Next Article in Journal
The Role of Pyrazolo[3,4-d]pyrimidine-Based Kinase Inhibitors in The Attenuation of CCl4-Induced Liver Fibrosis in Rats
Next Article in Special Issue
Relevant Membrane Transport Proteins as Possible Gatekeepers for Effective Pharmacological Ascorbate Treatment in Cancer
Previous Article in Journal
Mechanism of Action of Natural Compounds in Peripheral Multiorgan Dysfunction and Hippocampal Neuroinflammation Induced by Sepsis
Previous Article in Special Issue
Swietenine Alleviates Nonalcoholic Fatty Liver Disease in Diabetic Mice via Lipogenesis Inhibition and Antioxidant Mechanisms
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Antioxidants
Volume 12
Issue 3
10.3390/antiox12030636
antioxidants-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Molecular Hydrogen: From Molecular Effects to Stem Cells Management and Tissue Regeneration

by
Mikhail Yu. Artamonov
1,2,*,
Andrew K. Martusevich
1,3,
Felix A. Pyatakovich
2,
Inessa A. Minenko
1,2,
Sergei V. Dlin
2 and
Tyler W. LeBaron
4,5,*
1
Laboratory of Translational Free Radical Biomedicine, Sechenov University, 119991 Moscow, Russia
2
MJA Research and Development, Inc., East Stroudsburg, PA 18301, USA
3
Laboratory of Medical Biophysics, Privolzhsky Research Medical University, 603005 Nizhny Novgorod, Russia
4
Department of Kinesiology and Outdoor Recreation, Southern Utah University, Cedar City, UT 84720, USA
5
Molecular Hydrogen Institute, Enoch, UT 84721, USA
*
Authors to whom correspondence should be addressed.
Antioxidants 2023, 12(3), 636; https://doi.org/10.3390/antiox12030636
Submission received: 23 January 2023 / Revised: 21 February 2023 / Accepted: 22 February 2023 / Published: 3 March 2023
(This article belongs to the Special Issue From Nature to Synthetic Small Molecule Antioxidants: New Candidates in Drug Discovery)
Browse Figures
Review Reports Versions Notes

Abstract

:
It is known that molecular hydrogen is a relatively stable, ubiquitous gas that is a minor component of the atmosphere. At the same time, in recent decades molecular hydrogen has been shown to have diverse biological effects. By the end of 2022, more than 2000 articles have been published in the field of hydrogen medicine, many of which are original studies. Despite the existence of several review articles on the biology of molecular hydrogen, many aspects of the research direction remain unsystematic. Therefore, the purpose of this review was to systematize ideas about the nature, characteristics, and mechanisms of the influence of molecular hydrogen on various types of cells, including stem cells. The historical aspects of the discovery of the biological activity of molecular hydrogen are presented. The ways of administering molecular hydrogen into the body are described. The molecular, cellular, tissue, and systemic effects of hydrogen are also reviewed. Specifically, the effect of hydrogen on various types of cells, including stem cells, is addressed. The existing literature indicates that the molecular and cellular effects of hydrogen qualify it to be a potentially effective agent in regenerative medicine.

1. Introduction

In recent decades, medical gases have deservedly attracted much attention from specialists in the field of biomedicine. At the same time, the spectrum of gases for which biological effects have been discovered and a beneficial effects have been observed is quite wide and continues to increase [1,2,3]. Initially, the concept of “medical gases” extended only to oxygen and hyperbaric O2 procedures, followed by the introduction of the inhalation of anesthetics and ozone into medical practice. At the same time, among these gases, only ozone had specific bioregulatory effects, while other factors either contributed to the elimination of hypoxia, or had a systemic anesthetic effect, being considered as a pharmacological (synthetic) agent.
The prospect of using endogenously formed low-molecular-weight gaseous compounds as regulators began to arise only after the establishment of the biological activity of nitrogen monoxide (i.e., nitric oxide; NO•), for which the Nobel Prize in Medicine and Physiology was awarded [4]. Later, the ability of other substances—previously considered exclusively as toxic—to act as endogenous gaso-transmitters was discovered. These substances formed a triumvirate, which, in addition to nitric oxide, included hydrogen sulfide and carbon monoxide [5].
In parallel, ideas were developed about the biological properties of inert gases (helium, argon, xenon, etc.) which are chemically inactive under standard conditions, but show a modulating effect on cells and tissues [6,7,8,9]. These ideas served as the basis for the creation of innovative therapeutic technologies, the prospects of which continue to be studied and expanded upon.
Recently, molecular hydrogen, which has several unique characteristics, has occupied a special place in medical gas therapy. This gas, which has no specific color or smell, is created from the lightest chemical element, is ubiquitous, and, due to its size and minimal molecular weight, can penetrate through any biological barrier [10,11,12]. Many supplements and antioxidants require specific transporters to enter the cells and realize their effect, whereas H2 does not need them due it is smaller molecular weight/size (Figure 1). The high bioavailability of H2 satisfies the first requirement of any pharmacological agent to have a biological effect. However, there are additional properties that are needed to explain the breadth of the biomodulating and, consequently, therapeutic effect of this gas.
The body of knowledge in the field of H2 biomedicine is being actively updated, including about 100 randomized controlled trials and more than 2000 articles that have been published by the end of 2022 (Figure 2). Various aspects of the issue are considered in detail, but the focus of research is largely shifted towards the cardiac [11,13], neurological [14,15], and radioprotective effects [16,17] of hydrogen. Several studies assessed the possibility and expediency of using hydrogen in oncological diseases [18,19,20]. On the other hand, cellular effects, which are fundamentally significant for regenerative medicine, are revealed only indirectly. In this regard, the purpose of this review is to systematize ideas about the nature, features, and mechanisms of the influence of H2 on cells, specifically stem cells.

2. A Brief Outline of the History of the Discovery of Molecular Hydrogen as a Biological Agent and the Formation of Hydrogen Biomedicine

Hydrogen in free form was first experimentally obtained in 1671 by Robert Boyle [21] and identified as an independent chemical element in 1766 by Henry Cavendish [22]. Interestingly, by the end of the eighteenth century, Thomas Beddoes had completed the first documented attempt at the medical use of hydrogen for the treatment of patients with tuberculosis [23,24]. Until around 1969, the possibility of endogenous production of H2 in the human body from intestinal bacteria was not known [25,26].
One of the earliest direct uses of hydrogen was in deep sea diving. For example, Lanphier (1972) used Hydroliox (a mixture of hydrogen, helium, and oxygen) to prevent the development of decompression syndrome and nitrogen anesthesia in divers working at great depths [27]. One of the most famous early publications in this field belongs to Doyle et al. (1975), who showed a marked regression of squamous skin carcinoma in mice under the influence of H2 supplied under increased pressure (8 ATM) [26]. They used a gas mixture containing 97.5% hydrogen and 2.5% oxygen. Since that time, isolated reports have appeared on the effectiveness of the use of H2 for other applications [28,29]. However, an article in 2007 by Ohsawa et al. was the trigger for an rapid increase in the interest of specialists into the biological and medical effects of hydrogen [30]. The article presents the results of a successful treatment using inhalation of H2 to prevent the damage induced from ischemia–reperfusion after ischemic stroke in a rat model [30]. The researchers suggested that the main mechanism for achieving this clinical effect is the relief of oxidative stress induced by these pathological conditions.
Most recently, hydrogen therapy was included in the protocol for the management of patients with COVID-19 in China (Chinese Clinical Guidelines (7th edition) for COVID-19 Pneumonia Diagnosis and Treatment, issued by China National Health Commission). For this purpose, based on extensive experimental and clinical studies, it appears that inhalation of a mixture of 66.6% H2 and 33.3% oxygen significantly reduces the rate of deterioration of respiratory lung function in a new coronavirus infection, as well as the development of emphysema and inflammatory reactions in lung tissue in various acute and chronic diseases [31].

3. Routes of Introducing Molecular Hydrogen into the Body

Currently, the range of routes of introducing H2 into the body is extremely wide (Figure 2). First, it is important to emphasize that these methods differ not only in the convenience of application for a specific pathology (e.g., in the case of the treatment of dermatological diseases, hydrogen baths may be the preferred option), but also in the pharmacokinetics of the molecule, which alters its pharmacological activity [32].
Historically, the first way of introducing hydrogen is the use of hyperbaric chambers with an atmosphere rich in hydrogen gas [26]. Despite the encouraging results obtained in the experiments by Dole et al. (1975), work using such a technology was not continued, which may be due to the difficulties of its practical implementation [26].
The most common options for molecular hydrogen therapy are the inhalation of H2-containing gas mixtures of various compositions, the use of hydrogen-saturated water, and the infusion/injection of a sodium chloride solution saturated with H2 (Figure 2) [12]. Each of these pathways has its own characteristics, advantages, and disadvantages, as well as possible different molecular mechanisms of action.
Most studies aimed at evaluating the effectiveness of the use of H2 have used hydrogen-saturated solutions (i.e., hydrogen water, hydrogen saline, etc.). However, studies on the inhalation of hydrogen, especially in clinical use, are increasing [11,17,30,31]. Inhalation of H2 is a fairly simple way of exposure for both laboratory animals and humans. Indeed, this was the method employed by Ohsawa et al. using the rat model of ischemia–reperfusion [30]. In addition, an important advantage of the technology is the possibility of the strict dosing of hydrogen by regulating the exposure time and concentration of H2 in the gas mixture [32,33]. On the other hand, molecular hydrogen is a combustible and explosive gas in the case of its reaction with oxygen. It is assumed that the risk of such a negative effect is quite high when the concentration of H2 in the gas mixture is higher than 4% [17,32,33]. Nevertheless, in some cases, gas mixtures with a high hydrogen content are used, but with special safety requirements. For example, 66.67% H2 and 33.33% O2 is used in the treatment of patients with COVID-19, which is the same hydrogen therapy protocol that has been introduced in China [34]. The effectiveness of H2 inhalation in chronic obstructive pulmonary disease [35,36] and severe bronchial asthma [37] has also been reported. The expediency of such an approach is associated with the variable dose dependence of the antioxidant and anti-inflammatory properties of H2 [32,38].
Considering the physicochemical characteristics and the extremely small size and molecular weight of H2, hydrogen inhalation has ample opportunities for systemic action. Since it easily diffuses through the walls of the alveoli, hydrogen diffuses into the blood plasma and is transported to various organs and tissues. Experimental studies by Cole et al. (2021) have shown that in healthy animals, inhalation of a gas mixture containing 2.4% hydrogen continuously for 72 h does not cause any changes in physiological parameters [39]. At the same time, sanogenetic effects on various organs and tissues have been demonstrated in numerous studies [31,32,33,34,35,36,37].
The most convenient way of introducing molecular hydrogen in clinical practice is drinking water saturated with molecular hydrogen; this option eliminates the explosion and fire hazard of the therapy and ensures its portability, opening up the possibility for the widespread use of H2-containing water. However, this path also has disadvantages associated with low gas solubility [32]. It is known that the saturation of dissolved hydrogen is 0.78 mM (1.57 mg/L) at normal atmospheric pressure and room temperature [40]. This circumstance may be significant since it does not always allow achieving the necessary dose of the molecule to ensure a full clinical effect. In addition, when using this route, it should be considered that the prepared hydrogen water should be applied immediately, since it has a very short period of maintaining the concentration of H2. Moreover, upon ingestion of hydrogen water, a significant amount (>90%) is lost via normal expiration [41]. This at least indicates the high uptake of H2 to pass through the gastrointestinal tract and into the venous system where it reaches the lungs and is exhaled. At the same time, the distribution of hydrogen in various tissues and organs after drinking hydrogen water is not the same. In particular, the penetration of H2 into brain cells when using the route of administration under consideration is minimal [42], which may be of fundamental importance for determining indications for its clinical use.
These above reasons necessitated the search for alternative ways of delivering H2 to tissues, including the creation of nanocomposites with a delayed release of gas [43]. It was assumed that these nanocomposites would be included in the oral tablet form, which would ensure maximum compliance for patients. Such targeted H2 therapy can be carried out using hybrid palladium nanocrystals. This approach was tested in experimental conditions in a model of oncopathology, which allowed not only the confirmation of its anticarcinogenic activity, but also its protection of unchanged cells against hyperthermia [44], as well as the manifestation of oxidative stress and damage induced by ischemia and reperfusion [43,45]. The possibility of using various elements as a basis for hydrogen-releasing nanocomposites (in particular, silicon particles [43]) should be emphasized.
A technology fundamentally similar to the creation of nanocrystals as carriers of H2 is the use of microbubble systems (Figure 2). In recent years, it has been suggested that a specific delivery of hydrogen using microbubbles provides maximum bioavailability and a minimization of “transport losses” of the molecule [46]. An important advantage of this pathway is the possibility of introducing significantly higher amounts of gas compared to the intake of water that has been saturated with H2. The effectiveness of the method was demonstrated in a model of ischemic myocardial injury in rats [46].
The third main route of introducing H2 into the body is the use of injections and infusions of an H2-saturated isotonic saline solution [17,32,33]. The specified path also has advantages and disadvantages. For one, this path allows the dosing of the injected amount of hydrogen with high accuracy, the use of different concentrations, an increase in the bioavailability of the agent to the target organ, and, if necessary, a carrying out of the topical effects on strictly defined areas of tissues (e.g., surface localization or areas of catheterization and injection). At the same time, injections of hydrogen solutions pose a certain risk of invasiveness and, consequently, infection, while also requiring the involvement of experienced medical personnel for manipulation. The administration of these solutions is mainly performed intravenously (in patients) or intraperitoneally (in experimental studies using laboratory animals) [17]. In our opinion, the clinical potential of this route of administration is not fully developed, as evidenced the rich experience of intravenous ozone therapy, also based on the effects of a medical gas [47,48,49].
Currently, the literature describes alternative routes of using molecular hydrogen, which use both its systemic and local action (Figure 2). In particular, an example of the effective administration of H2 in dermatology and cosmetology is the use of hydrogen baths for psoriasis [50] and liposuction [51]. A variant of H2 therapy close to this technology is the use of eye drops saturated with the gas in question for the treatment of ischemic lesions of the iris of the eye, as well as the suppression of apoptosis [52]. Stimulation of the endogenous synthesis of H2 by symbiotic microflora is of particular interest. It has been shown that oral administration of lactulose increases the synthesis of H2 by bacteria of the gastrointestinal tract [53]. Moreover, a hydrogen breathing test has been proposed to determine the state of the intestinal microflora by its ability to generate molecular hydrogen [54]. It is important to emphasize that hydrogen is synthesized by microorganisms together with other gases (for example, methane) [55]. At the same time, the amount of hydrogen produced is the result of the balance of activity of the H2-producing (hydrogenogenic) and H2-utilizing (hydrogenotrophic) intestinal microbes [56].
A few more exclusive H2 pathways should also be noted, including probe feeding with the inclusion of a solution saturated with H2 [57], introduction during hemodialysis [58], local treatment of the skin surface [59], the addition of hydrogen to the preservation medium for transplanted organs to prevent cold damage [60], and the washing of various body cavities.
As mentioned previously, different routes of administration differ not only in their proximity to the point of exposure, but also in their pharmacokinetics [32]. In particular, it was found that the concentration of hydrogen in the blood increases rapidly after inhalation, but 3 min after cessation, it decreases to 1/40 of the peak value [61]. At the same time, the amount of hydrogen in arterial blood during inhalation always exceeds that in venous blood, which may indicate the diffusion of the gas into the tissues [61]. It is also shown that the peak values during inhalation of H2 and the intake of hydrogen water are achieved at the same time (e.g., 10–30 min depending on concentration/dose). However, the duration that H2 remains in the body before returning to baseline lasts longer than 30 min [62]. It should be noted that the effect on molecular cascades (e.g., on the expression of NF-KB and other regulatory proteins in liver tissue) is more pronounced for hydrogen water, and the combination of its intake with H2 inhalation enhances the effect [62]. Interestingly, the tissue concentration of H2 was significantly higher and persisted for a longer time after inhalation compared to drinking hydrogen water [42]. Naturally, with intravenous administration of isotonic solutions saturated with hydrogen, the peak breath concentration of the molecule is reached as quickly as possible, within 1 min [10].
Thus, at present, there is a wide range of routes of introducing molecular hydrogen into the body, differing not only in the topical and physico–chemical parameters, but also in the pharmacokinetics of the action of the molecule.

4. Characteristics of Molecular and Cellular Aspects of the Biological Action of H2

The combination of routes of introducing H2 into the body indicated in the previous section is necessary for the realization of numerous biological and beneficial effects of this gaseous molecule. These include antioxidant, anti-apoptotic, anti-inflammatory activity, the regulation of gene expression, etc. However, diverse molecular mechanisms are primarily involved that mediate the unique effects of molecular hydrogen (Figure 3).

4.1. Antioxidant Effects

Historically, the first and most significant molecular cascade activated by H2 is its effect on free radical processes in biological fluids (primarily in blood) and tissues [30]. Oxidant homeostasis is an interaction and balance of free radical generation and utilization by enzyme and non-enzyme antioxidant systems [63,64]. The spectrum of the main molecules and ions involved in free radical reactions includes a set of oxidative oxygen (e.g., hydroxyl radical, superoxide radical, ozone, singlet oxygen, hydrogen peroxide, etc.), nitrogen (e.g., nitric oxide, nitrosonium, peroxynitrite), halogen (e.g., hypochlorite), and lipid (e.g., lipooxyl radical) species [63,64,65]. Under physiological conditions, these bio-oxidants participate in various extracellular and intracellular processes, including signaling cascades, in which they act as primary or secondary messengers [63]. The majority of the reactive oxygen species inside a cell is generated in the mitochondrial electron transport chain, primarily by complexes 1 and 3 [66]. In addition, free radicals are formed with the participation of NADPH-oxidase, NO-synthases, xanthine oxidase, cytochrome p450, aldehyde dehydrogenase, hemoproteins, etc. [67]. Under the influence of adverse factors of various nature (physical, chemical, biological, etc.) or the presence of systemic or local pathology, the imbalance between the excessive generation of these oxidants and the activity of their detoxification by enzymatic and non–enzymatic antioxidant systems form a special pathological condition—oxidative stress [68,69,70,71]. This condition is one of the most universal and serves as a component of the pathogenesis of a wide range of diseases by inducing damage to cells [70,72]. Therefore, the relief of oxidative stress should be considered as a significant goal of complex treatment.
Currently, many studies have assumed that the effect of H2 on the state of oxidative metabolism consists of the direct capture of free radicals and a regulatory effect on antioxidant systems. The first component of the antioxidant effect of the gas in question is realized by the direct interaction of hydrogen with toxic oxidants, primarily hydroxyl (•OH) and peroxynitrite (ONOO−) [30]. This is of fundamental importance, since it is these oxidant molecules that have the maximum oxidative activity, which is shown using a specific fluorescent probe (2′,7′-dichlorodihydrofluorescin; DCF) (Figure 4) [73]. It should be emphasized that H2 is a new type of antioxidant, since it selectively disposes of •OH and ONOO− without rendering a significant effect on the level of hydrogen peroxide and the superoxide radical, and thus does not violate the mechanisms of cellular signaling [32,74]. It is important to emphasize that the neutralization of radicals can occur in the extracellular space (including in biological fluids), as well as in any cell compartments, including plasma and mitochondrial membranes, due to the unique small size of the H2 molecule, which gives it a high permeability through any biological barriers [74,75].
Hydrogen can also have an antioxidant effect by stimulating the corresponding antioxidant enzymes. In 2001, Gharib et al. demonstrated that H2 inhalation enhanced the catalytic properties of superoxide dismutase [76]. This effect was due to the induction of the Nrf2 pathway [77]. This factor directly increases the expression of several antioxidant enzymes and proteasomes, as well as hemoxygenase-1 [78,79]. The stimulating effect of H2 on catalase and myeloperoxidase activity was also noted [80]. In addition, the ability of H2 to inhibit the expression of genes associated with the production of peroxynitrite has been established [81].
An additional mechanism for the realization of the antioxidant effect of hydrogen is the effect on signal-regulating kinase-1 (ASK1) and the regulatory pathway of mitogen-activated protein kinase (p38-MAPK), which mediates the antioxidant activity of the compound and its anti-apoptotic properties [33]. Stimulation of these cascades leads to the inhibition of NADPH oxidase activity and, consequently, a decrease in the rate of free radical generation. The combination of these effects makes it possible to characterize H2 as a universal broad-spectrum antioxidant.

4.2. Anti-Inflammatory Effects

The anti-inflammatory effects of H2 are closely associated with its antioxidant and anti-inflammatory effects and involve similar or identical mechanisms in their implementation. For example, as discussed in the previous section, molecular hydrogen influences ASK1- and p38 MAPK-dependent regulatory pathways, which are also involved in inflammation. Excessive generation of bioradicals can stimulate an inflammatory response due to activation of NF-kB, the p53 gene, hypoxia-inducible factor-1α, matrix metalloproteinases, etc. [82,83].
It was revealed that at an early stage of the inflammatory reaction, the use of H2 reduces the degree of infiltration of neutrophils and macrophages by inhibiting the expression of cell adhesion molecules (ICAM-1) and several chemokines (including MIP-1a and MIP-2) [84]. In addition, the agent in question reduces the concentration of proinflammatory cytokines (IL-1β, TNF-α, IL-6, IFN-γ, etc.) and several colony-stimulating factors (GMCSF, G-CSF), as well as factor HMGB-1 [85]. Special attention should be paid to the data that hydrogen-saturated water inhibits the main regulatory inflammatory cascade triggered by NF-kB [86]. This factor, induced by IL-1β and TNF-α, as well as by reactive oxygen species, is an important H2 mediator by the following mechanisms:
-
inhibition of the activity of NF-kB itself and its associated cytokines [87];
-
blockade of factor translocation from the cytoplasm to nucleus [88,89];
-
an increase in the level of IkB, which hinders the binding of NF-kB to DNA [88,89,90].
Another potential mechanism of the anti-inflammatory action of H2 is the activation of IL-10, which directly suppresses the intensity of the inflammatory response at the local level (e.g., in wound tissues) or at the whole-body level [88,89]. Additionally, the positive effect of hydrogen on the balance of subtypes of T-helper cells and their ratios relative to T-regulatory lymphocytes and mast cells was reported [88,89,90]. These effects may contribute the increase in the concentration of IL-10 following H2 administration. The combined molecular response of these components due to the action of H2 mediates not only the anti-inflammatory, but also the immunomodulatory effect of the medical gas.

4.3. Anti-Apoptotic Effects

It is known that apoptosis is a classic process of programmed cell death, which allows destroying the target cell without triggering an inflammatory reaction [88]. Apoptosis, depending on its features, can acts in various physiological and pathological processes, and therefore its regulation is fundamentally important for the functioning of the body [90,91]. Modern ideas about the molecular mechanisms of apoptosis include sequential activation of cysteine proteases called effector caspases [92], endonucleases, and aggregates of Bcl family proteins [91,93].
It is shown that H2 can have multifactorial effects on the process of autophagy [38]. In general, this gas inhibits apoptosis by affecting the signaling pathways regulating apoptosis and its associated proteins, including phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt), and 3ß-kinase glycogen synthase (GSK3ß) [94]. The use of hydrogen negatively affects the degree of activation of the cascades, including ASK1/JNK [95], ERK 1/2, and MEK 1/2, and inhibits of the activity of caspases 3, 8, and 9, as well as the Bcl/Bax system [95,96]. In addition, the anti-apoptotic effect of H2 is closely associated with the two effects described above, since reducing the severity of inflammatory reactions and relieving oxidative stress reduces the need for cell removal by apoptosis [97]. A similar effect is exerted by influences that contribute to maintaining the integrity and functional activity of mitochondria [98]. The regulation of autophagy serves to reduce the intensity of apoptosis, forming an important balance between these processes.
It should be noted that in some cases, the use of H2 can also have a pro-apoptotic effect. In particular, in some types of cancer, the medical gas stimulates early and late apoptosis, which makes it possible to effectively remove tumor cells from the body, reduce the level of proliferation in the tumor tissue, and increase the rate of its destruction [99]. At the same time, the mechanisms underlying such a paradoxical effect have not been practically studied. Thus, it is possible to state the specific directional nature (promotion or inhibition) of the influence of H2 on the processes of apoptosis.

4.4. Regulation of Pyroptosis

Pyroptosis is a relatively new form of programmed cell death, fundamentally different from apoptosis in that it induces an inflammatory reaction. Inflammation in this case is provoked by the activation of pattern-recognizing receptors in special structures called inflammasomes [100]. It is believed that this mechanism has a protective quality, but excessive stimulation of this process contributes to the development or progression of pathology. The factors contributing to the induction of pyroptosis include reactive oxygen species, casapase-1, and the inflammasomes [101]. According to the data presented above, molecular hydrogen has an anti-inflammatory and antioxidant effect, which makes it possible to block all these factors, preventing excessive activation of pyroptosis. In addition, hydrogen can inhibit pyroptosis-initiated inflammatory diseases by reducing free radicals as substrates of oxidative stress and NLRP3 depression, which allows the preservation of tissue function and its micro- and macrostructure [102].

4.5. Modulation of Autophagy

Autophagy, also called partial macro-autophagy, is a catabolic process that supports cellular homeostasis and is implemented with the participation of lysosomes and the ubiquitin–proteasome system [103]. This process, which initially has exclusively physiological significance, under certain conditions (in particular, under the action of stressors of abnormal intensity and/or duration) acquires a disadaptive character [104]. It has been shown that H2 can have a dualistic effect on the autophagy process. On the one hand, hydrogen can stimulate a specific nucleotide-bearing domain and inhibit NLRP3 in macrophages and limit inflammatory reactions [88,105]. This makes it possible to achieve a protective effect by stimulating autophagy and providing an “intracellular renewal” procedure.
On the other hand, in some pathological conditions, autophagy acquires the character of being impaired or excessive. Under these conditions, it is advisable not to stimulate, but to inhibit this process [33]. In particular, in acute pulmonary pathology caused by lipopolysaccharide of pathogenic bacteria, the use of H2 limits excessive autophagy [33]. Similarly, in brain injuries, hydrogen therapy contributes to the inhibition of autophagy, which increases the survival of endothelial cells in the microcirculatory bed of brain tissue [106].

4.6. Cellular and Tissue Effects of Molecular Hydrogen

The numerous molecular effects of molecular hydrogen naturally cause the formation of shifts in the functioning of cells and tissues, and the nature of the modulating action of H2 directly depends on the path of the compound entering the body (Figure 5). Thus, when using H2 in the form of inhalation or through the intake of H2-saturated water, tissue barriers must be overcome for dissemination throughout the body (hemato–alveolar or enteral). In these locations, it is assumed that the local action of the compound will be realized while hydrogen will penetrate the alveolocytes/enterocytes, inducing a combination of the molecular effects shown in the diagram. The most significant among these effects are the antioxidant effect, post-translational modifications, shifts in the level of phosphorylation of various proteins, and the modulation of the structural and functional status of mitochondria. In addition, H2 entering the nucleus is possible, and regulation of gene expression, as well as epigenetic control—perhaps via the prevention of oxidative modification of DNA and histone proteins—can occur.
After overcoming tissue barriers at the site of primary contact, as well as when using injection of hydrogen solutions, H2 enters the blood, where it also has several significant effects. In this biological fluid, the cornerstone action is the modulation of oxidative metabolism with the capture of toxic radicals and the rejuvenation of endogenous antioxidants. However, alternative effects should also be considered, including the effect on blood clotting factor and surface receptor structures. In principle, an anti-atherogenic effect is also possible due to the protection of endotheliocytes with respect to oxidative damage.
Further transport of H2 to various organs and tissues ensures the development of systemic effects, which include:
-
organoprotective effects;
-
minimization of the consequences of ischemic–reperfusion lesions;
-
limitation of systemic inflammatory responses;
-
antitumor effects;
-
anti-aging effects;
-
increasing the body’s resistance to stressors of various nature;
-
improved exercise tolerance.
In addition, there is evidence for the modulating effect of molecular hydrogen on various types of metabolism (in particular, lipid, protein, and carbohydrate metabolism) [107]. Perhaps a combination of molecular/cellular, and systemic effects presupposes a regulatory role of H2 in the management of the state of various cells, including stem cells.

5. The Effect of Molecular Hydrogen on Various Cell Pools and Regeneration Processes

As already mentioned, the multifactorial biological activity of H2 creates prerequisites for its modulating effect on the processes of cell formation, starting with early precursors—stem cells. This hypothesis is confirmed in the available experimental data obtained in vitro and in vivo and testifying to the positive effect of H2 on all stages of the formation of differentiated cells (Figure 6).
In studies performed on the model of aplastic anemia, it was shown that the use of H2 influences mesenchymal stem cells, as it contributes to an increase in the number of colony-forming units [85,108]. In addition, the introduction of hydrogen positively modulates the state and functional activity of mitochondria in various cancer cells [109]. In particular, this is ensured by the activation of genes responsible for the synthesis of components of complex I of the electron transport chain [109]. The second factor is the fact that the benefits of H2 to the mitochondria include an increase in the mass of this organelle, the concentration of the superoxide radical within it, and an increased membrane potential [109]. These effects together provide an increase in cellular proliferation, at least in some types of cancer cells.
Special attention should be paid to the effect of H2 on mtUPR as a recently identified mediator involved in mitochondrial function [110] and cell survival in adverse conditions [111]. This effect may be associated with the stimulation of HSP production [112]. The stimulating effect of hydrogen on mtUPR is manifested as a change in the level of phosphorylation of eIF2a [112] and shifts in the expression of ATF4 [113] and ATF5 [114]. Such a cascade response provides activation of the protein folding processes. Additionally, this response is facilitated by the induction of HSP60 [115], leading to an increase in collagen synthesis, which is necessary for both cell growth and the formation of intercellular matter. Another factor by which hydrogen may increase its cellular proliferation is its ability to activate GFAP (glial fibrillary acidic protein), a marker of differentiation in glioblastoma cells [116].
An important aspect ensuring the activation of the processes of proliferation, differentiation, and growth of emerging cells is the development of the microenvironment of stem cells. This is facilitated by an increase in the number of colony-forming factors, as well as the regulating effect of cytokines. In particular, the use of H2 induces the activation of CCL-2, which leads to a decrease in the level of proinflammatory cytokines (TNFα, IL-6, IFN-y) [113]. The second mechanism determining the decrease in the concentration of these cytokines is the inhibition of NF-kB, which can also be activated by H2 [117]. In addition, another antioxidation/detoxification enzyme induced by H2 is hemoxygenase-1. This enzyme acts as a strong antioxidant [118] and promotes the stimulation of the synthesis of the anti-inflammatory cytokine IL-10 and the formation of differentiation markers on the cell surface [117]. Although several studies have used various types of cancer cells, the collective results indicate that H2 may provide conditions for the accelerated proliferation, differentiation, and growth of stem cells.
This property of H2 is of great importance for regenerative medicine since its principal task is to develop the most sparing technologies for stimulating tissue regeneration processes. The combination of molecular, cellular, and tissue effects of H2 suggest its multifaceted, pro-regenerative activity, some aspects of which are presented in Figure 7. In particular, the ability of H2 to reduce free radical damage is its fundamental value. Relieving pronounced oxidative stress that inevitably occurs in the tissues of a wound or other tissue defect is key for cellular regeneration [119,120]. The creation of favorable conditions for the restoration of the cellular composition of the tissue is also attained by an anti-inflammatory effect [120,121,122] as well as the formation of intercellular substance components (in particular, collagen). Direct replacement of cellular deficiency occurs due to activation of mesenchymal stem cells, and a stimulation of their proliferation and differentiation which occurs under the influence of molecular hydrogen. This process is additionally induced and regulated by a set of pro-regenerative cytokines and cell migration into a definitive niche, which is facilitated by activation of the expression of cell adhesion molecules [123]. In general, the effect of H2 on the state of mesenchymal stem cells and on tissue regeneration processes should be considered favorable.

6. Conclusions

In conclusion, molecular hydrogen, the lightest and most ubiquitous medical gas, has a wide range of biological activities and is mainly characterized by its antioxidant, anti-inflammatory, and anti-apoptotic actions. It is also involved in the regulation of the expression of numerous genes, the protection of various biomacromolecules from oxidative damage, the stimulation of energy production (ATP) [124,125], and other effects. At the same time, despite the sharp increase in the number of studies and publications on the biomedical applications of molecular hydrogen, the issue of its use as a pro-regenerative agent has not been fully explored. There are numerous advantages in using this molecule due to the wide breadth of molecular responses that it causes. Therefore, conducting targeted research in this area can open new horizons of regenerative medicine and create an innovative technology for accelerated tissue repair.

Author Contributions

Conceptualization, A.K.M., M.Y.A. and T.W.L.; resources, I.A.M.; data curation, F.A.P.; writing—original draft preparation, A.K.M. and M.Y.A.; writing—review and editing, I.A.M., F.A.P., S.V.D. and T.W.L.; supervision, M.Y.A. All authors have read and agreed to the published version of the manuscript.

Funding

This research work was supported by the Academic leadership program Priority 2030 proposed by Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Zafonte, R.S.; Wang, L.; Arbelaez, C.A.; Dennison, R.; Teng, Y.D. Medical Gas Therapy for Tissue, Organ, and CNS Protection: A Systematic Review of Effects, Mechanisms, and Challenges. Adv. Sci. 2022, 9, 2104136. [Google Scholar] [CrossRef] [PubMed]
  2. Teng, Y.D.; Wang, L.; Kabatas, S.; Ulrich, H.; Zafonte, R.D. Cancer Stem Cells or Tumor Survival Cells? Stem Cells Dev. 2018, 27, 1466–1478. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Nazarov, E.I.; Khlusov, I.A.; Noda, M. Homeostatic and endocrine responses as the basis for systemic therapy with medical gases: Ozone, xenon and molecular hydrogen. Med. Gas Res. 2021, 11, 174–186. [Google Scholar] [CrossRef] [PubMed]
  4. Vanin, A.F. Physico-Chemistry of Dinitrosyl Iron Complexes as a Determinant of Their Biological Activity. Int. J. Mol. Sci. 2021, 22, 10356. [Google Scholar] [CrossRef]
  5. Olas, B. Gasomediators (·NO, CO, and H₂S) and their role in hemostasis and thrombosis. Clin. Chim. Acta 2015, 445, 115–121. [Google Scholar] [CrossRef] [PubMed]
  6. Dickinson, R.; Franks, N.P. Bench-to-bedside review: Molecular pharmacology and clinical use of inert gases in anesthesia and neuroprotection. Crit. Care 2010, 14, 229. [Google Scholar] [CrossRef] [Green Version]
  7. Deng, R.M.; Li, H.Y.; Li, X.; Shen, H.T.; Wu, D.G.; Wang, Z.; Chen, G. Neuroprotective effect of helium after neonatal hypoxic ischemia: A narrative review. Med. Gas Res. 2021, 11, 121–123. [Google Scholar] [CrossRef]
  8. Winkler, D.A.; Thornton, A.; Farjot, G.; Katz, I. The diverse biological properties of the chemically inert noble gases. Pharmacol. Ther. 2016, 160, 44–64. [Google Scholar] [CrossRef]
  9. Martusevich, A.; Surovegina, A.; Popovicheva, A.; Didenko, N.; Artamonov, M.; Nazarov, V. Some Beneficial Effects of Inert Gases on Blood Oxidative Metabolism: In Vivo Study. BioMed Res. Int. 2022, 2022, 5857979. [Google Scholar] [CrossRef]
  10. 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, 1–21. [Google Scholar] [CrossRef] [Green Version]
  11. Shen, M.; Zhang, H.; Yu, C.; Wang, F.; Sun, X. A review of experimental studies of hydrogen as a new therapeutic agent in emergency and critical care medicine. Med. Gas Res. 2014, 4, 17. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Hirano, S.I.; Ichikawa, Y.; Kurokawa, R.; Takefuji, Y.; Satoh, F. A “philosophical molecule,” hydrogen may overcome senescence and intractable diseases. Med. Gas Res. 2020, 10, 47–49. [Google Scholar] [CrossRef] [PubMed]
  13. Tao, G.; Song, G.; Qin, S. Molecular hydrogen: Current knowledge on mechanism in alleviating free radical damage and diseases. Acta Biochim. Biophys. Sin. 2019, 51, 1189–1197. [Google Scholar] [CrossRef] [PubMed]
  14. Wang, L.; Zhao, C.; Wu, S.; Xiao, G.; Zhuge, X.; Lei, P.; Xie, K. Hydrogen gas treatment improves the neurological outcome after traumatic brain injury via increasing miR-21 expression. Shock 2018, 50, 308–315. [Google Scholar] [CrossRef] [PubMed]
  15. Wu, J.; Wang, R.; Yang, D.; Tang, W.; Chen, Z.; Sun, Q.; Liu, L.; Zang, R. Hydrogen postconditioning promotes survival of rat retinal ganglion cells against ischemia/reperfusion injury through the PI3K. Akt pathway. Biochem. Biophys. Res. Commun. 2018, 495, 2462–2468. [Google Scholar] [CrossRef]
  16. Hirano, S.-I.; Ichikawa, Y.; Sato, B.; Yamamoto, H.; Takefuji, Y.; Satoh, F. Molecular Hydrogen as a Potential Clinically Applicable Radioprotective Agent. Int. J. Mol. Sci. 2021, 22, 4566. [Google Scholar] [CrossRef]
  17. Hu, Q.; Zhou, Y.; Wu, S.; Wu, W.; Deng, Y.; Shao, A. Molecular hydrogen: A potential radioprotective agent. Biomed. Pharmacother. 2020, 130, 110589. [Google Scholar] [CrossRef]
  18. Runtuwene, J.; Amitani, H.; Amitani, M.; Asakawa, A.; Cheng, K.C.; Inui, K. Hydrogen-water enhances 5-fluorouracil-induced inhibition of colon cancer. PeerJ 2015, 3, e859. [Google Scholar] [CrossRef] [Green Version]
  19. Hirano, S.-I.; Yamamoto, H.; Ichikawa, Y.; Sato, B.; Takefuji, Y.; Satoh, F. Molecular Hydrogen as a Novel Antitumor Agent: Possible Mechanisms Underlying Gene Expression. Int. J. Mol. Sci. 2021, 22, 8724. [Google Scholar] [CrossRef]
  20. Wang, D.; Wang, L.; Zhang, Y.; Zhao, Y.; Chen, G. Hydrogen gas inhibits lung cancer progression through targeting SMC. Biomed. Pharmacol. 2018, 104, 788–797. [Google Scholar] [CrossRef]
  21. Boyle, R. Tracts written by the honourable Robert Boyle Containing New Experiments Touching the Relation Betwixt Flame And Air: And About Explosions: An Hydrostatical Discourse Occasion’d by Some Objections of Dr. Henry More Against Some Explications of New Experiments Made by the Author of these Tracts: To Which is Annex’t, an Hydrostatical Letter, Dilucidating an Experiment about a Way of Weighing Water in Water; Printed for Richard Davis, Book-Seller in Oxon. 1672. Available online: https://quod.lib.umich.edu/e/eebo2/A29057.0001.001/1:21.1?rgn=div2;view=fulltext (accessed on 22 January 2023).
  22. Cavendish, H. XIX. Three papers, containing experiments on factitious air. Phil. Trans. R. Soc. 1766, 56, 141–184. [Google Scholar] [CrossRef]
  23. Beddoes, T. A Letter to Erasmus Darwin, M.D. On A New Method of Treating Pulmonary Consumption, and Some Other Diseases Hitherto Found Incurable; Bulgin & Rosser: Bristol, UK, 1793. [Google Scholar]
  24. Beddoes, T. Considerations on the Medicinal Use, and on the Production of Factitious Airs. Ann. Med. 1796, 1, 245–265. [Google Scholar]
  25. Levitt, M.D. Production and excretion of hydrogen gas in man. N. Engl. J. Med. 1969, 281, 122–127. [Google Scholar] [CrossRef] [PubMed]
  26. Dole, M.; Wilson, F.R.; Fife, W.P. Hyperbaric hydrogen therapy: A possible treatment for cancer. Science 1975, 190, 152–154. [Google Scholar] [CrossRef]
  27. Lanphier, E.H. Human respiration under increased pressures. Symp. Soc. Exp. Biol. 1972, 26, 379–394. [Google Scholar] [PubMed]
  28. van Haaster, D.J.; Hagedoorn, P.L.; Jongejan, J.A.; Hagen, W.R. On the relationship between affinity for molecular hydrogen and the physiological directionality of hydrogenases. Biochem. Soc. Trans. 2005, 33 Pt 1, 12–14. [Google Scholar] [CrossRef]
  29. Yanagihara, T.; Arai, K.; Miyamae, K.; Sato, B.; Shudo, T.; Yamada, M.; Aoyama, M. Electrolyzed Hydrogen-Saturated Water for Drinking Use Elicits an Antioxidative Effect: A Feeding Test with Rats. Biosci. Biotechnol. Biochem. 2005, 69, 1985–1987. [Google Scholar] [CrossRef] [Green Version]
  30. Ohsawa, I.; Ishikawa, M.; Takahashi, K.; Watanabe, M.; Nishimaki, K.; Yamagata, K. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat. Med. 2007, 13, 688–694. [Google Scholar] [CrossRef]
  31. Guan, W.J.; Chen, R.C.; Zhong, N.S. Strategies for the prevention and management of coronavirus disease 2019. Eur. Respir. J. 2020, 55, 2000597. [Google Scholar] [CrossRef] [Green Version]
  32. Tian, Y.; Zhang, Y.; Wang, Y.; Chen, Y.; Fan, W.; Zhou, J.; Qiao, J. Hydrogen, a Novel Therapeutic Molecule, Regulates Oxidative Stress, Inflammation, and Apoptosis. Front. Physiol. 2021, 12, 789507. [Google Scholar] [CrossRef]
  33. Fu, Z.; Zhang, J. Molecular hydrogen is a promising therapeutic agent for pulmonary disease. J. Zhejiang Univ. Sci. B 2022, 23, 102–122. [Google Scholar] [CrossRef] [PubMed]
  34. Guan, W.J.; Wei, C.H.; Chen, A.L.; Sun, X.C.; Guo, G.Y.; Zou, X.; Shi, J.D.; Lai, P.Z.; Zheng, Z.G.; Zhong, N.S. Hydrogen/oxygen mixed gas inhalation improves disease severity and dyspnea in patients with Coronavirus disease 2019 in a recent multicenter, open-label clinical trial. J. Thorac. Dis. 2020, 12, 3448–3452. [Google Scholar] [CrossRef] [PubMed]
  35. Liu, X.; Ma, C.; Wang, X.; Wang, W.; Li, Z.; Wang, X.; Wang, P.; Sun, W.; Xue, B. Hydrogen coadministration slows the development of COPD-like lung disease in a cigarette smoke-induced rat model. Int. J. Chron. Obstruct. Pulmon. Dis. 2017, 12, 1309–1324. [Google Scholar] [CrossRef] [Green Version]
  36. Zheng, Z.G.; Sun, W.Z.; Hu, J.Y.; Jie, Z.J.; Xu, J.F.; Cao, J.; Song, Y.L.; Wang, C.H.; Wang, J.; Zhao, H.; et al. Hydrogen/oxygen therapy for the treatment of an acute exacerbation of chronic obstructive pulmonary disease: Results of a multicenter, randomized, double-blind, parallel-group controlled trial. Respir. Res. 2021, 22, 149. [Google Scholar] [CrossRef]
  37. Huang, P.; Wei, S.; Huang, W.; Wu, P.; Chen, S.; Tao, A.; Wang, H.; Liang, Z.; Chen, R.; Yan, J.; et al. Hydrogen gas inhalation enhances alveolar macrophage phagocytosis in an ovalbumin-induced asthma model. Int. Immunopharmacol. 2019, 74, 105646. [Google Scholar] [CrossRef] [PubMed]
  38. 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]
  39. Cole, A.R.; Sperotto, F.; DiNardo, J.A.; Carlisle, S.; Rivkin, M.J.; Sleeper, L.A.; Kheir, J.N. Safety of prolonged inhalation of hydrogen gas in air in healthy adults. Crit. Care Explor. 2021, 3, e543. [Google Scholar] [CrossRef] [PubMed]
  40. Asada, R.; Tazawa, K.; Sato, S.; Miwa, N. Effects of hydrogen-rich water prepared by alternating-current-electrolysis on antioxidant activity, DNA oxidative injuries, and diabetes related markers. Med. Gas Res. 2020, 10, 114–121. [Google Scholar] [CrossRef] [PubMed]
  41. Shimouchi, A.; Nose, K.; Shirai, M.; Kondo, T. Estimation of molecular hydrogen consumption in the human whole body after the ingestion of hydrogen-rich water. Adv. Exp. Med. Biol. 2012, 737, 245–250. [Google Scholar] [CrossRef]
  42. Liu, C.; Kurokawa, R.; Fujino, M.; Hirano, S.; Sato, B.; Li, X.K. Estimation of the hydrogen concentration in rat tissue using an airtight tube following the administration of hydrogen via various routes. Sci. Rep. 2014, 4, 5485. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Kawamura, M.; Imamura, R.; Kobayashi, Y.; Taniguchi, A.; Nakazawa, S.; Kato, T.; Namba-Hamano, T.; Abe, T.; Uemura, M.; Kobayashi, H.; et al. Oral administration of Si-based agent attenuates oxidative stress and ischemia-reperfusion injury in a rat model: A novel hydrogen administration method. Front. Med. 2020, 7, 95. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Zhao, P.H.; Jin, Z.K.; Chen, Q.; Meng, J.; Lu, X.; He, Q. Local generation of hydrogen for enhanced photothermal therapy. Nat. Commun. 2018, 9, 4241. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Kou, Z.; Zhao, P.H.; Wang, Z.H.; Jin, Z.; Chen, L.; Su, B.L.; He, Q. Acid-responsive H2-releasing Fe nanoparticles for safe and effective cancer therapy. J. Mater. Chem. B 2019, 7, 2759–2765. [Google Scholar] [CrossRef]
  46. He, Y.; Zhang, B.; Chen, Y.; Jin, Q.; Wu, J.; Yan, F. Image-guided hydrogen gas delivery for protection from myocardial ischemia-reperfusion injury via microbubbles. ACS Appl. Mater. Interfaces 2017, 9, 21190–21199. [Google Scholar] [CrossRef] [PubMed]
  47. Katiukhin, L.N. Influence of the course of treatment by injections of ozonized saline on rheological properties of erythrocytes in patients with complex pathology. Hum. Physiol. 2016, 42, 672–677. [Google Scholar] [CrossRef]
  48. Martusevich, A.K.; Peretyagin, S.P.; Ruchin, M.V.; Struchkov, A.A. Ozone Therapy in Patients with Burn Disease. J. Biomed. Sci. Eng. 2018, 11, 27–35. [Google Scholar] [CrossRef] [Green Version]
  49. Martínez-Sánchez, G.; Schwartz, A.; Di Donna, V. Potential Cytoprotective Activity of Ozone Therapy in SARS-CoV-2/COVID-19. Antioxidants 2020, 9, 389. [Google Scholar] [CrossRef]
  50. Zhu, Q.; Wu, Y.; Li, Y.; Chen, Z.; Wang, L.; Xiong, H.; Dai, E.; Wu, J.; Fan, B.; Ping, L.; et al. Positive effects of hydrogen-water bathing in patients of psoriasis and parapsoriasis en plaques. Sci. Rep. 2018, 8, 8051. [Google Scholar] [CrossRef] [Green Version]
  51. Asada, R.; Saitoh, Y.; Miwa, N. Effects of hydrogen-rich water bath on visceral fat and skin blotch, with boiling-resistant hydrogen bubbles. Med. Gas Res. 2019, 9, 68–73. [Google Scholar] [CrossRef]
  52. Oharazawa, H.; Igarashi, T.; Yokota, T.; Fujii, H.; Suzuki, H.; Machide, M. Protection of the retina by rapid diffusion of hydrogen: Administration of hydrogen-loaded eye drops in retinal ischemia-reperfusion injury. Invest. Ophthalmol. Vis. Sci. 2010, 51, 487–492. [Google Scholar] [CrossRef]
  53. 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]
  54. Zhang, M.; Xu, Y.; Zhang, J.; Sun, Z.; Ban, Y.; Wang, B.; Hou, X.; Cai, Y.; Li, J.; Wang, M.; et al. Application of methane and hydrogen-based breath test in the study of gestational diabetes mellitus and intestinal microbes. Diabetes Res. Clin. Pract. 2021, 176, 108818. [Google Scholar] [CrossRef] [PubMed]
  55. Jahng, J.; Jung, I.S.; Choi, E.J.; Conklin, J.L.; Park, H. The effects of methane and hydrogen gases produced by enteric bacteria on ileal motility and colonic transit time. Neurogastroenterol. Motil. 2012, 24, 185-e92. [Google Scholar] [CrossRef] [PubMed]
  56. Ge, L.; Qi, J.; Shao, B.; Ruan, Z.; Ren, Y.; Sui, S.; Wu, X.; Sun, X.; Liu, S.; Li, S.; et al. Microbial hydrogen economy alleviates colitis by reprogramming colonocyte metabolism and reinforcing intestinal barrier. Gut Microbes 2022, 14, 2013764. [Google Scholar] [CrossRef] [PubMed]
  57. 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] [PubMed] [Green Version]
  58. 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]
  59. Ostojic, S.M. Molecular Hydrogen in Sports Medicine: New Therapeutic Perspectives. Int. J. Sports Med. 2015, 36, 273–279. [Google Scholar] [CrossRef] [Green Version]
  60. Noda, K.; Shigemura, N.; Tanaka, Y.; Kawamura, T.; Hyun Lim, S.; Kokubo, K. A novel method of preserving cardiac grafts using a hydrogen-rich water bath. J. Heart Lung Transpl. 2013, 32, 241–250. [Google Scholar] [CrossRef]
  61. Sano, M.; Ichihara, G.; Katsumata, Y.; Hiraide, T.; Hirai, A.; Momoi, M. Pharmacokinetics of a single inhalation of hydrogen gas in pigs. PLoS ONE 2020, 15, e0234626. [Google Scholar] [CrossRef]
  62. Sobue, S.; Yamai, K.; Ito, M.; Ohno, K.; Iwamoto, T. Simultaneous oral and inhalational intake of molecular hydrogen additively suppresses signaling pathways in rodents. Mol. Cell Biochem. 2015, 403, 231–241. [Google Scholar] [CrossRef]
  63. Genestra, M. Oxyl radicals, redox-sensitive signalling cascades and antioxidants. Cell Signal. 2007, 19, 1807–1819. [Google Scholar] [CrossRef] [PubMed]
  64. Sies, H. Oxidative stress: A concept in redox biology and medicine. Redox Biol. 2015, 4, 180–183. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Dan Dunn, J.; Alvarez, L.A.; Zhang, X.; Soldati, T. Reactive oxygen species and mitochondria: A nexus of cellular homeostasis. Redox Biol. 2015, 6, 472–485. [Google Scholar] [CrossRef] [PubMed]
  66. Liu, Y.; Fiskum, G.; Schubert, D. Generation of reactive oxygen species by the mitochondrial electron transport chain. J. Neurochem. 2002, 80, 780–787. [Google Scholar] [CrossRef] [PubMed]
  67. Halliwell, B.; Gutteridge, J. Free Radicals in Biology and Medicine, 5th ed.; Oxford University Press: Oxford, UK, 2015. [Google Scholar] [CrossRef]
  68. Grassi, D.; Desideri, G.; Ferri, L.; Aggio, A.; Tiberti, S.; Ferri, C. Oxidative stress and endothelial dysfunction: Say no to cigarette smoking! Curr. Pharm. Des. 2010, 16, 2539–2550. [Google Scholar] [CrossRef]
  69. Harma, M.I.; Harma, M.; Erel, O. Measuring plasma oxidative stress biomarkers in sport medicine. Eur. J. Appl. Physiol. 2006, 97, 505–508. [Google Scholar] [CrossRef]
  70. Kim, Y.W.; Byzova, T.V. Oxidative stress in angiogenesis and vascular disease. Blood 2014, 123, 625–631. [Google Scholar] [CrossRef] [Green Version]
  71. Tanriverdi, H.; Evrengul, H.; Kuru, O.; Tanriverdi, S.; Seleci, D.; Enli, Y.; Kaftan, A.H.; Kilic, M. Cigarette smoking induced oxidative stress may impair endothelial function and coronary blood flow in angiographically normal coronary arteries. Circ. J. 2006, 70, 593–599. [Google Scholar] [CrossRef] [Green Version]
  72. Burton, G.J.; Jauniaux, E. Oxidative stress. Best Pract. Res. Clin. Obstet. Gynaecol. 2011, 25, 287–299. [Google Scholar] [CrossRef] [Green Version]
  73. Setsukinai, K.; Urano, Y.; Kakinuma, K.; Majima, H.J.; Nagano, T. Development of novel fluorescence probes that can reliably detect reactive oxygen species and distinguish specific species. J. Biol. Chem. 2003, 278, 3170–3175. [Google Scholar] [CrossRef] [Green Version]
  74. 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]
  75. Ohta, S. Molecular hydrogen as a novel antioxidant: Overview of the advantages of hydrogen for medical applications. Methods Enzymol. 2015, 555, 289–317. [Google Scholar] [CrossRef]
  76. 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]
  77. Zhang, H.Q.; Davies, K.J.A.; Forman, H.J. Oxidative stress response and Nrf2 signaling in aging. Free Radic. Biol. Med. 2015, 88, 314–336. [Google Scholar] [CrossRef] [Green Version]
  78. Xie, K.L.; Zhang, Y.; Wang, Y.Q.; Meng, X.; Wang, Y.; Yu, Y.; Chen, H. Hydrogen attenuates sepsis-associated encephalopathy by NRF2 mediated NLRP3 pathway inactivation. Inflamm. Res. 2020, 69, 697–710. [Google Scholar] [CrossRef]
  79. Yu, Y.; Yang, Y.Y.; Yang, M.; Wang, C.; Xie, K.; Yu, Y. Hydrogen gas reduces HMGB1 release in lung tissues of septic mice in an Nrf2/ HO-1-dependent pathway. Int. Immunopharmacol. 2019, 69, 11–18. [Google Scholar] [CrossRef]
  80. Cai, W.W.; Zhang, M.H.; Yu, Y.S.; Cai, J.H. Treatment with hydrogen molecule alleviates TNFα-induced cell injury in osteoblast. Mol. Cell. Biochem. 2013, 373, 1–9. [Google Scholar] [CrossRef]
  81. Shinbo, T.; Kokubo, K.; Sato, Y.; Hagiri, S.; Hataishi, R.; Hirose, M.; Kobayashi, H. Breathing nitric oxide plus hydrogen gas reduces ischemia-reperfusion injury and nitrotyrosine production in murine heart. Am. J. Physiol. Circ. Physiol. 2013, 305, 542–550. [Google Scholar] [CrossRef] [Green Version]
  82. Forrester, S.J.; Kikuchi, D.S.; Hernandes, M.S.; Xu, Q.; Griendling, K.K. Reactive oxygen species in metabolic and inflammatory signaling. Circ. Res. 2018, 122, 877–902. [Google Scholar] [CrossRef]
  83. Rimessi, A.; Previati, M.; Nigro, F.; Wieckowski, M.R.; Pinton, P. Mitochondrial reactive oxygen species and inflammation: Molecular mechanisms, diseases and promising therapies. Int. J. Biochem. Cell Biol. 2016, 81 Pt B, 281–293. [Google Scholar] [CrossRef]
  84. Chen, M.; Zhang, J.; Chen, Y.; Qiu, Y.; Luo, Z.; Zhao, S.; Du, L.; Tian, D. Hydrogen protects lung from hypoxia/re-oxygenation injury by reducing hydroxyl radical production and inhibiting inflammatory responses. Sci. Rep. 2018, 8, 8004. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Zhao, S.; Mei, K.; Qian, L.; Yang, Y.; Liu, W.; Huang, Y.; Zhang, C.; Sun, X.; Liu, C.; Li, B.; et al. Therapeutic effects of hydrogen-rich solution on aplastic anemia in vivo. Cell. Physiol. Biochem. 2013, 32, 549–560. [Google Scholar] [CrossRef] [PubMed]
  86. Wang, X.; Yu, P.; Yang, Y.; Liu, X.; Jiang, J.; Liu, D.; Xue, G. Hydrogen-rich saline resuscitation alleviates inflammation induced by severe burn with delayed resuscitation. Burns 2015, 41, 379–385. [Google Scholar] [CrossRef] [PubMed]
  87. Schulze-Osthoff, K.; Los, M.; Baeuerle, P.A. Redox signalling by transcription factors NF-κB and AP-1 in lymphocytes. Biochem. Pharmacol. 1995, 50, 735–741. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Shao, A.; Wu, H.; Hong, Yu.; Tu, S.; Sun, X.; Wu, Q.; Zhao, Q.; Zhang, J.; Sheng, J. Hydrogen-rich saline attenuated subarachnoid hemorrhage-induced early brain injury in rats by suppressing inflammatory response: Possible involvement of NF-κB pathway and NLRP3 inflammasome. Mol. Neurobiol. 2016, 53, 3462–3476. [Google Scholar] [CrossRef]
  89. Zhang, G.; Li, Z.; Meng, C.; Kang, J.; Zhang, M.; Ma, L.; Zhou, H. The anti-inflammatory effect of hydrogen on lung transplantation model of pulmonary microvascular endothelial cells during cold storage period. Transplantation 2018, 102, 1253–1261. [Google Scholar] [CrossRef]
  90. Radyuk, S.N. Mechanisms Underlying the Biological Effects of Molecular Hydrogen. Curr. Pharm. Des. 2021, 27, 626–735. [Google Scholar] [CrossRef]
  91. Elmore, S. Apoptosis: A review of programmed cell death. Toxicol. Pathol. 2007, 35, 495–516. [Google Scholar] [CrossRef]
  92. Singh, R.; Letai, A.; Sarosiek, K. Regulation of apoptosis in health and disease: The balancing act of BCL-2 family proteins. Nat. Rev. Mol. Cell Biol. 2019, 20, 175–193. [Google Scholar] [CrossRef]
  93. Shalini, S.; Dorstyn, L.; Dawar, S.; Kumar, S. Old, new and emerging functions of caspases. Cell Death Differ. 2015, 22, 526–539. [Google Scholar] [CrossRef] [Green Version]
  94. Westphal, D.; Kluck, R.M.; Dewson, G. Building blocks of the apoptotic pore: How Bax and Bak are activated and oligomerize during apoptosis. Cell Death Differ. 2014, 21, 196–205. [Google Scholar] [CrossRef] [Green Version]
  95. Chen, K.; Wang, N.; Diao, Y.; Dong, W.; Sun, Y.; Liu, L.; Wu, X. Hydrogen-rich saline attenuates brain injury induced by cardiopulmonary bypass and inhibits microvascular endothelial cell apoptosis via the PI3K/Akt/GSK3β signaling pathway in rats. Cell. Physiol. Biochem. 2017, 43, 1634–1647. [Google Scholar] [CrossRef]
  96. Liu, Y.Q.; Liu, Y.F.; Ma, X.M.; Xiao, Y.D.; Wang, Y.B.; Zhang, M.Z.; Cheng, A.X.; Wang, T.T.; Li, J.L.; Zhao, P.X.; et al. Hydrogen-rich saline attenuates skin ischemia/reperfusion induced apoptosis via regulating Bax/Bcl-2 ratio and ASK-1/JNK pathway. J. Plast. Reconstr. Aesthetic Surg. 2015, 68, 147–156. [Google Scholar] [CrossRef]
  97. Mo, X.Y.; Li, X.M.; She, C.S.; Lu, X.Q.; Xiao, C.G.; Wang, S.H.; Huang, G.Q. Hydrogen-rich saline protects rat from oxygen glucose deprivation and reperfusion-induced apoptosis through VDAC1 via Bcl-2. Brain Res. 2019, 1706, 110–115. [Google Scholar] [CrossRef] [PubMed]
  98. Li, J.; Hong, Z.J.; Liu, H.; Zhou, J.; Cui, L.; Yuan, S.; Chu, X.; Yu, P. Hydrogen-rich saline promotes the recovery of renal function after ischemia/ reperfusion injury in rats via anti-apoptosis and anti-inflammation. Front. Pharmacol. 2016, 7, 106. [Google Scholar] [CrossRef] [Green Version]
  99. Jiao, Y.; Yu, Y.; Li, B.; Gu, X.; Xie, K.; Wang, G.; Yu, Y. Protective effects of hydrogen-rich saline against experimental diabetic peripheral neuro- pathy via activation of the mitochondrial ATP-sensitive potassium channel channels in rats. Mol. Med. Rep. 2020, 21, 282–290. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  100. Yang, Y.; Liu, P.Y.; Bao, W.; Chen, S.J.; Wu, F.S.; Zhu, P.Y. Hydrogen inhibits endometrial cancer growth via a ROS/NLRP3/caspase-1/GSDMD-mediated pyroptotic pathway. BMC Cancer 2020, 20, 28. [Google Scholar] [CrossRef]
  101. Shi, J.J.; Gao, W.Q.; Shao, F. Pyroptosis: Gasdermin-mediated programmed necrotic cell death. Trends Biochem. Sci. 2017, 42, 245–254. [Google Scholar] [CrossRef] [PubMed]
  102. Zha, Q.B.; Wei, H.X.; Li, C.G.; Liang, Y.D.; Xu, L.H.; Bai, W.J.; Pan, H.; He, X.H.; Ouyang, D.Y. ATP-induced inflammasome activation and pyroptosis is regulated by AMP-activated protein kinase in macrophages. Front. Immunol. 2016, 7, 597. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Nie, C.; Ding, X.A.R.; Zheng, M.; Li, Z.; Pan, S.; Yang, W. Hydrogen gas inhalation alleviates myocardial ischemia-reperfusion injury by the inhibition of oxidative stress and NLRP3-mediated pyrop- tosis in rats. Life Sci. 2021, 272, 119248. [Google Scholar] [CrossRef] [PubMed]
  104. Yang, Z.F.; Klionsky, D.J. Mammalian autophagy: Core molecular machinery and signaling regulation. Curr. Opin. Cell Biol. 2010, 22, 124–131. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  105. Maiuri, M.C.; Zalckvar, E.; Kimchi, A.; Kroemer, G. Self-eating and self-killing: Crosstalk between autophagy and apop-tosis. Nat. Rev. Mol. Cell Biol. 2007, 8, 741–752. [Google Scholar] [CrossRef] [PubMed]
  106. Chen, H.; Mao, X.; Meng, X.; Li, Y.; Feng, J.; Zhang, L.; Zhang, Y.; Wang, Y.; Yu, Y.; Xie, K. Hydrogen alleviates mitochondrial dysfunction and organ damage via autophagy-mediated NLRP3 inflammasome inactivation in sepsis. Int. J. Mol. Med. 2019, 44, 1309–1324. [Google Scholar] [CrossRef] [Green Version]
  107. Wang, Y.; Wang, L.; Hu, T.; Wang, F.; Han, Z.; Yin, Z.; Ge, X.; Xie, K.; Lei, P. Hydrogen improves cell viability partly through inhibition of autophagy and activation of PI3K/Akt/GSK3β signal pathway in a micro- vascular endothelial cell model of traumatic brain injury. Neurol. Res. 2020, 42, 487–496. [Google Scholar] [CrossRef]
  108. Adzavon, Y.M.; Xie, F.; Yi, Y.; Jiang, X.; Zhang, X.; He, J.; Zhao, P.; Liu, M.; Ma, S.; Ma, X. Long-term and daily use of molecular hydrogen induces reprogramming of liver metabolism in rats by modulating NADP/NADPH redox pathways. Sci. Rep. 2022, 12, 3904. [Google Scholar] [CrossRef]
  109. Kawasaki, H.; Guan, J.; Tamama, K. Hydrogen gas treatment prolongs replicative lifespan of bone marrow multipotential stromal cells in vitro while preserving differentiation and paracrine potentials. Biochem. Biophys. Res. Commun. 2010, 397, 608–613. [Google Scholar] [CrossRef]
  110. Hasegawa, T.; Ito, M.; Hasegawa, S.; Teranishi, M.; Takeda, K.; Negishi, S.; Nishiwaki, H.; Takeda, J.-i.; LeBaron, T.W.; Ohno, K. Molecular Hydrogen Enhances Proliferation of Cancer Cells That Exhibit Potent Mitochondrial Unfolded Protein Response. Int. J. Mol. Sci. 2022, 23, 2888. [Google Scholar] [CrossRef]
  111. Fiorese, C.J.; Schulz, A.M.; Lin, Y.F.; Rosin, N.; Pellegrino, M.W.; Haynes, C.M. The Transcription Factor ATF5 Mediates a Mammalian Mitochondrial UPR. Curr. Biol. 2016, 26, 2037–2043. [Google Scholar] [CrossRef] [Green Version]
  112. Wu, Z.; Senchuk, M.M.; Dues, D.J.; Johnson, B.K.; Cooper, J.F.; Lew, L.; Machiela, E.; Schaar, C.E.; DeJonge, H.; Blackwell, T.K.; et al. Mitochondrial unfolded protein response transcription factor ATFS-1 promotes longevity in a long-lived mitochondrial mutant through activation of stress response pathways. BMC Biol. 2018, 16, 147. [Google Scholar] [CrossRef] [Green Version]
  113. Lin, Y.F.; Haynes, C.M. Metabolism and the UPR(mt). Mol. Cell 2016, 61, 677–682. [Google Scholar] [CrossRef] [Green Version]
  114. Zhao, Y.S.; An, J.R.; Yang, S.; Guan, P.; Yu, F.Y.; Li, W.; Li, J.R.; Guo, Y.; Sun, Z.M.; Ji, E.S. Hydrogen and Oxygen Mixture to Improve Cardiac Dysfunction and Myocardial Pathological Changes Induced by Intermittent Hypoxia in Rats. Oxidative Med. Cell. Longev. 2019, 2019, 7415212. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  115. Wang, Y.T.; Lim, Y.; McCall, M.N.; Huang, K.T.; Haynes, C.M.; Nehrke, K.; Brookes, P.S. Cardioprotection by the mitochondrial unfolded protein response requires ATF. Am. J. Physiol. Heart Circ. Physiol. 2019, 317, H472–H478. [Google Scholar] [CrossRef]
  116. Berger, E.; Rath, E.; Yuan, D.; Waldschmitt, N.; Khaloian, S.; Allgauer, M.; Staszewski, O.; Lobner, E.M.; Schottl, T.; Giesbertz, P.; et al. Mitochondrial function controls intestinal epithelial stemness and proliferation. Nat. Commun. 2016, 7, 13171. [Google Scholar] [CrossRef] [Green Version]
  117. Liu, M.-Y.; Xie, F.; Zhang, Y.; Wang, T.-T.; Ma, S.-N.; Zhao, P.-X.; Zhang, X.; LeBaron, T.W.; Yan, X.-L.; Ma, X.-M. Molecular hydrogen suppresses glioblastoma growth via inducing the glioma stem-like cell differentiation. Stem Cell Res. Ther. 2019, 10, 145. [Google Scholar] [CrossRef] [Green Version]
  118. Fang, W.; Wang, G.; Tang, L.; Su, H.; Chen, H.; Liao, W.; Xu, J. Hydrogen gas inhalation protects against cutaneous ischaemia/reperfusion injury in a mouse model of pressure ulcer. J. Cell. Mol. Med. 2018, 22, 4243–4252. [Google Scholar] [CrossRef] [Green Version]
  119. Buchholz, B.M.; Masutani, K.; Kawamura, T.; Peng, X.; Toyoda, Y.; Billiar, T.R.; Bauer, A.J.; Nakao, A. Hydrogen-enriched preservation protects the isogeneic intestinal graft and amends recipient gastric function during transplantation. Transplantation 2011, 92, 985–992. [Google Scholar] [CrossRef]
  120. Deng, L.; Du, C.; Song, P.; Chen, T.; Rui, S.; Armstrong, D.G.; Deng, W. The Role of Oxidative Stress and Antioxidants in Diabetic Wound Healing. Oxidative Med. Cell. Longev. 2021, 2021, 8852759. [Google Scholar] [CrossRef]
  121. Lin, T.-K.; Zhong, L.; Santiago, J.L. Anti-Inflammatory and Skin Barrier Repair Effects of Topical Application of Some Plant Oils. Int. J. Mol. Sci. 2017, 19, 70. [Google Scholar] [CrossRef] [Green Version]
  122. Litwiniuk, M.; Krejner, A.; Speyrer, M.S.; Gauto, A.R.; Grzela, T. Hyaluronic Acid in Inflammation and Tissue Regeneration. Wounds 2016, 28, 78–88. [Google Scholar]
  123. Werner, S.; Grose, R. Regulation of wound healing by growth factors and cytokines. Physiol. Rev. 2003, 83, 835–870. [Google Scholar] [CrossRef] [Green Version]
  124. Dohi, K.; Kraemer, B.C.; Erickson, M.A.; McMillan, P.J.; Kovac, A.; Flachbartova, Z.; Hansen, K.M.; Shah, G.N.; Sheibani, N.; Salameh, T.; et al. Molecular hydrogen in drinking water protects against neurodegenerative changes induced by traumatic brain injury. PLoS ONE 2014, 9, e108034. [Google Scholar] [CrossRef] [Green Version]
  125. Noda, K.; Tanaka, Y.; Shigemura, N.; Kawamura, T.; Wang, Y.; Masutani, K.; Sun, X.; Toyoda, Y.; Bermudez, C.A.; Nakao, A. Hydrogen-supplemented drinking water protects cardiac allografts from inflammation-associated deterioration. Transpl. Int. 2012, 25, 1213–1222. [Google Scholar] [CrossRef]
Antioxidants 12 00636 g001 550
Figure 1. Relative size of molecular hydrogen and some antioxidants based on differences in their molecular weights, not their actual effective diameter size (e.g., kinetic diameter or Stokes–Einstein radius).
Figure 1. Relative size of molecular hydrogen and some antioxidants based on differences in their molecular weights, not their actual effective diameter size (e.g., kinetic diameter or Stokes–Einstein radius).
Antioxidants 12 00636 g001
Antioxidants 12 00636 g002 550
Figure 2. Routes of molecular hydrogen administration.
Figure 2. Routes of molecular hydrogen administration.
Antioxidants 12 00636 g002
Antioxidants 12 00636 g003 550
Figure 3. Molecular effects of hydrogen in living organisms. The figure shows some of the proposed mechanisms by which the main effects of hydrogen are mediated on the molecular and cellular level. The brown links represent shifts in regulatory molecules that lead to the development of specific cellular effects (indicated by green blocks). Abbreviations: MAPK–mitogen-activated protein kinase, HO–heme oxygenase, TNF–tumor necrosis factor, SOD–superoxide dismutase, MPO–myeloperoxidase, NOS–nitric oxide synthase (inducible–iNOS; endothelial–eNOS), GPx–glutathione peroxidase, Cas–caspase, HMGB1-high-mobility group protein B1, NLRP–Nucleotide-binding oligomerization domain, Th–T-cytotoxic lymphocyte.
Figure 3. Molecular effects of hydrogen in living organisms. The figure shows some of the proposed mechanisms by which the main effects of hydrogen are mediated on the molecular and cellular level. The brown links represent shifts in regulatory molecules that lead to the development of specific cellular effects (indicated by green blocks). Abbreviations: MAPK–mitogen-activated protein kinase, HO–heme oxygenase, TNF–tumor necrosis factor, SOD–superoxide dismutase, MPO–myeloperoxidase, NOS–nitric oxide synthase (inducible–iNOS; endothelial–eNOS), GPx–glutathione peroxidase, Cas–caspase, HMGB1-high-mobility group protein B1, NLRP–Nucleotide-binding oligomerization domain, Th–T-cytotoxic lymphocyte.
Antioxidants 12 00636 g003
Antioxidants 12 00636 g004 550
Figure 4. Relative oxidative potential of some bio-oxidants from [73].
Figure 4. Relative oxidative potential of some bio-oxidants from [73].
Antioxidants 12 00636 g004
Antioxidants 12 00636 g005 550
Figure 5. Common cellular, tissue, and systemic effects of molecular hydrogen. The figure demonstrates the pharmacokinetics of molecular hydrogen depending on the route by which it enters the body. In the locations in which hydrogen directly exerts an effect, its molecular mechanisms are shown. Abbreviations: I/R–ischemia and reperfusion, HSP–heat shock protein.
Figure 5. Common cellular, tissue, and systemic effects of molecular hydrogen. The figure demonstrates the pharmacokinetics of molecular hydrogen depending on the route by which it enters the body. In the locations in which hydrogen directly exerts an effect, its molecular mechanisms are shown. Abbreviations: I/R–ischemia and reperfusion, HSP–heat shock protein.
Antioxidants 12 00636 g005
Antioxidants 12 00636 g006 550
Figure 6. The influence of molecular hydrogen on the state of stem cells. This diagram shows the molecular regulators (indicated by red clouds) and the cellular effects caused by them (green blocks) that are significant for the functioning of stem cells. Abbreviations: HSP–heat shock protein, CFU–colony-forming unit, HO–heme oxygenase, TNF–tumor necrosis factor, IFN–interferon, CD–cluster differentiation marker, MSC–mesenchymal stem cell, GFAP—glial fibrillary acidic protein, IL–interleukin.
Figure 6. The influence of molecular hydrogen on the state of stem cells. This diagram shows the molecular regulators (indicated by red clouds) and the cellular effects caused by them (green blocks) that are significant for the functioning of stem cells. Abbreviations: HSP–heat shock protein, CFU–colony-forming unit, HO–heme oxygenase, TNF–tumor necrosis factor, IFN–interferon, CD–cluster differentiation marker, MSC–mesenchymal stem cell, GFAP—glial fibrillary acidic protein, IL–interleukin.
Antioxidants 12 00636 g006
Antioxidants 12 00636 g007 550
Figure 7. The influence of molecular hydrogen on tissue regeneration. The figure illustrates the effects of molecular hydrogen, potentially significant for stimulating the regeneration and differentiation of stem cells. Abbreviations: IL–interleukin, TGF–tumor growth factor, ROS–reactive oxygen species, RNS–reactive nitrogen species, VEGF–vasculo-endothelial growth factor, IGF—insulin-like growth factor, ICAM-intercellular adhesion molecule, MCP-monocyte chemotactic protein.
Figure 7. The influence of molecular hydrogen on tissue regeneration. The figure illustrates the effects of molecular hydrogen, potentially significant for stimulating the regeneration and differentiation of stem cells. Abbreviations: IL–interleukin, TGF–tumor growth factor, ROS–reactive oxygen species, RNS–reactive nitrogen species, VEGF–vasculo-endothelial growth factor, IGF—insulin-like growth factor, ICAM-intercellular adhesion molecule, MCP-monocyte chemotactic protein.
Antioxidants 12 00636 g007
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

Artamonov, M.Y.; Martusevich, A.K.; Pyatakovich, F.A.; Minenko, I.A.; Dlin, S.V.; LeBaron, T.W. Molecular Hydrogen: From Molecular Effects to Stem Cells Management and Tissue Regeneration. Antioxidants 2023, 12, 636. https://doi.org/10.3390/antiox12030636

AMA Style

Artamonov MY, Martusevich AK, Pyatakovich FA, Minenko IA, Dlin SV, LeBaron TW. Molecular Hydrogen: From Molecular Effects to Stem Cells Management and Tissue Regeneration. Antioxidants. 2023; 12(3):636. https://doi.org/10.3390/antiox12030636

Chicago/Turabian Style

Artamonov, Mikhail Yu., Andrew K. Martusevich, Felix A. Pyatakovich, Inessa A. Minenko, Sergei V. Dlin, and Tyler W. LeBaron. 2023. "Molecular Hydrogen: From Molecular Effects to Stem Cells Management and Tissue Regeneration" Antioxidants 12, no. 3: 636. https://doi.org/10.3390/antiox12030636

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop