Hydrogen can exert antioxidant and anti-apoptotic activities via selectively neutralizing the cytotoxic ROS, such as the ·OH and ONOO–. Meanwhile, the signaling ROS playing metabolic roles, such as the superoxide and hydrogen, are far less affected. Unlike some antioxidant supplements with strong reductive reactivity, hydrogen neither disturbs the physiological oxidation reactions nor disrupts the essential defensive mechanisms.

Hydrogen can penetrate the membranes and diffuse into organelles (eg, the mitochondria and nuclear DNA), and thereby get access to the intracellular source of cytotoxic ROS. Based on the favorable distribution characteristic, hydrogen is highly effective for reducing the level of cytotoxic ROS, which impair the nuclear DNA and mitochondria. From the aspect of safety, hydrogen is advantageous to many other antioxidants as it shows no 0cytotoxicity even at high concentrations. These advantages indicate that the application of hydrogen therapy might act as a safe and effective strategy against ROS-related disorders without giving rise to serious side effects.

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Source: https://www.ncbi.nlm.nih.gov/pubmed/24915536

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The ROS could upregulate the expression levels of vascular endothelial growth factor (VEGF) and enhance VEGF receptor activity via complex signaling networks. VEGF can give rise to choroidal neovascularization (CNV) in the DR and has been considered as a therapeutic target in clinical practice. Therefore, the anti-VEGF property should be considered as another functional factor for hydrogen-induced protection. Studies indicate that hydrogen might act as a valid candidate in the further clinical treatment of DR. Although the possible effect of hydrogen has not been clinically verified in DR patients hitherto, a randomized, double-blind, placebo-controlled, crossover study has already found that the supplementation of HRS improved lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance. These hydrogen-induced effects might be potentially applied to diabetic complications, especially to DR, in which metabolic disorder plays a pivotal role.

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Excessive exposure to light can induce the formation and accumulation of ROS in retinas and eventually results in the photoreceptors’ apoptosis. Hitherto, two independent studies have found that saturated hydrogen saline can protect the retina from light-induced damage by attenuating oxidative stress. Investigations using the electron microscope found that the hydrogen treatment could protect the cellular organelles of the photoreceptors against light-induced injury. To some extent, the microstructure results verify that hydrogen can penetrate the membranes and then enter the nucleus and mitochondria. Moreover, the retinal malondialdehyde concentration, a presumptive marker of lipid peroxidation, is significantly reduced by hydrogen therapy, indicating that the protective effects of hydrogen could be ascribed to its antioxidant properties. The encouraging findings based on the phototoxic models verify the efficacy of hydrogen to arrest photoreceptor degeneration and cast light on the discovery of a novel therapeutic to prevent the retinal damages in age-related macular degeneration or retinitis pigmentosa.

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Molecular hydrogen has recently been verified to have protective and therapeutic value as an antioxidant through its ability to selectively reduce cytotoxic ROS such as hydroxyl radical (OH). Unlike most well-known antioxidants, which are unable to successfully target organelles, hydrogen has advantageous distribution characteristics enabling it to penetrate biomembranes and diffuse into the cytosol, mitochondria, and nucleus. Intriguingly, hydrogen does not disturb the metabolic oxidation-reduction reactions, innate immune system, or physiologic parameters. It has been found that hydrogen selectively quenches detrimental ROS such as OH and ONOO, while maintaining metabolic oxidation-reduction reaction and other less potent ROS, such as superoxide anion radical (O2), hydrogen peroxide (H2O2), and nitric oxide (NO). Consequently, hydrogen might be an effective antioxidant to protect against lens damage, and it is important to further explore the biological mechanism underlying its potential therapeutic effects.

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Corneal alkali injury often causes extensive damage to the ocular surface and the whole anterior eye segment leading to partial or total vision loss. Immediately after corneal injury,

Such as alkali burns or irradiation of the cornea with UVB rays, oxidative stress appears in the cornea. The activities as well as expressions of corneal antioxidant enzymes substantially decrease, whereas the activities of prooxidant enzymes (e.g., oxidases that generate reactive oxygen species, ROS) remain at physiological levels or even increase. The antioxidant/ prooxidant imbalance appears leading to oxidative stress. ROS are insufficiently cleaved. With the effort to substitute the weakened functions of naturally occurring antioxidants, several synthetic antioxidants have been topically applied on the ocular surface to suppress oxidative stress and enable corneal healing. A study proposed that H2 has the potential as a novel effective antioxidant in preventive and therapeutic applications.

According to these authors, H2 has many advantages as a mild but effective antioxidant: H2 rapidly diffuses into tissues and cells, and it is not mild enough either to disturb metabolic redox reactions or to affect ROS that function in cell signaling. H2 is an inert gas and only the strong oxidants, for example, hydroxyl radicals and peroxynitrite, can oxidize it. In other words, H2 reacts with strong oxidants such as hydroxyl radical and peroxynitrite in cells, and thus it is a potent agent for preventive and therapeutic antioxidant applications. H2 can be consumed in the human body in various ways, including inhaling H2, drinking hydrogen water (H2-dissolved water), taking a hydrogen bath, injecting H2-dissolved saline, dropping H2 onto the eye, and increasing the production of intestinal H2 by bacteria. Whereas, drinking hydrogen-rich water is the easiest and most effective way to consume hydrogen in the body.

A study proposed that if alkali-injured eyes irrigated with H2 solution of 0.5–0.6 ppm for 30 min. The concentration of H2 effectively suppressed oxidative stress in the cornea and reduced corneal neovascularization. The injured eyes were irrigated with H2 solution (H2 in PBS) or PBS free of H2 immediately after the injury and then repeatedly for five days. Results showed that after H2 treatment corneal transparency that was lost after the injury quickly renewed and central corneal thickness that increased after the injury reached physiological levels. On day 20 after the injury in H2 treated corneas the intracorneal inflammation was suppressed, the retrocorneal membrane was not developed, and corneal neovascularization was reduced. This was in contrast to PBS treated alkali-injured corneas, where the intracorneal inflammation was highly developed together with the retrocorneal membrane, and corneas were largely vascularized.

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Source: https://www.nature.com/articles/nm1577
http://iovs.arvojournals.org/article.aspx?articleid=2126880

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Oxidative stress has been reported in many diseases in which the production of ROS and the oxidative modification of various biomolecules underlie their pathophysiology, especially inflammation-associated processes. There is evidence that oxidative stress is a key factor contributing to inflammatory conditions such as recurrent aphthous stomatitis, which causes a wound in the oral mucosa with no well-established underlying cause. During wound-induced inflammation, ROS and inflammatory cytokines are released from immune system cells to kill microorganisms. The production of ROS in the inflammatory process leads to marked inflammation during which various chemoattractants are secreted. Chemotactic stimulation of phagocytosis induces the activation of a membrane-bound enzyme system that transfers electrons from cytosolic nicotinamide adenine dinucleotide phosphate (NADP⁺) to extracellular oxygen, resulting in the production of the superoxide radical, a well-established ROS.

Molecular hydrogen is the simplest element in nature and is of therapeutic and preventive interest because of its biological activities, including its antioxidant and anti-inflammatory activities in most tissues of model animals. There are a number of advantages of hydrogen as a potential antioxidant: it is mild enough not to disturb metabolic redox reactions or to affect ROS, which functions in cell signaling, and it also has favorable distribution characteristics with respect to its physical ability to penetrate biomembranes and diffuse through barriers into cellular components. Molecular hydrogen has also been reported to reduce the levels of proinflammatory cytokines and suppress inflammation. Recently, hydrogen-rich water, a colorless and odorless liquid, was found to possess strong antioxidant and anti-inflammatory activity. A study has indicated that oral administration of hydrogen-rich water has beneficial effects on oral palatal wound healing. It is conceivable that orally administered molecular hydrogen could improve local redox balance as well as decrease circulating oxidative stress.

Molecular hydrogen has potential as a novel antioxidant in preventive and therapeutic applications, in addition to its anti-inflammatory effects. It has also been reported that molecular hydrogen activates the nuclear factor-E2 related factor 2 (Nrf2)/antioxidant defense pathway. The translocation of Nrf2 into the nucleus leads to upregulation of the expression of genes encoding phase 2 enzymes involved in defense systems against oxidative stress and other toxic sources. Nrf2 cooperates with the antioxidant defense system to regulate genes such as heme oxygenase 1 (HO-1) and NAD(P)H quinine oxidoreductase 1 (NQO-1).

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Schizophrenia is a serious mental disorder in which people interpret reality abnormally. Schizophrenia may result in some combination of hallucinations, delusions, and extremely disordered thinking and behavior that impairs daily functioning, and can be disabling.
People with schizophrenia require lifelong treatment. Early treatment may help get symptoms under control before serious complications develop and may help improve the long-term outlook.

Mitochondria and Schizophrenia

Mitochondrial dysfunction in schizophrenia is frequently reported. Moreover, mitochondrial disorders can present with psychosis. mtDNA plays a role in the neurobiology of schizophrenia. Mitochondrial gene expression is changed in schizophrenia. The number of mitochondria in schizophrenia is reduced compared to normal controls. This change in mitochondria may be associated with differential responsiveness to treatment. However, it is not clear whether this number is adaptive or an etiological link to this disorder.

Schizophrenia and Oxidative stress

The role of oxidative stress in the neurobiology of schizophrenia is a promising target to provide new therapeutic interventions]. This is grounded on data that the antioxidant defense system is impaired in schizophrenia. In comparison to normal controls, the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) are decreased while the levels of malondialdehyde (MDA) are increased in chronic schizophrenia. Reduced cellular respiration and complex I abnormalities in schizophrenia are possible endophenotypic biomarkers for schizophrenia. Furthermore, the severity of neurological soft signs in patients with schizophrenia is associated with the level of decreased superoxide dismutase activity.

What Hydrogen does?

Hydrogen gas has many biological properties that make it an appealing candidate agent for a diversity of disorders sharing inflammatory, oxidative, and apoptotic mechanisms. Hydrogen is hypothesized as a potential therapy for different oxidative stress-related diseases like Autism, Parkinson’s disease, schizophrenia, etc. Drinking water enriched with hydrogen was shown to decreases oxidative stress through scavenging hydroxyl radicals. As myDNA plays a role in the neurobiology of schizophrenia, a randomized controlled trial indicated that hydrogen-enriched water decreased mitochondrial dysfunction and inflammation in patients with mitochondrial myopathies. Due to its very small molecular size, hydrogen can easily penetrate organelles such as mitochondria as well as the nucleus. It is inert at room temperature and in the absence of catalysts. It additionally easily crosses the blood-brain barrier, which facilitates access to the target organs and subcellular components.

Hydrogen reacts with free hydroxyl radicals but does not appear to react to other reactive oxygen species. This is a theoretical advantage, as low levels of these radicals have physiologically relevant signaling effects. It protects against secondary oxidative damage to the brain in a variety of models by reacting with hydroxyl radicals. Hydroxyl radical is produced via the Fenton reaction in submitochondrial particles under oxidative stress. Molecular hydrogen (H2) reacts with strong oxidants, such as hydroxyl and nitrosyl radicals in cells, allowing to use of its potential for preventive and therapeutic applications in situations with excessive free radicals formation.

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Bipolar disorder is a mental illness marked by extreme shifts in mood. Symptoms can include an extremely elevated mood called mania. They can also include episodes of depression. Bipolar disorder is also known as bipolar disease or manic depression. People with bipolar disorder may have trouble managing everyday life tasks at school or work, or maintaining relationships.
Bipolar mood disorder is a relatively common neuropsychiatric disorder with an estimated prevalence of 1% to 2%, and a high burden of disease. There is a high rate of medical comorbidity including diabetes and the metabolic syndrome, cardiovascular morbidity, and obesity, all of which are associated with inflammatory changes and oxidative stress. These comorbidities lead to a novel hypothesis that bipolar disorder is a part of a multi-system inflammatory process.

Mitochondria and Bipolar Disorder

Mitochondria are necessary for the generation of energy and synaptic signaling. Mitochondrial dysfunction appears to be involved in the pathophysiology of bipolar disorder. The prevalence of the bipolar disorder in patients with mitochondrial cytopathies is higher than among healthy controls. Mitochondrial DNA deletions are increased. Mitochondrial dysfunction has thus been hypothesizing as a molecular basis of bipolar disorder. It is suggested that novel therapeutic agents for treating bipolar mood disorder should target mitochondrial function.

Bipolar Disorder and oxidative stress

The generation of oxidatively generated free radicals is core to life and is normally tightly controlled. Reactive oxygen species (ROS) production and metabolism appear to play an important role in the pathophysiology of bipolar disorder. Not only are both total glutathione and reduced glutathione levels, which are core parts of the intrinsic anti-oxidative system decreased in bipolar disorder, but antioxidant enzyme activities are also impaired. Levels of key redox enzymes including SOD and catalase have been reported to be lower in patients with bipolar disorder. Nitrous oxide (NO) is implicated in the generation of psychotic symptoms such as delusions in bipolar disorder. A meta-analysis reported that the level of NO appears to be significantly increased in bipolar disorder. Moreover, the level of thiobarbituric acidic reactive substances (TBARS), a marker of lipid peroxidation through a reaction between free radicals and lipid structures, is increased during manic episodes and remission. This finding suggests that oxidative damage to lipid structures is probably continued during the course of bipolar disorder.

How hydrogen helps in treating Bipolar Disorder?

Molecular hydrogen is an odorless and tasteless gas that has the ability to rapidly diffuse through lipid membranes and enter the cell, where it easily penetrates organelles such as mitochondria as well as the nucleus. Molecular Hydrogen is an effective medication for the prevention of long-term relapse in bipolar mood disorder. Molecular Hydrogen also has effects through its impact on inflammation and by the prevention of oxidative stress and cytokine changes. These anti-inflammatory and anti-oxidative effects are potentially neuroprotective. Molecular Hydrogen increases mitochondrial respiratory chain enzyme activities, particularly complex 1, that may be linked to its therapeutic efficacy and increases mitochondrial energy production. Molecular Hydrogen has many biological properties that make it an appealing candidate agent for a diversity of disorders sharing inflammatory, oxidative, and apoptotic mechanisms.

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