Next Article in Journal
Mechanisms of Mitochondrial Oxidative Stress in Brain Injury: From Pathophysiology to Therapeutics
Next Article in Special Issue
Mitochondria-Stimulating and Antioxidant Effects of Slovak Propolis Varieties on Bovine Spermatozoa
Previous Article in Journal
Effects of Acute Red Spinach Extract Ingestion on Repeated Sprint Performance in Division I NCAA Female Soccer Athletes
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

The On/Off History of Hydrogen in Medicine: Will the Interest Persist This Time Around?

1
Department of Kinesiology and Outdoor Recreation, Southern Utah University, Cedar City, UT 84720, USA
2
Molecular Hydrogen Institute, Enoch, UT 84721, USA
3
Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-855, Japan
4
School of Applied Sciences, University of the West of England, Bristol BS16 1QY, UK
*
Authors to whom correspondence should be addressed.
Oxygen 2023, 3(1), 143-162; https://doi.org/10.3390/oxygen3010011
Submission received: 15 February 2023 / Revised: 23 February 2023 / Accepted: 27 February 2023 / Published: 14 March 2023
(This article belongs to the Special Issue Feature Papers in Oxygen Volume Ⅱ)

Abstract

:
Over 2000 publications including more than 100 human studies seem to indicate that humans have only recently benefited from or known about the medical effects of H2 within the past 15 years. However, we have unknowingly benefited from H2 since the dawn of time, from H2-producing bacteria to the use of naturally occurring hydrogen-rich waters. Moreover, the first writings on the therapeutic effects of H2 date to around 1793. Since then, papers appeared sporadically in the literature every few decades but never exploded until Ohsawa et al. again demonstrated hydrogen’s therapeutic effects in 2007. This landmark paper appears to have been the spark that ignited the medical interest in hydrogen. Although H2 was used in the 1880s to locate intestinal perforations, in the 1940s in deep sea diving, and in the 1960s to measure blood flow, H2 was largely viewed as biologically inert. This review highlights the history of hydrogen in the genesis/evolution of life and its medicinal and non-medicinal use in humans. Although hydrogen medicine has a long and erratic history, perhaps future history will show that, this time around, these 15 years of ignited interest resulted in a self-sustaining explosion of its unique medical effects.

1. Introduction

Molecular hydrogen (H2 gas) is well known for its many industrial uses [1,2], and has been essentially considered to be biologically inert, as well as being relatively insoluble. However, recent biomedical research shows that hydrogen has great potential as a therapeutic molecule [3]. Although the research is still in its relative infancy, over 1300 publications suggest that it has potential therapeutic effects in over 170 different human and animal disease models, and in essentially every organ of the human body [4]. Although it is already known that other gases, such nitric oxide [5] hydrogen sulfide [6], and carbon monoxide [7] have significant biological effects, hydrogen gas came to the forefront of medical gas research in 2007, when an article published in Nature Medicine [8] demonstrated its neuroprotective effects following middle cerebral artery occlusion. Fewer than 50 articles were published regarding hydrogen as potential medical gas pre-2007, compared to over 2000 articles within the past 12 years. Figure 1 illustrates this rather exponential increase in publications on molecular hydrogen. However, the primary targets and molecular mechanisms of hydrogen gas remain elusive [9].

2. Hydrogen History

There appear to be five different areas involving hydrogen research that converged following the announcement of Oshawa et al. in 2007 [8] that molecular hydrogen could exert positive biological effects. These areas include the uses of hydrogen in (i) the genesis and evolution of life, (ii) humans for non-medicinal purposes, (iii) natural “miracle” waters, (iv) electrolyzed reduced water, and (v) therapeutic and medical applications. Figure 2 shows an annotated timeline regarding hydrogen history.

3. Hydrogen in the Genesis and Evolution of Life and Effects in Plants

3.1. Hydrogen Chemistry

Hydrogen in the atomic form is the simplest element, consisting of only one electron and one proton, but it exists primarily in its diatomic form (H2). It is a tasteless, odorless, colorless, and non-toxic nonmetallic gas [10]. Hydrogen is at the center of the prevailing cosmological model that describes the early development of the universe [11] as well as the origin of life itself [12,13].
By fusion hydrogen is converted into helium, which then undergoes the triple-α process to form the lightest biogenic element, carbon. Biologically relevant elements, such as oxygen, nitrogen, sulfur, and phosphorus, as well as the other elements, were formed in a similar manner. In an exothermic reaction, hydrogen reduces these elements to form the important molecules ammonia (NH3), methane (CH4), water (H2O), cyanide (HCN), and hydrogen sulfide (H2S) [14]. Indeed, hydrogen can be considered to be the ancestor of not only the elements of the universe but also the molecules of life.
Hydrogen has rich chemistry and can readily participate in oxidation–reduction reactions (e.g., hydride transfer, electron acceptor or donor with dehydrogenases, and hydrogenation of alkenes in the presence of a catalyst), and is central to the definition of Brønsted–Lowry acid–base reactions (i.e., donating a hydrogen cation, “H+”, or accepting one to be an acid or a base, respectively).
Molecular hydrogen is the most energy dense molecule by mass in the universe, being over three times more energy dense than gasoline [15]. It is interesting that given the fact that a ratio between oxidation and reduction is required for the existence of life, that the two elements that characterize these extremes are oxygen and hydrogen, which react together to produce the universal solvent H2O, which allows life to exist.
Over the years much attention has been given to oxygen, both in its role for life and in its role for death by forming cytotoxic reactive oxygen species (ROS) [16]. ROS have been implicated in the pathogenesis and progression of virtually every disease [17]. Nevertheless, research also shows that ROS existence is pivotal for normal cellular function, cell signaling, protein folding, cell proliferation, etc. [18]. Thus, it is the dysregulation of ROS, too much or too little, that is the problem [19]. This can lead to conditions referred to oxidative stress (too much oxidation) or the opposite, i.e., reductive stress [20]. The intracellular redox activity is therefore a balance, impinged upon by the accumulation of ROS, and maintained by redox active molecules such as glutathione (as in the GSH:GSSG couple). Perturbation of this redox balance can lead to disease or cell death, often through apoptotic pathways [21]. It is into this complex web of redox molecules that H2 must fit if it has effects on biological systems.

3.2. Hydrogen and Genesis and Evolution of Life

Cellular redox homeostasis is maintained by various dehydrogenase enzymes [22]. The Ni/Fe hydrogen dehydrogenase (hydrogenase) enzyme can catalyze the reversible oxidation of hydrogen gas (H2 ↔ 2H+ +2e). It is amongst the oldest enzymes (3.8 billion years old), which demonstrates that life had to develop a way to activate molecular hydrogen at ambient temperature and pH [23]. Perhaps this ability was needed to help maintain the balance between oxidation and reduction [24,25,26]. As an example, generation of H2 and the concomitant reduction of oxidation are important for the survival of Klebsiella pneumonia in the oral cavity [27].
Furthermore, according to the various theories of eukaryotic genesis (e.g., endosymbiotic theory, hydrogen hypothesis, etc., which involve hydrogenases, hydrosomes, and mitochondria), hydrogen has been intimately involved throughout the origins and evolution of life [12,28]. Perhaps hydrogen gas served as a signaling molecule in these early organisms, and, although they lost their ability to produce hydrogen gas, some of hydrogen’s targets and functions are conserved [29]. Although humans lack the hydrogenase enzyme, recent research shows that hydrogenases are ubiquitously distributed among many lower eukaryotes [30]. Indeed, genes that bear the hallmark signature of the Fe–hydrogenase are found in the genomes of higher eukaryotes including humans [30]. The presence of basal levels of hydrogen in the human body may suggest that it has a physiological role [31]. The adoption of what would be commonly available molecules in the early evolution of life, some of which would have even been toxic, into the normal signaling roles in cells has been noted for ROS and reactive nitrogen species such as nitric oxide [32], so it is not much a leap to suggest that hydrogen was also adopted for positive uses.
It is likely that if hydrogen gas were completely removed, then the physiological significance of hydrogen gas would also be lost; however, due to the presence of certain bacteria, neither hydrogen gas nor its molecular targets may have been fully eliminated. Indeed, many plants, insects, animals, and humans have developed a mutualistic relationship with hydrogen-producing bacteria [33,34,35,36]. If this hypothesis is true, then exogenous hydrogen should still exert a biological effect on those organisms.

3.3. Hydrogen in Plants and Agriculture

As already discussed, many, insects, animals, and humans have developed a mutualistic relationship with hydrogen-producing bacteria [33,36], and plants too seem to be affected by the presence of H2. It has recently been found that exogenous hydrogen exerts a protective effect on a number of different plants including alfalfa [37], arabidopsis [38], cucumber [39], rice [40], and radish sprouts [41].
Preliminary evidence was reported that the plasma membrane vesicles of Vigna radiata hypocotyls and Capsicum annuum stems can both oxidize and produce molecular hydrogen [42]. A proposed “hydrogenase-like complex” in the plasma membrane may act as an electron/proton donor by oxidation of H2 or an electron/proton acceptor by producing H2. It is postulated that this function might help to maintain the plant redox homeostasis, and the observed effects of H2 on plants may be mediated by a bidirectional H2 metabolism activity [42].
Despite the unknown exact molecular mechanisms of molecular hydrogen in plants, the beneficial effects have continued to be reported. In a review article [43], we summarized some of the studies showing that the treatment of plants and plant products with H2 alleviates plant stress and slows crop senescence. Many of these effects appear to be mediated by the alteration of the antioxidant capacity of plant cells [43]. More recently, reviews of the use of H2 in agriculture as well as in postharvest storage have appeared [43,44,45], and the number of papers on hydrogen effects in plants has escalated (Figure 3).

4. Hydrogen Use in Humans for Non-Medicinal Purposes

There are six primary practices involving hydrogen gas and humans that have been occurring for many years, without always acknowledging hydrogen as a medically or biologically active gas.

4.1. Biodegradable Implants

In 1878, magnesium metal gained attention in the orthopedic and biomedical engineering fields as a promising candidate for biodegradable implants, such as wires, plates, sheets, rods, screws, and pegs [47]. The magnesium implantation slowly dissolves in the body releasing hydrogen gas and magnesium ions (Mg + 2H2O → Mg(OH)2 + H2). Magnesium alloy implants are still being researched today [47,48,49]. Perhaps a previously unknown benefit of these implants is the release of hydrogen gas [50], which may help explain the regeneration of nerves and only mild inflammation of tissues [49]. Indeed, magnesium-based implants have been shown to have anti-tumor activity by inducing the p53-mediated lysosome–mitochondria apoptosis signaling pathway [51].

4.2. Bodily Wounds

Molecular hydrogen was used in 1888 to locate penetrating wounds (i.e., gunshot and knife wounds) in the gastro-intestinal tract by rectal insufflation [52,53]. This was a major medical advancement because if there was a penetrating wound of the GI tract, then it was inevitably fatal unless treated by suture. However, confirming that there really was a hole was risky. Dr. Senn who developed this method of using H2 gas reasoned that a wound in the GI tract should be located in the same method as how a plumber locates a leak in a pipe. Dr. Senn performed several animal and human experiments showing the efficacy and safety of this method. He observed that it is more difficult to inflate the alimentary canal from the mouth to the anus compared from the anus to the mouth. The technique involved injecting H2 from an elastic syringe connected to a balloon full of hydrogen gas. The inflation was traceable by percussion and manipulation. Rectal insufflation would cause gas bubbles to accumulate outside of the intestines around the wound. In order to prove that the bubbles were from the H2, the surgeon would then light a match and ignite the hydrogen. There would be a slight explosive effect and would then burn with a characteristic blue flame. The burning of the hydrogen gas was encouraged for diagnostic and aseptic purposes. Rectal insufflation of hydrogen gas was shown to be an infallible test in every instance when the apparatus was working correctly. It was also noted that hydrogen gas was devoid of any toxic properties, and it was nonirritating when in contact with the most sensitive tissues [53].

4.3. Diving

In 1941, it was shown that breathing a 97% hydrogen and 3% oxygen mixture at 10 atm was well tolerated and safe [54]. This resulted in the use of hydrogen in deep sea diving to prevent decompression sickness in 1943 by the Swedish Royal Navy [55,56] and has continued to be used since. Often a mixture of oxygen and helium (e.g., Heliox, Trimix [57]) is used for this purpose and is not flammable. However, despite its inherent flammability, since H2 is the lightest gas, half the weight of helium and less narcotic, it is a viable alternative to conventional diving gases. For example, hydreliox is a breathing gas mixture of hydrogen, helium, and oxygen [58]. In the case of very deep diving, Hydrox is used, which is a mixture of 96% hydrogen and 4% oxygen [59,60].
Because scuba diving increases oxidative stress [61], perhaps an additional and previously unknown benefit to using hydrogen in deep sea diving is its ability to reduce oxidative stress in these individuals [62]. Interestingly, hydrogen-rich saline was protective against decompression sickness in rats [63]. Diving would be an interesting model to further explore the effects of hydrogen on biological systems, if nothing else, to confirm hydrogen as a safe therapeutic agent.

4.4. Blood Flow

Hydrogen gas was again linked to medical applications in 1963 for the ease and accuracy in measuring local blood flow [64]. This concept has been used to study the blood flow of the cervix [65,66], gastric mucosa [67,68,69,70], kidneys [71,72], placenta and fetal tissue [73], liver [74], heart [75], spinal cord [76], pancreas [77,78], skin [79], and other uses [72,75,76,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111]. It would be interesting if, due to the cell modulating effects of hydrogen gas, use of this molecule in these types of studies produced unexpected effects. Of course, other medical gases, such as nitric oxide and H2S also have known effects on vasorelaxation and hence blood flow [112], with therapeutic agents being developed based on both of these molecules [113]. Again, the effects of H2 would need to fit into this complex regulatory mechanism.

4.5. Malabsorption

Hydrogen gas is also produced by intestinal bacteria upon fermentation of non-digestible carbohydrates, which is estimated to be approximately 13.6 L/day [114]. Some of the hydrogen is removed by bacterial metabolism, about 14% is absorbed into the blood and exhaled via the lungs [115], and the rest is excreted as flatus [114]. However, the levels of H2 production can be much higher in conditions of carbohydrate malabsorption. Thus, at least as early as 1969, the breath level of hydrogen gas has been used as a diagnostic indicator to test for carbohydrate malabsorption [116,117,118,119,120,121,122] and small intestinal bacterial overgrowth [123,124]. This type of testing is still commonly done today. Unfortunately, since increased breath hydrogen is diagnostically associated with an unfavorable condition, it might seem counterintuitive to realize that H2 from intestinal bacteria also has many benefits [125], as discussed later (see: Section 7). However, it is interesting to note that increased levels of breath hydrogen gas may contribute to the longevity of Japanese centenarians [126].

4.6. Detecting Achlorhydria

Achlorhydria is the absence or reduction of hydrochloric acid in the digestion system, and as such can lead to a variety of medical conditions. Low stomach acid also results in impaired digestion including decreased absorption of certain vitamins, minerals, and nutrients, as well as increased propensity for digestive tract infections. In 1985, hydrogen gas production was used to assess achlorhydria by having patients ingest 10 to 200 mg of elemental magnesium and measuring the breath hydrogen produced by the reaction Mg + 2HCl → MgCl2 + H2 [127,128,129,130].

5. Hydrogen in Natural “Healing” or “Curative” Spring Waters

The easiest and often most effective method for hydrogen administration is simply ingesting water containing dissolved hydrogen gas [131], referred to as hydrogen-rich water, making the water have potential medicinal-like properties.
The idea of “curative waters” seems to be prevalent throughout the history of mankind, including the writings of Hippocrates [132] and Herodotus with the concept of the Fountain of Youth [133]. Although much of the sentiments surrounding these so-called “healing waters” is that of folklore, magic, and pseudoscience [134], there are many cases where these waters have been scientifically documented to have therapeutic effects due to the water containing important constituents that many people were lacking (e.g., minerals) [135,136,137]; as well as gaseous hydrogen sulfide [6].
Investigations of some “curative waters” (e.g., Nordenau, Germany; Tlacote, Mexico; Hita Tenryosui, Japan; Nadone, India, etc.) have been reported to indeed exert therapeutic effects [138,139,140]. Intriguingly, there are reports that some of these waters contain small levels of dissolved molecular hydrogen [138,140,141,142,143,144]. In the late 1990s and early 2000s, a few procedural observational studies were performed on hundreds of diabetic patients who drank these claimed natural healing waters. The preliminary reports show that the patients had reduced levels of cholesterol, glucose, glycated hemoglobin (HbA1c), oxidative stress, serum creatinine, blood pressure, and exhibited other physiological health improvements [145,146,147,148,149,150,151]. After the realization that molecular hydrogen had therapeutic effects, it was conjectured that observed benefits from these so-called “curative waters” were due to the natural dissolved hydrogen in these waters [140].
The presence of molecular hydrogen in these waters may be a result of either abiotic origin (e.g., subsurface basalt-catalyzed water hydrolysis, serpentinization) [152,153,154], or biotic origin (e.g., hydrogen gas-producing bacteria) [155,156,157,158,159]. For example, H2 produced between basalt and groundwater in the Columbia River Basalt aquifer at 1.2 km depth may serve as the energy source for methanogens [154]. Indeed, H2-consuming methanogens thrive at depth of 200 m in Lidy Hot Springs, Idaho, USA [160]. Depending on the conditions of temperature and pressure, the concentration of hydrogen can range from >0.1 mM to well over 10 mM. This is significantly higher than normal saturation at standard ambient temperature and pressure (i.e., 0.8 mM) [161]. However, although it is possible that the mentioned waters have molecular hydrogen, there is no credible evidence or details regarding their concentration. It is, therefore, unclear if these waters truly do (or did) contain clinically meaningful dissolved levels of molecular hydrogen [162]. It may be worth revisiting some of these potential spring waters using modern assaying techniques to ascertain if hydrogen is an active molecule accounting for any effects reported.

6. Hydrogen in Alkaline Ionized Water

The generation of hydrogen from electricity was accomplished as early as 1789 by Van Troostwijk and Deiman using an electrostatic generator [163]. Shortly after, Nicholson and Carlisle reported that an electrical current from the voltaic pile (the first battery) could induce the decomposition of water into hydrogen and oxygen (i.e., electricity + 2H2O → H2(g) + O2(g)), a process called water electrolysis [164]. The hydrogen gas is formed at the cathode via proton (H+) reduction (2 H+(aq) + 2e → H2(g)), and oxygen gas is formed at the anode by oxidation of hydroxide ions (2 H2O(l) → O2(g) + 4 H+(aq) + 4e) [164]. A semi-permeable membrane that is impermeable to H+ and OH ions separates the anode from the cathode electrodes. The water at the cathode is alkaline and contains hydrogen gas, whereas the anode is acidic and contains oxygen gas (and often chlorine species due to voltage overpotential, which makes chloride ions more favorably discharged). Water produced at the cathode was referred to as “electrolyzed reduced water” (ERW) [138]. ERW has an alkaline pH, a negative oxidation reduction potential (ORP), and contains various levels of dissolved H2 gas.
ERW research started in Japan in 1931 where it is was initially applied to agriculture [140], and over the decades started to be viewed as beneficial for human consumption. Clinical studies were conducted to demonstrate safety so that these devices could be sold to the public. In 1965, under the Pharmaceutical Affairs Law, the Japanese Ministry of Health, Labor and Welfare approved these water electrolysis devices as safe and to be helpful with a variety of gastrointestinal symptoms [138,165,166,167]. However, as ERW became more popular, especially in the 1980s, anecdotal health claims continued to grow, which promoted investigative research in the 1990s [168]. Many cellular and animal studies confirmed that ERW had beneficial actions including antioxidant and anti-inflammatory effects [168]. However, it was not fully confirmed until after 2007 that molecular hydrogen was the exclusive agent in ERW responsible for these beneficial effects [168]. For the majority of ERW history, the involvement of molecular hydrogen was disregarded because H2 was considered to be a biologically inert byproduct of electrolysis. Unfortunately, with no mechanistic explanation for why/how ERW is exerting these biological benefits, it becomes difficult to accept, and even more difficult to sell to customers. Regrettably, this contributed to a plethora of pseudoscientific conjectures used to explain the observed benefits of ERW. Some of these claims include (i) the alkaline pH to neutralize toxic waste, (ii) increased oxygen to energize the cells, (iii) altered water structure (e.g., microclusters) to increase cellular hydration, and (iv) a negative oxidation–reduction potential ORP indicating an antioxidant effect, but attributed to ideas such as solvated electrons, atomic hydrogen radicals, negative hydrogen ions, mineral hydrides, hydroxide ions, etc. [168].
As research on and interest in ERW continued, each claim was scrutinized and/or investigated, and one by one refuted until finally it was determined that hydrogen gas was the exclusive agent responsible for both the negative ORP [169] and the therapeutic effects [168]. Many articles have demonstrated that when H2 gas is removed from ERW the therapeutic benefits are eliminated, as has been extensively reviewed [168]. Thus, despite benefits from ERW being observed at least as early as 1931, it was not known for over a half a century that these benefits were due to hydrogen gas. In fact, the majority of the early ERW articles did not report the concentration of H2, which is a standard procedure now [168]. Unfortunately, many ERW proponents still do not recognize the importance of molecular hydrogen and continue promulgating some of the scientifically implausible and scientifically refuted concepts to explain ERW instead of focusing on the simplicity of molecular hydrogen [168]. Importantly, many electrolysis devices and new hydrogen water technologies have now been developed that focus on producing high concentrations of molecular hydrogen without altering the pH [170]. These new technologies circumvent the potential safety concerns with ERW as well as the unique conditions that ERW devices require to make clinically relevant concentrations of dissolved H2 [170].

7. Hydrogen in Therapeutic and Medical Applications

One of the earliest reports that hydrogen has medicinal properties was in the summer of 1793 by Thomas Beddoes (1760–1808), in a public letter he wrote to Erasmus Darwin, Charles Darwin’s grandfather: A letter to Erasmus Darwin, M.D. on a new method of treating pulmonary consumption, and some other diseases hitherto found incurable. Beddoes was working at the Medical Pneumatic Institute in Bristol, UK. However, this paper was of limited scope.
In 1798 the Italian (from Naples) physicist Tiberius Cavallo (1749–1809), who moved to London in 1779, wrote a much longer treatise on his investigations on respiration: An essay on the medicinal properties of factitious air. With an Appendix, on the Nature of Blood. [171]. In this he discusses the therapeutic use of hydrogen. He reports that inhaling the hydrogen produced by the reaction of vitriolic acid (sulfuric acid) and iron is beneficial for inflammation of the lungs, coughs, and other disorders related to inflammation. He reported that in conditions where there is “tightness about the regions of the lungs and a hard cough”, that a significant and “almost instantaneous relief has been frequently obtained by breathing a mixture of 4 quarts of hydrogen and 20 quarts of common air.” [171].
Similar work was carried out under the instruction of Beddoes in Bristol by Humphry Davy (1778–1829: famous for the invention of the mining safety lamp, the Davy Lamp). In 1800 Davy wrote a very long treatise on the effects of nitrous oxide, and even contemplated its anesthetic effects. It was entitled Researches, Chemical and Philosophical; chiefly concerning nitrous oxide, or dephlogisticated nitrous air, and its respiration. As a “control” Davy used a variety of gases, including hydrogen which he compared to nitrous oxide (N2O). He used his gases including hydrogen on a range of organisms, including several mammals, insects, amphibians, fish, snails, and worms, in what by today’s standards would be considered inappropriate experiments. He also performed a wide range of self-experimentation, and gave his gases to friends and patients, some of whom were famous and renowned people. For more details of what Beddoes, Cavallo, and Davy said in their papers, see our “sister” review [Hancock and LeBaron: N.B. paper has been accepted, waiting for ref].
It was not until 1975 that the potential medical benefits of H2 were again investigated, this time as a hyperbaric hydrogen treatment for skin cancer in mice [172]. Dole and colleagues of Baylor University and Texas A&M reported in the journal Science the significant positive biological effects of hyperbaric hydrogen treatment on skin cancer in mice [172]. However, in 1978, Roberts from the Southern Research Institute of Birmingham, Alabama was unable to recapture these remarkable results using solid transplantable tumors in mice [109].
In 1988, Neale presented a hypothesis that intestinal hydrogen gas produced via intestinal bacteria could be an effective antioxidant based on its standard reduction potential [173]. Nearly 20 years later the protective effects of hydrogen via intestinal microbiota were verified by a report from the Forsyth Institute in Boston MA and the University of Florida [174]. They found that reconstitution of intestinal microbiota with H2-producing E. coli, but not H2-deficient mutant E. coli, was protective against Concanavalin A-induced hepatitis. Anti-diabetic drugs, α-glucosidase inhibitors [175,176], turmeric [177], and milk [178] increase breath hydrogen concentrations in humans. The α-glucosidase inhibitor, acarbose, has unidentified additional effects on prevention of cardiovascular disease and hypertension [176]. Turmeric has long been known to have therapeutic potential for many human diseases [179]. The effects of these compounds may be accounted for by bacterial production of H2. Additionally, ingestion of the dietary fiber pectin or high-amylose maize, which increases cecal hydrogen production, relieved ischemia-reperfusion injury in rats [180].
In 1996, David Jones wrote in the “Daedalus” column for Nature, described as one of the longest-running jokes on the scientific scene, about the benefits of hydrogen gas as an antioxidant against the hydroxyl radical and to help decrease inflammation. His parody continued about fictitious “DREADCO chemists” creating solubilized hydrogen beverages [181]. Many of the fictious ideas regarding hydrogen in this column have now ironically, and perhaps fortuitously, become reality.
Jones’s column about hydrogen prompted Gharib and colleagues in 2001, to examine the effect of two weeks of 70% hydrogen gas on a mouse model of schistosomiasis-associated chronic liver inflammation [182]. The mice exhibited improved hemodynamics, increased antioxidant enzyme activities, increased nitric oxide synthase II activity, and decreased fibrosis and tumor necrosis factor-α levels.
Despite these favorable effects, there was very little interest in the biomedical applications of H2, perhaps stemming from the fact that hyperbaric H2 therapy was not a clinically viable option. This, due to the fact that H2 gas is highly flammable in the presence of oxygen, which we obviously need to breath to sustain life. Thus, hydrogen therapy seemed clinically infeasible. However, the research increased exponentially after 2007, when Ohsawa and colleagues published their report in Nature Medicine [8]. They reported that a concentration of only 2–4% H2 gas (which is below the flammability level) significantly reduced the cerebral infarct volumes in a rat model of ischemia-reperfusion injury induced by a middle cerebral artery occlusion. The authors further demonstrated that dissolved hydrogen in the media of cultured cells, at biologically feasible concentrations, selectively reduced levels of toxic hydroxyl radicals (OH), but did not decrease other physiologically important reactive oxygen/nitrogen species (ROS/RNS) (e.g., superoxide, nitric oxide, hydrogen peroxide) [8]. Fifteen years later, the research on H2 gas has resulted in over 2000 publications on regarding its potential medical applications. Over 100 human studies show translational potential from animals to humans in a wide range of diseases. These include conditions such as metabolic syndrome [183,184], diabetes [185], hyperlipidemia [186], Parkinson’s disease [187], cognitive impairments [188], rheumatoid arthritis [189], chronic hepatitis B [190], vascular function [191], exercise performance [192,193], cerebral infarction [194], and others as reviewed previously [4,195]. In 2017, a clinical trial using inhalation of hydrogen gas was approved as an advanced medicine by the Ministry of Health, Labor, and Welfare of the Japanese for the treatment of post-cardiac arrest syndrome [196].
In 2019 the world was hit by a pandemic caused by the virus SARS-CoV-2, leading to a disease called COVID-19. Millions of people around the globe were affected. As of the end of February 2023, the World Health Organization (WHO) reported that there were 755,703,002 confirmed cases, and 6,836,825 deaths [https://covid19.who.int/ (accessed on 15 January 2023)]. Hydrogen treatment has been used in clinical trials for COVID-19, and used in hospitals in some regions, with positive effects [197,198].

8. Physicochemical Properties of Hydrogen

The molecular weight of hydrogen gas is the lowest of all molecules. It is hard to envisage how it would be recognized by a classical receptor mechanism, so there must be some other modes of action [199]. It will also not react with thiols in the classical way suggested for nitric oxide, H2S, and other ROS. It has a very high kinetic diffusivity and has the highest effusion rate. This makes storage of hydrogen gas or hydrogen water very difficult. Hydrogen can easily permeate plastic containers, and can cause hydrogen embrittlement in metals [200]. At room temperature, solubilized hydrogen at 0.78 mM has a half-life of approximately 2 h depending on the volume of water and the exposed surface area [201]. H2 will rapidly revert to the gas phase, meaning any enriched solution needs to be made and used fresh, which needs to be considered if used therapeutically or in agriculture [43].

9. Pharmacological Activities of Hydrogen

The pharmacological activities of hydrogen seem to be as diverse as there are numbers of conditions. Hydrogen modulates signal transduction, miRNA expression, protein phosphorylation cascades, and mitochondrial activity. However, the underlying molecular mechanisms and primary targets by which hydrogen exerts these pleotropic biological effects remains elusive. Although some of the effects are thought to be mediated by the hydroxyl radical scavenging capacity of H2, it is unlikely that all the effects are affected by this mechanism [195]. However, a recent study suggested that Fe–porphyrin, which is rich in mitochondria and erythrocytes, acts as a redox-related biosensor of H2 [202]. It also catalyzes the reaction of H2 with hydroxyl radicals, as well as with CO2 molecules to produce the gasotransmitter carbon monoxide, which is known to have profound therapeutic effects [202,203]. Recent research also points to the benefits of molecular hydrogen on the functional state of erythrocytes in a model of simulated chronic heart failure. It was found that in rats, inhalation of 2% H2 resulted in an increase in ATP and 2,3-bisphosphoglycerate, and consequently improved microcirculation and oxygen transport [204]. They also found that H2 administration decreased lipid peroxidation and increased levels of catalase [204]. The upregulation of endogenous antioxidants by molecular hydrogen has been frequently reported [195]. Specifically, H2 has been demonstrated to induce the translocation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf-2) into the nucleus [205]. The activation of the Nrf2/keap1 pathway and the downstream induction of heme-1 oxygenase play important roles in the antioxidant activities of molecular hydrogen [206]. Several other properties and interactions have been mooted for how H2 interacts with biological systems, including through its redox potential [199] or in a physical interaction which is akin to that of Xenon. Such mechanisms have recently been reviewed [207], but much more experimental work needs to be undertaken to support or confirm such actions of H2.

10. Methods of Administration

There are several methods for hydrogen gas administration, including inhalation of H2 gas [208], tube feeding of H2-rich solution [209], intravenous injection of H2-rich saline [210], H2-rich dialysis solution for hemodialysis [211], hyperbaric H2 chamber [172], bathing in H2-rich water [212], increasing H2 production by intestinal bacteria [213], topical application [214], oral ingestion of hydrogen-producing tablets [215], and simply drinking hydrogen-rich water (HRW) [183]. HRW can be prepared by bubbling H2 gas into water under pressure, electrolysis of water (2H2O → 2H2 + O2), and by reaction with metallic magnesium (Mg + 2H2O → H2 + Mg(OH)2) or other metals [195]. Several products from ready-to-drink beverages in aluminum pouches/cans [216] and electrolytic devices to H2-producing tablets and inhalation machines are readily available to consumers. However, not all products may produce/contain concentrations of H2 equivalent to or with the stability of those used in human studies [170].

11. Conclusions

Hydrogen as a medical therapy has been around for a very long time, often in situations where it was not realized that the presence of H2 was the active agent. The history of the impact of H2 on biological systems can probably be traced back to the writing of Hippocrates [132] and Herodotus with the concept of the Fountain of Youth [133]. However, the first evidence of experiments with H2 and medicine probably stem from the late 18th century. Thomas Beddoes seemed to be determined to bring the use of gases to the medical world, with the instigation of the Medical Pneumatic Institution. He published about hydrogen in 1793, for example. Perhaps it was fortuitous that he employed the brilliant Humphry Davy, but his work at the institute brought nitrous oxide (N2O) use to the forefront, despite it being known by Priestley previously, for example. Slightly before this, Tiberius Cavallo was working on respiration. Interestingly, both Cavallo and Davy used hydrogen, in what appears to be control experiments—or were they hoping hydrogen might be useful in its own right?
Regardless of the wide-ranging work, and very long papers by Cavallo and Davy, and indeed Beddoes [paper has been accepted, waiting for ref], very little traction was seen in the biological hydrogen world (the Medical Pneumatic Institution closed in 1802). H2 gas was found to be useful for diving in the 1940s, but its wider medical effects were largely ignored. In 1975, Dole et al. [172] brought hydrogen back into the literature, but it was not until 2007 [8] that many researchers took much notice of H2. Since then, it has been worked on by groups around the world and even used to aid people during the recent SARS-CoV-2 pandemic [197,198].
Despite the skepticism of people including David Jones in 1996, and the skepticism of the properties of spring waters and the pseudoscience surrounding its use, there is now a significant body of literature showing that H2 has positive medical effects [195], potentially useful for neurodegenerative diseases, diabetes, and even in sports to enhance performance and for helping in sports-induced injury [193].
There has been a rich, and a rather on and off history of hydrogen in medicine, but now in the 21st century it is time for this often overlooked molecule to take a more central stage and be considered for wider medical use. Perhaps this time the interest in the medical effects of H2 will not wane as it has through history.

Author Contributions

T.W.L. conceived this paper and wrote the first draft. J.T.H. contributed ideas and edited the manuscript. K.O. revised the original draft and edited the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

The works presented in this article were partially supported by Grants-in-Aid from the Japan Agency for Medical Research and Development (JP21gm1010002).

Acknowledgments

JTH acknowledges the access of literature through the UWE library services.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Ramachandran, R. An overview of industrial uses of hydrogen. Int. J. Hydrogen Energy 1998, 23, 593–598. [Google Scholar] [CrossRef]
  2. Nakamura, D.N. Hydrogen, What a Gas. Hydrocarb. Process. 1993, 72, 23. [Google Scholar]
  3. Ohta, S. Molecular hydrogen as a preventive and therapeutic medical gas: Initiation, development and potential of hydrogen medicine. Pharmacol. Ther. 2014, 144, 1–11. [Google Scholar] [CrossRef] [Green Version]
  4. Ichihara, M.; Sobue, S.; Ito, M.; Ito, M.; Hirayama, M.; Ohno, K. Beneficial biological effects and the underlying mechanisms of molecular hydrogen—Comprehensive review of 321 original articles. Med. Gas Res. 2015, 5, 12. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Palmer, R.M.; Ferrige, A.; Moncada, S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987, 327, 524–526. [Google Scholar] [CrossRef] [PubMed]
  6. Olson, K.R. The therapeutic potential of hydrogen sulfide: Separating hype from hope. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2011, 301, R297–R312. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Meng, C.; Ma, L.; Niu, L.; Cui, X.; Liu, J.; Kang, J.; Liu, R.; Xing, J.; Jiang, C.; Zhou, H. Protection of donor lung inflation in the setting of cold ischemia against ischemia-reperfusion injury with carbon monoxide, hydrogen, or both in rats. Life Sci. 2016, 151, 199–206. [Google Scholar] [CrossRef] [PubMed]
  8. Ohsawa, I.; Ishikawa, M.; Takahashi, K.; Watanabe, M.; Nishimaki, K.; Yamagata, K.; Katsura, K.; Katayama, Y.; Asoh, S.; Ohta, S. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat. Med. 2007, 13, 688–694. [Google Scholar] [CrossRef]
  9. Dixon, B.J.; Tang, J.; Zhang, J.H. The evolution of molecular hydrogen: A noteworthy potential therapy with clinical significance. Med. Gas Res. 2013, 3, 10. [Google Scholar] [CrossRef] [Green Version]
  10. Huang, C.S.; Kawamura, T.; Toyoda, Y.; Nakao, A. Recent advances in hydrogen research as a therapeutic medical gas. Free Radic. Res. 2010, 44, 971–982. [Google Scholar] [CrossRef]
  11. Black, J.H. Chemistry and cosmology. Faraday Discuss. 2006, 133, 27–32, discussion 83–102, 449–152. [Google Scholar] [CrossRef] [PubMed]
  12. Martin, W.; Muller, M. The hydrogen hypothesis for the first eukaryote. Nature 1998, 392, 37–41. [Google Scholar] [CrossRef] [PubMed]
  13. Huber, C.; Wachtershauser, G. alpha-Hydroxy and alpha-amino acids under possible Hadean, volcanic origin-of-life conditions. Science 2006, 314, 630–632. [Google Scholar] [CrossRef] [PubMed]
  14. Ehrenfreund, P.; Irvine, W.; Becker, L.; Blank, J.; Brucato, J.R.; Colangeli, L.; Derenne, S.; Despois, D.; Dutrey, A.; Fraaije, H.; et al. Astrophysical and astrochemical insights into the origin of life. Rep. Prog. Phys. 2002, 65, 1427–1487. [Google Scholar] [CrossRef] [Green Version]
  15. Jain, I.P. Hydrogen the fuel for 21st century. Int. J. Hydrogen Energy 2009, 34, 7368–7378. [Google Scholar] [CrossRef]
  16. Hamanaka, R.B.; Chandel, N.S. Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes. Trends Biochem. Sci. 2010, 35, 505–513. [Google Scholar] [CrossRef] [Green Version]
  17. Beckman, K.B.; Ames, B.N. The free radical theory of aging matures. Physiol. Rev. 1998, 78, 547–581. [Google Scholar] [CrossRef] [Green Version]
  18. Dickinson, B.C.; Chang, C.J. Chemistry and biology of reactive oxygen species in signaling or stress responses. Nat. Chem. Biol. 2011, 7, 504–511. [Google Scholar] [CrossRef] [Green Version]
  19. Finkel, T. Signal transduction by reactive oxygen species. J. Cell Biol. 2011, 194, 7–15. [Google Scholar] [CrossRef] [Green Version]
  20. Rajasekaran, N.S.; Varadharaj, S.; Khanderao, G.D.; Davidson, C.J.; Kannan, S.; Firpo, M.A.; Zweier, J.L.; Benjamin, I.J. Sustained activation of nuclear erythroid 2-related factor 2/antioxidant response element signaling promotes reductive stress in the human mutant protein aggregation cardiomyopathy in mice. Antioxid. Redox Signal. 2011, 14, 957–971. [Google Scholar] [CrossRef] [Green Version]
  21. Hancock, J.T.; Desikan, R.; Neill, S.J. Cytochrome c, glutathione, and the possible role of redox potentials in apoptosis. Ann. N. Y. Acad. Sci. 2003, 1010, 446–448. [Google Scholar] [CrossRef] [PubMed]
  22. Marchitti, S.A.; Chen, Y.; Thompson, D.C.; Vasiliou, V. Ultraviolet radiation: Cellular antioxidant response and the role of ocular aldehyde dehydrogenase enzymes. Eye Contact Lens 2011, 37, 206–213. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Happe, R.P.; Roseboom, W.; Pierik, A.J.; Albracht, S.P.; Bagley, K.A. Biological activation of hydrogen. Nature 1997, 385, 126. [Google Scholar] [CrossRef] [PubMed]
  24. Lloyd, D.; Ralphs, J.R.; Harris, J.C. Giardia intestinalis, a eukaryote without hydrogenosomes, produces hydrogen. Microbiology 2002, 148, 727–733. [Google Scholar] [CrossRef] [Green Version]
  25. Shirahata, S.; Kabayama, S.; Nakano, M.; Miura, T.; Kusumoto, K.; Gotoh, M.; Hayashi, H.; Otsubo, K.; Morisawa, S.; Katakura, Y. Electrolyzed-reduced water scavenges active oxygen species and protects DNA from oxidative damage. Biochem. Biophys. Res. Commun. 1997, 234, 269–274. [Google Scholar] [CrossRef]
  26. Nie, W.; Tang, H.; Fang, Z.; Chen, J.; Chen, H.; Xiu, Q. Hydrogenase: The next antibiotic target? Clin. Sci. 2012, 122, 575–580. [Google Scholar] [CrossRef] [Green Version]
  27. Kanazuru, T.; Sato, E.F.; Nagata, K.; Matsui, H.; Watanabe, K.; Kasahara, E.; Jikumaru, M.; Inoue, J.; Inoue, M. Role of hydrogen generation by Klebsiella pneumoniae in the oral cavity. J. Microbiol. 2010, 48, 778–783. [Google Scholar] [CrossRef]
  28. Hackstein, J.H.; Akhmanova, A.; Boxma, B.; Harhangi, H.R.; Voncken, F.G. Hydrogenosomes: Eukaryotic adaptations to anaerobic environments. Trends Microbiol. 1999, 7, 441–447. [Google Scholar] [CrossRef]
  29. Embley, T.M.; van der Giezen, M.; Horner, D.S.; Dyal, P.L.; Bell, S.; Foster, P.G. Hydrogenosomes, mitochondria and early eukaryotic evolution. IUBMB Life 2003, 55, 387–395. [Google Scholar] [CrossRef]
  30. Horner, D.S.; Heil, B.; Happe, T.; Embley, T.M. Iron hydrogenases--ancient enzymes in modern eukaryotes. Trends Biochem. Sci. 2002, 27, 148–153. [Google Scholar] [CrossRef]
  31. George, J.F.; Agarwal, A. Hydrogen: Another gas with therapeutic potential. Kidney Int. 2010, 77, 85–87. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Hancock, J.T. Harnessing Evolutionary Toxins for Signaling: Reactive Oxygen Species, Nitric Oxide and Hydrogen Sulfide in Plant Cell Regulation. Front. Plant Sci. 2017, 8, 189. [Google Scholar] [CrossRef] [Green Version]
  33. Ballor, N.R.; Leadbetter, J.R. Analysis of extensive [FeFe] hydrogenase gene diversity within the gut microbiota of insects representing five families of Dictyoptera. Microb. Ecol. 2012, 63, 586–595. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Tanabe, H.; Sasaki, Y.; Yamamoto, T.; Kiriyama, S.; Nishimura, N. Suppressive Effect of High Hydrogen Generating High Amylose Cornstarch on Subacute Hepatic Ischemia-reperfusion Injury in Rats. Biosci. Microbiota Food Health 2012, 31, 103–108. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Ley, R.E.; Peterson, D.A.; Gordon, J.I. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 2006, 124, 837–848. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Maimaiti, J.; Zhang, Y.; Yang, J.; Cen, Y.P.; Layzell, D.B.; Peoples, M.; Dong, Z. Isolation and characterization of hydrogen-oxidizing bacteria induced following exposure of soil to hydrogen gas and their impact on plant growth. Environ. Microbiol. 2007, 9, 435–444. [Google Scholar] [CrossRef]
  37. Cui, W.; Fang, P.; Zhu, K.; Mao, Y.; Gao, C.; Xie, Y.; Wang, J.; Shen, W. Hydrogen-rich water confers plant tolerance to mercury toxicity in alfalfa seedlings. Ecotoxicol. Environ. Saf. 2014, 105, 103–111. [Google Scholar] [CrossRef]
  38. Xie, Y.; Mao, Y.; Zhang, W.; Lai, D.; Wang, Q.; Shen, W. Reactive Oxygen Species-Dependent Nitric Oxide Production Contributes to Hydrogen-Promoted Stomatal Closure in Arabidopsis. Plant Physiol. 2014, 165, 759–773. [Google Scholar] [CrossRef] [Green Version]
  39. Lin, Y.; Zhang, W.; Qi, F.; Cui, W.; Xie, Y.; Shen, W. Hydrogen-rich water regulates cucumber adventitious root development in a heme oxygenase-1/carbon monoxide-dependent manner. J. Plant Physiol. 2014, 171, 1–8. [Google Scholar] [CrossRef]
  40. Xu, S.; Zhu, S.; Jiang, Y.; Wang, N.; Wang, R.; Shen, W.; Yang, J. Hydrogen-rich water alleviates salt stress in rice during seed germination. Plant Soil 2013, 370, 47–57. [Google Scholar] [CrossRef]
  41. Su, N.; Wu, Q.; Liu, Y.; Cai, J.; Shen, W.; Xia, K.; Cui, J. Hydrogen-rich water reestablishes ROS homeostasis but exerts differential effects on anthocyanin synthesis in two varieties of radish sprouts under UV-A irradiation. J. Agric. Food Chem. 2014, 62, 6454–6462. [Google Scholar] [CrossRef] [PubMed]
  42. Zhang, X.; Xie, F.; Zhang, Z.; Adzavon, Y.M.; Su, Z.; Zhao, Q.; LeBaron, T.W.; Li, Q.; Lyu, B.; Liu, G.; et al. Hydrogen Evolution and Absorption Phenomena in the Plasma Membrane of Vigna radiata and Capsicum annuum. J. Plant Growth Regul. 2022, 42, 249–259. [Google Scholar] [CrossRef]
  43. Hancock, J.T.; LeBaron, T.W.; May, J.; Thomas, A.; Russell, G. Molecular Hydrogen: Is This a Viable New Treatment for Plants in the UK? Plants 2021, 10, 2270. [Google Scholar] [CrossRef] [PubMed]
  44. Hancock, J.T.; Russell, G.; Stratakos, A.C. Molecular Hydrogen: The Postharvest Use in Fruits, Vegetables and the Floriculture Industry. Appl. Sci. 2022, 12, 10448. [Google Scholar] [CrossRef]
  45. Cai, C.; Zhao, Z.; Zhang, Y.; Li, M.; Li, L.; Cheng, P.; Shen, W. Molecular Hydrogen Improves Rice Storage Quality via Alleviating Lipid Deterioration and Maintaining Nutritional Values. Plants 2022, 11, 2588. [Google Scholar] [CrossRef]
  46. Xie, Y.; Mao, Y.; Lai, D.; Zhang, W.; Shen, W. H(2) enhances arabidopsis salt tolerance by manipulating ZAT10/12-mediated antioxidant defence and controlling sodium exclusion. PLoS ONE 2012, 7, e49800. [Google Scholar] [CrossRef] [Green Version]
  47. Witte, F. The history of biodegradable magnesium implants: A review. Acta Biomater. 2010, 6, 1680–1692. [Google Scholar] [CrossRef]
  48. Kuhlmann, J.; Bartsch, I.; Willbold, E.; Schuchardt, S.; Holz, O.; Hort, N.; Hoche, D.; Heineman, W.R.; Witte, F. Fast escape of hydrogen from gas cavities around corroding magnesium implants. Acta Biomater. 2013, 9, 8714–8721. [Google Scholar] [CrossRef] [Green Version]
  49. Vennemeyer, J.J.; Hopkins, T.; Hershcovitch, M.; Little, K.D.; Hagen, M.C.; Minteer, D.; Hom, D.B.; Marra, K.; Pixley, S.K. Initial observations on using magnesium metal in peripheral nerve repair. J. Biomater. Appl. 2015, 29, 1145–1154. [Google Scholar] [CrossRef]
  50. Noviana, D.; Paramitha, D.; Ulum, M.F.; Hermawan, H. The effect of hydrogen gas evolution of magnesium implant on the postimplantation mortality of rats. J. Orthop. Transl. 2016, 5, 9–15. [Google Scholar] [CrossRef] [Green Version]
  51. Zan, R.; Wang, H.; Cai, W.; Ni, J.; Luthringer-Feyerabend, B.J.; Wang, W.; Peng, H.; Ji, W.; Yan, J.; Xia, J. Controlled release of hydrogen by implantation of magnesium induces P53-mediated tumor cells apoptosis. Bioact. Mater. 2022, 9, 385–396. [Google Scholar] [CrossRef] [PubMed]
  52. Senn, N. Rectal insufflation of hydrogen gas an infallible test in the diagnosis of visceral injury of the gastro intestinal canal in penetrating wounds of the abdomen. Read in the Section on Surgery, at the Thirty-ninth Annual Meeting of the American Medical Association, May, 9, 1888, and illuistrated by three experiments on dogs. J. Am. Med. Assoc. 1888, 10, 767–777. [Google Scholar]
  53. Pilcher, J.E. Senn on the Diagnosis of Gastro-Intestinal Perforation by the Rectal Insufflation of Hydrogen Gas. Ann. Surg. 1888, 8, 190–204. [Google Scholar] [CrossRef] [PubMed]
  54. Case, E.M.; Haldane, J.B. Human physiology under high pressure: I. Effects of Nitrogen, Carbon Dioxide, and Cold. J. Hyg. 1941, 41, 225–249. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Fahlman, A.; Kaveeshwar, J.A.; Tikuisis, P.; Kayar, S.R. Calorimetry and respirometry in guinea pigs in hydrox and heliox at 10-60 atm. Pflugers Arch. 2000, 440, 843–851. [Google Scholar] [CrossRef] [PubMed]
  56. Bjurstedt, H.; Severin, G. The prevention of decompression sickness and nitrogen narcosis by the use of hydrogen as a substitute for nitrogen, the Arne Zetterstrom method for deep-sea diving. Mil. Surg. 1948, 103, 107–116. [Google Scholar] [CrossRef] [PubMed]
  57. Brubakk, M.; Neuman, T.S. Bennett and Elliott’s Physiology and Medicine of Diving, Alf O. Respir. Care 2004, 49, 427. [Google Scholar]
  58. Abraini, J.H.; Gardette-Chauffour, M.C.; Martinez, E.; Rostain, J.C.; Lemaire, C. Psychophysiological reactions in humans during an open sea dive to 500 m with a hydrogen-helium-oxygen mixture. J. Appl. Physiol. 1994, 76, 1113–1118. [Google Scholar] [CrossRef]
  59. Fife, W. The Use of Non-Explosive Mixtures of Hydrogen and Oxygen for Diving. 1979. Available online: https://repository.library.noaa.gov/view/noaa/12070 (accessed on 15 January 2023).
  60. Kot, J. Extremely deep recreational dives: The risk for carbon dioxide (CO2) retention and high pressure neurological syndrome (HPNS). Int. Marit. Health 2012, 63, 49–55. [Google Scholar]
  61. Perovic, A.; Unic, A.; Dumic, J. Recreational scuba diving: Negative or positive effects of oxidative and cardiovascular stress? Biochem. Med. 2014, 24, 235–247. [Google Scholar] [CrossRef]
  62. Ohta, S. Molecular hydrogen is a novel antioxidant to efficiently reduce oxidative stress with potential for the improvement of mitochondrial diseases. Biochim. Biophys. Acta 2012, 1820, 586–594. [Google Scholar] [CrossRef] [PubMed]
  63. Ni, X.X.; Cai, Z.Y.; Fan, D.F.; Liu, Y.; Zhang, R.J.; Liu, S.L.; Kang, Z.M.; Liu, K.; Li, R.P.; Sun, X.J.; et al. Protective effect of hydrogen-rich saline on decompression sickness in rats. Aviat. Space Environ. Med. 2011, 82, 604–609. [Google Scholar] [CrossRef] [PubMed]
  64. Aukland, K.; Berliner, R.W.; Bower, B.F. Measurement of Local Blood Flow with Hydrogen Gas. Fed. Proc. 1963, 22, 218. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Klingenb, I.; Aukland, K. Measurement of Human Uterine Cervical Blood Flow by Local Hydrogen Gas Clearance. Acta Obstet. Gynecol. Scand. 1969, 48, 455–469. [Google Scholar] [CrossRef] [PubMed]
  66. Sakiyama, T. The cervical blood flow using hydrogen gas clearance method. Nihon Sanka Fujinka Gakkai Zasshi 1984, 36, 579–588. [Google Scholar]
  67. Kamata, T.; Hiratani, S.; Nakatani, M.; Kobayashi, K.; Yamamoto, S. Trial in determination of the blood flow of the gastric mucosa by a hydrogen gas clearance method--intragastric fixation of an improved electrode. Nihon Shokakibyo Gakkai Zasshi 1982, 79, 1643. [Google Scholar]
  68. Cheung, L.Y.; Sonnenschein, L.A. Measurement of regional gastric mucosal blood flow by hydrogen gas clearance. Am. J. Surg. 1984, 147, 32–37. [Google Scholar] [CrossRef]
  69. Ashley, S.W.; Cheung, L.Y. Measurements of gastric mucosal blood flow by hydrogen gas clearance. Am. J. Physiol. 1984, 247, G339–G345. [Google Scholar] [CrossRef]
  70. Leung, F.W.; Washington, J.; Kauffman, G.; Guth, P.H. Endoscopic Measurement of Gastric-Mucosal Blood-Flow by Hydrogen Gas Clearance in Conscious Dogs. Gastrointest. Endosc. 1984, 30, 150. [Google Scholar]
  71. Nissenkorn, I.; Kaspi, T.; Shalit, M.; Servadio, C. Use of hydrogen gas clearance for measurement of renal circulation. An experimental study. Urology 1983, 22, 525–528. [Google Scholar] [CrossRef]
  72. Leung, F.W. Endoscopic Measurement of Human Gastric-Mucosal Blood-Flow by Hydrogen Gas Clearance. Gastrointest. Endosc. 1988, 34, 206–207. [Google Scholar]
  73. Arai, T.; Yagi, Y.; Tsuru, A.; Izumi, R. Placental and Fetal Tissue Blood-Flow Measurement by Electrolytically Generated Hydrogen Gas Clearance Method. Clin. Exp. Hypertens. Part B-Hypertens. Pregnancy 1984, 3, 445. [Google Scholar]
  74. Gouma, D.J.; Coelho, J.C.; Schlegel, J.; Fisher, J.D.; Li, Y.F.; Moody, F.G. Estimation of hepatic blood flow by hydrogen gas clearance. Surgery 1986, 99, 439–445. [Google Scholar]
  75. Kawajiri, F.; Kawasuji, M.; Aoyama, T.; Sakakibara, N. Intraoperative Measurement of Myocardial Blood-Flow by Electrolytic Hydrogen Gas Clearance Method. Jpn. Circ. J.-Engl. Ed. 1986, 50, 464–465. [Google Scholar] [CrossRef]
  76. Harakawa, I.; Yano, T.; Sakurai, T.; Nishikimi, N.; Nimura, Y. Measurement of spinal cord blood flow by an inhalation method and intraarterial injection of hydrogen gas. J. Vasc. Surg. 1997, 26, 623–628. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Nishiwaki, H.; Satake, K.; Koh, I.; Nagai, Y.; Tanaka, H.; Umeyama, K. Pancreatic microcirculation of dogs measured by hydrogen gas generated by electrolysis. Pancreas 1986, 1, 324–329. [Google Scholar] [CrossRef]
  78. Nishiwaki, H.; Satake, K.; Ko, I.; Tanaka, H.; Kanazawa, G.; Nagai, Y.; Umeyama, K. Measurement of pancreatic microcirculation using hydrogen gas generated by electrolysis in dogs. Nihon Geka Gakkai Zasshi 1986, 87, 1443–1448. [Google Scholar]
  79. Nohara, S.; Nakamura, H.; Okada, A. Measurement of skin blood flow using inhaled hydrogen gas clearance method. Kokyu To Junkan 1986, 34, 771–776. [Google Scholar]
  80. Aukland, K.; Bower, B.F.; Berliner, R.W. Measurement of Local Blood Flow with Hydrogen Gas. Circ. Res. 1964, 14, 164–187. [Google Scholar] [CrossRef] [Green Version]
  81. Aukland, K.; Berliner, R.W. Renal Medullary Countercurrent System Studied with Hydrogen Gas. Circ. Res. 1964, 15, 430–442. [Google Scholar] [CrossRef] [Green Version]
  82. Ianchuk, P.I.; Palatnyi, T.P.; Rusinchuk Ia, I. Modification of electrode for regional mucose blood flow measurements with the aid of hydrogen gas clearance. Ross. Fiziol. Zh. Im. I. M. Sechenova 2005, 91, 1108–1110. [Google Scholar] [PubMed]
  83. Oohata, Y.; Mibu, R.; Hotokezaka, M.; Ikeda, S.; Nakahara, S.; Itoh, H. Comparison of blood flow assessment between laser doppler velocimetry and the hydrogen gas clearance method in ischemic intestine in dogs. Am. J. Surg. 1990, 160, 511–514. [Google Scholar] [CrossRef]
  84. Makino, T. Measurement of hepatic blood flow by the hydrogen gas clearance method. Experimental and clinical observations. Nihon Ika Daigaku Zasshi 1990, 57, 137–146. [Google Scholar] [CrossRef] [Green Version]
  85. Leung, F.W. Comparison of blood flow measurements by hydrogen gas clearance and laser Doppler flowmetry in the rat duodenum. Scand. J. Gastroenterol. 1990, 25, 429–434. [Google Scholar] [CrossRef] [PubMed]
  86. Metzger, H.P. The hydrogen gas clearance method for liver blood flow examination: Inhalation or local application of hydrogen? Adv. Exp. Med. Biol. 1989, 248, 141–149. [Google Scholar] [CrossRef] [PubMed]
  87. Leung, F.W. Intravenous Corticotropin Releasing-Factor Significantly Increases Duodenal Mucosal Blood-Flow Measured by Hydrogen Gas Clearance. Clin. Res. 1988, 36, A132. [Google Scholar]
  88. Kiyotaki, S. An experimental study on the tissue blood flow under hyperthermia in the normal rat bladder and bladder tumor--a hydrogen gas clearance method. Nihon Hinyokika Gakkai Zasshi 1988, 79, 287–296. [Google Scholar] [CrossRef] [Green Version]
  89. Eguchi, Y.; Enomoto, T.; Koji, T.; Morita, O. Measurement of blood flow rate of oral mucosa using the electrolytic regional blood flowmeter. Part 1. Studies on electrifying conditions and diffusion of hydrogen gas. Shigaku 1988, 76, 54–58. [Google Scholar]
  90. Soybel, D.I.; Wan, Y.L.; Ashley, S.W.; Yan, Z.Y.; Ordway, F.S.; Cheung, L.Y. Endoscopic Measurements of Canine Colonic Mucosal Blood-Flow Using Hydrogen Gas Clearance. Gastroenterology 1987, 92, 1045–1050. [Google Scholar] [CrossRef]
  91. Kawashima, H.; Sakamoto, W.; Nishijima, T.; Yasumoto, R.; Kobayakawa, H.; Umeda, M.; Maekawa, M. The local blood flow of the rabbit bladder measured by electrochemically generated hydrogen gas. Hinyokika Kiyo 1987, 33, 1603–1607. [Google Scholar]
  92. Iwamoto, K.; Watanabe, J.; Atsumi, F. Effects of urethane anesthesia and age on organ blood flow in rats measured by hydrogen gas clearance method. J. Pharmacobiodyn. 1987, 10, 280–284. [Google Scholar] [CrossRef] [PubMed]
  93. Gana, T.J.; Huhlewych, R.; Koo, J. Focal gastric mucosal blood flow by laser-Doppler and hydrogen gas clearance: A comparative study. J. Surg. Res. 1987, 43, 337–343. [Google Scholar] [CrossRef] [PubMed]
  94. Yoshida, M.; Ueda, S.; Machida, J.; Soejima, H.; Ikegami, K. Studies on the regional blood flow of the rabbit kidney by means of electrolytic hydrogen gas clearance method. Nihon Jinzo Gakkai Shi 1986, 28, 203–209. [Google Scholar] [PubMed]
  95. Washabau, R.J.; Strombeck, D.R.; Buffington, C.A.; Harrold, D. Use of Pulmonary Hydrogen Gas Excretion to Detect Carbohydrate Malabsorption in Dogs. J. Am. Vet. Med. Assoc. 1986, 189, 674–679. [Google Scholar]
  96. Leung, F.W.; Morishita, T.; Guth, P.H. Comparison of Reflectance Spectrophotometry with Invivo Microscopy and Hydrogen Gas Clearance. Gastroenterology 1986, 90, 1518. [Google Scholar]
  97. Aukland, K. Citation-Classic—Measurement of Local Blood-Flow with Hydrogen Gas. Cc/Life Sci. 1986, 20. [Google Scholar]
  98. Suzuki, S.; Isshiki, N.; Ogawa, Y.; Ohtsuka, M.; Nose, K.; Nishimura, R. Measurement of cutaneous blood flow by clearance of hydrogen gas generated by electrolysis. Ann. Plast. Surg. 1985, 15, 183–189. [Google Scholar] [CrossRef]
  99. Leung, F.W.; Guth, P.H.; Scremin, O.; Golanska, E.; Kauffman, G. Comparison of Blood-Flow Measurements by Aminopyrine Clearance, Hydrogen Gas Clearance and Electromagnetic Flow Probe in the Rabbit. Gastroenterology 1984, 86, 1160. [Google Scholar]
  100. Narita, H.; Kato, M.; Akimoto, K.; Miyashige, M.; Sekiguchi, H.; Fujino, Y.; Mikuniya, A.; Onodera, K. Evaluation for Effects of Partial Coronary-Occlusion and or Intravenous Nitroglycerin Administration on Transmural Distribution of Coronary Blood-Flow by Hydrogen Gas Clearance Method. Jpn. Circ. J. -Engl. Ed. 1983, 47, 993–994. [Google Scholar]
  101. Koshu, K.; Kamiyama, K.; Oka, N.; Endo, S.; Takaku, A.; Saito, T. Measurement of regional blood flow using hydrogen gas generated by electrolysis. Stroke 1982, 13, 483–487. [Google Scholar] [CrossRef] [Green Version]
  102. Ogata, K.; Whiteside, L.A.; Lesker, P.A. Subchondral route for nutrition to articular cartilage in the rabbit. Measurement of diffusion with hydrogen gas in vivo. J. Bone Joint Surg. Am. 1978, 60, 905–910. [Google Scholar] [CrossRef] [PubMed]
  103. Nordby, H.K.; Flood, S. A long term observation of local cerebral blood flow using the hydrogen gas clearance technique. Acta Neurochir. 1976, 35, 65–69. [Google Scholar] [CrossRef] [PubMed]
  104. Sem-Jacobsen, C.W.; Styri, O.B.; Mohn, E. Measurements in man of focal intracerebral blood flow around depth-electrodes with hydrogen gas. Prog. Brain Res. 1972, 35, 105–113. [Google Scholar] [CrossRef]
  105. Nakamura, T.; Suzuki, T.; Tsuiki, K.; Tominaga, S. Non-nutritional blood flow in skeletal muscle determined with hydrogen gas. Tohoku J. Exp. Med. 1972, 106, 135–145. [Google Scholar] [CrossRef] [Green Version]
  106. Gumbmann, M.R.; Williams, S.N.; Booth, A.N. The quantitative collection and determination of hydrogen gas from the rat and factors affecting its production. Proc. Soc. Exp. Biol. Med. 1971, 137, 1171–1175. [Google Scholar] [CrossRef] [PubMed]
  107. Aune, S. Transperitoneal exchange. II. Peritoneal blood flow estimated by hydrogen gas clearance. Scand. J. Gastroenterol. 1970, 5, 99–104. [Google Scholar] [CrossRef]
  108. Shinohara, Y.; Meyer, J.S.; Kitamura, A.; Toyoda, M.; Ryu, T. Measurement of cerebral hemispheric blood flow by intracarotid injection of hydrogen gas. Validation of the method in the monkey. Circ. Res. 1969, 25, 735–745. [Google Scholar] [CrossRef] [Green Version]
  109. Roberts, B.J.; Fife, W.P.; Corbett, T.H.; Schabel, F.M., Jr. Response of five established solid transplantable mouse tumors and one mouse leukemia to hyperbaric hydrogen. Cancer Treat. Rep. 1978, 62, 1077–1079. [Google Scholar]
  110. Ashikawa, K.; Inooka, E.; Yanagiya, T.; Kitaoka, S.; Ishide, N.; Isoyama, S.; Takishima, T.; Suzuki, N. Quantitative-Analysis of Heterogenous Distribution of Myocardial Blood-Flow by Coronary Sinus Hydrogen Gas Clearance. Jpn. Circ. J. -Engl. Ed. 1975, 39, 1016. [Google Scholar]
  111. Wodick, R.; Lubbers, D.W.; Grunewald, W. Evaluation procedure for the determination of organ blood flow after breathing hydrogen gas mixtures. Pflugers Arch. 1969, 307, R51. [Google Scholar]
  112. Nagpure, B.; Bian, J.-S. Interaction of hydrogen sulfide with nitric oxide in the cardiovascular system. Oxidative Med. Cell. Longev. 2016, 2016, 6904327. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Li, L.; Fox, B.; Keeble, J.; Salto-Tellez, M.; Winyard, P.G.; Wood, M.E.; Moore, P.K.; Whiteman, M. The complex effects of the slow-releasing hydrogen sulfide donor GYY 4137 in a model of acute joint inflammation and in human cartilage cells. J. Cell. Mol. Med. 2013, 17, 365–376. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  114. Nakamura, N.; Lin, H.C.; McSweeney, C.S.; Mackie, R.I.; Gaskins, H.R. Mechanisms of microbial hydrogen disposal in the human colon and implications for health and disease. Annu. Rev. Food Sci. Technol. 2010, 1, 363–395. [Google Scholar] [CrossRef] [PubMed]
  115. Olson, J.W.; Maier, R.J. Molecular hydrogen as an energy source for Helicobacter pylori. Science 2002, 298, 1788–1790. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  116. Calloway, D.H.; Murphy, E.L.; Bauer, D. Determination of lactose intolerance by breath analysis. Am. J. Dig. Dis. 1969, 14, 811–815. [Google Scholar] [CrossRef] [PubMed]
  117. Levitt, M.D. Production and excretion of hydrogen gas in man. N. Engl. J. Med. 1969, 281, 122–127. [Google Scholar] [CrossRef]
  118. Niu, H.C.; Schoeller, D.A.; Klein, P.D. Improved gas chromatographic quantitation of breath hydrogen by normalization to respiratory carbon dioxide. J. Lab. Clin. Med. 1979, 94, 755–763. [Google Scholar]
  119. Carter, E.A.; Bloch, K.J.; Cohen, S.; Isselbacher, K.J.; Walker, W.A. Use of hydrogen gas (H2) analysis to assess intestinal absorption. Studies in normal rats and in rats infected with the nematode, Nippostrongylus brasiliensis. Gastroenterology 1981, 81, 1091–1097. [Google Scholar] [CrossRef]
  120. Griffin, G.C.; Kwong, L.K.; Morrill, J.S.; Vreman, H.J.; Stevenson, D.K. Hydrogen gas excretion after sucrose gavage in the fasted rat. Am. J. Clin. Nutr. 1984, 40, 758–762. [Google Scholar] [CrossRef]
  121. Washabau, R.J.; Strombeck, D.R.; Buffington, C.A.; Harrold, D. Evaluation of intestinal carbohydrate malabsorption in the dog by pulmonary hydrogen gas excretion. Am. J. Vet. Res. 1986, 47, 1402–1406. [Google Scholar]
  122. Oku, T.; Nakamura, S. Comparison of digestibility and breath hydrogen gas excretion of fructo-oligosaccharide, galactosyl-sucrose, and isomalto-oligosaccharide in healthy human subjects. Eur. J. Clin. Nutr. 2003, 57, 1150–1156. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  123. Kerlin, P.; Wong, L. Breath hydrogen testing in bacterial overgrowth of the small intestine. Gastroenterology 1988, 95, 982–988. [Google Scholar] [CrossRef]
  124. Urita, Y.; Watanabe, T.; Maeda, T.; Arita, T.; Sasaki, Y.; Ishii, T.; Yamamoto, T.; Kugahara, A.; Nakayama, A.; Nanami, M.; et al. Extensive atrophic gastritis increases intraduodenal hydrogen gas. Gastroenterol. Res. Pract. 2008, 2008, 584929. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  125. Zhai, X.; Chen, X.; Shi, J.; Shi, D.; Ye, Z.; Liu, W.; Li, M.; Wang, Q.; Kang, Z.; Bi, H.; et al. Lactulose ameliorates cerebral ischemia-reperfusion injury in rats by inducing hydrogen by activating Nrf2 expression. Free Radic. Biol. Med. 2013, 65, 731–741. [Google Scholar] [CrossRef] [PubMed]
  126. Aoki, Y. Increased concentrations of breath hydrogen gas in Japanese centenarians. Anti-Aging Med. 2013, 10, 101–105. [Google Scholar]
  127. Sack, D.A.; Stephensen, C.B. Liberation of hydrogen from gastric acid following administration of oral magnesium. Dig. Dis. Sci. 1985, 30, 1127–1133. [Google Scholar] [CrossRef]
  128. Stephensen, C.B.; Leon-Barua, R.; Sack, R.B.; Sack, D.A. Comparison of noninvasive breath hydrogen test for gastric acid secretion to standard intubation test in adults. Dig. Dis. Sci. 1987, 32, 973–977. [Google Scholar] [CrossRef]
  129. Humbert, P.; Lopez de Soria, P.; Fernandez-Banares, F.; Junca, J.; Boix, J.; Planas, R.; Quer, J.C.; Domenech, E.; Gassull, M.A. Magnesium hydrogen breath test using end expiratory sampling to assess achlorhydria in pernicious anaemia patients. Gut 1994, 35, 1205–1208. [Google Scholar] [CrossRef] [Green Version]
  130. Christ, A.D.; Sarker, S.; Bauerfeind, P.; Drewe, J.; Meier, R.; Gyr, K. Assessment of gastric acid output by H2 breath test. Scand. J. Gastroenterol. 1994, 29, 973–978. [Google Scholar] [CrossRef]
  131. Ohno, K.; Ito, M.; Ichihara, M.; Ito, M. Molecular hydrogen as an emerging therapeutic medical gas for neurodegenerative and other diseases. Oxid. Med. Cell Longev. 2012, 2012, 353152. [Google Scholar] [CrossRef] [Green Version]
  132. Moss, G.A. Water and health: A forgotten connection? Perspect Public Health 2010, 130, 227–232. [Google Scholar] [CrossRef] [PubMed]
  133. Hopkins, E.W. The fountain of youth. J. Am. Orient. Soc. 1905, 26, 1–67. [Google Scholar] [CrossRef]
  134. Forster, M.M. Mineral springs and miracles. Can. Fam. Physician 1994, 40, 729–737. [Google Scholar]
  135. Baudish, O. Magic and science of natural healing waters. J. Chem. Educ. 1939, 16, 440. [Google Scholar] [CrossRef]
  136. Darnaud, C. Indications for alkaline mineral water cure in diabetes mellitus. Toulouse Med. 1951, 52, 277–284. [Google Scholar]
  137. Powell, R.H. Remedial effects of mineral waters, home and foreign. Assoc. Med. J. 1854, 2, 500–506. [Google Scholar] [CrossRef] [Green Version]
  138. Henry, M.; Chambron, J. Physico-Chemical, Biological and Therapeutic Characteristics of Electrolyzed Reduced Alkaline Water (ERAW). Water 2013, 5, 2094–2115. [Google Scholar] [CrossRef]
  139. Li, Y.P.; Teruya, K.; Katakura, Y.; Kabayama, S.; Otsubo, K.; Morisawa, S.; Ishii, Y.; Gadek, Z.; Shirahata, S. Effect of reduced water on the apoptotic cell death triggered by oxidative stress in pancreatic b HIT-T15 cell. Anim. Cell Technol. Meets Genom. 2005, 2, 121–124. [Google Scholar]
  140. Shirahata, S.; Hamasaki, T.; Teruya, K. Advanced research on the health benefit of reduced water. Trends Food Sci. Technol. 2012, 23, 124–131. [Google Scholar] [CrossRef] [Green Version]
  141. Zhang, J.Y.; Liu, C.; Zhou, L.; Qu, K.; Wang, R.; Tai, M.H.; Lei Lei, J.C.; Wu, Q.F.; Wang, Z.X. A review of hydrogen as a new medical therapy. Hepatogastroenterology 2012, 59, 1026–1032. [Google Scholar] [CrossRef]
  142. Li, Y.; Nishimura, T.; Teruya, K.; Maki, T.; Komatsu, T.; Hamasaki, T.; Kashiwagi, T.; Kabayama, S.; Shim, S.Y.; Katakura, Y.; et al. Protective mechanism of reduced water against alloxan-induced pancreatic beta-cell damage: Scavenging effect against reactive oxygen species. Cytotechnology 2002, 40, 139–149. [Google Scholar] [CrossRef] [PubMed]
  143. Shirahata, S.A.N.E.T.A.K.A. Reduced water for prevention of diseases. Anim. Cell Technol. Basic Appl. Asp. 2002, 12, 25–30. [Google Scholar]
  144. Amitani, H.; Asakawa, A.; Cheng, K.; Amitani, M.; Kaimoto, K.; Nakano, M.; Ushikai, M.; Li, Y.; Tsai, M.; Li, J.B.; et al. Hydrogen improves glycemic control in type1 diabetic animal model by promoting glucose uptake into skeletal muscle. PLoS ONE 2013, 8, e53913. [Google Scholar] [CrossRef]
  145. Gadek, Z.; Li, Y.; Shirahata, S. Changes in the Relevant Test Parameters of 219 Diabetes Patients under the Influence of the So Called “Nordenau—Phenomenon” in the Prospective Observation Procedure. In Animal Cell Technology: Basic & Applied Aspects; Yagasaki, K., Miura, Y., Hatori, M., Normura, Y., Eds.; Springer: Amsterdam, The Netherlands, 2003; pp. 405–409. [Google Scholar]
  146. Gadek, Z.; Shirahata, S. Changes in the Relevant Test Parameters of 101 Diabetes Patients under the Influence of the So-Called “Nordenau-Phenomenon”. In Animal Cell Technology: Basic & Applied Aspects; Shirahata, S., Teruya, K., Katakura, Y., Eds.; Springer: Amsterdam, The Netherlands, 2002; pp. 427–431. [Google Scholar]
  147. Gadek, Z.; Li, Y.; Shirahata, S. Influence of natural reduced water on relevant tests parameters and reactive oxygen species concentration in blood of 320 diabetes patients in the prospective observation procedure. In Animal Cell Technology: Basic & Applied Aspects; Iijima, S., Nishijima, K., Eds.; Springer: Amsterdam, The Netherlands, 2006; pp. 377–385. [Google Scholar]
  148. Gadek, Z.; Hamasaki, T.; Shirahata, S. Therapy. In Animal Cell Technology: Basic & Applied Aspects; Shirahata, S., Ikura, K., Nagao, M., Ichikawa, A., Teruya, K., Eds.; Springer: Amsterdam, The Netherlands, 2009; pp. 267–271. [Google Scholar]
  149. Shirahata, S.; Li, Y.; Hamasaki, T.; Gadek, Z.; Teruya, K.; Kabayama, S.; Otsubo, K.; Morisawa, S.; Ishi, Y.; Katakura, Y. Redox Regulation by Reduced Waters as Active Hydrogen Donors and Intracellular ROS Scavengers for Prevention of type 2 Diabetes. In Cell Technology for Cell Products; Smith, R., Ed.; Springer: Amsterdam, The Netherlands, 2007; pp. 99–101. [Google Scholar]
  150. Seifert, D.J. The Nordenau-Phenomenon—Facts and Hypotheses. In Animal Cell Technology: Products from Cells, Cells as Products, Proceedings of the 16th ESACT Meeting, Lugano, Switzerland, 25–29 April 1999; Bernard, A., Griffiths, B., Noé, W., Wurm, F., Eds.; Springer: Amsterdam, The Netherlands, 2000; pp. 525–527. [Google Scholar]
  151. Shirahata, S. Anti-Oxidative Water Improves Diabetes. 2001. Available online: https://link.springer.com/chapter/10.1007/978-94-010-0369-8_137 (accessed on 15 January 2023).
  152. Spear, J.R.; Walker, J.J.; McCollom, T.M.; Pace, N.R. Hydrogen and bioenergetics in the Yellowstone geothermal ecosystem. Proc. Natl. Acad. Sci. USA 2005, 102, 2555–2560. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  153. Schulte, M.; Blake, D.; Hoehler, T.; McCollom, T. Serpentinization and its implications for life on the early Earth and Mars. Astrobiology 2006, 6, 364–376. [Google Scholar] [CrossRef]
  154. Stevens, T.O.; McKinley, J.P. Lithoautotrophic Microbial Ecosystems in Deep Basalt Aquifers. Science 1995, 270, 450–455. [Google Scholar] [CrossRef]
  155. Wilson, S.T.; del Valle, D.A.; Robidart, J.C.; Zehr, J.P.; Karl, D.M. Dissolved hydrogen and nitrogen fixation in the oligotrophic North Pacific Subtropical Gyre. Environ. Microbiol. Rep. 2013, 5, 697–704. [Google Scholar] [CrossRef]
  156. Scranton, M.; Novelli, C.P.; Loud, A.P. The distribution and cycling of hydrogen gas in the waters of two anoxic marine environments. Limnol. Oceanogr. 1984, 29, 993–1003. [Google Scholar] [CrossRef] [Green Version]
  157. Conrad, R.; Bonjour, F.; Aragno, M. Aerobic and anaerobic microbial consumption of hydrogen in geothermal spring water. FEMS Microbiol. Lett. 1985, 29, 201–205. [Google Scholar] [CrossRef]
  158. Boyd, E.S.; Hamilton, T.L.; Spear, J.R.; Lavin, M.; Peters, J.W. [FeFe]-hydrogenase in Yellowstone National Park: Evidence for dispersal limitation and phylogenetic niche conservatism. ISME J. 2010, 4, 1485–1495. [Google Scholar] [CrossRef]
  159. Conrad, R.; Aragno, M.; Seiler, W. Production and consumption of hydrogen in a eutrophic lake. Appl. Environ. Microbiol. 1983, 45, 502–510. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  160. Lin, L.-H.; Slater, G.F.; Sherwood Lollar, B.; Lacrampe-Couloume, G.; Onstott, T.C. The yield and isotopic composition of radiolytic H2, a potential energy source for the deep subsurface biosphere. Geochim. Cosmochim. Acta 2005, 69, 893–903. [Google Scholar] [CrossRef] [Green Version]
  161. McMahon, S.; Parnell, J.; Blamey, N.J. Evidence for Seismogenic Hydrogen Gas, a Potential Microbial Energy Source on Earth and Mars. Astrobiology 2016, 16, 690–702. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  162. Ostojic, S.M. Are there natural spring waters rich in molecular hydrogen? Trends Food Sci. Technol. 2019, 90, 157. [Google Scholar] [CrossRef]
  163. Smolinka, T.; Bergmann, H.; Garche, J.; Kusnezoff, M. Chapter 4—The history of water electrolysis from its beginnings to the present. In Electrochemical Power Sources: Fundamentals, Systems, and Applications; Smolinka, T., Garche, J., Eds.; Elsevier: Amsterdam, The Netherlands, 2022; pp. 83–164. [Google Scholar]
  164. Zoulias, E.; Varkaraki, E.; Lymberopoulos, N.; Christodoulou, C.N.; Karagiorgis, G.N. A review on water electrolysis. Tcjst 2004, 4, 41–71. [Google Scholar]
  165. Fujiyama, Y.; Kitahora, T. Alkaline electrolytic water (alkali ions water) for drinking water in medicine. Mizu No Tokusei Atarashii Riyo Gijutsu Enu-Ti-Esu Tokyo 2004, 348–357. [Google Scholar]
  166. Tashiro, H.; Kitahora, T.; Fujiyama, Y.; Banba, T. Clinical evaluation of alkali-ionized water for chronic diarrhea-placebo-controlled double blind study. Dig. Absorpt. 2000, 23, 52–56. [Google Scholar]
  167. Yan, P.; Daliri, E.B.; Oh, D.H. New Clinical Applications of Electrolyzed Water: A Review. Microorganisms 2021, 9, 136. [Google Scholar] [CrossRef]
  168. LeBaron, T.W.; Sharpe, R.; Ohno, K. Electrolyzed Reduced Water: Review I. Molecular Hydrogen Is the Exclusive Agent Responsible for the Therapeutic Effects. Int. J. Mol. Sci. 2022, 23, 14750. [Google Scholar] [CrossRef]
  169. LeBaron, T.W.; Sharpe, R. ORP should not be used to estimate or compare concentrations of aqueous H2: An in silico analysis and narrative synopsis. Front. Food Sci. Technol. 2022, 2, 26. [Google Scholar] [CrossRef]
  170. LeBaron, T.W.; Sharpe, R.; Ohno, K. Electrolyzed Reduced Water: Review II: Safety Concerns and Effectiveness as a Source of Hydrogen Water. Int. J. Mol. Sci. 2022, 23, 14508. [Google Scholar] [CrossRef]
  171. Cavallo, T. An Essay on the Medicinal Properties of Factitious Airs: With an Appendix on the Nature of Blood; Gale: Farmington Hills, MI, USA, 1798. [Google Scholar]
  172. Dole, M.; Wilson, F.R.; Fife, W.P. Hyperbaric hydrogen therapy: A possible treatment for cancer. Science 1975, 190, 152–154. [Google Scholar] [CrossRef] [PubMed]
  173. Neale, R.J. Dietary fibre and health: The role of hydrogen production. Med. Hypotheses 1988, 27, 85–87. [Google Scholar] [CrossRef]
  174. Kajiya, M.; Sato, K.; Silva, M.J.; Ouhara, K.; Do, P.M.; Shanmugam, K.T.; Kawai, T. Hydrogen from intestinal bacteria is protective for Concanavalin A-induced hepatitis. Biochem. Biophys. Res. Commun. 2009, 386, 316–321. [Google Scholar] [CrossRef] [PubMed]
  175. Suzuki, Y.; Sano, M.; Hayashida, K.; Ohsawa, I.; Ohta, S.; Fukuda, K. Are the effects of alpha-glucosidase inhibitors on cardiovascular events related to elevated levels of hydrogen gas in the gastrointestinal tract? FEBS Lett. 2009, 583, 2157–2159. [Google Scholar] [CrossRef] [Green Version]
  176. Chiasson, J.L.; Josse, R.G.; Gomis, R.; Hanefeld, M.; Karasik, A.; Laakso, M.; Group, S.-N.T.R. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: The STOP-NIDDM trial. JAMA 2003, 290, 486–494. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  177. Shimouchi, A.; Nose, K.; Takaoka, M.; Hayashi, H.; Kondo, T. Effect of dietary turmeric on breath hydrogen. Dig. Dis. Sci. 2009, 54, 1725–1729. [Google Scholar] [CrossRef] [PubMed]
  178. Shimouchi, A.; Nose, K.; Yamaguchi, M.; Ishiguro, H.; Kondo, T. Breath hydrogen produced by ingestion of commercial hydrogen water and milk. Biomark. Insights 2009, 4, 27–32. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  179. Prasad, S.; Gupta, S.C.; Tyagi, A.K.; Aggarwal, B.B. Curcumin, a component of golden spice: From bedside to bench and back. Biotechnol. Adv. 2014, 32, 1053–1064. [Google Scholar] [CrossRef] [PubMed]
  180. Nishimura, N.; Tanabe, H.; Sasaki, Y.; Makita, Y.; Ohata, M.; Yokoyama, S.; Asano, M.; Yamamoto, T.; Kiriyama, S. Pectin and high-amylose maize starch increase caecal hydrogen production and relieve hepatic ischaemia-reperfusion injury in rats. Br. J. Nutr. 2012, 107, 485–492. [Google Scholar] [CrossRef] [Green Version]
  181. Jones, D. Gas Therapy. Nature 1996, 383, 676. [Google Scholar] [CrossRef]
  182. Gharib, B.; Hanna, S.; Abdallahi, O.M.; Lepidi, H.; Gardette, B.; De Reggi, M. Anti-inflammatory properties of molecular hydrogen: Investigation on parasite-induced liver inflammation. Comptes Rendus Acad. Sci. III 2001, 324, 719–724. [Google Scholar] [CrossRef] [PubMed]
  183. Nakao, A.; Toyoda, Y.; Sharma, P.; Evans, M.; Guthrie, N. Effectiveness of hydrogen rich water on antioxidant status of subjects with potential metabolic syndrome-an open label pilot study. J. Clin. Biochem. Nutr. 2010, 46, 140–149. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  184. LeBaron, T.W.; Singh, R.B.; Fatima, G.; Kartikey, K.; Sharma, J.P.; Ostojic, S.M.; Gvozdjakova, A.; Kura, B.; Noda, M.; Mojto, V.; et al. The Effects of 24-Week, High-Concentration Hydrogen-Rich Water on Body Composition, Blood Lipid Profiles and Inflammation Biomarkers in Men and Women with Metabolic Syndrome: A Randomized Controlled Trial. Diabetes Metab. Syndr. Obes. 2020, 13, 889–896. [Google Scholar] [CrossRef] [Green Version]
  185. Kajiyama, S.; Hasegawa, G.; Asano, M.; Hosoda, H.; Fukui, M.; Nakamura, N.; Kitawaki, J.; Imai, S.; Nakano, K.; Ohta, M.; et al. Supplementation of hydrogen-rich water improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance. Nutr. Res. 2008, 28, 137–143. [Google Scholar] [CrossRef]
  186. Song, G.; Li, M.; Sang, H.; Zhang, L.; Li, X.; Yao, S.; Yu, Y.; Zong, C.; Xue, Y.; Qin, S. Hydrogen-rich water decreases serum LDL-cholesterol levels and improves HDL function in patients with potential metabolic syndrome. J. Lipid Res. 2013, 54, 1884–1893. [Google Scholar] [CrossRef] [Green Version]
  187. Yoritaka, A.; Takanashi, M.; Hirayama, M.; Nakahara, T.; Ohta, S.; Hattori, N. Pilot study of H(2) therapy in Parkinson’s disease: A randomized double-blind placebo-controlled trial. Mov. Disord. 2013, 28, 836–839. [Google Scholar] [CrossRef]
  188. Nishimaki, K.; Asada, T.; Ohsawa, I.; Nakajima, E.; Ikejima, C.; Yokota, T.; Kamimura, N.; Ohta, S. Effects of Molecular Hydrogen Assessed by an Animal Model and a Randomized Clinical Study on Mild Cognitive Impairment. Curr. Alzheimer Res. 2018, 15, 482–492. [Google Scholar] [CrossRef] [Green Version]
  189. Ishibashi, T.; Sato, B.; Rikitake, M.; Seo, T.; Kurokawa, R.; Hara, Y.; Naritomi, Y.; Hara, H.; Nagao, T. Consumption of water containing a high concentration of molecular hydrogen reduces oxidative stress and disease activity in patients with rheumatoid arthritis: An open-label pilot study. Med. Gas Res. 2012, 2, 27. [Google Scholar] [CrossRef] [Green Version]
  190. Xia, C.; Liu, W.; Zeng, D.; Zhu, L.; Sun, X.; Sun, X. Effect of hydrogen-rich water on oxidative stress, liver function, and viral load in patients with chronic hepatitis B. Clin. Transl. Sci. 2013, 6, 372–375. [Google Scholar] [CrossRef] [Green Version]
  191. Sakai, T.; Sato, B.; Hara, K.; Hara, Y.; Naritomi, Y.; Koyanagi, S.; Hara, H.; Nagao, T.; Ishibashi, T. Consumption of water containing over 3.5 mg of dissolved hydrogen could improve vascular endothelial function. Vasc. Health Risk Manag. 2014, 10, 591–597. [Google Scholar] [CrossRef] [Green Version]
  192. Ostojić, S.M.; Stojanović, M.D.; Calleja-Gonzalez, J.; Obrenović, M.D.; Veljović, D.; Međedović, B.; Kanostrevac, K.; Stojanović, M.; Vukomanović, B. Drinks with alkaline negative oxidative reduction potential improve exercise performance in physically active men and women: Double-blind, randomized, placebo-controlled, cross-over trial of efficacy and safety. Serb. J. Sport. Sci. 2011, 5, 83–89. [Google Scholar]
  193. LeBaron, T.W.; Laher, I.; Kura, B.; Slezak, J. Hydrogen gas: From clinical medicine to an emerging ergogenic molecule for sports athletes (1). Can. J. Physiol. Pharmacol. 2019, 97, 797–807. [Google Scholar] [CrossRef] [PubMed]
  194. Ono, H.; Nishijima, Y.; Ohta, S.; Sakamoto, M.; Kinone, K.; Horikosi, T.; Tamaki, M.; Takeshita, H.; Futatuki, T.; Ohishi, W.; et al. Hydrogen Gas Inhalation Treatment in Acute Cerebral Infarction: A Randomized Controlled Clinical Study on Safety and Neuroprotection. J. Stroke Cerebrovasc. Dis. 2017, 26, 2587–2594. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  195. LeBaron, T.W.; Kura, B.; Kalocayova, B.; Tribulova, N.; Slezak, J. A New Approach for the Prevention and Treatment of Cardiovascular Disorders. Molecular Hydrogen Significantly Reduces the Effects of Oxidative Stress. Molecules 2019, 24, 2076. [Google Scholar] [CrossRef] [Green Version]
  196. Tamura, T.; Hayashida, K.; Sano, M.; Onuki, S.; Suzuki, M. Efficacy of inhaled HYdrogen on neurological outcome following BRain Ischemia During post-cardiac arrest care (HYBRID II trial): Study protocol for a randomized controlled trial. Trials 2017, 18, 488. [Google Scholar] [CrossRef] [Green Version]
  197. Russell, G.; Rehman, M.; LeBaron, T.W.; Veal, D.; Adukwu, E.; Hancock, J.T. An Overview of SARS-CoV-2 (COVID-19) Infection: The Importance of Molecular Hydrogen as an Adjunctive Therapy. React. Oxyg. Species 2020, 10, 150–165. [Google Scholar] [CrossRef]
  198. Alwazeer, D.; Liu, F.F.; Wu, X.Y.; LeBaron, T.W. Combating Oxidative Stress and Inflammation in COVID-19 by Molecular Hydrogen Therapy: Mechanisms and Perspectives. Oxid. Med. Cell Longev. 2021, 2021, 5513868. [Google Scholar] [CrossRef] [PubMed]
  199. Hancock, J.T.; LeBaron, T.W.; Russell, G. Molecular Hydrogen: Redox Reactions and Possible Biological Interactions. React. Oxyg. Species 2021, 11, m17–m25. [Google Scholar] [CrossRef]
  200. Li, X.; Ma, X.; Zhang, J.; Akiyama, E.; Wang, Y.; Song, X. Review of hydrogen embrittlement in metals: Hydrogen diffusion, hydrogen characterization, hydrogen embrittlement mechanism and prevention. Acta Metall. Sin. (Engl. Lett.) 2020, 33, 759–773. [Google Scholar] [CrossRef]
  201. Fujita, K.; Seike, T.; Yutsudo, N.; Ohno, M.; Yamada, H.; Yamaguchi, H.; Sakumi, K.; Yamakawa, Y.; Kido, M.A.; Takaki, A.; et al. Hydrogen in drinking water reduces dopaminergic neuronal loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. PLoS ONE 2009, 4, e7247. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  202. Jin, Z.; Zhao, P.; Gong, W.; Ding, W.; He, Q. Fe-porphyrin: A redox-related biosensor of hydrogen molecule. Nano Res. 2023, 16, 2020–2025. [Google Scholar] [CrossRef]
  203. Sun, X.; Ohta, S.; Zhang, J.H. Discovery of a hydrogen molecular target. Med. Gas Res. 2023, 13, 41–42. [Google Scholar] [CrossRef] [PubMed]
  204. Deryugina, A.V.; Danilova, D.A.; Pichugin, V.V.; Brichkin, Y.D. The Effect of Molecular Hydrogen on Functional States of Erythrocytes in Rats with Simulated Chronic Heart Failure. Life 2023, 13, 418. [Google Scholar] [CrossRef] [PubMed]
  205. Kura, B.; Bagchi, A.K.; Singal, P.K.; Barancik, M.; LeBaron, T.W.; Valachova, K.; Soltes, L.; Slezak, J. Molecular hydrogen: Potential in mitigating oxidative-stress-induced radiation injury (1). Can. J. Physiol. Pharmacol. 2019, 97, 287–292. [Google Scholar] [CrossRef]
  206. Slezak, J.; Kura, B.; LeBaron, T.W.; Singal, P.K.; Buday, J.; Barancik, M. Oxidative Stress and Pathways of Molecular Hydrogen Effects in Medicine. Curr. Pharm. Des. 2021, 27, 610–625. [Google Scholar] [CrossRef]
  207. Hancock, J.T.; Russell, G.; Craig, T.J.; May, J.; Morse, H.R.; Stamler, J.S. Understanding Hydrogen: Lessons to Be Learned from Physical Interactions between the Inert Gases and the Globin Superfamily. Oxygen 2022, 2, 578–590. [Google Scholar] [CrossRef]
  208. Hayashida, K.; Sano, M.; Ohsawa, I.; Shinmura, K.; Tamaki, K.; Kimura, K.; Endo, J.; Katayama, T.; Kawamura, A.; Kohsaka, S.; et al. Inhalation of hydrogen gas reduces infarct size in the rat model of myocardial ischemia-reperfusion injury. Biochem. Biophys. Res. Commun. 2008, 373, 30–35. [Google Scholar] [CrossRef]
  209. Li, Q.; Kato, S.; Matsuoka, D.; Tanaka, H.; Miwa, N. Hydrogen water intake via tube-feeding for patients with pressure ulcer and its reconstructive effects on normal human skin cells in vitro. Med. Gas Res. 2013, 3, 20. [Google Scholar] [CrossRef] [Green Version]
  210. Cui, Y.; Zhang, H.; Ji, M.; Jia, M.; Chen, H.; Yang, J.; Duan, M. Hydrogen-rich saline attenuates neuronal ischemia--reperfusion injury by protecting mitochondrial function in rats. J. Surg. Res. 2014, 192, 564–572. [Google Scholar] [CrossRef]
  211. Nakayama, M.; Nakano, H.; Hamada, H.; Itami, N.; Nakazawa, R.; Ito, S. A novel bioactive haemodialysis system using dissolved dihydrogen (H2) produced by water electrolysis: A clinical trial. Nephrol. Dial. Transplant. 2010, 25, 3026–3033. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  212. Kato, S.; Saitoh, Y.; Iwai, K.; Miwa, N. Hydrogen-rich electrolyzed warm water represses wrinkle formation against UVA ray together with type-I collagen production and oxidative-stress diminishment in fibroblasts and cell-injury prevention in keratinocytes. J. Photochem. Photobiol. B 2012, 106, 24–33. [Google Scholar] [CrossRef] [PubMed]
  213. Chen, X.; Zhai, X.; Shi, J.; Liu, W.W.; Tao, H.; Sun, X.; Kang, Z. Lactulose mediates suppression of dextran sodium sulfate-induced colon inflammation by increasing hydrogen production. Dig. Dis. Sci. 2013, 58, 1560–1568. [Google Scholar] [CrossRef] [PubMed]
  214. Ostojic, S.M.; Vukomanovic, B.; Calleja-Gonzalez, J.; Hoffman, J.R. Effectiveness of oral and topical hydrogen for sports-related soft tissue injuries. Postgrad. Med. 2014, 126, 187–195. [Google Scholar] [CrossRef]
  215. Ostojic, S.M.; Korovljev, D.; Stajer, V.; Javorac, D. 28-days Hydrogen-rich Water Supplementation Affects Exercise Capacity in Mid-age Overweight Women: 2942 Board# 225. Med. Sci. Sport. Exerc. 2018, 50, 728–729. [Google Scholar]
  216. LeBaron, T.W.; Kharman, J.; McCullough, M.L. An H2-infused, nitric oxide-producing functional beverage as a neuroprotective agent for TBIs and concussions. J. Integr. Neurosci. 2021, 20, 667–676. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Articles Published Relating to Molecular Hydrogen and Electrolyzed Reduced Water (ERW). Articles with “molecular hydrogen” in the title but not “hydrogen bonding” were counted each year. Similarly, articles with “electrolyzed reduced water”, “alkaline water”, or “alkaline ionized water” in the title or abstract were counted each year. Note that some searched articles are not directly relevant to the biological/medical effects of H2.
Figure 1. Articles Published Relating to Molecular Hydrogen and Electrolyzed Reduced Water (ERW). Articles with “molecular hydrogen” in the title but not “hydrogen bonding” were counted each year. Similarly, articles with “electrolyzed reduced water”, “alkaline water”, or “alkaline ionized water” in the title or abstract were counted each year. Note that some searched articles are not directly relevant to the biological/medical effects of H2.
Oxygen 03 00011 g001
Figure 2. Timeline of important events involving hydrogen as an important molecule. ERW (electrolyzed reduced water), JMHLW (Japanese Ministry of Health Labor and Welfare).
Figure 2. Timeline of important events involving hydrogen as an important molecule. ERW (electrolyzed reduced water), JMHLW (Japanese Ministry of Health Labor and Welfare).
Oxygen 03 00011 g002
Figure 3. Articles Published Relating to Molecular Hydrogen in Plants. Articles with both “molecular hydrogen” and “plant” either in the title or abstract were counted since 2012 when the effect of H2 on plants was first published [46]. Note that some searched articles are not directly relevant to the effects of H2 on plants.
Figure 3. Articles Published Relating to Molecular Hydrogen in Plants. Articles with both “molecular hydrogen” and “plant” either in the title or abstract were counted since 2012 when the effect of H2 on plants was first published [46]. Note that some searched articles are not directly relevant to the effects of H2 on plants.
Oxygen 03 00011 g003
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

LeBaron, T.W.; Ohno, K.; Hancock, J.T. The On/Off History of Hydrogen in Medicine: Will the Interest Persist This Time Around? Oxygen 2023, 3, 143-162. https://doi.org/10.3390/oxygen3010011

AMA Style

LeBaron TW, Ohno K, Hancock JT. The On/Off History of Hydrogen in Medicine: Will the Interest Persist This Time Around? Oxygen. 2023; 3(1):143-162. https://doi.org/10.3390/oxygen3010011

Chicago/Turabian Style

LeBaron, Tyler W., Kinji Ohno, and John T. Hancock. 2023. "The On/Off History of Hydrogen in Medicine: Will the Interest Persist This Time Around?" Oxygen 3, no. 1: 143-162. https://doi.org/10.3390/oxygen3010011

Article Metrics

Back to TopTop