Radiation research最新文献

Leukemia stem cells (LSCs) are a key factor leading to the recurrence and drug resistance in acute myeloid leukemia (AML). Notably, the persistence of radiotherapy-resistant LSCs has been identified as a critical determinant of post-hematopoietic stem cell transplantation (HSCT) relapse. Herein, we report glutathione peroxidase 1 (GPX1) as a promising target for eliminating LSCs after exposure to ionizing radiation. Silencing GPX1 in LSCs robustly triggers cell death and cell cycle arrest, thereby enhancing the radiosensitivity of LSCs. Specifically, GPX1 maintains the survival and proliferation of LSCs by regulating redox homeostasis. Upon GPX1 knockdown, intracellular reactive oxygen species (ROS) accumulate, which in turn impairs the function of BCL2 and ultimately triggers LSC apoptosis. After radiation exposure, ROS scavengers can effectively rescue GPX1 knockdown-induced LSC apoptosis and restore their impaired proliferative capacity. Accordingly, our study reveals GPX1 function in LSC maintenance and radiation tolerance, providing a therapeutic opportunity for ablating LSCs and for AML targeted therapy.

The long durations of the proposed NASA Mars missions will expose astronauts to space radiation (SR), which has detrimental effects on brain function that could impair their ability to appropriately cope with any additional unexpected stress they may encounter. Space radiation could also alter stress-related learning and effects may vary with individual differences in stress resilience and vulnerability. Therefore, determining how astronauts may respond to unforeseen mission-related stressors will be crucial for understanding and mitigating factors that would threaten mission success. In this study, we assessed freezing behavior, body temperature [as a measure of stress-induced hyperthermia (SIH)], and sleep quality and duration in rats exposed to radiation and trained in contextual conditioned fear (CF) using footshock stress. We also assessed whether responses differed in stress resilience and vulnerability phenotypes in our established model based on different sleep responses to stress. Space radiation resulted in increased freezing, increased SIH and significant alterations in sleep with some variations in stress resilience and vulnerability rats. Space radiation also reduced extinction of fear-conditioned freezing, SIH, and sleep responses. The data are discussed in the context of the impact of space radiation on stress-induced alterations in emotional learning and its potential impact on astronaut health and mission performance.

DNA is highly susceptible to damage from high-energy particles, making molecular-level computation of DNA damage essential for understanding the underlying molecular mechanisms. In this study, we conducted an in-depth investigation of DNA strand breaks. We computed hydrogen-abstraction preferences from deoxyribose by hydroxyl radicals using the DNA segment of the nucleosome tetramer structure (Protein Data Bank entry 1ZBB) enclosed in a 2.5-fold water box. Additionally, we explored the equilibrium distribution of the neutral sugar radical deoxynucleosides. Our findings indicate that the reaction preference is primarily governed by solvent accessibility. Using this model, we calculated the number of DNA strand breaks induced by hydroxyl radicals generated by water radiolysis, a form of indirect damage. Combined with the modified number of strand breaks from direct damage, we achieved agreement with experimental yields of SSBs and DSBs. This study combines Geant4-DNA Monte Carlo calculations with Gaussian Density Functional Theory calculations, offering valuable insights into the biological effects and therapeutic implications of early DNA damage, particularly in the context of structurally elucidated DNA.

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.