Radiation research最新文献

With the increasing use of radiation in medical and other settings, the potential effects of low-dose radiation on coronary heart disease including myocardial infarction (MI) are of great public health concern. The impact of low-dose radiation on myocardial infarction incidence remains controversial. The purpose of this study was to examine whether atomic bomb radiation exposure (dose < 4 Gy) is associated with the incidence of myocardial infarction. This prospective cohort study included 11,838 Japanese atomic bomb survivors with individually estimated radiation doses from the Adult Health Study cohort who had no history of myocardial infarction or radiotherapy at the first visit. Participants were followed until the earliest of first occurrence of an myocardial infarction, death, or the end of 2015 (57 years maximum). The incidence of myocardial infarctions (non-fatal and fatal), categorized by graded diagnostic accuracy, and the dose-response relationship of atomic bomb radiation were analyzed using Cox proportional hazards models. A total of 515 incident myocardial infarctions were documented, consisting of 188 definite, 30 probable, and 15 possible non-fatal myocardial infarctions, along with 282 fatal myocardial infarctions. For definite and probable non-fatal myocardial infarctions with high diagnostic accuracy, no significant association with radiation was found for both sexes combined [hazard ratio (HR) at 1 Gy = 1.17; 95% confidence interval (CI): 0.91-1.51], but sex-stratified analyses indicated a higher HR for females than for males [at 1 Gy, HRfemale = 1.42 (95% CI:1.02-1.98), HRmale=1.02, 95% CI: 0.74-1.41], although the difference was not statistically significant (P = 0.12). No statistically significant modification of radiation effect was identified by city, age at exposure, attained age, time since exposure, smoking, or alcohol use. For all myocardial infarctions, including possible non-fatal myocardial infarction and fatal myocardial infarction with low diagnostic accuracy, the HRs at 1 Gy were 1.04 (95% CI: 0.86-1.25) for both sexes combined, 1.14 (95% CI: 0.88-1.47) for females, and 0.96 (95% CI: 0.75-1.22) for males. Findings from this long-term cohort study of atomic bomb survivors suggest an association between exposure to atomic bomb radiation and the incidence of myocardial infarction in females, but not in males. Further studies are necessary to clarify the reasons underlying the sex difference in dose-response relationship for myocardial infarction.

Exposure to space radiation poses various health risks, so accurately estimating radiation dose in space is crucial. Herein, we integrated 301 transcriptomic profiles from 30 spaceflight datasets and developed radiation-dose estimation models for the space environment using a genetic algorithm. Two models were constructed in this work: one using gene expression fold changes as input (fold change model) and the other using gene degrees as input (degree model). Of note, we initially constructed a single sample network (SSN) for each spaceflight sample, respectively, and the degrees that represented the node (gene) features were extracted from the SSNs. Moreover, we not only constructed estimation models applicable to all tissues (overall models) but also developed specific models for each tissue (tissue models), enabling our models to be used across various task scenarios. According to the experimental results, all models demonstrate excellent performance in radiation dose estimation during spaceflight, and our genetic algorithm models achieve good predictive performance with a limited number of genes. We identified radiation-responsive genes, mainly involved in DNA repair, cell cycle, protein/amino acid metabolic pathways, energy metabolic pathways, nervous system development and differentiation, and cancer pathways. Through the expression and interaction patterns of these genes, we found that the space radiation environment could induce health risks such as cancers, psychiatric/neurological disorders, liver injury/toxicity disorders. In summary, the presented approach yields promising results for estimating radiation doses and supports the assessment of radiation risks in space environments.

Many mechanisms have been proposed to explain the normal tissue-sparing effect observed with FLASH radiation therapy. However, a satisfactory explanation has not been found. While the hypothesis of transient hypoxia through radiochemical oxygen depletion (ROD) initially seemed promising, experimental evidence and simulations have led to this mechanism falling out of favor. In this work, we briefly review the oxygen diffusion theory of August Krogh and present an updated version that includes a more detailed mechanism of oxygen diffusion in tissues and within cells. Specifically, we show that oxygen is removed from the cell nucleus, a process named the Hoover® effect. This effect provides a basis for explaining the biphasic oxygen enhancement ratio phenomenon, which creates a volume-based enhancement to the FLASH sparing effect at low pO2 away from capillaries. Additionally, the differential depletion of oxygen inside and outside the cell nucleus may lead to Hoover-assisted radiochemical oxygen depletion and enhanced transient hypoxia of the cell nucleus. Thus, the Hoover effect is a passive biomolecular oxygen vacuum diffusion pump that reduces the concentration of oxygen in the cell nucleus and is hypothesized to provide a mechanism for radiochemical oxygen depletion as a primary cause of the FLASH effect.

This study aims to elucidate the processes involved in radiation-induced liver injury and subsequent hepatocyte proliferation, and to identify novel metabolic profiles associated with progression of liver injury and hepatocyte proliferation. Six-week-old male Sprague-Dawley rats were exposed to a single 25 Gy dose of radiation to the whole liver to induce a model of radiation-induced liver injury and subsequent hepatocyte proliferation. Liver injury and hepatocyte proliferation were assessed using a range of techniques, including Masson's trichrome staining, liver histopathology, ELISA, immunohistochemistry, and Western blotting. Dynamic changes in metabolic profiles and biomarker concentrations in liver tissue were investigated using ultra-performance liquid chromatography and quadrupole time-of-flight mass spectrometry. After radiation exposure, acute radiation-induced liver dysfunction occurs, but then there is gradual recovery over time, concomitant with the onset of hepatocyte proliferation. Metabolomic analysis of liver tissues at different time points, specifically day 1, day 8, day 15, and day 30 postirradiation, revealed notable differences in all 22 metabolites, with a predominance of lipid metabolites. Among them, 9 metabolites showed more than a twofold change on days 15 and 30. We validated the correlation between these 9 metabolites with injury scores and Ki-67 positive cells (%). Notably, there was a strong negative correlation between glycerylphosphorylethanolamine (GPE) and the injury score (correlation coefficient: -0.701) and between 1-hexadecanoyl-2-(5-hydroxy-8-oxo-6E-octenoyl)-sn-glycero-3-phosphoserine (PHOOA-PS) and the Ki-67 positive cells (%) (correlation coefficient: -0.824). Additionally, GPE has significant value in differentiating the degree of injury [area under the curve (AUC) = 0.958]. This study successfully established a rat model of radiation-induced hepatic injury and subsequent hepatocyte proliferation, shedding light on dynamic metabolic changes at different times.

DNA double-strand breaks (DSBs) are the most severe type of DNA damage in living organisms and are primarily repaired by two pathways: non-homologous end joining (NHEJ) and homologous recombination (HR). DNA ligase IV (LIG4) is essential for the final step of NHEJ, where it facilitates the rejoining of DSBs. Loss-of-function mutations in the LIG4 gene result in LIG4 syndrome, a condition characterized by combined immunodeficiency, developmental delay, microcephaly and radiosensitivity. In this study, we investigated cellular senescence, radiosensitivity, and X-ray radiation-induced chromosome aberrations induced in newly developed Lig4 mutant (Lig4W447C/W447C) mouse cells. The results showed that Lig4W447C/W447C cells exhibited accelerated cellular senescence, possibly due to increased accumulation of spontaneous DSBs. Radiosensitivity assays revealed that Lig4W447C/W447C cells were four times more radiosensitive than wild-type cells. Moreover, analysis of both X-ray radiation-induced chromatid-type and chromosome-type aberrations revealed that both break-type aberrations (e.g., fragments) and exchange-type aberrations (e.g., dicentrics) were increased in Lig4W447C/W447C cells compared to wild-type cells. These results suggest that in addition to causing inefficient DNA break, end-joining, the novel mutation in Lig4 may promote misrejoining of X-ray radiation-induced DSBs.

Total-body irradiation (TBI) and partial-body irradiation (PBI) after a radiological or nuclear event result in acute radiation syndrome. Such radiation-induced injuries require immediate diagnosis and treatment. New strategies are required for radiation biodosimetry, along with the advancement of mitigation measures. Understanding gene expression alterations in irradiated cells pretreated with medical countermeasure (MCM) reveals the complex cellular responses to radiation and the radioprotective efficacy of MCM. In this study, we analyzed transcriptomic responses in irradiated nonhuman primate (NHP) tissues pretreated with gamma-tocotrienol (GT3) to evaluate GT3 efficacy and irradiation's tissue impact. Transcriptomic responses are evaluated for gender differences. Additionally, we compared spleen responses with those of lung and jejunum. Our study demonstrates that the spleen is vulnerable to radiation-induced gene expression changes compared to the lung and jejunum. Both TBI and PBI significantly impacted pathways related to cell proliferation, immune function, pathogen response, and disease processes. We identified radiation-induced alterations in p53 signaling and its target gene expression across spleen, lung, and jejunum, with p53 activation attenuated in the spleen than in the other organs. No significant sex-based differences were observed in irradiated NHPs. In addition, a lower dose of GT3 pretreatment was ineffective in protecting against a supralethal 12 Gy radiation dose in either model. Overall, these findings provide important insights into the molecular changes induced by GT3 treatment and radiation, highlighting opportunities to identify biomarkers of radiation injury and to develop MCMs.

Radiation chemical studies together with theoretical calculations have confirmed that 5-selenocyanato-2'-deoxyuridine (SeCNdU) and 5-trifluoromethanesulfonyl-2'-deoxyuridine (OTfdU) undergo dissociation induced by an excess electron attachment and established these nucleosides as potential radiosensitizers. Here, the sensitizing properties of SeCNdU and OTfdU at the cellular level have been verified to determine whether these analogs can effectively enhance ionizing radiation-induced cell death. The cytotoxicity and radiosensitizing activity of the tested compounds were examined in breast (MCF-7) and prostate (PC3) cancer cells. The viability of cells treated with the analogs was tested using the MTT assay. The clonogenic assay was used to quantify reproductive cell survival after treatment of the compounds with ionizing radiation. For preliminary investigation of the mechanisms of potential radiosensitization by the derivatives, cell cycle phase distribution and histone H2AX phosphorylation as a marker of DNA strand breaks were assessed using flow cytometry. The results show the radiosensitizing properties of SeCNdU on the MCF-7 line, with a dose enhancement factor of 1.6. The same derivative had no effect on the PC3 line. Radiosensitization was also associated with an increase in histone H2AX phosphorylation, which correlates with the number of DNA double breaks. This derivative also slightly influenced distribution of cells through the cell cycle. The OTfdU derivative showed no biological effect on either of the tested lines. In conclusion, SeCNdU treatment enhanced the radiosensitivity of breast cancer cells in a manner associated at least partially with double-strand break formation. OTfdU had no radiosensitizing effect against prostate and breast cancer lines.

Head and neck squamous cell carcinoma (HNSCC) resistance to radiotherapy has prompted a need to develop adaptive radiation therapy protocols to improve patient outcomes. This study investigates the hypothesis that lipid metabolism regulates cell cycle phase-specific radiation sensitivity of HNSCC cells. Previous studies have shown that HNSCC tumors with a higher proportion of G0/G1 phase cells (low proliferative index, LPI) are more resistant to radiation compared to HNSCC tumors with a higher proportion of S/G2 phase cells (high proliferative index, HPI). RNA-seq and bioinformatics identified lipid metabolism as the major intrinsic pathway that differs between HPI and LPI HNSCC cultures. mRNA and protein levels of G0/G1 Switch 2 gene (G0S2), regulator of quiescence and lipid metabolism, were upregulated in LPI compared to HPI HNSCC cultures. G0S2 negatively regulates adipose triglyceride lipase (ATGL), resulting in less lipolytic activity. siG0S2 treatment of LPI cultures recruited cells into the proliferative cycle and exacerbated radiation sensitivity. To override G0S2 action, we incubated LPI cultures with the fatty acid palmitate and examined cellular metabolic stress markers. Compared to controls, LPI cultures treated with palmitate showed increased reactive oxygen species levels, lipid peroxidation and oxygen consumption rate coupled with increased mitochondrial fission. Furthermore, using the fluorescent based cell cycle real-time imaging system, we showed that palmitate treatment sustained cell proliferation (higher S/G2) compared to controls (higher G1). Palmitate treatment resulted in significant sensitization to radiation treatment and enhanced the efficacy of poly (ADP-ribose) polymerase (PARP) inhibitors. In summary, we demonstrate that G0S2-dependent lipid metabolism regulates cell cycle phase-specific radiation sensitivity of HNSCC cells and identify G0S2 and free fatty acids as novel targets for radiation therapy.

Radiation-induced heart disease (RIHD) has become an unavoidable and challenging problem that greatly impacts the outcomes of patients with tumors undergoing radiotherapy. Many studies have shown the positive effects of tanshinone IIA on cardiac function; however, its exact role and the underlying mechanism in RIHD remain unclear. This study aimed to investigate the mechanism of RIHD and examine the protective effects of tanshinone IIA. We developed in vitro and in vivo models of RIHD and assessed the damage caused by X-ray radiation to mice hearts and H9c2 cells using echocardiography, myocardial enzyme analysis, histopathology, transmission electron microscopy, Western blotting, and immunohistochemistry, to thoroughly explore the therapeutic potential and mechanism of tanshinone IIA on radiation-induced heart injury. Based on the results from various experiments, we confirmed that X-rays can trigger an increase in brain natriuretic peptide (BNP), creatine kinase-MB (CK-MB), and lactate dehydrogenase (LDH) levels, along with myocardial tissue edema, nuclear dissolution, and mitochondrial damage in mice. H9c2 cell activity declined, LDH levels rose, and mitochondrial damage occurred. Similarly, there was an increase in calcium ion flow, expression of calcium-related proteins, and pyroptosis-related proteins. After treatment with tanshinone IIA, the damage to the mouse heart and myocardial cells was partially reversed, with reductions in calcium ion flow and the expression of calcium- and pyroptosis-related proteins. These findings suggest that tanshinone IIA alleviates myocardial injury in RIHD by restoring calcium homeostasis and inhibiting pyroptosis.

Individual differences in the effects of ionizing radiation on humans remain poorly understood. Although studies on atomic bomb survivors have demonstrated that the hemizygous glycophorin A (GPA) gene mutant fraction (GPA Mf) in erythrocytes increases significantly with increasing radiation dose, there are large individual differences in the GPA Mf. Persistent GPA mutations are believed to be derived from mutations in long-lived hematopoietic stem cells (HSCs), and genetic background related to DNA repair may contribute to individual differences in HSC mutational potential after radiation exposure. In this study, we investigated three single-nucleotide polymorphisms (SNPs) in ERCC5 that play an important role in nucleotide excision repair (NER) of DNA damage caused by radiation exposure and are involved in cancer susceptibility. We found that these SNPs affect the relationship between radiation exposure and GPA Mf in erythrocytes and identified a highly significant interaction between radiation dose and one SNP (rs751402), located 2 kb upstream of ERCC5 (P = 9.3 × 10-6). This suggests that the radiation dose response of GPA Mf is partly influenced by the genotype of ERCC5. Furthermore, the slope of the GPA Mf dose-response curve was significantly higher in the cancer group than in the cancer-free group among Hiroshima survivors whose rs751402 genotype was the major homozygote. These findings suggest that ERCC5 may play a crucial role in the individual differences observed in HSC somatic gene mutability, as well as in cancer susceptibility after radiation exposure.