He received "SFRR Japan Award of Scientific Excellent" in 2017 in recognition of his outstanding work. ??
Oral mucositis (OM) is a common and painful complication of radiotherapy for head and neck cancer. Hangeshashinto (HST), a Japanese traditional medicine, is known to alleviate radiotherapy- and/or chemotherapy-induced OM; however, the detailed mechanism has not yet been clarified. The aim of the present study was to clarify the details of the antioxidative functions of HST against reactive oxygen species (ROS) produced by radiation. The hydroxyl radical (•OH)–scavenging ability and the reduction ability was simultaneously measured using a modified electron paramagnetic resonance (EPR) spin-trapping method. The superoxide (O2•−)–scavenging ability was estimated by an EPR redox probing method. Water suspensions of powdered HST and of its seven constitutive crude drugs were tested. In addition, some of the main water-soluble ingredients of the crude drugs were also tested. HST was found to scavenge both •OH and O2•−. Furthermore, HST was observed to reduce relatively stable nitroxyl radicals. Glycyrrhizae Radix (kanzo), Ginseng Radix (ninjin), Zizyphi Fructus (taiso) and glycyrrhizin (an ingredient of kanzo) were all found to be relatively good •OH scavengers. Scutellariae Radix (ogon) and Coptidis Rhizoma (oren) demonstrated reducing ability. In addition, acteoside and berberine chloride, which are water-soluble ingredients of ogon and oren, respectively, also demonstrated reducing ability. Oren exhibited oxidative ability at higher concentrations, which may have a function in maintaining catalytic redox action. The antioxidative function of HST probably worked via a balance of scavenging ROS, reducing stable free radicals, and some minor oxidizing activities.
The effects of radiation on living animals are caused by two different mechanisms, i.e., direct and indirect effects. The direct effect is mainly DNA strands breaks, and the indirect effect is oxidative damage mediated by reactive oxygen species (ROS). Various ROS, such as hydroxyl radical ( · OH), superoxide ( · O 2 Ϫ ), and hydrogen peroxide (H 2 O 2 ), were produced by ionizing radiation in living animals. It has been assumed that the generation of · OH, hydrated electrons, and hydrogen radicals could be attributed to the ionization of water, and that · O 2 Ϫ and H 2 O 2 are formed by reacting with dissolved oxygen. Around 70% of the radiation effects on living organisms are based on indirect effects. It is well known that the lethal effect of X-rays on mammalian cells under aerobic conditions is higher than under anaerobic conditions, the so-called oxygen effect of radiation; therefore, the detection and quantification of oxygen-mediated free radical reactions is quite important to estimate the biological efficiency of radiation.Nitroxyl radicals have been used as in vivo redox probes for experimental animals by means of in vivo electron paramagnetic resonance (EPR) spectroscopy and/or imaging. 1,2) Nitroxyl radicals underwent one electron reduction by reactions with oxidoreductases in mitochondria and microsomes, 3,4) antioxidants, 5,6) and other free radical species 7,8) in a living body. The nitroxyl radicals lost their paramagnetism by one electron reduction and were mainly converted to the corresponding diamagnetic hydroxylamines. 9,10) When a living body was exposed to oxidative stress of · O 2 Ϫ and/or · OH, the in vivo EPR signal decay rate of the nitroxyl radicals increased.11,12) A common oxidative stress producing such ROS is ionizing radiation. The b-ray irradiation can significantly decrease the EPR signal of a nitroxyl radical in a solution containing glutathione (GSH).13) The in vivo decay rate of a nitroxyl radical in the rat bile flow significantly increased by b-ray irradiation to the liver. 13)The chemical reduction process of nitroxyl radicals by ROS was moved by two steps. First, the nitroxyl radicals are oxidized to oxoammonium cation by · O 2 Ϫ and/or · OH. Next, oxoammonium cations are reduced to hydroxylamine by receiving a hydrogen atom from hydrogen donors (H-donors), such as reduced GSH, reduced b-nicotinamide adenine dinucleotide (NADH) and reduced b-nicotinamide adenine dinucleotide phosphate (NADPH). Overall, the nitroxyl radicals undergo one-electron reduction by a reaction with · O 2 Ϫ and/or · OH in the presence of H-donors; therefore, the total ROS, i.e., · O 2 Ϫ and · OH, generation can be estimated indirectly by the amount of reduction of nitroxyl radicals.In this study, the stability and reactivity of nitroxyl radicals in the reaction mixture containing an H-donor, i.e., GSH, NADH, or NADPH, were tested. Using a suitable reaction mixture, the amounts of free radical reactions caused by low linear-energy-transfer (LET) irradiation, i.e., b-, g-, and Xray, at a dose lower ...
Temperature-dependent free radical reactions were investigated using nitroxyl radicals as redox probes. Reactions of two types of nitroxyl radicals, TEMPOL (4-hydroxyl-2,2,6,6-tetramethylpiperidine-N-oxyl) and carbamoyl-PROXYL (3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-N-oxyl), were tested in this paper. Heating a solution containing a nitroxyl radical and a reduced form of glutathione (GSH) caused temperature-dependent decay of electron paramagnetic resonance (EPR) signal of the nitroxyl radical. Heating a solution of the corresponding hydroxylamine form of the nitroxyl radical showed EPR signal recovery. The GSH-dependent reduction of nitroxyl radicals at 70°C was suppressed by antioxidants, spin trapping agents, and/or bubbling N2 gas, although heating carbamoyl-PROXYL with GSH showed temporarily enhanced signal decay by bubbling N2 gas. Since SOD could restrict the GSH-dependent EPR signal decay of TEMPOL, O2•− is related with this reaction. O2•− was probably generated from dissolved oxygen in the reaction mixture. Oxidation of the hydroxylamines at 70°C was also suppressed by bubbling N2 gas. Heating a solution of spin trapping agent, DMPO (5,5-dimethyl-1-pyrroline-N-oxide) showed a temperature-dependent increase of the EPR signal of the hydroxyl radical adduct of DMPO. Synthesis of hydroxyl radical adduct of DMPO at 70°C was suppressed by antioxidants and/or bubbling N2 gas. The results suggested that heating an aqueous solution containing oxygen can generate O2•−.
The glutathione (GSH)-mediated superoxide (O2•−) generation in an aqueous solution and relation of hydrogen peroxide (H2O2) and effect of catalase were investigated. GSH-induced O2•− generation in hyperthermal temperatures was measured by the nitroblue tetrazolium (NBT) mehod. Heating an aqueous solution containing GSH caused superoxide from dissolved O2. H2O2 was generated simultaneously in this reaction mixture probably from the hydroperoxy radical (HO2•), which is equilibrated with O2•− in an aqueous condition, and then H2O2 consumed O2•−. Coexisting catalase in the reaction mixture, as a result, could increase O2•− generation. The catalase-exaggerated extracellular O2•− generation could give a harmful effect to living cells. This GSH-induced oxidative stress can be a part of mechanisms of hyperthermia therapy.
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