Radiation research最新文献

Space radiation, primarily originating from galactic cosmic rays, is mainly composed of protons. Given NASA's plans for manned lunar and Mars missions, it is critical to assess the risk of proton radiation in disrupting tissue homeostasis, including in the intestine, which is a highly radiosensitive organ that harbors trillions of bacteria on the luminal surface. One-carbon metabolism encompasses the folate and methionine cycle and plays a crucial role in maintaining tissue homeostasis by regulating methylation, reductive metabolism, and nucleotide synthesis. However, the effects of proton radiation on intestinal one-carbon metabolism and the luminal microbiome profile are unknown. To address this, 6-month-old male C57BL/6J mice were exposed to a single dose of 0.5 Gy or 1.0 Gy of protons (150 MeV/n; dose rate = 35-55 cGy/min). Nine months after irradiation, significant shifts in the one-carbon metabolism pathway were detected in the mouse proximal jejunum and colon. These changes were exhibited as a loss of intra-intestinal methionine, s-adenosylmethionine, and glutathione tissue concentrations, with more pronounced effects being observed in the proximal jejunum compared to the colon. This resulted in the loss of DNA methylation within long-interspersed nucleotide element-1 (LINE-1), indicative of a global hypomethylative phenotype. Molecular changes were characterized by substantial dysregulation of gene expression in the proximal jejunum, where the most pronounced changes were associated with the dramatic loss of Nos2 expression and reactivation of Casp14, suggesting potential shifts in amino acid utilization and restoration of epithelial barriers in the gut. Furthermore, claudins Cldn5, Cldn6, and Cldn10 were substantially modulated in the proximal jejunum of exposed mice. Gross shifts in the microbiota profiles were exhibited as increases in both overall richness and diversity, however, at the expense of commensal bacterial species, like Akkermansia. The extent of the observed alterations was not congruent with the relatively low doses used in the study, the late time-point, and the overall lack of histomorphological alterations. Altogether, our findings demonstrate that exposure to space-relevant proton radiation causes substantial and persistent changes in the mouse gut. The degree and nature of the observed effects suggest the potential for negative health consequences after exposure to proton radiation during deep space exploration.

Radiation-induced brain injury (RIBI) continues to pose a significant clinical problem linked to neuroinflammation, oxidative stress, and neuronal death. This research evaluates the neuroprotective efficacy of oxytetracycline (OTC) in mitigating RIBI, examining its effects on behavioral, histological, biochemical, and metabolic characteristics. Female Wistar albino rats were categorized into three groups: a control group, a group subjected to brain irradiation with saline, and a group subjected to brain irradiation with oxytetracycline therapy at a dosage of 30 mg/kg/day for 15 days. Behavioral results were assessed through daily sociability, open-field, and passive avoidance learning tests. Biochemical studies included the quantification of inflammatory and oxidative stress indicators, including TNF-α, malondialdehyde (MDA), and superoxide dismutase (SOD). Histopathological assessments focused on neuronal integrity and astrocytic activity in hippocampus (CA1 and CA3 areas) and cerebellar tissues. Magnetic resonance (MR) spectroscopy was used to evaluate metabolic alterations, including lactate, N-acetylaspartate (NAA), and creatine (Cr) concentrations. oxytetracycline therapy markedly decreased oxidative stress indicators, including malondialdehyde (MDA), and restored antioxidant enzyme activity (SOD). Inflammatory markers such as TNF-α, Iba-1, and TLR-4 were reduced, however levels of neurotrophic factors (NGF and NRG-1) remained constant. Improvements in behavior were seen in friendliness, memory retention, and inquisitive behaviors. Histopathological analysis indicated maintained neuronal integrity and diminished GFAP immunostaining in the hippocampus and cerebellum. MR spectroscopy revealed reduced lactate levels and normalized NAA and Cr levels, indicating metabolic stability. Thus, oxytetracycline has neuroprotective properties that act via mitigation of inflammation, decreasing oxidative stress, and maintaining neuronal integrity. Furthermore, its capacity to alleviate metabolic dysfunction enhances its prospective use in safeguarding cognitive and neurological processes. These findings underscore the therapeutic efficacy of oxytetracycline in mitigating radiation-induced cerebral damage.

Ultra-high dose-rate radiotherapy, also known as FLASH radiotherapy (FLASH-RT), reduces radiation-induced damage in several organs. This study aimed to compare the effects of FLASH-RT and conventional dose-rate radiotherapy (CONV-RT) at 3 Gy and 5 Gy of total-body irradiation (TBI) on the survival of the hematopoietic system, peripheral blood cells, and immune-related responses. C57BL/6N male mice were divided into controls (0 Gy), FLASH-RT (109 Gy/s), and CONV-RT (0.067 Gy/s) groups. FLASH-RT was performed using the DIRAMS LINAC, producing 6-MeV electron beams. Irradiated mice were sacrificed on days 1, 2, 4, 7, 14, 21, and 28 after TBI at 3 Gy and 5 Gy. Peripheral blood cell counts were not significantly different between the FLASH-RT and CONV-RT groups, except for platelets on days 2-28 after 5 Gy TBI. FLASH-RT initially caused a greater reduction in myeloblasts in bone marrow, platelets and eosinophils in peripheral blood than CONV-RT. The white pulp area in the spleen decreased from days 1-7 after TBI, but gradually increased from day 14 after FLASH-RT, with the white pulp area in the FLASH-RT group being significantly larger than that in the CONV-RT group at day 14 and 28. The T-lymphocytes of the CONV-RT group recovered less than those of the FLASH-RT group at day 14 after 3 Gy and at day 28 after 5 Gy, respectively. FLASH-RT can induce similar damage and recovery patterns in the hematopoietic system as CONV-RT, but FLASH-RT might cause a faster recovery of T-lymphopenia than CONV-RT.

Ferroptosis, an iron-dependent type of regulated cell death (RCD), has recently been associated with radiation efficacy. However, the impact of ferroptosis inducers (FINs) on colorectal cancer (CRC) cell lines varies tremendously. This study aims to elucidate the importance of ferroptosis in radiation-induced RCD, comparing it with apoptosis and necroptosis. Human CRC cell lines (DLD-1, HT29, HCT116), and a murine CRC cell line (CT26) were included in this study. radiation-induced RCD was assessed by flow cytometric analysis. To determine the precise percentage of cells undergoing RCD, a colony formation assay (CFA) was employed following treatment with the cell death inhibitors ferrostatin-1, Z-VAD-FMK or necrostatin-1. The impact of hypoxia (1% O2) and fractionation on RCD percentages was analysed using a CFA. In vitro results were confirmed in 3D spheroid models and validated in a CT26 tumor model. Radiation significantly elevated the levels of apoptosis, necroptosis and ferroptosis, irrespective of oxygen concentration. Inhibition of ferroptosis reduced cell death similarly to the inhibition of apoptosis and necroptosis. These findings were confirmed in 3D models. Hypoxia and fractionation decreased overall RCD. In vivo experiments confirmed the pivotal role of ferroptosis, showing it to be similarly involved as necroptosis and greater than apoptosis. Ferroptosis is equally involved in radiation-induced RCD in CRC cells compared to apoptosis and necroptosis. However, its importance decreases under hypoxic conditions and after fractionation. Nonetheless, the reduction was less pronounced than for necroptosis, suggesting that ferroptosis is an ideal type of RCD to trigger in a clinical setting. Overall, this study highlights the potential of FINs as effective clinical radiosensitizers.

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.

The variation of the oxygen enhancement ratio (OER) across linear energy transfer (LET) currently lacks a comprehensive mechanistic interpretation and a mechanistic model. Our earlier research revealed a significant correlation between the distribution of double-strand breaks (DSBs) within 3D genome and radiation-induced cell death, which offers valuable insights into the oxygen effect. We propose a model where the reaction of oxygen is represented as the probability of inducing DNA strand breaks. Then it is integrated into a track-structure Monte Carlo simulation to investigate the impact of oxygen on the distribution of DSBs within 3D genome. Using the parameters from our previous study, we calculate the OER values related to cell survival. Results show that the incidence ratios of clustered DSBs within a single topologically associating domain (TAD) (case 2) and within frequently interacting TADs (case 3) under aerobic and hypoxic conditions align with the trend in the OER of cell survival across LET. Our OER curves exhibit good correspondence with experimental data. This study provides a potentially mechanistic explanation for changes in OER across LET. High-LET irradiation leads to dense ionization events, resulting in an overabundance of lesions that readily induce case 2 and case 3, which have substantially higher probabilities of cell killing than other damage patterns. This may contribute to the main mechanism governing the variation of OER for high LET. Our study further underscores the importance of the DSB distribution within 3D genome in the context of radiation-induced cell death.

Survivors of the hematopoietic acute radiation syndrome (H-ARS) face delayed effects of acute radiation exposure (DEARE), including chronic immune suppression and thymic involution, for which no effective countermeasures exist. We previously demonstrated that 16,16-dimethyl prostaglandin E2 (dmPGE2) enhances H-ARS survival when administered prior to irradiation. Here, we investigated its long-term radiation protective effects on immune reconstitution at 6 and 12 months after exposure in a lethal total-body irradiation (TBI) mouse model. C57BL/6J mice received dmPGE2 30 min prior to TBI (PGE-pre-irradiation), 24 h after TBI [prostaglandin E (PGE)-postirradiation], or vehicle (Veh), with non-irradiated mice included as controls. Surviving mice treated with Veh prior to TBI exhibited persistent thymic involution, decreased thymocyte subsets, and diminished splenic T and B cells, alongside elevated bone marrow (BM) and serum IL-6, KC, MCP-1, and G-CSF levels with reduced MIP-1β, reflecting systemic immune dysregulation. Treatment of mice with dmPGE2 pre-irradiation significantly prevented these effects with mice exhibiting enhanced thymocyte maturation, increased splenic lymphocytes, preservation of the thymic cortex/medulla ratio, attenuated BM/serum cytokine disturbance, and generation of functional lymphocytes in vitro. Administration of dmPGE2 at 24 h postirradiation had minimal effect. Competitive BM transplantation and in vitro co-culture studies in mice receiving dmPGE2 pre-irradiation revealed that dmPGE2 enhanced BM lymphoid progenitor cell differentiation and function. RNA sequencing of phenotypically defined hematopoietic stem cells (HSC) at 24 h after TBI from mice treated with dmPGE2 30 min prior to TBI showed upregulation of genes associated with lymphopoiesis, notably Flt3, involved in hematopoietic cell proliferation and survival, and Dntt, involved in the development of T and B cells. These findings demonstrate that dmPGE2 can prevent radiation-induced long-term immune suppression by protecting lymphoid progenitors, suggesting its potential as a radioprotectant for radiation accident victims and radiotherapy patients.

High-energy neutron radiation (HENR) induces severe cellular and tissue damage, yet effective prophylactic agents remain limited. In this study, the TLR2/NOD2 co-agonist CL429 was evaluated for its radioprotective potential against 14.1 MeV neutron exposure. A murine HENR model was established, and absorbed doses were calculated using the specific kinetic energy method. Pretreatment with CL429 significantly improved survival outcomes, with survival rates reaching 90% and prolonged survival times observed. CL429 administration markedly increased the organ indices of the spleen, thymus, and testis, reduced splenocyte apoptosis to near-normal levels, and restored leukocyte and platelet counts in the early postirradiation phase. Flow cytometry and Western blot analyses indicated that CL429 upregulated TLR2 and NOD2 expression, accompanied by activation of downstream signaling pathways. These findings suggest that CL429 confers significant protection against neutron radiation-induced injury, potentially through the dual activation of TLR2/NOD2-mediated protective mechanisms.

Inflammation is the initial immune response activated to protect an organism's integrity after cell or tissue damage caused by infectious agents or physical trauma, such as exposure to ionizing radiation. The mechanisms behind ionizing radiation-induced inflammation are not fully understood in untransformed human cells, especially at high dose exposures that can also cause cell death. Radiation-induced genotoxic stress triggers the cellular DNA damage response, and interactions between this pathway and inflammation may be crucial in determining the fate of irradiated cells. We studied how primary human vascular endothelial cells, telomerase-immortalized foreskin microvascular cells, blood mononuclear cells, and primary skin fibroblasts respond to radiation doses from 2 to 10 Gy for up to 24 h after exposure, prior to cell death. In endothelial cells, exposure to 10 Gy, but not lower doses, caused a temporary increase in the transcription of genes coding for inflammatory factors before the activation of DNA damage response genes. This early inflammatory reaction depends on ATM activity, which coordinates the DNA damage response, and is not observed in blood cells or fibroblasts. Additionally, we saw an increase in cytokine production and adhesion molecule expression in endothelial cells. This inflammatory response may contribute to changes in the immune microenvironment of irradiated cells.

Contralateral breast (CB) cancer is the most common subsequent cancer among breast cancer survivors, and radiotherapy has been linked to CB cancer risk. The purpose of this work was to evaluate doses to subregions of the contralateral breast from historical breast cancer treatments carried out in the United States between 1990 and 2012. We extracted treatment data from radiation therapy summaries for 2,442 radiotherapy patients during that period. We estimated CB doses for five breast regions: the upper inner quadrant (UIQ), lower inner quadrant, upper outer quadrant, lower outer quadrant (LOQ), and nipple, using extracted data and out-of-beam CB dose measurements. The mean treatment dose was approximately 5,000 cGy for tangential fields, which comprised 84% of the photon fields, and this remained constant throughout our study period. Most of the dose to the contralateral breast was from the tangential fields, and it varied by contralateral breast region. The UIQ of the contralateral breast received the highest median dose which decreased by 23% from 185 cGy in 1990-1994 to 143 cGy in 2005 and later (P < 0.0001). The LOQ dose received the lowest dose, which also decreased by 24% from 74 to 56 cGy (P < 0.0001). This decrease was due to the reduction in the utilization of physical wedges and an increase in the field-in-field technique, particularly after 2005. We observed a significant reduction in CB doses from breast radiotherapy in the United States between 1990 and 2010, which can be attributed to the impact of advanced radiotherapy techniques.