Kazunori Anzai

Fukushima Daiichi Nuclear Power Plant accident: facts, environmental contamination, possible biological effects, and countermeasures

On March 11, 2011, an earthquake led to major problems at the Fukushima Daiichi Nuclear Power Plant. A 14-m high tsunami triggered by the earthquake disabled all AC power to Units 1, 2, and 3 of the Power Plant, and carried off fuel tanks for emergency diesel generators. Despite many efforts, cooling systems did not work and hydrogen explosions damaged the facilities, releasing a large amount of radioactive material into the environment. In this review, we describe the environmental impact of the nuclear accident, and the fundamental biological effects, acute and late, of the radiation. Possible medical countermeasures to radiation exposure are also discussed.

Edaravone containing isoindoline nitroxides for the potential treatment of cardiovascular ischaemia

A novel antioxidant for the potential treatment of ischaemia was designed by incorporating an isoindoline nitroxide into the framework of the free radical scavenger edaravone. 5-(3-Methyl-pyrazol-5-ol-1-yl)-1,1,3,3-tetramethylisoindolin-2-yloxyl 7 was prepared by N-arylation of 3-methyl-5-pyrazolone with 5-iodo-1,1,3,3-tetramethylisoindoline-2-yloxyl 8 in the presence of catalytic copper(I)iodide. Evaluation of 7, its methoxyamine derivative 10 and 5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl (CTMIO) against edaravone 1 in ischaemic rat atrial cardiomyocytes revealed significant decreases in cell death after prolonged ischaemia for each agent; however the protective effect of the novel antioxidant 7 (showing greater than 85% reduction in cell death at 100 μM) was significantly enhanced over that of edaravone 1 alone. Furthermore, the activity for 7 was found to be equal to or greater than the potent cardioprotective agent N6-cyclopentyladenosine (CPA). The methoxyamine adduct 10 and edaravone 1 showed no difference between the extent of reduction in cell death whilst CTMIO had only a modest protective effect.

Tanshinone IIA attenuates H2O2-induced injury in human umbilical vein endothelial cells

The injury of endothelial cell is the critical event of vascular disease. In endothelial cell, oxidative stress is regarded as critical to pathogenic factors in endothelial cell injury and apoptosis. Tanshinone IIA is the main effective component of Salvia miltiorrhiza known as Danshen in traditional Chinese medicine for treating cardiovascular disorders, but the mechanism by which it exerts the protective effect is not well established. The present study was designed to test the hypothesis that tanshinone IIA can inhibit hydrogen peroxide ( H(2)O(2) )-induced injury and unravel its intracellular mechanism in human umbilical vein endothelial cells (HUVECs). In this study, HUVECs were treated with tanshinone IIA in the presence/absence of H(2)O(2) . The protective effects of tanshinone IIA against H(2)O(2) were evaluated. Our results show that HUVECs incubated with 200 μM H(2)O(2) had significantly decreased the viability of endothelial cells, which was accompanied with apparent cell apoptosis, the activation of caspase-3 and the upregulation of p53 expression, which was known to play a key role in H(2)O(2) -induced cell apoptosis. However, pretreatment with tanshinone IIA (3-10 μM) resulted in a significant resistance to H(2)O(2) -induced apoptosis. In addition, pretreatment with tanshinone IIA decreased the activity of caspase-3 and p53 expression. Tanshinone IIA also induced activating transcription factor (ATF) 3 expression; while knockdown of ATF-3 with ATF-3 siRNAsignificantly reduced tanshinone IIAs protective effect. In conclusion, the present study shows that tanshinone IIA can protect endothelial cells against oxidative injury induced by H(2)O(2) , suggesting that this compound may constitute a promising intervention against cardiovascular disorders and ATF-3 may play an important role in this process.

Density of Hydroxyl Radicals Generated in an Aqueous Solution by Irradiating Carbon-Ion Beam

The density of hydroxyl radicals (·OH) produced in aqueous samples by exposure to X-ray or carbon-ion beams was investigated. The generation of ·OH was detected by the electron paramagnetic resonance (EPR) spin-trapping technique using 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) as the spin-trapping agent. When the concentration of DMPO is in excess of the generated ·OH, the production of DMPO-OH (spin-trapped ·OH) should be saturated. Reaction mixtures containing several concentrations (0.5-1685u2009mM) of DMPO were then irradiated by a 32u2009Gy 290u2009MeV carbon-ion beam (C290-beam) or X-ray. C290-beam irradiation was performed at the Heavy-Ion Medical Accelerator in Chiba (HIMAC, National Institute of Radiological Sciences, Chiba, Japan), applying different linear energy transfers (LET) (20-169u2009keV/µm). The amount of DMPO-OH in the irradiated samples was detected by EPR spectroscopy. The generation of DMPO-OH increased with the concentration of initial DMPO, displayed a shoulder around 3.3u2009mM DMPO, and reached a plateau. This plateau suggests that the generated ·OH were completely trapped. Another linear increase in DMPO-OH measured in solutions with higher DMPO concentrations suggested very dense ·OH generation (>1.7u2009M). Generation of ·OH is expected to be localized on the track of the radiation beam, because the maximum concentration of measured DMPO-OH was 40u2009µM. These results suggested that both sparse (≈3.3u2009mM) and dense (>1.7u2009M) ·OH generation occurred in the irradiated samples. The percentage of dense ·OH generation increased with increasing LET. Different types of dense ·OH generation may be expected for X-ray and C290-beams.

Lineal energy-based evaluation of oxidative DNA damage induced by proton beams and X-rays

Abstract Purpose: To determine the oxidative capabilities of proton beams compared to X-rays based on lineal energy (y). Materials and methods: Microdosimetry was used to determine y-values of 155 MeV protons. Salmon testes deoxyribonucleic acid (ST-DNA) in solution and human tumor cells (MOLT-4) were irradiated with 200 kV X-rays (X) or 155 MeV protons at their plateau (P) and near their Bragg-peak (B). 8-Hydroxydeoxyguanosine (8-OHdG) production was determined by high performance liquid chromatography. Double-strand breaks (DSB) in ST-DNA were evaluated by agarose gel electrophoresis and DSB in cell nuclei were evaluated by immunocytochemical analysis of phosphorylated histone H2AX (γH2AX) foci. Edaravone was used as a radical scavenger. Results: 8-OHdG yields in ST-DNA were significantly higher with X than with P or B, and they were significantly higher with P than with B. DSB yields in ST-DNA were higher with P than with B or X, although not statistically significant, and were nearly equal with B and X. Although γH2AX foci formation in MOLT-4 cells after each irradiation type was nearly identical, the addition of edaravone significantly inhibited foci formation only with X. Conclusions: Our results indicated that radical-induced indirect DNA damage was significantly lower with proton beams than with X-rays.

Comparison of in Vivo and in Vitro Antioxidative Parameters for Eleven Food Factors

In vivo antioxidative activity assays against reactive oxygen species generated in mitochondria, together with in vitro two radical-scavenging assays, electrochemical measurements, and theoretical calculations of ionization potentials (IP), were carried out for eleven food factors. Lycopene, with the smallest IP value, showed the highest anti-apoptotic activity.

Gamma-tocopherol-N,N-dimethylglycine ester as a potent post-irradiation mitigator against whole body X-irradiation-induced bone marrow death in mice

We examined the radioprotective and mitigative effects of gamma-tocopherol-N,N-dimethylglycine ester (GTDMG), a novel water-soluble gamma-tocopherol derivative, against X-irradiation-induced bone marrow death in mice. Mice (C3H, 10 weeks, male) were injected intraperitoneally with GTDMG suspended in a 0.5% methyl cellulose solution before or after receiving of 7.5-Gy whole body X-irradiation. GTDMG significantly enhanced the 30-day survival rate when given 30 min before or immediately after the irradiation. Its mitigative activity (administered after exposure) was examined further in detail. The optimal concentration of GTDMG given immediately after irradiation was around 100 mg/kg body weight (bw) and the 30-day survival rate was 97.6 ± 2.4%. When GTDMG was administered 1, 10 and 24 h post-irradiation, the survival rate was 85.7 ± 7.6, 75.0 ± 9.7 and 36.7 ± 8.8%, respectively, showing significant mitigation even at 24 h after irradiation (P < 0.05). The value of the dose reduction factor (100 mg/kg bw, given intraperitoneally (i.p.) immediately after irradiation) was 1.25. GTDMG enhanced the recovery of red blood cell-, white blood cell-, and platelet-counts after irradiation and significantly increased the number of endogenous spleen colonies (P < 0.05). Subcutaneous (s.c.) administration also had mitigative effects. In conclusion, GTDMG is a potent radiation mitigator.

Scavenging of reactive oxygen species induced by hyperthermia in biological fluid

The scavenging activity of rat plasma against hyperthermia-induced reactive oxygen species was tested. The glutathione-dependent reduction of a nitroxyl radical, 4-hydroxyl-2,2,6,6-tetramethylpiperidine-N-oxyl, which was restricted by adding superoxide dismutase or by deoxygenating the reaction mixture, was applied to an index of superoxide (O2•−) generation. A reaction mixture containing 0.1 mM 4-hydroxyl-2,2,6,6-tetramethylpiperidine-N-oxyl and 1 mM glutathione was prepared using 100 mM phosphate buffer containing 0.05 mM diethylenetriaminepentaacetic acid. The reaction mixture was kept in a screw-top vial and incubated in a water bath at 37 or 44°C. The time course of the electron paramagnetic resonance signal of 4-hydroxyl-2,2,6,6-tetramethylpiperidine-N-oxyl in the reaction mixture was measured by an X-band EPR spectrometer (JEOL, Tokyo, Japan). When the same experiment was performed using rat plasma instead of 100 mM PB, the glutathione-dependent reduction of 4-hydroxyl-2,2,6,6-tetramethylpiperidine-N-oxyl, i.e., generation of O2•−, was not obtained. Only the first-order decay reduction of 4-hydroxyl-2,2,6,6-tetramethylpiperidine-N-oxyl, which indicates direct reduction of 4-hydroxyl-2,2,6,6-tetramethylpiperidine-N-oxyl, was obtained in rat plasma. Adding 0.5% albumin to the phosphate buffer reaction mixture could almost completely inhibit O2•− generation at 37°C. However, addition of 0.5% albumin could not inhibit O2•− generation at 44°C, i.e., hyperthermic temperature. Ascorbic acid also showed inhibition of O2•− generation by 0.01 mM at 37°C, but 0.02 mM or more could inhibit O2•− generation at 44°C. A higher concentration of ascorbic acid showed first-order reduction, i.e., direct one-electron reduction, of 4-hydroxyl-2,2,6,6-tetramethylpiperidine-N-oxyl. Hyperthermia-induced O2•− generation in rat plasma can be mostly inhibited by albumin and ascorbic acid in the plasma.