RESUMO
In patients with high-level radiation exposure, gastrointestinal injury is the main cause of death. Despite the severity of damage to the gastrointestinal tract, no specific therapeutic option is available. Tauroursodeoxycholic acid (TUDCA) is a conjugated form of ursodeoxycholic acid that suppresses endoplasmic reticulum (ER) stress and regulates various cell-signaling pathways. We investigated the effect of TUDCA premedication in alleviating intestinal damage and enhancing the survival of C57BL/6 mice administered a lethal dose (15Gy) of focal abdominal irradiation. TUDCA was administered to mice 1 h before radiation exposure, and reduced apoptosis of the jejunal crypts 12 h after irradiation. At later timepoint (3.5 days), irradiated mice manifested intestinal morphological changes that were detected via histological examination. TUDCA decreased the inflammatory cytokine levels and attenuated the decrease in serum citrulline levels after radiation exposure. Although radiation induced ER stress, TUDCA pretreatment decreased ER stress in the irradiated intestinal cells. The effect of TUDCA indicates the possibility of radiation therapy for cancer in tumor cells. TUDCA did not affect cell proliferation and apoptosis in the intestinal epithelium. TUDCA decreased the invasive ability of the CT26 metastatic colon cancer cell line. Reduced invasion after TUDCA treatment was associated with decreased matrix metalloproteinase (MMP)-7 and MMP-13 expression, which play important roles in invasion and metastasis. This study shows a potential role of TUDCA in protecting against radiation-induced intestinal damage and inhibiting tumor cell migration without any radiation and radiation therapy effect.
Assuntos
Apoptose , Estresse do Retículo Endoplasmático , Camundongos Endogâmicos C57BL , Protetores contra Radiação , Ácido Tauroquenodesoxicólico , Animais , Ácido Tauroquenodesoxicólico/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos da radiação , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Protetores contra Radiação/farmacologia , Camundongos , Masculino , Intestinos/efeitos da radiação , Intestinos/efeitos dos fármacos , Intestinos/patologia , Modelos Animais de Doenças , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos da radiação , Mucosa Intestinal/patologia , Mucosa Intestinal/metabolismo , Lesões Experimentais por Radiação/prevenção & controle , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/tratamento farmacológico , Lesões Experimentais por Radiação/metabolismo , Metaloproteinase 13 da Matriz/metabolismo , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiaçãoRESUMO
Welding fumes contain harmful metals and gas by-products associated with development of lung dysfunction, asthma, bronchitis, and lung cancer. Two prominent welding fume particulate metal components are nanosized iron (Fe) and manganese (Mn) which might induce oxidative stress and inflammation resulting in pulmonary injury. Welding fume toxicity may be dependent upon metal nanoparticle (NP) components. To examine toxicity of welding fume NP components, a system was constructed for controlled and continuous NP generation from commercial welding and customized electrodes with varying proportions of Fe and Mn. Aerosols generated consisted of nanosized particles and were compositionally consistent with each electrode. Human alveolar lung A459 epithelial cells were exposed to freshly generated metal NP mixtures at a target concentration of 100 µg/m3 for 6 hr and then harvested for assessment of cytotoxicity, generation of reactive oxygen species (ROS), and alterations in the expression of genes and proteins involved in metal regulation, inflammatory responses, and oxidative stress. Aerosol exposures decreased cell viability and induced increased ROS production. Assessment of gene expression demonstrated variable up-regulation in cellular mechanisms related to metal transport and storage, inflammation, and oxidative stress based upon aerosol composition. Specifically, interleukin-8 (IL-8) demonstrated the most robust changes in both transcriptional and protein levels after exposure. Interleukin-8 has been determined to serve as a primary cytokine mediating inflammatory responses induced by welding fume exposures in alveolar epithelial cells. Overall, this study demonstrated variations in cellular responses to metal NP mixtures suggesting compositional variations in NP content within welding fumes may influence inhalation toxicity.
Assuntos
Ferro , Pulmão , Manganês , Nanopartículas Metálicas , Exposição Ocupacional , Soldagem , Nanopartículas Metálicas/toxicidade , Ferro/toxicidade , Manganês/toxicidade , Humanos , Células A549 , Eletrodos , Espécies Reativas de Oxigênio/análise , Proteínas de Transporte de Cátions/genética , Inflamação/induzido quimicamente , Citocinas/análise , Quimiocinas/análise , Transferrina/análise , Pulmão/patologiaRESUMO
All eukaryotic cells, including oocytes, utilize an engine called cyclin-dependent kinase (Cdk) to drive the cell cycle. Cdks are activated by a co-factor called cyclin, which regulates their activity. The key Cdk-cyclin complex that regulates the oocyte cell cycle is known as Cdk1-cyclin B1. Recent studies have elucidated the roles of other cyclins, such as B2, B3, A2, and O, in oocyte cell cycle regulation. This review aims to discuss the recently discovered roles of various cyclins in mouse oocyte cell cycle regulation in accordance with the sequential progression of the cell cycle. In addition, this review addresses the translation and degradation of cyclins to modulate the activity of Cdks. Overall, the literature indicates that each cyclin performs unique and redundant functions at various stages of the cell cycle, while their expression and degradation are tightly regulated. Taken together, this review provides new insights into the regulatory role and function of cyclins in oocyte cell cycle progression.
Assuntos
Ciclinas , Oócitos , Animais , Camundongos , Ciclo Celular , Divisão Celular , Células Eucarióticas , Quinases Ciclina-DependentesRESUMO
The adverse effects of radiation are proportional to the total dose and dose rate. We aimed to investigate the effects of radiation dose rate on different organs in mice. The mice were subjected to low dose rate (LDR, ~3.4 mGy/h) and high dose rate (HDR, ~51 Gy/h) radiation. LDR radiation caused severe tissue toxicity, as observed in the histological analysis of testis. It adversely influenced sperm production, including sperm count and motility, and induced greater sperm abnormalities. The expression of markers of early stage spermatogonial stem cells, such as Plzf, c-Kit, and Oct4, decreased significantly after LDR irradiation, compared to that following exposure of HDR radiation, in qPCR analysis. The compositional ratios of all stages of spermatogonia and meiotic cells, except round spermatid, were considerably reduced by LDR in FACS analysis. Therefore, LDR radiation caused more adverse testicular damage than that by HDR radiation, contrary to the response observed in other organs. Therefore, the dose rate of radiation may have differential effects, depending on the organ; it is necessary to evaluate the effect of radiation in terms of radiation dose, dose rate, organ type, and other conditions.
Assuntos
Espermatogênese/efeitos da radiação , Testículo/efeitos da radiação , Animais , Relação Dose-Resposta à Radiação , Raios gama , Masculino , Camundongos , Modelos Animais , Doses de Radiação , Espermátides/citologia , Espermátides/efeitos da radiação , Espermatogônias/citologia , Espermatogônias/efeitos da radiação , Espermatozoides/citologia , Espermatozoides/efeitos da radiação , Testículo/citologiaRESUMO
BACKGROUND: The relationship between visceral adiposity and the incidence of functional dyspepsia (FD) has not yet been studied. The purpose of the present study is to evaluate the association between visceral adiposity and the risk of FD. METHODS: This is a case-control study that compares the abdominal adipose tissue area between subjects with FD and control subjects without FD, who underwent abdomen computerized tomography (CT) for health examinations in a tertiary center. Retrospectively, a telephone survey was conducted to diagnose FD using the Rome III criteria. We measured various indices of obesity including body mass index (BMI), waist circumference (WC), visceral adipose tissue (VAT) area, subcutaneous adipose tissue (SAT) area and the VAT/SAT ratio in order to evaluate the association between FD and abdominal adiposity. KEY RESULTS: A total of 363 subjects were included in the present study. FD was diagnosed in 90 subjects (24.8%). In the univariate analysis, WC, VAT area, TAT area, VAT/SAT ratio, and the presence of erosive esophagitis were significantly higher in the FD group than in the non-FD group. In the multivariate analysis, a higher VAT area (odds ratio (OR), 3.76; 95% confidence interval (CI), 1.24-11.40; highest quartile vs lowest quartile, p = 0.019) and VAT/SAT ratio (OR, 2.35; 95% CI, 1.27-4.32; highest quartile vs lowest quartile, p = 0.006) were independently associated with a risk of FD. CONCLUSION AND INFERENCES: Visceral adiposity as measured by the VAT area and VAT/SAT ratio is associated with an increased risk of FD.
Assuntos
Dispepsia/etiologia , Gordura Intra-Abdominal/patologia , Obesidade Abdominal/complicações , Adulto , Análise de Variância , Índice de Massa Corporal , Estudos de Casos e Controles , Dispepsia/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade Abdominal/diagnóstico , Risco , Gordura Subcutânea/patologia , Circunferência da CinturaRESUMO
OBJECTIVES: There are several studies considering obesity as the risk factor for various lower gastrointestinal symptoms. But the relationship between visceral abdominal obesity and the incidence of irritable bowel syndrome (IBS) is not studied yet. The aim of this study was to investigate the association between visceral adipose tissue (VAT) and the risk of IBS. METHODS: This is a case-control study comparing the VAT area between subjects with IBS (IBS group) and controls without IBS (non IBS group), who underwent abdomen computerized tomography (CT) for routine health checkup from January 2012 to August 2013 in a health promotion center. A telephone survey was retrospectively conducted to diagnose IBS by Rome III criteria. The association between IBS and abdominal obesity was evaluated by measuring VAT, subcutaneous adipose tissue (SAT), VAT/SAT ratio, body mass index (BMI) and waist circumference (WC). RESULTS: The prevalence of IBS was 19.9% (67/336) among all enrolled subjects. In the univariate analysis, VAT area, VAT/SAT ratio, waist circumference, the presence of reflux esophagitis and the ratio of females were significantly higher in the IBS group than in the non IBS group. However, a higher BMI or a higher SAT area is not associated with an increased risk of IBS. In the multivariate analysis, a higher VAT area (odds ratio (OR)=9.42, 95% confidence interval (CI): 2.90-30.64, highest tertile vs. lowest tertile, P=0.001), VAT/SAT ratio (OR=10.15, 95% CI: 3.05-33.58, highest tertile vs. lowest tertile, P=0.001) and waist circumference (OR=7.81, 95% CI: 2.13-28.66, highest tertile vs. lowest tertile, P=0.002) were independently associated with a risk of IBS. Only in the IBS-D group, not in the IBS-C, visceral adiposity was associated with an increased risk of IBS. CONCLUSIONS: Visceral adiposity measured by VAT, VAT/SAT, and waist circumference is associated with an increased risk of IBS, especially of IBS-D. However, neither SAT nor BMI are associated with an increased risk of IBS.
Assuntos
Constipação Intestinal/epidemiologia , Diarreia/epidemiologia , Esofagite Péptica/epidemiologia , Síndrome do Intestino Irritável/epidemiologia , Obesidade Abdominal/epidemiologia , Adulto , Índice de Massa Corporal , Constipação Intestinal/etiologia , Diarreia/etiologia , Endoscopia do Sistema Digestório , Feminino , Humanos , Gordura Intra-Abdominal/diagnóstico por imagem , Síndrome do Intestino Irritável/complicações , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Obesidade Abdominal/diagnóstico por imagem , República da Coreia/epidemiologia , Fatores de Risco , Fatores Sexuais , Gordura Subcutânea/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Circunferência da CinturaRESUMO
BACKGROUND: Silibinin has been known for its role in anti-cancer and radio-protective effect. Radiation therapy for treating lung cancer might lead to late-phase pulmonary inflammation and fibrosis. Thus, this study aimed to investigate the effects of silibinin in radiation-induced lung injury with a mouse model. METHODS: In this study, we examined the ability of silibinin to mitigate lung injury in, and improve survival of, C57BL/6 mice given 13 Gy thoracic irradiation and silibinin treatments orally at 100 mg/kg/day for seven days after irradiation. In addition, Lewis lung cancer (LLC) cells were injected intravenously in C57BL/6 mice to generate lung tumor nodules. Lung tumor-bearing mice were treated with lung radiation therapy at 13 Gy and with silibinin at a dose of 100 mg/day for seven days after irradiation. RESULTS: Silibinin was shown to increase mouse survival, to ameliorate radiation-induced hemorrhage, inflammation and fibrosis in lung tissue, to reduce the number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) and to reduce inflammatory cell infiltration in the respiratory tract. In LLC tumor injected mice, lung tissue from mice treated with both radiation and silibinin showed no differences compared to lung tissue from mice treated with radiation alone. CONCLUSIONS: Silibinin treatment mitigated the radiation-induced lung injury possibly by reducing inflammation and fibrosis, which might be related with the improved survival rate. Silibinin might be a useful agent for lung cancer patients as a non-toxic complementary approach to alleviate the side effects by thorax irradiation.
Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Experimentais , Lesões Experimentais por Radiação/tratamento farmacológico , Silimarina/administração & dosagem , Lesão Pulmonar Aguda/etiologia , Administração Oral , Animais , Antioxidantes/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Neoplasias Pulmonares/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Silybum marianum , Lesões Experimentais por Radiação/complicações , SilibinaRESUMO
BACKGROUND: Neuroendocrine tumors (NETs) of the esophagus are extremely rare, and few cases have been reported worldwide. Thus, a comprehensive nationwide study is needed to understand the characteristics of and treatment strategy for esophageal NETs. METHODS: We collected data on esophageal NET patients from 25 hospitals in Korea from 2002-2012. The incidence, location, clinical symptoms, histopathology, treatment response, and the biochemical, radiologic and endoscopic characteristics of esophageal NETs were surveyed. RESULTS: Among 2,037 NETs arising in different gastrointestinal sites, esophageal NETs were found in 26 cases (1.3%). The mean patient age was 60.12 ± 9.30 years with a 4:1 male predominance. In endoscopic findings, 76.9% (20/26) of NETs were located in the lower third of the esophagus and the mean size was 2.34 ± 1.63 cm. At diagnosis, more than half the patients (15/26, 57.7%) had regional lymph node metastasis or widespread metastasis. Endoscopic resection was conducted in three cases, and in all three of them, lymph node metastasis was not found and tumor size was below 1.0 cm. All tumors were completely removable through endoscopic procedures and there was no recurrence during the follow-up period. Eighteen other patients received an operation, chemotherapy or both. Among them, nine patients (50.0%) expired because of the progression of their cancer or post-operative complications. In Kaplan-Meier survival analysis, only tumor size (more than 2.0 cm) showed prognostic significance (P = 0.045). CONCLUSIONS: Despite the general assumption that gastrointestinal NETs are benign and slow-growing tumors, the prognosis of advanced esophageal NETs is not favorable.
Assuntos
Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/terapia , Idoso , Neoplasias Esofágicas/epidemiologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Tumores Neuroendócrinos/epidemiologia , Prognóstico , República da Coreia/epidemiologiaRESUMO
BACKGROUND: Although epidemiologic and animal studies suggest a vegetarian diet protects against the development of colorectal cancer, the relationship between vegetarian diet and incidence of colorectal adenoma is not yet conclusive, especially for Asians. AIM: The purpose of this study was to examine the protective effect of a vegetarian diet against colorectal adenoma and advanced adenoma. METHODS: This cross-sectional study compared the prevalence of colorectal adenoma among Buddhist priests, who are obligatory vegetarians, with that among age and sex-matched controls. All the subjects underwent health checkups in a health-promotion center in Korea. RESULT: Colorectal adenoma and advanced adenoma were both more prevalent in the general population group than in the Buddhist priest group (25.2 vs. 17.9 %, 6.7 vs. 2.0 %). However, the prevalence of metabolic syndrome, high body mass index, and waist circumference were higher in the Buddhist priest group. According to univariate analysis, non-vegetarian diet (general population) significantly increased the prevalence of colorectal adenoma and advanced adenoma compared with a vegetarian diet (Buddhist priests) (OR 1.54, 95 % CI 1.08-2.21, P = 0.018; OR 3.60, 95 % CI 1.53-8.48, P = 0.003). In a conditional regression analysis model, non-vegetarian diet was also a significant risk factor for colorectal adenoma and advanced adenoma (OR 1.52, 95 % CI 0.75-2.07, P = 0.043; OR 2.94, CI 0.97-7.18, P = 0.036). CONCLUSIONS: Vegetarianism may be effective in preventing both colorectal adenoma and advanced adenoma in Asians.
Assuntos
Adenoma/prevenção & controle , Povo Asiático , Neoplasias Colorretais/prevenção & controle , Dieta Vegetariana , Adulto , Idoso , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
Inhalation of welding fumes can cause metal accumulation in the brain, leading to Parkinsonian-like symptoms. Metal accumulation and altered neurochemical profiles have been observed using magnetic resonance imaging (MRI) in highly exposed welders, being associated with decreased motor function and cognition. While MRI is impractical to use as a health risk assessment tool in occupational settings, toenail metal levels are easier to assess and have been demonstrated to reflect an exposure window of 7-12 months in the past. Yet, it is unclear whether toenail metal levels are associated with brain metal levels or changes in metabolism, which are the root of potential health concerns. This study investigates whether toenail manganese (Mn) and iron (Fe) levels, assessed at several time points, correlate with brain Mn and Fe levels, measured by MRI, as well as brain GABA, glutamate (Glu), and glutathione (GSH) levels, measured by Magnetic Resonance Spectroscopy (MRS), in seventeen Mn-exposed welders. Quantitative T1 and R2* MRI maps of the whole brain, along with GABA, Glu, and GSH MRS measurements from the thalamus and cerebellum were acquired at baseline (T0). Toenail clippings were collected at T0 and every three months after the MRI for a year to account for different exposure periods being reflected by toenail clippings and MRI. Spearman correlations of toenail metal levels were run against brain metal and metabolite levels, but no significant associations were found for Mn at any timepoint. Cerebellar GSH positively correlated with toenail Fe clipped twelve months after the MRI (p = 0.05), suggesting an association with Fe exposure at the time of the MRI. Neither thalamic GABA nor Glu correlated with toenail Fe levels. In conclusion, this study cannot support toenail Mn as a proxy for brain Mn levels or metabolic changes, while toenail Fe appears linked to brain metabolic alterations, underscoring the importance of considering other metals, including Fe, in studying Mn neurotoxicity.
RESUMO
PURPOSE: People are exposed to low-dose radiation in medical diagnosis, occupational, or life circumstances, but the effect of low-dose radiation on human health is still controversial. The biological effects of radiation below 100 mGy are still unproven. In this study, we observed the effects of low-dose radiation (100 mGy) on gene expression in human coronary artery endothelial cells (HCAECs) and its effect on molecular signaling. MATERIALS AND METHODS: HCAECs were exposed to 100 mGy ionizing radiation at 6 mGy/h (low-dose-rate) or 288 mGy/h (high-dose-rate). After 72 h, total RNA was extracted from sham or irradiated cells for Quant-Seq 3'mRNA-Seq, and bioinformatic analyses were performed using Metascape. Gene profiling was validated using qPCR. RESULTS: Compared to the non-irradiated control group, 100 mGy of ionizing radiation at 6 mGy/h altered the expression of 194 genes involved in signaling pathways related to heart contraction, blood circulation, and cardiac myofibril assembly differentially. However, 100 mGy at 288 mGy/h altered expression of 450 genes involved in cell cycle-related signaling pathways, including cell division, nuclear division, and mitosis differentially. Additionally, gene signatures responding to low-dose radiation, including radiation dose-specific gene profiles (HIST1H2AI, RAVER1, and POTEI) and dose-rate-specific gene profiles (MYL2 for the low-dose-rate and DHRS9 and CA14 for the high-dose-rate) were also identified. CONCLUSIONS: We demonstrated that 100 mGy low-dose radiation could alter gene expression and molecular signaling pathways at the low-dose-rate and the high-dose-rate differently. Our findings provide evidence for further research on the potential impact of low-dose radiation on cardiovascular function.
Assuntos
Biologia Computacional , Vasos Coronários , Relação Dose-Resposta à Radiação , Células Endoteliais , Transcriptoma , Humanos , Vasos Coronários/efeitos da radiação , Vasos Coronários/citologia , Células Endoteliais/efeitos da radiação , Células Endoteliais/metabolismo , Transcriptoma/efeitos da radiação , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos da radiação , Doses de Radiação , Transdução de Sinais/efeitos da radiaçãoRESUMO
PURPOSE: The dicentric chromosome assay (DCA), often referred to as the 'gold standard' in radiation dose estimation, exhibits significant challenges as a consequence of its labor-intensive nature and dependency on expert knowledge. Existing automated technologies face limitations in accurately identifying dicentric chromosomes (DCs), resulting in decreased precision for radiation dose estimation. Furthermore, in the process of identifying DCs through automatic or semi-automatic methods, the resulting distribution could demonstrate under-dispersion or over-dispersion, which results in significant deviations from the Poisson distribution. In response to these issues, we developed an algorithm that employs deep learning to automatically identify chromosomes and perform fully automatic and accurate estimation of diverse radiation doses, adhering to a Poisson distribution. MATERIALS AND METHODS: The dataset utilized for the dose estimation algorithm was generated from 30 healthy donors, with samples created across seven doses, ranging from 0 to 4 Gy. The procedure encompasses several steps: extracting images for dose estimation, counting chromosomes, and detecting DC and fragments. To accomplish these tasks, we utilize a diverse array of artificial neural networks (ANNs). The identification of DCs was accomplished using a detection mechanism that integrates both deep learning-based object detection and classification methods. Based on these detection results, dose-response curves were constructed. A dose estimation was carried out by combining a regression-based ANN with the Monte-Carlo method. RESULTS: In the process of extracting images for dose analysis and identifying DCs, an under-dispersion tendency was observed. To rectify the discrepancy, classification ANN was employed to identify the results of DC detection. This approach led to satisfaction of Poisson distribution criteria by 32 out of the initial pool of 35 data points. In the subsequent stage, dose-response curves were constructed using data from 25 donors. Data provided by the remaining five donors served in performing dose estimations, which were subsequently calibrated by incorporating a regression-based ANN. Of the 23 points, 22 fell within their respective confidence intervals at p < .05 (95%), except for those associated with doses at levels below 0.5 Gy, where accurate calculation was obstructed by numerical issues. The accuracy of dose estimation has been improved for all radiation levels, with the exception of 1 Gy. CONCLUSIONS: This study successfully demonstrates a high-precision dose estimation method across a general range up to 4 Gy through fully automated detection of DCs, adhering strictly to Poisson distribution. Incorporating multiple ANNs confirms the ability to perform fully automated radiation dose estimation. This approach is particularly advantageous in scenarios such as large-scale radiological incidents, improving operational efficiency and speeding up procedures while maintaining consistency in assessments. Moreover, it reduces potential human error and enhances the reliability of results.
Assuntos
Aberrações Cromossômicas , Redes Neurais de Computação , Doses de Radiação , Humanos , Aberrações Cromossômicas/efeitos da radiação , Relação Dose-Resposta à Radiação , Algoritmos , Distribuição de Poisson , Aprendizado ProfundoRESUMO
Although there are several types of radiation exposure, it is debated whether lowdoserate (LDR) irradiation (IR) affects the body. Since the small intestine is a radiationsensitive organ, the present study aimed to evaluate how it changes when exposed to LDR IR and identify the genes sensitive to these doses. After undergoing LDR (6.0 mGy/h) γ radiation exposure, intestinal RNA from BALB/c mice was extracted 1 and 24 h later. Mouse whole genome microarrays were used to explore radiationinduced transcriptional alterations. Reverse transcriptionquantitative (RTq) PCR was used to examine time and dosedependent radiation responses. The histopathological status of the jejunum in the radiated mouse was not changed by 10 mGy of LDR IR; however, 23 genes were upregulated in response to LDR IR of the jejunum in mice after 1 and 24 h of exposure. Upregulated genes were selected to validate the results of the RNA sequencing analysis for RTqPCR detection and results showed that only Na+/K+ transporting subunit α4, glucose6phosphatase catalytic subunit 2 (G6PC2), mucin 6 (MUC6) and transient receptor potential cation channel subfamily V member 6 levels significantly increased after 24 h of LDR IR. Furthermore, G6PC2 and MUC6 were notable genes induced by LDR IR exposure according to protein expression via western blot analysis. The mRNA levels of G6PC2 and MUC6 were significantly elevated within 24 h under three conditions: i) Exposure to LDR IR, ii) repeated exposure to LDR IR and iii) exposure to LDR IR in the presence of inflammatory bowel disease. These results could contribute to an improved understanding of immediate radiation reactions and biomarker development to identify radiationsusceptible individuals before histopathological changes become noticeable. However, further investigation into the specific mechanisms involving G6PC2 and MUC6 is required to accomplish this.
Assuntos
Glucose-6-Fosfatase , Doenças Inflamatórias Intestinais , Mucina-6 , Animais , Masculino , Camundongos , Relação Dose-Resposta à Radiação , Raios gama/efeitos adversos , Glucose-6-Fosfatase/metabolismo , Glucose-6-Fosfatase/genética , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Doenças Inflamatórias Intestinais/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos da radiação , Mucosa Intestinal/patologia , Intestinos/efeitos da radiação , Intestinos/patologia , Jejuno/efeitos da radiação , Jejuno/metabolismo , Jejuno/patologia , Camundongos Endogâmicos BALB C , Mucina-6/metabolismo , Mucina-6/genéticaRESUMO
The comprehensive genomic impact of ionizing radiation (IR), a carcinogen, on healthy somatic cells remains unclear. Using large-scale whole-genome sequencing (WGS) of clones expanded from irradiated murine and human single cells, we revealed that IR induces a characteristic spectrum of short insertions or deletions (indels) and structural variations (SVs), including balanced inversions, translocations, composite SVs (deletion-insertion, deletion-inversion, and deletion-translocation composites), and complex genomic rearrangements (CGRs), including chromoplexy, chromothripsis, and SV by breakage-fusion-bridge cycles. Our findings suggest that 1 Gy IR exposure causes an average of 2.33 mutational events per Gb genome, comprising 2.15 indels, 0.17 SVs, and 0.01 CGRs, despite a high level of inter-cellular stochasticity. The mutational burden was dependent on total irradiation dose, regardless of dose rate or cell type. The findings were further validated in IR-induced secondary cancers and single cells without clonalization. Overall, our study highlights a comprehensive and clear picture of IR effects on normal mammalian genomes.
Assuntos
Rearranjo Gênico , Translocação Genética , Humanos , Animais , Camundongos , Mutação , Genômica , Inversão Cromossômica , MamíferosRESUMO
Cancer stem cells (CSCs) are one of the main reasons behind cancer recurrence due to their resistance to conventional anti-cancer therapies. Thus, many efforts are being devoted to developing CSC-targeted therapies to overcome the resistance of CSCs to conventional anti-cancer therapies and decrease cancer recurrence. Differentiation therapy is one potential approach to achieve CSC-targeted therapies. This method involves inducing immature cancer cells with stem cell characteristics into more mature or differentiated cancer cells. In this study, we found that a CDK4 inhibitor sensitized MDA-MB-231 cells but not MCF7 cells to irradiation. This difference appeared to be associated with the relative percentage of CSC-population between the two breast cancer cells. The CDK4 inhibitor induced differentiation and reduced the cancer stem cell activity of MDA-MB-231 cells, which are shown by multiple marker or phenotypes of CSCs. Thus, these results suggest that radiosensitization effects may be caused by reducing the CSC-population of MDA-MB-231 through the use of the CDK4 inhibitor. Thus, further investigations into the possible application of the CDK4 inhibitor for CSC-targeted therapy should be performed to enhance the efficacy of radiotherapy for breast cancer.
Assuntos
Neoplasias da Mama/terapia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Células-Tronco Neoplásicas/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias da Mama/radioterapia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Feminino , Humanos , Terapia de Alvo Molecular , Células-Tronco Neoplásicas/efeitos da radiaçãoRESUMO
When replacing percutaneous endoscopic gastrostomy (PEG) tubes, an internal bolster may be retrieved either percutaneously or endoscopically. The aim of this study was to compare the complications of percutaneous and endoscopic method during PEG tube replacement. The medical records of 330 patients who received PEG tube replacement were retrospectively analyzed. According to the removal method of internal bolster, we categorized as endoscopic group and percutaneous group. Demographic data, procedure-related complications and risk factors were investigated. There were 176 cases (53.3%) in endoscopic group and 154 cases (46.7%) in percutaneous group. The overall immediate complication rate during PEG tube replacement was 4.8%. Bleeding from the stoma (1.3%) occurred in percutaneous group, whereas esophageal mucosal laceration (7.4%) and microperforation (0.6%) occurred in endoscopic group. The immediate complication rate was significantly lower in the percutaneous method (OR, 6.57; 95% CI, 1.47-29.38, P=0.014). In multivariate analysis, old age was a significant risk factor of esophageal laceration and microperforation during PEG tube replacement (OR, 3.83; 95% CI, 1.04-14.07, P=0.043). The percutaneous method may be more safe and feasible for replacing PEG tubes than the endoscopic method in old patients.
Assuntos
Gastrostomia/métodos , Complicações Pós-Operatórias , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Demografia , Perfuração Esofágica/etiologia , Feminino , Gastroscopia , Gastrostomia/efeitos adversos , Hemorragia/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
PURPOSE: Although the adverse health risks associated with low-dose radiation (LDR) are highly debated, relevant data on neuronal function following chronic LDR exposure are still lacking. MATERIALS AND METHODS: To confirm the effect of chronic LDR on the progression of Alzheimer's disease (AD), we investigated changes in behavior and neuroinflammation after radiation exposure in wild-type (WT) and 5xFAD (TG) mice, an animal model of AD. WT and TG mice, classified by genotyping, were exposed to low-dose-rate radiation for 112 days, with cumulative doses of 0, 0.1, and 0.3 Gy, then evaluated using the open-field and Y-maze behavioral function tests. Changes in the levels of APP processing- and neuroinflammation-related genes were also investigated. RESULTS: No apparent change was evident in either non-spatial memory function or locomotor activity, as examined by the Y-maze and open field tests, respectively. Although chronic LDR did not affect the levels of APP processing, gliosis (Iba1 and GFAP), or inflammatory cytokines (IL-1ß, IL-6, and TNF-α), the levels of IFN-γ were significantly downregulated in TG mice following LDR exposure. In an additional analysis, we examined the genes related to IFN signaling and found that the levels of interferon induced transmembrane protein 3 (IFITM3) were decreased significantly in TG mice following LDR with 0.1 or 0.3 Gy. CONCLUSIONS: Therefore, this study revealed the possibility that LDR could affect the progression of AD, which may be associated with decreased IFN-related signaling, especially IFITM3. Our findings suggest that further studies are required regarding the potential role of LDR in the progression of AD.
Assuntos
Doença de Alzheimer , Animais , Camundongos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Modelos Animais de Doenças , Imunidade Inata , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Doenças Neuroinflamatórias , Radiação IonizanteRESUMO
Low-dose radiation is generally considered less harmful than high-dose radiation. However, its impact on ovaries remains debated. Since previous reports predominantly employed low-dose radiation delivered at a high dose rate on the ovary, the effect of low-dose radiation at a low dose rate on the ovary remains unknown. We investigated the effect of low-dose ionizing radiation delivered at a low dose rate on murine ovaries. Three- and ten-week-old mice were exposed to 0.1 and 0.5 Gy of radiation at a rate of 6 mGy/h and monitored after 3 and 30 days. While neither body weight nor ovarian area showed significant changes, ovarian cells were damaged, showing apoptosis and a decrease in cell proliferation after exposure to 0.1 and 0.5 Gy radiation. Follicle numbers decreased over time in both age groups proportionally to the radiation dose. Younger mice were more susceptible to radiation damage, as evidenced by decreased follicles in 3-week-old mice after 30 days of 0.1 Gy exposure, while 10-week-old mice showed reduced follicles only following 0.5 Gy exposure. Primordial or primary follicles were the most vulnerable to radiation. These findings suggest that even low-dose radiation, delivered at a low dose rate, can adversely affect ovarian function, particularly in the early follicles of younger mice.
Assuntos
Folículo Ovariano , Ovário , Feminino , Camundongos , AnimaisRESUMO
Inflammatory bowel diseases could be diagnosed in major measure by diagnostic imaging; however, radiation exposure in the intestine may also contribute to the progression of these pathologies. To better understand the impact of radiation in the presence of bowel disease, we administered dextran sodium sulfate (DSS) to C57BL/6 mice to induce colitis and exposed to radiation at abdominal area. We observed that abdominal irradiation (13 Gy) aggravates the DSS-induced decrease in survival rate (0%), body weight (74.54 ± 3.59%) and colon length (4.98 ± 0.14 cm). Additionally, abdominal irradiation markedly increased in colonic inflammation levels (3.16 ± 0.16) compared with that of DSS-induced sham mice. Furthermore, abdominal irradiation also increased the mRNA expression levels of inflammatory genes, such as cyclooxygenase-2 (13.10 folds), interleukin-6 (48.83 folds) and tumor necrosis factor-alpha (42.97 folds). We conclude that abdominal irradiation aggravates the detrimental effects of DSS-induced colitis in mice, which might be a useful guideline for inflammatory bowel disease patients.
Assuntos
Colite , Doenças Inflamatórias Intestinais , Animais , Camundongos , Camundongos Endogâmicos C57BL , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/metabolismo , Colite/induzido quimicamente , Colite/metabolismo , Interleucina-6/efeitos adversos , Interleucina-6/genética , Interleucina-6/metabolismo , Sulfato de Dextrana/efeitos adversosRESUMO
The purpose of this study was to establish the dose-response curves for biological dosimetry of the Dong Nam Institute of Radiological and Medical Sciences to monitor radiation exposure of local residents in the vicinity of the nuclear power plant. The blood samples of five healthy volunteers were irradiated with gamma ray, and each sample was divided equally for analysis of chromosomal aberrations by Giemsa staining and three-color fluorescence in situ hybridization painting of the triplet (chromosomes #1, #2, and #4). The results of chromosomal aberrations followed the Poisson distribution in all individual and averaged data which include inter-individual variation in radiation susceptibility. Cytogenetics Dose Estimate Software version 5.2 was used to fit the dose-response curve and to determine the coefficients of linear-quadratic equations. The goodness of fit of the curves and statistical significance of fitted α and ß-coefficients were confirmed in both Giemsa-based dicentric analysis and FISH-based translocation analysis. The coefficients calculated from the five-donor average data were almost identical in both of the analyses. We also present the results that the dose-response curve for dicentric chromosomes plus fragments could be more effective for dose estimation following low-dose radiation accidents.