Synchrotron-generated microbeam X-rays are emerging as a novel promising therapeutic strategy for the treatment of drug-resistant epilepsy. One important limiting factor of radiotherapy for the treatment of drug-resistant epilepsy, brain tumors and metastases is the onset of cognitive deficits and dementia due to the reduction of hippocampal neurogenesis. The long-term safety of synchrotron-generated X-ray microbeam irradiation is a concern for translating this novel irradiation technique to humans. Here we show the effects of synchrotron-generated X-ray microbeam irradiation of the dorsal hippocampus in healthy rats in the short-, mid- and long-term. Healthy rats were irradiated with either homogeneous broadbeams (10 Gy) or 2 arrays composed of 10 parallel microbeams each (75 μm wide, spaced 400 μm center-to-center, 300 or 600 Gy) in the cerebral cortex and the dorsal hippocampus. Rats underwent behavioral testing, histological and immunohistochemical analysis, and stereological counts of proliferating cells in the hippocampal dentate gyrus. X-ray microbeam irradiation delivering peak doses of 300 Gy reduced depressive-like behavior, and this antidepressant effect was associated with an increase of hippocampal dentate gyrus neurogenesis in the short-, mid- and long-term. Spontaneous locomotor activity, hippocampal-mediated cognition and microvessels were not affected by X-ray microbeam irradiation. These data shed light on the long-term radiobiology of microbeams in the central nervous system and lay the groundwork for their use in treating drug-resistant epilepsy and other neurological disorders associated with reduced neurogenesis.
With the increasing use of computed tomography, the biological effects of low-dose ionizing radiation (LDIR) have gained attention. However, its effects on B lymphocytes remain understudied. We investigated LDIR-induced oxidative stress in lymphocytes to establish a theoretical basis for clinical radiation safety. First, we demonstrated that LDIR induces a rapid oxidative response in the human B-lymphoblastoid cell line IM-9. Reactive oxygen species (ROS) levels increased at 0.25 h and decreased at 1 h after LDIR. In parallel, the number and intensity of γ-H2A.X and 53BP1 DNA damage foci significantly increased in the irradiated group. Transcriptome analysis identified Forkhead box protein O1 (FOXO1) as a key gene. Western blotting analysis showed that Sirtuin-1 (SIRT1) activity decreased at 0.25 h after irradiation, while the activity of FOXO1 and acetylated FOXO1 increased. Superoxide dismutase 2 (SOD2) activity decreased initially and then increased at 1 h. A co-immunoprecipitation (Co-IP) assay confirmed the interaction between FOXO1 and SIRT1, supporting their coordinated role in oxidative regulation. LDIR induced oxidative stress via the SIRT1/FOXO1 axis. These results demonstrate that early ROS accumulation suppresses SIRT1 activity, impedes FOXO1 deacetylation, and transiently reduces SOD2 activity, followed by a compensatory induction of SOD2 to restore redox balance.
As human space missions venture further beyond low Earth orbit, understanding the skeletal risks posed by prolonged exposure to the space environment becomes increasingly urgent. This review examines the effects of ionizing radiation on bone structure and homeostasis, focusing primarily on bone rather than bone marrow. While bone loss due to microgravity is well established, radiation-induced bone degeneration remains less thoroughly characterized. We compare space radiation with diagnostic and therapeutic exposures, highlighting key differences in dose rates, particle types, and biological outcomes. At the structural level, both low and high linear energy transfer (LET) radiation reduce trabecular bone volume, with high LET exposures causing more severe damage. At the cellular level, radiation disrupts osteoblast differentiation, promotes osteoclastogenesis, and induces apoptosis of osteocytes, leading to imbalanced bone remodeling. These effects are exacerbated when combined with mechanical unloading. Pharmacologic countermeasures such as parathyroid hormone (PTH), teriparatide, sclerostin-neutralizing antibody, and bisphosphonates, as well as antioxidant-rich diets, show promise in mitigating radiation-induced bone loss. However, most studies rely on acute, high-dose models that fail to replicate the chronic low-dose conditions of spaceflight. Future work should focus on osteocyte-specific responses, cellular proliferation after exposure to low dose high LET radiation, the long-term impact of chronic radiation, and how current countermeasures perform under realistic spaceflight conditions.
Neutron radiation poses significant risks not only to astronauts but also to patients receiving boron neutron capture radiotherapy. Previous studies have demonstrated that the ferroptosis inhibitor liproxstatin-1 (Lip-1) can mitigate damage caused by low-linear energy transfer (LET) radiation. However, the role and mechanism of Lip-1 in mitigating neutron radiation-induced damage remain unclear. This study aimed to investigate the effect of Lip-1 on neutron radiation damage. Our data indicated that Lip-1 treatment significantly attenuated bone marrow and spleen damage induced by neutron radiation. Specifically, the number of white blood cells, neutrophils, and lymphocytes in the Lip-1-treated group of mice was higher than in mice of the irradiated group. Additionally, Lip-1 treatment alleviated intestinal injury following irradiation, increased the Ki67 positivity rate, and reduced the TUNEL positivity rate. In vitro, Lip-1 significantly promoted cell proliferation and inhibited cell death following irradiation. Mechanistically, Lip-1 mitigated the release of ferrous ions by reducing reactive oxygen species (ROS) levels. Western blotting analysis showed that the expression of GPX4 was upregulated in the Lip-1-treated group. Also, transcriptome sequencing further suggested that Lip-1 plays a key role in regulating DNA damage. The comet assay and γ-H2AX immunofluorescence staining confirmed that Lip-1 significantly enhanced DNA damage repair. Collectively, these findings suggested that Lip-1 exhibits potential protective effects against neutron radiation by inhibiting ferroptosis and enhancing DNA damage repair both in vitro and in vivo, positioning it as a promising medical countermeasure for neutron radiation protection.
Immediate early response gene-3 (IER3/IEX-1) encodes a radiation-inducible stress-response adaptor protein that integrates pro-survival signaling pathways, yet the upstream mechanisms regulating its expression after irradiation remain incompletely understood. Here we investigated whether lysophosphatidic acid receptor (LPAR) signaling regulates IEX-1 expression during the radiation response and examined the radiobiological consequences of IEX-1 deficiency. LPAR activation enhanced IEX-1 expression in irradiated mouse whole blood, bone marrow, intestinal mucosa, and intestinal enteroids. In addition, IEX-1-deficient mice exhibited increased susceptibility to lethal radiation injury after total-body or partial body irradiation, while IEX-1-deficient enteroids displayed delayed growth and altered ERK phosphorylation kinetics. Together, these findings identify IEX-1 as a previously unrecognized downstream target of LPAR signaling after irradiation.
