6.7 folds, respectively, when compared to the controls (8% O2; p<0.01). Exo-pMSC increased hPMEC migration by 1.6 fold compared to the control (p<0.05) and increased hPMEC tube formation by 7.2 fold (p<0.05). MS analysis identified 390 different proteins involved in cytoskeleton organization, development, immunomodulatory, and cell-to-cell communication. The data obtained support the hypothesis that pMSC-derived exosomes may contribute to placental vascular adaptation to low oxygen tension under both physiological and pathological conditions.
Fetoplacental Vascular Endothelial Dysfunction as an Early Phenomenon in the Programming of Human Adult Diseases in Subjects Born from Gestational Diabetes Mellitus or Obesity in Pregnancy
Andrea Leiva,Fabián Pardo,Marco A. Ramírez,Marcelo Farías,Paola Casanello,Luis Sobrevia
Journal of Diabetes Research , 2011, DOI: 10.1155/2011/349286
Abstract: Gestational diabetes mellitus (GDM) and obesity in pregnancy (OP) are pathological conditions associated with placenta vascular dysfunction coursing with metabolic changes at the fetoplacental microvascular and macrovascular endothelium. These alterations are seen as abnormal expression and activity of the cationic amino acid transporters and endothelial nitric oxide synthase isoform, that is, the “endothelial L-arginine/nitric oxide signalling pathway.” Several studies suggest that the endogenous nucleoside adenosine along with insulin, and potentially arginases, are factors involved in GDM-, but much less information regards their role in OP-associated placental vascular alterations. There is convincing evidence that GDM and OP prone placental endothelium to an “altered metabolic state” leading to fetal programming evidenced at birth, a phenomenon associated with future development of chronic diseases. In this paper it is suggested that this pathological state could be considered as a metabolic marker that could predict occurrence of diseases in adulthood, such as cardiovascular disease, obesity, diabetes mellitus (including gestational diabetes), and metabolic syndrome. 1. Introduction Pregnancy is a physiological state with a complex anatomical and functional interaction between mother and fetus [1]. When this interaction is not a success, the mother, the fetus, or both exhibit functional impairments. Complications of pregnancy are important causes of maternal mortality, where gestational diabetes mellitus (GDM) and obesity of the mother in pregnancy (OP) are major obstetric pathologies. Fetal-maternal interaction could result in metabolic disturbances leading, for example, to placental and endothelial dysfunction [2, 3]. Endothelial dysfunction is defined as an altered capacity of the endothelium to take up and metabolize the cationic amino acid L-arginine, the substrate for nitric oxide (NO) synthesis via NO synthases (NOS) [4, 5]. Interestingly, it is reported that GDM and OP are pathological conditions associated with altered L-arginine transport and NO synthesis (i.e., the “L-arginine/NO signalling pathway”), probably due to altered uptake and metabolism of adenosine [6, 7], an endogenous nucleoside acting as vasodilator in most vascular beds [8, 9]. These pathophysiological characteristics are considered key in the establishment of a “programmed state” of the developing fetus (i.e., “fetal programming”). This concept refers to the impact of abnormal intrauterine conditions on the development of diseases in adulthood and becomes a key mechanism
Insulin-Increased L-Arginine Transport Requires A2A Adenosine Receptors Activation in Human Umbilical Vein Endothelium
Enrique Guzmán-Gutiérrez, Francisco Westermeier, Carlos Salomón, Marcelo González, Fabián Pardo, Andrea Leiva, Luis Sobrevia
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0041705
Abstract: Adenosine causes vasodilation of human placenta vasculature by increasing the transport of arginine via cationic amino acid transporters 1 (hCAT-1). This process involves the activation of A2A adenosine receptors (A2AAR) in human umbilical vein endothelial cells (HUVECs). Insulin increases hCAT-1 activity and expression in HUVECs, and A2AAR stimulation increases insulin sensitivity in subjects with insulin resistance. However, whether A2AAR plays a role in insulin-mediated increase in L-arginine transport in HUVECs is unknown. To determine this, we first assayed the kinetics of saturable L-arginine transport (1 minute, 37°C) in the absence or presence of nitrobenzylthioinosine (NBTI, 10 μmol/L, adenosine transport inhibitor) and/or adenosine receptors agonist/antagonists. We also determined hCAT-1 protein and mRNA expression levels (Western blots and quantitative PCR), and SLC7A1 (for hCAT-1) reporter promoter activity. Insulin and NBTI increased the extracellular adenosine concentration, the maximal velocity for L-arginine transport without altering the apparent Km for L-arginine transport, hCAT-1 protein and mRNA expression levels, and SLC7A1 transcriptional activity. An A2AAR antagonist ZM-241385 blocked these effects. ZM241385 inhibited SLC7A1 reporter transcriptional activity to the same extent in cells transfected with pGL3-hCAT-1?1606 or pGL3-hCAT-1?650 constructs in the presence of NBTI + insulin. However, SLC7A1 reporter activity was increased by NBTI only in cells transfected with pGL3-hCAT-1?1606, and the ZM-241385 sensitive fraction of the NBTI response was similar in the absence or in the presence of insulin. Thus, insulin modulation of hCAT-1 expression and activity requires functional A2AAR in HUVECs, a mechanism that may be applicable to diseases associated with fetal insulin resistance, such as gestational diabetes.
Gestational Diabetes Reduces Adenosine Transport in Human Placental Microvascular Endothelium, an Effect Reversed by Insulin
Carlos Salomón, Francisco Westermeier, Carlos Puebla, Pablo Arroyo, Enrique Guzmán-Gutiérrez, Fabián Pardo, Andrea Leiva, Paola Casanello, Luis Sobrevia
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0040578
Abstract: Gestational diabetes mellitus (GDM) courses with increased fetal plasma adenosine concentration and reduced adenosine transport in placental macrovascular endothelium. Since insulin modulates human equilibrative nucleoside transporters (hENTs) expression/activity, we hypothesize that GDM will alter hENT2-mediated transport in human placental microvascular endothelium (hPMEC), and that insulin will restore GDM to a normal phenotype involving insulin receptors A (IR-A) and B (IR-B). GDM effect on hENTs expression and transport activity, and IR-A/IR-B expression and associated cell signalling cascades (p42/44 mitogen-activated protein kinases (p42/44mapk) and Akt) role in hPMEC primary cultures was assayed. GDM associates with elevated umbilical whole and vein, but not arteries blood adenosine, and reduced hENTs adenosine transport and expression. IR-A/IR-B mRNA expression and p42/44mapk/Akt ratios (‘metabolic phenotype’) were lower in GDM. Insulin reversed GDM-reduced hENT2 expression/activity, IR-A/IR-B mRNA expression and p42/44mapk/Akt ratios to normal pregnancies (‘mitogenic phenotype’). It is suggested that insulin effects required IR-A and IR-B expression leading to differential modulation of signalling pathways restoring GDM-metabolic to a normal-mitogenic like phenotype. Insulin could be acting as protecting factor for placental microvascular endothelial dysfunction in GDM.
Mice Long-Term High-Fat Diet Feeding Recapitulates Human Cardiovascular Alterations: An Animal Model to Study the Early Phases of Diabetic Cardiomyopathy
Sebastián D. Calligaris, Manuel Lecanda, Felipe Solis, Marcelo Ezquer, Jaime Gutiérrez, Enrique Brandan, Andrea Leiva, Luis Sobrevia, Paulette Conget
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0060931
Abstract: Background/Aim Hypercaloric diet ingestion and sedentary lifestyle result in obesity. Metabolic syndrome is a cluster of clinical features secondary to obesity, considered as a pre-diabetic condition and recognized as an independent risk factor for cardiovascular diseases. To better understand the relationship between obesity, metabolic syndrome and cardiovascular disease as well as for the development of novel therapeutic strategies, animal models that reproduce the etiology, course and outcomes of these pathologies are required. The aim of this work was to characterize the long-term effects of high-fat diet-induced obesity on the mice cardiovascular system, in order to make available a new animal model for diabetic cardiomyopathy. Methods/Results Male C57BL/6 mice were fed with a standardized high-fat diet (obese) or regular diet (normal) for 16 months. Metabolic syndrome was evaluated testing plasma glucose, triglycerides, cholesterol, insulin, and glucose tolerance. Arterial pressure was measured using a sphygmomanometer (non invasive method) and by hemodynamic parameters (invasive method). Cardiac anatomy was described based on echocardiography and histological studies. Cardiac function was assessed by cardiac catheterization under a stress test. Cardiac remodelling and metabolic biomarkers were assessed by RT-qPCR and immunoblotting. As of month eight, the obese mice were overweight, hyperglycaemic, insulin resistant, hyperinsulinemic and hypercholesterolemic. At month 16, they also presented normal arterial pressure but altered vascular reactivity (vasoconstriction), and cardiac contractility reserve reduction, heart mass increase, cardiomyocyte hypertrophy, cardiac fibrosis, and heart metabolic compensations. By contrast, the normal mice remained healthy throughout the study. Conclusions Mice fed with a high-fat diet for prolonged time recapitulates the etiology, course and outcomes of the early phases of human diabetic cardiomyopathy.
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