Hydrogen is Emerging as a Medical Gas (Part 2)


Antioxidant-Like Effect

It was initially suggested that the beneficial effect of hydrogen was due to an antioxidant as hydrogen selectively neutralized cytotoxic hydroxyl radicals 1 in vitro. However, although H2 reduces *OH radicals 2, as has been shown in various systems 1, 4, 5, it may not occur via direct scavenging, and it also cannot fully explain all the benefits of hydrogen 6. For example, in a double-blinded placebo controlled trial in rheumatoid arthritis 3, hydrogen had a residual effect that continued improving the disease symptoms for four weeks after hydrogen administration was terminated 3. Many cell studies also show that pre-treatment with hydrogen has marked beneficial effects even when the assault (e.g. toxin, radiation, injury, etc.) is administered long after all the hydrogen has dissipated out of the system 7, 8, 9. Additionally, the rate constants of hydrogen against the hydroxyl radical are relatively slow (4.2 x 107 M-1 sec-1) 2, and the concentration of hydrogen at the cellular level is also quite low (micromolar levels), thus making it unlikely that H2 could effectively compete with the numerous other nucleophilic targets of the cell 10. Lastly, if the mechanism were primarily associated with scavenging of hydroxyl radicals, then we should see a greater effect from inhalation compared to drinking, but this is not always the case 11, 12. In short, we consider it inaccurate or at least incomplete to claim that the benefits of hydrogen are due to its acting directly as a powerful antioxidant. Indeed, hydrogen is selective because it is a very weak antioxidant and thus does not neutralize important ROS or disturb important biological signaling molecules. Nevertheless, a metabolic tracer study 13 using deuterium gas demonstrated that, under physiological conditions, deuterium gas is oxidized, and the oxidation rate of hydrogen increases with an increasing amount of oxidative stress 14, but the physicochemical mechanism for this may still not be direct radical scavenging 13. However, not all studies show that hydrogen is oxidized via mammalian tissues 15, and it has also been reported that deuterium gas did not exert a therapeutic effect in the model studied whereas 1H did (unpublished data).

NRF2 Pathway

Unlike conventional antioxidants 16, hydrogen does have the ability to reduce excessive oxidative stress 6, but only under conditions where the cell is experiencing abnormally high levels of oxidative stress that would be harmful and not hormetic.

One mechanism that hydrogen uses to protect against oxidative damage is by the activation of the Nrf2-Keap1 system and subsequent induction of the antioxidant response element (ARE) pathway, which leads to the production of various cyto-protective proteins like glutathione, catalase, superoxide dismutase, glutathione per-oxidase, heme-1 oxygenase, etc. 17, 18, 19. In some disease models, the benefits of hydrogen are negated by using Nrf2 gene knockouts 20, 21, Nrf2 genetic silencing using iRNA 22, or pharmacologically blocking the Nrf2 pathway 23, 24. Importantly, hydrogen only activates the Nrf2 pathway when there is an assault (e.g. toxin, injury, etc.) 23 as opposed to constituently acting as a promoter, which could be harmful 25, 26. The method that hydrogen activates the Nrf2 pathway remains unclear 17.

Cell Modulation

Besides the potential scavenging of hydroxyl radicals and/or activation of the Nrf2 pathway, hydrogen may ameliorate oxidative stress via a cell modulating effect 17 and reduce the formation of free radicals 27, such as down regulating the NADPH oxidase system 28. The various cell modulating effects of hydrogen are responsible for mediating the anti-inflammatory, anti-allergy, and anti-obesity effects of hydrogen. Hydrogen has been shown to downregulate pro-inflammatory cytokines (e.g. IL-1, IL-6, IL-8, etc.) 29, attenuate the activation of TNF-a 3, NF-?B 30, NFAT 12, 31, NLRP3 32, 33, HMGB1 34, and other inflammatory mediators 17. Additionally, hydrogen has beneficial effects on obesity and metabolism by increasing the expression of FGF21 35, PGC-1a 36, PPARa 36, and more. 37. Additional 2nd messenger molecules or transcription factors affected by hydrogen include ghrelin 38, JNK-1 28, ERK1/2 39, PKC 40, GSK 41, TXNIP 32, STAT3 42, ASK1 43, MEK 44, SIRT1 45, and many more. Over 200 bio-molecules are altered by hydrogen administration including over 1000 gene expressions.

However, the primary targets and master regulators responsible for these changes are still elusive 29. There are many feedback systems and loops to consider, which makes it difficult to determine if we are detecting the cause or the effect of hydrogen administration.

The exact mechanism of how hydrogen modulates signal transduction, gene expression, and protein phosphorylation is still being investigated 17. A recent publication 46 in Scientific Reports provides good evidence to suggest that one of the mechanisms through which hydrogen accomplishes the various cell-modulating effects is by modifying lipid per-oxidation in the cell membrane. In cultured cells, at biologically relevant concentrations, hydrogen suppressed the free radical chain reaction-dependent per-oxidation and recovered Ca2+-induced gene expressions, as determined by comprehensive micro-array analysis (see figure 6) 46.

Scientific Recognition of Hydrogen

Although the primary targets or exact biochemical mechanisms of hydrogen are still not fully understood, the therapeutic effect in cells, tissues, animals, humans and even plants 47 is becoming widely accepted due to the now over 500 peer-reviewed articles and the 1,600 researchers on the medical effects of hydrogen. The quality of the publications is also improving with an average impact factor (IF) of the journals publishing hydrogen is about 3. The table below shows a few of the studies published in the higher IF journals, which range from six to 27.

Future Directions

The goal of the Molecular Hydrogen Institute (MHI) is to help advance the research, education, and awareness of hydrogen as a therapeutic medical gas. It is uncommon to find a treatment that has both a high therapeutic potential and a high safety profile; hydrogen appears to fit this combination 6. Some researchers become interested in hydrogen simply due to its unforeseen ability to have a biological effect; with the realization that hydrogen is both safe and effective, a moral obligation develops to advance the research, education, and awareness of hydrogen as a medical gas.

Source: Molecular Hydrogen Institute


  1. Ohsawa, I., et al., Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med, 2007. 13(6): p. 688-694.
  2. Buxton, G.V., et al., Critical view of rate constants for reactions of hydrated electrons, hydrogen atoms and hydroxyl radicals (•OH/•OH-) in aqueous solution. J Phys Chem Ref Data, 1988. 17: p. 513-886.
  3. Ishibashi, T., et al., Therapeutic efficacy of infused molecular hydrogen in saline on rheumatoid arthritis: A randomized, double-blind, placebo-controlled pilot study. Int Immunopharmacol, 2014. 21(2): p. 468-473.
  4. Igarashi, T., et al., Hydrogen prevents corneal endothelial damage in phacoemulsification cataract surgery. Sci Rep, 2016. 6: p. 31190.
  5. Terasaki, Y., et al., Hydrogen therapy attenuates irradiation-induced lung damage by reducing oxidative stress. American Journal of Physiology – Lung Cellular and Molecular Physiology, 2011. 301(4): p. L415-26.
  6. Ohta, S., Molecular hydrogen as a novel antioxidant: overview of the advantages of hydrogen for medical applications. Methods Enzymol, 2015. 555: p. 289-317.
  7. Zhang, J.Y., et al., Protective role of hydrogen-rich water on aspirin-induced gastric mucosal damage in rats. World J Gastroenterol, 2014. 20(6): p. 1614-22.
  8. Gu, H., et al., Pretreatment with hydrogen-rich saline reduces the damage caused by glycerol-induced rhabdomyolysis and acute kidney injury in rats. J Surg Res, 2014. 188(1): p. 243-9.
  9. Kawasaki, H., J.J. Guan, and K. Tamama, Hydrogen gas treatment prolongs replicative lifespan of bone marrow multipotential stromal cells in vitro while preserving differentiation and paracrine potentials. Biochemical and Biophysical Research Communications, 2010. 397(3): p. 608-613.
  10. Wood, K.C. and M.T. Gladwin, The hydrogen highway to reperfusion therapy. Nat Med, 2007. 13(6): p. 673-674.
  11. Ito, M., et al., Drinking hydrogen water and intermittent hydrogen gas exposure, but not lactulose or continuous hydrogen gas exposure, prevent 6-hydorxydopamine-induced Parkinson’s disease in rats. Med Gas Res, 2012. 2(1): p. 15.
  12. Sobue, S., et al., Simultaneous oral and inhalational intake of molecular hydrogen additively suppresses signaling pathways in rodents. Mol Cell Biochem, 2015. 403(1-2): p. 231-41.
  13. Hyspler, R., et al., The Evaluation and Quantitation of Dihydrogen Metabolism Using Deuterium Isotope in Rats. PLoS One, 2015. 10(6): p. e0130687.
  14. Shimouchi, A., et al., Molecular hydrogen consumption in the human body during the inhalation of hydrogen gas. Adv Exp Med Biol, 2013. 789: p. 315-21.
  15. Kayar, S.R., et al., Hydrogen Gas Is Not Oxidized by Mammalian-Tissues under Hyperbaric Conditions. Undersea & Hyperbaric Medicine, 1994. 21(3): p. 265-275.
  16. McCall, M.R. and B. Frei, Can antioxidant vitamins materially reduce oxidative damage in humans? Free Radic Biol Med, 1999. 26(7-8): p. 1034-53.
  17. Ichihara, M., et al., Beneficial biological effects and the underlying mechanisms of molecular hydrogen – comprehensive review of 321 original articles. Med Gas Res, 2015. 5: p. 12.
  18. Yu, J., et al., Molecular hydrogen attenuates hypoxia/reoxygenation injury of intrahepatic cholangiocytes by activating Nrf2 expression. Toxicol Lett, 2015. 238(3): p. 11-19.
  19. Diao, M., et al., Hydrogen Gas Inhalation Attenuates Seawater Instillation-Induced Acute Lung Injury via the Nrf2 Pathway in Rabbits. Inflammation, 2016.
  20. Xie, K., et al., Nrf2 is critical in the protective role of hydrogen gas against murine polymicrobial sepsis. British Journal of Anaesthesia, 2012. 108(3): p. 538-539.
  21. Kawamura, T., et al., Hydrogen gas reduces hyperoxic lung injury via the Nrf2 pathway in vivo. Am J Physiol Lung Cell Mol Physiol, 2013. 304(10): p. L646-56.
  22. Xie, Q., et al., Hydrogen gas protects against serum and glucose deprivation induced myocardial injury in H9c2 cells through activation of the NFE2 related factor 2/heme oxygenase 1 signaling pathway. Mol Med Rep, 2014. 10(2): p. 1143-9.
  23. Hara, F., et al., Molecular Hydrogen Alleviates Cellular Senescence in Endothelial Cells. Circ J, 2016.
  24. Chen, H., et al., Molecular hydrogen protects mice against polymicrobial sepsis by ameliorating endothelial dysfunction via an Nrf2/HO-1 signaling pathway. Int Immunopharmacol, 2015. 28(1): p. 643-54.
  25. Wakabayashi, N., et al., Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nat Genet, 2003. 35(3): p. 238-45.
  26. Rajasekaran, N.S., et al., Sustained activation of nuclear erythroid 2-related factor 2/antioxidant response element signaling promotes reductive stress in the human mutant protein aggregation cardiomyopathy in mice. Antioxid Redox Signal, 2011. 14(6): p. 957-71.
  27. Sato, Y., 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): p. 346-350.
  28. Itoh, T., et al., Molecular hydrogen suppresses FcepsilonRI-mediated signal transduction and prevents degranulation of mast cells. Biochem Biophys Res Commun, 2009. 389(4): p. 651-6.
  29. Ohno, K., M. Ito, and M. Ichihara, Molecular hydrogen as an emerging therapeutic medical gas for neurodegenerative and other diseases. Oxidative Medicine and Cellular Longevity, 2012. 2012: p. 353152.
  30. Wang, C., et al., Hydrogen-rich saline reduces oxidative stress and inflammation by inhibit of JNK and NF-kappaB activation in a rat model of amyloid-beta-induced Alzheimer’s disease. Neuroscience Letters, 2011. 491(2): p. 127-32.
  31. Kishimoto, Y., et al., Hydrogen ameliorates pulmonary hypertension in rats by anti-inflammatory and antioxidant effects. J Thorac Cardiovasc Surg, 2015. 150(3): p. 645-654 e3.
  32. Ren, J.D., et al., Hydrogen-rich saline inhibits NLRP3 inflammasome activation and attenuates experimental acute pancreatitis in mice. Mediators Inflamm, 2014. 2014: p. 930894.
  33. Shao, A., et al., Hydrogen-Rich Saline Attenuated Subarachnoid Hemorrhage-Induced Early Brain Injury in Rats by Suppressing Inflammatory Response: Possible Involvement of NF-kappaB Pathway and NLRP3 Inflammasome. Mol Neurobiol, 2015.
  34. Xie, K.L., et al., [Effects of hydrogen gas inhalation on serum high mobility group box 1 levels in severe septic mice]. Zhejiang Da Xue Xue Bao Yi Xue Ban, 2010. 39(5): p. 454-7.
  35. Kamimura, N., et al., Molecular Hydrogen Improves Obesity and Diabetes by Inducing Hepatic FGF21 and Stimulating Energy Metabolism in db/db Mice. Obesity, 2011.
  36. Kamimura, N., et al., Molecular hydrogen stimulates the gene expression of transcriptional coactivator PGC-1 [alpha] to enhance fatty acid metabolism. NPJ Aging and Mechanisms of Disease, 2016. 2: p. 16008.
  37. Zhang, J.Y., et al., A Review of Hydrogen as a New Medical Therapy. Hepato-Gastroenterology, 2012. 59(116): p. 1026-1032.
  38. Matsumoto, A., et al., Oral ‘hydrogen water’ induces neuroprotective ghrelin secretion in mice. Sci Rep, 2013. 3: p. 3273.
  39. Sun, Y., et al., Treatment of hydrogen molecule abates oxidative stress and alleviates bone loss induced by modeled microgravity in rats. Osteoporos Int, 2013. 24(3): p. 969-78.
  40. Amitani, H., et al., Hydrogen Improves Glycemic Control in Type1 Diabetic Animal Model by Promoting Glucose Uptake into Skeletal Muscle. PLoS One, 2013. 8(1).
  41. Hong, Y., et al., Neuroprotective effect of hydrogen-rich saline against neurologic damage and apoptosis in early brain injury following subarachnoid hemorrhage: possible role of the Akt/GSK3beta signaling pathway. PLoS One, 2014. 9(4): p. e96212.
  42. Li, F.Y., et al., Consumption of hydrogen-rich water protects against ferric nitrilotriacetate-induced nephrotoxicity and early tumor promotional events in rats. Food Chem Toxicol, 2013. 61: p. 248-54.
  43. Itoh, T., et al., Molecular hydrogen inhibits lipopolysaccharide/interferon gamma-induced nitric oxide production through modulation of signal transduction in macrophages. Biochemical and Biophysical Research Communications, 2011. 411(1): p. 143-9.
  44. Cardinal, J.S., et al., Oral hydrogen water prevents chronic allograft nephropathy in rats. Kidney International, 2010. 77(2): p. 101-9.
  45. Lin, C.L., et al., Hydrogen-rich water attenuates amyloid beta-induced cytotoxicity through upregulation of Sirt1-FoxO3a by stimulation of AMP-activated protein kinase in SK-N-MC cells. Chem Biol Interact, 2015. 240: p. 12-21.
  46. Iuchi, K., et al., Molecular hydrogen regulates gene expression by modifying the free radical chain reaction-dependent generation of oxidized phospholipid mediators. Sci Rep, 2016. 6: p. 18971.
  47. Jin, Q., et al., Hydrogen gas acts as a novel bioactive molecule in enhancing plant tolerance to paraquat-induced oxidative stress via the modulation of heme oxygenase-1 signalling system. Plant Cell and Environment, 2013. 36(5): p. 956-69.
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