ABSTRACT
This study addresses the participation of radiation-induced free radicals, mainly nitric oxide (NO), in modulating the apoptotic response in an in vitro model of neural cortical precursor cells exposed to gamma-radiation. Cortical cells obtained from rats at 17 gestational day (GD) were irradiated with a dose of 2 Gy. The percentage of apoptotic cells was significantly increased 4h post-irradiation (pi). NO content showed a significant increase after 30 min pi and the rate of generation reached a maximum 1h pi. Luminol-dependent chemiluminescence (CL) was significantly higher in cells after 2h pi as compared to control cells and this profile was maintained up to 4 h pi. Supplementation with L-NAME significantly increased light emission. Administration of superoxide dismutase (SOD) following L-NAME addition prevented the observed changes due to L-NAME administration. The caspase inhibitor zDEVD-fmk significantly reduced the radical generation. Moreover, the cellular decrease in NO content occurred coincidentally with the rise in oxygen radical generation and the activation of caspase-3. In vitro irradiation of neural precursor cells allowed us to suggest that an early radiation-induced generation of NO could exert a neuroprotective role. However, despite this NO initial protective effect and its role modulating the response against gamma-radiation, NO generation was not able of fully preventing radiation-induced apoptosis.
Subject(s)
Apoptosis/radiation effects , Neurons/radiation effects , Reactive Oxygen Species/metabolism , Stem Cells/radiation effects , Animals , Caspase 3 , Caspases/metabolism , Cells, Cultured , Enzyme Inhibitors/pharmacology , Flow Cytometry , Gamma Rays , Luminescent Measurements , NG-Nitroarginine Methyl Ester/pharmacology , Nitrates/metabolism , Nitric Oxide/metabolism , Nitric Oxide Synthase Type I/antagonists & inhibitors , Nitrites/metabolism , Rats , Rats, Wistar , Superoxides/metabolismABSTRACT
Recent progress especially in the field of gene identification and expression has attracted greater attention to the genetic and epigenetic susceptibility to cancer, possibly enhanced by ionising radiation. This issue is especially important for radiation therapists since hypersensitive patients may suffer from adverse effects in normal tissues following standard radiation therapy, while normally sensitive patients could receive higher doses of radiation, offering a better likelihood of cure for malignant tumours. Although only a small percentage of individuals are "hypersensitive" to radiation effects, all medical specialists using ionising radiation should be aware of the aforementioned progress in medical knowledge. The present paper, the second of two parts, reviews human disorders known or strongly suspected to be associated with hypersensitivity to ionising radiation. The main tests capable of detecting such pathologies in advance are analysed, and ethical issues regarding genetic testing are considered. The implications for radiation protection of possible hypersensitivity to radiation in a part of the population are discussed, and some guidelines for nuclear medicine professionals are proposed.
Subject(s)
Genetic Diseases, Inborn/prevention & control , Genetic Predisposition to Disease/prevention & control , Radiation Injuries/genetics , Radiation Injuries/prevention & control , Radiation Protection/methods , Radiation Tolerance/genetics , Epigenesis, Genetic , Genetic Diseases, Inborn/diagnosis , Genetic Diseases, Inborn/etiology , Humans , Practice Guidelines as Topic , Practice Patterns, Physicians' , Radiation Injuries/diagnosis , Radiation, Ionizing , Risk Assessment/methods , Risk FactorsABSTRACT
Recent progress especially in the field of gene identification and expression has attracted greater attention to genetic and epigenetic susceptibility to cancer, possibly enhanced by ionising radiation. It has been proposed that the occurrence and severity of the adverse reactions to radiation therapy are also influenced by such genetic susceptibility. This issue is especially important for radiation therapists since hypersensitive patients may suffer from adverse effects in normal tissues following standard radiation therapy, while normally sensitive patients could receive higher doses of radiation offering a better likelihood of cure for malignant tumours. This paper, the first of two parts, reviews the main mechanisms involved in cell response to ionising radiation. DNA repair machinery and cell signalling pathways are considered and their role in radiosensitivity is analysed. The implication of non-targeted and delayed effects in radiosensitivity is also discussed.
Subject(s)
Bystander Effect/genetics , Bystander Effect/radiation effects , DNA Damage , DNA Repair/genetics , DNA Repair/radiation effects , Radiation Tolerance/genetics , Radiation, Ionizing , Animals , Cell Communication/genetics , Cell Communication/radiation effects , Dose-Response Relationship, Radiation , Epigenesis, Genetic/genetics , Epigenesis, Genetic/radiation effects , Humans , Radiation DosageABSTRACT
The immature and adult brain display clear differences in the way they respond to insults. The effects of prenatal irradiation on the developing brain are well known. Both epidemiological and experimental data indicate that ionizing radiation may disrupt developmental processes leading to deleterious effects on post-natal brain functions. A central role of reactive oxygen and nitrogen species (ROS/RNS) as important mediators in both neurotoxicity and neuroprotection has been demonstrated. However, data concerning the role of ROS/RNS in radiation-induced damage in the developing brain are scarce. The goal of this review was to summarize the current studies concerning the role of nitric oxide and its reactive intermediates in activation of signal transduction pathways involved in cellular radiation response, with particular focus on radiation-induced effects in the developing brain.
Subject(s)
Brain/growth & development , Brain/radiation effects , Nitric Oxide/physiology , Animals , Apoptosis , Humans , Oxidative Stress , Reactive Nitrogen Species/physiology , Reactive Oxygen SpeciesABSTRACT
Using primary cultures of neural precursor cells of cortex from developing rat brain, we demonstrated the involvement of caspase-3 in the apoptotic process induced by gamma irradiation. The precursor nature of cells was confirmed by nestin and GFAP immunoreactivity and by the capacity of differentiation in neuronal and glial cells after 5 days in culture. Neural precursors were irradiated with single doses ranging from 0.1 to 4Gy. Cellular death, determined 24 h post-irradiation (pi) was dose-dependent and the induction of apoptosis was confirmed by nuclear condensation, DNA fragmentation and hypodiploid DNA peak represented by the "sub G1" region. For the higher doses, apoptosis was evident after 4-6 h pi and increased during 24 h. Caspase-3 activity increased with doses and was maximal at 4-6 h pi with 3Gy and remained similar with 4Gy. The protection from radiation-induced apoptosis by caspase-3 inhibitor, zDEVD-fmk, confirmed that this enzyme is involved in the apoptotic mechanism in this system. The possibility of using this tissue culture system for studying the effects of ionizing radiation on morphological and molecular differentiation was considered.
Subject(s)
Apoptosis/radiation effects , Caspases/metabolism , Caspases/radiation effects , Cerebral Cortex/enzymology , Gamma Rays , Neurons/enzymology , Stem Cells/enzymology , Animals , Caspase 3 , Cell Survival/radiation effects , Cells, Cultured , Cerebral Cortex/cytology , Cerebral Cortex/radiation effects , Dose-Response Relationship, Radiation , Embryo, Mammalian , Enzyme Activation/radiation effects , Neurons/cytology , Neurons/radiation effects , Rats , Rats, Wistar , Stem Cells/cytology , Stem Cells/radiation effectsABSTRACT
Pregnant Wistar rats were exposed on day 17 of gestation to 1 Gy gamma irradiation from a Co(60) source. Even though it is established that gamma radiation-dependent damage is mainly due to free radical generation neither the ascorbyl radical/ascorbate ratio nor the lipid radical content in developing rat brain were affected by prenatal irradiation. A distinctive EPR signal for the adduct NO-Fe-MGD (g=2.03 and a(N)=12.5 G) was detected in brain homogenates prepared from irradiated rats. Nitric oxide (NO)-dependent EPR signal increased in a time-dependent manner up to 2h post-irradiation. NO concentration in unirradiated brains was 37+/-4 pmol/g brain and 45+/-2, 77+/-5 and 216+/-6 after 30, 60 and 120 min post-irradiation, respectively. Total nitric oxide synthase activity was increased by 77 and 51% after 30 and 60 min post-irradiation, respectively, and returned to control values after 120 min. Thus, increased NO steady-state concentration could be ascribed to an increase in NOS activity. Taken as a whole, these results suggest that NO might act to protect the developing brain from the cytotoxicity of reactive species.
Subject(s)
Brain/growth & development , Brain/radiation effects , Neuroprotective Agents , Nitric Oxide/pharmacology , Actins/metabolism , Animals , Ascorbic Acid/metabolism , Brain/drug effects , Brain Chemistry/radiation effects , Electron Spin Resonance Spectroscopy , Female , Free Radicals/metabolism , Gamma Rays , Lipid Metabolism , Lipid Peroxidation/drug effects , Microsomes/drug effects , Microsomes/metabolism , Nitric Oxide/metabolism , Nitric Oxide Synthase/metabolism , Nitric Oxide Synthase Type I , Nitric Oxide Synthase Type II , Rats , Rats, Wistar , Reverse Transcriptase Polymerase Chain Reaction , Thiobarbituric Acid Reactive Substances/metabolismABSTRACT
Oxidative stress and reticulocyte maturity index (RMI) were studied in 27 patients who underwent bone marrow transplantation (BMT). Plasmatic lipoperoxide levels of those patients with unfavorable evolution were significantly increased on days 12-14 post-transplant (median 1.83 microM, range 0.78-5.82) compared with preconditioning levels (median 1.05 microM, range 0.36-1.84) (p < 0.05). Patients with favorable evolution revealed significantly higher lipoperoxide levels during conditioning regime (median 1.42 microM, range 0.31-4.50) (p < 0.05). Starting from the 3rd post-transplant week a significant and continuous decrease was observed, with a median of 0.77 microM (range 0.21-1.48 p < 0.05) for the 3rd, and a median of 0.60 microM (range 0.11-1.48 for the 4th week (p < 0.01). A significant increase in total antioxidant activity was observed in the three patients who died up to the 35 days post-transplant. Recovery of bone marrow function was detected by RMI after a median time of 17 days (range 11-24) post-allogeneic transplantation. The threshold established for absolute neutrophil count was achieved after a median of 21 days (range 14-28) (p < 0.001). An increase of plasma lipoperoxides on days 12-14 post-transplant may be a predictive value of unfavourable evolution. RMI was the earlier indicator of engraftment in allogeneic BMT.
Subject(s)
Bone Marrow Transplantation , Bone Marrow/physiology , Oxidative Stress , Whole-Body Irradiation , Adolescent , Adult , Analysis of Variance , Bone Marrow/metabolism , Bone Marrow/radiation effects , Bone Marrow Cells , Child , Female , Humans , Lipid Peroxides/blood , Lipid Peroxides/metabolism , Male , Middle Aged , Neutrophils/physiology , Postoperative Period , Predictive Value of Tests , Prognosis , Reticulocyte Count , Reticulocytes/physiology , Transplantation, AutologousABSTRACT
Telomeres, functional complexes that protect eukaryotic chromosome ends, participate in the regulation of cell proliferation and could play a role in the stabilization of genomic regions in response to genotoxic stress. Their significance in human pathology becomes evident in several diseases sharing genomic instability as a common trait, in which alterations of the telomere metabolism have been demonstrated. Many of them are also associated with hypersensitivity to ionizing radiation and cancer susceptibility. Besides the specific proteins belonging to the telomeric complex, other proteins involved in the DNA repair machinery, such as ATM, BRCA1, BRCA2, PARP/tankyrase system, DNA-PK and RAD50-MRE11-NBS1 complexes, are closely related with the telomere. This suggests that the telomere sequesters DNA repair proteins for its own structure maintenance, which could also be released toward damaged sites in the genomic DNA. This communication describes essential aspects of telomere structure and function and their links with homologous recombination, non-homologous end-joining (NHEJ), V(D)J system and mismatch-repair (MMR). Several pathological conditions exhibiting alterations in some of these mechanisms are also considered. The cell response to ionizing radiation and its relationship with the telomeric metabolism is particularly taken into account as a model for studying genotoxicity.
Subject(s)
DNA Damage , DNA Repair , Telomere/physiology , Apoptosis/physiology , DNA Replication , Enzyme Activation , Humans , Telomerase/physiology , Telomere/radiation effectsABSTRACT
Los telómeros, complejos funcionales que protegen los extremos de los cromosomas eucariotes, participan en la regulación de la proliferación celular y pueden jugar un rol en la estabilización de cier-tas regiones del genoma en respuesta a estrés genotóxico. Su relevancia en patología humana se ha puesto de manifiesto en numerosas enfermedades que comparten como rasgo común la inestabilidad genómica, en las que se comprobaron alteraciones del metabolismo telomérico. Muchas de ellas se encuentran asociadas a hipersensi-bilidad a radiaciones ionizantes y susceptibilidad al cáncer. Además de las proteínas específicas que forman partedel complejo telomérico otras proteínas implicadas en la maquinaria de reparación del ADN tales como ATM,BRCA1, BRCA2 , sistema PARP/ tankirasa, complejo DNA-PK, y complejo RAD50- MRE11-NBS1, se encuentran en estrecha asociación con el mismo. Esto sugiere que el telómero secuestra proteínas de reparación para el mantenimiento de su propia estructura, las que podrían asimismo ser liberadas hacia sitios de daño en el ADN genómico. Esta comunicación describe los aspectos más relevantes de la estructura y función de los telómeros y su vinculación con los procesos de recombinación homóloga, recombinación no homóloga (NHEJ), sistema V(D)J y sistemas de reparación de apareamientos erróneos (MMR), considerando ciertas condiciones patológicas que exhiben alteraciones en algunos estos mecanismos. Se aborda en forma particular la respuesta celular a las ra-diaciones ionizantes y su relación con el metabolismo telomérico como un modelo de estudio de genotoxicidad
Subject(s)
Humans , DNA Damage , DNA Repair , Genome, Human , Telomere , Base Sequence , TelomereSubject(s)
Impacts of Polution on Health , Handbook , Public Health , Industrial Safety , ToxicologySubject(s)
Public Health , Impacts of Polution on Health , Toxicology , Industrial Safety , HandbookABSTRACT
Los telómeros, complejos funcionales que protegen los extremos de los cromosomas eucariotes, participan en la regulación de la proliferación celular y pueden jugar un rol en la estabilización de cier-tas regiones del genoma en respuesta a estrés genotóxico. Su relevancia en patología humana se ha puesto de manifiesto en numerosas enfermedades que comparten como rasgo común la inestabilidad genómica, en las que se comprobaron alteraciones del metabolismo telomérico. Muchas de ellas se encuentran asociadas a hipersensi-bilidad a radiaciones ionizantes y susceptibilidad al cáncer. Además de las proteínas específicas que forman partedel complejo telomérico otras proteínas implicadas en la maquinaria de reparación del ADN tales como ATM,BRCA1, BRCA2 , sistema PARP/ tankirasa, complejo DNA-PK, y complejo RAD50- MRE11-NBS1, se encuentran en estrecha asociación con el mismo. Esto sugiere que el telómero secuestra proteínas de reparación para el mantenimiento de su propia estructura, las que podrían asimismo ser liberadas hacia sitios de daño en el ADN genómico. Esta comunicación describe los aspectos más relevantes de la estructura y función de los telómeros y su vinculación con los procesos de recombinación homóloga, recombinación no homóloga (NHEJ), sistema V(D)J y sistemas de reparación de apareamientos erróneos (MMR), considerando ciertas condiciones patológicas que exhiben alteraciones en algunos estos mecanismos. Se aborda en forma particular la respuesta celular a las ra-diaciones ionizantes y su relación con el metabolismo telomérico como un modelo de estudio de genotoxicidad (AU)
Subject(s)
Humans , Telomere/genetics , DNA Repair , DNA Damage , Genome, Human , Telomere/metabolism , Telomere/physiology , Telomere/radiation effects , Base SequenceABSTRACT
Oxidative stress and reticulocyte maturity index (RMI) were studied in 27 patients who underwent bone marrow transplantation (BMT). Plasmatic lipoperoxide levels of those patients with unfavorable evolution were significantly increased on days 12-14 post-transplant (median 1.83 microM, range 0.78-5.82) compared with preconditioning levels (median 1.05 microM, range 0.36-1.84) (p < 0.05). Patients with favorable evolution revealed significantly higher lipoperoxide levels during conditioning regime (median 1.42 microM, range 0.31-4.50) (p < 0.05). Starting from the 3rd post-transplant week a significant and continuous decrease was observed, with a median of 0.77 microM (range 0.21-1.48 p < 0.05) for the 3rd, and a median of 0.60 microM (range 0.11-1.48 for the 4th week (p < 0.01). A significant increase in total antioxidant activity was observed in the three patients who died up to the 35 days post-transplant. Recovery of bone marrow function was detected by RMI after a median time of 17 days (range 11-24) post-allogeneic transplantation. The threshold established for absolute neutrophil count was achieved after a median of 21 days (range 14-28) (p < 0.001). An increase of plasma lipoperoxides on days 12-14 post-transplant may be a predictive value of unfavourable evolution. RMI was the earlier indicator of engraftment in allogeneic BMT.
ABSTRACT
Telomeres, functional complexes that protect eukaryotic chromosome ends, participate in the regulation of cell proliferation and could play a role in the stabilization of genomic regions in response to genotoxic stress. Their significance in human pathology becomes evident in several diseases sharing genomic instability as a common trait, in which alterations of the telomere metabolism have been demonstrated. Many of them are also associated with hypersensitivity to ionizing radiation and cancer susceptibility. Besides the specific proteins belonging to the telomeric complex, other proteins involved in the DNA repair machinery, such as ATM, BRCA1, BRCA2, PARP/tankyrase system, DNA-PK and RAD50-MRE11-NBS1 complexes, are closely related with the telomere. This suggests that the telomere sequesters DNA repair proteins for its own structure maintenance, which could also be released toward damaged sites in the genomic DNA. This communication describes essential aspects of telomere structure and function and their links with homologous recombination, non-homologous end-joining (NHEJ), V(D)J system and mismatch-repair (MMR). Several pathological conditions exhibiting alterations in some of these mechanisms are also considered. The cell response to ionizing radiation and its relationship with the telomeric metabolism is particularly taken into account as a model for studying genotoxicity.
ABSTRACT
Las patologías ictiosiformes son un grupo de genodermatosis caracterizadas por un patrón hiperqueratósico de distribución variable y con mayor o menor gradode compromiso general.La eritrodernia ictiosiforme congénita o feto eb aelequín constituye la forma más severa de la ictiosis presentado una evolución rápidamente fatal.La aplicación de las medidas de aepsia externa,así como el uso de retenoides ha permitido modificar el curso de la enfermedad y losgras sobrevidas prolongadas.A propósito de una observación se discuten aspectos relacionados con la enferemdad y otros que hacen a la ubicación de esta patología en el registro de las ictiosis,así como aspectos terapeúticos y evolutivos
Subject(s)
Humans , Infant, Newborn , Ichthyosiform Erythroderma, Congenital , Ichthyosis , Ichthyosis, Lamellar , PediatricsABSTRACT
Las patologías ictiosiformes son un grupo de genodermatosis caracterizadas por un patrón hiperqueratósico de distribución variable y con mayor o menor gradode compromiso general.La eritrodernia ictiosiforme congénita o feto eb aelequín constituye la forma más severa de la ictiosis presentado una evolución rápidamente fatal.La aplicación de las medidas de aepsia externa,así como el uso de retenoides ha permitido modificar el curso de la enfermedad y losgras sobrevidas prolongadas.A propósito de una observación se discuten aspectos relacionados con la enferemdad y otros que hacen a la ubicación de esta patología en el registro de las ictiosis,así como aspectos terapeúticos y evolutivos
