1,721,220 research outputs found
Chronic low-dose-rate ionising radiation affects the hippocampal phosphoproteome in the ApoE-/- Alzheimer's mouse model
No full textAccruing data indicate that radiation-induced consequences resemble pathologies of neurodegenerative diseases such as Alzheimer's. The aim of this study was to elucidate the effect on hippocampus of chronic low-dose-rate radiation exposure (1 mGy/day or 20 mGy/day) given over 300 days with cumulative doses of 0.3 Gy and 6.0 Gy, respectively. ApoE deficient mutant C57Bl/6 mouse was used as an Alzheimer's model. Using mass spectrometry, a marked alteration in the phosphoproteome was found at both dose rates. The radiation-induced changes in the phosphoproteome were associated with the control of synaptic plasticity, calciumdependent signalling and brain metabolism. An inhibition of CREB signalling was found at both dose rates whereas Rac1-Cofilin signalling was found activated only at the lower dose rate. Similarly, the reduction in the number of activated microglia in the molecular layer of hippocampus that paralleled with reduced levels of TNFa expression and lipid peroxidation was significant only at the lower dose rate. Adult neurogenesis, investigated by Ki67, GFAP and NeuN staining, and cell death (activated caspase-3) were not influenced at any dose or dose rate. This study shows that several molecular targets induced by chronic low-dose-rate radiation overlap with those of Alzheimer's pathology. It may suggest that ionising radiation functions as a contributing risk factor to this neurodegenerative disease
N6-isopentenyladenosine and analogs activate the NRF2-mediated antioxidant response
No full textN6-isopentenyladenosine (i6A), a naturally occurring modified nucleoside, inhibits the proliferation of human tumor cell lines in vitro, but its mechanism of action remains unclear. Treatment of MCF7 human breast adenocarcinoma cells with i6A or with three synthetic analogs (allyl6A, benzyl6A, and butyl6A) inhibited growth and altered gene expression. About 60% of the genes that were differentially expressed in response to i6A treatment were also modulated by the analogs, and pathway enrichment analysis identified the NRF2-mediated oxidative stress response as being significantly modulated by all four compounds. Luciferase reporter gene assays in transfected MCF7 cells confirmed that i6A activates the transcription factor NRF2. Assays for cellular production of reactive oxygen species indicated that i6A and analogs had antioxidant effects, reducing basal levels and inhibiting the H2O2- or 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced production in MCF7 or dHL-60 (HL-60 cells induced to differentiate along the neutrophilic lineage) cell lines, respectively. In vivo, topical application of i6A or benzyl6A to mouse ears prior to TPA stimulation lessened the inflammatory response and significantly reduced the number of infiltrating neutrophils. These results suggest that i6A and analogs trigger a cellular response against oxidative stress and open the possibility of i6A and benzyl6A being used as topical anti-inflammatory drugs. © 2014 The Authors
A mechanistic model for medulloblastoma induction in mice
No full textMedulloblastomas in Patched heterozygous mice (Ptc1+/- mice) are induced with high probability by ionizing radiation applied in the immediate post-natal period. A mathematical model is described here that accommodates the dependence of the medulloblastoma incidence on dose, age at exposure and age. The model assumes that the first step in the development of the cancer is already present in all cells of the patched mouse due to germ-line inactivation of one allele of the patched tumor suppressor gene. The subsequent rate-limiting step is dependent linearly on dose at least up to 3 Gy. The observed strong decrease in carcinogenic effect of radiation between exposure on day 1 and day 10 is described by a physiological elimination of target cells during post-natal maturation of the brain. A single malignant cell develops into a tumor following a gamma-distribution with mean of about 160 days. The multiplicity of medulloblastomas is predicted. © 2013 by Radiation Research Society. All rights of reproduction in any form reserved
Gender effect in experimental models of human medulloblastoma: Does the estrogen receptor β signaling play a role?
No full textBackground: The male-to-female sex ratio for medulloblastoma (MB) is approximately 1.5:1, female gender being also a favorable prognostic factor. This study aimed at evaluating the impact of gender on MB tumorigenesis. Methods: In vitro activity of 17β-estradiol (E2), DPN [2,3-bis(4-hydroxyphenyl)-propionitrile, a selective estrogen receptor β (ERβ)-agonist], PPT [4,4′,4′′-(4-Propyl-[1H]-pyrazole-1,3,5- triyl) trisphenol, a selective ERα-agonist] or DHT (5 alphadihydrotestosterone) was evaluated in three human MB cell lines. D283 Med cells were transplanted into athymic mice. Results: A significant expression of ERβ, with little or no ERα, and low AR (androgen receptor) was found in MB cell lines. The compounds tested did not affect cell proliferation. In vivo, we observed a significantly lower growth of D283 Med in nude female mice compared to males. At microscopic examination, tumors from females showed a shift towards differentiation, as evaluated by lower nestin, and higher NSE (neuron-specific enolase) and GFAP (glial fibrillary acidic protein) expression compared to males. Tumors from females also showed lower Ki67 and p53 expression. The wild-type ERβ protein (ERβ1) was lost in male tumors, while it was a permanent feature in females, and a strong negative correlation was found between Ki67 and ERβ1 expression. Conversely, tumor levels of ERβ2 and ERβ5 did not significantly differ between genders. Increased levels of cyclin-dependent kinase inhibitor p21 were observed in females, suggesting that estrogen may decrease tumor growth through blocking cell cycle progression. An inhibition of the insulin-like growth factor I (IGF-I) signaling was also evident in females. Conclusion: We provides mechanistic evidence supporting the idea that ERβ1 signaling may have pro-differentiation and tumor suppressive function in medulloblastomas. © 2014 Ciucci et al
Nanog-driven cell-reprogramming and self-renewal maintenance in Ptch1 +/- granule cell precursors after radiation injury
No full textMedulloblastoma (MB) is the most common pediatric brain tumor, comprising four distinct molecular variants, one of which characterized by activation of the Sonic Hedgehog (SHH) pathway, driving 25-30% of sporadic MB. SHH-dependent MBs arise from granule cell precursors (GCPs), are fatal in 40-70% of cases and radioresistance strongly contributes to poor prognosis and tumor recurrence. Patched1 heterozygous (Ptch1 +/-) mice, carrying a germ-line heterozygous inactivating mutation in the Ptch1 gene, the Shh receptor and negative regulator of the pathway, are uniquely susceptible to MB development after radiation damage in neonatal cerebellum. Here, we irradiated ex-vivo GCPs isolated from cerebella of neonatal WT and Ptch1 +/- mice. Our results highlight a less differentiated status of Ptch1-mutated cells after irradiation, influencing DNA damage response. Increased expression levels of pluripotency genes Nanog, Oct4 and Sal4, together with greater clonogenic potential, clearly suggest that radiation induces expansion of the stem-like cell compartment through cell-reprogramming and self-renewal maintenance, and that this mechanism is strongly dependent on Nanog. These results contribute to clarify the molecular mechanisms that control radiation-induced Shh-mediated tumorigenesis and may suggest Nanog as a potential target to inhibit for adjuvant radiotherapy in treatment of SHH-dependent MB. © 2017 The Author(s)
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
A multidisciplinary approach unravels early and persistent effects of X-ray exposure at the onset of prenatal neurogenesis
No full textBackground: In humans, in utero exposure to ionising radiation results in an increased prevalence of neurological aberrations, such as small head size, mental retardation and decreased IQ levels. Yet, the association between early damaging events and long-term neuronal anomalies remains largely elusive. Methods: Mice were exposed to different X-ray doses, ranging between 0.0 and 1.0 Gy, at embryonic days (E) 10, 11 or 12 and subjected to behavioural tests at 12 weeks of age. Underlying mechanisms of irradiation at E11 were further unravelled using magnetic resonance imaging (MRI) and spectroscopy, diffusion tensor imaging, gene expression profiling, histology and immunohistochemistry. Results: Irradiation at the onset of neurogenesis elicited behavioural changes in young adult mice, dependent on the timing of exposure. As locomotor behaviour and hippocampal-dependent spatial learning and memory were most particularly affected after irradiation at E11 with 1.0 Gy, this condition was used for further mechanistic analyses, focusing on the cerebral cortex and hippocampus. A classical p53-mediated apoptotic response was found shortly after exposure. Strikingly, in the neocortex, the majority of apoptotic and microglial cells were residing in the outer layer at 24 h after irradiation, suggesting cell death occurrence in differentiating neurons rather than proliferating cells. Furthermore, total brain volume, cortical thickness and ventricle size were decreased in the irradiated embryos. At 40 weeks of age, MRI showed that the ventricles were enlarged whereas N-acetyl aspartate concentrations and functional anisotropy were reduced in the cortex of the irradiated animals, indicating a decrease in neuronal cell number and persistent neuroinflammation. Finally, in the hippocampus, we revealed a reduction in general neurogenic proliferation and in the amount of Sox2-positive precursors after radiation exposure, although only at a juvenile age. Conclusions: Our findings provide evidence for a radiation-induced disruption of mouse brain development, resulting in behavioural differences. We propose that alterations in cortical morphology and juvenile hippocampal neurogenesis might both contribute to the observed aberrant behaviour. Furthermore, our results challenge the generally assumed view of a higher radiosensitivity in dividing cells. Overall, this study offers new insights into irradiation-dependent effects in the embryonic brain, of relevance for the neurodevelopmental and radiobiological field. © 2015 Verreet et al.; licensee BioMed Central
Neurocognitive decline following radiotherapy: Mechanisms and therapeutic implications
No full textThe brain undergoes ionizing radiation (IR) exposure in many clinical situations, particularly during radiotherapy for malignant brain tumors. Cranial radiation therapy is related with the hazard of long-term neurocognitive decline. The detrimental ionizing radiation effects on the brain closely correlate with age at treatment, and younger age associates with harsher deficiencies. Radiation has been shown to induce damage in several cell populations of the mouse brain. Indeed, brain exposure causes a dysfunction of the neurogenic niche due to alterations in the neuronal and supporting cell progenitor signaling environment, particularly in the hippocampus—a region of the brain critical to memory and cognition. Consequent deficiencies in rates of generation of new neurons, neural differentiation and apoptotic cell death, lead to neuronal deterioration and lasting repercussions on neurocognitive functions. Besides neural stem cells, mature neural cells and glial cells are recognized IR targets. We will review the current knowledge about radiation-induced damage in stem cells of the brain and discuss potential treatment interventions and therapy methods to prevent and mitigate radiation related cognitive decline
Acceleration of atherogenesis in ApoE-/- mice exposed to acute or low-dose-rate ionizing radiation
No full textThere is epidemiological evidence for increased non-cancer mortality, primarily due to circulatory diseases after radiation exposure above 0.5 Sv. We evaluated the effects of chronic low-dose rate versus acute exposures in a murine model of spontaneous atherogenesis. Female ApoE-/- mice (60 days) were chronically irradiated for 300 days with gamma rays at two different dose rates (1 mGy/day; 20 mGy/day), with total accumulated doses of 0.3 or 6 Gy. For comparison, age-matched ApoE-/- females were acutely exposed to the same doses and sacrificed 300 days post-irradiation. Mice acutely exposed to 0.3 or 6 Gy showed increased atherogenesis compared to age-matched controls, and this effect was persistent. When the same doses were delivered at low dose rate over 300 days, we again observed a significant impact on global development of atherosclerosis, although at 0.3 Gy effects were limited to the descending thoracic aorta. Our data suggest that a moderate dose of 0.3 Gy can have persistent detrimental effects on the cardiovascular system, and that a high dose of 6 Gy poses high risks at both high and low dose rates. Our results were clearly nonlinear with dose, suggesting that lower doses may be more damaging than predicted by a linear dose response
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