Browsing by Author "Sáez Pedraza, Pablo José"
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- ItemDisruption in connexin-based communication is associated with intracellular Ca²⁺ signal alterations in astrocytes from Niemann-Pick type C mice(2013) Sáez Pedraza, Pablo José; Orellana Roca, Juan Andrés; Vega-Riveros, Natalia; Figueroa, Vania A.; Hernández Trejo, Diego Eduardo; Castro, Juan Francisco; Klein Posternack, Andrés David; Jean X. Jiang; Zanlungo Matsuhiro, Silvana; Sáez Carreño, Juan CarlosReduced astrocytic gap junctional communication and enhanced hemichannel activity were recently shown to increase astroglial and neuronal vulnerability to neuroinflammation. Moreover, increasing evidence suggests that neuroinflammation plays a pivotal role in the development of Niemann-Pick type C (NPC) disease, an autosomal lethal neurodegenerative disorder that is mainly caused by mutations in the NPC1 gene. Therefore, we investigated whether the lack of NPC1 expression in murine astrocytes affects the functional state of gap junction channels and hemichannels. Cultured cortical astrocytes of NPC1 knock-out mice (Npc1⁻/⁻) showed reduced intercellular communication via gap junctions and increased hemichannel activity. Similarly, astrocytes of newborn Npc1⁻/⁻ hippocampal slices presented high hemichannel activity, which was completely abrogated by connexin 43 hemichannel blockers and was resistant to inhibitors of pannexin 1 hemichannels. Npc1⁻/⁻ astrocytes also showed more intracellular Ca²⁺ signal oscillations mediated by functional connexin 43 hemichannels and P2Y₁ receptors. Therefore, Npc1⁻/⁻ astrocytes present features of connexin based channels compatible with those of reactive astrocytes and hemichannels might be a novel therapeutic target to reduce neuroinflammation in NPC disease.
- ItemEndothelial dysfunction and reduced insulin response in umbilical vein from the offspring of maternal obesity pregnancies(2016) Villalobos Labra, Roberto Esteban; Pizarro, Carolina; Westermeier Lafuente, Francisco David; Sáez Pedraza, Pablo José; Sobrevía Luarte, Luis Alberto; Farías Jofré, Marcelo EnriqueINTRODUCTION: Maternal obesity (MO) has been recognized as a risk factor for maternal and fetal complications, including offspring´s insulin resistance (IR) later in life. We evaluated the effect of MO in endothelial cells function and umbilical vein vasodilatation in response to insulin. METHODS: Primary cultures of human umbilical vein endothelial cells (HUVEC) and rings were isolated from normal (HUVEC-N) or MO (HUVEC-OB) pregnancies attending to Pontificia Universidad Católica de Chile Hospital. Total and/or phosphorylated level of IRS-1, Akt, MAPK and eNOS, were measured by western blot in protein extracts of cells exposed to insulin (1 nM, 30 min). Wire myography was used to evaluate functional effect of insulin in umbilical vein rings. Cellular nitric oxide (NO) availability was measured using the fluorescent probe diaminofluorescein (DAF). Values are Mean±S.E.M. RESULTS: MO was associated with inhibition of IRS-1 and reduced phosphorylation of Akt (2,24±0,06 vs 6,85±0,12; p<0,01) and MAPK (4,13±0,65 vs 13,12±1,67; p<0,01) in response to insulin, in HUVEC. We found that total eNOS and the activating phosphorylation on Ser1177 was reduced (0,98±0,03 vs 5,45±0,85; p<0,01) in HUVEC-OB compared to HUVEC-N. Conversely, the inhibitory phosphorylation on Thr495 was increased (1,88±0,08 vs 1,51±0,14; p<0,01) in HUVEC-OB. Also, HUVEC-N exposed to insulin (1nM) showed increased levels of NO at 5, 15 and 30 min of incubation, an effect blocked by the inhibitor of NOS L-NAME. In contrast, insulin did not increase NO production in HUVECOB. Finally, vein rings from MO showed abolished relaxation in response to insulin, meanwhile rings from normal pregnancies showed a 20% of insulin dilator effect, which was blocked by L-NAME. CONCLUSIONS: We have shown evidence that MO promotes less vasodilation of umbilical vein in response to insulin, due to an inhibitory state of insulin signaling and eNOS activation, with the consequent absence of insulin-dependent NO production by HUVEC affected by MO.
- ItemHuman mesenchymal stem cells derived from adipose tissue reduce functional and tissue damage in a rat model of chronic renal failure.(2013) Villanueva, S.; Céspedes Fierro, Carlos Mauricio.; Sáez Pedraza, Pablo José; Vio Lagos, Carlos P.
- ItemLinoleic acid induces opening of connexin26 hemichannels through a PI3K/Akt/Ca2+-dependent pathway(2013) Figueroa, V.; Sáez Pedraza, Pablo José; Salas Andrade, Daniela Paz.; Sáez, Juan Carlos
- ItemMaternal obesity and neonatal insulin resistance in the origin of metabolic syndrome in childhood(2013) Farías Jofré, Marcelo Enrique; Villalobos Labra, Roberto Esteban; Sáez Pedraza, Pablo José; Westermeier Lafuente, Francisco David; Poblete Lizana, José Andrés; Kusanovic, Juan Pedro; Mardones S., Francisco; Sobrevía Luarte, Luis AlbertoObesity during pregnancy has been recognized as an independent risk factor for maternal and fetal complications, including congenital anomalies, gestational diabetes mellitus, gestational hypertension and preeclampsia, caesarean delivery, macrosomia (birth weight > 4000 g), increased neonatal adiposity and hyperinsulinemia. In addition to perinatal complications associated to maternal obesity, rising epidemiological evidence has suggested the intrauterine programming of whole body insulin resistance (IR) in the offspring of obese pregnant woman, evaluated both at early neonatal stage and at young adulthood. Our cohort data showed association among elevated neonatal anthropometry measurements (birth weight and height) and increased levels of waist circumpherence and blood pressure in childohood, two components of the metabolic syndrome (MetS). In the other hand, the homeostasis model assesment index of insulin resistance (HOMA-IR) was correlated to the number of MetS components in this population. In order to describe potential mechanisms of relationship between maternal obesity and future development of MetS, we have evaluated modulators of neonatal insulin signaling pathway in human and animal models of maternal obesity. We have found increased levels of neonatal insulin secretion (serum C-peptide) and sub-clinical markers of cellular insulin resistance and endoplasmic reticulum stress (ER-stress) in offsprings of women with maternal weight excess. The ER stress response has been related to IR and diabetes mellitus development in multiple models of obesity. Thus, a mechanistic link could be proposed between maternal obesity, ER stress and IR in fetal tissues as part of the physiopathology route that connects abnormal intrauterine nutrition with elevated risk of MetS in childhood.
- ItemMesenchymal stem cell injection ameliorates chronic renal failure in a rat model(2011) Villanueva, S.; Céspedes Fierro, Carlos Mauricio.; Sáez Pedraza, Pablo José; Vio Lagos, Carlos P.
- ItemNeonates from women with pregestational maternal obesity show reduced umbilical vein endothelial response to insulin(2019) Villalobos Labra, Roberto Esteban; Westermeier, F.; Pizarro, C.; Sáez Pedraza, Pablo José; Pardo, F.; Kusanovic, Juan Pedro; Mardones, Francisco; Poblete L., José A.; Sobrevía Luarte, Luis Alberto; Farías Jofré, Marcelo Enrique; Toledo, F.
- ItemOpening of pannexin- and con nexin-based channels increases the excitability of nodose ganglion sensory neurons(2014) Retamal Lucero, Mauricio Antonio.; Sáez Pedraza, Pablo José; Sáez, Juan Carlos
- ItemPannexin1 channels act downstream of P2X 7 receptors in ATP-induced murine T-cell death(2014) Shoji, Kenji F.; Sáez Pedraza, Pablo José; Harcha, Paloma A.; Aguila, Hector L.; Sáez, Juan Carlos
- ItemPannexin1 channels act downstream of P2X(7) receptors in ATP-induced murine T-cell death(2014) Shoji Sánchez, Kenji Fabricio.; Sáez Pedraza, Pablo José; Harcha Soazo, Paloma Andrea; Sáez, Juan Carlos
- ItemRegulation of Hemichannels and Gap Junction Channels by Cytokines in Antigen-Presenting Cells(2014) Sáez Pedraza, Pablo José; Shoji Sánchez, Kenji Fabricio.; Aguirre Ducler, Adam Jesús; Sáez, Juan Carlos