Examinando por Autor "Olivares, Pedro"
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Ítem Green by design: Convergent synthesis, computational analyses, and activity evaluation of new fxa inhibitors bearing peptide triazole linking units(MDPI, 2022-01) Rodríguez, Diego F.; Durán-Osorio, Francisca; Duarte, Yorley; Olivares, Pedro; Moglie, Yanina; Dua, Kamal; Zacconi, Flavia C.Green chemistry implementation has led to promising results in waste reduction in the pharmaceutical industry. However, the early sustainable development of pharmaceutically active compounds and ingredients remains a considerable challenge. Herein, we wish to report a green synthesis of new pharmaceutically active peptide triazoles as potent factor Xa inhibitors, an important drug target associated with the treatment of diverse cardiovascular diseases. The new inhibitors were synthesized in three steps, featuring cycloaddition reactions (high atom economy), microwave-assisted organic synthesis (energy efficiency), and copper nanoparticle catalysis, thus featuring Earth-abundant metals. The molecules obtained showed FXa inhibition, with IC50-values as low as 17.2 μM and no associated cytotoxicity in HEK293 and HeLa cells. These results showcase the environmental potential and chemical implications of the applied methodologies for the development of new molecules with pharmacological potential.Ítem Multicomponent synthesis and photophysical study of novel α,β-unsaturated carbonyl depsipeptides and peptoids(Frontiers Media SA, 2023) González, Ricelia; Murillo-López, Juliana; Rabanal-León, Walter; Prent-Peñaloza, Luis; Concepción, Odette; Olivares, Pedro; Duarte, Yorley; de la Torre, Alexander F.; Gutiérrez, Margarita; Caballero, JulioMulticomponent reactions were performed to develop novel α,β-unsaturated carbonyl depsipeptides and peptoids incorporating various chromophores such as cinnamic, coumarin, and quinolines. Thus, through the Passerini and Ugi multicomponent reactions (P-3CR and U-4CR), we obtained thirteen depsipeptides and peptoids in moderate to high yield following the established protocol and fundamentally varying the electron-rich carboxylic acid as reactants. UV/Vis spectroscopy was utilized to study the photophysical properties of the newly synthesized compounds. Differences between the carbonyl-substituted chromophores cause differences in electron delocalization that can be captured in the spectra. The near UV regions of all the compounds exhibited strong absorption bands. Compounds P2, P5, U2, U5, and U7 displayed absorption bands in the range of 250–350 nm, absorbing radiation in this broad region of the electromagnetic spectrum. A photostability study for U5 showed that its molecular structure does not change after exposure to UV radiation. Fluorescence analysis showed an incipient emission of U5, while U6 showed blue fluorescence under UV radiation. The photophysical properties and electronic structure were also determined by TD-DFT theoretical study. Copyright © 2023 González, Murillo-López, Rabanal-León, Prent-Peñaloza, Concepción, Olivares, Duarte, de la Torre, Gutiérrez and Caballero.Ítem Preventive Leptin Administration Protects Against Sepsis Through Improving Hypotension, Tachycardia, Oxidative Stress Burst, Multiple Organ Dysfunction, and Increasing Survival(Frontiers Media S.A., 2018-12) Vallejos, Alejandro; Olivares, Pedro; Varela, Diego; Echeverria, Cesar; Cabello Verrugio, Claudio; Pérez Leighton, Claudio; Simon, FelipeSepsis syndrome is the most important cause of mortality in critically ill patients admitted to intensive care units (ICUs). However, current therapies for its prevention and treatment are still unsatisfactory, and the mortality rate is still high. Non-septic ICU patients are vulnerable to acquire sepsis syndrome. Thus, a preventive treatment for this population is needed. During sepsis syndrome and endotoxemia, severe hypotension, tachycardia, oxidative and immune response increase, multiple organ dysfunction syndrome (MODS) and decreased survival are observed. Leptin administration protects against negative effects of sepsis syndrome and endotoxemia. Furthermore, it is has been reported that leptin elevates blood pressure mediated by sympathetic nervous system activation. However, whether leptin administration before sepsis induction mediates its protective effects during sepsis through blood pressure regulation is not known. Therefore, we investigated whether pre-treatment of leptin improves blood pressure and MODS, resulting in survival increase during endotoxemia. The results showed that leptin administration before endotoxemia induction reduced both the hypotension and tachycardia characteristically observed during endotoxemia. Notably, this protective effect was observed early and late in the course of endotoxemia. Endotoxemia-induced MODS decreased in leptin-treated rats, which was reflected in normal values for liver and kidney function, inhibition of muscle mass wasting and maintenance of glycemia. Furthermore, leptin pre-treatment decreased the oxidative stress burst in blood and blunted the increased pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 observed during endotoxemia. Remarkably, according to the leptin-induced increase in survival, leptin pre-administration decreased the risk for death associated with sepsis syndrome at early and late times after endotoxemia induction. These results show a potential preventive therapy against sepsis syndrome and endotoxemia in vulnerable patients, based in the beneficial actions of leptin. © Copyright © 2018 Vallejos, Olivares, Varela, Echeverria, Cabello-Verrugio, Pérez-Leighton and Simon.Ítem TRPM7 mediates kidney injury, endothelial hyperpermeability and mortality during endotoxemia(Springer Nature, 2020-02) Gatica, Sebastian; Villegas, Vicente; Vallejos, Alejandro; Olivares, Pedro; Aballai, Víctor; Lagos-Meza, Felipe; Echeverria, Cesar; Cabello-Verrugio, Claudio; Varela, Diego; Simon, Felipeepsis is the main cause of mortality in patients admitted to intensive care units. During sepsis, endothelial permeability is severely augmented, contributing to renal dysfunction and patient mortality. Ca2+ influx and the subsequent increase in intracellular [Ca2+]i in endothelial cells (ECs) are key steps in the establishment of endothelial hyperpermeability. Transient receptor potential melastatin 7 (TRPM7) ion channels are permeable to Ca2+ and are expressed in a broad range of cell types and tissues, including ECs and kidneys. However, the role of TRPM7 on endothelial hyperpermeability during sepsis has remained elusive. Therefore, we investigated the participation of TRPM7 in renal vascular hyperpermeability, renal dysfunction, and enhanced mortality induced by endotoxemia. Our results showed that endotoxin increases endothelial hyperpermeability and Ca2+ overload through the TLR4/NOX-2/ROS/NF-κB pathway. Moreover, endotoxin exposure was shown to downregulate the expression of VE-cadherin, compromising monolayer integrity and enhancing vascular hyperpermeability. Notably, endotoxin-induced endothelial hyperpermeability was substantially inhibited by pharmacological inhibition and specific suppression of TRPM7 expression. The endotoxin was shown to upregulate the expression of TRPM7 via the TLR4/NOX-2/ROS/NF-κB pathway and induce a TRPM7-dependent EC Ca2+ overload. Remarkably, in vivo experiments performed in endotoxemic animals showed that pharmacological inhibition and specific suppression of TRPM7 expression inhibits renal vascular hyperpermeability, prevents kidney dysfunction, and improves survival in endotoxemic animals. Therefore, our results showed that TRPM7 mediates endotoxemia-induced endothelial hyperpermeability, renal dysfunction, and enhanced mortality, revealing a novel molecular target for treating renal vascular hyperpermeability and kidney dysfunction during endotoxemia, sepsis, and other inflammatory diseases. © 2019, United States & Canadian Academy of Pathology.Ítem TRPM7 mediates kidney injury, endothelial hyperpermeability and mortality during endotoxemia(Springer Nature, 2020-02) Gatica, Sebastian; Villegas, Vicente; Vallejos, Alejandro; Olivares, Pedro; Aballai, Víctor; Lagos-Meza, Felipe; Echeverria, Cesar; Cabello-Verrugio, Claudio; Varela, Diego; Simon, FelipeSepsis is the main cause of mortality in patients admitted to intensive care units. During sepsis, endothelial permeability is severely augmented, contributing to renal dysfunction and patient mortality. Ca2+ influx and the subsequent increase in intracellular [Ca2+]i in endothelial cells (ECs) are key steps in the establishment of endothelial hyperpermeability. Transient receptor potential melastatin 7 (TRPM7) ion channels are permeable to Ca2+ and are expressed in a broad range of cell types and tissues, including ECs and kidneys. However, the role of TRPM7 on endothelial hyperpermeability during sepsis has remained elusive. Therefore, we investigated the participation of TRPM7 in renal vascular hyperpermeability, renal dysfunction, and enhanced mortality induced by endotoxemia. Our results showed that endotoxin increases endothelial hyperpermeability and Ca2+ overload through the TLR4/NOX-2/ROS/NF-κB pathway. Moreover, endotoxin exposure was shown to downregulate the expression of VE-cadherin, compromising monolayer integrity and enhancing vascular hyperpermeability. Notably, endotoxin-induced endothelial hyperpermeability was substantially inhibited by pharmacological inhibition and specific suppression of TRPM7 expression. The endotoxin was shown to upregulate the expression of TRPM7 via the TLR4/NOX-2/ROS/NF-κB pathway and induce a TRPM7-dependent EC Ca2+ overload. Remarkably, in vivo experiments performed in endotoxemic animals showed that pharmacological inhibition and specific suppression of TRPM7 expression inhibits renal vascular hyperpermeability, prevents kidney dysfunction, and improves survival in endotoxemic animals. Therefore, our results showed that TRPM7 mediates endotoxemia-induced endothelial hyperpermeability, renal dysfunction, and enhanced mortality, revealing a novel molecular target for treating renal vascular hyperpermeability and kidney dysfunction during endotoxemia, sepsis, and other inflammatory diseases. © 2019, United States & Canadian Academy of Pathology.