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Pluripotent stem cells (PSCs) have the potential to differentiate to any of the other organs. The genome DNA integrity of PSCs is maintained by a high level of transcription for a number of genes involved in DNA repair, cell cycle and apoptosis. However, it remains unclear how high the frequency of genetic mutation is and how these DNA repair factors function in PSCs. In this study, we employed Sup F assay for the measurement of mutation frequency after UV-C irradiation in induced pluripotent stem cells (iPSCs) as PSC models and neural progenitor cells (NPCs) were derived from iPSCs as differentiated cells. iPSCs and NPCs exhibited a lower mutation frequency compared with the original skin fibroblasts. In RNA-seq analysis, iPSCs and NPCs showed a high expression of RAD18, which is involved in trans-lesion synthesis (TLS) for the emergency tolerance system during the replication process of DNA. Although RAD18 is involved in both error free and error prone TLS in somatic cells, it still remains unknown the function of RAD18 in PSCs. In this study we depleted of the RAD18 by siRNA knockdown resulted in decreased frequency of mutation in iPSCs and NPCs. Our results will provide information on the genome maintenance machinery in PSCs.

The typical indication of radon therapy is rheumatoid arthritis. Although there are several reports that radon therapy has regulation effects on Th17 cells, there has been no study reporting that radon inhalation affects the immune balance among Th1, Th2, and Th17. The purpose of this study is to examine the cytokine changes after radon inhalation. BALB/c mice inhaled radon at 2,000 Bq/m3 for 2 or 4 weeks. SKG/Jcl mice inhaled radon at 2,000 Bq/m3 for 4 weeks after zymosan administration. The results showed that radon inhalation for 4 weeks activated the immune response of Th1, Th2, and Th17. Moreover, the balance among them was not lost by radon inhalation. Radon inhalation for 4 weeks decreased superoxide dismutase activity and increased catalase activity in spleen. These findings suggest that an imbalance of oxidative stress may contribute to activate the immune response. Although zymosan administration activated Th17 immune response and decreased Th1 and Th2 immune response in SKG/Jcl mice, most cytokines related to Th1, Th2, and Th17 approached the normal level by radon inhalation. These findings suggested that radon inhalation has a different action between SKG/Jcl mice and normal BABL/c mice. This may indicate that radon inhalation has an immunomodulation function.

Radon inhalation decreases the level of lipid peroxide (LPO); this is attributed to the activation of antioxidative functions. This activation contributes to the beneficial effects of radon therapy, but there are no studies on the risks of radon therapy, such as DNA damage. We evaluated the effect of radon inhalation on DNA damage caused by oxidative stress and explored the underlying mechanisms. Mice were exposed to radon inhalation at concentrations of 2 or 20 kBq/m3 (for one, three, or 10 days). The 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels decreased in the brains of mice that inhaled 20 kBq/m3 radon for three days and in the kidneys of mice that inhaled 2 or 20 kBq/m3 radon for one, three or 10 days. The 8-OHdG levels in the small intestine decreased by approximately 20–40% (2 kBq/m3 for three days or 20 kBq/m3 for one, three or 10 days), but there were no significant differences in the 8-OHdG levels between mice that inhaled a sham treatment and those that inhaled radon. There was no significant change in the levels of 8-oxoguanine DNA glycosylase, which plays an important role in DNA repair. However, the level of Mn-superoxide dismutase (SOD) increased by 15–60% and 15–45% in the small intestine and kidney, respectively, following radon inhalation. These results suggest that Mn-SOD probably plays an important role in the inhibition of oxidative DNA damage.

It is held that the skin dose from radon progeny is not negligibly small and that introducing cancer is a possible consequence under normal circumstances as there are a number of uncertainties in terms of related parameters such as activity concentrations in air and water, target cells in skin, skin covering materials, and deposition velocities. An interesting proposal has emerged in that skin exposure to natural radon-rich thermal water as part of balneotherapy can produce an immune response to induce beneficial health effects. The goal of this study was to obtain generic dose coefficients with a focus on the radon progeny deposited on the skin in air or water in relation to risk or treatment assessments. We thus first estimated the skin deposition velocities of radon progeny in air and thermal water based on data from the latest human studies. Skin dosimetry was then performed under different assumptions regarding alpha-emitting source position and target cell (i.e. basal cells or Langerhans cells). Furthermore, the impact of the radon progeny deposition on effective doses from all exposure pathways relating to ‘radon exposure’ was assessed using various possible scenarios. It was found that in both exposure media, effective doses from radon progeny inhalation are one to four orders of magnitude higher than those from the other pathways. In addition, absorbed doses on the skin can be the highest among all pathways when the radon activity concentrations in water are two or more orders of magnitude higher than those in air.

Therapy using hot springs, including the high-level radioactive gas “radon”, is traditionally conducted as an alternative treatment for various diseases. Oxidative-stress-related diseases are inhibited by the enhancement of antioxidative functions following radon inhalation. We have reported that radon inhalation increased the level of anti-oxidants, such as glutathione (G-SH), in the brain and had a protective antioxidative effect against transient global cerebral ischemic injury. However, no studies have yet revealed the changes in G-SH associated substances after radon inhalation. In this study, we comprehensively analyzed several metabolites, focusing on G-SH. Mice were exposed to radon at concentrations of 200, 2000, or 20,000 Bq/m3 for 1, 3, or 10 days. We detected 27 metabolites in the mouse brains. The result showed that the L-methionine levels increased, whereas the levels of urea, glutathione, and sulfite ion decreased under any condition. Although the ratio of G-SH to oxidized glutathione (GS-SG) decreased, glutathione monosulfide (G-S-SH) and cysteine monosulfide (Cys-S-SH) increased after radon inhalation. G-S-SH and Cys-S-SH can produce a biological defense against the imbalance of the redox state at very low-dose irradiation following radon inhalation because they are strong scavengers of reactive oxygen species. Additionally, we performed an overall assessment of high-dimensional data and showed some specific characteristics. We showed the changes in metabolites after radon inhalation using partial least squares-discriminant analysis and self-organizing maps. The results showed the health effects of radon, especially the state of sulfur-related metabolites in mouse brains under the exposure conditions for radon therapy.

Although thoron inhalation exerts antioxidative effects in several organs, there are no reports on whether it inhibits oxidative stress-induced damage. In this study, we examined the combined effects of thoron inhalation and ascorbic acid (AA) administration on alcohol-induced liver damage. Mice were subjected to thoron inhalation at 500 or 2000 Bq/m3 and were administered 50% ethanol (alcohol) and 300 mg/kg AA. Results showed that although alcohol administration increased the levels of glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) in the serum, the combination of thoron inhalation (500 Bq/m3) and AA administration 24 h after alcohol administration effectively inhibited alcohol-induced liver damage. The combination of thoron inhalation (500 Bq/m3) and AA administration 24 h after alcohol administration increased catalase (CAT) activity. Alcohol administration significantly decreased glutathione (GSH) levels in the liver. The GSH content in the liver after 2000 Bq/m3 thoron inhalation was lower than that after 500 Bq/m3 thoron inhalation. These findings suggest that the combination of thoron inhalation at 500 Bq/m3 and AA administration has positive effects on the recovery from alcohol-induced liver damage. The results also suggested that thoron inhalation at 500 Bq/m3 was more effective than that at 2000 Bq/m3, possibly because of the decrease in GSH content in the liver. In conclusion, the combination of thoron inhalation at 500 Bq/m3 and AA administration promoted an early recovery from alcohol-induced liver damage.

Radon inhalation activates antioxidative functions in mouse organs, thereby contributing to inhibition of oxidative stress-induced damage. However, the specific redox state of each organ after radon inhalation has not been reported. Therefore, in this study, we evaluated the redox state of various organs in mice following radon inhalation at concentrations of 2 or 20 kBq/m3 for 1, 3 or 10 days. Scatter plots were used to evaluate the relationship between antioxidative function and oxidative stress by principal component analysis (PCA) of data from control mice subjected to sham inhalation. The results of principal component (PC) 1 showed that the liver and kidney had high antioxidant capacity; the results of PC2 showed that the brain, pancreas and stomach had low antioxidant capacities and low lipid peroxide (LPO) content, whereas the lungs, heart, small intestine and large intestine had high LPO content but low antioxidant capacities. Furthermore, using the PCA of each obtained cluster, we observed altered correlation coefficients related to glutathione, hydrogen peroxide and LPO for all groups following radon inhalation. Correlation coefficients related to superoxide dismutase in organs with a low antioxidant capacity were also changed. These findings suggested that radon inhalation could alter the redox state in organs; however, its characteristics were dependent on the total antioxidant capacity of the organs as well as the radon concentration and inhalation time. The insights obtained from this study could be useful for developing therapeutic strategies targeting individual organs.

Estimation of the effective inhalation dose of short half-life radon progeny requires the quantification of radon equilibrium equivalent activity concentrations (EEC, Ceq). The aim of the present study is to develop new methodology that focuses on spot measurements to determine EEC from single gross alpha counts and determine an optimised protocol. The core of the approach is to measure alpha particles over time when the radon progeny attached to the sampling filter are significantly disintegrated. The calibration curve of single counts to EEC is theoretically deduced and validated by a comparison test. The advantage of the present method is its minimal requirements, including the use of common instruments and simple sampling, alpha counting and analysis procedures. This approach offers an option for radon practitioners working in a variety of fields, as well as the possibility for non-experts to easily measure Ceq.

In specific situations such as bathing in a radon spa, where the radon activity concentration in thermal water is far higher than that in air, it has been revealed that radon uptake via skin can occur and should be considered for more precise dose evaluation. The primary aim of the present study was to numerically demonstrate the distribution as well as the degree of diffusion of radon in the skin, with a focus on its surface layer (i.e., stratum corneum). We developed a biokinetic model that included diffusion theory at the stratum corneum, and measured radon solubility in that tissue layer as a crucial parameter. The implementation of the model suggested that the diffusion coefficient in the stratum corneum was as low as general radon-proof sheets. After a 20-min immersion in water, the simulated depth profile of radon in the skin showed that the radon activity concentration at the top surface skin layer was approximately 103 times higher than that at the viable skin layer. The information on the position of radon as a radiation source would contribute to special dose evaluation where specific target cell layers are assumed for the skin.

Radon therapy using radon (222Rn) gas is classified into two types of treatment: inhalation of radon gas and drinking water containing radon. Although short- or long-term intake of spa water is effective in increasing gastric mucosal blood flow, and spa water therapy is useful for treating chronic gastritis and gastric ulcer, the underlying mechanisms for and precise effects of radon protection against mucosal injury are unclear. In the present study, we examined the protective effects of hot spring water drinking and radon inhalation on ethanol-induced gastric mucosal injury in mice. Mice inhaled radon at a concentration of 2000 Bq/m3 for 24 h or were provided with hot spring water for 2 weeks. The activity density of 222Rn ranged from 663 Bq/l (start point of supplying) to 100 Bq/l (end point of supplying). Mice were then orally administered ethanol at three concentrations. The ulcer index (UI), an indicator of mucosal injury, increased in response to the administration of ethanol; however, treatment with either radon inhalation or hot spring water inhibited the elevation in the UI due to ethanol. Although no significant differences in antioxidative enzymes were observed between the radon-treated groups and the non-treated control groups, lipid peroxide levels were significantly lower in the stomachs of mice pre-treated with radon or hot spring water. These results suggest that hot spring water drinking and radon inhalation inhibit ethanol-induced gastric mucosal injury.

Biodosimetry is a useful method for estimating personal exposure doses to ionizing radiation. Studies have identified metabolites in non-cellular biofluids that can be used as markers in biodosimetry. Levels of metabolites in blood cells may reflect health status or environmental stresses differentially. Here, we report changes in the levels of murine blood cell metabolites following exposure to X-rays in vivo. Levels of blood cell metabolites were measured by capillary electrophoresis time-of-flight mass spectrometry. The levels of 100 metabolites were altered substantially following exposure. We identified 2-aminobutyric acid, 2&prime, deoxycytidine, and choline as potentially useful markers of radiation exposure and established a potential prediction panel of the exposure dose using stepwise regression. Levels of blood cell metabolites may be useful biomarkers in estimating exposure doses during unexpected radiation incidents.

Radon therapy has been traditionally performed globally for oxidative stress-related diseases. Many researchers have studied the beneficial effects of radon exposure in living organisms. However, the effects of thoron, a radioisotope of radon, have not been fully examined. In this study, we aimed to compare the biological effects of radon and thoron inhalation on mouse organs with a focus on oxidative stress. Male BALB/c mice were randomly divided into 15 groups: sham inhalation, radon inhalation at a dose of 500 Bq/m3 or 2000 Bq/m3, and thoron inhalation at a dose of 500 Bq/m3 or 2000 Bq/m3 were carried out. Immediately after inhalation, mouse tissues were excised for biochemical assays. The results showed a significant increase in superoxide dismutase and total glutathione, and a significant decrease in lipid peroxide following thoron inhalation under several conditions. Additionally, similar effects were observed for different doses and inhalation times between radon and thoron. Our results suggest that thoron inhalation also exerts antioxidative effects against oxidative stress in organs. However, the inhalation conditions should be carefully analyzed because of the differences in physical characteristics between radon and thoron.

In our previous studies, we found that low-dose radiation inhibits oxidative stress–induced diseases due to increased antioxidants. Although these effects of low-dose radiation were demonstrated, further research was needed to clarify the effects. However, the analysis of oxidative stress is challenging, especially that of low levels of oxidative stress, because antioxidative substances are intricately involved. Thus, we proposed an approach for analysing oxidative liver damage via use of a self-organizing map (SOM)—a novel and comprehensive technique for evaluating hepatic and antioxidative function. Mice were treated with radon inhalation, irradiated with X-rays, or subjected to intraperitoneal injection of alcohol. We evaluated the oxidative damage levels in the liver from the SOM results for hepatic function and antioxidative substances. The results showed that the effects of low-dose irradiation (radon inhalation at a concentration of up to 2000 Bq/m3, or X-irradiation at a dose of up to 2.0 Gy) were comparable with the effect of alcohol administration at 0.5 g/kg bodyweight. Analysis using the SOM to discriminate small changes was made possible by its ability to ‘learn’ to adapt to unexpected changes. Moreover, when using a spherical SOM, the method comprehensively examined liver damage by radon, X-ray, and alcohol. We found that the types of liver damage caused by radon, X-rays, and alcohol have different characteristics. Therefore, our approaches would be useful as a method for evaluating oxidative liver damage caused by radon, X-rays and alcohol.

In this study, we compared the protective effects of radon inhalation and ascorbic acid administration on transient global cerebral ischemic injury in gerbils. Gerbils were treated with radon inhalation (2000 Bq/m3, 24 hours) or ascorbic acid (100, 300, or 500 mg/kg body weight). Then, transient global cerebral ischemia was induced by bilateral occlusion of the common carotid artery. Results showed that the number of damaged neurons was significantly increased in gerbils that underwent ischemia compared with that in control gerbils. However, the number of damaged neurons in gerbils treated with radon or 500 mg/kg of ascorbic acid before ischemia was significantly lower than gerbils who were subjected to ischemia without any pretreatment, and the protective effects of radon inhalation were similar to the effects of administering 500 mg/kg ascorbic acid. The levels of superoxide dismutase (SOD) and total glutathione (t-GSH) in brain tissue were increased to a similar extent by pretreatment with rado...

Radon inhalation brings pain relief for chronic constriction injury- (CCI-) induced neuropathic pain in mice due to the activation of antioxidative functions, which is different from the mechanism of the pregabalin effect. In this study, we assessed whether a combination of radon inhalation and pregabalin administration is more effective against neuropathic pain than radon or pregabalin only. Mice were treated with inhaled radon at a concentration of 1,000 Bq/m3for 24 hours and pregabalin administration after CCI surgery. In mice treated with pregabalin at a dose of 3 mg/kg weight, the 50% paw withdrawal threshold of mice treated with pregabalin or radon and pregabalin was significantly increased, suggesting pain relief. The therapeutic effects of radon inhalation or the combined effects of radon and pregabalin (3 mg/kg weight) were almost equivalent to treatment with pregabalin at a dose of 1.4 mg/kg weight or 4.1 mg/kg weight, respectively. Radon inhalation and the combination of radon and pregabalin increased antioxidant associated substances in the paw. The antioxidant substances increased much more in radon inhalation than in pregabalin administration. These findings suggested that the activation of antioxidative functions by radon inhalation enhances the pain relief of pregabalin and that this combined effect is probably an additive effect.

Although radon therapy is indicated for hyperuricemia, the underlying mechanisms of action have not yet been elucidated in detail. Therefore, we herein examined the inhibitory effects of radon inhalation and hot spring water drinking on potassium oxonate (PO)–induced hyperuricemia in mice. Mice inhaled radon at a concentration of 2000 Bq/m 3 for 24 h or were given hot spring water for 2 weeks. Mice were then administrated PO at a dose of 500 mg/kg. The results obtained showed that serum uric acid levels were significantly increased by the administration of PO. Radon inhalation or hot spring water drinking significantly inhibited elevations in serum uric acid levels through the suppression of xanthine oxidase activity in the liver. Radon inhalation activated anti-oxidative functions in the liver and kidney. These results suggest that radon inhalation inhibits PO-induced hyperuricemia by activating anti-oxidative functions, while hot spring water drinking may suppress PO-induced elevations in serum uric acid levels through the pharmacological effects of the chemical compositions dissolved in it.