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1.
Int J Mol Sci ; 22(19)2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34638618

RESUMO

Wildlife is chronically exposed to various sources of ionizing radiations, both environmental or anthropic, due to nuclear energy use, which can induce several defects in organisms. In invertebrates, reproduction, which directly impacts population dynamics, has been found to be the most radiosensitive endpoint. Understanding the underlying molecular pathways inducing this reproduction decrease can help in predicting the effects at larger scales (i.e., population). In this study, we used a life stage dependent approach in order to better understand the molecular determinants of reproduction decrease in the roundworm C. elegans. Worms were chronically exposed to 50 mGy·h-1 external gamma ionizing radiations throughout different developmental periods (namely embryogenesis, gametogenesis, and full development). Then, in addition to reproduction parameters, we performed a wide analysis of lipids (different class and fatty acid via FAMES), which are both important signaling molecules for reproduction and molecular targets of oxidative stress. Our results showed that reproductive defects are life stage dependent, that lipids are differently misregulated according to the considered exposure (e.g., upon embryogenesis and full development) and do not fully explain radiation induced reproductive defects. Finally, our results enable us to propose a conceptual model of lipid signaling after radiation stress in which both the soma and the germline participate.


Assuntos
Caenorhabditis elegans/efeitos da radiação , Metabolismo dos Lipídeos/efeitos da radiação , Reprodução/efeitos da radiação , Animais , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/fisiologia , Ácidos Graxos/metabolismo , Feminino , Raios gama/efeitos adversos , Masculino , Modelos Biológicos , Estresse Oxidativo/efeitos da radiação , Tolerância a Radiação , Reprodução/fisiologia
2.
Int J Mol Sci ; 22(17)2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34502232

RESUMO

Cellular senescence and its senescence-associated secretory phenotype (SASP) are widely regarded as promising therapeutic targets for aging-related diseases, such as osteoporosis. However, the expression pattern of cellular senescence and multiple SASP secretion remains unclear, thus leaving a large gap in the knowledge for a desirable intervention targeting cellular senescence. Therefore, there is a critical need to understand the molecular mechanism of SASP secretion in the bone microenvironment that can ameliorate aging-related degenerative pathologies including osteoporosis. In this study, osteocyte-like cells (MLO-Y4) were induced to cellular senescence by 2 Gy γ-rays; then, senescence phenotype changes and adverse effects of SASP on bone marrow mesenchymal stem cell (BMSC) differentiation potential were investigated. The results revealed that 2 Gy irradiation could hinder cell viability, shorten cell dendrites, and induce cellular senescence, as evidenced by the higher expression of senescence markers p16 and p21 and the elevated formation of senescence-associated heterochromatin foci (SAHF), which was accompanied by the enhanced secretion of SASP markers such as IL-1α, IL-6, MMP-3, IGFBP-6, resistin, and adiponectin. When 0.8 µM JAK1 inhibitors were added to block SASP secretion, the higher expression of SASP was blunted, but the inhibition in osteogenic and adipogenic differentiation potential of BMSCs co-cultured with irradiated MLO-Y4 cell conditioned medium (CM- 2 Gy) was alleviated. These results suggest that senescent osteocytes can perturb BMSCs' differential potential via the paracrine signaling of SASP, which was also demonstrated by in vivo experiments. In conclusion, we identified the SASP factor partially responsible for the degenerative differentiation of BMSCs, which allowed us to hypothesize that senescent osteocytes and their SASPs may contribute to radiation-induced bone loss.


Assuntos
Reabsorção Óssea/patologia , Diferenciação Celular , Senescência Celular , Raios gama/efeitos adversos , Células-Tronco Mesenquimais/patologia , Osteócitos/patologia , Comunicação Parácrina , Animais , Reabsorção Óssea/etiologia , Reabsorção Óssea/metabolismo , Masculino , Células-Tronco Mesenquimais/efeitos da radiação , Camundongos , Camundongos Endogâmicos BALB C , Osteócitos/efeitos da radiação , Osteogênese
3.
Int J Mol Sci ; 22(17)2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34502247

RESUMO

Previously, we showed that a nitric oxide synthase (NOS) inhibitor, compound T1023, induces transient hypoxia and prevents acute radiation syndrome (ARS) in mice. Significant efficacy (according to various tests, dose modifying factor (DMF)-1.6-1.9 against H-ARS/G-ARS) and safety in radioprotective doses (1/5-1/4 LD10) became the reason for testing its ability to prevent complications of tumor radiation therapy (RT). Research methods included studying T1023 effects on skin acute radiation reactions (RSR) in rats and mice without tumors and in tumor-bearing animals. The effects were evaluated using clinical, morphological and histological techniques as well as RTOG classification. T1023 administration prior to irradiation significantly limited the severity of acute RSR. This was due to a decrease in radiation alteration of the skin and underlying tissues, and the preservation of the functional activity of cell populations that are critical in the pathogenesis of radiation burn. The DMF values for T1023 for skin protection were 1.4-1.7. Moreover, its radioprotective effect was fully selective to normal tissues in RT models of solid tumors-T1023 reduced the severity of acute RSR and did not modify the antitumor effects of γ-radiation. The results indicate that T1023 can selectively protect the non-malignant tissues against γ-radiation due to hypoxic mechanism of action and potentiate opportunities of NOS inhibitors in RT complications prevention.


Assuntos
Carcinoma de Ehrlich/radioterapia , Raios gama/efeitos adversos , Óxido Nítrico Sintase/antagonistas & inibidores , Protetores contra Radiação/farmacologia , Radiodermatite/tratamento farmacológico , Sarcoma Experimental/radioterapia , Tioureia/análogos & derivados , Animais , Carcinoma de Ehrlich/patologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos ICR , Proteção Radiológica/métodos , Radiodermatite/etiologia , Radiodermatite/patologia , Ratos , Ratos Sprague-Dawley , Sarcoma Experimental/patologia , Tioureia/farmacologia
4.
Cells ; 10(9)2021 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-34572124

RESUMO

Early life radiation exposure causes abnormal brain development, leading to adult depression. However, few studies have been conducted to explore pre- or post-natal irradiation-induced depression-related neuropathological changes. Relevant molecular mechanisms are also poorly understood. We induced adult depression by irradiation of mice at postnatal day 3 (P3) to reveal hippocampal neuropathological changes and investigate their molecular mechanism, focusing on MicroRNA (miR) and its target mRNA and protein. P3 mice were irradiated by γ-rays with 5Gy, and euthanized at 1, 7 and 120 days after irradiation. A behavioral test was conducted before the animals were euthanized at 120 days after irradiation. The animal brains were used for different studies including immunohistochemistry, CAP-miRSeq, Real-Time Quantitative Reverse Transcription PCR (qRT-PCR) and western blotting. The interaction of miR-34a-5p and its target T-cell intracytoplasmic antigen-1 (Tia1) was confirmed by luciferase reporter assay. Overexpression of Tia1 in a neural stem cell (NSC) model was used to further validate findings from the mouse model. Irradiation with 5 Gy at P3 induced depression in adult mice. Animal hippocampal pathological changes included hypoplasia of the infrapyramidal blade of the stratum granulosum, aberrant and impaired cell division, and neurogenesis in the dentate gyrus. At the molecular level, upregulation of miR-34a-5p and downregulation of Tia1 mRNA were observed in both animal and neural stem cell models. The luciferase reporter assay and gene transfection studies further confirmed a direct interaction between miR-43a-5p and Tia1. Our results indicate that the early life γ-radiation-activated miR-43a-5p/Tia1 pathway is involved in the pathogenesis of adult depression. This novel finding may provide a new therapeutic target by inhibiting the miR-43a-5p/Tia1 pathway to prevent radiation-induced pathogenesis of depression.


Assuntos
Giro Denteado/patologia , Depressão/patologia , Raios gama/efeitos adversos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , MicroRNAs/genética , Neurogênese , Antígeno-1 Intracelular de Células T/metabolismo , Animais , Apoptose , Proliferação de Células , Giro Denteado/efeitos da radiação , Depressão/etiologia , Depressão/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Antígeno-1 Intracelular de Células T/genética
5.
Int J Mol Sci ; 22(18)2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34575874

RESUMO

Intestinal injury caused by ionizing radiation (IR) is a main clinical issue for patients with cancer receiving abdominal or pelvic radiotherapy. Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone that the pineal gland in the brain normally secretes. The study aimed to disclose the potential function of melatonin in intestinal injury induced by IR and its mechanism. Pretreatment with melatonin enhanced the 30-day survival rate of the irradiated mice and promoted the recovery of the intestinal epithelium and hematopoietic function following abdominal irradiation (ABI). Melatonin altered the gene profile of the small intestines from mice following ABI. The enriched biological process terms for melatonin treatment prior to radiation were mainly involved in the immune process. LPS/IL-1-mediated inhibition of RXR Function, TWEAK signaling, and Toll-like receptor signaling were the most activated canonical pathways targeted by melatonin. An upstream analysis network showed that Tripartite motif-containing 24 (TRIM24) was the most significantly inhibited and S100 calcium binding protein A9 (S100A9) activated. TRIM24 activated atherogenesis and cell viability in breast cancer cell lines and S100A9 inhibited the metabolism of amino acids. Melatonin has radioprotective effects on ABI-caused intestinal injury. The mechanisms behind the beneficial effects of melatonin were involved in activation of the immunity. It is necessary to conduct further experiments to explore the underlying mechanisms.


Assuntos
Neoplasias da Mama/metabolismo , Proteínas de Transporte/genética , Intestinos/lesões , Melatonina/farmacologia , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Abdome/efeitos da radiação , Animais , Calgranulina B/metabolismo , Proteínas de Transporte/metabolismo , Sobrevivência Celular , Citocina TWEAK/metabolismo , Dano ao DNA/efeitos da radiação , Feminino , Raios gama/efeitos adversos , Hematopoese/efeitos da radiação , Humanos , Linfócitos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Nucleares/metabolismo , Fenótipo , Lesões Experimentais por Radiação/tratamento farmacológico , Radiação Ionizante , Receptores X de Retinoides/metabolismo , Fatores de Transcrição/metabolismo , Irradiação Corporal Total
6.
Int J Mol Sci ; 22(18)2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34575973

RESUMO

Radiation damages many cellular components and disrupts cellular functions, and was previously reported to impair locomotion in the model organism Caenorhabditis elegans. However, the response to even higher doses is not clear. First, to investigate the effects of high-dose radiation on the locomotion of C. elegans, we investigated the dose range that reduces whole-body locomotion or leads to death. Irradiation was performed in the range of 0-6 kGy. In the crawling analysis, motility decreased after irradiation in a dose-dependent manner. Exposure to 6 kGy of radiation affected crawling on agar immediately and caused the complete loss of motility. Both γ-rays and carbon-ion beams significantly reduced crawling motility at 3 kGy. Next, swimming in buffer was measured as a motility index to assess the response over time after irradiation and motility similarly decreased. However, swimming partially recovered 6 h after irradiation with 3 kGy of γ-rays. To examine the possibility of a recovery mechanism, in situ GFP reporter assay of the autophagy-related gene lgg-1 was performed. The fluorescence intensity was stronger in the anterior half of the body 7 h after irradiation with 3 kGy of γ-rays. GFP::LGG-1 induction was observed in the pharynx, neurons along the body, and the intestine. Furthermore, worms were exposed to region-specific radiation with carbon-ion microbeams and the trajectory of crawling was measured by image processing. Motility was lower after anterior-half body irradiation than after posterior-half body irradiation. This further supported that the anterior half of the body is important in the locomotory response to radiation.


Assuntos
Autofagia/efeitos da radiação , Locomoção/efeitos da radiação , Doses de Radiação , Animais , Autofagia/fisiologia , Caenorhabditis elegans/fisiologia , Caenorhabditis elegans/efeitos da radiação , Relação Dose-Resposta à Radiação , Raios gama/efeitos adversos , Humanos , Locomoção/fisiologia , Irradiação Corporal Total/efeitos adversos
7.
Sci Rep ; 11(1): 15873, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34354115

RESUMO

Gottingen minipigs mirror the physiological radiation response observed in humans and hence make an ideal candidate model for studying radiation biodosimetry for both limited-sized and mass casualty incidents. We examined the whole blood gene expression profiles starting one day after total-body irradiation with increasing doses of gamma-rays. The minipigs were monitored for up to 45 days or time to euthanasia necessitated by radiation effects. We successfully identified dose- and time-agnostic (over a 1-7 day period after radiation), survival-predictive gene expression signatures derived using machine-learning algorithms with high sensitivity and specificity. These survival-predictive signatures fare better than an optimally performing dose-differentiating signature or blood cellular profiles. These findings suggest that prediction of survival is a much more useful parameter for making triage, resource-utilization and treatment decisions in a resource-constrained environment compared to predictions of total dose received. It should hopefully be possible to build such classifiers for humans in the future.


Assuntos
Células Sanguíneas/efeitos da radiação , Irradiação Corporal Total/efeitos adversos , Irradiação Corporal Total/mortalidade , Animais , Biomarcadores/sangue , Relação Dose-Resposta à Radiação , Raios gama/efeitos adversos , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Prognóstico , Lesões por Radiação/sangue , Lesões por Radiação/genética , Suínos , Porco Miniatura/sangue , Porco Miniatura/metabolismo , Transcriptoma/genética
8.
Radiat Environ Biophys ; 60(3): 397-410, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34287697

RESUMO

Reliable data on the effects of chronic prenatal exposure to low dose (LD) of ionizing radiation in humans are missing. There are concerns about adverse long-term effects that may persist throughout postnatal life of the offspring. Due to their slow cell cycle kinetics and life-long residence time in the organism, mesenchymal stem cells (MSCs) are more susceptible to low level genotoxic stress caused by extrinsic multiple LD events. The aim of this study was to investigate the effect of chronic, prenatal LD gamma irradiation to the biology of MSCs later in life. C3H mice were exposed in utero to chronic prenatal irradiation of 10 mGy/day over a period of 3 weeks. Two years later, MSCs were isolated from the bone marrow and analyzed in vitro for their radiosensitivity, for cellular senescence and for DNA double-strand break recognition after a second acute gamma-irradiation. In addition to these cellular assays, changes in protein expression were measured using HPLC-MS/MS and dysregulated molecular signaling pathways identified using bioinformatics. We observed radiation-induced proteomic changes in MSCs from the offspring of in utero irradiated mice (leading to ~ 9.4% of all detected proteins being either up- or downregulated) as compared to non-irradiated controls. The proteomic changes map to regulation pathways involved in the extracellular matrix, the response to oxidative stress, and the Wnt signaling pathway. In addition, chronic prenatal LD irradiation lead to an increased rate of in vitro radiation-induced senescence later in life and to an increased number of residual DNA double-strand breaks after 4 Gy irradiation, indicating a remarkable interaction of in vivo radiation in combination with a second acute dose of in vitro radiation. This study provides the first insight into a molecular mechanism of persistent MSC damage response by ionizing radiation exposure during prenatal time and will help to predict therapeutic safety and efficacy with respect to a clinical application of stem cells.


Assuntos
Raios gama/efeitos adversos , Células-Tronco Mesenquimais/efeitos da radiação , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Proteoma/efeitos da radiação , Animais , Bioensaio , Células Cultivadas , Senescência Celular/efeitos da radiação , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Reparo do DNA , Desenvolvimento Embrionário , Feminino , Masculino , Troca Materno-Fetal , Células-Tronco Mesenquimais/metabolismo , Camundongos Mutantes , Gravidez , Via de Sinalização Wnt
9.
Int J Radiat Biol ; 97(9): 1166-1180, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34259614

RESUMO

PURPOSE: DNA, the hereditary material of a human cell generally exists as Watson-Crick base paired double-stranded B-DNA. Studies suggest that DNA can also exist in non-B forms, such as four stranded G-quadruplexes (G4 DNA). Recently, our studies revealed that the regions of DNA that can fold into G-quadruplex structures are less sensitive to ionizing radiation (IR) compared to B-DNA. Importantly, we reported that the planar G-quartet of a G4 structure is shielded from radiation induced DNA breaks, while the single- and double-stranded DNA regions remained susceptible. Thus, in the present study, we investigate whether telomeric repeat DNA present at the end of telomere, known to fold into G4 DNA can protect from radiation induced damages including strand breaks, oxidation of purines and bulky adduct formation on DNA. MATERIALS AND METHODS: For plasmid irradiation assay, plasmids containing human telomeric repeat DNA sequence TTAGGG (0.8 kb or 1.8 kb) were irradiated with increasing doses of IR along with appropriate control plasmids and products were resolved on 1% agarose gel. Radioprotection was evaluated based on extent of conversion of supercoiled to nicked or linear forms of the DNA following irradiation. Formation of G-quadruplex structure on supercoiled DNA was evaluated based on circular dichroism (CD) spectroscopy studies. Cleavage of radiation induced oxidative damage and extent of formation of nicks was further evaluated using base and nucleotide excision repair proteins. RESULTS: Results from CD studies showed that the plasmid DNA harboring human telomeric repeats (TTAGGG) can fold into G-quadruplex DNA structures. Further, results showed that human telomeric repeat sequence when present on a plasmid can protect the plasmid DNA against IR induced DNA strand breaks, unlike control plasmids bearing random DNA sequence. CONCLUSIONS: Human telomeric repeat sequence when present on plasmids can fold into G-quadruplex DNA structures, and can protect the DNA against IR induced DNA strand breaks and oxidative damage. These results in conjunction with our previous studies suggest that telomeric repeat sequence imparts less sensitivity to IR and thus telomeres of chromosomes are protected from radiation.


Assuntos
Adutos de DNA/genética , Adutos de DNA/efeitos da radiação , Quadruplex G/efeitos da radiação , Raios gama/efeitos adversos , Estresse Oxidativo/genética , Estresse Oxidativo/efeitos da radiação , Telômero/genética , Sequência de Bases , Humanos , Telômero/efeitos da radiação
10.
Int J Radiat Biol ; 97(9): 1206-1216, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34264173

RESUMO

PURPOSE: Intestinal damage induced by radiation exposure is a major clinic concern of radiotherapy for patients with abdominal or pelvic tumor. Melatonin (N-acetyl-5-methoxytryptamine) is likely be an ideal radioprotector to protect individuals from radiation exposure. The study aimed to define the role of melatonin in small intestinal damage caused by abdominal irradiation (ABI). MATERIALS AND METHODS: 30-day survival rate and pathological histology of the intestines from melatonin-treated mice after 13 Gy ABI exposure was first detected. Next, quantitative proteomics analysis of the small intestines tissue was examined and GO term and KEGG pathways analysis were performed. RESULTS: Melatonin treatment before ABI exposure significantly increased 30-day survival rate to 83% and ameliorated damage to the intestinal epithelial cells. Melatonin significantly altered the proteins profile of the small intestines following irradiation. For the irradiated mice treated with melatonin in comparison with the irradiated mice, the enriched GO terms were mainly involved in defense response to other organism (BP, GO: 0098542), response to other organism (BP, GO: 0051707), anion transmembrane transporter activity (MF, GO: 0008509), and secondary active transmembrane transporter activity (MF, GO: 0015291). In the process of antioxidant activity (MF, GO: 0016209), melatonin treatment prior to radiation exhibited high protein levels of Sod3 and Gpx3. The markedly KEGG pathways for melatonin treatment prior to radiation mainly included protein digestion and absorption (ko 04974) and mineral absorption (ko 04978). p53 signaling pathway and DNA repair pathways were enriched in melatonin treated mice. The amount of radiation-induced DNA damage and the cell apoptosis of the small intestines was decreased in the melatonin-treated mice. CONCLUSIONS: Melatonin may protect small intestines from radiation damage through increasing DNA repair and decreasing cell apoptosis of the small intestines. Our data provided perspective for the study of melatonin in mitigating ABI-caused intestinal damage.


Assuntos
Raios gama/efeitos adversos , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Melatonina/farmacologia , Proteômica , Protetores contra Radiação/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Dano ao DNA , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/efeitos da radiação , Intestino Delgado/citologia , Intestino Delgado/efeitos da radiação , Masculino , Camundongos
11.
Sci Rep ; 11(1): 14578, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34272409

RESUMO

Mamuju is one of the regions in Indonesia which retains natural conditions but has relatively high exposure to natural radiation. The goals of the present study were to characterize exposure of the entire Mamuju region as a high natural background radiation area (HNBRA) and to assess the existing exposure as a means for radiation protection of the public and the environment. A cross-sectional study method was used with cluster sampling areas by measuring all parameters that contribute to external and internal radiation exposures. It was determined that Mamuju was a unique HNBRA with the annual effective dose between 17 and 115 mSv, with an average of 32 mSv. The lifetime cumulative dose calculation suggested that Mamuju residents could receive as much as 2.2 Sv on average which is much higher than the average dose of atomic bomb survivors for which risks of cancer and non-cancer diseases are demonstrated. The study results are new scientific data allowing better understanding of health effects related to chronic low-dose-rate radiation exposure and they can be used as the main input in a future epidemiology study.


Assuntos
Radiação de Fundo/efeitos adversos , Exposição à Radiação/efeitos adversos , Exposição à Radiação/análise , Medição de Risco/métodos , Estudos Transversais , Raios gama/efeitos adversos , Humanos , Indonésia , Estilo de Vida , Doses de Radiação , Exposição à Radiação/prevenção & controle , Proteção Radiológica/métodos , Radônio/análise , Fatores de Risco
12.
Artigo em Inglês | MEDLINE | ID: mdl-34266630

RESUMO

In order to assess the health risk of low-dose radiation to radiation professionals, monitoring is performed through chromosomal aberration analysis and micronuclei (MN) analysis. MN formation has drawbacks for monitoring in the low-dose range. Nucleoplasmic bridge (NPB) analysis, with a lower background level, has good dose-response relationships at both high and relatively low dose ranges. Dicentric and ring chromosomes were analyzed in 199 medical radiation professionals, and NPB/MN yields were analyzed in 205 radiation professionals. The effects of sex, age of donor, types of work, and length of service on these cytogenetic endpoints were also analyzed. The yields of the three cytogenetic endpoints were significantly higher in radiation professionals versus controls. Frequencies of dicentric plus ring chromosomes were affected by length of service. NPB frequencies were influenced by type of work and length of service. MN yields were affected not only by types of work and length of service but also by donor sex and age. In conclusion, dicentric plus ring chromosomes, NPB, and MN can be induced by low-dose radiation in radiation professionals. NPB is a potential biomarker to assess the health risk of occupational low-dose radiation exposure.


Assuntos
Raios gama/efeitos adversos , Linfócitos/efeitos da radiação , Exposição Ocupacional/efeitos adversos , Lesões por Radiação/genética , Adulto , Idoso , Núcleo Celular/efeitos da radiação , Aberrações Cromossômicas/efeitos da radiação , Análise Citogenética/métodos , Citogenética/métodos , Dano ao DNA/efeitos da radiação , Feminino , Humanos , Masculino , Micronúcleos com Defeito Cromossômico/efeitos da radiação , Testes para Micronúcleos/métodos , Pessoa de Meia-Idade , Radiação Ionizante , Adulto Jovem
13.
Environ Mol Mutagen ; 62(7): 422-427, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34296472

RESUMO

It is well-known that the cytotoxicity and mutagenic effects of high dose rate (HDR) ionizing radiation (IR) are increased by increasing the dose but less is known about the effects of chronic low dose rate (LDR). In vitro, we have shown that in addition to the immediate interaction of IR with DNA (the direct and indirect effects), low doses and chronic LDR exposure induce endogenous oxidative stress. During elevated oxidative stress, reactive oxygen species (ROS) react with DNA modifying its structure. Here, BL6 mice were exposed to IR at LDR and HDR and were then sacrificed 3 hours and 3 weeks after exposure to examine early and late effects of IR. The levels of micronuclei, MN, were determined in bone marrow cells. Our data indicate that the effects of 200 mGy on MN-induction are transient, but 500 and 1000 mGy (both HDR and LDR) lead to increased levels of MN up to 3 weeks after the exposure.


Assuntos
Células da Medula Óssea/patologia , Raios gama/efeitos adversos , Micronúcleos com Defeito Cromossômico/efeitos da radiação , Irradiação Corporal Total/efeitos adversos , Animais , Células da Medula Óssea/efeitos da radiação , Relação Dose-Resposta à Radiação , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Testes para Micronúcleos
14.
Nat Commun ; 12(1): 3279, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34078883

RESUMO

Targeting the molecular pathways underlying the cardiotoxicity associated with thoracic irradiation and doxorubicin (Dox) could reduce the morbidity and mortality associated with these anticancer treatments. Here, we find that vascular endothelial cells (ECs) with persistent DNA damage induced by irradiation and Dox treatment exhibit a fibrotic phenotype (endothelial-mesenchymal transition, EndMT) correlating with the colocalization of L1CAM and persistent DNA damage foci. We demonstrate that treatment with the anti-L1CAM antibody Ab417 decreases L1CAM overexpression and nuclear translocation and persistent DNA damage foci. We show that in whole-heart-irradiated mice, EC-specific p53 deletion increases vascular fibrosis and the colocalization of L1CAM and DNA damage foci, while Ab417 attenuates these effects. We also demonstrate that Ab417 prevents cardiac dysfunction-related decrease in fractional shortening and prolongs survival after whole-heart irradiation or Dox treatment. We show that cardiomyopathy patient-derived cardiovascular ECs with persistent DNA damage show upregulated L1CAM and EndMT, indicating clinical applicability of Ab417. We conclude that controlling vascular DNA damage by inhibiting nuclear L1CAM translocation might effectively prevent anticancer therapy-associated cardiotoxicity.


Assuntos
Anticorpos Neutralizantes/farmacologia , Cardiomiopatias/prevenção & controle , Cardiotoxicidade/prevenção & controle , Doxorrubicina/toxicidade , Raios gama/efeitos adversos , Molécula L1 de Adesão de Célula Nervosa/genética , Animais , Antibióticos Antineoplásicos/toxicidade , Cardiomiopatias/etiologia , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Cardiotoxicidade/etiologia , Cardiotoxicidade/genética , Cardiotoxicidade/metabolismo , Estudos de Casos e Controles , Técnicas de Cocultura , Dano ao DNA , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Células Endoteliais/efeitos da radiação , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos da radiação , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Miócitos Cardíacos/efeitos da radiação , Molécula L1 de Adesão de Célula Nervosa/antagonistas & inibidores , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genética
15.
Int J Radiat Biol ; 97(9): 1252-1260, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34138661

RESUMO

PURPOSE: The cytokinesis-block micronucleus (MN) assay is a widely used technique in basic radiobiology research, human biomonitoring studies and in vitro radiosensitivity testing. Fresh whole blood cultures are commonly used for these purposes, but immediate processing of fresh samples can be logistically challenging. Therefore, we aimed at establishing a protocol for the MN assay on cryopreserved whole blood, followed by a thorough evaluation of the reliability of this assay for use in radiosensitivity assessment in patients. MATERIALS AND METHODS: Whole blood samples of 20 healthy donors and 4 patients with a primary immunodeficiency disease (PID) were collected to compare the results obtained with the MN assay performed on fresh versus cryopreserved whole blood samples. MN yields were scored after irradiation with 220 kV X-rays (dose rate 3 Gy/min), with doses ranging from 0.5-2 Gy. RESULTS: The application of the MN assay on cryopreserved blood samples was successful in all analyzed samples. The radiation-induced MN and NDI scores in fresh and cryopreserved blood cultures were found to be similar. Acceptable inter-individual and intra-individual variabilities in MN yields were observed. Repeated analysis of cryopreserved blood cultures originating from the same blood sample, thawed at different time points, revealed that MN values remain stable for cryopreservation periods up to one year. Finally, radiosensitive patients were successfully identified using the MN assay on cryopreserved samples. CONCLUSIONS: To our knowledge, this study is the first report of the successful use of cryopreserved whole blood samples for application of the MN assay. The data presented here demonstrate that the MN assay performed on cryopreserved whole blood is reliable for radiosensitivity testing. Our results also support its wider use in epidemiological, biomonitoring and genotoxicity studies. The presented method of cryopreservation of blood samples might also benefit other assays.


Assuntos
Células Sanguíneas/citologia , Células Sanguíneas/efeitos da radiação , Criopreservação , Citocinese/genética , Citocinese/efeitos da radiação , Feminino , Raios gama/efeitos adversos , Humanos , Masculino , Testes para Micronúcleos , Tolerância a Radiação
16.
Radiat Res ; 196(3): 284-296, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34153091

RESUMO

Thrombocytopenia is a major complication in hematopoietic-acute radiation syndrome (H-ARS) that increases the risk of mortality from uncontrolled hemorrhage. There is a great demand for new therapies to improve survival and mitigate bleeding in H-ARS. Thrombopoiesis requires interactions between megakaryocytes (MKs) and endothelial cells. 16, 16-dimethyl prostaglandin E2 (dmPGE2), a longer-acting analogue of PGE2, promotes hematopoietic recovery after total-body irradiation (TBI), and various angiotensin-converting enzyme (ACE) inhibitors mitigate endothelial injury after radiation exposure. Here, we tested a combination therapy of dmPGE2 and lisinopril to mitigate thrombocytopenia in murine models of H-ARS following TBI. After 7.75 Gy TBI, dmPGE2 and lisinopril each increased survival relative to vehicle controls. Importantly, combined dmPGE2 and lisinopril therapy enhanced survival greater than either individual agent. Studies performed after 4 Gy TBI revealed reduced numbers of marrow MKs and circulating platelets. In addition, sublethal TBI induced abnormalities both in MK maturation and in in vitro and in vivo platelet function. dmPGE2, alone and in combination with lisinopril, improved recovery of marrow MKs and peripheral platelets. Finally, sublethal TBI transiently reduced the number of marrow Lin-CD45-CD31+Sca-1- sinusoidal endothelial cells, while combined dmPGE2 and lisinopril treatment, but not single-agent treatment, accelerated their recovery. Taken together, these data support the concept that combined dmPGE2 and lisinopril therapy improves thrombocytopenia and survival by promoting recovery of the MK lineage, as well as the MK niche, in the setting of H-ARS.


Assuntos
16,16-Dimetilprostaglandina E2/uso terapêutico , Síndrome Aguda da Radiação/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Plaquetas/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Transtornos Hemorrágicos/tratamento farmacológico , Lisinopril/uso terapêutico , Megacariócitos/efeitos dos fármacos , Trombocitopenia/tratamento farmacológico , Trombopoese/efeitos dos fármacos , Síndrome Aguda da Radiação/complicações , Animais , Plaquetas/efeitos da radiação , Medula Óssea/efeitos dos fármacos , Medula Óssea/efeitos da radiação , Proteína C-Reativa/análise , Radioisótopos de Césio , Avaliação Pré-Clínica de Medicamentos , Células Endoteliais/efeitos da radiação , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/efeitos da radiação , Feminino , Raios gama/efeitos adversos , Transtornos Hemorrágicos/etiologia , Megacariócitos/efeitos da radiação , Camundongos , Camundongos Endogâmicos C57BL , Selectina-P/análise , Agregação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos da radiação , Fator Plaquetário 4/análise , Lesões Experimentais por Radiação/tratamento farmacológico , Lesões Experimentais por Radiação/etiologia , Trombocitopenia/etiologia , Trombopoese/efeitos da radiação , Irradiação Corporal Total , Fator de von Willebrand/análise
17.
An. Facultad Med. (Univ. Repúb. Urug., En línea) ; 8(1): e203, jun. 2021. tab, graf
Artigo em Espanhol | LILACS, BNUY, UY-BNMED | ID: biblio-1248717

RESUMO

El vino tinto variedad Vitis vinifera L. cv Tannat en los últimos años ha tomado relevancia por su alta concentración de polifenoles, esto le podría significar un rol protector sobre el genoma disminuyendo la formación de lesiones oxidativas. Los efectos a nivel celular de las radiaciones ionizantes en blancos como el ADN, componentes de cascadas de transducción de señales, resultan en lesiones letales, mutagénicas y recombinogénicas y en retardos en el ciclo celular. Se utilizó como modelo eucariota poblaciones de Saccharomyces cerevisiae en fase exponencial expuestas a radiación gamma (200 Gy) en presencia, o ausencia, de vino Tannat (10 % v/v) o de ácido tánico (60 µg/mL). Se estimaron las probabilidades de sobrevida y frecuencia mutagénica en distintas condiciones. Las muestras celulares expuestas a radiación ionizante presentaron una fracción de sobrevida de 0.21 ± 0.02 mientras que en las muestras irradiadas en presencia de vino Tannat o de ácido tánico la fracción de sobrevida fue de 0.33 ± 0.03 y 0.30 ± 0.03 respectivamente. Se observó en las poblaciones irradiadas un aumento significativo de la probabilidad de mutagénesis. En el caso de los tratamientos combinados se observó que la frecuencia mutagénica fue significativamente menor (gamma Tannat: 33%, gamma ácido tánico: 45% ). Estos resultados preliminares podrían indicar radioprotección moderada por parte de los compuestos estudiados, efecto que podría explicarse por las interacciones redox del ácido tánico y polifenoles contenidos en el vino con los radicales libres formados por las radiaciones ionizantes, además de la activación de vías de reparación genómica.


The red wine variety Vitis vinifera L. cv Tannat in recent years has gained relevance due to its high concentration of polyphenols, this could mean a protective role on the genome, reducing the formation of oxidative lesions. The effects at the cellular level of ionizing radiation on targets such as DNA, components of signal transduction cascades, result in lethal, mutagenic and recombinogenic lesions and delays in the cell cycle. Exponential phase populations of Saccharomyces cerevisiae exposed to gamma radiation (200 Gy) in the presence or absence of Tannat wine (10% v / v) or tannic acid (60 µg / ml) were used as a eukaryotic model. The probabilities of survival and mutagenic frequency in different conditions were estimated. Cellular samples exposed to ionizing radiation presented a survival fraction of 0.21 ± 0.02, while in samples irradiated in the presence of Tannat wine or tannic acid, the survival fraction was 0.33 ± 0.03 and 0.30 ± 0.03 respectively. A significant increase in the probability of mutagenesis was observed in irradiated populations. In the case of the combined treatments, it was observed that the mutagenic frequency was significantly lower (Tannat gamma: 33%, Tannic acid gamma: 45%). These preliminary results could indicate moderate radioprotection by the compounds studied, an effect that could be explained by the redox interactions of tannic acid and polyphenols contained in wine with the free radicals formed by ionizing radiation, in addition to the activation of genomic repair pathways.


A variedade de vinho tinto Vitis vinifera L. cv Tannat nos últimos anos tem ganhado relevância devido à sua alta concentração de polifenóis, o que pode significar um papel protetor do genoma, reduzindo a formação de lesões oxidativas. Os efeitos no nível celular da radiação ionizante em alvos como o DNA, componentes de cascatas de transdução de sinal, resultam em lesões letais, mutagênicas e recombinogênicas e atrasos no ciclo celular. Populações de fase exponencial de Saccharomyces cerevisiae expostas à radiação gama (200 Gy) na presença ou ausência de vinho Tannat (10% v / v) ou ácido tânico (60 µg / ml) foram utilizadas como modelo eucariótico. Foram estimadas as probabilidades de sobrevivência e frequência mutagênica em diferentes condições. As amostras celulares expostas à radiação ionizante apresentaram uma fração de sobrevivência de 0,21 ± 0,02, enquanto nas amostras irradiadas na presença de vinho Tannat ou ácido tânico, a fração de sobrevivência foi de 0,33 ± 0,03 e 0,30 ± 0,03, respectivamente. Um aumento significativo na probabilidade de mutagênese foi observado nas populações irradiadas. No caso dos tratamentos combinados, observou-se que a frequência mutagênica foi significativamente menor (Tannat gama: 33%, ácido tânico gama: 45%). Esses resultados preliminares podem indicar radioproteção moderada pelos compostos estudados, efeito que pode ser explicado pelas interações redox do ácido tânico e polifenóis contidos no vinho com os radicais livres formados pela radiação ionizante, além da ativação de vias de reparo genômico.


Assuntos
Animais , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Taninos/farmacologia , Mutagênese/efeitos dos fármacos , Polifenóis/farmacologia , Raios gama/efeitos adversos , Protetores contra Radiação/farmacologia , Taxa de Sobrevida , Quimioterapia Combinada , Taxa de Mutação
18.
Sci Rep ; 11(1): 11452, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34075076

RESUMO

Using a ground-based model to simulate spaceflight [21-days of single-housed, hindlimb unloading (HLU) combined with continuous low-dose gamma irradiation (LDR, total dose of 0.04 Gy)], an in-depth survey of the immune and hematological systems of mice at 7-days post-exposure was performed. Collected blood was profiled with a hematology analyzer and spleens were analyzed by whole transcriptome shotgun sequencing (RNA-sequencing). The results revealed negligible differences in immune differentials. However, hematological system analyses of whole blood indicated large disparities in red blood cell differentials and morphology, suggestive of anemia. Murine Reactome networks indicated majority of spleen cells displayed differentially expressed genes (DEG) involved in signal transduction, metabolism, cell cycle, chromatin organization, and DNA repair. Although immune differentials were not changed, DEG analysis of the spleen revealed expression profiles associated with inflammation and dysregulated immune function persist to 1-week post-simulated spaceflight. Additionally, specific regulation pathways associated with human blood disease gene orthologs, such as blood pressure regulation, transforming growth factor-ß receptor signaling, and B cell differentiation were noted. Collectively, this study revealed differential immune and hematological outcomes 1-week post-simulated spaceflight conditions, suggesting recovery from spaceflight is an unremitting process.


Assuntos
Raios gama/efeitos adversos , Hematopoese/imunologia , Hematopoese/efeitos da radiação , Elevação dos Membros Posteriores , Transdução de Sinais/efeitos da radiação , Animais , Relação Dose-Resposta à Radiação , Feminino , Camundongos
19.
Sci Rep ; 11(1): 11449, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34075191

RESUMO

To date, the United States Food and Drug Administration (FDA) has approved four drugs to mitigate hematopoietic acute radiation syndrome and all four are repurposed radiomitigators. There are several additional drug candidates currently under evaluation that may also be helpful for use during a widespread emergency. One possible candidate is Ex-Rad, also known as ON01210, a chlorobenzyl sulfone derivative (organosulfur compound), which is a novel, small-molecule kinase inhibitor with demonstrated efficacy in the murine model. In this study, we have evaluated the metabolomic and lipidomic profiles in serum samples of nonhuman primates (NHPs) treated with Ex-Rad after exposure to ionizing radiation. Two different dose administration schedules (Ex-Rad I administered 24 and 36 h post-irradiation, and Ex-Rad II administered 48 and 60 h post-irradiation), were used and evaluated using a global molecular profiling approach. We observed alterations in biochemical pathways relating to inflammation and oxidative stress after radiation exposure that were alleviated in animals that received Ex-Rad I or Ex-Rad II. The results from this study lend credence to the possible radiomitigative effects of this drug possibly via a dampening of metabolism-based tissue injury, thus aiding in recovery of vital, radiation-injured organ systems.


Assuntos
Raios gama/efeitos adversos , Metaboloma , Lesões Experimentais por Radiação , Sulfonamidas/farmacologia , Animais , Macaca mulatta , Masculino , Metaboloma/efeitos dos fármacos , Metaboloma/efeitos da radiação , Lesões Experimentais por Radiação/sangue , Lesões Experimentais por Radiação/tratamento farmacológico
20.
Sci Rep ; 11(1): 13498, 2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34188100

RESUMO

Mitotic cell fusion induced Premature Chromosome Condensation (G0-PCC) assay in human lymphocytes allows rapid detection of cytogenetic damage in interphase stage, within few hours after blood collection. Hence, it is the most suitable method for rapid and high dose biodosimetry. Mitotic cells, used for G0-PCC could be either freshly isolated or previously cryo-preserved. However, under emergency scenarios, only cryo-preserved cells can be relied upon, fresh isolation will only delay the process by 18-24 h. Impact of cryopreservation on mitotic cells and their efficacy to induce PCC are not reported. In the present study, we investigated effect of cryopreservation on mitotic cells and refined the parameters for G0-PCC. More than 95% of the cells were recoverable after 4 months of cryopreservation, within 20 min recovery at 37 °C, without significant change in the mitotic index or viability. Recovered mitotic cells have shown mitotic index of 89 ± 4% and viability of 90 ± 4%, similar to that of freshly isolated cells. Decrease in metaphases was observed within 40 min after recovery as the mitotic cells progressed through cell cycle and reduced to 21% at 1.5 h. Nevertheless, in presence of Colcemid, the cells progressed slowly and considerably high metaphase index (60%) persisted up to ~ 2 h. The recovered cells efficiently fused with lymphocytes and induced PCC. Average PCC index varied from 10 to 20%, which did not change with cryopreservation duration. Post fusion incubation duration of 2 h was found to be optimum for proper chromosome condensation. In conclusion, use of cryo-preserved mitotic cells is the most practical approach for rapid biodosimetry. The cells can be recovered quickly and efficiently without alteration in viability or mitotic index. Recovered cells are fully competent to induce G0-PCC.


Assuntos
Aberrações Cromossômicas/efeitos da radiação , Cromossomos Humanos , Criopreservação , Raios gama/efeitos adversos , Linfócitos/metabolismo , Mitose/efeitos da radiação , Humanos , Linfócitos/patologia , Doses de Radiação , Radiometria
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