嚴重缺氧/缺血會引起組織病理變化和細胞死亡,重複缺氧前處理(HP)可防止隨後嚴重的缺氧/缺血壓力。我假設缺氧前處理可以經由與1α缺氧誘發因子(HIF-1α)/活性氧(reactive oxygen species, ROS)相關的防禦機制來保護大鼠肝臟免於受到缺血/再灌注損傷。過多的活性氧（ROS）透過增加凋亡相關的Bax/Bcl-2比例可能會引發十二指腸和腎臟損傷。含有溶解氫分子的抗氧化水（antioxidant water, AW）具有安全的抗氧化活性,可保護十二指腸組織和腎臟免受氧化損傷。
缺氧前處理是讓雌性Wistar大鼠進入低壓缺氧室(5500米,每天15小時),而其他大鼠則保持在海平面高度(SL)。夾住大鼠的肝門靜脈導致肝缺血45分鐘,然後重新輸注6小時。我以70μL, 100％的醋酸,刺激十二指腸粘膜表面10秒建立了雌性Wistar大鼠十二指腸潰瘍模型。大鼠接受5/6腎臟移除術來引發慢性腎衰竭。我使用通過鎂合金濾心的含氫抗氧化水體外實驗來評估清除過氧化氫和次氯酸活性能力以及體內實驗探討飲用抗氧化水對醋酸誘發大鼠十二指腸潰瘍的影響。我使用西方墨點法和硝基藍四氮唑(NBT)/3-硝基酪氨酸(3-NT)染色來評估細胞核萃取物中的1α缺氧誘發因子、錳超氧化物歧化酶(MnSOD)、銅鋅超氧化物歧化酶(CuZnSOD)、過氧化氫酶、Bad、Bcl-xL、Caspase 3、聚腺苷酸二磷酸核糖基聚合酶(PARP)、Bax/Bcl-2、粒線體Bcl-xL和細胞質細胞色素C的表現量。透過免疫細胞化學法觀察庫佛氏細胞浸潤和TUNEL檢測細胞凋亡。通過超靈敏的化學發光放大法檢測肝腎表面、膽汁和血液的活性氧數值。檢測血漿中的ALT和AST值來評估肝功能。我測量了醋酸誘導大鼠十二指腸潰瘍的十二指腸近端黏液中的錳超氧化物歧化酶量。
隨著缺氧前處理的時間,細胞核轉譯1α缺氧誘發因子、Bcl-xL、錳超氧化物歧化酶、銅鋅超氧化物歧化酶、過氧化氫酶蛋白表現顯現增加。缺氧前處理誘發增加的肝臟1α缺氧誘發因子和Bcl-xL表現可以經由1α缺氧誘發因子抑制劑YC-1而抑制。肝缺血/再灌注增強了細胞Bad轉錄到粒線體,細胞色素C釋放到細胞質, 並活化Caspase 3/聚腺苷酸二磷酸核糖基聚合酶相關的細胞凋亡, 造成活性氧、骨髓過氧化酵素活性、 庫佛氏細胞浸潤、ALT和AST值增加。缺氧前處理顯著改善肝缺血/再灌注引發的氧化壓力、細胞凋亡、粒線體和肝臟功能障礙。與蒸餾水或自來水相比, 抗氧化水含有約50 ppb的溶解氫分子, 顯示出較低的氧化還原電位（-150 mV）和有效清除過氧化氫而不是次氯酸的活性。醋酸損傷1天和3天引起體重減輕並導致嚴重的十二指腸潰瘍和膠原蛋白沉積。與自來水飲用相比,每天飲用抗氧化水可以顯著緩解體重減輕和十二指腸纖維化,有效保留十二指腸完整性和錳超氧化物歧化酶量。我的電解還原水溶解了35ppb氫, 酸鹼pH值大於9.0。體外和體內結果顯現,慢性腎功能衰竭增加了活性氧, Bax/Bcl-2比例、Caspase 3表現和細胞凋亡,進而導致腎損傷。在腎臟表面檢測到的活性氧量與腎組織和血液中硝基藍四氮唑沉積相關,如果每天攝入電解還原水就會減少。
總之, 缺氧前處理增強了缺氧誘發因子1α /活性氧相關反應, 增強粒線體 Bcl-xL 蛋白表現,保護肝臟免受缺血/再灌注損傷。飲用抗氧化水可以透過溶解的氫分子直接清除自由基的能力來提供十二指腸保護以及減少慢性腎衰竭產生的大量活性氧和細胞凋亡。

Severe hypoxia/ischemia can initiate tissue pathology change and cell death, but repeated hypoxic preconditioning (HP) protected against subsequent severe hypoxia/ischemic stress. I hypothesized that HP can protect the liver of rats from ischemic/reperfusion damage through the defense mechanism associated with hypoxia-induced factor 1α (HIF-1α)/reactive oxygen species (ROS). Exaggerated reactive oxygen (ROS) production may initiate duodenal damage caused by acetic acid and kidney damage by increasing the Bax/Bcl-2 ratio of pro-apoptosis factor. Antioxidant water (AW) containing dissolved molecular hydrogen had a safe antioxidant activity and protected duodenal tissue and kidney from oxidative damage.
HP induction was to keep female Wistar rats in a hypobaric hypoxia chamber (5, 500 m, 15 hours/day), while other rats remain at sea level (SL). The rats' portal veins were blocked, causing liver ischemia for 45 minutes and then re-infusion for 6 hours. I established a model of duodenal ulcer in female Wistar rats, with a content of 70 μL, 100% acetic acid, and 10 s on the surface of the duodenum mucosa. The rats received 5/6 nephrectomy to induce chronic renal failure. I used antioxidant water made from a modified magnesium alloy to assess the in vitro H2O2 and HOCl scavenging activity and the effect of AW drinking on the in vivo rat acetic acid-induced duodenal ulcer. I used Western blot and nitroblue tetrazolium (NBT)/3-nitrotyrosine (3-NT) stain to evaluate HIF-1α in nuclear extract, MnSOD, CuZnSOD, catalase, Bad/Bcl-xL/Caspase 3/poly-(ADP-ribose) polymerase (PARP), Bax/Bcl-2, mitochondrial Bcl-xL and cytosolic cytochrome c expression. Kupffer cell infiltration and TUNEL-apoptosis were observed by immunocytochemistry. The ROS values of liver surface, renal surface, bile and whole blood were detected by ultrasensitive chemiluminescence-amplification method. Liver function was assessed with plasma ALT and AST. The expression of manganese superoxide dismutase (MnSOD) was measured in the scraping of the proximal duodenal mucus of rats duodenum ulcers in acetic acid induction.
The nuclear translocation of HIF-1α and Bcl-xL, MnSOD, CuZnSOD, and Catalase protein expression were increased after HP in a time-dependent manner. The response of HP enhanced hepatic HIF-1α and Bcl-xL expression was inhibited by HIF-1α inhibitor YC-1. ROS levels, myeloperoxidase activity, Kupffer cell infiltration, ALT and AST levels were increased by hepatic ischemia/ reperfusion with the enhancement of cytosolic Bad translocation to mitochondria, release of cytochrome c to cytosol, and activation of Caspase 3/PARP mediated apoptosis. HP significantly improved liver ischemic/ reperfusion -enhanced oxidative stress, apoptosis, mitochondrial, and liver dysfunction. Compared to distilled water or tap water, the established AW contained dissolved molecular hydrogen of about 50 ppb and exhibited a lower redox potential (-150 mV) and an efficient H2O2 instead of HOCl scavenging activity. After 1 day and 3 days of acetic acid injury caused weight loss, it induced severe duodenal ulcers and collagen deposition. Compared with tap water drinking, daily AW drinking significantly reduced weight loss and duodenal fibrosis, effectively preserving the duodenal integrity and MnSOD expression. The electrolyzed reduced water had 35 ppb dissolved hydrogen and pH>9.0. In vitro and in vivo results showed that chronic renal failure increased the production of ROS and increased the mechanism of apoptosis, including increased Bax/Bcl-2 ratio, Caspase 3 expression and apoptosis formation, which in turn leaded to kidney damage. The ROS levels detected on the kidney surface was associated with increased ROS levels in NBT accumulation in kidney tissue and blood, which were reduced by daily intake of electrolyzed reduced water.
In summary, HP enhanced HIF-1α/ROS dependent cascades to enhance mitochondrial Bcl-xL protein expression and protect liver from ischemia/reperfusion damage. AW drinking may give the duodenal protection and reduce the apoptosis in chronic renal failure through the direct removal capacity of the molecular hydrogen it dissolved.

1. Chien CT, Lee PH, Chen CF, Ma MC, Lai MK, Hsu SM. De novo demonstration and co-localization of free-radical production and apoptosis formation in rat kidney subjected to ischemia/reperfusion. Journal of the American Society of Nephrology : JASN. 2001;12(5):973-82.
2. Huang KC, Yang CC, Lee KT, Chien CT. Reduced hemodialysis-induced oxidative stress in end-stage renal disease patients by electrolyzed reduced water. Kidney Int. 2003;64(2):704-14. doi: 10.1046/j.1523-1755.2003.00118.x.
3. Huang KC, Yang CC, Hsu SP, Lee KT, Liu HW, Morisawa S, et al. Electrolyzed-reduced water reduced hemodialysis-induced erythrocyte impairment in end-stage renal disease patients. Kidney Int. 2006;70(2):391-8. doi: 10.1038/sj.ki.5001576.
4. Yan H, Tian H, Kinjo T, Hamasaki T, Tomimatsu K, Nakamichi N, et al. Extension of the lifespan of Caenorhabditis elegans by the use of electrolyzed reduced water. Biosci Biotechnol Biochem. 2010;74(10):2011-5. doi: 10.1271/bbb.100250.
5. Buttke TM, Sandstrom PA. Oxidative stress as a mediator of apoptosis. Immunology Today. 1994;15(1):7-10. doi: https://doi.org/10.1016/0167-5699(94)90018-3.
6. Yang CC, Yao CA, Yang JC, Chien CT. Sialic acid rescues repurified lipopolysaccharide-induced acute renal failure via inhibiting TLR4/PKC/gp91-mediated endoplasmic reticulum stress, apoptosis, autophagy, and pyroptosis signaling. Toxicological sciences : an official journal of the Society of Toxicology. 2014;141(1):155-65. doi: 10.1093/toxsci/kfu121.
7. Cotran RS, Kumar V and Collins T. (1998). In Robbins Pathologic Basis of Disease. 6th edn. WB Saunders Company: Philadelphia.
8. Bernaudin M, Nedelec AS, Divoux D, MacKenzie ET, Petit E, Schumann-Bard P. Normobaric hypoxia induces tolerance to focal permanent cerebral ischemia in association with an increased expression of hypoxia-inducible factor-1 and its target genes, erythropoietin and VEGF, in the adult mouse brain. J Cereb Blood Flow Metab. 2002;22(4):393-403. doi: 10.1097/00004647-200204000-00003.
9. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74(5):1124-36.
10. Sorimachi T, Nowak TS, Jr. Pharmacological manipulations of ATP-dependent potassium channels and adenosine A1 receptors do not impact hippocampal ischemic preconditioning in vivo: evidence in a highly quantitative gerbil model. J Cereb Blood Flow Metab. 2004;24(5):556-63. doi: 10.1097/00004647-200405000-00010.
11. Mocanu MM, Steare SE, Evans MC, Nugent JH, Yellon DM. Heat stress attenuates free radical release in the isolated perfused rat heart. Free Radic Biol Med. 1993;15(4):459-63.
12. Ostadal B, Ostadalova I, Dhalla NS. Development of cardiac sensitivity to oxygen deficiency: comparative and ontogenetic aspects. Physiol Rev. 1999;79(3):635-59. doi: 10.1152/physrev.1999.79.3.635.
13. Yellon DM, Downey JM. Preconditioning the myocardium: from cellular physiology to clinical cardiology. Physiol Rev. 2003;83(4):1113-51. doi: 10.1152/physrev.00009.2003.
14. Hausenloy D, Wynne A, Duchen M, Yellon D. Transient mitochondrial permeability transition pore opening mediates preconditioning-induced protection. Circulation. 2004;109(14):1714-7. doi: 10.1161/01.CIR.0000126294.81407.7D.
15. Uchiyama T, Engelman RM, Maulik N, Das DK. Role of Akt signaling in mitochondrial survival pathway triggered by hypoxic preconditioning. Circulation. 2004;109(24):3042-9. doi: 10.1161/01.CIR.0000130647.29030.90.
16. Kapitsinou PP, Haase VH. Molecular mechanisms of ischemic preconditioning in the kidney. Am J Physiol Renal Physiol. 2015;309(10):F821-34. doi: 10.1152/ajprenal.00224.2015.
17. Bolli R. The late phase of preconditioning. Circ Res. 2000;87(11):972-83.
18. Rafiee P, Shi Y, Kong X, Pritchard KA, Jr., Tweddell JS, Litwin SB, et al. Activation of protein kinases in chronically hypoxic infant human and rabbit hearts: role in cardioprotection. Circulation. 2002;106(2):239-45.
19. Williams RS, Benjamin IJ. Protective responses in the ischemic myocardium. J Clin Invest. 2000;106(7):813-8. doi: 10.1172/JCI11205.
20. Depre C, Wang L, Sui X, Qiu H, Hong C, Hedhli N, et al. H11 kinase prevents myocardial infarction by preemptive preconditioning of the heart. Circ Res. 2006;98(2):280-8. doi: 10.1161/01.RES.0000201284.45482.e8.
21. Ostadal B, Kolar F, Pelouch V, Prochazka J, Widimsky J. Intermittent high altitude and the cardiovascular system. In: Nagano, M, Takeda, N, Dhalla, NS (Eds.), The Adapted Heart. Raven Press, New York, 1994:173-82.
22. Yeh CH, Hsu SP, Yang CC, Chien CT, Wang NP. Hypoxic preconditioning reinforces HIF-alpha-dependent HSP70 signaling to reduce ischemic renal failure-induced renal tubular apoptosis and autophagy. Life Sci. 2010;86(3-4):115-23. doi: 10.1016/j.lfs.2009.11.022.
23. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995;92(12):5510-4.
24. Hu S, Yan G, Xu H, He W, Liu Z, Ma G. Hypoxic preconditioning increases survival of cardiac progenitor cells via the pim-1 kinase-mediated anti-apoptotic effect. Circ J. 2014;78(3):724-31.
25. Date T, Mochizuki S, Belanger AJ, Yamakawa M, Luo Z, Vincent KA, et al. Expression of constitutively stable hybrid hypoxia-inducible factor-1alpha protects cultured rat cardiomyocytes against simulated ischemia-reperfusion injury. Am J Physiol Cell Physiol. 2005;288(2):C314-20. doi: 10.1152/ajpcell.00374.2004.
26. Chien CT, Chang TC, Tsai CY, Shyue SK, Lai MK. Adenovirus-mediated bcl-2 gene transfer inhibits renal ischemia/reperfusion induced tubular oxidative stress and apoptosis. Am J Transplant. 2005;5(6):1194-203. doi: 10.1111/j.1600-6143.2005.00826.x.
27. Kim SC, Byun SH, Yang CH, Kim CY, Kim JW, Kim SG. Cytoprotective effects of Glycyrrhizae radix extract and its active component liquiritigenin against cadmium-induced toxicity (effects on bad translocation and cytochrome c-mediated PARP cleavage). Toxicology. 2004;197(3):239-51. doi: 10.1016/j.tox.2004.01.010.
28. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997;91(4):479-89.
29. Matsumori Y, Northington FJ, Hong SM, Kayama T, Sheldon RA, Vexler ZS, et al. Reduction of caspase-8 and -9 cleavage is associated with increased c-FLIP and increased binding of Apaf-1 and Hsp70 after neonatal hypoxic/ischemic injury in mice overexpressing Hsp70. Stroke. 2006;37(2):507-12. doi: 10.1161/01.STR.0000199057.00365.20.
30. Uchida T, Rossignol F, Matthay MA, Mounier R, Couette S, Clottes E, et al. Prolonged hypoxia differentially regulates hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha expression in lung epithelial cells: implication of natural antisense HIF-1alpha. J Biol Chem. 2004;279(15):14871-8. doi: 10.1074/jbc.M400461200.
31. Asma MB, Mohamed AZ, Kaouther HA, Abdel -H édi M, Dalila SM, Joan RC, Hassen BA. Ischemic preconditioning reduces endoplasmic reticulum stress and upregulates hypoxia inducible factor-1a in ischemic kidney: the role of nitric oxide. Journal of Biomedical Science 2012, 19:7. doi: 10.1186/1423-0127-19-7.
32. Rossert J, Fouqueray B, Boffa J-J. Anemia management and the delay of chronic renal failure progression. Journal of the American Society of Nephrology : JASN. 2003;14:S173-7. doi: 10.1097/01.ASN.0000070079.54912.B6.
33. Huang KC, Hsu SP, Yang CC, OuYang P, Lee KT, Morisawa S, et al. Electrolysed-reduced water dialysate improves T-cell damage in end-stage renal disease patients with chronic haemodialysis. Nephrology Dialysis Transplantation. 2010;25(8):2730-7. doi: 10.1093/ndt/gfq082.
34. Meguid El Nahas A, Bello AK. Chronic kidney disease: the global challenge. Lancet. 2005;365(9456):331-40. doi: 10.1016/s0140-6736(05)17789-7.
35. Chien CT, Fan SC, Lin SC, Kuo CC, Yang CH, Yu TY, et al. Glucagon-like peptide-1 receptor agonist activation ameliorates venous thrombosis-induced arteriovenous fistula failure in chronic kidney disease. Thromb Haemost. 2014;112(5):1051-64. doi: 10.1160/th14-03-0258.
36. Halliwell B, Gutteridge JM, Cross CE. Free radicals, antioxidants, and human disease: where are we now? The Journal of laboratory and clinical medicine. 1992;119(6):598-620.
37. Jialal I, Fuller CJ, Huet BA. The effect of alpha-tocopherol supplementation on LDL oxidation. A dose-response study. Arterioscler Thromb Vasc Biol. 1995;15(2):190-8. doi: 10.1161/01.atv.15.2.190.
38. Shirahata S, Kabayama S, Nakano M, Miura T, Kusumoto K, Gotoh M, et al. Electrolyzed-reduced water scavenges active oxygen species and protects DNA from oxidative damage. Biochem Biophys Res Commun. 1997;234(1):269-74. doi: 10.1006/bbrc.1997.6622.
39. Sieron A, Kawczyk-Krupka A, Gadowska-Cicha A. [The role of free radicals in inflammatory states, ulceration, and ulcers of the stomach and duodenum]. Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego. 2001;10:113-6.
40. Leon-Barua R, Berendson-Seminario R, Recavarren-Arce S, Gilman RH. Geographic factors probably modulating alternative pathways in Helicobacter pylori-associated gastroduodenal pathology: a hypothesis. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 1997;25(5):1013-6.
41. Chen DL, Chen TW, Chien CT, Li PC. Intravenous low redox potential saline attenuates FeCl3-induced vascular dysfunction via downregulation of endothelial H2O2, CX3CL1, intercellular adhesion molecule-1, and p53 expression. Translational Research. 2011;157(5):306-19. doi: https://doi.org/10.1016/j.trsl.2010.12.012.
42. Imai K, Kotani T, Tsuda H, Mano Y, Nakano T, Ushida T, et al. Neuroprotective potential of molecular hydrogen against perinatal brain injury via suppression of activated microglia. Free Radical Biology and Medicine. 2016;91:154-63. doi: https://doi.org/10.1016/j.freeradbiomed.2015.12.015.
43. Lin Y, Kashio A, Sakamoto T, Suzukawa K, Kakigi A, Yamasoba T. Hydrogen in drinking water attenuates noise-induced hearing loss in guinea pigs. Neurosci Lett. 2011;487(1):12-6. doi: 10.1016/j.neulet.2010.09.064.
44. Tao B, Liu L, Wang N, Wang W, Jiang J, Zhang J. Effects of hydrogen-rich saline on aquaporin 1, 5 in septic rat lungs. The Journal of surgical research. 2016;202(2):291-8. doi: 10.1016/j.jss.2016.01.009.
45. Kim MJ, Kim HK. Anti-diabetic effects of electrolyzed reduced water in streptozotocin-induced and genetic diabetic mice. Life Sciences. 2006;79(24):2288-92. doi: https://doi.org/10.1016/j.lfs.2006.07.027.
46. Tsai CF, Hsu YW, Chen WK, Chang WH, Yen CC, Ho YC, et al. Hepatoprotective effect of electrolyzed reduced water against carbon tetrachloride-induced liver damage in mice. Food and Chemical Toxicology. 2009;47(8):2031-6. doi: https://doi.org/10.1016/j.fct.2009.05.021.
47. Park SK, Qi XF, Song SB, Kim DH, Teng YC, Yoon YS, et al. Electrolyzed-reduced water inhibits acute ethanol-induced hangovers in Sprague-Dawley rats. Biomedical research (Tokyo, Japan). 2009;30(5):263-9. doi: 10.2220/biomedres.30.263.
48. Hanaoka K. Antioxidant effects of reduced water produced by electrolysis of sodium chloride solutions. Journal of Applied Electrochemistry. 2001;31:1307-13. doi: 10.1023/A:1013825009701.
49. Li Y, Nishimura T, Teruya K, Maki T, Komatsu T, Hamasaki T, et al. Protective mechanism of reduced water against alloxan-induced pancreatic beta-cell damage: Scavenging effect against reactive oxygen species. Cytotechnology. 2002;40(1-3):139-49. doi: 10.1023/A:1023936421448.
50. Yang CC, Lin LC, Wu MS, Chien CT, Lai MK. Repetitive hypoxic preconditioning attenuates renal ischemia/reperfusion induced oxidative injury via upregulating HIF-1 alpha-dependent bcl-2 signaling. Transplantation. 2009;88(11):1251-60. doi: 10.1097/TP.0b013e3181bb4a07.
51. Chien CT, Chang WT, Chen HW, Wang TD, Liou SY, Chen TJ, et al. Ascorbate supplement reduces oxidative stress in dyslipidemic patients undergoing apheresis. Arterioscler Thromb Vasc Biol. 2004;24(6):1111-7. doi: 10.1161/01.atv.0000127620.12310.89.
52. Yu HJ, Lin BR, Lee HS, Shun CT, Yang -C, Lai TY, et al. Sympathetic vesicovascular reflex induced by acute urinary retention evokes proinflammatory and proapoptotic injury in rat liver. American journal of physiology Renal physiology. 2005;288(5):F1005-14. doi: 10.1152/ajprenal.00223.2004.
53. Chien CT, Shyue SK, Lai MK. Bcl-xL augmentation potentially reduces ischemia/reperfusion induced proximal and distal tubular apoptosis and autophagy. Transplantation. 2007;84(9):1183-90. doi: 10.1097/01.tp.0000287334.38933.e3.
54. Saitoh Y, Harata Y, Mizuhashi F, Nakajima M, Miwa N. Biological safety of neutral-pH hydrogen-enriched electrolyzed water upon mutagenicity, genotoxicity and subchronic oral toxicity. Toxicology and industrial health. 2010;26(4):203-16. doi: 10.1177/0748233710362989.
55. Yu HJ, Chien CT, Lai YJ, Lai MK, Chen CF, Levin RM, et al. Hypoxia preconditioning attenuates bladder overdistension-induced oxidative injury by up-regulation of Bcl-2 in the rat. J Physiol. 2004;554(Pt 3):815-28. doi: 10.1113/jphysiol.2003.056002.
56. Zhao L, Liu X, Liang J, Han S, Wang Y, Yin Y, et al. Phosphorylation of p38 MAPK mediates hypoxic preconditioning-induced neuroprotection against cerebral ischemic injury via mitochondria translocation of Bcl-xL in mice. Brain Res. 2013;1503:78-88. doi: 10.1016/j.brainres.2013.01.051.
57. Chen WL, Wang CC, Lin YJ, Wu CP, Hsieh CH. Cycling hypoxia induces chemoresistance through the activation of reactive oxygen species-mediated B-cell lymphoma extra-long pathway in glioblastoma multiforme. J Transl Med. 2015;13:389. doi: 10.1186/s12967-015-0758-8.
58. Chen CF, Chien CT, Fang HS, Chiu IS. Effects of atrial natriuretic factor in chronic hypoxic spontaneously hypertensive rats. Hypertension. 1991;18(3):355-9. doi: 10.1161/01.hyp.18.3.355.
59. Osada M, Imaoka S, Sugimoto T, Hiroi T, Funae Y. NADPH-cytochrome P-450 reductase in the plasma membrane modulates the activation of hypoxia-inducible factor 1. J Biol Chem. 2002;277(26):23367-73. doi: 10.1074/jbc.M112413200.
60. Prieto I, Monsalve M. ROS homeostasis, a key determinant in liver ischemic-preconditioning. Redox Biol. 2017;12:1020-5. doi: 10.1016/j.redox.2017.04.036.
61. Guo Y, Feng L, Zhou Y, Sheng J, Long D, Li S, et al. Systematic review with meta-analysis: HIF-1alpha attenuates liver ischemia-reperfusion injury. Transplantation reviews (Orlando, Fla). 2015;29(3):127-34. doi: 10.1016/j.trre.2015.05.001.
62. Amador A, Grande L, Marti J, Deulofeu R, Miquel R, Sola A, et al. Ischemic pre-conditioning in deceased donor liver transplantation: a prospective randomized clinical trial. Am J Transplant. 2007;7(9):2180-9. doi: 10.1111/j.1600-6143.2007.01914.x.
63. Luks AM, Swenson ER. Evaluating the Risks of High Altitude Travel in Chronic Liver Disease Patients. High altitude medicine & biology. 2015;16(2):80-8. doi: 10.1089/ham.2014.1122.
64. Pratico D. Antioxidants and endothelium protection. Atherosclerosis. 2005;181(2):215-24. doi: 10.1016/j.atherosclerosis.2005.03.005.
65. Abbasciano V, Sartori S, Trevisani L, Girometti R, Ranzini M, Nielsen I, et al. Comparison of magnesium concentration in serum, erythrocytes and gastric tissue in two groups of patients affected by chronic gastritis, Helicobacter pylori negative and positive. Magnesium research. 2003;16(4):281-6.
66. Zhang J, Liu C, Zhou L, Qu K, Wang R-T, Tai M-h, et al. A Review of Hydrogen as a New Medical Therapy. Hepato-gastroenterology. 2012;59:1026-32. doi: 10.5754/hge11883.
67. Huang CS, Kawamura T, Toyoda Y, Nakao A. Recent advances in hydrogen research as a therapeutic medical gas. Free Radic Res. 2010;44(9):971-82. doi: 10.3109/10715762.2010.500328.
68. Ohta S. Molecular hydrogen as a preventive and therapeutic medical gas: initiation, development and potential of hydrogen medicine. Pharmacol Ther. 2014;144(1):1-11. doi: 10.1016/j.pharmthera.2014.04.006.
69. Sung JJ, Kuipers EJ, El-Serag HB. Systematic review: the global incidence and prevalence of peptic ulcer disease. Aliment Pharmacol Ther. 2009;29(9):938-46. doi: 10.1111/j.1365-2036.2009.03960.x.
70. Augusto AC, Miguel F, Mendonca S, Pedrazzoli J, Jr., Gurgueira SA. Oxidative stress expression status associated to Helicobacter pylori virulence in gastric diseases. Clinical biochemistry. 2007;40(9-10):615-22. doi: 10.1016/j.clinbiochem.2007.03.014.
71. Xue J, Shang G, Tanaka Y, Saihara Y, Hou L, Velasquez N, et al. Dose-dependent inhibition of gastric injury by hydrogen in alkaline electrolyzed drinking water. BMC Complement Altern Med. 2014;14:81. doi: 10.1186/1472-6882-14-81.
72. Chen JF, Liu H, Ni HF, Lv LL, Zhang MH, Zhang AH, et al. Improved mitochondrial function underlies the protective effect of pirfenidone against tubulointerstitial fibrosis in 5/6 nephrectomized rats. PLoS One. 2013;8(12):e83593. doi: 10.1371/journal.pone.0083593.
73. Docherty NG, O'Sullivan OE, Healy DA, Fitzpatrick JM, Watson RW. Evidence that inhibition of tubular cell apoptosis protects against renal damage and development of fibrosis following ureteric obstruction. Am J Physiol Renal Physiol. 2006;290(1):F4-13. doi: 10.1152/ajprenal.00045.2005.
74. Hsu SP, Wu MS, Yang CC, Huang KC, Liou SY, Hsu SM, et al. Chronic green tea extract supplementation reduces hemodialysis-enhanced production of hydrogen peroxide and hypochlorous acid, atherosclerotic factors, and proinflammatory cytokines. Am J Clin Nutr. 2007;86(5):1539-47. doi: 10.1093/ajcn/86.5.1539.
75. Yang CC, Hsu SP, Wu MS, Hsu SM, Chien CT. Effects of vitamin C infusion and vitamin E-coated membrane on hemodialysis-induced oxidative stress. Kidney Int. 2006;69(4):706-14. doi: 10.1038/sj.ki.5000109.