Free Radicals - Mandarin Version

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Information about Free Radicals - Mandarin Version
Health & Medicine

Published on March 20, 2014

Author: WongSookYen



Discover how free radicals harm your body and eventually kills you off over time.

氧自由基概論 (Introduction to Oxygen Radicals ) 呂鋒洲 Fung-Jou Lu 中山醫學大學應化系1及醫學研究所2 1.Department of Applied Chemistry,Chung Shan Medical Unuversity. 2.Institure of Medicine, Chung Shan Medical Unuversity. Research field in free radicals 自由基的研究領域自由基的研究領域 1.Redox Chemistry and Antioxidants 氧化還原化學與抗氧劑 2.Radiation Exposed systems 暴露於輻射線系統 3.NO and related Radicals 一氧化氮及相關的自由基 4.DNA Damage and Repair DNA損害及修護 5.Oxidized Lipoproteins 氧化的脂蛋白 6.Lipid Peroxidation 脂質過氧化作用 7.Membrane Damage7.Membrane Damage 細胞膜損害 8.Gene Expression and Oxidative Damage 基因表達和氧化損害 9.Free Radicals and Prostaglandins 自由基和前列腺素 10.Oxidant and Antioxidant Reactions in Plants,Food, Cosmetics etc. 氧化劑和抗氧化劑在食物,植物 及化粧品中的反應 11.Antioxidant Defenses 抗氧化劑防禦系統 12.Inflammation 發炎 13.Ischemia-Reperfusion 缺血再灌血 14.Free Radicals in Cancerogensis 自由基與癌症之形成

15.Reactive Species in Metabolic Disorders 活性氧與代謝尞亂 16.Free Radicals in Medicine (Lung Kideny Nervous System 16.Free Radicals in Medicine (Lung, Kideny, Nervous System, Muscle, Liver, Eye, skin, Red Cells, Heart) 自由基與醫學 Discoveries of Oxygen 1.Joseph Priestley (1733-1804), an English clergyman and chemist 牧師牧師 2.Antoine Lavoisier (1743-1794), a French chemist. ANTOINE LAOISIER (1743- 94)1.Certain chemicals gained weight when they burned. 2.He learned that Priestlry had discovered a GAS that seemed to help things burn.GAS that seemed to help things burn. 3.He himself did some experiments and named the gas“oxygen”. 4.He showed that body uses inhaled “oxygen”to metabolized food. JOSPH PRIESTLEY (1733-1804) 1.In 1774, he obtained a pure sample of gas by, heating mercuric oxide using the sun’s rays through a lens. 2.He called the gas“dephogisticated air (缺乏燃素之空氣)”:(缺乏燃素之空氣)”: (1)Things burned more brightly in the “air” (2) When he breathed some of the“air” , his breath felt light and easy. (3)No color, odor, or taste. Characteristics of the oxygen molecule (dioxygen)molecule (dioxygen) 1.Burning quickly (exploding) 2.Radiating light and heat. 3.High oxidizing potential (+0.81 V ) 4.Producing energy (113.5 Kcal per mole of oxygen)

5.Life is substained by capturning this energy as ATP (adenosine triphosphate) Problems of Dioxygen 1.low solubility in water: 3.1 % (v/v) at 20 ℃ 2.Toxic intermediates. Fig. Bonding in The Diatomic Oxygen Moleule Reactive Oxygen Species(ROS) andand Free Radicals(FR) FREE RAIDCALS(FR) Any atom or molecule that has one or more unpaired electrons: O • • OH LOO • LO • CCl 3 • NO • O • 2 ROS:Reactive Oxygen Species ROI: Reactive Oxygen Intermediates 1O2 • OH H O O • 2 • OH H2O2 LOO • LO • NO •

REACTIVE OXYGEN SPECIES(ROS) 1.superoxide: O • 2 2.hydrogen peroxide: H2O2 3.hydroxyl radicals : • OH 4.singlet oxygen:1O2 In a broder sense: 1.peroxide 2.hydroperoxide 3.epoxide metabolites of endogenous lipidendogenous lipid 4.xenobiotics which have chemically reactive oxygen- containing functional group. It is hardly possible to separate the biological processes evoked by ROS or RF: ROS-RF Figure 4 The relation between reactive oxygen species (ROS) and free radicals. LOO • lipid peroxyl radical; LO • , lipid alkoxyl radical.

Figure. Myeloperoxidase (MPO) – hydrogen peroxide-halide bactericidal activity of neutrophils NADP+ and HADPH : oxidized and reduced forms of nicotinamide-adenine dinucleotide phosphate. SINGLET OXYGEN: 1O2SINGLET OXYGEN: O2 1O2 + 1O2 2 3O2 + hv (480, 520, 580, 635 nm) Fig. Lipid peroxidation produced singlet oxygen and ultra-weak chemiluminescence 肌纖維膜 肌漿網 肌原纖維肌漿網 Fig. Myocardial Injury Induced by singlet oxygen

LIPID PEROXIDATION A radical chain peroxidation of polyunsaturated fatty acids including free or esterified unsaturated fatty acids.unsaturated fatty acids. ( phospholipids in cell membranes )

LIPID HYDROPEROXIDES PEROXYNITRITE ANION (ONOO - ) O • 2 + NO .... ONOO - Toxicity of peroxynitrite anion: PARS: Poly-ADP-Ribosyltransferase

SOURCE OF ROS-IN HUMANSSOURCE OF ROS-IN HUMANS 1.Ionizing radiation : (1)Direct or target effect: direct hits on target atoms or molecules, such as proteins,lipids or DNA , producting organic radicals. (2) Indirect effect: radiolysis of cellular water, with the formation of ROS-FR Injuring and killing cells: mutation,cancers. Injuring and killing cells: mutation, cancers 2.Cigarette smokes 3.Air pollutant ( eg. NOx) 4.Many pigmented conditions 5.Exposure to light : singlet oxygen foramtion 6.some drug : tetracycline 7.Some constituents of cosmetics: cause damage to the skin by UV irradiation 8.Leakages of electrons of the cellular electron transport chains, such as those of : (1) Mitochondria(1) Mitochondria (2) NADPH-cytochrome-P-450 reductase/ cytochrome P-450 system involved in drug and the processes of oxygenase action and others. 9.Ischemia /reperfusion injury: 缺血再灌血傷害 (1)xanthine /xanthine oxidase: a leading candidate, particularlya leading candidate, particularly in the intestine (2) neutrophils :activated or trapped in the microvasculature site 10.Activated neutrophil, monocytes 單核白血球 macrophages 巨噬細胞 eosinophils 嗜曙紅細胞 11.transition metals: iron and copper

THE MOST IMPORTANT SOURCES OF ROS-FR INSOURCES OF ROS-FR IN HUMAN : 1. those from cigarette smoke, 2. those produced by neutrophils at the inflammation sitethe inflammation site 3. those produced and amplied by transition metals. FREE RADICAL DAMAGE TO MEMBRANES PROTECTION AGAINST ROS-FR INJURY

Figure 3. Micronutrient interactions in the antioxidant defense system. FREE RADICALS AND DISEASESDISEASES 1.ATHEROSCLEROSIS 動脈硬化動脈硬化動脈硬化動脈硬化 2.CHRONIC INFLAMMATION 慢性發炎慢性發炎慢性發炎慢性發炎 3.AUTOIMMUNE DISEASES 自體免疫疾病自體免疫疾病自體免疫疾病自體免疫疾病 3.AUTOIMMUNE DISEASES 自體免疫疾病自體免疫疾病自體免疫疾病自體免疫疾病 4.ISCHEMIA/REOXYGENATION INJURY 缺血缺血缺血缺血////再灌血引起傷害再灌血引起傷害再灌血引起傷害再灌血引起傷害 5.LUNG DAMAGE AND THE ADULT RESPIRATORY SYNDROME 肺損害和成人呼吸症候群肺損害和成人呼吸症候群肺損害和成人呼吸症候群肺損害和成人呼吸症候群 6.EXERCISE-INDUCED OXIDANT DAMAE 運動誘導的傷害運動誘導的傷害運動誘導的傷害運動誘導的傷害DAMAE 運動誘導的傷害運動誘導的傷害運動誘導的傷害運動誘導的傷害 7.AGEING 老化老化老化老化 8.CANCER 癌症癌症癌症癌症 9.RADIATION DISEASE 放射線照射疾病放射線照射疾病放射線照射疾病放射線照射疾病 10.MYOCADIAL INFRACTION 心肌梗塞心肌梗塞心肌梗塞心肌梗塞心肌梗塞心肌梗塞心肌梗塞心肌梗塞 11.CATARACT 白內障白內障白內障白內障 12.DIABETS MELLITUS 糖尿病糖尿病糖尿病糖尿病 ATHEROSCLEROSIS 動脈硬化動脈硬化動脈硬化動脈硬化

(New Eng J Med 320 , 915-924 , 1989.) ISCHEMIAAND REPERFUSION INJURY 缺血再灌血引起的傷害缺血再灌血引起的傷害缺血再灌血引起的傷害缺血再灌血引起的傷害缺血再灌血引起的傷害缺血再灌血引起的傷害缺血再灌血引起的傷害缺血再灌血引起的傷害 Reperfusion Injury in the Intestines Xanthine oxidase-based generation of superoxide is the initial trigger ofsuperoxide is the initial trigger of reperfusion injury. Endothelial Cell Trigger Mechanism Fig.1 Xanthine oxidase may serve as the initial source of free radical generation in postischaemic reperfusion injury. Fig.1 Free radical-mediated reperfusion injury appears to start at the microvascular level, at the interface of the endothelium with the bloodstream.

Free radical-mediated reperfusion injury has also been found to be important in a number of other organs including : stomach Reperfusion Injury in other organs stomach liver heart kidney central nervous system DIABETES MELLITUS 糖尿病糖尿病糖尿病糖尿病 Glycation of Protein as a source of superoxide A role for oxygen radicals as second massagers Ralf Schreck and Patrick A. BaeuerleRalf Schreck and Patrick A. Baeuerle Trend in Biology 1, 39-42,1991 FREE RADICAL : second messengers and mediators ofmessengers and mediators of tissue destruction CRITERION FOR A SECOND MESSENGER 1.increased by an extracellular ligands intracellular signaling reaction

Fig 9. signal transduction pathway for NF- κB activation. J Immuno. 153,5008,1994 烏腳病病人血清脂質過氧化物 呂鋒洲 呂靜儀 台灣醫誌 1987;86:76-80 自由基與各種疾病自由基與各種疾病自由基與各種疾病自由基與各種疾病自由基與各種疾病自由基與各種疾病自由基與各種疾病自由基與各種疾病 台北市立仁愛醫院醫師 施益民 台大醫學院生化所教授 呂鋒洲 當代醫學 第十六卷 第五期 54 中華民國七十八年五月 2003 Active Hydrogen 2007

1995 ELECTROLYZED-REDUCED WATER SCAVENGES SUPEROXIDE ANION RADICALS IN THE WHOLE BLOOD OF PATIENTS WITH ACUTE PANCREATITIS Fung-Jou Lu1, Tien-Shang Huang2 , Rung-Jiun Gan1 , Ruey-Shiung Lin4 , Min-Ling Liao3 , Shinkatsu Morisawa3 , Kazumichi Otsubo3Liao , Shinkatsu Morisawa , Kazumichi Otsubo 1Department of Biochemistry , 2Department of Medicine , College of Medicine , National Taiwan University , Taipei , Taiwan , Republic of china , 3Nihon Trim Co. ,Ltd.,Japan 4institute of Public Health , College of Public Health , NTU. 1997 2009

Mechanism O • 2 + e- + 2 H+ H2O2 H2O2+ e- • OH + OH-H2O2+ e OH + OH OH-+ e- + H+ H2O H+ + H- H2 2•OH ++++ H2 2 H2O 活性氧與活性氫 (Active Oxygen and Active Hydrogen)(Active Oxygen and Active Hydrogen) O2+ 2 H2 2 H2O (活性氧) (活性氫) O • 2 H2 (氫分子) • OH H2O2 H+ (正氫離子) H- (負氫離子) H2 H+ + H- H- H0+ e • H0 H++ e • 正氫離子 負氫離子氫原子 + 質子 質子 + 質子 (電子)(電子) 電子 質子 H+ H0 H- 質子 (1個質子) (1個質子+1個電子) (1個質子+2個電子) (電子) (電子) H-(1) (2 ) H+ + 2e- O • 2 O2 e- e- +2H+ H2O2 e- +2H+ 2 H2O e- + H+ 2 H2O 2 •OH e- + H+ H2

e- : J.L. Oschman (2007) H+ : S. Shirahata (1997) H- : Patrick Flanagan (2002) H2 : I.Ohsawa (2007) 回歸自然回歸自然回歸自然回歸自然 2 H2OO2 + 2H2 The EndThe End Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals Nature medicine 13: 688-694, 2007 94 H H O H H 2 H2+ O2 2 H2O CuO Molecular hydrogen (H2) is a colorless, odorless, nonmetallic, tasteless, highly flammable diatomic gas which is mainly used in fossil fuel processing and ammonia production. 95 O O H H O H H Zn+ H2SO4 -> ZnSO4 + H2 Zn CuSO 4 CuO + H2 -> Cu + H2O Production of free radicals Arachidonic acidO2 Xanthine/hypoxanthi neO2 mitochondrial respiratory chain O2COX, LOX NADPH NADP+,H+ H2O, O2 XO NADPH oxidase SOD Fenton reaction 12 3 4 96 .O2 - H2O2 .OHO2 H2O L-Arginine NOS SOD Fenton reaction H+, e_ HOCl H+, Cl- MP O H2O 2H2OH2OONOO- H2O 2 NO- CAT O2 2GSH GSSH GPx GR .O2 -,2H+ O2 Fe2+, e_ Fe +

ROS .O2 - H2O2.OH .NO- Strong oxidant species Low conc. High conc. Neurotransmitter dilation of blood vessels react with nucleic acids, lipids and proteins. regulatory signaling molecules signal transduction cascades regulate biological processes apoptosis, cell proliferation and differentiation myeloperoxidase hypochlorous acid dilation of blood vessels 97 Oxidative stress antimycinA menadione 1.In cell culture 2.In cell-free system assay ROS detection Oxidative marker Mitochondria function Cell viability Spin-trapping Experiment Design Fenton reaction 98 2.In cell-free system 4.In rat model Brain ischemia/reperfusion 3.Primary culture Spin-trapping oxygen glucose deprivation Fenton reaction Chemical reaction H2 detection Infarct size Behavior Oxidative marker ROS detection ROS detection Cell viability 0.4M Pa O2 0.4M Pa H2 0.4M Pa CO2 5%CO2 1%FBS 75%H2, 20%O2, 5%CO2 2hrs DMEM dilu medium Mixed gas medium (vol, vol, vol) 1%FBS 99 H2 or O2 electrode closed culture flask fill with mix gas PC12 cell medium with or without H2 Antimycin A mitoSOX (. O2 -indicator) H DCF H2 selectively reduces .OH in cultured cells 1.In cell culture Antimycin A ROS detection Antimycin A ( mitochondrial respiratory complex III inhibitor) 30min H2DCF (H2O2 indicator) fluorescence probe Mito SOX H2DCF DAF-2DA HPF DAF-2 DA (NO. indicator) 100 H2 dissolved in culture medium reduces .OH in cultured cells. HH22 selectively reducesselectively reduces ..OH in cultured cellsOH in cultured cells 1.In cell culture Antimycin A ROS detection HPF(2-[6-(4,-hydroxy)phenoxy-3H-xanthen-3-on-9-yl] benzoate): OH . indicator 101 2-deoxy-D-glucose Pyruvate (glycolysis inhibitor) H2 prevented the decline of the mitochondrial membrane potential H2 prevented a decrease in the cellular levels of ATP synthesized in mitochondria. H2 selectively reduces .OH in cultured cells 1.In cell culture Antimycin A Mitochondria function TMRM: dependent of the mitochondrial membrane potential MitoTracker Green: independent of the mitochondrial membrane potential (glycolysis inhibitor) 30min Antimycin A ATP assay 102

H2 protect nuclear DNA from oxidation, as shown by decreased levels of oxidized guanine (8-OH-G) H2 decreased levels of HNE,an end- product of lipid peroxides, indicating that it protected lipids from peroxidation. HH22 dissolved in medium protects cultured cells againstdissolved in medium protects cultured cells against .. OHOH 1.In cell culture Antimycin A Oxidative marker HNE: 4-hydroxyl-2-nonenalAntimycin A (24h) Immunostaining 103 H2 dissolved in medium protected cells from death in a dose-dependent manner HH22 dissolved in medium protects cultured cells against OHdissolved in medium protects cultured cells against OH 1.In cell culture Antimycin A Cell viability 104 H2O2 .OH Fenton reaction Cu2+ Cu+ Vit C PC12 cells were exposed to intracellular OH produced by the Fenton reaction. HH22 dissolved in medium protects cultured cells againstdissolved in medium protects cultured cells against .. OHOH 1.In cell culture Fenton reaction Cell viability 105 DMPO-OH 1.In cell culture Fenton reaction Antimycin A Spin-trapping Spin-trapping identifies a free radical that is reduced by H2 electron spin resonance (ESR) signals Spin-trapping reagent: 5,5-dimethyl-1-pyrroline N-oxide (DMPO) antimycin A: DMPO-OH and DMPO-H; porphyrins: DMPO-H 106 Levels of ROS and RNS remaining after incubation with 0.6 mM of H2 at 23 ℃. HH22 selectively reducesselectively reduces .. OH and ONOOOH and ONOO–– in cellin cell--free systemsfree systems 2. Cell-free system Chemical reaction ROS detection Stock solution Stock solutionxanthine-xanthine oxidase reaction The spontaneous reaction of NOC7 107 Fenton reaction Neocortical cell under N2 or H2 OGD Ten min after reperfusion, cells were stained with HPF H2 protects neurons from in vitro ischemia and reperfusion 3.Primary culture oxygen glucose deprivation ROS detection OGD (oxygen glucose deprivation) 60min Reperfusion with medium (O2, glucose) Mock: medium containing glucose and oxygen 10min ROS assay 10min O G D 108

OGD 24h Neocortical cell under N2 or H2 OGD H2 protects neurons from in vitro ischemia and reperfusion 3.Primary culture oxygen glucose deprivation Cell viability TUJ-1 (green): neuron-specific Ab PI (red) 24h Mock: medium containing glucose and oxygen OGD OGD 109 OGD (oxygen glucose deprivation) 60min Reperfusion with medium (O2, glucose) 24h assay 1hr Anesthetize (halothane & mixture of N2O and O2 (70%:30%, vol/vol)) Arterial (A) and venous (V) blood were collected, and the amount of H2 was examined by gas chromatography. Inhalation of H2 gas protects brain injury by reperfusion 4.In rat model Ischemia/reprofussion H2 detection H2: O2: N2O (vol/vol/vol) 0%: 30%: 70% 2%: 30%: 68% 4%: 30%: 66% middle cerebral artery (MCA) occlusion 90min N2O and O2 (70%:30%, vol/vol)) monitor physiological parameters maintain temperature reperfusion 30min 1h 110 The amount of H2 dissolved in venous blood was less than that in artery blood, suggesting that H2 had been incorporated into tissues. One day after MCA occlusion, the forebrain was sliced into six coronal sequential sections and stained with the mitochondrial respiratory substrate TTC(2,3,5- triphenyltetrazolium chloride). IInhalation of Hnhalation of H22 gas protectgas protectss brain injury by reperfusionbrain injury by reperfusion 4.In rat model Ischemia/reprofussion Infarct size Edaravone: treatment of cerebral infarction in Japan FK506: clinical trials for cerebral infarction in the United States 1day 111 Inhalation of H2 gas improved brain injury after 1 week. Inhalation of H2 suppresses the progression of damage 4.In rat model Ischemia/reprofussion Infarct size Stain: hematoxylin and eosin (HE) 112 Inhalation of H2 gas improved brain injury after 1 week. Inhalation of H2 suppresses the progression of damage 4.In rat model Ischemia/reprofussion Physiology H2 H2 H2 0: no neurological deficit 1: failure to fully extend the right forepaw 2: circling to the right 3: falling to the right 4: unable to walk spontaneously 5:dead 113 H2 (DNA oxidation) (lipid oxidation) Inhalation of H2 suppresses the progression of damage 4.In rat model Ischemia/reprofussion Oxidative marker 114 Iba1 (a microglial marker) GFAP(astrocytes marker) H2-teratment decreased the acculation of microglia and astrocytes, indicative of inflammation and remodeling

Conclusion This study suggests that H2 protects cells and tissue against strong oxidative stress by scavenging . OH. 115Wood, K.C., and Gladwin, M.T., Nat Med 2007;13, 673- 674 stress by scavenging . OH. Academic influence of this paper 60 ?! 20 18 1. The study by Ohsawa et al. (Nat Med 2007; 13, 688-694) , is very important in showing of relieving the oxidative damage. 2. It attracted attention quickly and widely, and had been cited more than 60 times until now. 3. The idea that H2 is a therapeutic molecule has also been proved by other groups in other models. 4. The effect of molecular hydrogen as a therapeutic gas has been extensively studied. 116 0 20 40 60 2007 2008 2009 2010 3 6 24 0 10 Japan USA China 5 10 0 10 20 Hydrogen gas Hydroge n water Hydroge n saline 14 12 7 Thanks for your attentionThanks for your attention 117 1.Ohsawa I, Ishikawa M, Takahashi K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med, 2007; 13: 688-94. 2. Katherine C, Wood, Mark T Gladwin. The hydrogen highway to reperfusion therapy. Nat Med, 2007; 13: 673-4. 3. Fukuda KI, Asoh S, Ishikawa M, et al. Inhalation of hydrogen gas suppresses hepatic injury caused by ischemia/reperfusion through reducing oxidative stress. Biochem Biophys Res Commun, 2007; 361: 670-4 4. Hayashida K, Sano M, Ohsawa I, et al. Inhalation of hydrogen gas reduces infarct size in the rat model of myocardial ischemia- reperfusion injury. Biochem Biophys Res Commun, 2008,373(1):30-5. 5. Buchholz BM, Kaczorowski DJ, Sugimoto R, et al. Hydrogen inhalation ameliorates oxidative stress in transplantation induced intestinal graft injury.Am J Transplant. 2008; 8(10):2015-24 6. Cai JM, Kang ZM, Liu W, et al. Hydrogen therapy reduces apoptosis in neonatal hypoxia-ischemia rat model. Neurosci lett 2008,441(2):167-72 7. Kajiyama S, Hasegawa G, Asano M, et al. Supplementation of hydrogen-rich water improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance, Nutr. Res, 2008,28:137-43 8. Ohsawa I, Nishimaki K, Yamagata K, et al. Consumption of hydrogen water prevents atherosclerosis in apolipoprotein E knockout mice.Biochem Biophys Res Commun, 2008, 377(4):1195-8 9. Sato Y, Kajiyama S, Amano A, et al. Hydrogen-rich pure water prevents superoxide formation in brain slices of vitamin C-depleted SMP30/GNL knockout mice. Biochem Biophys Res Commun, 2008; 375(3):346-50. 118 SMP30/GNL knockout mice. Biochem Biophys Res Commun, 2008; 375(3):346-50. 10. Nagata K, Nakashima-Kamimura N, Mikami T, et al. Consumption of Molecular Hydrogen Prevents the Stress-Induced Impairments in Hippocampus-Dependent Learning Tasks during Chronic Physical Restraint in Mice. Neuropsychopharmacology. 2009; 34(2):501-8. 11. Cai JM, Kang ZM, Liu K, et al. Neuroprotective effects of hydrogen saline in neonatal hypoxia-ischemia rat model. Brain Res. 2009;1256:129-37. 12. Nakashima-Kamimura N, Mori T, Ohsawa I, Asoh S, Ohta S.Molecular hydrogen alleviates nephrotoxicity induced by an anti- cancer drug cisplatin without compromising anti-tumor activity in mice.Cancer Chemother Pharmacol. 2009; 64(4):753-61. 13. Zheng XF, Mao YF, Cai JM, Li YH, Liu WW, Sun PL, Zhang JH, Sun XJ, Yuan.HB Hydrogen-Rich Saline Protects against Intestinal Ischemia/Reperfusion Injury in Rats Free Radical Res.2009; 43(5):478-84. 14. Fu Y, Ito M, Fujita Y, et al. Molecular hydrogen is protective against 6-hydroxydopamine-induced nigrostriatal degeneration in a rat model of Parkinson’s disease. Neurosci lett. 2009; 453(2):81-5. 15. Matchett GA, Fathali N, Hasegawa Y, et al. Hydrogen gas is ineffective in moderate and severe neonatal hypoxia-ischemia rat models.Brain Res. 2009; 1259:90-7. 16. Mao YF, Zheng XF, Cai JM, et al. Hydrogen-rich saline reduces lung injury induced by intestinal ischemia/reperfusion in rats. Biochem Biophys Res Commun.2009; 381(4):602-5. 17. Akito Shimouchi, Kazutoshi Nose, Makoto Yamaguchi, Hiroshi Ishiguro Takaharu Kondo. Breath Hydrogen Produced by Ingestion of Commercial Hydrogen Water and Milk.Biomarker Insights 2009:4 27-32. 18. Kikkawa YS, Nakagawa T, Horie RT, Ito J.Hydrogen protects auditory hair cells from free radicals.Neuroreport. 2009;20(7):689- 94. 19. Suzuki Y, Sano M, Hayashida K, Ohsawa I, Ohta S, Fukuda K. Are the effects of α-glucosidase inhibitors on cardiovascular events related to elevated levels of hydrogen gas in the gastrointestinal tract? FEBS Lett. 2009; 583(13):2157-9. 20. Kajiya M, Sato K, Silva MJ, Ouhara K, Do PM, Shanmugam KT, Kawai T. Hydrogen from intestinal bacteria is protective for Concanavalin A-induced hepatitis. Biochem Biophys Res Commun. 2009; 386(2):316-21. 21. Kajiya M, Silva MJ, Sato K, Ouhara K, Kawai T. Hydrogen mediates suppression of colon inflammation induced by dextran sodium sulfate. Biochem Biophys Res Commun. 2009; 386(1):11-5. 22. Sun Q, Kang ZM, Cai JM, Liu WW, Liu Y. Zhang JH, Denoblec PJ, Tao HY, Sun XJ.Hydrogen-rich saline protects myocardium against ischemia/reperfusion injury in rats Exp Biol Med.2009; in press 23. Chen H, Sun YP, Hu PF, Liu WW, Xiang HG, Li Y,Yan RL, Su N, Ruan CP, Sun XJ, Wang Q.The effects of hydrogen-rich saline on the contractile and structural changes of intestine induced by ischemia-reperfusion in rats. J Surg Res.2009; in press pdf 24. Liu C, Cui JG, Sun Q, Cai JM. Hydrogen therapy may be an effective and specific novel treatment for acute radiation syndrome. Medical Hypotheses.2010;74(1): 146-146 119 radiation syndrome. Medical Hypotheses.2010;74(1): 146-146 25. Shimouchi A, Nose K, Takaoka M, Hayashi H, Kondo T. Effect of dietary turmeric on breath hydrogen. Dig Dis Sci. 2009 ;54(8):1725-9. 26. Oharazawa H et al.Rapid Diffusion of Hydrogen Protects the Retina: Administration to the Eye of Hydrogen-Containing Saline in Retinal Ischemia-Reperfusion Injury. Investigative Ophthalmology & Visual Science 2009 27. Xu J, Zhou JR, Cai JM, Zhu Z, Sun XJ, Jiang CL.Anti-inflammation effects of hydrogen saline in LPS activated macrophages and carrageenan induced paw oedema. Inflammation Res.2009 in press 28. Itoh T, et al. Molecular hydrogen suppresses FcεRI-mediated signal transduction and prevents degranulation of mast cells. Biochem Biophys Res Commun. 2009; 389(4):651-656 29. Fujita K, Seike T, Yutsudo N, Ohno M, Yamada H, et al. Hydrogen in Drinking Water Reduces Dopaminergic Neuronal Loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Mouse Model of Parkinson’s Disease. PLoS ONE. 2009; 4(9): e7247. 30. Xie KL et al. Protective Effects of Hydrogen Gas on Murine Polymicrobial Sepsis via Reducing Oxidative Stress and HMGB1 Release. Shock 2009 31. Qian LR et al. Radioprotective effect of hydrogen in cultured cells and mice. Free Radical Res. 2009 32. Cardinal JS, Zhan J, Wang Y, Sugimoto R, Tsung A, McCurry KR, Billiar TR, Nakao Oral hydrogen water prevents chronic allograft nephropathy in rats. Kidney Int. 2009 Nov 11. 33. Y. Saitoh, Y. Yoshimura, K. Nakano, N. Miwa. Platinum nanocolloid-supplemented hydrogendissolved water inhibits growth of human tongue carcinoma cells preferentially over normal cells. Exp Oncol 2009 ;31(3):156–162 matrix Inner- mambran e Intermambrane space Antimycin A Menadion eE 120 ROS reduction Lipid oxidation, protein denature , DNA damage CAT Ohta. Nippon Ronen Igakkai Zasshi. 2008;45(4):355-62

Advantages 1. H2 will react with only the strongest oxidants. (have no serious unwanted side effects) 2. H2 is mild enough not to disturb metabolic oxidation reduction reactions or to disrupt ROS involved in cell signaling unlike some antioxidant supplements with strong reductive reactivity. (Bjelakovic, al., 2007) 3. H2 can successfully reach target organelles. (James, A.M. et al., 2005) 4. H2 can penetrate biomembranes and diffuse into the cytosol, mitochondria and nucleus. 5. Its ability to protect nuclear DNA and mitochondria suggests that it could reduce the risk of life style related diseases and cancer. 121 • Acute oxidative stress may be caused by several factors, including inflammation, intense exercise, cardiac infarction, cessation of blood flow and organ transplantation. • Treatment: H2 dissolved in saline could easily be delivered intravascularly. • Prevention: H2 saturated in water could be administered. 122 123 Cardinal JS, Zhan J, Wang Y, Sugimoto R, Tsung A, McCurry KR, Billiar TR, Nakao Oral hydrogen water prevents chronic allograft nephropathy in rats. Kidney Int. 2009 Nov 11. Itoh T, et al. Molecular hydrogen suppresses FcεRI-mediated signal transduction and prevents degranulation of mast cells. Biochem Biophys Res Commun. 2009; 389(4):651- 656 124 Ohta S.Hydrogen gas and hydrogen water act as a therapeutic and preventive antioxidant with a novel concept. Nippon Ronen Igakkai Zasshi. 125

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