Browsing by Author "Casanello Toledo, Paola Cecilia"

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    5, '-ectonucleotidase mediates multiple-drug resistance in glioblastoma multiforme cells
    (2013) Quezada, Claudia; Garrido, Wallys; Oyarzún, Carlos; Fernández, Katia; Segura Segura, Rodrigo; Melo, Rómulo; Casanello Toledo, Paola Cecilia; Sobrevía Luarte, Luis Alberto; San Martin, Rody
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    Arginase-2 is cooperatively up-regulated by nitric oxide and histone deacetylase inhibition in human umbilical artery endothelial cells
    (2016) Krause Leyton, Bernardo; Hernández, C.; Caniuguir, A.; Vásquez Devaud, P.; Carrasco Wong, I.; Uauy, Ricardo; Casanello Toledo, Paola Cecilia
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    Arginase-endothelial nitric oxide synthase imbalance contributes to endothelial dysfunction during chronic intermittent hypoxia
    (2015) Krause Leyton, Bernardo; Del Rio, Rodrigo; Moya, Esteban A.; Marquez Gutiérrez, Mónica; Casanello Toledo, Paola Cecilia; Iturriaga Agüera, Rodrigo
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    Assessment of in vivo fetal growth and placental vascular function in a novel intrauterine growth restriction model of progressive uterine artery occlusion in guinea pigs
    (2016) Krause B.; Herrera, E.; Alegría, R.; Farías Jofré, Marcelo Enrique; Díaz López, F.; Hernández, C.; Uauy, Ricardo; Regnault, T.; Casanello Toledo, Paola Cecilia; Krause Leyton, Bernardo
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    Carbon monoxide (CO): A key vasodilator in the pulmonary circulation in the llama neonate
    (2006) Herrera, E.A.; Reyes, V.R.; Riquelme, R.A.; Sanhueza, E.M.; Ebensperger, G.; Ebensperger González, Roberto Alejandro; Casanello Toledo, Paola Cecilia; Martinez, G.; Llanos, A.J.
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    Chronic Intermittent Hypoxia-Induced Vascular Dysfunction in Rats is Reverted by N-Acetylcysteine Supplementation and Arginase Inhibition
    (2018) Krause, Bernardo J.; Casanello Toledo, Paola Cecilia; Dias, Ana C.; Arias, Paulina; Velarde, Victoria; Arenas Menéndez, German Alberto; Preite, Marcelo Daniel; Iturriaga Agüera, Rodrigo
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    Conceptos generales de epigenética: proyecciones en pediatría
    (2016) Krause Leyton, Bernardo; Castro Rodríguez, José Antonio; Uauy, Ricardo; Casanello Toledo, Paola Cecilia
    La asociación entre factores ambientales presentes durante el desarrollo embrionario/fetal y enfermedades que puedan presentarse durante la vida representa un campo de creciente interés. En este contexto la evidencia actual apoya fuertemente que alteraciones en el crecimiento intrauterino y durante los primeros años de vida presentan una fuerte influencia en el riesgo de padecer enfermedades crónicas que en muchos casos pudiera ser mayor que la carga genética del paciente. La persistencia y reproducibilidad de los fenotipos asociados a alteraciones en el desarrollo temprano sugieren la participación de mecanismos moleculares que registran dichas modificaciones (i.e. mecanismos epigenéticos) generando una «reprogramación» celular y fisiológica. Esta revisión es la introducción a una serie de 5 artículos en torno a la participación de los mecanismos epigenéticos en el desarrollo de enfermedades crónicas (i.e. cardiovasculares, metabólicas, asma/alergias y cáncer) y su relación con el origen de dichas enfermedades en etapas tempranas del desarrollo. El objetivo de esta serie es mostrar el estado actual de esta área de la investigación y presentar los desafíos e interrogantes futuros en los cuales la pediatría tiene un papel preponderante, desarrollando estrategias para la prevención, detección precoz y seguimiento.
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    Conceptual basis for prescriptive growth standards from conception to early childhood: present and future
    (2013) Uauy, Ricardo; Casanello Toledo, Paola Cecilia; Krause Leyton, Bernardo; Kuzanovic, Juan Pablo; Corvalán, Camila
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    Congenital diaphragmatic hernia: phosphodiesterase-5 and Arginase inhibitors prevent pulmonary vascular hypoplasia in rat lungs
    (2022) Toso, Alberto; Aranguiz, Óscar; Cespedes, Carlos; Navarrete, Orieta; Hernández, Cherie; Vio, Carlos P.; Luco Illanes, Matías Fernando; Casanello Toledo, Paola Cecilia; Kattan Said, Alberto Javier
    Background Severe pulmonary hypoplasia related to congenital diaphragmatic hernia (CDH) continues to be a potentially fatal condition despite advanced postnatal management strategies. Objective To evaluate the effect of the antenatal sildenafil and 2(S)-amino-6-boronohexanoic acid (ABH-Arginase inhibitor) on lung volume, pulmonary vascular development, and nitric oxide (NO) synthesis in a Nitrofen-induced CDH rat model. Methods Nitrofen-induced CDH rat model was used. Nitrofen was administrated on embryonic day(E) 9,5. At E14, five intervention groups were treated separately: Nitrofen, Nitrofen+Sildenafil, Nitrofen+ABH, Nitrofen+Sildenafil+ABH and Control. At term, offspring's lungs were weighed, some paraffin-embedded for histology, others snap-frozen to analyze eNOS, Arginase I-II expression, and activity. Results In CDH-bearing offsprings, ABH or Sildenafil+ABH preserved the total lung/body-weight index (p < 0.001), preventing pulmonary vascular smooth muscle cell hyperproliferation and improving lung morphometry. Sildenafil+ABH increased 1.7-fold the lung nitrite levels (p < 0.01) without changes in eNOS expression. Sildenafil and ABH improved the number of pulmonary vessels. Conclusion These results suggest that in this CDH rat model, the basal activity of Arginase participates in the lung volume and, together with phosphodiesterase-5, regulates NOS activity in the term fetal lung. The combined treatment (Sildenafil+ABH) could revert some of the pulmonary features in CDH by improving the local NO synthesis and preventing smooth muscle cell hyperproliferation. Impact This study presents Arginase inhibition as a new therapeutic target and the importance of the combined antenatal treatment to improve pulmonary vascular development in a congenital diaphragmatic hernia (CDH) rat model. This study shows that the action of an Arginase inhibitor (ABH) enhances the effects already described for sildenafil in this model. These results reinforce the importance of prenatal treatments' synergy in recovering the hypoplastic lung in the Nitrofen-induced CDH rat model.
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    d-glucose increased l-arginine transport and nitric oxide synthesis through an autocrine mechanism involving TGF-β1 and TGF-β receptor II (TβRII) in human umbilical vein endothelium
    (2006) Vásquez, Rodrigo; Farías Jofré, Marcelo Enrique; San Martín, Rody; Casanello Toledo, Paola Cecilia; Sobrevía Luarte, Luis Alberto
    High D-glucose increases L-arginine transport, nitric oxide (NO) synthesis, and release of Transforming Growth Factor β1 (TGF-β1) in human umbilical vein endothelium (HUVEC). Changes in cell proliferation in response to D-glucose have been explained by a TGF-β1 autocrine mechanism in this cell type. However, the involvement of TGF-β1 and TGF-β1 receptor II (TβRII) on D-glucose effect on endothelial L-arginine/NO pathway has not been reported. L-[3H]Arginine transport (100 μM, 2 μCi/ml) and endothelial NO synthase (eNOS) activity [L-[3H]citrulline formation from L-[3H]arginine, 4 μCi/ml, 30 min, ± NG-nitro-L-arginine methyl ester (L-NAME), 100 μM] were determined in primary cultures of HUVEC exposed (6 h) to 5 mM (normal) or 25 mM (high) D-glucose, in absence or presence of TGF-β1 (2 ng/ml). Supernatant TGF-β1 level was measured by ELISA. HUVEC were infected (2% sera for 12 h) with an adenovirus expressing a negative dominant truncated TβRII (AdTβRIIt). Expression of TβRIIt was determined by Western blot. High D-glucose and TGF-β1 [half maximal effect (Ks): 0.28 ng/ml] increased L-arginine transport, effects that were significantly (P< 0.005) reduced in AdTβRIIt infected cells. L-Arginine transport was not further increased in non-infected infected cells co-incubated with high D-glucose and TGF-β1. However, L-arginine transport in AdTβRIIt infected cells co-incubated with these molecules was reduced. High D-glucose and TGF-β1 increased L-citrulline formation only in non-infected cells. High D-glucose also increased supernatant TGF-β1 level. We propose that stimulation of endothelial L-arginine/NO pathway by high D-glucose could result from a mechanism involving activation of TβRII by TGF-β1 as a consequence of increased release of this growth factor in HUVEC. Supported by FONDECYT 1030781 & 1030607 (Chile). R.V. holds a DIPUC-School of Medicine PhD (Chile) fellowship. M.F. holds CONICYT and School of Medicine–PhD (Chile) fellowships
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    D-Glucose increases the expression and activity of hCAT-1 and Spl binding to SLC7A1 promoter in human umbilical vein endothelium
    (2008) González Ortiz, Marcelo Andrés; Farías Jofré, Marcelo Enrique; Casanello Toledo, Paola Cecilia; Sobrevía Luarte, Luis Alberto
    L-Arginine is mainly transported by the human cationic amino acid transporter 1 (hCAT-1, protein codified by the gene SLC7A1) in human umbilical vein endothelial cells (HUVEC). hCAT-1 mediated L-arginine transport and nitric oxide (NO) synthesis are increased by 25 mM D-glucose in this cell type. Since Sp1 is a transcription factor activated by NO, we studied whether high D-glucose effect on transport was due to altered expression of hCAT-1 and abundance and activity of the transcription factor Sp1 in primary cultures of HUVEC. D-Glucose (25 mM, 24 hours) increased (~3.2 fold) the maximal velocity (Vmax), without altering the apparent Km, of L-arginine transport compared with cells in 5 mM D-glucose. High D-glucose also increased the hCAT-1 mRNA number of copies (~5-fold) and protein abundance (~2-fold), and Sp1 nuclear abundance and binding to SLC7A1 promoter region (−177 to −103 bp from ATG). Thus, the stimulatory effect of D-glucose on L-arginine transport could result from increased expression of hCAT-1 due to increased activity of Sp1 on the promoter of SLC7A1 in HUVEC.
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    Early origins of allergy and asthma (ARIES): study protocol for a prospective prenatal birth cohort in Chile.
    (2020) Hernández Vargas, Caroll Daffner; Casanello Toledo, Paola Cecilia; Harris D., Paul R.; Castro Rodríguez, José Antonio; Iturriaga, Carolina; Pérez Mateluna, Guillermo; Farías Jofré, Marcelo Enrique; Urzúa, Marcela; Hernández Carreño, Cherie Francisca; Serrano Honeyman, Carolina; Hernández Vargas, Caroll Daffner; Casanello Toledo, Paola Cecilia; Harris D., Paul R.; Castro Rodríguez, José Antonio; Iturriaga, Carolina; Pérez Mateluna, Guillermo; Farías Jofré, Marcelo Enrique; Urzúa, Marcela; Hernández Carreño, Cherie Francisca; Serrano Honeyman, Carolina
    Abstract Background Growing evidence shows that atopic dermatitis (AD), food allergy (FA), allergic rhinitis, and asthma are largely determined during the first 1000 days (time elapsed from conception to the 2nd birthday). The ARIES birth cohort aims to determine prenatal and perinatal conditions, as well as genetic and epigenetic factors, that participate in the early setting of immune responses, and the role of these in the later determination of the risk of allergic diseases and asthma in the offspring. Methods We have designed a birth cohort of 250 families with prenatal recruitment (~ 14 weeks). We will genotype relevant allergy/asthma-associated variants in trios and will perform immunophenotyping and evaluation of allergy biomarkers in cord blood. At 1 and 2 years of age we will assess if infants have developed allergic sensitization, AD, FA, as well as biomarkers of asthma including the asthma predictive index. We will also evaluate how maternal conditions modify immune programming through epigenetic modifications and will then depict newborn epigenetic cues of allergy/asthma risk. Next, we will assess composition/diversity of maternal gut, placenta, breastmilk and infant gut microbiome and their association with immunophenotype and biomarkers at birth, and clinical outcomes at age 1 and 2. Finally, we plan to assess how environmental exposures (perinatal outdoor and indoor pollution, allergens and endotoxin) affect the incidence of allergic sensitization, AD, FA, and risk of asthma. Discussion The in-depth study of the ARIES birth cohort shall provide crucial information to understand the rising incidence of allergies and asthma in developing countries, and hopefully provide cues on how to prevent and treat these diseases. Trial registration clinicaltrials.gov NCT04186949, retrospectively registered on December 5, 2019.
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    Efectividad de las intervenciones en dieta y actividad física en mujeres con malnutrición por exceso durante el período preconcepcional sobre los resultados en la progenie: Una revisión de alcance.
    (2023) Izurieta Repenning, Javiera Paz; Casanello Toledo, Paola Cecilia; Pontificia Universidad Católica de Chile. Facultad de Medicina
    La obesidad es una enfermedad crónica no transmisible que predispone al desarrollo de otras enfermedades. Padecer esta condición al momento de la gestación aumenta el riesgo de desarrollar estas enfermedades en la descendencia. La evidencia disponible indica que las intervenciones en el periodo pregestacional en mujeres en edad fértil, especialmente aquellas que presentan malnutrición por exceso, tienen una magnitud de efecto positivo sobre la descendencia. A través de una revisión de alcance se recopiló evidencia del efecto de las intervenciones en dieta y actividad física en el periodo pregestacional en mujeres en edad fértil, que busquen o no un embarazo, que presenten malnutrición por exceso sobre los resultados perinatales en la progenie. Se utilizaron las bases de datos Web of Science y PubMed. Como resultado de esta investigación se concluyó que las intervenciones en actividad física y dieta en el período preconcepcional tienen efectos positivos en el feto y su vida postnatal. Intervenciones en dieta, además ayudan a disminuir el riesgo del bajo peso al nacer, niños pequeños y grandes para la edad gestacional. Tomar acciones sobre el cuidado preconcepcional es clave para combatir desde el inicio del ciclo de vida el riesgo de desarrollar enfermedades crónicas no transmisibles.
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    Effectiveness of a normative nutrition intervention (diet, physical activity and breastfeeding) on maternal nutrition and offspring growth : the Chilean maternal and infant nutrition cohort study (CHiMINCs)
    (2015) Casanello Toledo, Paola Cecilia; Kusanovic, Juan Pedro; Uauy, Ricardo; Garmendia, María Luisa.; Corvalán, Camila.; Araya, Marcela.
    Abstract Background Maternal obesity before and during pregnancy predicts maternal and infant risks of obesity and its associated metabolic conditions. Dietary and physical activity recommendations during pregnancy as well as weight monitoring are currently available in the Chilean primary health care system. However some of these recommendations are not updated and most of them are poorly implemented. We seek to assess the effectiveness of an intervention that enhances the implementation of updated nutrition health care standards (diet, physical activity, and breastfeeding promotion) during pregnancy on maternal weight gain and infant growth. Methods Design & Setting: Cluster randomized controlled trial. The cluster units will be 12 primary health care centers from two counties (La Florida and Puente Alto) from the South-East Area of Santiago randomly allocated to: 1) enhanced nutrition health care standards (intervention group) or 2) routine care (control group). Participants: Women seeking prenatal care before 15 weeks of gestation, residing within a catchment area of selected health centers, and who express that they are not planning to change residence will be invited to participate in the study. Pregnant women classified as high risk according to the Chilean norms (i.e age <16 or >40 years, multiple gestation, pre-gestational medical conditions, previous pregnancy-related issues) and/or underweight will be excluded. Intervention: Pregnant women who attend intervened health care centers starting at their first prenatal visit will receive advice regarding optimal weight gain during pregnancy and diet and physical activity counseling-support. Pregnant women who attend control health clinics will receive routine antenatal care according to national guidelines. We plan to recruit 200 women in each health center. Assuming a 20 % loss to follow up, we expect to include 960 women per arm. Main outcome measures: 1) Achievement of adequate weight gain based on IOM 2009 recommendations and adequate glycaemic control at 24-28 weeks of pregnancy according to ADA 2011, and 2) healthy infant growth during the first year of age based on WHO standards. Discussion We expect that the intervention will benefit the participants in achieving adequate weight gain & metabolic control during pregnancy as well as adequate infant growth as a result of an increased impact of standard nutrition and health care practices. Gathered information should contribute to a better understanding of how to develop effective interventions to halt the maternal obesity epidemic and its associated co-morbidities in the Chilean population. Trial registration Clinicaltrials.gov Identifier: NCT01916603
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    Effectiveness of a normative nutrition intervention in Chilean pregnant women on maternal and neonatal outcomes: the CHiMINCs study
    (2020) Garmendia, M. L.; Corvalán, C.; Araya, M.; Casanello Toledo, Paola Cecilia; Kusanovic, Juan Pedro; Uauy, Ricardo
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    Effectiveness on maternal and offspring metabolic control of a home-based dietary counseling intervention and DHA supplementation in obese/overweight pregnant women (MIGHT study) : a randomized controlled trial-Study protocol
    (2018) Garmendia, María Luisa; Corvalán, Camila; Casanello Toledo, Paola Cecilia; Araya, Marcela; Flores, Marcela; Bravo, Alfredo; Kusanovic, Juan Pedro; Olmos Coelho, Pablo Roberto; Uauy, Ricardo
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    Endothelial eNOS/arginase imbalance contributes to vascular dysfunction in IUGR umbilical and placental vessels
    (2013) Krause Leyton, Bernardo; Carrasco-Wong, I; Caniuguir, A.; Carvajal C., Jorge A.; Casanello Toledo, Paola Cecilia
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    Epigenética en enfermedades alérgicas y asma
    (2016) Castro Rodríguez, José Antonio; Krause Leyton, Bernardo; Uauy, Ricardo; Casanello Toledo, Paola Cecilia
    Las enfermedades alérgicas y el asma son el resultado de complejas interacciones entre la predisposición genética y factores ambientales. El asma es una de las enfermedades crónicas más prevalentes en niños. En este artículo se revisan algunos factores ambientales como la exposición a alérgenos, tabaco, bacterias, componentes microbianos, dieta, obesidad y estrés, que intervienen durante la vida intrauterina y la infancia en la regulación epigenética de las enfermedades alérgicas y el asma. La revisión se realiza en tres tipos de modelos: in-vitro, animales y humanos.
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    Epigenetics and obesity
    (2016) Casanello Toledo, Paola Cecilia; Krause Leyton, Bernardo; Castro Rodríguez, José Antonio; Uauy, Ricardo
    La evidencia indica que la exposición a diversas condiciones ambientales en etapas tempranas de la vida puede inducir alteraciones persistentes en el epigenoma. Los estudios epigenómicos en sujetos obesos han permitido evaluar el papel de los mecanismos epigenéticos en el origen y desarrollo de la obesidad. La presente revisión aborda estudios que dan cuenta de la asociación entre la obesidad y metilación global del genoma (ADN), analizando el potencial impacto de intervenciones previas y posteriores al nacimiento que afectan la metilación del ADN y la obesidad en etapas más avanzadas de la vida. Estudios realizados principalmente en leucocitos, han logrado identificar sitios del ADN diferencialmente metilados asociados con obesidad. Estudios hasta la fecha no han demostrado que dichos cambios en metilación sean revertidos luego de bajar de peso. Esto contrasta con resultados iniciales en este campo, que sugieren que existirían marcadores epigenéticos presentes desde el nacimiento que permitirían definir el riesgo de obesidad durante el curso de la vida. La evidencia actual sugiere que algunas marcas epigenéticas son modificables, basándonos en la exposición en la vida intrauterina y también por los hábitos dietarios y de actividad fisica durante las etapas del crecimiento y en la adultez. Esto sugiere que existe la oportunidad de intervenir durante la gestación o en la vida posnatal temprana, que modificaría los perfiles epigenéticos desfavorables e idealmente contribuiría a prevenir la obesidad en los sujetos o poblaciones susceptibles. La evidencia indica que la exposición a diversas condiciones ambientales en etapas tempranas de la vida puede inducir alteraciones persistentes en el epigenoma. Los estudios epigenómicos en sujetos obesos han permitido evaluar el papel de los mecanismos epigenéticos en el origen y desarrollo de la obesidad. La presente revisión aborda estudios que dan cuenta de la asociación entre la obesidad y metilación global del genoma (ADN), analizando el potencial impacto de intervenciones previas y posteriores al nacimiento que afectan la metilación del ADN y la obesidad en etapas más avanzadas de la vida. Estudios realizados principalmente en leucocitos, han logrado identificar sitios del ADN diferencialmente metilados asociados con obesidad. Estudios hasta la fecha no han demostrado que dichos cambios en metilación sean revertidos luego de bajar de peso. Esto contrasta con resultados iniciales en este campo, que sugieren que existirían marcadores epigenéticos presentes desde el nacimiento que permitirían definir el riesgo de obesidad durante el curso de la vida. La evidencia actual sugiere que algunas marcas epigenéticas son modificables, basándonos en la exposición en la vida intrauterina y también por los hábitos dietarios y de actividad fisica durante las etapas del crecimiento y en la adultez. Esto sugiere que existe la oportunidad de intervenir durante la gestación o en la vida posnatal temprana, que modificaría los perfiles epigenéticos desfavorables e idealmente contribuiría a prevenir la obesidad en los sujetos o poblaciones susceptibles.
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    Equilibrative nucleoside transporters in fetal endothelial dysfunction in diabetes mellitus and hyperglycaemia
    (2009) Westermeier Lafuente, Francisco David; Puebla Aracena, Carlos Alberto; Vega Pizarro, José Luis Eduardo; Farías Jofré, Marcelo Enrique; Escudero Orozco, Carlos Alonso; Casanello Toledo, Paola Cecilia; Sobrevía Luarte, Luis Alberto
    Diabetes mellitus types 1 and 2, and gestational diabetes are characterized by abnormal D-glucose metabolism and hyperglycaemia, and induce foetal endothelial dysfunction with implications in adult life increasing the risk of vascular diseases. Synthesis of nitric oxide (NO) and uptake of L-arginine (i.e. the L-arginine/NO signalling pathway) and adenosine (a vasoactive endogenous nucleoside) by the umbilical vein endothelium is altered in pathological pregnancies, including pregnancies with pre-established diabetes mellitus or in gestational diabetes. The mechanisms underlying these alterations include differential expression of equilibrative nucleoside transporters (ENTs), amino acid transporters and NO synthases (NOS). Modulation of ENTs and NOS expression and activity in endothelium involves several signalling molecules, including protein kinase C, mitogen-activated protein kinases p42 and p44, calcium and phosphatidyl inositol 3 kinase. Elevated extracellular D-glucose and diabetes alters human endothelial function. However, information regarding modulation the transport capacity as well as expression of ENTs is limited. This review focuses on the effect of diabetes mellitus and gestational diabetes, and hyperglycaemia on the reported mechanisms described for transcriptional and posttranscriptional regulation of ENTs, and the potential consequences for foetal endothelial function in these pathologies. Recent available information regarding functional consequences of an abnormal environment on the functionality of the endothelium from microvasculature of the human placenta is mentioned. The available information is scarce, but it could contribute to a better understanding of the cell and molecular basis of the altered vascular endothelial function in this pathological conditions, emphasizing the key role of this type of epithelium in fetal-placental function and the normal foetal development and growth.