3 research outputs found

    Chemotherapeutic effect of SR9009, a REV-ERB agonist, on the human glioblastoma T98G cells

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    Glioblastoma multiforme is the most aggressive brain tumor, and human T98G cells constitute a useful glioblastoma multiforme model to evaluate the chemotherapeutic agents. Modern life (shiftwork, jetlag, etc.) may cause circadian disorganization promoting higher cancer risk and metabolic disorders. Although little is known about the tumor-intrinsic circadian clock function, pharmacological modulation of circadian components may offer selective anticancer strategies. REV-ERBs are heme-binding circadian clock components acting as repressors of processes involved in tumorigenesis such as metabolism, proliferation, and inflammation. A synthetic pyrrole derivative (SR9009) that acts as REV-ERBs-specific agonists exhibits potent in vivo activity on metabolism and tumor cell viability. Here, we investigated SR9009 effects on T98G cell viability, differential chemotherapy time responses, and underlying metabolic processes (reactive oxygen species [ROS] and lipid droplets [LDs]) and compared it with the proteasome inhibitor Bortezomib treatment. SR9009-treated cells exhibited significant reduction in cell viability with consequences on cell cycle progression. Dexamethasone synchronized cells displayed differential time responses to SR9009 treatment with highest responses 18 to 30 h after synchronization. SR9009 treatment decreased ROS levels while Bortezomib increased them. However, both treatments significantly increased LD levels, whereas the combined treatment showed additive or synergistic effects between both drugs. In addition, we extended these studies to HepG2 cells which also showed a significant decrease in cell viability and ROS levels and the increase in LD levels after SR9009 treatment. Our results suggest that the pharmacological modulation of the tumor-intrinsic clock by REV-ERB agonists severely affects cell metabolism and promotes cytotoxic effects on cancer cells.Fil: Wagner, Paula Micaela. Consejo Nacional de Investigaciones Cient铆ficas y T茅cnicas. Centro Cient铆fico Tecnol贸gico Conicet - C贸rdoba. Centro de Investigaciones en Qu铆mica Biol贸gica de C贸rdoba. Universidad Nacional de C贸rdoba. Facultad de Ciencias Qu铆micas. Centro de Investigaciones en Qu铆mica Biol贸gica de C贸rdoba; ArgentinaFil: Monjes, Natalia Maribel. Consejo Nacional de Investigaciones Cient铆ficas y T茅cnicas. Centro Cient铆fico Tecnol贸gico Conicet - C贸rdoba. Centro de Investigaciones en Qu铆mica Biol贸gica de C贸rdoba. Universidad Nacional de C贸rdoba. Facultad de Ciencias Qu铆micas. Centro de Investigaciones en Qu铆mica Biol贸gica de C贸rdoba; ArgentinaFil: Guido, Mario Eduardo. Consejo Nacional de Investigaciones Cient铆ficas y T茅cnicas. Centro Cient铆fico Tecnol贸gico Conicet - C贸rdoba. Centro de Investigaciones en Qu铆mica Biol贸gica de C贸rdoba. Universidad Nacional de C贸rdoba. Facultad de Ciencias Qu铆micas. Centro de Investigaciones en Qu铆mica Biol贸gica de C贸rdoba; Argentin

    Circadian Regulation and Clock-Controlled Mechanisms of Glycerophospholipid Metabolism from Neuronal Cells and Tissues to Fibroblasts

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    Along evolution, living organisms developed a precise timekeeping system, circadian clocks, to adapt life to the 24-h light/dark cycle and temporally regulate physiology and behavior. The transcriptional molecular circadian clock and metabolic/redox oscillator conforming these clocks are present in organs, tissues, and even in individual cells, where they exert circadian control over cellular metabolism. Disruption of the molecular clock may cause metabolic disorders and higher cancer risk. The synthesis and degradation of glycerophospholipids (GPLs) is one of the most highly regulated metabolisms across the 24-h cycle in terms of total lipid content and enzyme expression and activity in the nervous system and individual cells. Lipids play a plethora of roles (membrane biogenesis, energy sourcing, signaling, and the regulation of protein-chromatin interaction, among others), making control of their metabolism a vital checkpoint in the cellular organization of physiology. An increasing body of evidence clearly demonstrates an orchestrated and sequential series of events occurring in GPL metabolism across the 24-h day in diverse retinal cell layers, immortalized fibroblasts, and glioma cells. Moreover, the clock gene Per1 and other circadian-related genes are tightly involved in the regulation of GPL synthesis in quiescent cells. However, under proliferation, the metabolic oscillator continues to control GPL metabolism of brain cancer cells even after molecular circadian clock disruption, reflecting the crucial role of the temporal metabolism organization in cell preservation. The aim of this review is to examine the control exerted by circadian clocks over GPL metabolism, their synthesizing enzyme expression and activities in normal and tumorous cells of the nervous system and in immortalized fibroblasts.Fil: Guido, Mario Eduardo. Consejo Nacional de Investigaciones Cient铆ficas y T茅cnicas. Centro Cient铆fico Tecnol贸gico Conicet - C贸rdoba. Centro de Investigaciones en Qu铆mica Biol贸gica de C贸rdoba. Universidad Nacional de C贸rdoba. Facultad de Ciencias Qu铆micas. Centro de Investigaciones en Qu铆mica Biol贸gica de C贸rdoba; Argentina. Universidad Nacional de C贸rdoba. Facultad de Ciencias Qu铆micas. Departamento de Qu铆mica Biol贸gica; ArgentinaFil: Monjes, Natalia Maribel. Consejo Nacional de Investigaciones Cient铆ficas y T茅cnicas. Centro Cient铆fico Tecnol贸gico Conicet - C贸rdoba. Centro de Investigaciones en Qu铆mica Biol贸gica de C贸rdoba. Universidad Nacional de C贸rdoba. Facultad de Ciencias Qu铆micas. Centro de Investigaciones en Qu铆mica Biol贸gica de C贸rdoba; Argentina. Universidad Nacional de C贸rdoba. Facultad de Ciencias Qu铆micas. Departamento de Qu铆mica Biol贸gica; ArgentinaFil: Wagner, Paula Micaela. Consejo Nacional de Investigaciones Cient铆ficas y T茅cnicas. Centro Cient铆fico Tecnol贸gico Conicet - C贸rdoba. Centro de Investigaciones en Qu铆mica Biol贸gica de C贸rdoba. Universidad Nacional de C贸rdoba. Facultad de Ciencias Qu铆micas. Centro de Investigaciones en Qu铆mica Biol贸gica de C贸rdoba; Argentina. Universidad Nacional de C贸rdoba. Facultad de Ciencias Qu铆micas. Departamento de Qu铆mica Biol贸gica; ArgentinaFil: Salvador, Gabriela Alejandra. Consejo Nacional de Investigaciones Cient铆ficas y T茅cnicas. Centro Cient铆fico Tecnol贸gico Conicet - Bah铆a Blanca. Instituto de Investigaciones Bioqu铆micas de Bah铆a Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioqu铆micas de Bah铆a Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biolog铆a, Bioqu铆mica y Farmacia; Argentin

    Tobacco hairy root's peroxidases are rhythmically controlled by phenol exposure

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    Plants like almost all living organisms, have developed a biological clock or circadian clock (CC) capable of synchronizing and adjusting various metabolic and physiological processes at certain times of the day and in a period of 24 h. This endogenous timekeeping is able to predict the environmental changes providing adaptive advantages against stressful conditions. Therefore, the aim of this work was to analyze the possible link between metabolism of xenobiotic compounds (MXC) and the CC. Synchronized Nicotiana tabacum hairy roots (HRs) were used as a validated plant model system, and peroxidases (PODs), key enzymes of the phase I in the MCX, were evaluated after phenol treatment. Two POD genes were selected and their temporal expression profiles as well as the total POD activity were analyzed in order to find circadian oscillations either under control conditions or phenol treatment. It was demonstrated that these PODs genes showed oscillatory profiles with an ultradian period (period length shorter than the circadian period), and preserving the same phases and expression peaks still under phenol treatment. The total PODs activity showed also a marked oscillatory behavior mainly in phenol-treated HRs with the highest levels at ZT23. Untreated HRs showed decrease and increase in the intensity of some basic isoforms at light and dark phase, respectively, while in phenol- treated HRs, an increase in the intensity of almost all isoforms was observed, mainly during the dark phase, being coincident with the high PODs activity detected at ZT23. The periodic analysis determined an ultradian period either in total POD activity or in the POD activity of isoform VI, being 18.7 and 15.3 h, respectively. Curiously, in phenol treated HRs, the period length of total POD activity was longer than in untreated HRs, suggesting that phenol could induce a marked oscillatory behavior in the POD activity with better performance during the dark phase, which explain the higher phenol removal efficiencies at ZT23. These findings showed novel information about the performance of PODs, which would be rhythmically controlled at biochemical level, by phenol exposure.Fil: Sosa Alderete, Lucas Gast贸n. Universidad Nacional de Rio Cuarto. Facultad de Cs.exactas Fisicoquimicas y Naturales. Instituto de Biotecnologia Ambiental y Salud. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Cordoba. Instituto de Biotecnologia Ambiental y Salud.; Argentina. Universidad Nacional de R铆o Cuarto. Facultad de Ciencias Exactas Fisicoqu铆micas y Naturales. Departamento de Biolog铆a Molecular; ArgentinaFil: Ronchi, Hebe Luz. Universidad Nacional de Rio Cuarto. Facultad de Cs.exactas Fisicoquimicas y Naturales. Instituto de Biotecnologia Ambiental y Salud. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Cordoba. Instituto de Biotecnologia Ambiental y Salud.; Argentina. Universidad Nacional de R铆o Cuarto. Facultad de Ciencias Exactas Fisicoqu铆micas y Naturales. Departamento de Biolog铆a Molecular; ArgentinaFil: Monjes, Natalia Maribel. Consejo Nacional de Investigaciones Cient铆ficas y T茅cnicas. Centro Cient铆fico Tecnol贸gico Conicet - C贸rdoba. Centro de Investigaciones en Qu铆mica Biol贸gica de C贸rdoba. Universidad Nacional de C贸rdoba. Facultad de Ciencias Qu铆micas. Centro de Investigaciones en Qu铆mica Biol贸gica de C贸rdoba; Argentina. Universidad Nacional de C贸rdoba. Facultad de Ciencias Qu铆micas. Departamento de Qu铆mica Biol贸gica; ArgentinaFil: Agostini, Elizabeth. Universidad Nacional de Rio Cuarto. Facultad de Cs.exactas Fisicoquimicas y Naturales. Instituto de Biotecnologia Ambiental y Salud. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Cordoba. Instituto de Biotecnologia Ambiental y Salud.; Argentina. Universidad Nacional de R铆o Cuarto. Facultad de Ciencias Exactas Fisicoqu铆micas y Naturales. Departamento de Biolog铆a Molecular; Argentin
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