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Recent Advances in Hydrogen Research as a Therapeutic Medical Gas
Abstract
Recent basic and clinical research has revealed that hydrogen is an important physiological regulatory factor with antioxidant, anti-inflammatory and anti-apoptotic protective effects on cells and organs. Therapeutic hydrogen has been applied by different delivery methods including straightforward inhalation, drinking hydrogen dissolved in water and injection with hydrogen-saturated saline. This review summarizes currently available data regarding the protective role of hydrogen, provides an outline of recent advances in research on the use of hydrogen as a therapeutic medical gas in diverse models of disease and discusses the feasibility of hydrogen as a therapeutic strategy. It is not an overstatement to say that hydrogen's impact on therapeutic and preventive medicine could be enormous in the future.
... However, oxygen therapy might cause the accumulation of distal bronchial viscous secretions because of positive pressure ventilation mode, and thus increase airway resistance, aggravate systemic hypoxia [15]. In recent years, molecular hydrogen treatment has the potential to preventive and therapeutic applications against many diseases due to its extensive effects, such as antioxidant, anti-inflammatory, antiapoptotic [16,17]. More importantly, the small molecular properties of hydrogen enable it can rapidly reaches the alveoli, suggest a unique advantage for lung disease [18]. ...
... In the entire matched group, the median length of hospitalization for patients who inhaled hydrogen/oxygen were 12 days (95% CI, [9][10][11][12][13][14][15] and patients who inhaled oxygen were 13 days (95% CI, [11][12][13][14][15][16][17][18][19][20], with a HR of 1.91 (95% CI, 1.25-2.92; p < 0.05; Fig. 2). ...
... The length of hospitalization in unmatched patients from real-world setting and 1:1 matched patients were also analyzed as sensitivity analysis. The 4.5-day shorten with hydrogen/ oxygen therapy was observed in the real-world data from all unmatched patients (11.5 days [95%CI: [10][11][12][13] vs. 16 days [95%CI: [14][15][16][17][18]; p < 0.001; Additional file 1: Fig. S1A) and 2-day shorten in the 1:1 matched patients (12 days [95%CI: [9][10][11][12][13][14] vs. 14 days [95%CI: [11][12][13][14][15][16]; p = 0.019; Additional file 1: Fig. S1B). ...
Background
Hydrogen/oxygen therapy contribute to ameliorate dyspnea and disease progression in patients with respiratory diseases. Therefore, we hypothesized that hydrogen/oxygen therapy for ordinary coronavirus disease 2019 (COVID-19) patients might reduce the length of hospitalization and increase hospital discharge rates.
Methods
This retrospective, propensity-score matched (PSM) case–control study included 180 patients hospitalized with COVID-19 from 3 centers. After assigned in 1:2 ratios by PSM, 33 patients received hydrogen/oxygen therapy and 55 patients received oxygen therapy included in this study. Primary endpoint was the length of hospitalization. Secondary endpoints were hospital discharge rates and oxygen saturation (SpO2). Vital signs and respiratory symptoms were also observed.
Results
Findings confirmed a significantly lower median length of hospitalization (HR = 1.91; 95% CIs, 1.25–2.92; p < 0.05) in the hydrogen/oxygen group (12 days; 95% CI, 9–15) versus the oxygen group (13 days; 95% CI, 11–20). The higher hospital discharge rates were observed in the hydrogen/oxygen group at 21 days (93.9% vs. 74.5%; p < 0.05) and 28 days (97.0% vs. 85.5%; p < 0.05) compared with the oxygen group, except for 14 days (69.7% vs. 56.4%). After 5-day therapy, patients in hydrogen/oxygen group exhibited a higher level of SpO2 compared with that in the oxygen group (98.5%±0.56% vs. 97.8%±1.0%; p < 0.001). In subgroup analysis of patients received hydrogen/oxygen, patients aged < 55 years (p = 0.028) and without comorbidities (p = 0.002) exhibited a shorter hospitalization (median 10 days).
Conclusion
This study indicated that hydrogen/oxygen might be a useful therapeutic medical gas to enhance SpO2 and shorten length of hospitalization in patients with ordinary COVID-19. Younger patients or those without comorbidities are likely to benefit more from hydrogen/oxygen therapy.
... In fact, H 2 selectively reduces highly cytotoxic reactive oxygen/nitrogen species (ROS/RNS or RONS), being the main cause of oxidative stress in cells, such as hydroxyl radical ( • OH) and peroxynitrite (ONOO -) [2,3]. Moreover, it has been demonstrated from many cellular and animal experiments that molecular hydrogen exerts clear preventive and therapeutic effects on a variety of pathologies [4][5][6], including metabolic syndrome [7][8][9], diabetes [10], cancer [11], chronic hepatitis B [12], ischemia/reperfusion (I/R) injury [13,14], radiation injury [15,16], etc. In addition to the antioxidative action, hydrogen gas has more beneficial functions such as anti-inflammation, anti-apoptosis, anti-allergy and stimulation of energy metabolism [17][18][19][20]. ...
... The first way is direct mechanisms, where H 2 reacts with hydroxyl radicals ( • OH) and peroxynitrite (ONOO -), resulting in reduction of RONS [1,28,29]. In the second indirect way, the oxidative stress can be reduced by inducing antioxidation systems, such as myeloperoxidase [30], superoxide dismutase [10], catalase [30], and heme oxygenase-1 (HO-1) [6]. These enzymes were found to mediate the H 2 effects through modulation of signal transduction [31,32] and alteration of gene expressions [33,34]. ...
... This is in agreement with the previous theoretical studies[64,65]. However, the other radicals are difficult to be scavenged by only H 2 itself due to their relatively lower reactivities.The clinical experiments confirm that a mild H 2 exhibits various biological effects in vivo[5,6,19,20], implying that either H 2 may be dissociated into H atoms by enzymes withFig. 6 Isosurface view of frontier molecular orbitals including HOMO-1, HOMO, LUMO, and LUMO+1 in FeP(Im)-H-RONS complexes. ...
Recently molecular hydrogen has been found to exhibit antioxidation activity through many clinical experiments, but the mechanism has not been fully understandable at atomic level. In this work, we perform systematic ab initio calculations of protoheme-hydrogen complexes to clarify the antioxidation mechanism of molecular hydrogen. We make molecular modeling of iron--protoporphyrin coordinated by imidazole, FeP(Im), and its hydrogen as well as dihydrogen complexes, together with reactive oxygen/nitrogen species (RONS). We carry out structural optimization and Mulliken charge analysis, revealing the two kinds of bonding characteristics between FeP(Im) and H 2 ; dihydrogen bonding in the end-on asymmetric configuration and Kubas bonding in the side-on symmetric configuration of H 2 molecule. The activation barriers for adsorption and dissociation of H 2 on and further desorption of H atom from FeP(Im) are found to be below 64 kcal/mol at most, which is remarkably lower than the H-H bond breaking energy of 107 kcal/mol in free H 2 molecule. We find that the hydrogen bond dissociation energies of FeP(Im)-H 2 and -H complexes are lower than those of RONS-H complexes, indicating the decisive role of protoheme as an effective catalyst in RONS antioxidation by molecular hydrogen in vivo.
... Ayrıca gazın solunması kan basıncını etkilememektedir. Fakat tehlikeli durum oluşturmaması için hidrojen konsantrasyonu, ticari olarak temin edilebilen araçlarla izlenmeli ve sürdürülmelidir [10]. ...
... Aynı zamanda hidrojenle zenginleştirilmiş su tüketiminin hidrojen inhalasyonuyla karşılaştırılabilir etkileri bulunmaktadır (Antioksidan, antiinflamatuar, antiapoptotik). Hidrojenle zenginleştirilmiş su, hidrojen gazının suda yüksek basınç altında çözülmesi, elektroliz yoluyla hidrojenin suda çözülmesi ve magnezyumun su ile reaksiyona sokulması gibi çeşitli yöntemlerle elde edilebilmektedir [10,11]. ...
... Fakat sudaki hidrojenin zamanla kaybolması ve midede veya bağırsakta bir miktar hidrojen kaybının yaşanması, uygulanan hidrojen konsantrasyonunun kontrol edilmesini zorlaştırmaktadır. H2'nin enjekte edilebilir bir hidrojenli salin yoluyla uygulanması, hidrojenin daha kolay kontrol edilebilir olmasını sağlamaktadır [9,10]. Hidrojence zengin salin enjeksiyonu umut verici bir klinik yöntemdir. ...
ABSTRACT:
Molecular hydrogen, which has the H2 formula, is a colorless, odorless, tasteless, non-metallic and non-toxic gas. Molecular hydrogen has a high diffusion rate and spreads rapidly in biological tissues and cells. Molecular hydrogen does not change the body's redox reactions and does not cause any side effects. H2 is a selective antioxidant due to its ability to neutralize strong oxidants such as hydroxyl radicals in cells. This case increases the potential use of molecular hydrogen for preventative and therapeutic applications. In addition, by regulating various gene expressions, H2 exhibits anti-inflammatory and anti-apoptotic properties. At the same time, unlike the drugs used in the treatment of diseases, H2 penetrates the cell membrane easily. Inhaling hydrogen gas, drinking hydrogen water, injection of hydrogen-enriched saline, bathing with a hydrogen-rich water, and hydrogen-rich eye drops are the common methods of molecular hydrogen applications in the health field. Numerous studies on the biological and medical benefits of hydrogen have been carried out up to date, and research is still ongoing. As a result; due to its beneficial effects on the body and the absence of side effects, molecular hydrogen can have promising potential applications against many diseases.
ÖZET:
H2 formülüne sahip olan moleküler hidrojen, renksiz, kokusuz, tatsız, metalik olmayan ve toksik olmayan bir gazdır. Moleküler hidrojen (H2), yüksek difüzyon hızına sahiptir ve biyolojik doku ve hücrelerde hızla yayılır. Moleküler hidrojen, vücudun redoks reaksiyonlarını değiştirmemekte ve hiçbir yan etki göstermemektedir. Hücrelerdeki hidroksil radikal gibi güçlü oksidanları inhibe etme özelliğinden dolayı seçici bir antioksidandır. Bu durum, moleküler hidrojenin önleyici ve tedavi edici uygulamalar için potansiyelini arttırmaktadır. Ek olarak, çeşitli gen ifadelerini düzenleyerek, antiinflamatuar ve antiapoptik özellik sergilemektedir. Aynı zamanda hastalıkların tedavisinde kullanılan ilaçların aksine moleküler hidrojen, hücre zarına kolaylıkla nüfuz etmektedir. Hidrojen gazı solumak, hidrojenle zenginleştirilmiş su içmek, hidrojenle zenginleştirilmiş salin enjeksiyonu, hidrojenli su banyosu yapmak ve hidrojenli göz damlaları kullanmak sağlık alanında moleküler hidrojen uygulamasının yaygın yöntemleridir. Bugüne kadar hidrojenin biyolojik ve tıbbi faydaları üzerine çok sayıda çalışma yapılmıştır ve araştırmalar halen devam etmektedir. Sonuç olarak; vücuttaki olumlu etkileri, yan etkisinin bulunmaması sebebiyle, moleküler hidrojen birçok hastalığa karşı umut verici bir potansiyele sahiptir.
... Among many antioxidant-application strategies, hydrogen molecules (H 2 ) are utilized as a novel medical gas with antioxidant properties [2,12,13]. Numerous experimental and clinical studies have demonstrated that hydrogen could protect cells, tissues and organs from oxidative stress-induced injuries by scavenging ROS [14,15]. Hydrogen-enriched electrolyzed water is guaranteed for safety in human body, and hydrogen also has beneficial effects on the human body, including preventive effects on many diseases and radiationprotective effects [16][17][18][19]. ...
... Various anti-aging agents were used, such as an inhibitor for skin wrinkles [6][7][8][9]14,[20][21][22][23][24][25][26], an inhibitor for skin blotch [6,9,12,22,[24][25][26][27], a conditioner for sebum [1,11] and agents with moisturizing activity [7,8,10,15,20,22,[25][26][27][28]. Most of them have antioxidant effects. ...
... Thus, the HW bath in combination with the HW poultice on concerned skin parts exerts diverse beneficial effects on cosmetological aspects of human skin appearances such as wrinkles, blotches and oiliness/moisture. In the future, the issue is whether to promote the expression of stress-related genes such as COX-2, p53, Nfr2, MAPK signaling by hydrogen water, as well as other antioxidants [15,20,21]. Similar effects of the hydrogenrich water bath could be considered for other tissues and blood/capillaries, helping the systemic improvements of health. ...
Hydrogen-rich warm water (HW) has not been verified yet for skin anti-aging effects. Daily 10 min HW (dissolved hydrogen: 338–682 μg/mL, 41 °C) bathing and skin poultice with HW-impregnated towels for 11–61 days were demonstrated to improve wrinkle degrees (29 skin-loci) from 3.14 ± 0.52 to 1.52 ± 0.74 (p < 0.001) and blotch degrees (23 loci) from 3.48 ± 0.67 to 1.74 ± 0.86 (p < 0.001) in five healthy subjects (49–66 years old), by densito-/planimetrically evaluating with an Image-J software, and ranked into six hierarchies (0, 1–5). Meanwhile, skin oiliness was evaluated to increase for the oil-poor skins, but inversely decrease for excessively oily skins, suggesting the HW’s function as skin-oiliness modulation, with an appreciably negative correlation in prior oiliness contents versus change after HW application (r = −0.345, 23 loci). Skin moisture increased upon HW application, with a negative correlation (r = −0.090, 23 loci) in prior moisture contents versus post-HW-application moisture-changing rates, meaning that HW application compensated moisture for water-deficient skins (27.5–40% moisture), but not for wet skins (>41% moisture). Thus, the HW bath together with HW poultice exerted beneficial effects on skin appearances such as wrinkles, blotches and moisture/oiliness, some of which might ensue from enhanced antioxidant ability in blood, as was previously demonstrated for the HW bath.
... Helium gas is known to have a low density and molecular weight (MW). However, molecular hydrogen, which has a lower molecular weight, has been suggested to be a potential therapy for preventive and therapeutic applications against many diseases because in addition to its rapid diffusion, it has protective antioxidant, anti-inflammatory, anti-apoptotic effects [23,24]. Studies have shown that molecular hydrogen, as the lightest and smallest gas molecule, has a unique function as an antioxidant to improve lung function [7,24,25]. ...
... However, molecular hydrogen, which has a lower molecular weight, has been suggested to be a potential therapy for preventive and therapeutic applications against many diseases because in addition to its rapid diffusion, it has protective antioxidant, anti-inflammatory, anti-apoptotic effects [23,24]. Studies have shown that molecular hydrogen, as the lightest and smallest gas molecule, has a unique function as an antioxidant to improve lung function [7,24,25]. Therefore, it has been proposed that the inhalation of a hydrogen/oxygen mixture may be an alternative therapy for COPD [7,15]. The efficacy of hydrogen/oxygen therapy in patients with tracheal stenosis has already been demonstrated [26]. ...
Background: Recently, chronic lung diseases have been found to be associated with marked inflammation and oxidative stress, which leads to fibrosis in the lungs and chronic respiratory failure. This study aims to determine if hydrogen-rich water (HRW) can enhance oxygen saturation among patients with chronic lung diseases. Methods: Ten patients with chronic lung diseases due to COPD (n = 7), bronchial asthma (n = 2), and tuberculosis of the lung (n = 1) with oxygen saturation of 90–95% were provided high-concentration (>5 mM) HRW using H2-producing tablets for 4 weeks. Oxygen saturation was measured via oximeter and blood pressure via digital automatic BP recorder. Results: HRW administration was associated with a significant increase in oxygen saturation (SpO2) and decrease in TBARS, MDA, and diene conjugates, with an increase in vitamin E and nitrite levels, compared to baseline levels. Physical training carried out after HRW therapy appeared to increase exercise tolerance and decrease hypoxia, as well as delay the need for oxygen therapy. Conclusion: Treatment with HRW in patients with hypoxia from chronic lung diseases may decrease oxidative stress and improve oxygen saturation in some patients. HRW therapy may also provide increased exercise tolerance in patients with chronic hypoxia, but further research is needed.
... [2] The therapeutic medical gas hydrogen, as a drug gas molecule, has the potential to be a new adjunctive treatment for AD. [3,4] In recent years, hydrogen molecules have been found to have a wide range of antioxidant, anti-inflammatory, anti-apoptotic, and rapid diffusion effects, selectively reducing reactive oxygen species and being an antioxidant with neuroprotective properties. [5,6] Hydrogen was found to improve memory loss in AD model mice and to have a therapeutic effect on cognitive dysfunction. ...
... [24,25] Hydrogen as a drug gas molecule is therefore an ideal adjunct to oxygen inhalation, and inhalation of a hydrogen-oxygen mixture is a new adjunctive treatment for AD with a good safety profile. [3,4] Our study showed that the improvement of MMSE score, MoCA score and ADAS-Cog score of the patients in the observation group after treatment was better than that in the control group, indicating that donepezil combined with hydrogen-oxygen mixture inhalation in the treatment of patients with AD can better improve the cognitive function of the patients. Meanwhile, the improvement of ADL score of patients in the observation group was better than that in the control group after treatment, indicating that donepezil combined with hydrogen-oxygen mixture inhalation can better improve the ability of daily living of patients with AD. ...
To investigate the clinical effect of donepezil combined with hydrogen-oxygen mixture inhalation in the treatment of patients with Alzheimer disease (AD), a total of 273 AD patients admitted to our hospital from March 2018 to March 2022 were retrospectively analyzed and assigned into an observation group (n = 138) and a control group (n = 135) according to the different treatment that they received. The control group was treated with donepezil tablets, while the observation group was treated with donepezil tablets combined with hydrogen-oxygen mixture inhalation. The scores of mini-mental state examination (MMSE), Montreal Cognitive Assessment (MoCA), Alzheimer's Disease Assessment Scale-Cognition, activity of daily living scale (ADL) and the P300 event-related potential were compared between the 2 groups. After treatment, MMSE score, MoCA score, and ADL score in both groups increased after treatment (P < .01), while the improvement in the observation group was more significant than that in the control group (P < .001 for MMSE, P = .003 for MoCA, and P = .013 for ADL). The scores of Alzheimer's Disease Assessment Scale-Cognition in the observation group decreased after treatment (P < .05), while the improvement in the observation group was more significant than that in the control group (P = .005). After treatment, the latency of P300 in both groups was shortened (P < .01), and the improvement in the observation group was more significant than that in the control group (P < .001). The amplitude of the observation group increased after treatment (P < .01), and the improvement of the observation group was significant than that of the control group (P = .007). The clinical efficacy of donepezil combined with hydrogen-oxygen mixture inhalation in the treatment of AD is better than that of donepezil alone, which is worthy of further study.
... Research on hydrogen therapy for diseases has been extensive in recent years, [26][27][28][29] and the most prominent and clear mechanism of its therapeutic effect is the antioxidative effect. Hydrogen can selectively neutralize highly toxic free radicals, [30][31][32] such as hydroxyl radicals (-OH) and peroxynitrite anions (ONOO-), while having no neutralizing effect on free radicals with physiological activity. ...
... The mechanisms of inflammation that cause damage to the body include promoting excessive activation of the immune system and the release of inflammatory factors. Multiple studies in recent years have found that molecular hydrogen can reduce the production of inflammatory factors 28,38,39 and increase the release of anti-inflammatory factors, thereby playing an anti-inflammatory role. Hydrogen gas also has anti-apoptotic effects 32,40,41 and affects the hormone levels and activity. ...
Chronic nasal mucosal inflammatory disease is a common nasal disease, which is involved by inflammatory cells and a variety of cytokines. Its main pathological features are inflammatory reaction, increased secretion, mucosal swelling and thickening of nasal cavity or paranasal sinuses.It mainly includes chronic rhinitis (divided into allergic rhinitis, non-allergic rhinitis), chronic sinusitis (divided into with nasal polyps, without nasal polyps type), etc.The main symptoms of chronic rhinitis are nasal itching, sneezing, runny nose, and nasal congestion. The main symptoms of chronic sinusitis are nasal congestion, purulent or sticky nasal discharge, headache, and reduced sense of smell. They are a type of disease with a high incidence rate and seriously affect the quality of human life.Although the etiology and treatment of this type of disease have been extensively studied, there are still many aspects that are unclear.Currently, oxidative stress is believed to be an important link in the pathogenesis of chronic inflammatory diseases of the nasal mucosa. Therefore, anti-oxidative stress is a direction of research for the treatment of chronic nasal mucosal inflammatory diseases.Hydrogen, as a medically therapeutic gas, has been extensively studied for its antioxidant, anti-inflammatory, and anti-damage properties, and has been used in the treatment of various diseases.Although there are relatively few studies on the use of hydrogen for nasal inflammation, its positive effects have also been found. This article systematically summarizes the relevant research on the use of hydrogen to improve chronic nasal mucosal inflammation, with the aim of clarifying the ideas and indicating the direction for further research in the future.
... Its molecular form, hydrogen gas (H 2 ), is colorless, odorless, rare in Earth's atmosphere, and is gaining recognition as a novel energy source [14]. Evidently, H 2 is a potent antioxidative and anti-inflammatory agent with promising potential for medical applications [15,16]. However, because H 2 is flammable, explosive, and dangerous, the much safer hydrogen-rich water (HRW) is often used to replace hydrogen. ...
... In humans, the consumption of HRW by adults effectively alleviated the symptoms of diabetes [18], mitigated cisplatin-induced nephrotoxicity [19], and prevented the risk occurrence of chronic allograft nephropathy after undergoing renal transplantation [20]. The evidence accumulated by these studies suggests that H 2 could protect various cells, tissues, and organs against oxidative injury [15,21,22]. In plants, experiments have shown that H 2 could promote growth vigor and seed germination in certain crops (soybean, barley, canola, spring wheat and mung bean) [23,24], promote the synthesis of anthocyanin in radish sprouts [25], and delay the post-harvest ripening and senescence of kiwifruit [26]. ...
Bispyribac-sodium (BS) is an herbicide often used to control weeds in rice fields. Hydrogen-rich water (HRW) has recently been recommended for alleviating adverse effects, but whether and how HRW alleviates the injury to rice from exposure to BS is still largely unknown. In this study, a greenhouse hydroponic experiment showed that BS alone could substantially inhibit the plant height and fresh weight of both indica and japonica rice seedlings. For indica rice, its pretreatment with HRW at 75% saturation could markedly alleviate the impact on its size but not so with either 50% or 100% HRW. For japonica rice, all the concentrations of HRW used in this study (50%, 75%, and 100% HRW) were capable of reversing the plant size reductions. Further results revealed that the HRW supplement could increase the activity of antioxidative enzymes, including that of catalase (CAT), superoxide dismutase (SOD), and peroxidase (POD), which assist in the effective removal of ROS (reactive oxygen species). Subsequent results demonstrated a weaker inhibition of the acetolactate synthase (ALS) enzyme within five days by BS in rice seedlings pretreated with HRW than those receiving the BS treatment alone, and that the HRW pretreatment can hasten the rate at which BS is degraded in rice. Taken together, these findings strongly suggest that pretreatment with HRW may offer a promising and effective strategy to improve the ability of rice to tolerate BS.
... In the past decade, molecular hydrogen has been identified as a potent pathophysiological agent to alleviate inflammation, apoptosis, and oxidative stress [193]. There are different modes of administration of molecular hydrogen into the human body; these include inhalation of H 2 [194] (Table 1), drinking H 2 water [131], injections either with molecular hydrogen or hydrogen-rich saline [163], H 2 rich bath [195], increasing the quantity of H 2 producing bacteria, and H 2 eye drops [196] . ...
... Hydrogen inhalation produces instant effects, but the administration is impractical continuously. Keeping in mind the safety concerns, a controlled method for easy administration is solubilized hydrogen (hydrogen-rich water) [193]. Hydrogen-rich water can be made by dissolving electrolyzed hydrogen into distilled water, hydrogen into water under pressure, and magnesium in water [195]. ...
Molecular hydrogen proved itself as a novel therapeutic candidate and has been thriving from the beginning with its potential clinical significance, higher affinity, and cellular integrity and permeability. Hydrogen Therapy (HT) has gained scientists' attention with the proven clinical ability to attenuate chronic inflammation, diminish oxidative stress, restrict apoptosis, minimize cellular injury, and refine tissue functioning. Therapeutic Implementation of H2 for disease prevention and treatment is a newly emerging field with limited knowledge available on formulations, tissue-specific effects, efficacy, and safety. This article will discuss HT's therapeutic potential for its efficacy and safety in cardiovascular, respiratory, hematological, metabolic, infectious, and neurodegenerative disorders. In addition to this, the molecular mechanisms and nanotechnological implications of hydrogen therapy will be discussed in detail. Finally, the article will provide insight into advancements and automation, future perspectives, and recommendations. There is a need to study and conduct higher-scale trials targeting personalized treatments under molecular and genetic vitals.
... Basic and clinical studies have shown that H 2 is an important regulator with antioxidant, anti-inflammatory, and antiapoptotic effects [7]. H 2 showed to have an antiinflammatory effect in LPS-activated macrophages, according to Hong et al. [8], by inhibiting the release of proinflammatory cytokines and increasing the release of the anti-inflammatory cytokine, which could be mediated by HO-1. ...
... When protein aggregates become toxic, autophagy is activated, and once excessive autophagy DOI: 10.1159/000520981 causes tissue damage, autophagy is blocked. H 2 appears to play a regulatory role [7]. Guan et al. [23] revealed that H 2 was able to ameliorate chronic intermittent hypoxia (CIH)-induced kidney injury by decreasing ER stress and activating autophagy by inhibiting OS-dependent p38 and JNK MAPK activation. ...
Background:
Hydrogen is a chemical substance that has yet to be widely used in medicine. However, recent evidence indicates that hydrogen has multi-faceted pharmacological effects such as antioxidant, anti-inflammatory, and antiapoptotic properties. An increased number of studies are being conducted on the application of hydrogen in various diseases, especially those affecting the renal system.
Summary:
Hydrogen can be inhaled, as a gas or liquid, and can be administered orally, intravenously, or locally. Hydrogen can rapidly enter suborganelles such as mitochondria and nucleus by simple diffusion, producing reactive oxygen species (ROS) and triggering DNA damage. Hydrogen can selectively scavenge hydroxyl radical (•OH) and peroxynitrite (ONOO-), but not other reactive oxygen radicals with physiological functions, such as peroxyanion (O2-) and hydrogen peroxide (H2O2). Although the regulatory effect of hydrogen on the signal transduction pathway has been confirmed, the specific mechanism of its influence on signal molecules remains unknown. Although many studies have investigated the therapeutic and preventive effects of H2 in cellular and animal experiments, clinical trials are few and still far behind. As a result, more clinical trials are required to investigate the role of hydrogen in kidney disease, as well as the effect of its dose, timing, and form on the overall efficacy. Large-scale randomized controlled clinical trials will be required before hydrogen can be used to treat renal illnesses.
Key messages:
This article reviews the mechanisms of hydrogen in the treatment of renal disease and explores the possibilities of its use in clinical practice.
... [9][10][11][12] Numerous experimental and clinical studies have demonstrated that hydrogen can protect cells, tissues, and organs from oxidative stress-induced injuries by scavenging ROS. 13,14 Hydrogenrich water also can increase the antioxidant capacity in cultured human gingival fibroblasts. 15 Hydrogen-enriched electrolyzed water is guaranteed for safety in human body 16 and hydrogen also has beneficial effects on the human body, including preventive effects on the development of metabolic syndrome, 10,17 improvement of lipid metabolism, 18 antiinflammatory effects, 19,20 reductive relieving effects on the side effects of oxidative cancer treatment, 21 and improvement of autonomic nerve functions. ...
... Therefore, hydrogen molecules can be distributed in the blood and tissues of an organism. 13,33 For example, it has been reported that after drinking hydrogenrich water, the concentration of hydrogen in exhaled breath from healthy adults reaches a peak at 15 minutes in a dosedependent manner. 34 Meanwhile, under inflammation and oxidative stress, the native CRP as the pentamer can be converted into monomeric CRP (Figure 11). ...
This study compared the effects of hydrogen-water (HW) bath on the oxygen radical absorption-based antioxidant capacity and the inflammatory indicator, C-reactive protein (CRP), in serum between healthy volunteers and inflammatory/collagen disease-patients. The HW bath apparatus supplied nano-bubbles with a diameter of 110 ± 10 nm and 338-682 μg/L of dissolved hydrogen after 120 minutes electrolysis, and nano-bubbles increased to 9.91 × 107/mL along with the increase of correlative dissolved hydrogen. Ten-minute HW bath increased the oxygen radical absorption-based antioxidant capacity to 110.9 ± 9.2% at post-bathing 120 minutes, although unaltered with 10-minute normal water bath at 40°C in healthy subjects. The CRP level was repressed to 70.2 ± 12.1% at 120 minutes after HW bath, although rather increased for normal water bath. In the patients with connective tissue diseases, the CRP level was repressed to 3-24% upon 9 days to 4 months of HW bathing. In another six patients with diverse autoimmune-related diseases, upon daily HW bathing as long as 2-25 months, the pre-bathing CRP level of 5.31 mg/dL decreased to 0.24 mg/dL being within the standard-range, with relief of visible inflammatory symptoms for some cases. Thus, the HW bath with high-density nano-bubbles has beneficial effects on serum antioxidant capacity, inflammation, and the skin appearance. The study was approved by the Committee of Ethics, Japanese Center of Anti-Aging Medical Sciences (Authorization No. H-15-03-2, on January 15, 2019), which was a non-profitable organization officially authenticated by the Hiroshima Prefecture Government of Japan.
... Furthermore, hydrogen gas is lighter than air, as exemplified by its use in aircraft [64], so it is difficult to use as a treatment for ground-level plants. In the biomedical field this can be overcome by inhalation [65], but this is not an option for plants unless H 2 is used within a closed environment, which would require additional safety protocols. The volume of H 2 needed to treat widespread fields would simply not be practical from a production/delivery/application, or even from a cost analysis, point of view. ...
... Useful in biomedical arenas. [65,89] Hydrogen-rich water (HRW) ...
Despite being trialed in other regions of the world, the use of molecular hydrogen (H2) for enhanced plant growth and the postharvest storage of crops has yet to be widely accepted in the UK. The evidence that the treatment of plants and plant products with H2 alleviates plant stress and slows crop senescence continues to grow. Many of these effects appear to be mediated by the alteration of the antioxidant capacity of plant cells. Some effects seem to involve heme oxygenase, whilst the reduction in the prosthetic group Fe3+ is also suggested as a mechanism. Although it is difficult to use as a gaseous treatment in a field setting, the use of hydrogen-rich water (HRW) has the potential to be of significant benefit to agricultural practices. However, the use of H2 in agriculture will only be adopted if the benefits outweigh the production and application costs. HRW is safe and relatively easy to use. If H2 gas or HRW are utilized in other countries for agricultural purposes, it is tempting to suggest that they could also be widely used in the UK in the future, particularly for postharvest storage, thus reducing food waste.
... It can also be applied transdermally by applying H 2 saturated water or mixing chemicals together that react to form H 2 [2,3]. All these approaches achieve a transient increase in the concentration of H 2 , along with beneficial effects on cell function [4][5][6][7][8]. Although administration of H 2 by inhalation or ingestion is the predominant method, application of H 2 transdermally provides targeted delivery to specific tissue, allowing for a local effect with a powerful H 2 concentration gradient. ...
Molecular hydrogen (H2) emerged a decade ago as a potent therapeutic and is attracting more and more attention. The beneficial effects of H2
... Molecular hydrogen, as an inert gas with ability of antioxidant, anti-inflammatory, anti-apoptotic and rapid diffuses, has been widely considered as an effective strategy for various diseases in the past few years. 11,12 Recently, hydrogen has shown nonnegligible therapeutic effects in diabetes mellitus. It is reported that the supplement of hydrogen molecule significantly reduces FPG and improve insulin sensitivity in diabetic animal models. ...
Aim:
To evaluate the real-life effectiveness and safety of Chinese patients with type 2 diabetes mellitus (T2DM) receiving hydrogen inhalation (HI) treatment as a supplementary treatment.
Methods:
This retrospective, multicenter, observational 6-months clinical study included T2DM patients maintaining HI, visited at 4 time points. The primary outcome is the mean change in glycated hemoglobin (HbA1c) at the end of the study compared to baseline. The secondary outcome is analyzing the mean change of fasting plasma glucose (FPG), weight, lipid profile, insulin dose and homeostasis model assessment. Linear regression and logistics regression are applied to evaluate the effect of HI after the treatment.
Results:
Of the 431 patients comprised, it is observed a significant decrease in HbA1c level (9.04±0.82% at baseline to 8.30±0.99% and 8.00±0.80% at the end, p<0.001), FPG (165.6±40.2 mg/dL at baseline to 157.1±36.3mg/dL and 143.6±32.3mg/dL at the end, p<0.001), weight (74.7±7.1kg at baseline to 74.8±10.0kg and 73.6±8.1kg at the end, p<0.001), insulin dose (49.3±10.8U/d at baseline to 46.7±8.0U/d and 45.2±8.7U/d, p<0.001). The individuals in subgroup with higher baseline HbA1c and longer daily HI time duration gain greater HbA1c decrease after 6 months. Linear regression shows that higher baseline HbA1c level and shorter diabetes duration are significantly in relation to greater HbA1c reduction. Logistics regression reveals that lower weight is associated with a higher possibility of reaching HbA1c<7%. The most common adverse event is hypoglycemia.
Conclusion:
HI therapy significantly improves glycemic control, weight, insulin dose, lipid metabolism, β-cell function and insulin resistance of patients with type 2 diabetes after 6 months. Higher baseline HbA1c level and shorter diabetes duration is related to greater clinical response to HI.
... Within the scope of PD, it is known that the levels of reactive oxygen species are strictly controlled by various antioxidant mechanisms in healthy dopaminergic neurons (Puspita et al., 2017;Amri et al., 2017). This group of neurons is susceptible to oxidative stress since numerous oxidants are produced in enzymatic and non-enzymatic reactions that DA suffers when released into the synaptic cleft or cytosol (Huang et al., 2010). ...
L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia is a side effect of Parkinson's disease treatment and it is characterized by atypical involuntary movements. A link between neuroinflammation and L-DOPA-induced dyskinesia has been documented. Hydrogen gas (H2) has neuroprotective effects in Parkinson's disease models and has a major anti-inflammatory effect. Our objective is to test the hypothesis that H2 inhalation reduces L-DOPA-induced dyskinesia. 15 days after 6-hydroxydopamine lesions of dopaminergic neurons were made (microinjection into the medial forebrain bundle), chronic L-DOPA treatment (15 days) was performed. Rats were exposed to H2 (2% gas mixture, 1 h) or air (controls) before L-DOPA injection. Abnormal involuntary movements and locomotor activity were conducted. Striatal microglia and astrocyte was analyzed and striatal and plasma samples for cytokines evaluation were collected after the abnormal involuntary movements analysis. H2 inhalation attenuated L-DOPA-induced dyskinesia. The gas therapy did not impair the improvement of locomotor activity achieved by L-DOPA treatment. H2 inhalation reduced activated microglia in the lesioned striatum, which is consistent with the observed reduced pro-inflammatory cytokines levels. Display of abnormal involuntary movements was positively correlated with plasma IL-1β and striatal TNF-α levels and negatively correlated with striatal IL-10 levels. Prophylactic H2 inhalation decreases abnormal involuntary movements in a preclinical L-DOPA-induced dyskinesia model. The H2 antidyskinetic effect was associated with decreased striatal and peripheral inflammation. This finding has a translational importance to L-DOPA-treated parkinsonian patients' well-being.
... Indeed, numerous literature have shown that hydrogen gas treatment ameliorated IR injury in experimental models, including cardiac ischemia, intestinal or lung transplantation, as well as hemorrhagic shock. 5,6 Although the precise mechanisms are not fully understood, hydrogen gas exhibits anti-oxidative effects partly through eliminating ROS. In addition, hydrogen gas exerts antiinflammatory and anti-apoptotic effects under various physiological and pathological conditions. ...
Objectives
Crush syndrome (CS) is characterized by a systemic manifestation of traumatic rhabdomyolysis, leading to multiple organ dysfunction and death. Ischemia-reperfusion (IR) injury is commonly responsible for systemic response. Extending studies have shown that hydrogen gas treatment ameliorated IR injury in numerous experimental models; however, its effect on CS has not been well examined. This study aimed to investigate the effects of hydrogen gas inhalation following crush injury in an experimental model of CS.
Methods
Male Sprague-Dawley rats were subjected to experimental CS by applying a total of 3.0 kg weight to both hindlimb under general anesthesia for 6 h. Immediately after decompression, the animals were randomly placed in a gas chamber filled with either air or 1.3% hydrogen gas. Animals were sacrificed 18 h or 24 h following gas exposure for non-survival studies or for survival study, respectively.
Results
The rats with hydrogen treatment ( n = 6) had a higher 24-h survival than the rats with air treatment ( n = 9) (100% vs. 44%, p = 0.035). Lactate concentrations (2.9 ± 0.2 vs. 2.2 ± 0.2 mmol/L, p = 0.040) and creatine kinase (34,178 ± 13,580 vs. 5005 ± 842 IU/L, p = 0.016) were lower in the hydrogen group compared with the air group 18 h after decompression ( n = 4 in the air group, and n = 5 in the H 2 group). Histological analysis revealed that the damage to the rectus femoris muscle and kidney appeared to be ameliorated by hydrogen treatment.
Conclusion
Hydrogen gas inhalation may be a promising therapeutic approach in the treatment of CS.
... Hydrogen in the atomic form is the simplest element, consisting of only one electron and one proton, but it exists primarily in its diatomic form (H 2 ). It is a tasteless, odorless, colorless, and non-toxic nonmetallic gas [10]. Hydrogen is at the center of the prevailing cosmological model that describes the early development of the universe [11] as well as the origin of life itself [12,13]. ...
Over 2000 publications including more than 100 human studies seem to indicate that humans have only recently benefited from or known about the medical effects of H2 within the past 15 years. However, we have unknowingly benefited from H2 since the dawn of time, from H2-producing bacteria to the use of naturally occurring hydrogen-rich waters. Moreover, the first writings on the therapeutic effects of H2 date to around 1793. Since then, papers appeared sporadically in the literature every few decades but never exploded until Ohsawa et al. again demonstrated hydrogen’s therapeutic effects in 2007. This landmark paper appears to have been the spark that ignited the medical interest in hydrogen. Although H2 was used in the 1880s to locate intestinal perforations, in the 1940s in deep sea diving, and in the 1960s to measure blood flow, H2 was largely viewed as biologically inert. This review highlights the history of hydrogen in the genesis/evolution of life and its medicinal and non-medicinal use in humans. Although hydrogen medicine has a long and erratic history, perhaps future history will show that, this time around, these 15 years of ignited interest resulted in a self-sustaining explosion of its unique medical effects.
... Many microalgae and cyanobacteria can express hydrogenases that reduce protons to gaseous H 2 (11). Since the antioxidant property of H 2 in animals was observed by Ohsawa et al. (12), H 2 is gradually regarded as a therapeutic medical gas (13). In plants, H 2 has been found to act as one of the beneficial gasotransmitters in responses to various abiotic stresses (14), including cadmium exposure in alfalfa (15) and cucumber (16), and salinity in Arabidopsis (17). ...
Although molecular hydrogen has potential therapeutic effects in animals, whether or how this gas functions in plant disease resistance has not yet been elucidated. RSV was considered the most devastating plant virus in rice, since it could cause severe losses in field production.
... As a therapeutic medical gas, hydrogen (H 2 ) has several properties such as antioxidants, reducing inflammation in cell tissues, and inert. [1][2] H 2 is aided to the body via various routes such as inhalation of hydrogen-containing air (HCA), oral ingestion using hydrogen-rich water (HRW), and H 2 saline injection. ...
As a therapeutic medical gas, hydrogen (H2) has several properties such as antioxidants,
reducing inflammation in cell tissues, and inert.[1-2] H2 is aided to the body via various
routes such as inhalation of hydrogen-containing air (HCA), oral ingestion using
hydrogen-rich water (HRW), and H2 saline injection.
Recently many products for HCA and HRW therapy have been manufactured
and marketed. However, this product has never been checked regarding its safety,
especially regarding the impurities in the gas. Furthermore, the H2 production from the
electrolysis process has been known to be accompanied by side product gas such as
hydrocarbons and CO. Therefore, we have investigated the impurities content in the HCA
and HRW therapy products using gas chromatography (GC) instrument. First, gas
reference standards (GRS) measurements were used to calibrate the instrument and
determine the gas separation. For example, for the detection of hydrocarbons, the
instrument setup is as follows: the gas column was alumina; the detector was a flame
ionization detector (FID); the detector temperature was 250 °C, and the oven temperature
was 100 °C. Afterward, the 10 HCA and HRW devices samples were measured using
the setup.
The results show that H2 gas generated from the devices contains impurities
from hydrocarbons (with the maximum value) CH4(5.38 µmol/mol), C2H6 (1.2 µmol/mol),
C2H4 (1.22 µmol/mol), C3H8 (1.17 µmol/mol), C4H10 (2.08 µmol/mol), C2H2 (1.00
µmol/mol), C4H8 (2.85 µmol/mol), and C4H6 (1.14 µmol/mol). A Molseive column then
replaced the gas column to detect CO. Measurement shows the maximum CO impurities
in the samples is 13.2 µmol/mol. These findings reveal that while hydrogen gas has a
positive impact on the body, negative consequences might arise due to the presence of
other gases from the electrolysis process.
... Previous studies have demonstrated that feed supplemented with C. butyricum can boost growth performance, balance intestinal flora, and promote immune responses in broilers (Cassir et al. 2016;Huang et al. 2019;Han et al. 2018). Butyric acid is the most important metabolite of C. butyricum and endows C. butyricum with antioxidant effects on the colonic mucosa (Hamer et al. 2009;Ohsawa et al. 2007;Huang et al. 2010). However, there are only few reports on the effects of C. butyricum on anti-oxidant activity in broilers. ...
Low-protein (LP) feeds are used in the poultry industry to combat the increasing consumption of protein resources and reduce environmental pollution caused by excessive nitrogen excretion. Dietary supplementation of protease or Clostridium butyricum increases the growth performance of broilers; however, it is unclear whether they counteract the negative effects of LP diets. The effects of protease and C. butyricum on growth performance, intestinal morphology, anti-oxidant capacity, anti-inflammatory response, and microbial community of broilers have not been studied extensively. Here, 450 healthy 1-day-old Cobb500 broilers were allocated to five groups, according to different diets: basal diet (Control); LP diet (LP; 2% less crude protein than the control); LP diet + 200 g/t HuPro protease (LPH); LP diet + 1.0 × 10⁹ CFU/t C. butyricum (LPC); and basal diet + 200 g/t oxytetracycline (Antibiotic). Supplementing both C. butyricum and protease improved the growth performance of broilers. The supplementation of HuPro protease under low-protein conditions could achieve a breeding effect similar to that of the positive control (Antibiotic). Supplementing C. butyricum could maintain intestinal barrier function, alleviate the inflammatory response, and increase ileal and cecal short-chain fatty acid concentrations. Both C. butyricum and protease altered the bacterial diversity in the cecum, increased Bacteroidetes abundance, and resulted in higher abundance of Rikenellaceae RC9 gut spp. and lower abundance of Alistipes spp. in broilers. This study demonstrates the positive effects of proteases and C. butyricum on broilers and serves as a reference for the selection of appropriate supplementation for broilers in the poultry industry.
Key points
• Low-protein diet had a negative effect on growth performance of broilers.
• Protease significantly reduced feed conversion rate.
• Clostridium butyricum had positive effects on broilers.
... Recent studies have shown that hydrogen gas (H 2 ) is an important physiological regulatory factor with antioxidant, anti-inflammatory, and anti-apoptotic properties [26]. In the present study, we investigated the protective effects of H 2 treatment in LPS-induced ALI mice. ...
Background
Chronic inflammation and oxidant/antioxidant imbalance are two main pathological features associated with lipopolysaccharide (LPS)-induced acute lung injury (ALI). The following study investigated the protective role of hydrogen (H2), a gaseous molecule without known toxicity, in LPS-induced lung injury in mice and explored its potential molecular mechanisms.
Methods
Mice were randomly divided into three groups: H2 control group, LPS group, and LPS + H2 group. The mice were euthanized at the indicated time points, and the specimens were collected. The 72 h survival rates, cytokines contents, pathological changes, expression of Toll-like receptor 4 (TLR4), and oxidative stress indicators were analyzed. Moreover, under different culture conditions, RAW 264.7 mouse macrophages were used to investigate the potential molecular mechanisms of H2 in vitro. Cells were divided into the following groups: PBS group, LPS group, and LPS + H2 group. The cell viability, intracellular ROS, cytokines, and expression of TLR4 and nuclear factor kappa-B (NF-κB) were observed.
Results
Hydrogen inhalation increased the survival rate to 80%, reduced LPS-induced lung damage, and decreased inflammatory cytokine release in LPS mice. Besides, H2 showed remarked anti-oxidative activity to reduce the MDA and NO contents in the lung. In vitro data further indicated that H2 down-regulates the levels of ROS, NO, TNF-α, IL-6, and IL-1β in LPS-stimulated macrophages and inhibits the expression of TLR4 and the activation of nuclear factor kappa-B (NF-κB).
Conclusion
Hydrogen gas alleviates lipopolysaccharide-induced acute lung injury and inflammatory response most probably through the TLR4-NF-κB pathway.
... Its molecular form, hydrogen gas (H2), is a colorless, odorless and tasteless gas. Since H2 was first purified by Robert Boyle in 1671, it has been known as a reducing gas [1]. The production of H2 was first observed in bacteria [2] and then in green algae [3]. ...
Hydrogen gas (H2) is a unique molecular messenger, which is known to be involved in diverse physiological processes in plants, from seed germination to seedling growth to regulation of environmental stresses. In this review, we focus on the role of H2 in plant responses to abiotic stresses, such as temperature, osmotic stress, light, paraquat (PQ)-induced oxidative stresses, and metal stresses. In general, H2 can alleviate environmental stresses by improving the antioxidant defense system, photosynthetic capacity, re-establishing ion homeostasis and glutathione homeostasis, maintaining nutrient element homeostasis, mediating glucose metabolism and flavonoid pathways, regulating heme oxygenase-1 (HO-1) signaling, and interaction between H2 and nitric oxide (NO), carbonic oxide (CO), or plant hormones. In addition, some genes modulated by H2 under abiotic stresses are also discussed. Detailed evidence of molecular mechanisms for H2-mediated particular pathways under abiotic stress, however, is scarce. Further studies regarding the regulatory roles of H2 in modulating abiotic stresses research should focus on the molecular details of the particular pathways that are activated in plants. More research work will improve knowledge concerning possible applications of hydrogen-rich water (HRW) to respond to abiotic stresses with the aim of enhancing crop quality and economic value.
... Safety In its gaseous state H2 has a flammability range of 4% -94% at standard pressure and temperature. 48 Therefore calculations assessing the inhalation volume of H2 should be conducted before administration. For example, if a patient is experiencing rapid or shallow breathing, or has a chronic lung condition, it would be beneficial to conduct a simple spirometry test to ensure accurate measurement of tidal volume and H2 consumption, using the formula: (mL/sec): H2 / (Breath -H2) x 100 H2 is classified as a 'generally regarded as safe' (GRAS) product by the Food and Drug Administration (U.S.), 49 and is regarded as a food supplement (E949) under part C group I of regulation 1129/2011 in the European Union 50,51 and U.K. 52 ...
Coronavirus Infectious Disease 2019 (COVID-19) is caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2) that emerged as a novel pathogen of global concern in the latter stages of 2019. COVID-19 is a highly contagious disease which can be transmitted through aerosol droplets and surface-to-host contact. Both symptomology and the severity of disease can vary wildly between individuals, from asymptomatic but infectious, to those that require critical care. Due to the neoteric emergence of SARS-CoV-2, current treatment strategies are not yet well developed and rely on the repurposing of such medications as antiviral, corticosteroid, immunosuppressant and oxygen (O2) therapies. However, the minimal efficacy of these interventions is concerning. In addition to the acute infection that prevails, it is estimated that up to 30% of adults who contract COVID-19 develop chronic symptoms lasting longer than 12 weeks. It is also estimated that 15% of children aged 2-16 years have developed long-lasting sequelae associated with SARS-CoV-2 infection. According to recent clinical data, molecular hydrogen (H2) and oxy-hydrogen (H2/O2) therapies successfully remediated the debilitating effects of SARS-CoV-2 infection in adults. By acting as an effective anti-inflammatory and antioxidative agent, it is reported that H2 administration can improve recovery through abatement of the hyperinflammatory cytokine cascade and reduction of inhalation resistance in patients with mild-moderate disease symptoms. In this review, the authors investigate the clinical and empirical evidence relating to treating the symptoms of both acute and chronic COVID-19 with H2-containing therapeutics.
... Molecular hydrogen (H2) is a colorless, tasteless, odorless, flammable gas [1]. H2 is also a minimal molecule that can quickly diffuse through the alveoli into the blood and circulate throughout the body during breathing. ...
This research examined the effects of single-dose molecular hydrogen (H2) supplements on acid-base status and local muscle deoxygenation during rest, high-intensity intermittent training (HIIT) performance, and recovery. Ten healthy, trained subjects in a randomized, double-blind, crossover design received H2-rich calcium powder (HCP) (1500 mg, containing 2.544 μg of H2) or H2-depleted placebo (1500 mg) supplements 1 h pre-exercise. They performed six bouts of 7 s all-out pedaling (HIIT) at 7.5% of body weight separated by 40 s pedaling intervals, followed by a recovery period. Blood gases' pH, PCO2, and HCO3 − concentrations were measured at rest. Muscle deoxygenation (deoxy[Hb + Mb]) and tissue O2 saturation (StO2) were determined via time-resolved near-infrared spectroscopy in the vastus lateralis (VL) and rectus femoris (RF) muscles from rest to recovery. At rest, the HCP group had significantly higher PCO2 and HCO3 − concentrations and a slight tendency toward acidosis. During exercise, the first HIIT bout's peak power was significantly higher in HCP (839 ± 112 W) vs. Placebo (816 ± 108 W, p = 0.001), and HCP had a notable effect on significantly increased deoxy[Hb + Mb] concentration during HIIT exercise, despite no differences in heart rate response. The HCP group showed significantly greater O2 extraction in VL and micro-vascular (Hb) volume in RF during HIIT exercise. The HIIT exercise provided significantly improved blood flow and muscle reoxygenation rates in both the RF and VL during passive recovery compared to rest in all groups. The HCP supplement might exert ergogenic effects on high-intensity exercise and prove advantageous for improving anaerobic HIIT exercise performance.
... Over the past few years, uses of H2 have been largely anticipated as novel medical treatments (29). H2 has been employed in different forms to various disease models, and research on its curative effects has progressed rapidly (16,30). In the present study, H2-induced ADSCs were confirmed to exhibit a high biocompatibility in vitro based on MTT and Live-Dead Cell Staining (Fig. 2). ...
Background and objectives:
This study aims to clarify the systems underlying regulation and regulatory roles of hydrogen combined with 5-Aza in the myogenic differentiation of adipose mesenchymal stem cells (ADSCs).
Methods and results:
In this study, ADSCs acted as an in vitro myogenic differentiating mode. First, the Alamar blue Staining and mitochondrial tracer technique were used to verify whether hydrogen combined with 5-Aza could promote cell proliferation. In addition, this study assessed myogenic differentiating markers (e.g., Myogenin, Mhc and Myod protein expressions) based on the Western blotting assay, analysis on cellular morphological characteristics (e.g., Myotube number, length, diameter and maturation index), RT-PCR (Myod, Myogenin and Mhc mRNA expression) and Immunofluorescence analysis (Desmin, Myosin and β-actin protein expression). Finally, to verify the mechanism of myogenic differentiation of hydrogen-bound 5-Aza, we performed bioinformatics analysis and Western blot to detect the expression of p-P38 protein. Hydrogen combined with 5-Aza significantly enhanced the proliferation and myogenic differentiation of ADSCs in vitro by increasing the number of single-cell mitochondria and upregulating the expression of myogenic biomarkers such as Myod, Mhc and myotube formation. The expressions of p-P38 was up-regulated by hydrogen combined with 5-Aza. The differentiating ability was suppressed when the cells were cultivated in combination with SB203580 (p38 MAPK signal pathway inhibitor).
Conclusions:
Hydrogen alleviates the cytotoxicity of 5-Aza and synergistically promotes the myogenic differentiation capacity of adipose stem cells via the p38 MAPK pathway. Thus, the mentioned results present insights into myogenic differentiation and are likely to generate one potential alternative strategy for skeletal muscle related diseases.
... 3 With the progression of this research field, many other mechanisms of molecular hydrogen in addition to antioxidation have been identified, including anti-inflammation, anti-apoptosis, and multiple cellular pathways adjustment. 4 Molecular hydrogen was also used to treat various diseases or pathological changes, such as ischemia-reperfusion injury, sepsis, liver injury, kidney injury, lung injury, and brain injury. [5][6][7][8][9] On the basis of these studies, numerous relevant products emerged, for instance, medical hydrogen gas generator, hydrogen-rich water, and hydrogen-rich saline, and several clinical investigations were conducted. ...
The medical use of molecular hydrogen, including hydrogen-rich water and hydrogen gas, has been extensively explored since 2007. This article aimed to demonstrate the trend in medical research on molecular hydrogen. A total of 1126 publications on hydrogen therapy were retrieved from the PubMed database until July 30, 2021. From 2007 to 2020, the number of publications in this field had been on an upward trend. Medical Gas Research, Scientific Report and Shock have contributed the largest number of publications on this topic. Researchers by the name of Xue-Jun Sun, Ke-Liang Xie and Yong-Hao Yu published the most studies in the field. Analysis of the co-occurrence of key words indicated that the key words "molecular hydrogen," "hydrogen-rich water," "oxidative stress," "hydrogen gas," and "inflammation" occurred most frequently in these articles. "Gut microbiota," "pyroptosis," and "COVID-19" occurred the most recently among the keywords. In summary, the therapeutic application of molecular hydrogen had attracted much attention in these years. The advance in this field could be caught up by subscribing to relevant journals or following experienced scholars. Oxidative stress and inflammation were the most important research directions currently, and gut microbiota, pyroptosis, and coronavirus disease 2019 might become hotspots in the future.
... H 2 is considered nontoxic in breathing gas mixture even at high concentrations of up to 49% vol/vol [97] and its role in cellular function, cell signalling, and the tissue healing process via biochemical and biomechanical (owing to gas accumulation in the tissue) pathways has been gradually uncovered in some recent studies. H 2 is a well-known reductive and therapeutic gas [98,99] that can efficiently decrease oxidative stress [100] and inflammation [101]. H 2 attenuated lipopolysaccharide (LPS)-induced inflammation by reducing the cytotoxic reactive oxygen species (ROS) that are produced in the inflamed tissues [102]. ...
Mg-based alloys as revolutionary implantable biomaterials have increasingly attracted considerable attention, owing to their biodegradability in vivo and beneficial effects on biological systems. The degradation process and products of Mg-based alloys have been reported to exhibit significant biological effects on host-tissue responses. However, these effects have not yet been fully understood. This review systemically summarizes and analyses the current understandings and recent research progress in this area. The primary focal points are the biological effects and related mechanisms associated with the degradation behaviour of Mg-based alloys. The biological impacts of the degradation products are elucidated and the arguable or controversial issues are also discussed, providing a pathway toward a greater understanding of the biological implications of Mg-based alloys. Furthermore, based on these biological implications, the restorative potential of Mg-based alloys for applications in tissue repair and regeneration is summarized. Finally, outlooks on biosafety evaluation and design strategies for Mg-based alloy implants are briefly discussed. © 2022 Institute of Materials, Minerals and Mining and ASM International Published by Taylor & Francis on behalf of the Institute and ASM International.
... Hydrogen (H 2 ) is an important physiological regulatory factor that has protective effects of anti-oxidation, anti-inflammation, and anti-apoptosis on cells and organs (Huang et al., 2010b). H 2 can reduce oxidative stress (Song et al., 2011), promote the scavenging of free radicals, and inhibit vascular aging (Iketani et al., 2018). ...
Endotoxins and other harmful substances may cause an increase in permeability in endothelial cells (ECs) monolayers, as well as ECs shrinkage and death to induce lung damage. Lipopolysaccharide (LPS) can impair endothelial progenitor cells (EPCs) functions, including proliferation, migration, and tube formation. EPCs can migrate to the damaged area, differentiate into ECs, and participate in vascular repair, which improves pulmonary capillary endothelial dysfunction and maintains the integrity of the endothelial barrier. Hydrogen (H2) contributes to the repairment of lung injury and the damage of ECs. We therefore speculate that H2 protects the EPCs against LPS-induced damage, and it’s mechanism will be explored. The bone marrow-derived EPCs from ICR Mice were treated with LPS to establish a damaged model. Then EPCs were incubated with H2, and treated with PI3K inhibitor LY294002 and endothelial nitric oxide synthase (eNOS) inhibitor L-NAME. MTT assay, transwell assay and tube formation assay were used to detect the proliferation, migration and angiogenesis of EPCs. The expression levels of target proteins were detected by Western blot. Results found that H2 repaired EPCs proliferation, migration and tube formation functions damaged by LPS. LY294002 and L-NAME significantly inhibited the repaired effect of H2 on LPS-induced dysfunctions of EPCs. H2 also restored levels of phosphor-AKT (p-AKT), eNOS and phosphor-eNOS (p-eNOS) suppressed by LPS. LY294002 significantly inhibited the increase of p-AKT and eNOS and p-eNOS expression exposed by H2. L-NAME significantly inhibited the increase of eNOS and p-eNOS expression induced by H2. H2 repairs the dysfunctions of EPCs induced by LPS, which is mediated by PI3K/AKT/eNOS signaling pathway.
... Hydrogen gas (H 2 ) is a novel antioxidant, which was first reported by as being able to alleviate oxidative stress by suppressing hydroxyl radicals (•OH) and peroxynitrite (ONOO-) [12]. Hydrogen has been reported to possess antioxidative, anti-inflammation, and antiapoptosis effects [13] and demonstrated as a novel therapy for different diseases such as cerebral, myocardial, hepatic, renal, and intestinal diseases [14][15][16][17][18][19][20]. Especially, hydrogen inhalation can alleviate hypertoxic lung injury in rats [21] and protect mice against cigarette-induced chronic obstructive pulmonary disease (COPD) [22]. ...
Acute respiratory distress syndrome (ARDS) causes uncontrolled pulmonary inflammation, resulting in high morbidity and mortality in severe cases. Given the antioxidative effect of molecular hydrogen, some recent studies suggest the potential use of molecular hydrogen as a biomedicine for the treatment of ARDS. In this study, we aimed to explore the protective effects of magnesium hydride (MgH2) on two types of ARDS models and its underlying mechanism in a lipopolysaccharide (LPS)-induced ARDS model of the A549 cell line. The results showed that LPS successfully induced oxidative stress, inflammatory reaction, apoptosis, and barrier breakdown in alveolar epithelial cells (AEC). MgH2 can exert an anti-inflammatory effect by down-regulating the expressions of inflammatory cytokines (IL-1β, IL-6, and TNF-α). In addition, MgH2 decreased oxidative stress by eliminating intracellular ROS, inhibited apoptosis by regulating the expressions of cytochrome c, Bax, and Bcl-2, and suppressed barrier breakdown by up-regulating the expression of ZO-1 and occludin. Mechanistically, the expressions of p-AKT, p-mTOR, p-P65, NLRP3, and cleaved-caspase-1 were decreased after MgH2 treatment, indicating that AKT/mTOR and NF-κB/NLRP3/IL-1β pathways participated in the protective effects of MgH2. Furthermore, the in vivo study also demonstrated that MgH2-treated mice had a better survival rate and weaker pathological damage. All these findings demonstrated that MgH2 could exert an ARDS-protective effect by regulating the AKT/mTOR and NF-κB/NLRP3/IL-1β pathways to suppress LPS-induced inflammatory reaction, oxidative stress injury, apoptosis, and barrier breakdown, which may provide a potential strategy for the prevention and treatment of ARDS.
... Gao et al. suggested that CaOx crystal could induce inflammatory reaction and oxidative stress through Akt, ERK1/2, and P38 MAPK pathways and affect amino acid metabolism and fatty acids β oxidation, resulting in kidney injury. Besides, according to a series of studies on the treatment of crystalline kidney injury, hydrogen-rich water (HRW), which has been used in the medical field, attracted our attention due to its activities of anti-oxidation, anti-inflammation, anti-fibrosis, and anti-apoptosis (12). The primary advantages of HRW are that it is a portable, easily administered, and safe means of delivering hydrogen. ...
... The search for a simple method to delay or halt the ageing process has been going on for centuries based on efficient anti-oxidant products. Growing evidence of the ability of hydrogen, either as a gas or solution, to scavenge and selectively inactivate ROS suggest that it could exert protective effects (20). Bathing every day for 3 months in waters containing molecular hydrogen (N=18) has been shown to decrease the oxidation-reduction potential (ORP) and increased the elasticity of human skin (21,22). ...
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.
... Hydrogen gas is the lightest known gas. It is colorless and odorless, with only 1/14 of the density of air [9]. Hydrogen gas has strong reducibility and is mainly used as a reducing agent in various industrial reactions to provide electrons to oxidizing substances [10]. ...
As a small-molecule reductant substance, hydrogen gas has an obvious antioxidant function. It can selectively neutralize hydroxyl radicals (•OH) and peroxynitrite (ONOO•) in cells, reducing oxidative stress damage. The purpose of this study was to investigate the effect of hydrogen gas (3%) on early chronic liver injury (CLI) induced by CCl4 and to preliminarily explore the protective mechanism of hydrogen gas on hepatocytes by observing the expression of uncoupling protein 2 (UCP2) in liver tissue. Here, 32 rats were divided into four groups: the control group, CCl4 group, H2 (hydrogen gas) group, and CCl4 + H2 group. The effect of hydrogen gas on early CLI was observed by serological tests, ELISA, hematoxylin and eosin staining, and oil red O staining. Immunohistochemical staining and Western blotting were used to observe the expression of UCP2 in liver tissues. We found that CCl4 can induce significant steatosis in hepatocytes. When the hydrogen gas was inhaled, hepatocyte steatosis was reduced, and the UCP2 expression level in liver tissue was increased. These results suggest that hydrogen gas might upregulate UCP2 expression levels, reduce the generation of intracellular oxygen free radicals, affect lipid metabolism in liver cells, and play a protective role in liver cells.
... H 2 gas is flammable at temperatures in excess of 527 • C and is known to explode in a rapid chain reaction with O 2 [110]. According to contemporary reports, H 2 should not exceed 4.6% in air and 4.1% by volume in pure oxygen gas [111]. Hydrogen, as a pure gas, is an explosion risk and therefore it is not safe, or practical, to store such a volatile gas in the clinical environment. ...
Since the late 18th century, molecular hydrogen (H2) has been shown to be well tolerated, firstly in animals, and then in humans. However, although research into the beneficial effects of molecular hydrogen in both plant and mammalian physiology is gaining momentum, the idea of utilising this electrochemically neutral and non-polar diatomic compound for the benefit of health has yet to be widely accepted by regulatory bodies worldwide. Due to the precise mechanisms of H2 activity being as yet undefined, the lack of primary target identification, coupled with difficulties regarding administration methods (e.g., dosage and dosage frequencies, long-term effects of treatment, and the patient’s innate antioxidant profile), there is a requirement for H2 research to evidence how it can reasonably and most effectively be incorporated into medical practice. This review collates and assesses the current information regarding the many routes of molecular hydrogen administration in animals and humans, whilst evaluating how targeted delivery methods could be integrated into a modern healthcare system.
... Over the past few years, uses of H 2 have been largely anticipated as novel medical treatments [29]. H 2 has been employed in different forms to various disease models, and research on its curative effects has progressed rapidly [30,31]. In the present study, H 2 -induced ADSCs were con rmed to exhibit a high biocompatibility in vitro based on MTT and Live-Dead Cell Staining (Fig. 2). ...
Purpose: This study aims to clarify the systems underlying regulation and regulatory roles of hydrogen in the myogenic differentiation of adipose mesenchymal stem cells (ADSCs).
Materials and methods: In this study, ADSCs acted as an in vitro myogenic differentiating mode. First, the Alamar blue Staining and mitochondrial tracer technique were used to verify whether hydrogen could promote cell proliferation. In addition, this study assessed myogenic differentiating markers (e.g., Myogenin, Mhc and Myod protein expressions) based on the Western blotting assay, analysis on cellular morphological characteristics (e.g., Myotube number, length, diameter and maturation index), RT-PCR (Mhc and Myod mRNA expression) and Immunofluorescence analysis (Desmin, Myosin and β-actin protein expression). Lastly, to verify the myogenic differentiating system of hydrogen, Western blotting assay was performed to detect p38 and p-p38 proteins expressions.
Results: Hydrogen can remarkably enhance the proliferation of ADSCs in vitro by increasing the number of single-cell mitochondria and by up-regulating the expression of myogenic biomarkers (e.g., Myod, Mhc and myotube formation). The expressions of both p38 and p-p38 were up-regulated by hydrogen. The differentiating ability was suppressed when the cells were cultivated in combination with SB203580 (p38 MAPK signal pathway inhibitor).
Conclusions: The present study initially indicated that hydrogen can promote myogenic differentiation via the p38 MAPK pathway. Thus, the mentioned results present insights into myogenic differentiation and are likely to generate one potential alternative strategy for skeletal muscle related diseases.
Background:
Lung contusion caused by blunt chest trauma evokes a severe inflammatory reaction in the pulmonary parenchyma that may be associated with acute respiratory distress syndrome. Although hydrogen gas has antioxidant and anti-inflammatory effects and is protective against multiple types of lung injury at safe concentrations, the effects of inhaled hydrogen gas on blunt lung injury have not been previously investigated. Therefore, using a mouse model, we tested the hypothesis that hydrogen inhalation after chest trauma would reduce pulmonary inflammation and acute lung injury associated with lung contusion.
Methods:
Inbred male C57BL/6 mice were randomly divided into 3 groups: sham with air inhalation, lung contusion with air inhalation, and lung contusion with 1.3% hydrogen inhalation. Experimental lung contusion was induced using a highly reproducible and standardized apparatus. Immediately after induction of lung contusion, mice were placed in a chamber exposed to 1.3% hydrogen gas in the air. Histopathological analysis and real-time polymerase chain reaction in lung tissue and blood gas analysis were performed 6 hours after contusion.
Results:
Histopathological examination of the lung tissue after contusion revealed perivascular/intra-alveolar hemorrhage, perivascular/interstitial leukocyte infiltration, and interstitial/intra-alveolar edema. These histological changes and the extent of lung contusion, as determined by computed tomography, were significantly mitigated by hydrogen inhalation. Hydrogen inhalation also significantly reduced inflammatory cytokine and chemokine mRNA levels and improved oxygenation.
Conclusion:
Hydrogen inhalation therapy significantly mitigated inflammatory responses associated with lung contusion in mice. Hydrogen inhalation therapy may be a supplemental therapeutic strategy for treating lung contusion.
Background:
Activated inflammatory cells produce reactive oxygen species (ROS) to eliminate pathogens. Under normal conditions, the pathogens are taken care of, and tissues are repaired. However, in periodontal disease, persistent inflammation causes increased ROS release and impaired healing. Therefore, removal of overproduced ROS using antioxidants is necessary. Hydrogen water has an antioxidative effect on cells and impedes oxidative stress-related disorders.
Aim:
To study the effect of hydrogen water on cell viability, migration, and its antioxidative potential in fibroblasts obtained from chronic periodontitis patients.
Materials and methods:
The gingival tissue samples were obtained from 26 subjects (13 periodontally healthy individuals and 13 chronic periodontitis patients) and processed. The human gingival fibroblasts were cultured and the assays were commenced once adequate growth was detected. The effect of hydrogen water on cell viability was checked by neutral red assay, while the migration potential was assessed by transwell migration assay. The antioxidative potential of hydrogen water was evaluated by CUPRAC assay.
Statistical analysis:
Intergroup comparison was done using Mann-Whitney U-test. Intragroup comparison was done using Wilcoxon signed-rank test.
Results:
Hydrogen water was nontoxic to the fibroblasts at 24 h and 48 h. The intergroup comparison of the cell viability between hydrogen water-treated periodontally healthy gingival fibroblasts (HF) and fibroblasts from patients with chronic periodontitis (CF) showed a statistically significant (P = 0.00) difference at 24 h and 48 h. Hydrogen water also positively influenced the migratory capacity. Hydrogen water-treated fibroblasts obtained from chronic periodontitis patients showed more migration in comparison to the healthy group (P = 0.00). Hydrogen water showed an antioxidative potential. The maximum potential was seen in relation to the fibroblasts obtained from chronic periodontitis patients at 48 h.
Conclusion:
Hydrogen water was nontoxic, increased the migratory capacity, and showed an antioxidative potential on human fibroblasts obtained from periodontally healthy individuals and patients with chronic periodontitis.
Iron is the trace element of natural selection by the biological systems due to its versatile coordination chemistry, and is recently explored for medicinal and diagnostic applications. Photo-activated states of iron complexes exhibiting substitution, dissociation, isomerization reactions, intramolecular redox reactions or energy transfer to other molecules have attracted the attention across the globe for the potent applications in photo-chemotherapy. There is a significant advancement on the development of iron-based complexes for photochemotherapeutic applications. Here in we reviewed the photo-activated states and photochemistry of iron complexes, and recent advances made in the area of photochemotherapy of iron complexes relevant to the photochemistry of iron complexes.
Recently, molecular hydrogen has been found to exhibit antioxidation activity through many clinical experiments, but the mechanism has not been fully understandable at atomic level. In this work, we perform systematic ab initio calculations of protoheme-hydrogen complexes to clarify the antioxidation mechanism of molecular hydrogen. We make molecular modeling of iron–protoporphyrin coordinated by imidazole, FeP(Im), and its hydrogen as well as dihydrogen complexes, together with reactive oxygen/nitrogen species (RONS). We carry out structural optimization and Mulliken charge analysis, revealing the two kinds of bonding characteristics between FeP(Im) and H\(_{2}\): dihydrogen bonding in the end-on asymmetric configuration and Kubas bonding in the side-on symmetric configuration of H\(_{2}\) molecule. The activation barriers for adsorption and dissociation of H\(_{2}\) on and further desorption of H atom from FeP(Im) are found to be below 2.78 eV at most, which is remarkably lower than the H–H bond breaking energy of 4.64 eV in free H\(_{2}\) molecule. We find that the hydrogen bond dissociation energies of FeP(Im)–H\(_{2}\) and –H complexes are lower than those of RONS–H complexes, indicating the decisive role of protoheme as an effective catalyst in RONS antioxidation by molecular hydrogen in vivo.
Abstract:
Molecular hydrogen is a colorless, odorless, tasteless, non-toxic, flammable, and diatomic gas. Molecular hydrogen is dissolved directly in water to be used in the form of hydrogen-rich water (HRW) to keep the freshness of fruits and vegetables. The shelf-life of the product was increased and the quality attributes were maintained when hydrogen was applied to some food products such as milk, tea, and fruit juices. Some grain products and greens grew rapidly and their antioxidant substance levels increased when they were supplıed with hydrogen-rich water. Molecular hydrogen has shown an important application in food drying in recent years, and was used especially in reducing atmosphere drying (RAD) technology. Few studies have been conducted on the use of molecular hydrogen in food products. Due to its various positive effects, the use of molecular hydrogen in the food industries using different techniques and processes could be encouraged by the presence review.
Özet:
Moleküler hidrojen (H2) renksiz, kokusuz, tatsız, toksik olmayan, yanıcı ve diatomik bir gazdır. H2, direkt gaz formunda ve su içerisinde çözündürüldükten sonra hidrojenle zenginleştirilmiş su (HZS) şeklinde kullanılarak meyve ve sebzelerin taze kalmasını sağlar. Süt, çay ve meyve sularının kalite kriterlerini koruduğunu ve uzun süre depolanmasına yardımcı olduğu belirtilmektedir. Bazı tahıl ürünlerinin ve yeşilliklerinin hızlı bir şekilde büyümesine etki ettiği ve antioksidan maddelerinin aktivitesini artırdığı bildirilmektedir. Son yıllarda gıdaların kurutulmasında önemli bir yere sahip olan hidrojen gazı, özellikle indirgen atmosfer kurutma (İAK) teknolojisinde kullanılmaktadır. Moleküler hidrojenin gıdalarda kullanımı üzerine çok az sayıda çalışma yapılmıştır. Çeşitli olumlu etkileri sebebiyle, gıda endüstrisinde moleküler hidrojenin farklı teknikler ve prosesler kullanımının teşvik edilmesi sağlanmalıdır.
Hydrogen (H2) has been widely used in the chemical industry as a reducing agent. As the researches move along, increasing attention has been paid to its biological functions. The selective antioxidant effect of hydrogen is considered to be the main reason for medical applications. So far, many studies have confirmed its potential protective effects on ischemia/reperfusion injury of multiple organs, neurodegenerative diseases, bone and joint diseases, and respiratory diseases, opening a new era in the medical research and application of H2. Increasing studies have focused on its biological effects and molecular mechanisms in the treatment of different diseases. In this paper, we review the biological effects, molecular mechanisms and methods of H2 supply. We do hope that the advances in materials science can be better translated into medical applications and solve clinical problems. The medical application of H2 is promising, and how to prepare an H2 sustained-release system to achieve a sustained and stable H2 supply in the body and ultimately improve the therapeutic effect of H2 is a problem worthy of further investigation.
Many studies have shown that hydrogen has anti-inflammatory and anti-oxidant effects. Because of its ability to quickly pass through cell membranes, hydrogen has become a hot spot in the research of inflammatory diseases. Vitamin E glycerin (VEG) and hydrogen-rich Vitamin E glycerin (HR-VEG) were prepared, aiming to explore their anti-inflammatory activities in mice mastitis induced by Staphylococcus aureus (S. aureus). In the early part of this study, the prepared vitamin E medium (VEM) and hydrogen-rich vitamin E medium (HR-VEM) were added to mammary epithelial cells infected with S. aureus. HR-VEM was found to be more effective in reducing the phosphorylation of p65 and p38 and in reducing the production of interleukin-1 beta (IL-1β) than VEM. Whereafter, the mice model of mastitis was established by injecting S. aureus from the mammary duct. Then VEG and HR-VEG were applied to the mammary gland for seven consecutive days. After that, the clinical symptoms, histopathology, bacterial load, inflammatory factors, as well as the related pathway were analyzed. The results showed that HR-VEG can more significantly alleviate the damage of mammary tissue than VEG, and reduce the production of tumor necrosis factor-alpha (TNF-α), IL-1β and interleukin 6 (IL-6). In addition, HR-VEG inhibited the TLR2 and Nod2 signaling pathways and reduced the phosphorylation level of MAPK and NF-κB signaling pathways in S. aureus-induced murine mastitis. This study indicates that hydrogen helps to ameliorate S. aureus-induced mastitis in mice through attenuating TLR2 and Nod2 mediated NF-κB and MAPK activation.
Hydrogen has important values in industrial manufacture, medical health care and diverse energy application areas. Among the many possible approaches, convenient and safe hydrogen production from water electrolysis has always been a preferred in‐situ hydrogen supply technology. So far, many of the electrodes thus involved are based on rigid metals or conductive items which may encounter inconvenience or insufficiency sometimes. In order to achieve targeted release of hydrogen, appropriate administration of suitable flexible hydrogen evolution electrodes is the key. In recent years, gallium‐based liquid metals have emerged in the field of flexible and biological electrodes. Starting from this point, liquid metal is proposed here as a transformable amorphous electrode for hydrogen evolution in electrolytic water which may help mold new conceptual electrolysis and energy utilization ways. The electrochemical performances and flexible behaviors lying behind are investigated and clarified. According to the experiments, the catalytic activity of the liquid metal itself generally is not remarkable, but it would be significantly improved after being composited with certain active materials such as nickel. Further, the controllability, flexibility, and adaptability of liquid metal‐based amorphous materials which are unmatched by other electrode materials were evaluated. Overall, the motions of such shape transformable liquid metal electrodes could be controlled by electric or magnetic fields, and their deformations are compliantly adaptive to different spaces. This might easily expand the area of hydrogen evolution and lead to multi‐site in‐situ hydrogen production. The present study demonstrates the value of liquid metals in flexible energy systems and opens up more application possibilities for the electrolytic hydrogen production. This article is protected by copyright. All rights reserved.
Background: The two main causes of body inflammation caused by lipopolysaccharide (LPS) -induced acute lung injury (ALI) are chronic inflammation and oxidant / antioxidant imbalances. Hydrogen (H2), a gaseous molecule without known toxicity, could react with hydroxyl radical to remove the reactive oxygen species (ROS). Both in vivo and vitro studies support the protective effect of hydrogen on injuries caused by oxidative stress and inflammations.
Methods: In vivo study, mice were randomly divided into three groups: H2 control group, LPS group and LPS+H2 group. The mice were euthanized at the indicated time points and the specimens were collected. The 72h survival rates, cytokines contents, pathological changes, expression of Toll-like receptor 4(TLR4) and oxidative stress indicators were observed. In vitro study, according to different culture conditions, RAW 264.7 mouse macrophages were divided into the following groups: PBS group, LPS group and LPS+H2 group. The cell Viability, intracellular ROS, cytokines and expression of TLR4 and nuclear factor kappa-B (NF-κB) were observed.
Results: In vivo, the 72h survival rate of hydrogen inhalation mice was increased to 80%, and H2 significantly lighten LPS-induced lung damages and decreased inflammatory cytokine release. Besides, H2 showed remarked anti-oxidative activity to reduce the MDA and NO contents in lung. In vitro, H2 down-regulated the levels of ROS, NO, TNF-α, IL-6 and IL-1β in LPS-stimulated macrophages. Second, H2 inhibited the expression of TLR4 and the activation of nuclear factor kappa-B (NF-κB). In summary, these findings supported that H2 attenuates LPS-induced inflammatory responses, which may be mediated by TLR4-NF-κB pathway.
Social development is possible with agriculture. With the impact of environmental pollution, natural disasters, climate change, food security, and population growth, interdisciplinary "new agriculture" is becoming an important trend of modern agriculture. Hydrogen (H2) is the most common element on earth, making up more than 75% of the mass of the universe. Hydrogen gas is colorless, odorless, and tasteless and is considered a physiologically inert molecule and a potential source for clean energy in the future. Hydrogenated agriculture including mainly hydrogen-rich water (HRW) focuses on the molecular mechanisms underlying improved agricultural product quality. Studies have shown that H2 does not only affect plant growth and development but also affects the nutritional quality and shelf life of the fruit. Hydrogenated agriculture emerges as a promising technology for the sustainability of agricultural products in modern agricultural practices thanks to the different beneficial effects of H2 such as safety, nutritional and antioxidative properties, and high product productivity. In this review, the roles of H2 in plants, seed germination, seedling growth, root development, stomatal opening and closing, pre-harvest freshness, post-harvest freshness, and the changes caused by hydrogenated agriculture at various stages of the plant such as anthocyanin synthesis have been investigated.
The relevance of research on molecular hydrogen in the world has increased significantly, since it turned out to be an extremely unique reagent, since it has the ability to act at the cellular level. Hydrogen is able to cross the blood-brain barrier, penetrate into mitochondria and other areas of cells, where it exhibits antioxidant, anti-apoptotic, anti-inflammatory and cytoprotective properties. The aim of the scientific review is to theoretically substantiate the current state of the use of molecular hydrogen and hydrogen water in environmentally friendly and sports medicine. For this, evidence has been provided regarding the effect of consumption of molecular hydrogen and hydrogen water on changes in physiological and biochemical parameters, taking into account the oxidative stress caused by exercise. In addition, this review highlights possible future directions in this area of research.
Purpose
Oxidative damage and intestinal flora dysbiosis play important roles in the progression of chronic ulcerative colitis (UC). This study explored the effect and mechanism of molecular hydrogen in chronic UC.
Materials and methods
Male C57BL/6 mice (19.6 ± 0.4 g, 7 weeks) were randomly divided into 3 groups: normal control (NC) group, UC (Dextran Sulfate Sodium, DSS) group, and hydrogen-rich water (HRW, 0.8 ppm)-treated UC (DSS + HRW) group. Mice in the DSS treatment group were treated with DSS for the following 3 cycles to establish chronic UC model: the first 2 cycles consisted of 2.5% DSS for 5 days, followed by drinking water for 16 days, and a third cycle consisted of 2% DSS for 4 days, followed by drinking water for 10 days. The mice in the DSS + HRW group were administered HRW daily throughout the experiment.
Results
The mice in the DSS groups developed typical clinical signs of colitis. HRW treatment partially ameliorated colitis symptoms, improved histopathological changes, significantly increased glutathione (GSH) concentration and decreased TNF-α level. Notably, HRW treatment significantly inhibited the growth of Enterococcus faecalis, Clostridium perfringens and Bacteroides fragilis (P < 0.05 vs. DSS group), with the relative abundance that was close to the levels in the NC group. Microarray analysis revealed that 252 genes were significantly modified after HRW treatment compared with those in the DSS treatment alone group, and 17 genes were related to inflammation, including 9 interferon-stimulated genes (ISGs).
Conclusions
Hydrogen-rich water partially alleviates inflammation, oxidative stress and intestinal flora dysbiosis in DSS-induced chronic UC mice.
Birth asphyxia can cause moderate to severe brain injury. It is unclear to what degree apoptotic or necrotic mechanisms of cell death account for damage after neonatal hypoxia-ischemia (HI). In a 7-d-old rat HI model, we determined the contributions of apoptosis and necrosis to neuronal injury in adjacent Nissl-stained, hematoxylin and eosin-stained, and terminal deoxynucleotidyl transferase-mediated UTP nick end-labeled sections. We found an apoptotic-necrotic continuum in the morphology of injured neurons in all regions examined. Eosinophilic necrotic neurons, typical in adult models, were rarely observed in neonatal HI. Electron microscopic analysis showed "classic" apoptotic and necrotic neurons and "hybrid" cells with intermediate characteristics. The time course of apoptotic injury varied regionally. In CA3, dentate gyrus, medial habenula, and laterodorsal thalamus, the density of apoptotic cells was highest at 24-72 hr after HI and then declined. In contrast, densities remained elevated from 12 hr to 7 d after HI in most cortical areas and in the basal ganglia. Temporal and regional patterns of neuronal death were compared with expression of caspase-3, a cysteine protease involved in the execution phase of apoptosis. Immunocytochemical and Western blot analyses showed increased caspase-3 expression in damaged hemispheres 24 hr to 7 d after HI. A p17 peptide fragment, which results from the proteolytic activation of the caspase-3 precursor, was detected in hippocampus, thalamus, and striatum but not in cerebral cortex. The continued expression of activated caspase-3 and the persistence of cells with an apoptotic morphology for days after HI suggests a prolonged role for apoptosis in neonatal hypoxic ischemic brain injury.
This paper presents a composition method for stack-attributed tree transducers. Stackattributed tree transducers extend attributed tree transducers with a pushdown stack device for attribute values. Stack-attributed tree transducers are more powerful than attributed tree transducers due to the stack mechanism. We extend the existing composition method for attributed tree transducers to the composition method for stack-attributed tree transducers. The composition method is proved to be correct and to enjoy a closure property.
Metabolic syndrome is characterized by cardiometabolic risk factors that include obesity, insulin resistance, hypertension and dyslipidemia. Oxidative stress is known to play a major role in the pathogenesis of metabolic syndrome. The objective of this study was to examine the effectiveness of hydrogen rich water (1.5-2 L/day) in an open label, 8-week study on 20 subjects with potential metabolic syndrome. Hydrogen rich water was produced, by placing a metallic magnesium stick into drinking water (hydrogen concentration; 0.55-0.65 mM), by the following chemical reaction; Mg + 2H(2)O --> Mg (OH)(2) + H(2). The consumption of hydrogen rich water for 8 weeks resulted in a 39% increase (p<0.05) in antioxidant enzyme superoxide dismutase (SOD) and a 43% decrease (p<0.05) in thiobarbituric acid reactive substances (TBARS) in urine. Further, subjects demonstrated an 8% increase in high density lipoprotein (HDL)-cholesterol and a 13% decrease in total cholesterol/HDL-cholesterol from baseline to week 4. There was no change in fasting glucose levels during the 8 week study. In conclusion, drinking hydrogen rich water represents a potentially novel therapeutic and preventive strategy for metabolic syndrome. The portable magnesium stick was a safe, easy and effective method of delivering hydrogen rich water for daily consumption by participants in the study.
Background:
Small intestinal bacterial overgrowth (SIBO) is a condition in which excessive levels of bacteria, mainly the colonic-type species are present in the small intestine. Recent data suggest that SIBO may contribute to the pathophysiology of Irritable bowel syndrome (IBS). The purpose of this study was to identify potential predictors of SIBO in patients with IBS.
Methods:
Adults with IBS based on Rome II criteria who had predominance of bloating and flatulence underwent a glucose breath test (GBT) to determine the presence of SIBO. Breath samples were obtained at baseline and at 30, 45, 60, 75 and 90 minutes after ingestion of 50 g of glucose dissolved in 150 mL of water. Results of the glucose breath test, which measures hydrogen and methane levels in the breath, were considered positive for SIBO if 1) the hydrogen or methane peak was >20 ppm when the baseline was <10 ppm, or 2) the hydrogen or methane peak increased by 12 ppm when baseline was >or=10 ppm.
Results:
Ninety-eight patients were identified who underwent a GBT (mean age, 49 y; 78% female). Thirty-five patients (36%) had a positive GBT result suggestive of SIBO. A positive GBT result was more likely in patients >55 years of age (odds ratio [OR], 3.6; 95% confidence interval [CI], 1.4-9.0) and in females (OR, 4.0; 95% CI, 1.1-14.5). Hydrogen was detected more frequently in patients with diarrhea-predominant IBS (OR, 8; 95% CI, 1.4-45), and methane was the main gas detected in patients with constipation-predominant IBS (OR, 8; 95% CI, 1.3-44). There was no significant correlation between the presence of SIBO and the predominant bowel pattern or concurrent use of tegaserod, proton pump inhibitors, or opiate analgesics.
Conclusions:
Small intestinal bacterial overgrowth was present in a sizeable percentage of patients with IBS with predominance of bloating and flatulence. Older age and female sex were predictors of SIBO in patients with IBS. Identification of possible predictors of SIBO in patients with IBS could aid in the development of successful treatment plans.
It has been demonstrated that hydrogen can selectively reduce hydroxyl and peroxynitrite in vitro. Since most of the ionizing radiation-induced cellular damage is caused by hydroxyl radicals, this study was designed to test the hypothesis that hydrogen may be an effective radioprotective agent. This paper demonstrates that treating cells with hydrogen before irradiation could significantly inhibit ionizing irradiation(IR)-induced Human Lymphocyte AHH-1 cells apoptosis and increase cells viability in vitro. This paper also shows that hydrogen can protect gastrointestinal endothelia from radiation-induced injury, decrease plasma malondialdehyde (MDA) intestinal 8-hydroxydeoxyguanosine (8-OHDG) levels and increase plasma endogenous antioxidants in vivo. It is suggested that hydrogen has a potential as an effective and safe radioprotective agent.
Retinal ischemia-reperfusion (I/R) injury by transient elevation of intraocular pressure (IOP) is known to induce neuronal damage through the generation of reactive oxygen species. Study results have indicated that molecular hydrogen (H(2)) is an efficient antioxidant gas that selectively reduces the hydroxyl radical (*OH) and suppresses oxidative stress-induced injury in several organs. This study was conducted to explore the neuroprotective effect of H(2)-loaded eye drops on retinal I/R injury.
Retinal ischemia was induced in rats by raising IOP for 60 minutes. H(2)-loaded eye drops were prepared by dissolving H(2) gas into a saline to saturated level and administered to the ocular surface continuously during the ischemia and/or reperfusion periods. One day after I/R injury, apoptotic cells in the retina were quantified, and oxidative stress was evaluated by markers such as 4-hydroxynonenal and 8-hydroxy-2-deoxyguanosine. Seven days after I/R injury, retinal damage was quantified by measuring the thickness of the retina.
When H(2)-loaded eye drops were continuously administered, H(2) concentration in the vitreous body immediately increased and I/R-induced *OH level decreased. The drops reduced the number of retinal apoptotic and oxidative stress marker-positive cells and prevented retinal thinning with an accompanying activation of Müller glia, astrocytes, and microglia. The drops improved the recovery of retinal thickness by >70%.
H(2) has no known toxic effects on the human body. Thus, the results suggest that H(2)-loaded eye drops are a highly useful neuroprotective and antioxidative therapeutic treatment for acute retinal I/R injury.
It has been shown that molecular hydrogen (H(2)) acts as a therapeutic antioxidant and suppresses brain injury by buffering the effects of oxidative stress. Chronic oxidative stress causes neurodegenerative diseases such as Parkinson's disease (PD). Here, we show that drinking H(2)-containing water significantly reduced the loss of dopaminergic neurons in PD model mice using both acute and chronic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The concentration-dependency of H(2) showed that H(2) as low as 0.08 ppm had almost the same effect as saturated H(2) water (1.5 ppm). MPTP-induced accumulation of cellular 8-oxoguanine (8-oxoG), a marker of DNA damage, and 4-hydroxynonenal (4-HNE), a marker of lipid peroxidation were significantly decreased in the nigro-striatal dopaminergic pathway in mice drinking H(2)-containing water, whereas production of superoxide (O(2)*(-)) detected by intravascular injection of dihydroethidium (DHE) was not reduced significantly. Our results indicated that low concentration of H(2) in drinking water can reduce oxidative stress in the brain. Thus, drinking H(2)-containing water may be useful in daily life to prevent or minimize the risk of life style-related oxidative stress and neurodegeneration.
While it is well established that stroke and cerebral hypoperfusion are risk factors for Alzheimer's disease (AD), the molecular link between ischemia/hypoxia and amyloid precursor protein (APP) processing has only been recently established. Here we review the role of the release of reactive oxygen species (ROS) by the mitochondrial electron chain in response to hypoxia, providing evidence that hypoxia fosters the amyloidogenic APP processing through a biphasic mechanism that up-regulates Beta-secretase activity, which involves an early release of ROS and an activation of HIF-1Alpha.
Cisplatin is a widely used anti-cancer drug in the treatment of a wide range of tumors; however, its application is limited by nephrotoxicity, which is affected by oxidative stress. We have reported that molecular hydrogen (H(2)) acts as an efficient antioxidant (Ohsawa et al. in Nat Med 13:688-694, 2007). Here we show that hydrogen efficiently mitigates the side effects of cisplatin by reducing oxidative stress.
Mice were administered cisplatin followed by inhaling hydrogen gas (1% H(2) in air). Furthermore, instead of inhaling hydrogen gas, we examined whether drinking water containing hydrogen (hydrogen water; 0.8 mM H(2) in water) is applicable by examining oxidative stress, mortality, and body-weight loss. Nephrotoxicity was assessed by morphological changes, serum creatinine and blood urea nitrogen (BUN) levels.
Inhalation of hydrogen gas improved mortality and body-weight loss caused by cisplatin, and alleviated nephrotoxicity. Hydrogen was detected in blood when hydrogen water was placed in the stomach of a rat. Consuming hydrogen water ad libitum also reduced oxidative stress, mortality, and body-weight loss induced by cisplatin in mice. Hydrogen water improved metamorphosis accompanying decreased apoptosis in the kidney, and nephrotoxicity as assessed by serum creatinine and BUN levels. Despite its protective effects against cisplatin-induced toxicity, hydrogen did not impair anti-tumor activity of cisplatin against cancer cell lines in vitro and tumor-bearing mice in vivo.
Hydrogen has potential for improving the quality of life of patients during chemotherapy by efficiently mitigating the side effects of cisplatin.
Respiratory muscle weakness resulting from both diaphragmatic contractile dysfunction and atrophy has been hypothesized to contribute to the weaning difficulties associated with prolonged mechanical ventilation (MV). While it is clear that oxidative injury contributes to MV-induced diaphragmatic weakness, the source(s) of oxidants in the diaphragm during MV remain unknown. These experiments tested the hypothesis that xanthine oxidase (XO) contributes to MV-induced oxidant production in the rat diaphragm and that oxypurinol, a XO inhibitor, would attenuate MV-induced diaphragmatic oxidative stress, contractile dysfunction, and atrophy. Adult female Sprague-Dawley rats were randomly assigned to one of six experimental groups: 1) control, 2) control with oxypurinol, 3) 12 h of MV, 4) 12 h of MV with oxypurinol, 5) 18 h of MV, or 6) 18 h of MV with oxypurinol. XO activity was significantly elevated in the diaphragm after MV, and oxypurinol administration inhibited this activity and provided protection against MV-induced oxidative stress and contractile dysfunction. Specifically, oxypurinol treatment partially attenuated both protein oxidation and lipid peroxidation in the diaphragm during MV. Further, XO inhibition retarded MV-induced diaphragmatic contractile dysfunction at stimulation frequencies >60 Hz. Collectively, these results suggest that oxidant production by XO contributes to MV-induced oxidative injury and contractile dysfunction in the diaphragm. Nonetheless, the failure of XO inhibition to completely prevent MV-induced diaphragmatic oxidative damage suggests that other sources of oxidant production are active in the diaphragm during prolonged MV.
The National Cholesterol Education Program’s Adult Treatment Panel III report (ATP III)1 identified the metabolic syndrome as a multiplex risk factor for cardiovascular disease (CVD) that is deserving of more clinical attention. The cardiovascular community has responded with heightened awareness and interest. ATP III criteria for metabolic syndrome differ somewhat from those of other organizations. Consequently, the National Heart, Lung, and Blood Institute, in collaboration with the American Heart Association, convened a conference to examine scientific issues related to definition of the metabolic syndrome. The scientific evidence related to definition was reviewed and considered from several perspectives: (1) major clinical outcomes, (2) metabolic components, (3) pathogenesis, (4) clinical criteria for diagnosis, (5) risk for clinical outcomes, and (6) therapeutic interventions.
ATP III viewed CVD as the primary clinical outcome of metabolic syndrome. Most individuals who develop CVD have multiple risk factors. In 1988, Reaven2 noted that several risk factors (eg, dyslipidemia, hypertension, hyperglycemia) commonly cluster together. This clustering he called Syndrome X , and he recognized it as a multiplex risk factor for CVD. Reaven and subsequently others postulated that insulin resistance underlies Syndrome X (hence the commonly used term insulin resistance syndrome ). Other researchers use the term metabolic syndrome for this clustering of metabolic risk factors. ATP III used this alternative term. It avoids the implication that insulin resistance is the primary or only cause of associated risk factors. Although ATP III identified CVD as the primary clinical outcome of the metabolic syndrome, most people with this syndrome have insulin resistance, which confers increased risk for type 2 diabetes. When diabetes becomes clinically apparent, CVD risk rises sharply. Beyond CVD and type 2 diabetes, individuals with metabolic syndrome seemingly are susceptible to other conditions, notably polycystic ovary syndrome, fatty liver, cholesterol gallstones, asthma, sleep disturbances, and some …
Context The Third Report of the National Cholesterol Education Program Expert
Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in
Adults (ATP III) highlights the importance of treating patients with the metabolic
syndrome to prevent cardiovascular disease. Limited information is available
about the prevalence of the metabolic syndrome in the United States, however.Objective To estimate the prevalence of the metabolic syndrome in the United States
as defined by the ATP III report.Design, Setting, and Participants Analysis of data on 8814 men and women aged 20 years or older from the
Third National Health and Nutrition Examination Survey (1988-1994), a cross-sectional
health survey of a nationally representative sample of the noninstitutionalized
civilian US population.Main Outcome Measures Prevalence of the metabolic syndrome as defined by ATP III (≥3 of
the following abnormalities): waist circumference greater than 102 cm in men
and 88 cm in women; serum triglycerides level of at least 150 mg/dL (1.69
mmol/L); high-density lipoprotein cholesterol level of less than 40 mg/dL
(1.04 mmol/L) in men and 50 mg/dL (1.29 mmol/L) in women; blood pressure of
at least 130/85 mm Hg; or serum glucose level of at least 110 mg/dL (6.1 mmol/L).Results The unadjusted and age-adjusted prevalences of the metabolic syndrome
were 21.8% and 23.7%, respectively. The prevalence increased from 6.7% among
participants aged 20 through 29 years to 43.5% and 42.0% for participants
aged 60 through 69 years and aged at least 70 years, respectively. Mexican
Americans had the highest age-adjusted prevalence of the metabolic syndrome
(31.9%). The age-adjusted prevalence was similar for men (24.0%) and women
(23.4%). However, among African Americans, women had about a 57% higher prevalence
than men did and among Mexican Americans, women had about a 26% higher prevalence
than men did. Using 2000 census data, about 47 million US residents have the
metabolic syndrome.Conclusions These results from a representative sample of US adults show that the
metabolic syndrome is highly prevalent. The large numbers of US residents
with the metabolic syndrome may have important implications for the health
care sector.
We studied the role of reactive oxygen intermediates (ROls) in experimental liver metastasis induced in mice by the inoculation of COLON 26-M5 murine colon cancer cells, a highly metastatic variant of COLON 26 cells, and the effect of ROIs on the invasive capacity of the cells in an in vitro chemo-invasion assay model using reconstituted basement membrane matrigel. We also measured the release of ROIs from cells using electron spin resonance (ESR) spectrometry. Hydroxyl radicals (.OH) were constitutively released from the cells. This release was augmented by pre-treatment with phorbol 12-myristate 13-acetate (PMA). In experimental liver metastasis in CDF1 mice, the administration of recombinant human superoxide dismu-tase (r-hSOD) significantly increased the number of metastatic nodules, while administration of catalase significantly inhibited metastasis formation. In vitro pre-treatment of cells with PMA significantly increased the number of metastatic nodules. Invasive capacity of the cells was markedly augmented by pre-treatment with PMA. PMA-induced augmentation was significantly inhibited by the simultaneous addition of r-hSOD to the assay. Catalase had no significant effect. Our findings suggest that ROIs play an important role in tumor invasion and metastasis, and that hydrogen peroxide (H2O2) may contribute to the retention or extravasation of circulating tumor cells. Furthermore, the superoxide anion (O2-) released by tumor cells may play an important role in basement membrane degradation.
The pathogenesis of chronic rejection likely involves an interplay between immunogenic and nonimmunogenic factors. The objective of this study was to determine the influence of cold ischemic preservation injury on the rate of progression to chronic rejection in the Lewis to F344 cardiac allograft model.
To induce an ischemic injury, donor hearts were stored for 3 hr at 4 degrees C in University of Wisconsin solution before transplantation. Allografts were excised at 1, 7, and 90 days after transplantation or at rejection. Vasculopathy was graded for degree of intimal thickening based on the involvement of vascular perimeter and luminal compromise.
The degree of vessel injury in ischemic injured allografts at 90 days was significantly greater than in nonischemic injured allografts (2.8+/-0.4 vs. 1.6+/-0.5, P<0.05). Ischemic injury in syngeneic grafts did not induce a vasculopathy. Immunoperoxidase staining with R73 (anti-T cell) and ED1 (anti-macrophage) monoclonal antibodies revealed that, in ischemic injured allografts at 90 days after transplantation, the infiltrate was composed predominantly of T cells and macrophages. Additionally, ischemic injured allografts excised at 7 days after transplantation showed cellular infiltrates composed of R73-positive T cells and rare interleukin-2 receptor-positive cells, which was not observed in nonischemic allografts or ischemic syngeneic grafts.
The progression to chronic vasculopathy in this model is principally an immunologic process, which is accelerated by an ischemic insult to the allograft. The vascular injury is mediated in part by T cells and macrophages.
By its antioxidant effect, molecular hydrogen gas (H2) was reported to protect organs from tissue damage induced by ischemia reperfusion. To evaluate its anti-inflammatory effects, we established a mouse model of human inflammatory bowel disease (IBD) by supplying mice with water containing (1) dextran sodium sulfate (DSS) (5%), (2) DSS (5%) and H2, or (3) H2 only ad libitum up to 7 days. At day-7, DSS-induced pathogenic outcomes including, loss of body weight, increase of colitis score, pathogenic shortening of colon length, elevated level of IL-12, TNF-α and IL-1β in colon lesion, were significantly suppressed by the addition of H2 to DSS solution. Histological analysis also revealed that the DSS-mediated colonic tissue destruction accompanied by macrophage infiltration was remarkably suppressed by H2. Therefore, the present study indicated that H2 can prevent the development of DSS-induced colitis in mice.
It is well known that some intestinal bacteria, such as Escherichia coli, can produce a remarkable amount of molecular hydrogen (H2). Although the antioxidant effects of H2 are well documented, the present study examined whether H2 released from intestinally colonized bacteria could affect Concanavalin A (ConA)-induced mouse hepatitis. Systemic antibiotics significantly decreased the level of H2 in both liver and intestines along with suppression of intestinal bacteria. As determined by the levels of AST, ALT, TNF-α and IFN-γ in serum, suppression of intestinal bacterial flora by antibiotics increased the severity of ConA-induced hepatitis, while reconstitution of intestinal flora with H2-producing E. coli, but not H2-deficient mutant E. coli, down-regulated the ConA-induced liver inflammation. Furthermore, in vitro production of both TNF-α and IFN-γ by ConA-stimulated spleen lymphocytes was significantly inhibited by the introduction of H2. These results indicate that H2 released from intestinal bacteria can suppress inflammation induced in liver by ConA.
Oxidative stress is implicated in atherogenesis; however most clinical trials with dietary antioxidants failed to show marked success in preventing atherosclerotic diseases. We have found that hydrogen (dihydrogen; H2) acts as an effective antioxidant to reduce oxidative stress [I. Ohsawa, M. Ishikawa, K. Takahashi, M. Watanabe, K. Nishimaki, K. Yamagata, K. Katsura, Y. Katayama, S, Asoh, S. Ohta, Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals, Nat. Med. 13 (2007) 688–694]. Here, we investigated whether drinking H2-dissolved water at a saturated level (H2–water) ad libitum prevents arteriosclerosis using an apolipoprotein E knockout mouse (apoE−/−), a model of the spontaneous development of atherosclerosis. ApoE−/− mice drank H2–water ad libitum from 2 to 6 month old throughout the whole period. Atherosclerotic lesions were significantly reduced by ad libitum drinking of H2–water (p = 0.0069) as judged by Oil-Red-O staining series of sections of aorta. The oxidative stress level of aorta was decreased. Accumulation of macrophages in atherosclerotic lesions was confirmed. Thus, consumption of H2-dissolved water has the potential to prevent arteriosclerosis.
Protective effect of hydrogen (H(2)) gas on cardiac ischemia-reperfusion (I/R) injury has been demonstrated previously. This study was designed to test the hypothesis that hydrogen-rich saline (saline saturated with molecular hydrogen), which is easy to use, induces cardioprotection against ischemia (30 min) and reperfusion (24 h) injury in rats. Adult male Sprague-Dawley rats underwent 30-min occlusion of the left anterior descending (LAD) coronary artery and 24-h reperfusion. Intraperitoneal injection of hydrogen-rich saline before reperfusion significantly decreased plasma and myocardium malondialdehyde (MDA) concentration, decreased cardiac cell apoptosis, and myocardial 8-hydroxydeoxyguanosine (8-OHdG) in area at risk zones (AAR), suppressed the activity of caspase-3, and reduced infarct size. The heart function parameters including left ventricular systolic pressure (LVSP), left ventricular diastolic pressure (LVDP), +(dP/dt)(max) and -(dP/dt)(max) were also significantly improved 24 h after reperfusion. It is concluded that hydrogen-rich saline is a novel, simple, safe, and effective method to attenuate myocardial I/R injury.
Protective effect of hydrogen (H(2)) gas on cardiac ischemia-reperfusion (I/R) injury has been demonstrated previously. This study was designed to test the hypothesis that hydrogen-rich saline (saline saturated with molecular hydrogen), which is easy to use, induces cardioprotection against ischemia (30 min) and reperfusion (24 h) injury in rats. Adult male Sprague-Dawley rats underwent 30-min occlusion of the left anterior descending (LAD) coronary artery and 24-h reperfusion. Intraperitoneal injection of hydrogen-rich saline before reperfusion significantly decreased plasma and myocardium malondialdehyde (MDA) concentration, decreased cardiac cell apoptosis, and myocardial 8-hydroxydeoxyguanosine (8-OHdG) in area at risk zones (AAR), suppressed the activity of caspase-3, and reduced infarct size. The heart function parameters including left ventricular systolic pressure (LVSP), left ventricular diastolic pressure (LVDP), +(dP/dt)(max) and -(dP/dt)(max) were also significantly improved 24 h after reperfusion. It is concluded that hydrogen-rich saline is a novel, simple, safe, and effective method to attenuate myocardial I/R injury. Exp Biol Med 234:1212-1219, 2009
Hydrogen has been reported to selectively reduce the hydroxyl radical, the most cytotoxic of reactive oxygen species. In this study we investigated the effects of hydrogen-rich saline on the prevention of lung injury induced by intestinal ischemia/reperfusion (I/R) in rats.
Male Sprague-Dawley rats (n=30, 200-220g) were divided randomly into three experimental groups: sham operated, intestinal I/R plus saline treatment (5ml/kg, i.v.), and intestinal I/R plus hydrogen-rich saline treatment (5ml/kg, i.v.) groups. Intestinal I/R was produced by 90min of intestinal ischemia followed by a 4h of reperfusion.
Hydrogen-rich saline treatment decreased the neutrophil infiltration, the lipid membrane peroxidation, NF-kappaB activation and the pro-inflammatory cytokine interleukin IL-1beta and TNF-alpha in the lung tissues compared with those in saline-treated rat.
Hydrogen-rich saline attenuates lung injury induced by intestinal I/R.
Background:
Hydrogen has been considered as a novel antioxidant that prevents injuries resulted from ischemia-reperfusion (I/R) injury in various tissues. The study was designed to determine the effect of hydrogen-rich saline on the smooth muscle contractile response to KCl, and on epithelial proliferation and apoptosis of intestine subjected to I/R.
Methods:
Intestinal I/R injury was induced in Sprague-Dawley rats using bulldog clamps in superior mesenteric artery by 45 min ischemia followed by 1 h reperfusion. Rats were divided randomly into four groups: sham-operated, I/R, I/R plus saline treatment, and I/R plus hydrogen-rich saline treatment groups. Hydrogen-rich saline (>0.6 mM, 6 mL/kg) or saline (6 mL/kg) was administered, respectively, via tail vein 30 min prior to reperfusion. Following reperfusion, segments of terminal jejunum were rapidly taken and transferred into isolated organ bath and responses to KCl were recorded. Samples of terminal jejunum were also taken for measuring malondialdehyde and myeloperoxidase. Apoptosis in intestinal epithelium was determined with terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling technique (TUNEL). Expression and distribution of proliferating cell nuclear antigen (PCNA) were detected with immunohistochemistry.
Results:
Hydrogen-rich saline treatment significantly attenuated the severity of intestinal I/R injury, with inhibiting of I/R-induced apoptosis, and promoting enterocytes proliferation. Moreover, Hydrogen-rich saline treatment significantly limited the neutrophil infiltration, lipid oxidation, and ameliorated the decreased contractility response to KCl in the intestine subjected to I/R.
Conclusions:
These results suggest that hydrogen treatment has a protective effect against intestinal contractile dysfunction and damage induced by intestinal I/R. This protective effect is possibly due to its ability to inhibit I/R-induced oxidative stress, apoptosis, and to promote epithelial cell proliferation.
Hypoxia-ischemia (HI) brain injury is a major cause of neuronal cell death especially apoptosis in the perinatal period. This study was designated to examine the effect of hydrogen therapy on apoptosis in an established neonatal HI rat pup model. Seven-day-old rat pups were subjected to left common carotid artery ligation and then 90 min hypoxia (8% oxygen at 37 C). Immediately after HI insult, pups were placed into a chamber filled with 2% H(2) for 30 min, 60 min, or 120 min, respectively. 24 h after 2% H2 therapy, the pups were decapitated and brain injury was assessed by 2,3,5-triphenyltetrazoliumchloride (TTC), Nissl, and TUNEL staining, as well as caspase-3, caspase-12 activities in the cortex and hippocampus. H(2) treatment in a duration-dependent manner significantly reduced the number of positive TUNEL cells and suppressed caspase-3 and -12 activities. These results indicated H(2) administration after HI appeared to provide brain protection via inhibition of neuronal apoptosis. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
Hydrogen selectively reduces levels of hydroxyl radicals and alleviates acute oxidative stress in many models. Hydrogen-rich saline provides a high concentration of hydrogen that can be easily and safely applied.
In this study, we investigated the effects of hydrogen-rich saline on the prevention of liver injury induced by obstructive jaundice in rats.
Male Sprague-Dawley rats (n=56) were divided randomly into four experimental groups: sham operated, bile duct ligation (BDL) plus saline treatment [5 ml/kg, intraperitoneal (i.p.)], BDL plus low-dose hydrogen-rich saline treatment (5 ml/kg, i.p.) and BDL plus high-dose hydrogen-rich saline treatment (10 ml/kg, i.p.).
The liver damage was evaluated microscopically 10 days after BDL. Serum alanine aminotransferase and aspartate aminotransferase levels, tissue malondialdehyde content, myeloperoxidase activity, tumour necrosis factor-alpha, interleukin (IL)-1beta, IL-6 and high-mobility group box 1 levels were all increased significantly by BDL. Hydrogen-rich saline reduced levels of these markers and relieved morphological liver injury. Additionally, hydrogen-rich saline markedly increased the activities of anti-oxidant enzymes superoxide dismutase and catalase and downregulated extracellular signal-regulated protein kinase (ERK)1/2 activation.
Hydrogen-rich saline attenuates BDL-induced liver damage, possibly by the reduction of inflammation and oxidative stress and the inhibition of the ERK1/2 pathway.
In the present study, we examined the mechanisms of hydrogen-rich saline, a reported therapeutic antioxidant, in the treatment of acute spinal cord contusion injury. Male Sprague-Dawley rats were used to produce a standardized model of contuses spinal cord injury (125 kdyn force). Hydrogen-rich saline was injected intraperitoneally (5 ml/kg) immediately, and at 24 and 48 h after injury. All rats were sacrificed at 72 h after spinal cord injury (SCI). Apoptotic cell death, oxidative stress, inflammation, level of Brain derived neurotrophic factor (BDNF) were evaluated. In addition, locomotor behavior was assessed using the Basso, Beattice and Bresnahan (BBB) scale. We observed that administration of hydrogen-rich saline decreased the number of apoptotic cells, suppressed oxidative stress, and improved locomotor functions. Hydrogen-rich saline increased the release of BDNF. In conclusion, hydrogen-rich saline reduced acute spinal cord contusion injury, possibly by reduction of oxidative stress and elevation of BDNF.
Hydrogen-dissolved water has been suggested to be effective for alleviating the oxidative stress. In the present study, neutral-pH hydrogen-enriched electrolyzed water (NHE-water; dissolved hydrogen: 0.90-1.14 parts per million [ppm]; oxido-reduced potential: -150 approximately -80 mV), which was prepared with a water-electrolysis apparatus equipped with a non-diaphragm cell and a highly compressed activated-carbon block, was evaluated for the mutagenic and genotoxic potentials, at concentrations up to 100% dose/plate, and for the subchronic toxicity. NHE-water did not induce reverse mutations in Salmonella typhimurium strains TA100, TA1535, TA98 and TA1537, and Escherichia coli strain WP2uvrA, in either the absence or presence of rat liver S9 for exogenous metabolic activation. Similarly, NHE-water did not induce chromosome aberrations in Chinese hamster lung fibroblast cells (CHL/IU), in short-term (6-hour) tests, with or without rat liver S9, or in a continuous treatment (24-hour) test. To evaluate the subchronic toxicity, Crj:CD(SD) specific pathogen free (SPF)-rats were administered with NHE-water at a dose of 20 mL/kg/day for 28 days via intragastric infusion. NHE-water-related toxic changes were not seen in terms of any items such as clinical symptoms, body weight, food consumption, urinalysis, hematology, blood chemistry, necropsy, each organ weight and histopathology. Thus, the no-observable-adverse-effect level (NOAEL) for NHE-water was estimated to be greater than 20 mL/kg/day under the conditions examined, demonstrating the consistency with the expected safety for a human with a body weight of 60 kg to drink the NHE-water up to at least 1.2 L/day.
This study is to examine if hydrogen-rich saline reduced amyloid beta (Abeta) induced neural inflammation, and learning and memory deficits in a rat model. S-D male rats (n=84, 280-330g) were divided into three groups, sham-operated, Abeta1-42 injected and Abeta1-42 plus hydrogen-rich saline-treated animals. Hydrogen-rich saline (5ml/kg, i.p., daily) was injected for 14days after intracerebroventricular injection of Abeta1-42. The levels of MDA, IL-6 and TNF-alpha were assessed by biochemical and ELISA analysis. Morris Water Maze and open field task were used to assess the memory dysfunction and motor dysfunction, respectively. LTP were used to detect the electrophysiology changes, HNE and GFAP immunohistochemistry were used to assess the oxidative stress and glial cell activation. After Abeta1-42 injection, the levels of MDA, IL-6, and TNF-alpha were increased in brain tissues and hydrogen-rich saline treatment suppressed MDA, IL-6, and TNF-alpha concentration. Hydrogen-rich saline treatment improved Morris Water Maze and enhanced LTP in hippocampus blocked by Abeta1-42. Furthermore, hydrogen-rich saline treatment also decreased the immunoreactivitiy of HNE and GFAP in hippocampus induced by Abeta1-42. In conclusion, hydrogen-rich saline prevented Abeta-induced neuroinflammation and oxidative stress, which may contribute to the improvement of memory dysfunction in this rat model.