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Shin-ichi Hirano, Director and Chief Scientific Officer, MiZ Company Limited. 1969–1973: Undergraduate student, Faculty of Veterinary Medicine, Kagoshima University; 1988–1991: Graduate research student, Faculty of Veterinary medicine, Nippon Veterinary and Life Science University. Veterinarian (1973), Ph.D. in Veterinary medicine (Veterinary pharmacology, 1991). 1973–1998: Senior researcher, Mercian Corporation. 1998–2012: Research manager and Director, Mercian Cleantec Corporation. 2012–: Director and Chief Scientific Officer, MiZ Company Limited. Pharmacology, Toxicology, Hydrogen medicine. Academic councilor of Japanese Pharmacological Society (1994–). No. of published papers: 80.
While many antitumor drugs have yielded unsatisfactory therapeutic results, drugs are one of the most prevalent therapeutic measures for the treatment of cancer. The development of cancer largely results from mutations in nuclear DNA, as well as from those in mitochondrial DNA (mtDNA). Molecular hydrogen (H2), an inert molecule, can scavenge hydroxyl radicals (·OH), which are known to be the strongest oxidizing reactive oxygen species (ROS) in the body that causes these DNA mutations. It has been reported that H2 has no side effects, unlike conventional antitumor drugs, and that it is effective against many diseases caused by oxidative stress and chronic inflammation. Recently, there has been an increasing number of papers on the efficacy of H2 against cancer and its effects in mitigating the side effects of cancer treatment. In this review, we demonstrate the efficacy and safety of H2 as a novel antitumor agent and show that its mechanisms may not only involve the direct scavenging of ·OH, but also other indirect biological defense mechanisms via the regulation of gene expression.
Shin-Ichi Hirano; Haru Yamamoto; Yusuke Ichikawa; Bunpei Sato; Yoshiyasu Takefuji; Fumitake Satoh. Molecular Hydrogen as a Novel Antitumor Agent: Possible Mechanisms Underlying Gene Expression. International Journal of Molecular Sciences 2021, 22, 8724 .
AMA StyleShin-Ichi Hirano, Haru Yamamoto, Yusuke Ichikawa, Bunpei Sato, Yoshiyasu Takefuji, Fumitake Satoh. Molecular Hydrogen as a Novel Antitumor Agent: Possible Mechanisms Underlying Gene Expression. International Journal of Molecular Sciences. 2021; 22 (16):8724.
Chicago/Turabian StyleShin-Ichi Hirano; Haru Yamamoto; Yusuke Ichikawa; Bunpei Sato; Yoshiyasu Takefuji; Fumitake Satoh. 2021. "Molecular Hydrogen as a Novel Antitumor Agent: Possible Mechanisms Underlying Gene Expression." International Journal of Molecular Sciences 22, no. 16: 8724.
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 (·OH), 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.
Haru Yamamoto; Yusuke Ichikawa; Shin-Ichi Hirano; Bunpei Sato; Yoshiyasu Takefuji; Fumitake Satoh. Molecular Hydrogen as a Novel Protective Agent against Pre-Symptomatic Diseases. International Journal of Molecular Sciences 2021, 22, 7211 .
AMA StyleHaru Yamamoto, Yusuke Ichikawa, Shin-Ichi Hirano, Bunpei Sato, Yoshiyasu Takefuji, Fumitake Satoh. Molecular Hydrogen as a Novel Protective Agent against Pre-Symptomatic Diseases. International Journal of Molecular Sciences. 2021; 22 (13):7211.
Chicago/Turabian StyleHaru Yamamoto; Yusuke Ichikawa; Shin-Ichi Hirano; Bunpei Sato; Yoshiyasu Takefuji; Fumitake Satoh. 2021. "Molecular Hydrogen as a Novel Protective Agent against Pre-Symptomatic Diseases." International Journal of Molecular Sciences 22, no. 13: 7211.
Although ionizing radiation (radiation) is commonly used for medical diagnosis and cancer treatment, radiation-induced damages cannot be avoided. Such damages can be classified into direct and indirect damages, caused by the direct absorption of radiation energy into DNA and by free radicals, such as hydroxyl radicals (•OH), generated in the process of water radiolysis. More specifically, radiation damage concerns not only direct damages to DNA, but also secondary damages to non-DNA targets, because low-dose radiation damage is mainly caused by these indirect effects. Molecular hydrogen (H2) has the potential to be a radioprotective agent because it can selectively scavenge •OH, a reactive oxygen species with strong oxidizing power. Animal experiments and clinical trials have reported that H2 exhibits a highly safe radioprotective effect. This paper reviews previously reported radioprotective effects of H2 and discusses the mechanisms of H2, not only as an antioxidant, but also in intracellular responses including anti-inflammation, anti-apoptosis, and the regulation of gene expression. In doing so, we demonstrate the prospects of H2 as a novel and clinically applicable radioprotective agent.
Shin-Ichi Hirano; Yusuke Ichikawa; Bunpei Sato; Haru Yamamoto; Yoshiyasu Takefuji; Fumitake Satoh. Molecular Hydrogen as a Potential Clinically Applicable Radioprotective Agent. International Journal of Molecular Sciences 2021, 22, 4566 .
AMA StyleShin-Ichi Hirano, Yusuke Ichikawa, Bunpei Sato, Haru Yamamoto, Yoshiyasu Takefuji, Fumitake Satoh. Molecular Hydrogen as a Potential Clinically Applicable Radioprotective Agent. International Journal of Molecular Sciences. 2021; 22 (9):4566.
Chicago/Turabian StyleShin-Ichi Hirano; Yusuke Ichikawa; Bunpei Sato; Haru Yamamoto; Yoshiyasu Takefuji; Fumitake Satoh. 2021. "Molecular Hydrogen as a Potential Clinically Applicable Radioprotective Agent." International Journal of Molecular Sciences 22, no. 9: 4566.
Mitochondria are the largest source of reactive oxygen species (ROS) and are intracellular organelles that produce large amounts of the most potent hydroxyl radical (·OH). Molecular hydrogen (H2) can selectively eliminate ·OH generated inside of the mitochondria. Inflammation is induced by the release of proinflammatory cytokines produced by macrophages and neutrophils. However, an uncontrolled or exaggerated response often occurs, resulting in severe inflammation that can lead to acute or chronic inflammatory diseases. Recent studies have reported that ROS activate NLRP3 inflammasomes, and that this stimulation triggers the production of proinflammatory cytokines. It has been shown in literature that H2 can be based on the mechanisms that inhibit mitochondrial ROS. However, the ability for H2 to inhibit NLRP3 inflammasome activation via mitochondrial oxidation is poorly understood. In this review, we hypothesize a possible mechanism by which H2 inhibits mitochondrial oxidation. Medical applications of H2 may solve the problem of many chronic inflammation-based diseases, including coronavirus disease 2019 (COVID-19).
Shin-Ichi Hirano; Yusuke Ichikawa; Bunpei Sato; Haru Yamamoto; Yoshiyasu Takefuji; Fumitake Satoh. Potential Therapeutic Applications of Hydrogen in Chronic Inflammatory Diseases: Possible Inhibiting Role on Mitochondrial Stress. International Journal of Molecular Sciences 2021, 22, 2549 .
AMA StyleShin-Ichi Hirano, Yusuke Ichikawa, Bunpei Sato, Haru Yamamoto, Yoshiyasu Takefuji, Fumitake Satoh. Potential Therapeutic Applications of Hydrogen in Chronic Inflammatory Diseases: Possible Inhibiting Role on Mitochondrial Stress. International Journal of Molecular Sciences. 2021; 22 (5):2549.
Chicago/Turabian StyleShin-Ichi Hirano; Yusuke Ichikawa; Bunpei Sato; Haru Yamamoto; Yoshiyasu Takefuji; Fumitake Satoh. 2021. "Potential Therapeutic Applications of Hydrogen in Chronic Inflammatory Diseases: Possible Inhibiting Role on Mitochondrial Stress." International Journal of Molecular Sciences 22, no. 5: 2549.
Background Molecular hydrogen (H2) has been used in clinical cases. However, there are few studies of H2 therapy to treat sepsis, and anti-inflammatory mechanisms of H2 are mostly unknown. We aimed to confirm effects of H2 therapy on sepsis and reveal its therapeutic mechanism via RNA sequencing in multiple organs in septic mice. Methods Nine-week-old C57BL/6 male mice underwent cecal ligation and puncture (CLP) or sham procedure. Subsequently, the CLP model received immediate ± continuous inhalation of 7% H2. Mice were observed for a week to assess survival rates. Serum inflammatory cytokines were evaluated at 24 h after CLP procedure. Liver, intestine, and lungs in CLP mice receiving 24-h ± H2 therapy were assessed by RNA sequencing. Data were analyzed with Ingenuity Pathways Analysis (QIAGEN Inc). Results Seven-day survival rate in septic mice was significantly improved in the H2 inhalation group compared with that in the control group (75% versus 40%, P< 0.05). H2 treatment attenuated serum interleukin-6 and tumor necrosis factor-α levels at 24 h after CLP, and blood glucose levels were maintained in the H2-treated group. In RNA sequencing, canonical pathway analysis revealed inactivity of various inflammatory signaling pathways, for example, acute phase response signaling and STAT3 pathways, in the liver and intestine in the CLP model after 24-h H2 inhalation. We detected significantly decreased expressions of upstream regulator genes such as the CD14 antigen gene in the liver and various cytokine receptor genes in the intestine and lungs in the H2-treated group. Conclusions These findings may contribute to clarifying the mechanism of action of H2 therapy in sepsis.
Hiroshi Matsuura; Hisatake Matsumoto; Daisuke Okuzaki; Kentaro Shimizu; Hiroshi Ogura; Takeshi Ebihara; Tsunehiro Matsubara; Shin-Ichi Hirano; Takeshi Shimazu. Hydrogen Gas Therapy Attenuates Inflammatory Pathway Signaling in Septic Mice. Journal of Surgical Research 2021, 263, 63 -70.
AMA StyleHiroshi Matsuura, Hisatake Matsumoto, Daisuke Okuzaki, Kentaro Shimizu, Hiroshi Ogura, Takeshi Ebihara, Tsunehiro Matsubara, Shin-Ichi Hirano, Takeshi Shimazu. Hydrogen Gas Therapy Attenuates Inflammatory Pathway Signaling in Septic Mice. Journal of Surgical Research. 2021; 263 ():63-70.
Chicago/Turabian StyleHiroshi Matsuura; Hisatake Matsumoto; Daisuke Okuzaki; Kentaro Shimizu; Hiroshi Ogura; Takeshi Ebihara; Tsunehiro Matsubara; Shin-Ichi Hirano; Takeshi Shimazu. 2021. "Hydrogen Gas Therapy Attenuates Inflammatory Pathway Signaling in Septic Mice." Journal of Surgical Research 263, no. : 63-70.
Hydrogen (H2) is promising as an energy source for the next generation. Medical applications using H2 gas can be also considered as a clean and economical technology. Since the H2 gas based on electrolysis of water production has potential to expand the medical applications, the technology has been developed in order to safely dilute it and to supply it to the living body by inhalation, respectively. H2 is an inert molecule which can scavenge the highly active oxidants including hydroxyl radical (·OH) and peroxynitrite (ONOO−), and which can convert them into water. H2 is clean and causes no adverse effects in the body. The mechanism of H2 is different from that of traditional drugs because it works on the root of many diseases. Since H2 has extensive and various effects, it may be called a “wide spectrum molecule” on diseases. In this paper, we reviewed the current medical applications of H2 including its initiation and development, and we also proposed its prospective medical applications. Due to its marked efficacy and no adverse effects, H2 will be a next generation therapy candidate for medical applications.
Shin-Ichi Hirano; Yusuke Ichikawa; Bunpei Sato; Fumitake Satoh; Yoshiyasu Takefuji. Hydrogen Is Promising for Medical Applications. Clean Technologies 2020, 2, 529 -541.
AMA StyleShin-Ichi Hirano, Yusuke Ichikawa, Bunpei Sato, Fumitake Satoh, Yoshiyasu Takefuji. Hydrogen Is Promising for Medical Applications. Clean Technologies. 2020; 2 (4):529-541.
Chicago/Turabian StyleShin-Ichi Hirano; Yusuke Ichikawa; Bunpei Sato; Fumitake Satoh; Yoshiyasu Takefuji. 2020. "Hydrogen Is Promising for Medical Applications." Clean Technologies 2, no. 4: 529-541.
It has been revealed that the cause of senescence and diseases is associated with the reactive oxygen species “hydroxyl radicals” (·OH). Senescence and diseases may be overcome as long as we can scavenge •OH mostly produced in mitochondria. It is one and only one “molecular hydrogen” (H2) that can both penetrate into the mitochondria and scavenge the •OH. The H2 in the body can function in disease prevention and recovery. H2 gas is explosive so that a safe hydrogen inhaler has to be developed for home use. We would like to advocate the great use of H2.
Shin-Ichi Hirano; Yusuke Ichikawa; Ryosuke Kurokawa; Yoshiyasu Takefuji; Fumitake Satoh. A “philosophical molecule,” hydrogen may overcome senescence and intractable diseases. Medical Gas Research 2020, 10, 47 -49.
AMA StyleShin-Ichi Hirano, Yusuke Ichikawa, Ryosuke Kurokawa, Yoshiyasu Takefuji, Fumitake Satoh. A “philosophical molecule,” hydrogen may overcome senescence and intractable diseases. Medical Gas Research. 2020; 10 (1):47-49.
Chicago/Turabian StyleShin-Ichi Hirano; Yusuke Ichikawa; Ryosuke Kurokawa; Yoshiyasu Takefuji; Fumitake Satoh. 2020. "A “philosophical molecule,” hydrogen may overcome senescence and intractable diseases." Medical Gas Research 10, no. 1: 47-49.
Bacteria inhabiting the human gut metabolize microbiota-accessible carbohydrates (MAC) contained in plant fibers and subsequently release metabolic products. Gut bacteria produce hydrogen (H2), which scavenges the hydroxyl radical (•OH). Because H2 diffuses within the cell, it is hypothesized that H2 scavenges cytoplasmic •OH (cyto •OH) and suppresses cellular senescence. However, the mechanisms of cyto •OH-induced cellular senescence and the physiological role of gut bacteria-secreted H2 have not been elucidated. Based on the pyocyanin-stimulated cyto •OH-induced cellular senescence model, the mechanism by which cyto •OH causes cellular senescence was investigated by adding a supersaturated concentration of H2 into the cell culture medium. Cyto •OH-generated lipid peroxide caused glutathione (GSH) and heme shortage, increased hydrogen peroxide (H2O2), and induced cellular senescence via the phosphorylation of ataxia telangiectasia mutated kinase serine 1981 (p-ATMser1981)/p53 serine 15 (p-p53ser15)/p21 and phosphorylation of heme-regulated inhibitor (p-HRI)/phospho-eukaryotic translation initiation factor 2 subunit alpha serine 51 (p-eIF2α)/activating transcription factor 4 (ATF4)/p16 pathways. Further, H2 suppressed increased H2O2 by suppressing cyto •OH-mediated lipid peroxide formation and cellular senescence induction via two pathways. H2 produced by gut bacteria diffuses throughout the body to scavenge cyto •OH in cells. Therefore, it is highly likely that gut bacteria-produced H2 is involved in intracellular maintenance of the redox state, thereby suppressing cellular senescence and individual aging. Hence, H2 produced by intestinal bacteria may be involved in the suppression of aging.
Takahiro Sakai; Ryosuke Kurokawa; Shin-Ichi Hirano; Jun Imai. Hydrogen Indirectly Suppresses Increases in Hydrogen Peroxide in Cytoplasmic Hydroxyl Radical-Induced Cells and Suppresses Cellular Senescence. International Journal of Molecular Sciences 2019, 20, 456 .
AMA StyleTakahiro Sakai, Ryosuke Kurokawa, Shin-Ichi Hirano, Jun Imai. Hydrogen Indirectly Suppresses Increases in Hydrogen Peroxide in Cytoplasmic Hydroxyl Radical-Induced Cells and Suppresses Cellular Senescence. International Journal of Molecular Sciences. 2019; 20 (2):456.
Chicago/Turabian StyleTakahiro Sakai; Ryosuke Kurokawa; Shin-Ichi Hirano; Jun Imai. 2019. "Hydrogen Indirectly Suppresses Increases in Hydrogen Peroxide in Cytoplasmic Hydroxyl Radical-Induced Cells and Suppresses Cellular Senescence." International Journal of Molecular Sciences 20, no. 2: 456.
Molecular hydrogen (H2) is clinically administered; however, in some hospitals, H2 is given to patients without consideration of its safe use. In the present study, we prepared convenient and safe devices for the drinking of super-saturated H2 water, for intravenous drip infusion of H2-rich saline, and for the inhalation of H2 gas. In order to provide useful information for researchers using these devices, the changes in H2 concentration were studied. Our experimental results should contribute to the advance of non-clinical and clinical research in H2 medicine.
Ryosuke Kurokawa; Tomoki Seo; Bunpei Sato; Shin-Ichi Hirano; Fumitake Sato. Convenient methods for ingestion of molecular hydrogen: drinking, injection, and inhalation. Medical Gas Research 2015, 5, 13 .
AMA StyleRyosuke Kurokawa, Tomoki Seo, Bunpei Sato, Shin-Ichi Hirano, Fumitake Sato. Convenient methods for ingestion of molecular hydrogen: drinking, injection, and inhalation. Medical Gas Research. 2015; 5 (1):13.
Chicago/Turabian StyleRyosuke Kurokawa; Tomoki Seo; Bunpei Sato; Shin-Ichi Hirano; Fumitake Sato. 2015. "Convenient methods for ingestion of molecular hydrogen: drinking, injection, and inhalation." Medical Gas Research 5, no. 1: 13.