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Unsolved Problems and Potential for Coming Hydrogen Medicine (Title: Bold)

Shigeo Ohta (Name of a speaker and coauthors: Bold)

Department of Neurology Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan (Affiliation: italic)

E-mail address: ohta@nms.ac.jp

Keywords: mechanism, Ca2+-signaling, PGC-1treatment, Alzheimer’s disease. (3-5 keywords) Recent Photograph

H2 acts as a novel antioxidant to protect cells against oxidative stress [1]. Subsequently, numerous studies have indicated the potential applications of H2 in therapeutic and preventive medicine.Molecular mechanism to exhibit multiple functions by H2 (Subtitle: Bold) In the first paper [1], we presented that H2 reduces cytotoxic oxygen radicals in cultured cells. This finding has been reproducible and confirmed by several independent experiments; however, we did not mean that this concept could elucidate all the functions of multiple functions. On the other hand, H2 regulates various signal transduction pathways and the expression of many genes to exhibit multiple functions. We had better consider that the short- and long-term effects, and direct- and secondary action might be different. The target of H2 may not be specific, but may be abundant depending upon the situation. We challenged to determine how H2 regulates gene expression, and revealed that H2 regulates gene expression via the Ca2+ signaling pathway by direct modification of oxidized phospholipid mediators in a free radical-dependent manner, and consequently suppressed NFAT, a tanscription factor, leading to multiple functions including the suppression of inflammation [2]. Next, we found that H2 up-regulates the PPARα signaling pathway involved in fatty acid metabolism. As an early event, the gene expression of PGC-1α was transiently increased, followed by increased expression of FGF21. The expression of PGC-1α was indirectly regulated through sequential regulation by H2, 4-hydroxy-2-nonenal, an end-product of peroxides, and Akt/FoxO1 signaling, followed by stimulation of the PPARα pathway that up-regulates FGF21 and the fatty acid and steroid metabolism [3]. In these two experiments, the end-products of free radical chain reaction played roles as mediators in signal transduction. These findings linked the free radical chain reaction with signal transductions. Prevention and therapeutics of Alzheimer’s disease Most pharmaceutical companies have recently withdrawn from therapeutic drug development of Alzheimer's disease. Hydrogen may contribute to overcome the most serious issues. Drinking H2-water prevented the chronic stress-induced impairments in learning and memory by reducing oxidative stress in mice [4]. Thus, we assessed the effects of drinking H2

water on oxidative stress model mice, and found that drinking H2-water decreased oxidative stress markers and suppressed the decline of memory impairment and neurodegeneration. Moreover, the mean lifespan in the H2-water mice was longer than that of the control mice [5]. For a randomized double-blinded placebo-controlled clinical study on human subjects with MCI, 73 subjects drank ~300 mL of H2-water (H2-group) or placebo water (control group) per day, and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) scores

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were determined after 1 year. Carriers of the apolipoprotein E4 (APOE4) genotype in the H2-group were improved significantly on total ADAS-cog score and word recall task score (one of the sub-scores in the ADAS-cognitive score) [5]. Considering that more than half of AD patients are the APOE4 carriers, this study indicates a strong potential of H2 water for preventing many patients with dementia. Eleven patients with AD inhaled 3% H2 gas for 1 hr twice per day for 4 - 7 months. The patients were clinically evaluated using ADAS-cog. To reveal the integrity of the neurons, the neuronal bundles that pass through the hippocampus were visualized by a modified diffusion tensor imaging (DTI) technique using advanced magnetic-resonance imaging (MRI) at various fractional anisotropy (FA) values [6]. The mean ADAS-cog score change (n=11) was significantly improved to –2.7 after ~5 months treatment in comparison with that in non-treated patients (n=5) which worsened to +7. When two patients with an ADAS-cog score of more than 50 at the baseline were excluded, the mean ADAS-cog score change was –4.1. By objective DTI evaluation, inhalation of H2 gas significantly increased the hippocampal neuronal tract size at the higher FA values. The DTI change was correlated with the clinical improvement assessed by ADAS-cog scores. This clinical study indicates the significant improvement of AD patients by inhaling H2 gas as assessed by the DTI evaluation as well as a clinical test [6]. It is noteworthy that the improvement by H2 was greater than any medicines that had been approved.

References[1] Ohsawa, I. et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing

cytotoxic oxygen radicals. Nat Med 2007; 13(6): 688-694.[2] 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: 18971.

[3] Kamimura, N. et al., Molecular hydrogen stimulates the gene expression of transcriptional coactivator PGC-1α to enhance fatty acid metabolism. NPJ Aging Mech Dis 2016; 2: 16008.

[4] Nagata, K., et al. Consumption of molecular hydrogen prevents the stress-induced impairments in hippocampus-dependent learning tasks during chronic physical restraint in mice. Neuropsychopharmacology 2009; 34: 501-508.

[5] Nishimaki, K., et al., Effects of molecular hydrogen assessed by an animal model and a randomized clinical study on mild cognitive impairment. Curr Alzheimer Res 2018; 15(5): 482-492.

[6] Ono H, et al. Pilot Study on Therapeutic Inhalation of Hydrogen Gas for Improving Patients with Alzheimer’s Disease Assessed by Cognitive Subscale Scores and Magnetic Resonance Diffusion Tensor ImagingInt. J Alzheimers & Neuro Disorder 2018; 1: 004.

BiographyBackground (3 fields) : Molecular Cellular Biology, Mitochondria science, anti-agingShigeo Ohta received PhD from the University of Tokyo in 1979, and postdoctoral studies were performed in Biocenter, Basel University, Switzerland from 1981 to 1985. Next, he became an Associate Professor of Jichi Medical University from 1985 to 1994 and a Professor and Chairperson of Nippon Medical University from 1994 to 2017. He has published more than 250 papers in reputed journals. The total citation number is about 12,500. He is serving as the president of the Japanese BioMedical Society for Molecular Hydrogen, the honorary president of the International Society for hydrogen Medicine and Biology, and the president of

For Invited Speakers,Abstract should be 2 pages of A4 by single space. Font and font size should be “Times New Roman” or “symbol” and 11 point, respectively. Margins of top, bottom, and the sides should be 3 cm.

the Japanese Molecular Hydrogen Promote Association. He is currently a visiting Professor of Juntendo University, and a Professor Emeritus of Nippon Medical University.