PRESS RELEASE
July 9, 2021
MiZ Company Limited

Pre-symptomatic diseases (“mibyou”) can be prevented and improved withmolecular hydrogen
MiZ Company Limited, in collaboration with the University of California, Berkeleyand Professor Emeritus Yoshiyasu Takefuji of Keio University, has published a review
paper titled “Molecular Hydrogen as a Novel Protective Agent against Pre-SymptomaticDiseases” in the International Journal of Molecular Sciences.
The term “mibyou” refers to a state of health in which a disease is slowly progressingin the body, yet the symptoms are not apparent. The causes of “mibyou” are thought tobe oxidative stress and chronic inflammation, which is in turn the main cause of many
intractable diseases. In a previous paper, the authors reported the possible mechanisms bywhich molecular hydrogen scavenges hydroxyl radicals, which are reactive oxygen
species (Note 2) generated in the mitochondria (Note 1) of cells, to suppress theprogression of chronic inflammation. Based on these mechanism by which hydrogen
suppresses chronic inflammation, the authors showed in this review that hydrogen has thepotential to prevent and ameliorate various inflammatory diseases in their presymptomatic stages.
The paper was released online on July 5, 2021 (European time) in the International
Journal of Molecular Sciences (Impact Factor: 5.9), an international scientific openaccess journal published by MDPI, a Swiss-based publisher.

1. Background of the paper and the effects of hydrogen on chronic inflammation
Since chronic inflammation is involved in many diseases, it is often said that“chronic inflammation is at the root of all diseases”. Modern medicine can control acuteinflammatory diseases, while the same cannot be said for chronic inflammatory diseases.
Inflammation is triggered by the release of inflammatory cytokines (Note 3) produced bycertain types of white blood cells. Prolonged inflammation can damage the host organism
and induce chronic inflammation. In a previous paper, the authors reported that hydroxylradicals produced in the mitochondria activate the NLRP3 inflammasome (Note 4)
through a complex pathway, and that this stimulation triggers the production ofinflammatory cytokines. Since hydrogen is a selective scavenger of hydroxyl radicals in
the mitochondria, the authors showed that hydrogen can block such a cascade (Note 5)that leads to the activation of the NLRP3 inflammasome. Since hydrogen is the only
substance that can both enter the mitochondria and scavenge hydroxyl radicals, hydrogenhas novel prospects in curing chronic inflammatory diseases and many diseases related
to chronic inflammation.
2. “Mibyou” is caused by chronic inflammation
The term “mibyou” refers to a state of health in which a disease is slowly progressingin the body, yet the symptoms are not apparent. It can be broadly defined as a condition
between health and disease, as there is no clear boundary between the two. As introducedin the previous section, chronic inflammation is the cause of many intractable diseases,
and in this paper, the authors argue that chronic inflammation is involved in thepathogenesis of cancer, chronic kidney disease, type 2 diabetes, hepatitis, Parkinson'sdisease, Alzheimer's disease, and hypertension, and that hydrogen may suppress theactivation of NLRP3 in order to prevent and improve “mibyou”. The possibility of amechanism by which hydrogen suppresses the activation of NLRP3 to prevent or improve“mibyou” was demonstrated. As a specific example in which hydrogen has shown toimprove “mibyou”, two clinical trials have been reported corroborating that hydrogen
improves mild cognitive impairment (MCI), which is dementia (Alzheimer's disease) in
its pre-symptomatic state, which means that these papers support the effects of hydrogenin improving pre-symptomatic diseases. In addition, modern medicine is based on a oneto-one treatment for various diseases, whereas hydrogen showcases a characteristic“machine gun therapy” that can target chronic inflammation in various cells throughout
the body. Hydrogen is a substance that represents a completely different concept frommodern medicine; a new way of preventing and improving untreated diseases.
3. Article Information
Title: Molecular Hydrogen as a Novel Protective Agent against Pre-SymptomaticDiseases
Authors: Haru Yamamoto 1,2,, Yusuke Ichikawa 2, Shin-ichi Hirano3, Bunpei Sato3,
Yoshiyasu Takefuji4,5, and Fumitake Satoh3
Affiliations: 1 University of California, Berkeley, 2 MiZ Inc., 3 MiZ Company Limited,
4 Keio University, 5 Musashino University
Published Journal: International Journal of Molecular Science, 2021, 22, 7211.

URL: https://doi.org/10.3390/ijms22137211[Glossary](Note 1) Mitochondria: This is an intracellular organelle. It consists of two biologicalmembranes, has its own DNA, divides, and multiplies. Mitochondrial DNA is involved
in biological phenomena other than ATP synthesis (energy synthesis), and is also known
as a site for aerobic respiration.
(Note 2) Reactive oxygen species: A general term for oxygen in the air that has beentransformed into a highly reactive compound, and there are generally four types: thesuperoxide, hydroxyl radical, hydrogen peroxide, and singlet oxygen.
(Note 3) Inflammatory cytokines: Cytokines are proteins secreted mainly by immune
cells that play a role in transmitting information between cells. Among cytokines, thosethat cause inflammatory symptoms are called inflammatory cytokines.
(Note 4) Inflammasomes: Inflammasomes are complexes composed of multiple proteinsthat recognize foreign substances in the cytoplasm (e.g., components of pathogenic
microorganisms and uric acid crystals) as danger signals to the host cell in order to releaseinflammatory cytokines via intracellular signaling, playing an important role in theinduction and progression of inflammatory reactions.
(Note 5) Cascade: The original meaning is a string of beads, but in medical terms, it
refers to the phenomenon of stepwise amplification of a single signal through several
biochemical and physiological reactions.
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