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Molecular hydrogen (H2) has recently gained recognition for its potential preventative and therapeutic applications in a variety of human diseases. Studies have demonstrated H2-induced antioxidant effects, and further investigations have revealed its capacity to aid in the treatment of metabolic syndrome, organ injury, and cancer. This review covers approaches for effective H2 delivery and outlines recent advances in H2-based therapies. Additionally, it considers unresolved questions related to hydrogen medicine and calls for an increased role of H2 in the prevention and treatment of global health issues.
Oxidative stress in the cell is caused by the presence of excessive reactive oxygen species (ROS). These can result from a range of conditions, such as inflammation, tissue transplantation, vigorous exercise, ischemia and reperfusion injury, and others. Chronic or persistent oxidative stress is closely linked with multiple lifestyle-related diseases, aging, and cancer. Traditional clinical antioxidants have high toxicity, limiting their effectiveness and application for the treatment of diseases. Molecular hydrogen (H2) is a colorless and odorless gas that exhibits an antioxidant property and has emerged as a potential medical gas with wide uses. First reported in 1975 to be beneficial in mouse models of skin cancer, it was much later found to be effective against liver parasite infection-induced hepatitis. It has been observed that H2 neutralizes hydroxyl radicals and peroxynitrite, mediating oxidative stress and exhibiting anti-inflammatory and anti-apoptotic effects. This review covers recent advancements in the understanding of the potential preventive and therapeutic applications of H2 and its underlying molecular mechanisms.
POTENTIAL MECHANISMS OF H2 AS A THERAPEUTIC AGENT
The exact molecular mechanisms behind the effects of low-dose H2 remain unclear. H2 has the capacity to regulate signal transduction through various pathways, but its primary targets have yet to be identified. Therefore, investigating critical overlapping signaling molecules may help to map out the interplay between these pathways. Figure 1 proposes potential mechanisms in order to better explain the biological functions of H2 and its mode of action, though further research should be done to investigate other signaling pathways that may be involved in the mitigation of H2-related diseases. Additionally, it is essential to determine the exact targets and molecular mechanisms of H2 in order to gain a full understanding of its effects. Questions remain as to whether cross-talk occurs between signaling pathways and, if so, how it is triggered.
H2 has predominantly been studied for its antioxidant properties. As a selective scavenger of ·OH and ONOO-, it helps to prevent DNA fragmentation, lipid peroxidation, and protein inactivation that would otherwise result from their indiscriminate reaction with nucleic acids, lipids, and proteins. Furthermore, H2 does not interfere with normal physiological functions in vivo. Multiple studies have demonstrated H2’s ability to reduce oxidative stress markers like myeloperoxidase, malondialdehyde, 8-hydroxy-desoxyguanosine (8-OHdG), 8-iso-prostaglandin F2a, and thiobarbituric acid reactive substances in both human diseases and rodent models. Additionally, H2 has been shown to mitigate certain pathological processes in plants and preserve the freshness of fruits. Most recently, it was found that H2 can decrease ROS content in Ganoderma lucidum depending on the presence of glutathione peroxidase.
A 2001 study that demonstrated the anti-inflammatory effects of high-pressure hydrogen was the first to show H2’s potential in this area. Since then, it has been identified as having anti-inflammatory properties in many injury models. Its ability to reduce oxidative stress-induced inflammatory tissue injury is typically done so by decreasing pro-inflammatory and inflammatory cytokines, such as IL-1β, IL-6, TNF-α, intercellular cell adhesion molecule-1, HMGB-1, NF-κB, and prostaglandin E2. H2 also improved survival rates and lessened organ damage in septic mice due to the downregulation of early and late pro-inflammatory cytokines in serum and tissues, making it a possible prospect for conditions associated with inflammation-related sepsis/multiple organ dysfunction syndrome. Furthermore, data points to H2 being released from intestinal bacteria as a means of suppressing inflammation.
H2 has been observed to exert anti-apoptotic effects by either upregulating or downregulating apoptosis-related factors. It inhibits the expression of pro-apoptotic factors like B-cell lymphoma-2-associated X-protein, caspase-3, caspase-8, and caspase-12, while upregulating the anti-apoptotic factors B-cell lymphoma-2 and B-cell lymphoma-extra large. Additionally, H2 regulates signal transduction between pathways, as evidenced by its ability to activate the Akt/glycogen synthase kinase 3β (GSK3β) pathway in neurons and provide neuroprotective effects, as reported by Hong et al. in 2014.
Gene expression alterations
H2 has been observed to stimulate the expression of various genes, such as NF-κB, JNK, proliferation cell nuclear antigen, VEGF, GFAP, and creatine kinase. While some of these molecules may be indirect targets of H2, others may be direct targets. Additionally, evidence suggests that H2 can upregulate oxidoreduction-related genes in normal rat livers. Its anti-inflammatory and anti-apoptotic properties are believed to be expressed through the modulation of pro-inflammatory and inflammatory cytokines and apoptosis-related factors.
H2 as a gaseous signal modulator
Hydrogen (H2) has shown to have numerous therapeutic benefits for multiple diseases and conditions, such as reducing oxidative stress, inflammation, allergic reactions, and apoptosis. It does so by modulating various signaling pathways, including the extracellular signal-regulated protein kinase (ERK)1/2, NF-κB, JNK, nuclear factor-erythroid 2p45-related factor 2 (Nrf2), Toll-like receptor 4 (TLR4), Ras-ERK1/2-MEK1/2, Akt, and FcεRI pathways. The widespread effects of H2 may involve complex crosstalk among these pathways in a network of signaling molecules and require further research to fully understand its therapeutic benefits in vivo.
Materials and methods
For further studies, it is important to consider the use of animals and experimental design. Animal models such as Sprague-Dawley rats can be used in a randomized manner to investigate the therapeutic effects of H2. The rats should be divided into three groups, namely a control group, HRW group, and HI group, where the latter two are treated with H2 for 1 h, twice a day for six months. All the procedures should be done in compliance with the relevant regulations and guidelines for animal experimentations.
8. Comparison with the other medical gasses
Hydrogen (H2) is a medical gas that has recently gained attention due to its various therapeutic benefits with no cytotoxicity. While the primary targets of H2 are still being studied, research has shown that it may interact with other toxic medical gasses such as hydrogen sulfide (H2S), carbon monoxide (CO), and nitric oxide (NO) through its effects on mitochondrial cytochrome c oxidase. Combined administration of H2 with CO and NO has been found to provide enhanced therapeutic efficacy in patients experiencing ischemia/reperfusion injury by activating anti-oxidant and anti-inflammatory pathways. The production of these medical gases are catalyzed by different enzymes such as NO synthases, cystathionine gamma-lyase, cystathionine beta-synthase, and heme oxygenase-1 (HO-1). Unlike the other medical gasses, mammalian cells do not have an enzyme for producing intracellular H2.
Effects of molecular hydrogen have been observed essentially in all the tissues and disease states including the brain, spinal cord, eye, ear, lung, heart, liver, kidney, pancreas, intestine, blood vessel, muscle, cartilage, metabolism, perinatal disorders, and inflammation/allergy. Among them, marked effects are observed in ischemia/reperfusion disorders as well as in inflammatory disorders.
There are several ways to get molecular hydrogen into your system including drinking hydrogen infused water, H2 inhalation, taking an H2 bath, or putting H2-saline into the eyes. The easiest and probably most efficient method is by simply dropping an H2 tablet in water and then drinking it. In all cases, molecular hydrogen enters the bloodstream and is transported throughout the body.
Molecular hydrogen can also be applied directly to areas of the body where injury and pain occur.