{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T18:13:33Z","timestamp":1774030413947,"version":"3.50.1"},"reference-count":58,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T00:00:00Z","timestamp":1625443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mibyou, or pre-symptomatic diseases, refers to state of health in which a disease is slowly developing within the body yet the symptoms are not apparent. Common examples of mibyou in modern medicine include inflammatory diseases that are caused by chronic inflammation. It is known that chronic inflammation is triggered by the uncontrolled release of proinflammatory cytokines by neutrophils and macrophages in the innate immune system. In a recent study, it was shown that molecular hydrogen (H2) has the ability to treat chronic inflammation by eliminating hydroxyl radicals (\u00b7OH), a mitochondrial reactive oxygen species (ROS). In doing so, H2 suppresses oxidative stress, which is implicated in several mechanisms at the root of chronic inflammation, including the activation of NLRP3 inflammasomes. This review explains these mechanisms by which H2 can suppress chronic inflammation and studies its applications as a protective agent against different inflammatory diseases in their pre-symptomatic state. While mibyou cannot be detected nor treated by modern medicine, H2 is able to suppress the pathogenesis of pre-symptomatic diseases, and thus exhibits prospects as a novel protective agent.<\/jats:p>","DOI":"10.3390\/ijms22137211","type":"journal-article","created":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T04:18:21Z","timestamp":1625458701000},"page":"7211","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Molecular Hydrogen as a Novel Protective Agent against Pre-Symptomatic Diseases"],"prefix":"10.3390","volume":"22","author":[{"given":"Haru","family":"Yamamoto","sequence":"first","affiliation":[{"name":"Department of Molecular & Cell Biology, University of California, Berkeley, 3060 Valley Life Sciences Bldg #3140, Berkeley, CA 94720-3140, USA"},{"name":"MiZ Inc., 39899 Balentine Drive Suite 200, Newark, CA 94560, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yusuke","family":"Ichikawa","sequence":"additional","affiliation":[{"name":"MiZ Inc., 39899 Balentine Drive Suite 200, Newark, CA 94560, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8610-8922","authenticated-orcid":false,"given":"Shin-ichi","family":"Hirano","sequence":"additional","affiliation":[{"name":"Department of Research and Development, MiZ Company Limited, 2-19-15 Ofuna, Kamakura, Kanagawa 247-0056, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bunpei","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Research and Development, MiZ Company Limited, 2-19-15 Ofuna, Kamakura, Kanagawa 247-0056, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1826-742X","authenticated-orcid":false,"given":"Yoshiyasu","family":"Takefuji","sequence":"additional","affiliation":[{"name":"Faculty of Environment and Information Studies, Keio University, 5322 Endo, Fujisawa 252-0882, Japan"},{"name":"Faculty of Data Science, Musashino University, 3-3-3 Ariake, Koto-Ku, Tokyo 134-8181, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fumitake","family":"Satoh","sequence":"additional","affiliation":[{"name":"Department of Research and Development, MiZ Company Limited, 2-19-15 Ofuna, Kamakura, Kanagawa 247-0056, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Hirano, S., Ichikawa, Y., Sato, B., Yamamoto, H., Takefuji, Y., and Satoh, F. (2021). Potential Therapeutic Applications of Hydrogen in Chronic Inflammatory Diseases: Possible Inhibiting Role on Mitochondrial Stress. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052549"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Hirano, S., Ichikawa, Y., Sato, B., Satoh, F., and Takefuji, Y. (2020). Hydrogen Is Promising for Medical Applications. Clean Technol., 2.","DOI":"10.3390\/cleantechnol2040033"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.tem.2018.02.006","article-title":"Inadequate Production of H 2 by Gut Microbiota and Parkinson Disease","volume":"29","author":"Ostojic","year":"2018","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_4","unstructured":"Hirano, S., Ichikawa, Y., Sato, B., Takefuji, Y., and Satoh, F. (2021). The conventional drug acts as a \u2018rifle gun\u2019 while hydrogen as a \u2018machine gun\u2019. Med. Gas. Res., In press."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/s41577-019-0165-0","article-title":"The NLRP3 inflammasome: Molecular activation and regulation to therapeutics","volume":"19","author":"Swanson","year":"2019","journal-title":"Nat. Rev. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1002\/eji.201141436","article-title":"Mitochondria: Sovereign of inflammation?","volume":"41","author":"Tschopp","year":"2011","journal-title":"Eur. J. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.atherosclerosis.2017.10.027","article-title":"NLRP3 inflammasome pathways in atherosclerosis","volume":"267","author":"Baldrighi","year":"2017","journal-title":"Atherosclerosis"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Kelley, N., Jeltema, D., Duan, Y., and He, Y. (2019). The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20133328"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/nri.2016.58","article-title":"Inflammasomes: Mechanism of assembly, regulation and signalling","volume":"16","author":"Broz","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1038\/s41586-018-0372-z","article-title":"New mitochondrial DNA synthesis enables NLRP3 inflammasome activation","volume":"560","author":"Zhong","year":"2018","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"47","DOI":"10.4103\/2045-9912.279983","article-title":"A \u201cphilosophical molecule,\u201d hydrogen may overcome senescence and intractable diseases","volume":"10","author":"Hirano","year":"2020","journal-title":"Med. Gas. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.neulet.2011.01.022","article-title":"Hydrogen-rich saline reduces oxidative stress and inflammation by inhibit of JNK and NF-\u03baB activation in a rat model of amyloid-beta-induced Alzheimer\u2019s disease","volume":"491","author":"Wang","year":"2011","journal-title":"Neurosci. Lett."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1111\/j.1478-3231.2010.02254.x","article-title":"Hydrogen-rich saline protects against liver injury in rats with obstructive jaundice","volume":"30","author":"Liu","year":"2010","journal-title":"Liver Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.bbrc.2011.06.116","article-title":"Molecular hydrogen inhibits lipopolysaccharide\/interferon \u03b3-induced nitric oxide production through modulation of signal transduction in macrophages","volume":"411","author":"Itoh","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1080\/19490976.2016.1182288","article-title":"H2 metabolism is widespread and diverse among human colonic microbes","volume":"7","author":"Wolf","year":"2016","journal-title":"Gut Microbes"},{"key":"ref_16","first-page":"149","article-title":"Short-Term H2 Inhalation Improves Cognitive Function in Older Women: A Pilot Study","volume":"14","author":"Korovljev","year":"2020","journal-title":"Int. J. Gerontol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"482","DOI":"10.2174\/1567205014666171106145017","article-title":"Effects of Molecular Hydrogen Assessed by an Animal Model and a Randomized Clinical Study on Mild Cognitive Impairment","volume":"15","author":"Nishimaki","year":"2018","journal-title":"Curr. Alzheimer Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/nature01322","article-title":"Inflammation and cancer","volume":"420","author":"Coussens","year":"2002","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"75767","DOI":"10.18632\/oncotarget.20801","article-title":"Potential application of the oxidative nucleic acid damage biomarkers in detection of diseases","volume":"8","author":"Guo","year":"2017","journal-title":"Oncotarget"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1126\/sciadv.abb1421","article-title":"An artificial metalloenzyme for catalytic cancer-specific DNA cleavage and operando imaging","volume":"29","author":"Gao","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1038\/nrc3611","article-title":"Inflammation-induced cancer: Crosstalk between tumours, immune cells and microorganisms","volume":"13","author":"Elinav","year":"2013","journal-title":"Nat. Rev. Cancer."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s13045-019-0755-0","article-title":"Inflammasome inhibitors: Promising therapeutic approaches against cancer","volume":"12","author":"Xu","year":"2019","journal-title":"J. Hematol. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1016\/j.freeradbiomed.2010.09.006","article-title":"Oxidative stress, inflammation, and cancer: How are they linked?","volume":"49","author":"Reuter","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1186\/s12943-018-0900-3","article-title":"Role of the NLRP3 inflammasome in cancer","volume":"17","author":"Moossavi","year":"2018","journal-title":"Mol. Cancer."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.3389\/fimmu.2020.01444","article-title":"NLRP3 Inflammasome Activation in Cancer: A Double-Edged Sword","volume":"11","author":"Hamarsheh","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.kint.2016.08.023","article-title":"Transcription factor Nrf2 hyperactivation in early-phase renal ischemia-reperfusion injury prevents tubular damage progression","volume":"91","author":"Nezu","year":"2017","journal-title":"Kidney Int."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/s41581-019-0248-y","article-title":"Targeting the progression of chronic kidney disease","volume":"16","author":"Lamas","year":"2020","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/s41581-019-0158-z","article-title":"The role of inflammasomes in kidney disease","volume":"15","author":"Komada","year":"2019","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Rapa, S.F., Di Iorio, B.R., Campiglia, P., Heidland, A., and Marzocco, S. (2020). Inflammation and Oxidative Stress in Chronic Kidney Disease\u2014Potential Therapeutic Role of Minerals, Vitamins and Plant-Derived Metabolites. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21010263"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Kim, Y.G., Kim, S.-M., Kim, K.-P., Lee, S.-H., and Moon, J.-Y. (2019). The Role of Inflammasome-Dependent and Inflammasome-Independent NLRP3 in the Kidney. Cells, 8.","DOI":"10.3390\/cells8111389"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1111\/nep.12785","article-title":"The NLRP3 inflammasome in kidney disease and autoimmunity","volume":"21","author":"Hutton","year":"2016","journal-title":"Nephrology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/nrd4275","article-title":"Targeting inflammation in the treatment of type 2 diabetes: Time to start","volume":"13","author":"Donath","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_33","first-page":"1","article-title":"Contribution of adipose tissue inflammation to the development of type 2 diabetes mellitus","volume":"9","author":"Burhans","year":"2018","journal-title":"Compr. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1038\/nm.3265","article-title":"Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes","volume":"19","author":"Jourdan","year":"2013","journal-title":"Nat. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1089\/ars.2017.7313","article-title":"Mitochondria, the NLRP3 Inflammasome, and Sirtuins in Type 2 Diabetes: New Therapeutic Targets","volume":"29","author":"Apostolova","year":"2018","journal-title":"Antioxid. Redox Signal."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1186\/s12974-019-1498-0","article-title":"NLRP3 inflammasome as a potential treatment in ischemic stroke concomitant with diabetes","volume":"16","author":"Hong","year":"2019","journal-title":"J. Neuroinflammation"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Ding, S., Xu, S., Ma, Y., Liu, G., Jang, H., and Fang, J. (2019). Modulatory Mechanisms of the NLRP3 Inflammasomes in Diabetes. Biomolecules, 9.","DOI":"10.3390\/biom9120850"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1053\/j.gastro.2017.12.019","article-title":"Nuclear Receptor Subfamily 1 Group D Member 1 Regulates Circadian Activity Of NLRP3 Inflammasome to Reduce the Severity of Fulminant Hepatitis in Mice","volume":"154","author":"Pourcet","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1016\/j.jhep.2017.01.022","article-title":"NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice","volume":"66","author":"Mridha","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1002\/hep.26592","article-title":"NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation and fibrosis","volume":"59","author":"Wree","year":"2014","journal-title":"Hepatology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1038\/nrn3880","article-title":"Immune attack: The role of inflammation in Alzheimer disease","volume":"16","author":"Heppner","year":"2015","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1038\/nature11729","article-title":"NLRP3 is activated in Alzheimer \u2019s disease and contributes to pathology in APP\/PS1 mice","volume":"493","author":"Heneka","year":"2013","journal-title":"Nature"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1186\/s12974-018-1313-3","article-title":"Inflammation: The link between comorbidities, genetics, and Alzheimer\u2019s disease","volume":"16","author":"Newcombe","year":"2018","journal-title":"J. Neuroinflammation"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.trci.2018.06.014","article-title":"Inflammation as a central mechanism in Alzheimer\u2019s disease","volume":"4","author":"Kinney","year":"2018","journal-title":"Alzheimer\u2019s Dement. Transl. Res. Clin. Interv."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1007\/s12035-014-9053-6","article-title":"Mechanism of Oxidative Stress and Synapse Dysfunction in the Pathogenesis of Alzheimer\u2019s Disease: Understanding the Therapeutics Strategies","volume":"53","author":"Kamat","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.coi.2020.10.011","article-title":"The NLRP3 inflammasome triggers sterile neuroinflammation and Alzheimer\u2019s disease","volume":"68","author":"Milner","year":"2021","journal-title":"Curr. Opin. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"101192","DOI":"10.1016\/j.arr.2020.101192","article-title":"The involvement of NLRP3 inflammasome in the treatment of Alzheimer\u2019s disease","volume":"64","author":"Feng","year":"2020","journal-title":"Ageing Res. Rev."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Pajares, M., IRojo, A., Manda, G., Bosc\u00e1, L., and Cuadrado, A. (2020). Inflammation in Parkinson\u2019s Disease: Mechanisms and Therapeutic Implications. Cells, 9.","DOI":"10.3390\/cells9071687"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s13024-016-0094-3","article-title":"MicroRNA-7 targets Nod-like receptor protein 3 inflammasome to modulate neuroinflammation in the pathogenesis of Parkinson\u2019s disease","volume":"11","author":"Zhou","year":"2016","journal-title":"Mol. Neurodegener."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/s41531-017-0032-2","article-title":"Mitochondrial impairment in microglia amplifies NLRP3 inflammasome proinflammatory signaling in cell culture and animal models of Parkinson\u2019s disease","volume":"3","author":"Sarkar","year":"2017","journal-title":"NPJ Parkinsons Dis."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.bbi.2020.10.010","article-title":"Impaired autophagy in microglia aggravates dopaminergic neurodegeneration by regulating NLRP3 inflammasome activation in experimental models of Parkinson\u2019s disease","volume":"91","author":"Qin","year":"2021","journal-title":"Brain Behav. Immun."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1002\/mds.27874","article-title":"Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson\u2019s Disease","volume":"35","author":"Haque","year":"2020","journal-title":"Mov. Disord."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1860","DOI":"10.1080\/15548627.2019.1596481","article-title":"Small molecule-driven NLRP3 inflammation inhibition via interplay between ubiquitination and autophagy: Implications for Parkinson disease","volume":"15","author":"Han","year":"2019","journal-title":"Autophagy"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"210","DOI":"10.3389\/fnagi.2019.00210","article-title":"Parkinson\u2019s Disease: A Systemic Inflammatory Disease Accompanied by Bacterial Inflammagens","volume":"11","author":"Adams","year":"2019","journal-title":"Front. Aging Neurosci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.pneurobio.2013.04.004","article-title":"Mitochondrial dysfunction and oxidative stress in Parkinson\u2019s disease","volume":"107","author":"Subramaniam","year":"2013","journal-title":"Prog. Neurobiol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Socha, M.W., Malinowski, B., Puk, O., Dubiel, M., and Wici\u0144ski, M. (2020). The NLRP3 Inflammasome Role in the Pathogenesis of Pregnancy Induced Hypertension and Preeclampsia. Cells, 9.","DOI":"10.20944\/preprints202005.0357.v1"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e3074","DOI":"10.1038\/cddis.2017.470","article-title":"NLRP3 inflammasome activation contributes to VSMC phenotypic transformation and proliferation in hypertension","volume":"8","author":"Sun","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1093\/cvr\/cvy252","article-title":"Pharmacological inhibition of the NLRP3 inflammasome reduces blood pressure, renal damage, and dysfunction in salt-sensitive hypertension","volume":"115","author":"Krishnan","year":"2019","journal-title":"Cardiovasc. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/13\/7211\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:26:00Z","timestamp":1760163960000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/13\/7211"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,5]]},"references-count":58,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["ijms22137211"],"URL":"https:\/\/doi.org\/10.3390\/ijms22137211","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,5]]}}}