Hydrogen: an emerging medical gas

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Published: 2017-12-30 Author: Tyler W. Lebaron Sources: Molecular Hydrogen Foundation

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The idea of ​​therapeutic gas molecules is not a new concept. For example, carbon monoxide (CO), hydrogen sulfide (H 2S) and, of course, nitric oxide (NO *), which was initially ridiculed by skeptics but later received the Nobel Prize, they are all biologically active gases [6] However, it may still be hard to believe that H 2 can exert any biological effect, because unlike these other gases, hydrogen is a highly diffusible, non-reactive, non-radical neutral gas, thus it is unlikely to have specific binding sites or to interact with specificity at a specific receptor [7].

From an evolutionary perspective, it may not be unusual for hydrogen to exert a biological effect [8]. In addition to its role in the origins of the universe, hydrogen also participated in the genesis of life and played an active role in the evolution of eukaryotes [9]. Over millions of years of evolution, plants and animals have developed a mutualistic relationship with hydrogen-producing bacteria that results in basal levels of molecular hydrogen in eukaryotic systems. This constant exposure to molecular hydrogen may have preserved the original hydrogen targets, as can be extrapolated by genetic residues of hydrogenase enzymes in higher eukaryotes. Alternatively, but not exclusively, eukaryotes may have developed sensitivity to molecular hydrogen over millions of years of evolution [7, 10].

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ADMINISTRATION METHODS

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Molecular hydrogen can be administered by inhalation [11], ingestion of soluble (dissolved) hydrogen-rich solutions (eg, water, flavored drinks, etc.) [12], hydrogen-rich hemodialysis solution [13], intravenous injection hydrogen-rich saline [14], topical administration of hydrogen-rich media (eg, bath, shower, and creams) [15], hyperbaric treatment [2], ingestion of hydrogen-producing material after reaction with gastric acid [15], ingestion of digestible carbohydrates as a prebiotic to intestinal hydrogen-producing bacteria [16], rectal insufflation [17] and other methods. [fifteen].

PHARMACOKINETICS

Hydrogen's unique physicochemical properties of hydrophobicity, neutrality, size, mass, etc. they give it superior distribution properties that allow it to rapidly penetrate biomembranes (for example, cell membranes, blood-brain, placental and testicular barriers) and reach subcellular compartments (eg, mitochondria, nucleus, etc.) where it can exert its therapeutic effects [ fifteen].

Although several medical clinics in Japan use intravenous injection of hydrogen-rich saline, the most common methods are inhalation and consumption of hydrogen-rich water. The pharmacokinetics of each method is still under investigation, but depends on the dose, route, and timing. An article published in Nature's Scientific Reports [18] compared inhalation, injection and consumption with different concentrations of hydrogen and found useful information for clinical use. Based on this and several studies, we briefly summarize the pharmacokinetics of inhalation and alcohol consumption.

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HYDROGEN INHALATION

For inhalation, a 2-4% hydrogen gas mixture is common because it is below the flammability level; however, some studies use 66.7% H 2 and 33.3% O 2, which is non-toxic and effective, but is flammable. Inhalation of hydrogen reaches a maximum plasma level (ie, equilibrium based on Henry's Law) in approximately 30 minutes, and upon cessation of inhalation, return to baseline occurs in approximately 60 minutes.

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CONSUMPTION OF DISSOLVED HYDROGEN

The concentration / solubility of hydrogen in water at room temperature and standard pressure (SATP) is 0.8 mM or 1.6 ppm (1.6 mg / L). For reference, conventional water (eg, Tap, filtered, bottled, etc.) contains less than 0.0000002 ppm H2, which is well below the therapeutic level (see Questions and Answers 7-8). The 1.6 ppm concentration is easily achieved by many methods , such as simply bubbling hydrogen gas into the water. Due to the low molar mass of molecular hydrogen (i.e. 2.02 g / mol H 2 vs. 176.12 g / mol vitamin C), there are more hydrogen molecules in a 1.6 mg dose of H 2 than Those with vitamin C molecules in a 100-mg dose of pure vitamin C (ie 1.6 mg of H 2) have 0.8 millimoles of H 2 vs. 100 mg of vitamin C has 0.57 millimoles of vitamin C).

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The half-life of hydrogen-rich water is shorter than other carbonated beverages (for example, carbonated or hydrogen peroxide), but therapeutic levels can remain long enough to facilitate consumption. Ingestion of hydrogen-rich water produces a maximum increase in plasma and respiration concentration in 5-15 minutes in a dose-dependent manner (see figure). Increased hydrogen respiration is an indication that hydrogen diffuses through the submucosa and enters the systemic circulation where it is expelled into the lungs. This increase in blood and breath concentration returns to baseline in 45-90 minutes, depending on the dose ingested.

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PHARMACODYNAMICS

Although a significant amount of research in cells, tissues, animals, humans, and even plants has confirmed the effect of hydrogen on biological systems, the exact underlying molecular mechanisms and primary goals remain elusive [19].

ANTIOXIDANT EFFECT

Initially, it was suggested that the beneficial effect of hydrogen was due to an antioxidant such as hydrogen selectively neutralized by cytotoxic hydroxyl radicals [3] in vitro. However, H2 reduces * OH radicals [20], as has been shown in several systems [3, 21, 22], may not occur through direct scavenging, nor can it fully explain all the benefits of hydrogen [23 ]. For example, in a double-blind, placebo-controlled trial in rheumatoid arthritis [24], hydrogen had a residual effect that continued to improve disease symptoms for four weeks after hydrogen administration was discontinued [24]. Many cell studies also show that hydrogen pretreatment has marked beneficial effects even when the assault (eg, toxin, radiation, injury, etc.) is administered long after all hydrogen has dissipated from the system [25-27] . Additionally, 7 M -1 sec -1) [20], and the hydrogen concentration at the cellular level is also quite low (micromolar levels), making it unlikely that H 2 can compete effectively with the numerous other nucleophilic targets of the cell [28]. Finally, if the mechanism was primarily hydroxyl radical scavenging, then we should see a greater effect of inhalation compared to drinking, but this is not always the case [29,30]. In summary, we consider it to be inaccurate or at least incomplete to state that the benefits of hydrogen are due to its direct acting as a powerful antioxidant. In fact, hydrogen is selective because it is a very weak antioxidant and therefore does not neutralize important ROS. or altering important biological signaling molecules. However, a metabolic tracer study [31] with deuterium gas showed that, under physiological conditions, deuterium gas is oxidized, and the rate of hydrogen oxidation increases with a greater amount of oxidative stress [32], but the physical mechanism- chemical for this may not yet be direct radical scavenger [31]. However, not all studies show that hydrogen is oxidized through mammalian tissues [33], and it has also been reported that deuterium gas did not exert a therapeutic effect in the model studied, whereas 1 H (unpublished data ).

ROUTE NRF2

Unlike conventional antioxidants [34], hydrogen has the ability to reduce excessive oxidative stress [23], but only under conditions where the cell is experiencing abnormally high levels of oxidative stress that would be harmful and non-hormonal.

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One mechanism that hydrogen uses to protect against oxidative damage is through the activation of the Nrf2-Keap1 system and the subsequent induction of the antioxidant response element (ARE) pathway, which leads to the production of various cytoprotective proteins such as glutathione, catalase , superoxide dismutase, glutathione peroxidase, heme-1 oxygenase, etc. [5,35,36]. In some disease models, the benefits of hydrogen are negated by the use of Nrf2 knockouts [37, 38], Nrf2 gene silencing using iRNA [39], or pharmacological blocking of the Nrf2 pathway [40, 41]. Importantly, hydrogen only activates the Nrf2 pathway when there is an assault (eg, toxin, injury, etc.) [40] rather than acting constitutively as a promoter, which could be detrimental [42, 43]. The method that hydrogen activates the Nrf2 pathway remains unclear [5].

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CELLULAR MODULATION

In addition to the potential sequestration of hydroxyl radicals and / or activation of the Nrf2 pathway, hydrogen can improve oxidative stress through a cellular modulatory effect [5] and reduce the formation of free radicals [44], such as the negative regulation of the NADPH oxidase system. [Four. Five] . The various cellular modulating effects of hydrogen are responsible for mediating the anti-inflammatory, anti-allergic, and anti-obesity effects of hydrogen. Hydrogen has been shown to negatively regulate pro-inflammatory cytokines (eg, IL-1, IL-6, IL-8, etc.) [46], attenuate the activation of TNF-a [24], NF-? B [47], NFAT [30, 48], NLRP3 [49, 50], HMGB1 [51] and other inflammatory mediators [5]. Furthermore, hydrogen has beneficial effects on obesity and metabolism by increasing the expression of FGF21 [52], PGC-1a [53], PPARa [53], and more. [54]. Additional 2nd messenger molecules or transcription factors affected by hydrogen include ghrelin [55], JNK-1 [45], ERK1 / 2 [56], PKC [57], GSK [58], TXNIP [49], STAT3 [ 59], ASK1 [60], MEK [61], SIRT1 [62] and many more. More than 200 biomolecules are altered by the administration of hydrogen, including more than 1000 gene expressions.

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However, the primary objectives and the main regulators responsible for these changes remain elusive [46]. There are many feedback systems and loops to consider, making it difficult to determine if we are detecting the cause or effect of hydrogen delivery.

The exact mechanism of how hydrogen modulates signal transduction, gene expression, and protein phosphorylation is still being investigated [5]. A recent publication [63] in Scientific Reports provides good evidence to suggest that one of the mechanisms through which hydrogen achieves the various cell modulating effects is by modifying lipid peroxidation in the cell membrane. In cultured cells, at biologically relevant concentrations, hydrogen suppressed free radical chain peroxidation dependent reaction and recovered Ca 2+ induced gene expressions, as determined by comprehensive microarray analysis (see Figure 6) [63].

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SCIENTIFIC RECOGNITION OF HYDROGEN

Although the main targets or the exact biochemical mechanisms of hydrogen are not yet fully understood, the therapeutic effect in cells, tissues, animals, humans, and even plants [64] is being widely accepted due to the now 500 peer-reviewed articles. and the 1,600 researchers on the medical effects of hydrogen. Publication quality is also improving with an average impact factor (IF) of hydrogen publishing journals. The table below shows some of the studies published in the highest IF journals, ranging from six to 27.

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HYDROGEN AND IMMEDIATE MEDICAL APPLICATIONS

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Hydrogen as a medicinal gas is also growing because it has immediate medical applications to help with many of today's health crises [65, 66]. Dixon and his colleagues at Loma-Linda University reported that hydrogen has the potential to help with the top 8/10 disease deaths listed by the Centers for Disease Control [67]. Dr. Banks of the Washington VA / U reported that ingestion of hydrogen-rich water protected against neurodegenerative changes induced by traumatic brain injury in mice [68]. Their results show that hydrogen administration reduced brain edema, blocked pathological tau expression, and maintained ATP levels.

This and other studies have profound effects for events where brain injury (eg, concussion, chronic traumatic encephalopathy, etc.) is a common occurrence [69]. Although many people report dramatic effects of hydrogen therapy, from rapid relief of pain and inflammation to normalization of glucose and cholesterol levels, other people may not notice any immediate or observable benefits.

Hydrogen is not considered a dangerous substance and, as mentioned, it helps to return the cell / organ to homeostasis without causing major side effects. Although some researchers have noted that some people are more sensitive to hydrogen and experience greater effects. More human studies are needed to answer these questions.

HUMAN RESEARCH

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Although research on hydrogen appears promising in cell or animal models, further long-term clinical trials are required to confirm its efficacy in humans [70]. There are only a total of 40 human studies; few are in a randomized, double-blind, placebo-controlled mode with sufficient subject numbers. Some of these clinical studies suggest that ingestion of hydrogen-rich water was beneficial for metabolic syndrome [71], diabetes [72], and hyperlipidemia [73, 74].

Another 1-year placebo-controlled clinical study suggested that hydrogen-rich water is beneficial for Parkinson's disease [75], while other clinical studies suggest significant benefits for rheumatoid arthritis [24, 76], mitochondrial dysfunction [77] , exercise performance [78], athletic recovery time [79], wound healing [80-82],

More than 15 human studies have been completed with promising results, which are in the process of manuscript preparation and publication through the peer-reviewed process. Further studies in humans are required to determine the proper dose, timing, method of administration, and for which diseases, and potentially genotypes, hydrogen is most effective [7]. Hydrogen is still in its infancy, and more data is required before we can scientifically claim any real benefits, but the preliminary data is intriguing. Research on disease models, mechanisms of action, and clinical studies are particularly relevant because molecular hydrogen's high safety profile makes it a superior choice [89].

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SAFETY

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Hydrogen is produced naturally by the intestinal flora after fiber digestion [90]. A study from the University of Florida and the Forsythe Institute in Boston, Massachusetts, confirmed that hydrogen produced from bacteria exerts therapeutic effects [91]. They found that reconstitution of the gut microbiota with H 2-producing E. coli, but not H 2-deficient mutant E. coli, was protective against Concanvalin A-induced hepatitis.

Other studies also show that the hydrogen produced by bacteria from the administration of acarbose is therapeutic [92]. Perhaps this helps explain why a large clinical trial from the Journal of the American Medical Association (JAMA) found significant reductions in cardiovascular events by those taking the hydrogen-producing drug acarbose [92, 93]. These studies not only suggest the therapeutic action of molecular hydrogen, but also demonstrate its high safety profile. Hydrogen is very natural to our bodies, as we are exposed to it on a daily basis as a result of normal bacterial metabolism [1].

Furthermore, hydrogen gas has also been used in deep sea diving since the 1940s to prevent decompression sickness [94, 95]. Hundreds of human studies for deep-sea diving have shown that inhalation of hydrogen gas, orders of magnitude greater than required for therapeutic use, is well tolerated by the body without chronic toxic effects [96].

In some people, however, it is reported that hydrogen can lead to loose stools [97], and in rare cases with diabetics, hypoglycemia [77], which is controlled by reducing the level of insulin administered. Hundreds of studies on hydrogen from bacterial production, deep sea diving, and recent medical applications have revealed no direct harmful side effects of hydrogen administration at biologically therapeutic levels. Such a high safety profile can be considered paradoxical because chemotherapeutic agents that exert biological effects must have beneficial and harmful effects depending on the dosage, time, location, duration, etc. However, such deleterious effects have not yet been reported for hydrogen. Perhaps the ill effects are so transient and mild that they are masked by the beneficial effects, or are even the ones that mediate the beneficial effects through hormetic pathways.

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FUTURE DIRECTIONS

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The goal of the Molecular Hydrogen Foundation ( MHF) ) is to help advance research, education, and awareness of hydrogen as a medical therapeutic gas. It is not common to find a treatment that has a high therapeutic potential and a high safety profile; hydrogen seems to fit this combination [23]. Some researchers are interested in hydrogen simply because of its unforeseen ability to have a biological effect; With the realization that hydrogen is both safe and effective, a moral obligation develops to advance research, education, and knowledge of hydrogen as a medicinal gas.

We welcome other biomedical researchers to join us in elucidating the in vitro molecular mechanisms of hydrogen, to conduct well-controlled clinical trials in hydrogen in order to understand the best dosage, time, genotype, and method of administration of hydrogen. With only a few hundred peer-reviewed articles and a couple thousand biomedical researchers, hydrogen research is still in its infancy. However, preliminary studies suggest that molecular hydrogen is something that must be sought, investigated, and elucidated for the potential benefit of disease prevention and treatment.