Authors: Slat, Emily A.; Sponagel, Jasmin; Marpegan, Luciano; Simon, Tatiana; Kfoury, Najla; Kim, Albert; Binz, Andrea; Herzog, Erik D.; Rubin, Joshua B.
Publication Date: 2017.
Language: English.
Abstract:
The safety and efficacy of chemotherapeutics can vary as a function of the time of their delivery during the day. This study aimed to improve the treatment of glioblastoma (GBM), the most common brain cancer, by testing whether the efficacy of the DNA alkylator temozolomide (TMZ) varies with the time of its administration. We found cell-intrinsic, daily rhythms in both human and mouse GBM cells. Circadian time of treatment affected TMZ sensitivity of murine GBM tumor cells in vitro. The maximum TMZ-induced DNA damage response, activation of apoptosis, and growth inhibition occurred near the daily peak in expression of the core clock gene Bmal1. Deletion of Bmal1 (Arntl) abolished circadian rhythms in gene expression and TMZ-induced activation of apoptosis and growth inhibition. These data indicate that tumor cell-intrinsic circadian rhythms are common to GBM tumors and can regulate TMZ cytotoxicity. Optimization of GBM treatment by timing TMZ administration to daily rhythms should be evaluated in prospective clinical trials.
Author affiliation: Slat, Emily A.. Washington University in St. Louis; Estados Unidos
Author affiliation: Sponagel, Jasmin. Washington University in St. Louis; Estados Unidos
Author affiliation: Marpegan, Luciano. Washington University in St. Louis; Estados Unidos. Universidad Nacional de Quilmes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Author affiliation: Simon, Tatiana. Washington University in St. Louis; Estados Unidos
Author affiliation: Kfoury, Najla. Washington University in St. Louis; Estados Unidos
Author affiliation: Kim, Albert. Washington University in St. Louis; Estados Unidos
Author affiliation: Binz, Andrea. Washington University in St. Louis; Estados Unidos
Author affiliation: Herzog, Erik D.. Washington University in St. Louis; Estados Unidos
Author affiliation: Rubin, Joshua B.. Washington University in St. Louis; Estados Unidos
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Authors: Duhart, José Manuel; Brocardo, Lucila; Caldart Valle, Carlos Sebastian; Marpegan, Luciano; Golombek, Diego Andrés
Publication Date: 2017.
Language: English.
Abstract:
The mammalian circadian system is controlled by a central oscillator located in the suprachiasmatic nuclei (SCN) of the hypothalamus, in which glia appears to play a prominent role. Gliomas originate from glial cells and are the primary brain tumors with the highest incidence and mortality. Optic pathway/hypothalamic gliomas account for 4-7% of all pediatric intracranial tumors. Given the anatomical location, which compromises both the circadian pacemaker and its photic input pathway, we decided to study whether the presence of gliomas in the hypothalamic region could alter circadian behavioral outputs. Athymic nude mice implanted with LN229 human glioma cells showed an increase in the endogenous period of the circadian clock, which was also less robust in terms of sustaining the free running period throughout 2 weeks of screening. We also found that implanted mice showed a slower resynchronization rate after an abrupt 6 h advance of the light-dark (LD) cycle, advanced phase angle, and a decreased direct effect of light in general activity (masking), indicating that hypothalamic tumors could also affect photic sensitivity of the circadian clock. Our work suggests that hypothalamic gliomas have a clear impact both on the endogenous pacemaking of the circadian system, as well as on the photic synchronization of the clock. These findings strongly suggest that the observation of altered circadian parameters in patients might be of relevance for glioma diagnosis.
Author affiliation: Duhart, José Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina
Author affiliation: Brocardo, Lucila. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina
Author affiliation: Caldart Valle, Carlos Sebastian. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina
Author affiliation: Marpegan, Luciano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina
Author affiliation: Golombek, Diego Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Authors: Tinkum, Kelsey L.; White, Lynn S.; Marpegan, Luciano; Herzog, Erik; Piwnica Worms, David; Piwnica Worms, Helen
Publication Date: 2013.
Language: English.
Abstract:
Reporter mice that enable the activity of the endogenous p21 promoter to be dynamically monitored in real time in vivo and under a variety of experimental conditions revealed ubiquitous p21 expression in mouse organs including the brain. Low light bioluminescence microscopy was employed to localize p21 expression to specific regions of the brain. Interestingly, p21 expression was observed in the paraventricular, arcuate, and dorsomedial nuclei of the hypothalamus, regions that detect nutrient levels in the blood stream and signal metabolic actions throughout the body. These results suggested a link between p21 expression and metabolic regulation. We found that short-term food deprivation (fasting) potently induced p21 expression in tissues involved in metabolic regulation including liver, pancreas and hypothalamic nuclei. Conditional reporter mice were generated that enabled hepatocyte-specific expression of p21 to be monitored in vivo. Bioluminescence imaging demonstrated that fasting induced a 7-fold increase in p21 expression in livers of reporter mice and Western blotting demonstrated an increase in protein levels as well. The ability of fasting to induce p21 expression was found to be independent of p53 but dependent on FOXO1. Finally, occupancy of the endogenous p21 promoter by FOXO1 was observed in the livers of fasted but not fed mice. Thus, fasting promotes loading of FOXO1 onto the p21 promoter to induce p21 expression in hepatocytes.
Author affiliation: Tinkum, Kelsey L.. BRIGHT Institute; Estados Unidos. Mallinckrodt Institute of Radiology; Estados Unidos
Author affiliation: White, Lynn S.. Mallinckrodt Institute of Radiology; Estados Unidos. BRIGHT Institute; Estados Unidos
Author affiliation: Marpegan, Luciano. University of Washington; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Author affiliation: Herzog, Erik. University of Washington; Estados Unidos
Author affiliation: Piwnica Worms, David. Mallinckrodt Institute of Radiology; Estados Unidos. BRIGHT Institute; Estados Unidos
Author affiliation: Piwnica Worms, Helen. Mallinckrodt Institute of Radiology; Estados Unidos. BRIGHT Institute; Estados Unidos
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Authors: Leone, Maria Juliana; Beaule, C.; Marpegan, Luciano; Simon, T.; Herzog, E.D.; Golombek, Diego Andrés
Publication Date: 2015.
Language: English.
Abstract:
The suprachiasmatic nuclei, the main circadian clock in mammals, are entrained by light through glutamate released from retinal cells. Astrocytes are key players in glutamate metabolism but their role in the entrainment process is unknown. We studied the time dependence of glutamate uptake and glutamine synthetase (GS) activity finding diurnal oscillations in glutamate uptake (high levels during the light phase) and daily and circadian fluctuations in GS activity (higher during the light phase and the subjective day). These results show that glutamate-related astroglial processes exhibit diurnal and circadian variations, which could affect photic entrainment of the circadian system.
Author affiliation: Leone, Maria Juliana. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Author affiliation: Beaule, C.. Washington University in St. Louis; Estados Unidos
Author affiliation: Marpegan, Luciano. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Author affiliation: Simon, T.. Washington University in St. Louis; Estados Unidos
Author affiliation: Herzog, E.D.. Washington University in St. Louis; Estados Unidos
Author affiliation: Golombek, Diego Andrés. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Authors: Paladino, Natalia; Mul Fedele, Malena L.; Duhart, José Manuel; Marpegan, Luciano; Golombek, Diego A.
Publication Date: 2014.
Language: English.
Abstract:
Systemic low doses of the endotoxin lipopolysaccharide (LPS, 100 µg/kg) administered during the early night induce phase-delays of locomotor activity rhythms in mice. Our aim was to evaluate the role of tumor necrosis factor (Tnf)-alpha and its receptor 1/p55 (Tnfr1) in the modulation of LPS-induced circadian effects on the suprachiasmatic nucleus (SCN). We observed that Tnfr1-defective mice (Tnfr1 KO), although exhibiting similar circadian behavior and light response to that of control mice, did not show LPS-induced phase-delays of locomotor activity rhythms, nor LPS-induced cFos and Per2 expression in the SCN and Per1 expression in the paraventricular hypothalamic nucleus (PVN) as compared to wild-type (WT) mice. We also analyzed Tnfr1 expression in the SCN of WT mice, peaking during the early night, when LPS has a circadian effect. Peripheral inoculation of LPS induced an increase in cytokine/chemokine levels (Tnf, Il-6 and Ccl2) in the SCN and in the PVN. In conclusion, in this study, we show that LPS-induced circadian responses are mediated by Tnf. Our results also suggest that this cytokine stimulates the SCN after LPS peripheral inoculation; and the time-related effect of LPS (i.e. phase shifts elicited only at early night) might depend on the increased levels of Tnfr1 expression. We also confirmed that LPS modulates clock gene expression in the SCN and PVN in WT but not in Tnfr1 KO mice.
Author affiliation: Paladino, Natalia. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina
Author affiliation: Mul Fedele, Malena L.. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina
Author affiliation: Duhart, José Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina
Author affiliation: Marpegan, Luciano. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina
Author affiliation: Golombek, Diego A.. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Publication Date: 2013.
Language: English.
Abstract:
The mammalian circadian system controls biological rhythms by means of a central biological clock located in the suprachiasmatic nuclei (SCN) as well as diverse peripheral oscillators located throughout the body. Besides entrainment by the environment, rhythmic nervous and humoral factors are able to stimulate the clock and therefore close a feedback loop that fine-tunes the system. Among such factors, the immune system is clearly regulated by the circadian clock, with both cellular and humoral components experiencing daily rhythms in different tissues. We propose that immune factors are able to modulate the SCN and affect the phase of the oscillator. In addition, taking into account that astrocytes respond to cytokines and chemokines and might also secrete such molecules, as well as express immune-like receptors, we suggest that glial cells of the central nervous system play a key role as an interface between the immune and the circadian systems. The circadian modulation of the immune system opens a new perspective for the understanding of not only the origins of disease but also of physiological regulation of body functions. Conversely, immune factors are now being recognized as clock regulators, and astrocytes provide a link for such communication, adding another role to an increasing list of glial functions.
Author affiliation: Duhart, José Manuel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Author affiliation: Marpegan, Luciano. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Author affiliation: Leone, Maria Juliana. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Author affiliation: Golombek, Diego Andrés. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Authors: Franco, Diana Lorena; Canessa, Paulo; Bellora, Nicolás; Risau Gusman, Sebastian Luis; Olivares Yañez, Consuelo; Pérez Lara, Rodrigo; Libkind Frati, Diego; Larrondo, Luis F.; Marpegan, Luciano
Publication Date: 2017.
Language: English.
Abstract:
Circadian systems enable organisms to synchronize their physiology to daily and seasonal environmental changes relying on endogenous pacemakers that oscillate with a period close to 24 h even in the absence of external timing cues. The oscillations are achieved by intracellular transcriptional/translational feedback loops thoroughly characterized for many organisms, but still little is known about the presence and characteristics of circadian clocks in fungi other than Neurospora crassa. We sought to characterize the circadian system of a natural isolate of Aureobasidium pullulans, a cold-adapted yeast bearing great biotechnological potential. A. pullulans formed daily concentric rings that were synchronized by light/dark cycles and were also formed in constant darkness with a period of 24.5 h. Moreover, these rhythms were temperature compensated, as evidenced by experiments conducted at temperatures as low as 10 °C. Finally, the expression of clock-essential genes, frequency, white collar-1, white collar-2 and vivid was confirmed. In summary, our results indicate the existence of a functional circadian clock in A. pullulans, capable of sustaining rhythms at very low temperatures and, based on the presence of conserved clock-gene homologues, suggest a molecular and functional relationship to well-described circadian systems.
Author affiliation: Franco, Diana Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Instituto de Investigaciones en Biodiversidad y Medioambiente. Universidad Nacional del Comahue. Centro Regional Universidad Bariloche. Instituto de Investigaciones en Biodiversidad y Medioambiente; Argentina
Author affiliation: Canessa, Paulo. Universidad Andrés Bello; Chile. Millennium Nucleus for Fungal Integrative and Synthetic Biology; Chile
Author affiliation: Bellora, Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Instituto de Investigaciones en Biodiversidad y Medioambiente. Universidad Nacional del Comahue. Centro Regional Universidad Bariloche. Instituto de Investigaciones en Biodiversidad y Medioambiente; Argentina
Author affiliation: Risau Gusman, Sebastian Luis. Comisión Nacional de Energía Atómica. Centro Atómico Bariloche; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Author affiliation: Olivares Yañez, Consuelo. Pontificia Universidad Católica de Chile; Chile. Millennium Nucleus for Fungal Integrative and Synthetic Biology; Chile
Author affiliation: Pérez Lara, Rodrigo. Pontificia Universidad Católica de Chile; Chile. Millennium Nucleus for Fungal Integrative and Synthetic Biology; Chile
Author affiliation: Libkind Frati, Diego. Pontificia Universidad Católica de Chile; Chile. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Instituto de Investigaciones en Biodiversidad y Medioambiente. Universidad Nacional del Comahue. Centro Regional Universidad Bariloche. Instituto de Investigaciones en Biodiversidad y Medioambiente; Argentina
Author affiliation: Larrondo, Luis F.. Millennium Nucleus for Fungal Integrative and Synthetic Biology; Chile
Author affiliation: Marpegan, Luciano. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Authors: Kang Miller, Jae Eun; Granados Fuentes, Daniel; Wang, Thomas; Marpegan, Luciano; Holy, Timothy E.; Herzog, Erik D.
Publication Date: 2014.
Language: English.
Abstract:
Accumulating evidence suggests that the olfactory bulbs (OBs) function as an independent circadian system regulating daily rhythms in olfactory performance. However, the cells and signals in the olfactory system that generate and coordinate these circadian rhythms are unknown. Using real-time imaging of gene expression, we found that the isolated olfactory epithelium and OB, but not the piriform cortex, express similar, sustained circadian rhythms in PERIOD2 (PER2). In vivo, PER2 expression in the OB of mice is circadian, approximately doubling with a peak around subjective dusk. Furthermore, mice exhibit circadian rhythms in odor detection performance with a peak at approximately subjective dusk. We also found that circadian rhythms in gene expression and odor detection performance require vasoactive intestinal polypeptide (VIP) or its receptor VPAC2R. VIP is expressed, in a circadian manner, in interneurons in the external plexiform and periglomerular layers, whereas VPAC2R is expressed in mitral and external tufted cells in the OB. Together, these results indicate that VIP signaling modulates the output from the OB to maintain circadian rhythms in the mammalian olfactory system.
Author affiliation: Kang Miller, Jae Eun. Washington University in St. Louis; Estados Unidos
Author affiliation: Granados Fuentes, Daniel. Washington University in St. Louis; Estados Unidos
Author affiliation: Wang, Thomas. Washington University in St. Louis; Estados Unidos
Author affiliation: Marpegan, Luciano. Washington University in St. Louis; Estados Unidos. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Author affiliation: Holy, Timothy E.. Washington University in St. Louis; Estados Unidos
Author affiliation: Herzog, Erik D.. Washington University in St. Louis; Estados Unidos
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas