We recently published a paper describing that drinking hydrogen water (water infused with hydrogen gas) improved Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) scores in subjects with mild cognitive impairment (MCI) in apolipoprotein E4 (APOE4) genotype-carriers by a randomized, double-blind, placebo-controlled clinical trial [1]. In the present mini-review, we introduce molecular hydrogen (H2) as an emerging candidate for preventing Alzheimer’s disease (AD).

AD is a progressive multi-factorial neurodegenerative disorder, in which oxidative stress is widely accepted as one of the causative factors. Currently, no effective treatment is available likely because complicated multiple factors are involved in the pathophysiology of AD. Single modality of a specific target strategy for treating AD may not be successful, and future therapies based on a multiple-target strategy are needed to address the multiple aspects of AD and block its progression.

For a long time, H2 was believed to be a biologically inert and nonfunctional molecule in the body; however, we overturned this concept by demonstrating that H2 protected cultured cells and the brain against excess oxidative stress and proposed its potential for preventive and therapeutic applications. Subsequently, there have been about 1,000 papers published on 170 kinds of animal disease models and more than 30 clinical studies on the use of H2. These studies have revealed that H2 acts as a therapeutic and preventive antioxidant with multiple functions, including anti-inflammation, anti-allergy, anti-cell death, and stimulation of energy metabolism, all of which contribute to its marked efficacy in a variety of diseases. Figure 1 summarizes publications reporting the clinical efficacies by H2 on various kinds of human diseases. As a molecular mechanism by which H2 exerts the multiple functions, H2 might regulate various gene expression levels in indirect manners under transcription factors such as including NFAT and Nrf2.

H2 seems to differ from conventional pharmaceutical drugs because unlike H2 most drugs have specificity for and to act on their exact targets. Owing to its multiple functions and great efficacy coupled with its lack of adverse effects, H2 has great potential for preventing AD.

There are several methods to ingest or consume H2; inhaling H2 gas, drinking H2-dissolved in water (H2-water), injecting H2-dissolved in saline (H2-saline), taking an H2 bath, or dropping H2-saline into the eyes.

Osteoarthritis (OA) is a very common condition and leads to joint pain, disability, and price tag all over the world. Pathogenesis of OA is closely related to numerous inflammatory and apoptosis cytokines. Hydrogen (H2) reportedly exhibits a diversity of effects such as anti-apoptotic, anti-inflammatory, and anti-oxidative properties via the JNK pathway. However, it is unknown whether H2 has a protective effect against OA via the JNK signaling pathway. Therefore, the aim of this study was to figure out whether hydrogen has protective effect on chondrocyte and further explore the possible underlying mechanism.

The chondrocytes were obtained from the human cartilage tissues. Cells were stimulated by TBHP and treated with hydrogen. In vitro treatment effects were evaluated by Western blot assay, real-time PCR, immunofluorescence and TUNEL method. We conducted mice model of destabilization of the medial meniscus (DMM) and treated with hydrogen. In vivo treatment effects were evaluated by X-ray imaging assay, safranin O (SO) staining, TUNEL staining and immunohistochemical assay.

Our results showed that hydrogen can inhibit inflammatory factors (ADAMTS5 and MMP13) and apoptosis factors (cleaved caspase-3, cytochrome c, and Bax) in TBHP-induced chondrocytes. Furthermore, hydrogen can suppress the activation of JNK signaling pathway, whereas the effect of hydrogen can be abolished by anisomycin (a JNK activator). In vivo results showed that hydrogen can down-regulate the expression of p-JNK and cleaved caspase-3 expression.

We uncovered that hydrogen (H2) could alleviate apoptosis response and ECM degradation in human chondrocytes via inhibiting the activation of the JNK signaling pathway. Meanwhile, in the surgically-induced DMM mice model, treatment with hydrogen (H2) performed a significant role in OA progression.

Persistent oxidative stress plays an important role in a variety of pathologies, and the search for an effective and well tolerated antioxidant agent continues. Molecular hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. The non-specific mechanism of hydrogen as a therapeutic antioxidant gives it broad therapeutic potential across a wide range of medical applications, as has been shown by a substantial volume of preclinical data, as well as a growing body of clinical evidence. This review provides an overview of the therapeutic potential of hydrogen, in ageing and wellness applications as well as medical applications, including acute ischemia/reperfusion injury, inflammation and ulceration, metabolic disorders, neurodegenerative disorders, and cancer (anti-cancer effects, radiation toxicities, and side effects of cisplatin) with an emphasis on clinical data. Overall, this review shows that hydrogen is an effective antioxidant, anti inflammatory and cytoprotective agent.

Here we review the literature on the effects of molecular hydrogen (H2) on normal human subjects and patients with a variety of diagnoses, such as metabolic, rheumatic, cardiovascular and neuro-degenerative and other diseases, infections and physical and radiation damage as well as effects on aging and exercise. Although the effects of H2 have been studied in multiple animal models of human disease, such studies will not be reviewed in depth here. H2 can be administered as a gas, in saline implants or infusions, as topical solutions or baths or by drinking H2-enriched water. This latter method is the easiest and least costly method of administration. There are no safety issues with hydrogen; it has been used for years in gas mixtures for deep diving and in numerous clinical trials without adverse events, and there are no warnings in the literature of its toxicity or long-term exposure effects. Molecular hydrogen has proven useful and convenient as a novel antioxidant and modifier of gene expression in many conditions where oxidative stress and changes in gene expression result in cellular damage.

Deep burn wounds undergo a dynamic process known as wound progression that results in a deepening and extension of the initial burn area. The zone of stasis is more likely to develop more severe during wound progression in the presence of hypoperfusion. Hydrogen has been reported to alleviate injury triggered by ischaemia / reperfusion and burns in various organs by selectively quenching oxygen free radicals. The aim of this study was to investigate the possible protective effects of hydrogen against early burn-wound progression.

Deep-burn models were established through contact with a boiled, rectangular, brass comb for 20 s. Fifty-six Sprague-Dawley rats were randomly divided into sham, burn plus saline, and burn plus hydrogen-rich saline (HS) groups with sacrifice and analysis at various time windows (6 h, 24 h, 48 h) post burn. Indexes of oxidative stress, apoptosis and autophagy were measured in each group. The zone of stasis was evaluated using immunofluorescence staining, ELISA, and Western blot to explore the underlying effects and mechanisms post burn.

The burn-induced increase in malondialdehyde was markedly reduced with HS, while the activities of endogenous antioxidant enzymes were significantly increased. Moreover, HS treatment attenuated increases in apoptosis and autophagy postburn in wounds, according to the TUNEL staining results and the expression analysis of Bax, Bcl-2, caspase-3, Beclin-1 and Atg-5 proteins. Additionally, HS lowered the level of myeloperoxidase and expression of TNF-α, IL-1β, and IL-6 in the zone of stasis while augmenting IL-10. The elevated levels of Akt phosphorylation and NF-κB p65 expression post burn were also downregulated by HS management.

Hydrogen can attenuate early wound progression following deep burn injury. The beneficial effect of hydrogen was mediated by attenuating oxidative stress, which inhibited apoptosis and inflammation, and the Akt / NF-κB signalling pathway may be involved in regulating the release of inflammatory cytokines.

The aim of this study was to demonstrate the safety and efficacy of H2-saline infusion for treatment of rheumatoid arthritis (RA). We conducted a randomized, double-blind, placebo-controlled investigation of the infusion of 1 ppm H2-dissolved saline (H2-saline) in 24 RA patients. Patients were randomized 1:1 to receive 500 ml of either H2-saline or placebo-saline, which was drop infused intravenously (DIV) daily for 5 days. The disease activity score in 28 joints (DAS28) was measured at baseline, immediately post infusion, and after 4 weeks. Therapeutic effects of H2-saline on joint inflammation were estimated by measuring serum biomarkers for RA, tumor necrosis factor- α (TNFα), interleukin-6 (IL-6), matrix metalloproteinase-3 (MMP-3), and urinary 8-hydroxydeoxyguanosine (8-OHdG). In the H2-infused group, average DAS28 decreased from 5.18 ± 1.16 to 4.02 ± 1.25 immediately post infusion and reached 3.74 ± 1.22 after 4 weeks. No significant decrease in DAS28 was observed in the placebo group throughout the study. IL-6 levels in the H2 group significantly decreased in 4 weeks by 37.3 ± 62.0% compared to baseline, whereas it increased by 33.6 ± 34.4% in the placebo group. TNFα levels did not change re- markably in the H2 or placebo groups in 4 weeks post-infusion compared to baseline. The relative ratio of 8-OHdG in the H2 group also significantly decreased by 4.7%. After 4 weeks, MMP3 was significantly reduced by 19.2% ± 24.6% in the H2 group, and increased by 16.9% ± 50.2% in the placebo group. Drop infusion of H2 safely and effectively reduced RA disease activity.