Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

New Approaches for Hydrogen Therapy of Various Diseases

Author(s): Lei Zhang, Han Yu, Qiufen Tu, Qianjun He* and Nan Huang*

Volume 27, Issue 5, 2021

Published on: 11 December, 2020

Page: [636 - 649] Pages: 14

DOI: 10.2174/1381612826666201211114141

Price: $65


Hydrogen therapy has recently received increasing attention as an emerging and promising therapeutic technology due to its selective antioxidant property and cell energy regulatory capability in vivo. To solve the low solubility issue of hydrogen, a variety of nanomaterials and devices for hydrogen supply have recently been developed, aiming to increase the concentration of hydrogen in the specific disease site and realize controlled hydrogen release and combined treatment. In this review, we mainly focus on the latest advances in using hydrogen-generating devices and nanomaterials for hydrogen therapy. These developments include sustained release of H2, controlled release of H2, versatile modalities of synergistic therapy, etc. Also, bio-safety issues and challenges are discussed to further promote the clinical applications of hydrogen therapy and the development of hydrogen medicine.

Keywords: Hydrogen medicine, anti-inflammation, nanomaterials, devices, anti-oxidation, COVID-19.

Dole M, Wilson FR, Fife WP. Hyperbaric hydrogen therapy: a possible treatment for cancer. Science 1975; 190(4210): 152-4.
[] [PMID: 1166304]
Ge L, Yang M, Yang NN, Yin XX, Song WG. Molecular hydrogen: a preventive and therapeutic medical gas for various diseases. Oncotarget 2017; 8(60): 102653-73.
[] [PMID: 29254278]
Ohno K, Ito M, Ichihara M, Ito M. Molecular hydrogen as an emerging therapeutic medical gas for neurodegenerative and other diseases. Oxid Med Cell Longev 2012; 2012353152
[] [PMID: 22720117]
Ono H, Nishijima Y, Adachi N, et al. Hydrogen(H2) treatment for acute erythymatous skin diseases. A report of 4 patients with safety data and a non-controlled feasibility study with H2 concentration measurement on two volunteers. Med Gas Res 2012; 2(1): 14.
[] [PMID: 22607973]
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.
[] [PMID: 24769081]
Zhang JY, Liu C, Zhou L, et al. A review of hydrogen as a new medical therapy. Hepatogastroenterology 2012; 59(116): 1026-32.
[] [PMID: 22328284]
Kamimura N, Nishimaki K, Ohsawa I, Ohta S. Molecular hydrogen improves obesity and diabetes by inducing hepatic FGF21 and stimulating energy metabolism in db/db mice. Obesity (Silver Spring) 2011; 19(7): 1396-403.
[] [PMID: 21293445]
Matei N, Camara R, Zhang JH. Emerging mechanisms and novel applications of hydrogen gas therapy. Med Gas Res 2018; 8(3): 98-102.
[] [PMID: 30319764]
Itoh T, Fujita Y, Ito M, et al. Molecular hydrogen suppresses FcepsilonRI-mediated signal transduction and prevents degranulation of mast cells. Biochem Biophys Res Commun 2009; 389(4): 651-6.
[] [PMID: 19766097]
Yang Y, Zhu Y, Xi X. Anti-inflammatory and antitumor action of hydrogen via reactive oxygen species. Oncol Lett 2018; 16(3): 2771-6.
[] [PMID: 30127861]
Pérez-Herrero E, Fernández-Medarde A. Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy. Eur J Pharm Biopharm 2015; 93: 52-79.
[] [PMID: 25813885]
Roduner E. Size matters: why nanomaterials are different. Chem Soc Rev 2006; 35(7): 583-92.
[] [PMID: 16791330]
Wilczewska AZ, Niemirowicz K, Markiewicz KH, Car H. Nanoparticles as drug delivery systems. Pharmacol Rep 2012; 64(5): 1020-37.
[] [PMID: 23238461]
Kotagiri N, Sudlow GP, Akers WJ, Achilefu S. Breaking the depth dependency of phototherapy with Cerenkov radiation and low-radiance-responsive nanophotosensitizers. Nat Nanotechnol 2015; 10(4): 370-9.
[] [PMID: 25751304]
Lee JH, Jang JT, Choi JS, et al. Exchange-coupled magnetic nanoparticles for efficient heat induction. Nat Nanotechnol 2011; 6(7): 418-22.
[] [PMID: 21706024]
Idris NM, Gnanasammandhan MK, Zhang J, Ho PC, Mahendran R, Zhang Y. In vivo photodynamic therapy using upconversion nanoparticles as remote-controlled nanotransducers. Nat Med 2012; 18(10): 1580-5.
[] [PMID: 22983397]
Wan GY, Liu Y, Chen BW, Liu YY, Wang YS, Zhang N. Recent advances of sonodynamic therapy in cancer treatment. Cancer Biol Med 2016; 13(3): 325-38.
[] [PMID: 27807500]
Guan WJ, Wei CH, Chen AL, et al. Hydrogen/oxygen mixed gas inhalation improves disease severity and dyspnea in patients with Coronavirus disease 2019 in a recent multicenter, open-label clinical trial. J Thorac Dis 2020; 12(6): 3448-52.
[] [PMID: 32642277]
Liu X, Ma C, Wang X, et al. Hydrogen coadministration slows the development of COPD-like lung disease in a cigarette smoke-induced rat model. Int J Chron Obstruct Pulmon Dis 2017; 12: 1309-24.
[] [PMID: 28496315]
Zhao YS, An JR, Yang S, et al. Hydrogen and oxygen mixture to improve cardiac dysfunction and myocardial pathological changes induced by intermittent hypoxia in rats. Oxid Med Cell Longev 2019; 20197415212
[] [PMID: 30984338]
Zhang N, Deng C, Zhang X, Zhang J, Bai C. Inhalation of hydrogen gas attenuates airway inflammation and oxidative stress in allergic asthmatic mice. Asthma Res Pract 2018; 4(1): 3.
[] [PMID: 29568538]
Qiu X, Li H, Tang H, et al. Hydrogen inhalation ameliorates lipopolysaccharide-induced acute lung injury in mice. Int Immunopharmacol 2011; 11(12): 2130-7.
[] [PMID: 22015602]
Wang ST, Bao C, He Y, et al. Hydrogen gas (XEN) inhalation ameliorates airway inflammation in asthma and COPD patients. QJM 113: 870-5.
[] [PMID: 32407476]
National Health Commission. Digest of the 7th version of guidelines for the diagnosis and management of Covid-19 Available from:
Guan WJ, Chen RC, Zhong NS. Strategies for the prevention and management of coronavirus disease 2019. Eur Respir J 2020; 55(4)2000597
[] [PMID: 32217658]
Kang KM, Kang YN, Choi IB, et al. Effects of drinking hydrogen-rich water on the quality of life of patients treated with radiotherapy for liver tumors. Med Gas Res 2011; 1(1): 11.
[] [PMID: 22146004]
Chen JB, Kong XF, Lv YY, et al. “Real world survey” of hydrogen-controlled cancer: a follow-up report of 82 advanced cancer patients. Med Gas Res 2019; 9(3): 115-21.
[] [PMID: 31552873]
Wu Y, Yuan M, Song J, Chen X, Yang H. Hydrogen gas from inflammation treatment to cancer therapy. ACS Nano 2019; 13(8): 8505-11.
[] [PMID: 31329427]
Zhao P, Jin Z, Chen Q, et al. Local generation of hydrogen for enhanced photothermal therapy. Nat Commun 2018; 9(1): 4241.
[] [PMID: 30315173]
Balan G, Donald J, Balan D, et al. Hydrogen generating apparatus and components therefor. U.S. Patent 7,240,641,
Sillman J, Nygren L, Kahiluoto H, et al. Bacterial protein for food and feed generated via renewable energy and direct air capture of CO2: Can it reduce land and water use? Glob Food Secur 2019; 22: 25-32.
Marshall A, Børresen B, Hagen G, et al. Hydrogen production by advanced proton exchange membrane (PEM) water electrolysers-Reduced energy consumption by improved electrocatalysis. Energy 2007; 32(4): 431-6.
Pati S, Yoon KJ, Gopalan S, et al. Electrochemical characterization of a solid oxide membrane electrolyzer for production of high-purity hydrogen. Metall Mater Trans, B, Process Metall Mater Proc Sci 2009; 40(6): 1041.
Humphrey CE, Seal EH. Biophysical approach toward tumor regression in mice. Science 1959; 130(3372): 388-90.
[] [PMID: 13675762]
Nordenstrom BE. Preliminary trials of electrophoretic ionization in the treatment of malignant tumours. IRCS J Med Sci 1978; 6: 537.
Xin YL. Advances in the treatment of malignant tumours by electrochemical therapy (ECT). Eur J Surg Supplement Acta Chir Sup 1994; 574: 31-5.
Li K, Xin Y, Gu Y, Xu B, Fan D, Ni B. Effects of direct current on dog liver: possible mechanisms for tumor electrochemical treatment. Bioelectromagnetics 1997; 18(1): 2-7.
[<2:AID-BEM2>3.0.CO;2-6] [PMID: 9125228]
Ivić MLA, Petrović SD, Živković PM, et al. An electrochemical illustration of the mathematical modelling of chlorine impact and acidification in electrochemical tumour treatment and its application on an agar–agar gel system. Electroanal Chem 2003; 549: 129-35.
Soba A, Suárez C, González MM, et al. Integrated analysis of the potential, electric field, temperature, pH and tissue damage generated by different electrode arrays in a tumor under electrochemical treatment. Mater Comput Sim 2018; 146: 160-76.
Mokhtare A, Reddy MSK, Roodan VA, et al. The role of pH fronts, chlorination and physicochemical reactions in tumor necrosis in the electrochemical treatment of tumors: A numerical study. Electrochim Acta 2019; 307: 129-47.
Nordenström BEW. Electrochemical treatment of cancer. I: Variable response to anodic and cathodic fields. Am J Clin Oncol 1989; 12(6): 530-6.
[] [PMID: 2556014]
Chou CK, McDougall JA, Ahn C, Vora N. Electrochemical treatment of mouse and rat fibrosarcomas with direct current. Bioelectromagnetics 1997; 18(1): 14-24.
[<14:AID-BEM4>3.0.CO;2-8] [PMID: 9125227]
Hamasaki T, Nakamichi N, Teruya K, Shirahata S. Removal efficiency of radioactive cesium and iodine ions by a flow-type apparatus designed for electrochemically reduced water production. PLoS One 2014; 9(7)e102218
[] [PMID: 25029447]
Shirahata S, Hamasaki T, Teruya K. Advanced research on the health benefit of reduced water. Trends Food Sci Technol 2012; 23(2): 124-31.
Kashiwagi T, Yan H, Hamasaki T, et al. Electrochemically reduced water protects neural cells from oxidative damage. Oxid Med Cell Longev 2014; 2014869121
[] [PMID: 25383141]
Kinjo T, Ye J, Yan H, et al. Suppressive effects of electrochemically reduced water on matrix metalloproteinase-2 activities and in vitro invasion of human fibrosarcoma HT1080 cells. Cytotechnology 2012; 64(3): 357-71.
[] [PMID: 22695858]
Hamasaki T, Harada G, Nakamichi N, et al. Electrochemically reduced water exerts superior reactive oxygen species scavenging activity in HT1080 cells than the equivalent level of hydrogen-dissolved water. PLoS One 2017; 12(2)e0171192
[] [PMID: 28182635]
Frajese GV, Benvenuto M, Mattera R, et al. Electrochemically reduced water delays mammary tumors growth in mice and inhibits breast cancer cells survival in vitro. Evid Based Complement Alternat Med 2018; 20184753507
[] [PMID: 30402124]
Qi G, Wang B, Song X, et al. A green, efficient and precise hydrogen therapy of cancer based on in-vivo electrochemistry. Natl Sci Rev 2020; 7: 660-6.
Kim YK, Lee KB, Kim SY, Jang YS, Kim JH, Lee MH. Improvement of osteogenesis by a uniform PCL coating on a magnesium screw for biodegradable applications. Sci Rep 2018; 8(1): 13264.
[] [PMID: 30185820]
Chen Y, Xiao M, Zhao H, Yang B. On the antitumor properties of biomedical magnesium metal. J Mater Chem B Mater Biol Med 2015; 3(5): 849-58.
[] [PMID: 32262176]
Newell K, Franchi A, Pouysségur J, Tannock I. Studies with glycolysis-deficient cells suggest that production of lactic acid is not the only cause of tumor acidity. Proc Natl Acad Sci USA 1993; 90(3): 1127-31.
[] [PMID: 8430084]
Peng B, Chen J. Ammonia borane as an efficient and lightweight hydrogen storage medium. Energy Environ Sci 2008; 1(4): 479-83.
Stephens FH, Baker RT, Matus MH, Grant DJ, Dixon DA. Acid initiation of ammonia-borane dehydrogenation for hydrogen storage. Angew Chem Int Ed Engl 2007; 46(5): 746-9.
[] [PMID: 17131438]
Yang T, Jin Z, Wang Z, et al. Intratumoral high-payload delivery and acid-responsive release of H2 for efficient cancer therapy using the ammonia borane-loaded mesoporous silica nanomedicine. Appl Mater Today 2018; 11: 136-43.
Zheng YF, Gu XN, Witte F. Biodegradable metals. Mater Sci Eng Rep 2014; 77: 1-34.
Javanbakht S, Shaabani A. Carboxymethyl cellulose-based oral delivery systems. Int J Biol Macromol 2019; 133: 21-9.
[] [PMID: 30986470]
EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP), Bampidis V, Azimonti G, Bastos ML, et al. Safety and efficacy of sodium carboxymethyl cellulose for all animal species. EFSA J 2020; 18(7)e06211
Kou Z, Zhao P, Wang Z, et al. Acid-responsive H2-releasing Fe nanoparticles for safe and effective cancer therapy. J Mater Chem B Mater Biol Med 2019; 7(17): 2759-65.
[] [PMID: 32255077]
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.
[] [PMID: 19148645]
Fan M, Wen Y, Ye D, et al. Acid-responsive H2-releasing 2D MgB2 nanosheet for therapeutic synergy and side effect attenuation of gastric cancer chemotherapy. Adv Healthc Mater 2019; 8(13)e1900157
[] [PMID: 30968583]
Li G, Kobayashi H, Taylor JM, et al. Hydrogen storage in Pd nanocrystals covered with a metal-organic framework. Nat Mater 2014; 13(8): 802-6.
[] [PMID: 25017188]
Tang S, Chen M, Zheng N. Sub-10-nm Pd nanosheets with renal clearance for efficient near-infrared photothermal cancer therapy. Small 2014; 10(15): 3139-44.
[] [PMID: 24729448]
Xiao JW, Fan SX, Wang F, Sun LD, Zheng XY, Yan CH. Porous Pd nanoparticles with high photothermal conversion efficiency for efficient ablation of cancer cells. Nanoscale 2014; 6(8): 4345-51.
[] [PMID: 24622916]
Tang S, Chen M, Zheng N. Multifunctional ultrasmall Pd nanosheets for enhanced near-infrared photothermal therapy and chemotherapy of cancer. Nano Res 2015; 8(1): 165-74.
Zhou G, Wang YS, Jin Z, et al. Porphyrin-palladium hydride MOF nanoparticles for tumor-targeting photoacoustic imaging-guided hydrogenothermal cancer therapy. Nanoscale Horizons 2019; 4(5): 1185-93.
Zhang C, Zheng DW, Li CX, et al. Hydrogen gas improves photothermal therapy of tumor and restrains the relapse of distant dormant tumor. Biomaterials 2019; 223119472
[] [PMID: 31499254]
Liu WL, Liu T, Zou MZ, et al. Aggressive man-made red blood cells for hypoxia-resistant photodynamic therapy. Adv Mater 2018; 30(35)e1802006
[] [PMID: 30015997]
Liu Y, Ai K, Liu J, Deng M, He Y, Lu L. Dopamine-melanin colloidal nanospheres: an efficient near-infrared photothermal therapeutic agent for in vivo cancer therapy. Adv Mater 2013; 25(9): 1353-9.
[] [PMID: 23280690]
Wan WL, Lin YJ, Shih PC, et al. An In situ depot for continuous evolution of gaseous H2 mediated by a magnesium passivation/activation cycle for treating osteoarthritis. Angew Chem Int Ed Engl 2018; 57(31): 9875-9.
[] [PMID: 29923670]
Wan WL, Lin YJ, Chen HL, et al. In situ nanoreactor for photosynthesizing H2 gas to mitigate oxidative stress in tissue inflammation. J Am Chem Soc 2017; 139(37): 12923-6.
[] [PMID: 28870078]
Zhang B, Wang F, Zhou H, et al. Polymer dots compartmentalized in liposomes as a photocatalyst for in situ hydrogen therapy. Angew Chem Int Ed Engl 2019; 58(9): 2744-8.
[] [PMID: 30657623]
Wang L, Fernández-Terán R, Zhang L, et al. Organic polymer dots as photocatalysts for visible light-driven hydrogen generation. Angew Chem Int Ed Engl 2016; 55(40): 12306-10.
[] [PMID: 27604393]
Ohsawa I, Ishikawa M, Takahashi K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med 2007; 13(6): 688-94.
[] [PMID: 17486089]
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.
[] [PMID: 18541148]
Sun Q, Kang Z, Cai J, et al. Hydrogen-rich saline protects myocardium against ischemia/reperfusion injury in rats. Exp Biol Med (Maywood) 2009; 234(10): 1212-9.
[] [PMID: 19596825]
Kawamura T, Huang CS, Tochigi N, et al. Inhaled hydrogen gas therapy for prevention of lung transplant-induced ischemia/reperfusion injury in rats. Transplantation 2010; 90(12): 1344-51.
[] [PMID: 21048533]
He Y, Zhang B, Chen Y, et al. Image-guided hydrogen gas delivery for protection from myocardial ischemia-reperfusion injury via microbubbles. ACS Appl Mater Interfaces 2017; 9(25): 21190-9.
[] [PMID: 28557412]
Zhao Y, Zhao B. Oxidative stress and the pathogenesis of Alzheimer’s disease. Oxid Med Cell Longev 2013; 2013316523
[] [PMID: 23983897]
Zhang L, Zhao P, Yue C, et al. Sustained release of bioactive hydrogen by Pd hydride nanoparticles overcomes Alzheimer’s disease. Biomaterials 2019; 197: 393-404.
[] [PMID: 30703744]
Baym M, Stone LK, Kishony R. Multidrug evolutionary strategies to reverse antibiotic resistance. Science 2016; 351(6268)aad3292
[] [PMID: 26722002]
Yu S, Li G, Zhao P, et al. NIR‐laser‐controlled hydrogen‐releasing pdh nanohydride for synergistic hydrogen‐photothermal antibacterial and wound‐healing therapies. Adv Funct Mater 2019; 29(50)1905697
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(3): 137-43.
[] [PMID: 19083400]
Madamanchi NR, Runge MS. Mitochondrial dysfunction in atherosclerosis. Circ Res 2007; 100(4): 460-73.
[] [PMID: 17332437]
Willcox BJ, Curb JD, Rodriguez BL. Antioxidants in cardiovascular health and disease: key lessons from epidemiologic studies. Am J Cardiol 2008; 101(10A): 75D-86D.
[] [PMID: 18474278]
Simsek C, Daemen J, Zijlstra F. Developments in percutaneous coronary intervention and coronary stents. Ned Tijdschr Tandheelkd 2014; 121(7-8): 375-9.
[] [PMID: 25174186]
Räber L, Magro M, Stefanini GG, et al. Very late coronary stent thrombosis of a newer-generation everolimus-eluting stent compared with early-generation drug-eluting stents: a prospective cohort study. Circulation 2012; 125(9): 1110-21.
[] [PMID: 22302840]
Lee SY, Hur SH, Lee SG, et al. Optical coherence tomographic observation of in-stent neoatherosclerosis in lesions with more than 50% neointimal area stenosis after second-generation drug-eluting stent implantation. Circ Cardiovasc Interv 2015; 8(2)e001878
[] [PMID: 25613674]
Onuma Y, Serruys PW. Rather thick, yet antithrombogenic: Is the magmaris scaffold a new hope for bioresorbable coronary scaffold? Circ Cardiovasc Interv 2017; 10(8)e005663
[] [PMID: 28801542]
Hideo-Kajita A, Garcia-Garcia HM, Haude M, et al. First report of edge vascular response at 12 months of magmaris, a second-generation drug-eluting resorbable magnesium scaffold, assessed by grayscale intravascular ultrasound, virtual histology, and optical coherence tomography. A biosolve-II trial sub-study. Cardiovasc Revasc Med 2019; 20(5): 392-8.
[] [PMID: 31079817]
Takahashi M, Miyazaki S, Myojo M, et al. Impact of the distance from the stent edge to the residual plaque on edge restenosis following everolimus-eluting stent implantation. PLoS One 2015; 10(3)e0121079
[] [PMID: 25775115]
Takeuchi S, Wada K, Nagatani K, Osada H, Otani N, Nawashiro H. Hydrogen may inhibit collagen-induced platelet aggregation: an ex vivo and in vivo study. Intern Med 2012; 51(11): 1309-13.
[] [PMID: 22687834]
Qin ZX, Yu P, Qian DH, et al. Hydrogen-rich saline prevents neointima formation after carotid balloon injury by suppressing ROS and the TNF-α/NF-κB pathway. Atherosclerosis 2012; 220(2): 343-50.
[] [PMID: 22153150]
Chen Y, Xiong S, Zhao F, Lu X, Wu B, Yang B. Effect of magnesium on reducing the UV-induced oxidative damage in marrow mesenchymal stem cells. J Biomed Mater Res A 2019; 107(6): 1253-63.
[] [PMID: 30701665]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy