The 2011 Medical Molecular Hydrogen Symposium: An inaugural symposium of the journal Medical Gas Research

This report summarizes a brief description/history of the Hydrogen Research Meetings as well as key presentations/oral abstracts delivered in the most recent symposium. Additionally, we introduced 38 diseases and physiological states for which hydrogen exhibits beneficial effects.


Introduction
Novel medical gases are expected to provide us with more effective therapeutic interventions and preventive medicine. In the past decades, there has been extraordinary, rapid growth in our knowledge of gaseous molecules, including nitric oxide, carbon monoxide, and hydrogen sulfide, which have been known to play important roles in biological systems. Additionally, since Dr. Shigeo Ohta's group's pioneering paper was published in the June 2007 Nature Medicine showing the potency of hydrogen as a therapeutic gas for oxidative stress-mediated diseases including cerebral infarction [1], basic and clinical hydrogen research has resurfaced. In Japan, the birthplace of hydrogen gas research, Dr. Ohta (Nippon Medical School), who is currently serving as an Associate Editor of Medical Gas Research, organized annual "Medical Molecular Hydrogen Research Meetings" in 2009 and 2010 to provide investigators with focused opportunities to share their rapid scientific progress. Most recently, we organized the Medical Molecular Hydrogen Symposium on February 18-19, 2011 at the Nagoya University Hall (Figure 1). The latest meeting is a "kick-off" inaugural meeting for the newly launched journal Medical Gas Research (MGR), which aims to promote the exchange and dissemination of the latest scientific findings.
This report summarizes a brief description/history of the Hydrogen Research Meetings as well as key presentations/oral abstracts delivered in the most recent symposium.

First Medical Molecular Hydrogen Research Meeting, 2009
The first scientific meeting organized by Dr. Ohta was held on February 7, 2009 in Tokyo. 42 scientists and clinicians from 30 individual institutes were invited. The aim of the meeting was to unite innovative investigators to discuss and propagate medical hydrogen research. Dr. Ohta delivered the keynote presentation, in which he gave a brief history of hydrogen medicine and emphasized the huge impact of his report published in Nature Medicine. He pointed out the great interest in the field, expressed in more than 30 personal communications with investigators, and the resulting need to widen the scope of basic/clinical research to the whole world. He mentioned the successful application of hydrogen gas in a rat neonatal hypoxic brain injury model in collaboration with Dr. Xuejun Sun (Second Military Medical School, Shanghai, China) [2], who is currently serving as an Associate Editor. Dr. Atsunori Nakao (Department of Surgery, University of Pittsburgh), who is also an Associate Editor, presented the promising preliminary results of a collaborative study with Dr. Ohta's group in which hydrogen water was applied in a rat kidney transplant model. Dr. Nakao's report clearly showed survival benefits for transplant recipients. He received a research award at this meeting and his report was later published in Kidney International [3,4]. Dr. Takahisa Kawai (Forsythe Research Institute, Boston, MA, USA), who is an editorial board member, focused on hydrogen generated by intestinal bacteria. His initial studies elegantly demonstrated the critical physiological roles of gut microflora-derived hydrogen [5]. There was a general consensus that both clinicians and researchers in the field of molecular hydrogen research should gather and exchange accumulating knowledge in future annual meetings.

Second Medical Molecular Hydrogen Research Meeting, 2010
The second meeting was also organized by Dr. Ohta on February 3, 2010 in Tokyo. 47 basic scientists and clinical physicians, as well as 23 corporate participants were invited and shared the latest developments in medical issues related to hydrogen. This meeting hosted a keynote lecture, an invited lecture, two special lectures, and twelve platform presentations. After Dr. Ohta began his keynote lecture by remarking on the impressive progress over the last year, Dr. Sun gave an invited lecture and introduced the great effects of intraperitoneal administration of saline dissolved with H 2 in several model animals. Dr. Takashi Asada (Department of Psychiatry, Tsukuba University), an authority on Alzheimer disease, presented the results of clinical studies involving patients with mild cognitive impairment (MCI). He started clinical intervention studies on MCI patients by orally administering hydrogen water; the project is still in progress. Dr. Toru Yoshikawa (Kaohsiung Medical University, Taiwan) also gave a special lecture on the physical aspects of hydrogen effects. He presented the physical characteristics of molecular hydrogen's interaction with water in biological systems.

Third Medical Molecular Hydrogen Research Meeting, 2011
The third meeting was organized by Dr. Kenji Ohno (Nagoya University Graduate School of Medicine), an editorial board member, and held in Nagoya on Feb 18-19, 2011. This symposium mainly focused on molecular hydrogen and covered a wide-range of therapeutic gases, including hydrogen sulfide (H 2 S), nitric oxide (NO), and carbon monoxide (CO). A total of 98 academic and 53 corporate registrants attended the meeting from Japan (144), USA (5), Korea (1), and Taiwan (1). The meeting's timetable, titles, and speakers are summarized in Table 1. We also introduced 38 diseases and physiological states for which hydrogen exhibits beneficial effects ( Table 2).

Hydrogen
Dr. Ohta gave a keynote lecture and introduced a number of hydrogen's potent efficacies on a broad spectrum of diseases in animal and human models, as well as the emerging molecular bases of hydrogen's effects. He emphasized the following points: (i) In the three and a half years since the first hydrogen paper was published in Nature Medicine, more than 70 original papers have been published in leading biological/medical journals. Based on cumulative knowledge, beneficial biological effects of hydrogen have been established with no doubt. (ii) There are several ways to intake or consume hydrogen, including inhaling hydrogen gas, drinking water dissolved with hydrogen (hydrogen water), taking a hydrogen bath, injecting hydrogen saline, dropping hydrogen saline into the eye, and increasing production of intestinal hydrogen by bacteria. (iii) Hydrogen shows not only anti-oxidative stress effects, but also has various anti-inflammatory and anti-allergic effects. (iv) The primary molecular target of hydrogen remains unknown. In their first report published in 2007 [1], Dr. Ohta's group indicated that cells cultured in H 2 -rich medium were protected against oxidative stress by the hydroxyl radical-scavenging activity of H 2 ; however, recent evidence clearly shows that the scavenging property is not the only explanation for the potent beneficial effects of hydrogen. For example, the amount of orally administered H 2 may not be enough to scavenge hydroxyl radicals. In addition, it is likely that the dwell time of H 2 in the body is too short to scavenge a large amount of hydroxyl radicals that are continuously generated. (v) Several reports demonstrate an effect on the regulation of gene expressions and protein-phosphorylations; however, the transcriptional factors and kinases involved in the functions afforded by H 2 have not been identified. It also remains unknown whether the regulations are directly performed by H 2 . (vi) The amount of administered H 2 is independent of the extent of effects. Intestinal bacteria seem to produce more than 1 liter of H 2 gas per day, whereas the amount of H 2 originating from drinking hydrogen water is less than 50 ml. Nevertheless, additional H 2 in drinking hydrogen water is  Sixteen platform speakers presented clinical and basic aspects of the medical application of molecular hydrogen. Among them were three treatments for patients with neurological and dental diseases. Dr. Mikio Hirayama (Department of Neurology, Kasugai City Hospital) and his colleagues presented their clinical report of treatment for a patient with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episode (MELAS) syndrome. He reported that a 33-year-old female patient was successfully treated by drinking hydrogen-containing water for one and half years, which reduced the frequency of episodic cerebral ischemia. Dr. Tohru Ibi (Department of Neurology, Aichi Medical School) conducted an open label trial on mitochondrial disorders and inflammatory myopathies, and demonstrated a remarkable reduction of several serum markers specific for myelopathy. He also conducted a doubleblind crossover trial; however, the trial showed no significant effects, which was likely due to a small amount of hydrogen water and to a short observation period. Both reports suggest that oral administration of hydrogen water is likely to be effective for mitochondrial diseases. Dr. Noriyuki Tanaka (Uchida Dental Clinic) reported that direct dental application of hydrogen water on injured regions reduced inflammation and promoted healing in dental operations, including tooth extraction.

Cancer
Tongue carcinoma cells medium [45] Inflammation and allergy Allergy type I rodent water [46] Sepsis rodent gas [47] Zymosan-induced inflammation rodent gas [47] Others Multipotent stromal cells cells gas [48] Radiation injury cells medium [49,50] Although the observations are not directly relevant to diseases, Turmeric [51] and acarbose [52] increase hydrogen production by intestinal bacteria in humans. Dr. Michael P. Schoenfeld from NASA gave a special lecture on the potential application of H 2 to protect astronauts from radiation-mediated injury during long space travel. Cosmic radiation induces serious oxidative stress, which is one of the major issues to be resolved by hydrogen research.
Other Medical Gases (NO, CO, and H 2 S) Mammals produce NO, CO, and H 2 S by their native enzymes; however, mammals lack an enzyme to produce H 2 . All four gases modulate signaling pathways and have some therapeutic effects. Thus, we invited leading NO, CO, and H 2 S researchers to the symposium.
Dr. Hideo Kimura (National Center of Neurology and Psychiatry), an editorial board member, gave a special lecture on hydrogen sulfide (H 2 S). Dr. Kimura discovered biological roles for H 2 S. He reviewed studies on H 2 S from past to present and emphasized the potential for actual medical applications.
Dr. Nakao organized a mini-symposium on carbon monoxide (CO). In the mini-symposium, the discrepancy between the animal and human models was discussed. CO binds to human hemoglobin more strongly than to murine hemoglobin; this seems to be the reason why CO is more toxic in clinical studies.
Dr. Hirosuke Kobayashi (Department of Respiratory Medicine, Kitasato University), an editorial board member, organized a mini-symposium on nitric oxide (NO). Dr. Kobayashi explained the contradictory properties of NO; while it is medically beneficial, it is also toxic and enhances oxidative stress. NO has been approved as a therapeutic agent in clinical practice. He presented the amazing effects of inhaling an NO and H 2 mixture. NO enhances oxidative stress and induces production of peroxynitrite, and H 2 reduces peroxynitrite derived from NO. Indeed, he presented that the mixture of NO and H 2 improves the number of surviving myocytes in a rodent model of myocardial infarction. The mixture of NO and H 2 may be a promising modality for clinical applications.
In addition to NO, CO, and H 2 S, Dr. Zhang addressed potential effects of inhaled xeon and helium in animal models in his invited lecture.

Commercial products
Six companies financially supported the meeting by demonstrating their new commercial products. Melodian Co Ltd. presented a sports drink containing H 2 , and Miz Co Ltd. introduced an interesting device to prepare a clinically applicable H 2 -rich infusion solution by simply soaking an infusion bag in hydrogen water. With this method, no other treatment is necessary to prepare hydrogen infusion solution without opening the infusion bag. Taiyo Co Ltd. presented reasonably priced devices to measure H 2 gas in breath. Takaoka Co Ltd. demonstrated a tiny home apparatus to produce hydrogen water. Doctor's Choice Co Ltd. demonstrated powders to prepare a hydrogen bath at home using a new material that releases H 2 gas. These new products will help expand our knowledge and applicability of hydrogen research.