Research and development

This section introduces the research and development of our company.

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Overview of research and development

According to recent study results of gaseous molecules, various physiologic activities have been seen of gaseous molecules of nitric oxide, carbon monoxide, hydrogen sulfide and hydrogen within a living body. Ever since Osawa et al. reported in Nature Medicine (Ohsawa I, Ishikawa M, Takahashi K, et al : Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med, 2007, 13: 688-694) that hydrogen gas eliminates the hydroxyl radical with the strongest oxidizing power even in reactive oxygen species, research on molecular hydrogen has expanded exponentially.
　It is understood from recent study results that molecular hydrogen demonstrates not only an antioxidant effect, but also an anti-inflammatory effect, an antiallergic action, an anti-apoptotic action, a lipid hypermetabolic action, etc., and approximately 740 original theses on animal tests and clinical studies of the effects of molecular hydrogen have been reported until now.
　MiZ has foreseen the possibilities of medical use of molecular hydrogen for the past twenty years, drawn a conclusion that molecular hydrogen will provide a paradigm shift in medicine of the 21st Century, and researched and developed based on a main theme of pursuing ideal technology regarding a hydrogen administration method for clinical application to humans.
　Technologies regarding hydrogen administering methods developed by MiZ until now are (1) method of administering dissolved hydrogen orally, (2) method of adding hydrogen to a liquid drug and administering it by injection, intravenous drip, or the like, and (3) method of administering hydrogen gas as an exhaust gas. We believe that these technologies can inevitably contribute to medicine of the 21st Century.

Primary patents

  1. Title "PROCESS AND APPARATUS FOR PRODUCING HYDROGEN-CONTAINING BIOCOMPATIBLE SOLUTION" (JP4486157B, JP5266267B)
  2. Title "METHOD OF INHIBITING OXIDATION, WATER CAPABLE OF INHIBITING OXIDATION AND USE THEREOF" (JP4511361B)
  3. Title "HIGH CONCENTRATION HYDROGEN GAS SUPPLY APPARATUS FOR LIVING MATTER" (JP5100911B, 5502973B)
  4. Title "DEVICE FOR SELECTIVELY HYDROGENATING BIOCOMPATIBLE SOLUTION" (JP4652479B)
  5. Title "METHOD AND DEVICE FOR PRODUCING HYDROGEN-CONTAINING BIOLOGICAL APPLICATION SOLUTION" (JP5935954B)
  6. Title "SUPPLY DEVICE OF HYDROGEN GAS FOR LIVING BODY" (JP5091364B)
  7. Title "APPARATUS AND METHOD FOR PRODUCING HYDROGEN-CONTAINING LIQUID" (JP6340033B)
  8. Title "METHOD FOR OBTAINING HYDROGEN CONCENTRATION OF HYDROGEN-CONTAINING LIQUID AND HYDROGEN-CONTAINING 　　LIQUID PRODUCTION DEVICE" (JP6148759B)
  9. Title "HYDROGEN WATER GENERATING METHOD" (JP6169762B)
  10. Title "PERFORMANCE MAINTAINING METHOD IN ELECTROLYSIS FUNCTIONAL WATER PRODUCING DEVICE" (JP5103015B)

(Number of domestic registered patents：25, Number of foreign registered patents: 59)

List of Academic Papers

e-letters in Science
  1. Sato F, Hirano S, Kurokawa R, Ichikawa Y, Maruyama A, Takefuji Y. Radical curatives will play a key role in the universal health care. Science, 361/6404/eaat9644, 2018.
    http://science.sciencemag.org/content/361/6404/eaat9644/tab-e-letters
  2. Sato F, Hirano S, Kurokawa R, Ichikawa Y, Maruyama A, Takefuji Y. Who will be suffering from losing the Alzheimer’s gamble. Science, 361/6405/838, 2018.
    http://science.sciencemag.org/content/361/6405/838/tab-e-letters
Original papers or Reviews
  1. Hirano S, Ichikawa Y, Sato B, Takefuji Y, Satoh F. Molecular Hydrogen as a Medical Gas for the Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Potential Efficacy Based on a Literature Review. Front Neurol, 13: 841310.
  2. Hirano S, Yamamoto H, Ichikawa Y,Sato B,Takefuji Y,Satoh F. Molecular hydrogen as a novel antitumor agent: possible mechanism underlying gene expression. Int J Mol Sci, 22: 8724, 2021.
  3. Yamamoto H, Ichikawa Y, Hirano S, Sato B, Takefuji Y, Satoh F. Molecular hydrogen as a novel protective agent against pre-symptomatic diseases. Int J Mol Sci, 22: 7211, 2021.
  4. Hirano S, Ichikawa Y, Sato B, Yamamoto H, Takefuji Y, Satoh F. Molecular hydrogen as a potential clinically applicable radioprotective agent. Int J Mol Sci,　2021. 22, 4566.
  5. Hirano S, Aoki Y, Li XK, Ichimaru N, Takahara S, Takefuji Y. Protective effects of hydrogen gas inhalation on radiation-induced bone marrow damage in cancer patients: a retrospective observational study. Med Gas Res, 2021; 11(3): 104-109.
  6. Hirano S, Ichikawa Y, Sato B, Yamamoto H, Takefuji Y, Satoh F. Potential therapeutic applications of hydrogen in chronic inflammatory diseases: possible inhibiting role on mitochondrial stress. Int J Mol Sci, 22: 2549. 2021.
  7. Matsuura H, Matsumoto H, Okuzaki D, Shimizu K, Ogura H, Ebihara T, Matsubara T, Hirano S, Shimazu T. Hydrogen gas therapy attenuate inflammatory pathway signaling in septic mice. J Surg Res, 236: 63-70, 2021.
  8. Li S, Takahara T, Que W, Fujino M, Guo WZ, Hirano S, Ye LP, Li XK. Hydrogen-rich water protects liver injury in nonalcoholic steatohepatitis though HO-1 enhancement via IL-10 and Sirt 1 signaling. Am J Physiol Gastrointest Liver Physiol, 2021 Jan 13. doi 10.1152/ajpgi. 00158. 2020. Online ahead of print.
  9. Hori A, Sobue S, Kurokawa R, Hirano S, Ichihara M, Hotta N. Two-week continuous supplementation of hydrogen-rich water increases peak oxygen uptake during an incremental cycling exercise test in healthy humans. Med Gas Res, 10 (4): 163-169, 2020.
  10. Hirano S, Ichikawa Y, Sato B, Satoh F, Takefuji Y. Hydrogen is promising for medical applications. Clean Technol, 2020, 2 (4): 529-541.
  11. Ichikawa Y, Satoh B, Hirano S, Kurokawa R, Takefuji Y, Satoh F
    "Proposal of Next-Generation Medical Care "Mega-hydrogen Therapy"
    Medical Gas Research, 2020 ,Volume 10 , Issue 3 , Page 140-141
  12. Kayawake H, Chen-Yoshikawa TF, Saito M, Yamagishi H, Yoshizawa A, Hirano S, Kurokawa R, Date H. Protective effects of a hydrogen-rich preservation solution in a canine lung transplantation model. Ann Thorac Surg. 2020 Jul 7;S0003-4975(20)31108-5.　doi 10.1016j.athoracsur.2020.05.076. Online ahead of print.
    https://pubmed.ncbi.nlm.nih.gov/32649946/
  13. Hirano S, Ichikawa Y, Kurokawa R, Takefuji Y, Satoh F. A “Philosophical molecule”, hydrogen may overcome senescence and intractable diseases. Med Gas Res. 2020; 10 (1): 47-9.
  14. Wang P, Zhao P, Chen Z, Wu G, Fujino M, Zhang C, Zhou W, Zhao M, Hirano S, Li XK, Zhao L. Hydrogen gas attenuates hypoxic-ischemic brain injury via regulation of the MAPK/HO-1/PGC-α pathway in neonatal rats, Oxid. Med. Cell. Longev., Vol. 2020, Article ID 6978784, 2020.
    https://doi.org/10.1155/2020/6978784
  15. Yamamoto S, Torisu S, Amiya R, Kurokawa R, Hirano S, Ong BHE, Sonoda H, Kaneko Y, Mizutani S, Ikeda M, Naganobu K. Inhibitory effects of hydrogen gas inhalation to isoflurane-induced oxidative stress in healthy dogs. J Comparative Integrative Med, 26: 5-12, 2019.
  16. Saito M, Chen-Yoshikawa T, Takahashi M, Kayawake H, Yokoyama Y, Kurokawa R, Hirano S, Date H. Protective effects of a hydrogen-rich solution during cold ischemia in rat lung transplantation. J Thorac Cardiovasc Surg. 2019 Oct 30. pii. S0022-5223(19)32355-4. doi: 10. 1016/j.jtcvs. 2019. 09. 175. [Epub ahead of print].
    https://www.ncbi.nlm.nih.gov/pubmed/31780065
  17. Kurokawa R, Hirano S, Ichikawa Y, Matsuo G, Takefuji Y. Preventing explosions of hydrogen gas inhalers. Med Gas Res. 9 (3): 160-162, 2019.
    MedGasRes93160-8600447_235324.pdf
  18. Ozeki N, Yamawaki-Ogata A, Narita Y, Mii S, Ushida K, Ito M, Hirano S, Kurokawa R, Ohno K, Usui A. Hydrogen water alleviates obliterative airway disease in mice. Gen Thoracic Cardiovasc Surg, 2019 Aug 29. doi: 10. 1007/s11748-019-01195-3. [Epub ahead of print]
    https://www.ncbi.nlm.nih.gov/pubmed/31468277
  19. Sakai T, Kurokawa R, Hirano S, Imai J. Hydrogen indirectly suppresses increase of hydrogen peroxide in cytoplasmic・OH-induced cells and suppresses cellular senescence. Int J Mol Sci. 2019 Jan 21;20(2), 2019.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359316/pdf/ijms-20-00456.pdf
  20. Wu G, Chen Z, Wang P, Zhao M, Fujino M, Zhang C, Zhou W, Hirano S, Li XK, Zhao L. Hydrogen inhalation protects hypoxic-ischemia brain damage by attenuating inflammation and apoptosis in neonatal rats. Exp Biol Med (Maywood), 2019 Jun 12:1535370219855399. doi: 10.1177/1535370219855399. [Epub ahead of print]
    https://www.ncbi.nlm.nih.gov/pubmed/31189349
  21. Li S, Fujino M, Ichimaru N, Kurokawa R, Hirano S, Mou L, Takahara S, Takahara T, Li XK., Molecular hydrogen protects against ischemia-reperfusion injury in a mouse fatty liver model via regulating HO-1 and Sirt1 expression. Sci Rep. 2018 Sep 19;8(1):14019. doi: 10.1038/s41598-018-32411-4
    https://www.ncbi.nlm.nih.gov/pubmed/?term=Molecular+hydrogen+protects+against+ischemia-reperfusion+injury+in+a+mouse+fatty+liver+model+via+regulating+HO-1+and+Sirt1+expression
  22. Ikeda M, Shimizu K, Ogura H, Kurakawa T, Umemoto E, Motooka D, Nakamura S, Ichimaru N, Takeda K, Takahara S, Hirano S, Shimazu T., Hydrogen-rich saline regulates intestinal barrier dysfunction, dysbiosis, and bacterial translocation in a murine model of sepsis. Shock. 2018 Dec;50(6):640-647. doi: 10.1097/SHK.0000000000001098.
    https://www.ncbi.nlm.nih.gov/pubmed/?term=Hydrogen-Rich+Saline+Regulates+Intestinal+Barrier+Dysfunction%2C+Dysbiosis%2C+and+Bacterial+Translocation+in+a+Murine+Model+of+Sepsis
  23. Suzuki Y, Sato T, Sugimoto M, Baskoro H, Karasutani K, Mitsui A, Nurwidya F, Arano N, Kodama Y, Hirano S, Ishigami A, Seyama K, Takahashi K., Hydrogen-rich pure water prevents cigarette smoke-induced pulmonary emphysema in SMP30 knockout mice. Biochem Biophys Res Commun. 2017 Oct 7;492(1):74-81. doi: 10.1016/j.bbrc.2017.08.035. Epub 2017 Aug 12.
    https://www.ncbi.nlm.nih.gov/pubmed/?term=Hydrogen-rich+pure+water+prevents+cigarette+smoke-induced+pulmonary+emphysema+in+SMP30+knockout+mice
  24. Kurokawa R, Seo T, Sato B, Hirano S, Sato F. Convenient methods of molecular hydrogen: drinking, injection, and inhalation. Med Gas Res. 2015 Oct 26;5:13. doi: 10.1186/s13618-015-0034-2. eCollection 2015.
    https://www.ncbi.nlm.nih.gov/pubmed/?term=Convenient+methods+of+molecular+hydrogen%3A+drinking%2C+injection%2C+and+inhalation
  25. Ishibashi T, Ichikawa M, Sato B, Shibata S, Hara Y, Naritomi Y, Okazaki K, Nakashima Y, Iwamoto Y, Koyanagi S, Hara H, Nagao T. Improvement of psoriasis-associated arthritis and skin lesions by treatment with molecular hydrogen: A report of three cases. Mol Med Rep. 2015 Aug;12(2):2757-64. doi: 10.3892/mmr.2015.3707. Epub 2015 Apr 30.
    https://www.ncbi.nlm.nih.gov/pubmed/?term=Improvement+of+psoriasis-associated+arthritis+and+skin+lesions+by+treatment+with+molecular+hydrogen%3A+A+report+of+three+cases.
  26. Shigeta T, Sakamoto S, Li XK, Cai S, Liu C, Kurokawa R, Nakazawa A, Kasahara M, Uemoto S. Luminal injection of hydrogen-rich solution attenuates intestinal ischemia-reperfusion injury in rats. Transplantation. 2015 Mar;99(3):500-7. doi: 10.1097/TP.0000000000000510.
    https://www.ncbi.nlm.nih.gov/pubmed/?term=Luminal+injection+of+hydrogen-rich+solution+attenuates+intestinal+ischemia-reperfusion+injury+in+rats.
  27. Liu C, Kurokawa R, Fujino M, Hirano S, Sato B, Li XK. Estimation of the hydrogen concentration in rat tissue using an airtight tube following the administration of hydrogen via various routes. Sci Rep. 2014 Jun 30;4:5485. doi: 10.1038/srep05485. Erratum in: Sci Rep. 2015; 5: 9629.
    https://www.ncbi.nlm.nih.gov/pubmed/24975958
  28. Yamada T, Uchida K, Onuma K, Kuzuno J, Ujihira M, Inoue G, Sato B, Kurokawa R, Sakai R, Takaso M. Hydrogen supplementation of preservation solution improves viability of osteochondral grafts. Scientific World Journal. 2014; 2014:109876. doi: 10.1155/2014/109876. Epub 2014 Nov 19.
    https://www.ncbi.nlm.nih.gov/pubmed/?term=Hydrogen+supplementation+of+preservation+solution+improves+viability+of+osteochondral+grafts.
  29. Sakai T, Sato B, Hara K, Hara Y, Naritomi Y, Koyanagi S, Hara H, Nagao T, Ishibashi T. Consumption of water containing over 3.5 mg of dissolved hydrogen could improve vascular endothelial function. Vasc Health Risk Manag. 2014 Oct 17; 10:591-7. doi: 10.2147/VHRM.S68844. eCollection 2014.
    https://www.ncbi.nlm.nih.gov/pubmed/?term=Consumption+of+water+containing+over+3.5+mg+of+dissolved+hydrogen+could+improve+vascular+endothelial+function.
  30. Ishibashi T, Sato B, Shibata S, Sakai T, Hara Y, Naritomi Y, Koyanagi S, Hara H, Nagao T. Therapeutic efficacy of infused molecular hydrogen in saline on rheumatoid arthritis: a randomized, double-blind, placebo-controlled pilot study. Int Immunopharmacol. 2014 Aug;21(2):468-73. doi: 10.1016/j.intimp.2014.06.001. Epub 2014 Jun 11
    https://www.ncbi.nlm.nih.gov/pubmed/?term=Therapeutic+efficacy+of+infused+molecular+hydrogen+in+saline+on+rheumatoid+arthritis%3A+a+randomized%2C+double-blind%2C+placebo-controlled+pilot+study.
  31. Seo T, Kurokawa R, Sato B. A convenient method for determining the concentration of hydrogen in water: use of methylene blue with colloidal platinum. Med Gas Res. 2012 Jan 24;2:1. doi: 10.1186/2045-9912-2-1.
    https://www.ncbi.nlm.nih.gov/pubmed/?term=A+convenient+method+for+determining+the+concentration+of+hydrogen+in+water%3A+use+of+methylene+blue+with+colloidal+platinum.
  32. Ishibashi T, Sato B, Rikitake M, Seo T, Kurokawa R, Hara Y, Naritomi Y, Hara H, Nagao T, Consumption of water containing a high concentration of molecular hydrogen reduces oxidative stress and disease activity in patients with rheumatoid arthritis an open-label pilot study. Med Gas Res, 2012, 2: 27, 2012.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3563451/pdf/2045-9912-2-27.pdf
  33. Nakai Y, Sato B, Ushiama S, Okada S, Abe K, Arai S. Hepatic oxidoreduction-related genes are upregulated by administration of hydrogen-saturated drinking water. Biosci Biotechnol Biochem. 2011;75(4):774-6. Epub 2011 Apr 22.
    https://www.ncbi.nlm.nih.gov/pubmed/?term=Hepatic+oxidoreduction-related+genes+are+upregulated+by+administration+of+hydrogen-saturated+drinking+water.
  34. Yanagihara T, Arai K, Miyamae K, Sato B, Shudo T, Yamada M, Aoyama M. Electrolyzed hydrogen-saturated water for drinking use elicits an antioxidative effect: a feeding test with rats. Biosci Biotechnol Biochem. 2005 Oct;69(10):1985-7.
    https://www.ncbi.nlm.nih.gov/pubmed/?term=Electrolyzed+hydrogen-saturated+water+for+drinking+use+elicits+an+antioxidative+effect%3A+a+feeding+test+with+rats.