Oct 05, 2016

Reo Etani (Graduate School of Health Sciences, Okayama University)

Radon therapy is performed for various diseases, in particular, reactive oxygen species-related diseases. We previously demonstrated that radon inhalation activates anti-oxidative functions in various organs, indicating that radon inhalation activates a biological defense system in mouse tissues that inhibits oxidative stress-related diseases. Hyperuricemia is also one of the indications of radon therapy. Previous studies reported that drinking therapy is said to be effective for lowering a high serum uric acid level. However, the mechanisms of action of radon inhalation or hot spring water drinking on hyperuricemia currently remain unclear. Therefore, we herein examined the effects of radon inhalation and hot spring water drinking on potassium oxonate (PO)-induced hyperuricemia. Mice inhaled radon at a concentration of 2000 Bq/m3?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.

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Reference:

Reo Etani, Takahiro Kataoka, Norie Kanzaki, Akihiro Sakoda, Hiroshi Tanaka, Yuu Ishimori, Fumihiro Mitsunobu, and Kiyonori Yamaoka. Activation of antioxidative functions by radon inhalation enhances the mitigation effects of pregabalin on chronic constriction injury-induced neuropathic pain in mice. J Radiat Res. 2016 Jun; 57(3): 250-7. doi: 10.1093/jrr/rrw014. Published online 2016 Jun 21.

Sep 25, 2016

Daisuke Iizuka (Department of Experimental Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University) 

The demand for establishment of simplified biodosimetric method is increasing. Our aim in this study is to identify urinary radiation responsive molecules using high sensitivity mass spectrometry (Matrix-assisted laser desorption/ionization time of flight mass spectrometry, MALDI-TOF MS). We collected mouse urine before and after radiation exposure. Collected urine was separated by high performance liquid chromatography and then each fraction was analyzed by MALDI-TOF MS. As a result, we identified 2 candidates, hepcidin-2 and peptide fragment of kidney androgen regulated protein (KAP). We observed that the peak increases of hepcidin-2 in urine were delayed in a dose dependent manner (1 Gy and above), however peptide fragment of KAP showed no correlation with radiation dose. In addition, urinary hepcidin-2 increased twice (at 8 to 48 h, or at 120 to 168 h after irradiation) during observation period after exposed to relatively low dose radiation (0.25 and 0.5 Gy). This increase of urinary hepcidin-2 could, at least in part, be ascribed to increased expression of hepcidin-2 gene in liver. These results suggest that hepcidin-2 in mouse urine is a good candidate radiation responsive molecule at wide range of dose. 

Reference:
Iizuka D, Yoshioka S, Kawai H, Okazaki E, Kiriyama K, Izumi S, Nishimura M, Shimada Y, Kamiya K, Suzuki F. Hepcidin-2 in mouse urine as a candidate radiation-responsive molecule. 
J Radiat Res. 2016 Mar;57(2):142-9. doi: 10.1093/jrr/rrv098. Epub 2016 Jan 28.

Sep 22, 2016

Takahiro KATAOKA (Graduate School of Health Sciences, Okayama University) 

Radon therapy is performed for mainly pain-related diseases using radon hot springs in Japan and Europe. We previously demonstrated that radon inhalation brings pain relief for chronic constriction injury (CCI)-induced neuropathic pain in mice due to the activation of antioxidative functions. Not only radon but also pregabalin, which is a medicine, has adverse effects. Therefore, a combination of pregabalin and radon treatment has beneficial effects to reduce the adverse effects of pregabalin and the lung cancer risk caused by radon inhalation. The purpose of this study was to compare the mitigating effects on CCI of radon inhalation and pregabaline administration and to examine the combination effects of radon and pregabalin on CCI-induced neuropathic pain. Mice were treated with inhaled radon at a concentration of 1,000 Bq/m3 for 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 were 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. 

Reference:
Takahiro Kataoka, Shunsuke Horie, Reo Etani, Norie Kanzaki, Kaori Sasaoka, Yusuke Kobashi, Katsumi Hanamoto and Kiyonori Yamaoka. Activation of antioxidative functions by radon inhalation enhances the mitigation effects of pregabalin on chronic constriction injury-induced neuropathic pain in mice. 
Oxidative Medicine and Cellular Longevity, 2016, Article ID 9853692, 8 pages, 2016 (DOI: 10.1155/2016/9853692)

Sep 22, 2016

Nobuyuki HAMADA (Central Research Institute of Electric Power Industry) 

The lens of the eye has long been considered as a radiosensitive tissue, but recent research has suggested that the radiosensitivity is even greater than previously thought. The 2012 recommendation of the International Commission on Radiological Protection (ICRP) to substantially reduce the annual occupational equivalent dose limit for the ocular lens has now been adopted in the European Union and is under consideration around the rest of the world. However, ICRP clearly states that the recommendations are chiefly based on epidemiological evidence because there are a very small number of studies that provide explicit biological, mechanistic evidence at doses <2 Gy. This paper aims to present a review of recently published information on the biological and mechanistic aspects of cataracts induced by exposure to ionizing radiation (IR). The data were compiled by assessing the pertinent literature in several distinct areas which contribute to the understanding of IR induced cataracts, information regarding lens biology and general processes of cataractogenesis. Results from cellular and tissue level studies and animal models, and relevant human studies, were examined. The main focus was the biological effects of low linear energy transfer IR, but dosimetry issues and a number of other confounding factors were also considered. The results of this review clearly highlight a number of gaps in current knowledge. Overall, while there have been a number of recent advances in understanding, it remains unknown exactly how IR exposure contributes to opacification. A fuller understanding of how exposure to relatively low doses of IR promotes induction and/or progression of IR-induced cataracts will have important implications for prevention and treatment of this disease, as well as for the field of radiation protection. 

Reference:
Ainsbury EA et al. Ionizing radiation induced cataracts: Recent biological and mechanistic developments and perspectives for future research. 
Mutat Res. 2017. 770: in press, http://dx.doi.org/10.1016/j.mrrev.2016.07.010

Sep 22, 2016

Nobuyuki HAMADA (Central Research Institute of Electric Power Industry) 

Biological effectiveness of ionizing radiation differs with its linear energy transfer (LET) such that high-LET radiation is more effective for various biological endpoints than low-LET radiation. Human exposure to high-LET radiation occurs in cancer patients, nuclear workers, aviators, astronauts and other space travellers. From the radiation protection viewpoint, the ocular lens is among the most radiosensitive tissues in the body, and cataract (a clouding of the normally transparent lens) is classified as tissue reactions (formerly called nonstochastic or deterministic effects) with a threshold below which no effect would occur. To prevent radiation cataracts, the International Commission on Radiological Protection (ICRP) has recommended an equivalent dose limit for the lens according to the threshold for vision-impairing cataracts. ICRP recommended the threshold of >8 Gy in 1984 and an occupational dose limit of 150 mSv/year in 1980. These remained unchanged until 2011, when ICRP recommended lowering the threshold to 0.5 Gy and the dose limit to 20 mSv/year (averaged over 5 years with no single year exceeding 50 mSv). Although such reduction of the threshold was based on findings from low-LET radiation, the dose limit was recommended in Sv. Historically, the lens is the exceptional tissue for which ICRP had assigned a special factor in addition to a general radiation weighting factor, predicated on a belief that the lens is more vulnerable to high-LET radiation than other tissues. Considering such radiosensitive nature of the lens, a deeper understanding of a cataractogenic potential of high-LET radiation is indispensable. This review is thus designed to provide an update on the current knowledge as to high-LET radiation cataractogenesis. To this end, changes in ICRP recommendations on lenticular radiation protection, epidemiological and biological findings on high-LET cataractogenesis are reviewed, and future research needs are then discussed. 

Reference:
Hamada N, Sato T. Cataractogenesis following high-LET radiation exposure. 
Mutat Res. 2017. 770: in press, http://dx.doi.org/10.1016/j.mrrev.2016.08.005

Aug 28, 2016

Mikio Shimada (Tokyo Institute of Technology) 

The embryonic brain is one of the tissues most vulnerable to ionizing radiation. In this study, we showed that ionizing radiation induces apoptosis in the neural progenitors of the mouse cerebral cortex, and that the surviving progenitor cells subsequently develop a considerable amount of supernumerary centrosomes. When mouse embryos at Day 13.5 were exposed to γ-rays, brains sizes were reduced markedly in a dose-dependent manner, and these size reductions persisted until birth. Immunostaining with caspase-3 antibodies showed that apoptosis occurred in 35% and 40% of neural progenitor cells at 4 h after exposure to 1 and 2 Gy, respectively, and this was accompanied by a disruption of the apical layer in which mitotic spindles were positioned in unirradiated mice. At 24 h after 1 Gy irradiation, the apoptotic cells were completely eliminated and proliferation was restored to a level similar to that of unirradiated cells, but numerous spindles were localized outside the apical layer. Similarly, abnormal cytokinesis, which included multipolar division and centrosome clustering, was observed in 19% and 24% of the surviving neural progenitor cells at 48 h after irradiation with 1 and 2 Gy, respectively. Because these cytokinesis aberrations derived from excess centrosomes result in growth delay and mitotic catastrophe-mediated cell elimination, our findings suggest that, in addition to apoptosis at an early stage of radiation exposure, radiation-induced centrosome overduplication could contribute to the depletion of neural progenitors and thereby lead to microcephaly. 

Reference:
Shimada M, Matsuzaki F, Kato A, Kobayashi J, Matsumoto T, Komatsu K. 
Induction of Excess Centrosomes in Neural Progenitor Cells during the Development of Radiation-Induced Microcephaly 
PLoS One. 2016 Jul 1;11(7):e0158236. doi: 10.1371/journal.pone.0158236. eCollection 2016. PMID: 27367050