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Molecular hydrogen suppresses FcεRI-mediated signal transduction and prevents degranulation of mast cells

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Abstract

Molecular hydrogen ameliorates oxidative stress-associated diseases in animal models. We found that oral intake of hydrogen-rich water abolishes an immediate-type allergic reaction in mice. Using rat RBL-2H3 mast cells, we demonstrated that hydrogen attenuates phosphorylation of the FcepsilonRI-associated Lyn and its downstream signal transduction, which subsequently inhibits the NADPH oxidase activity and reduces the generation of hydrogen peroxide. We also found that inhibition of NADPH oxidase attenuates phosphorylation of Lyn in mast cells, indicating the presence of a feed-forward loop that potentiates the allergic responses. Hydrogen accordingly inhibits all tested signaling molecule(s) in the loop. Hydrogen effects have been solely ascribed to exclusive removal of hydroxyl radical. In the immediate-type allergic reaction, hydrogen exerts its beneficial effect not by its radical scavenging activity but by modulating a specific signaling pathway. Effects of hydrogen in other diseases are possibly mediated by modulation of yet unidentified signaling pathways. Our studies also suggest that hydrogen is a gaseous signaling molecule like nitric oxide.

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... H 2 was first reported to be a selective scavenger of • OH and peroxynitrite 2 . Cumulative evidence, however, suggests that H 2 functions as a signaling modulator [3][4][5] . In this study, we dissected the effects of H 2 on Wnt/β -catenin signaling. ...
... We found that intermittent H 2 treatment was less effective than continuous H 2 treatment on suppressing β -catenin level (Fig. 1g). H 2 has been reported to inhibit mitogen-activated protein (MAP) kinase signaling in cell lines and rodent disease models [3][4][5] . A previous report shows that inhibition of JNK, but not of ERK or p38 MAP kinase, decreases Wnt3a-induced β -catenin accumulation 18 . ...
... In addition, intermittent, but not continuous, inhalation of H 2 gas ameliorates a rat model of Parkinson's disease 17 . We have also shown that H 2 alters signaling activities in mast cells and macrophages without directly scavenging reactive oxygen/nitrogen species 3,4 . ...
Article
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Molecular hydrogen (H2) is effective for many diseases. However, molecular bases of H2 have not been fully elucidated. Cumulative evidence indicates that H2 acts as a gaseous signal modulator. We found that H2 suppresses activated Wnt/β-catenin signaling by promoting phosphorylation and degradation οf β-catenin. Either complete inhibition of GSK3 or mutations at CK1- and GSK3-phosphorylation sites of β-catenin abolished the suppressive effect of H2. H2 did not increase GSK3-mediated phosphorylation of glycogen synthase, indicating that H2 has no direct effect on GSK3 itself. Knock-down of adenomatous polyposis coli (APC) or Axin1, which form the β-catenin degradation complex, minimized the suppressive effect of H2 on β-catenin accumulation. Accordingly, the effect of H2 requires CK1/GSK3-phosphorylation sites of β-catenin, as well as the β-catenin degradation complex comprised of CK1, GSK3, APC, and Axin1. We additionally found that H2 reduces the activation of Wnt/β-catenin signaling in human osteoarthritis chondrocytes. Oral intake of H2 water tended to ameliorate cartilage degradation in a surgery-induced rat osteoarthritis model through attenuating β-catenin accumulation. We first demonstrate that H2 suppresses abnormally activated Wnt/β-catenin signaling, which accounts for the protective roles of H2 in a fraction of diseases.
... H 2 effectively reduces hydroxyl radicals and peroxynitrite in living cells, without affecting mitochondrial redox functions and ROS as a signaling molecule associated with normal mitochondrial oxidation-reduction reactions. Therefore, H 2 can potentially be used as an anti-inflammatory and anti-apoptotic agent in clinical practice [49][50][51]. Moreover, the effects of H 2 in suppressing allergic reactions and inflammation without directly scavenging ROS/RNS through various signaling pathways have been reported. ...
... These pathways are linked to inflammatory cytokines, such as tumor necrosis-α (TNF-α), IL-6, and IL-8, which can lead to the formation of psoriatic plaques [69,70]. Furthermore, evidence has shown that H 2 could suppress signaling pathways in allergies and inflammation without directly scavenging ROS/RNS [49,71]. Due to the intrinsic ability of the body to produce H 2 , its safe use is ensured [72]. ...
... Similarly, Kajisa et al. reported that H 2 treatment showed positive results in AD skin severity scores and reduced trans-epidermal water loss through the downregulation of IL-1β, and IL-33 and preventing the infiltration of mast cells at the lesion site, respectively [76]. Additionally, oral administration of hydrogen-rich water showed anti-allergic effects in vivo [49]. Moreover, Xie et al. also reported that H 2 exhibits anti-inflammatory properties against an animal inflammation model by partly reducing the levels of pro-inflammatory cytokines [77]. ...
Article
In today's society, healthy skin and a beautiful appearance are considered the foundation of general well-being. The skin is the largest organ of the body and plays an important role in protecting it against various factors such as environmental, physical, chemical, and biological hazards. These factors include mediators that lead to oxidation reactions that produce reactive oxygen/nitrogen species and additional oxidants in the skin cells. An increase in oxidants beyond the antioxidant capacity of its defense system causes oxidative stress and chronic inflammation in the body. This response can cause further disruption of collagen fibers and hinder the functioning of skin cells that may result in the development of various skin diseases including psoriasis, atopic dermatitis and aging. In this review, we summarized the present information related to the role of oxidative stress in the pathogenesis of dermatological disorders, and its impact on physical beauty and the daily lives of patients. We also discussed how molecular hydrogen exhibits a therapeutic effect against skin diseases via its effects on oxidative stress. Furthermore, findings from this summary review indicate that molecular hydrogen might be an effective treatment modality for the prevention and treatment of skin-related illnesses.
... H 2 effectively reduces hydroxyl radicals and peroxynitrite in living cells, without affecting mitochondrial redox functions and ROS as a signaling molecule associated with normal mitochondrial oxidation-reduction reactions. Therefore, H 2 can potentially be used as an anti-inflammatory and anti-apoptotic agent in clinical practice [49][50][51]. Moreover, the effects of H 2 in suppressing allergic reactions and inflammation without directly scavenging ROS/RNS through various signaling pathways have been reported. ...
... These pathways are linked to inflammatory cytokines, such as tumor necrosis-α (TNF-α), IL-6, and IL-8, which can lead to the formation of psoriatic plaques [69,70]. Furthermore, evidence has shown that H 2 could suppress signaling pathways in allergies and inflammation without directly scavenging ROS/RNS [49,71]. Due to the intrinsic ability of the body to produce H 2 , its safe use is ensured [72]. ...
... Similarly, Kajisa et al. reported that H 2 treatment showed positive results in AD skin severity scores and reduced trans-epidermal water loss through the downregulation of IL-1β, and IL-33 and preventing the infiltration of mast cells at the lesion site, respectively [76]. Additionally, oral administration of hydrogen-rich water showed anti-allergic effects in vivo [49]. Moreover, Xie et al. also reported that H 2 exhibits anti-inflammatory properties against an animal inflammation model by partly reducing the levels of pro-inflammatory cytokines [77]. ...
Article
In today's society, healthy skin and a beautiful appearance are considered the foundation of general well-being. The skin is the largest organ of the body and plays an important role in protecting it against various factors such as environmental, physical, chemical, and biological hazards. These factors include mediators that lead to oxidation reactions that produce reactive oxygen/nitrogen species and additional oxidants in the skin cells. An increase in oxidants beyond the antioxidant capacity of its defense system causes oxidative stress and chronic inflammation in the body. This response can cause further disruption of collagen fibers and hinder the functioning of skin cells that may result in the development of various skin diseases including psoriasis, atopic dermatitis, and aging. In this review, we summarized the present information related to the role of oxidative stress in the pathogenesis of dermatological disorders and its impact on physical beauty and the daily lives of patients. We also discussed how molecular hydrogen exhibits a therapeutic effect against skin diseases via its effects on oxidative stress. Furthermore, findings from this summary review indicate that molecular hydrogen might be an effective treatment modality for the prevention and treatment of skin-related illnesses.
... Studies using clinical and experimental animal models in which hydrogen has been applied by inhalation of hydrogen gas, consumption of hydrogen-rich water, injection with hydrogen-saturated saline, and culture in vitro on H 2 -rich media have revealed that hydrogen is an important bioactive factor with antioxidant, anti-inflammatory, and anti-apoptotic effects on cells, tissues, organs, and individuals against oxidative injury [1][2][3][4][5][6][7][8]. In plants, the protective roles have also been proven when seeds, seedlings, explants, and fruits were subjected to hydrogen treatment with hydrogen-rich water or media [9][10][11][12][13][14][18][19][20][21]. ...
... Molecular hydrogen (H 2 ) was first identified as an antioxidant that could selectively reduce cytotoxicity in animals [1]. Since then, the role of hydrogen in repairing many clinical disorders related to oxidative stress has been reported [2][3][4][5][6][7][8]. Hydrogen also acts as an antioxidant or signaling molecule in plant developmental processes and responses to environmental stresses. ...
Article
Full-text available
Hydrogen is a therapeutic antioxidant that has been used extensively in clinical trials. It also acts as a bioactive molecule that can alleviate abiotic stress in plants. However, the biological effects of hydrogen in somatic embryos and the underlying molecular basis remain largely unknown. In this study, the morphological and physiological influence of exogenous H2 treatment during somatic embryogenesis was characterized in Larix leptolepis Gordon. The results showed that exposure to hydrogen increased the proportions of active pro-embryogenic cells and normal somatic embryos. We sequenced mRNA and microRNA (miRNA) libraries to identify global transcriptome changes at different time points during H2 treatment of larch pro-embryogenic masses (PEMs). A total of 45,393 mRNAs and 315 miRNAs were obtained. Among them, 4253 genes and 96 miRNAs were differentially expressed in the hydrogen-treated libraries compared with the control. Further, a large number of the differentially expressed mRNAs and miRNAs were related to reactive oxygen species (ROS) homeostasis and cell cycle regulation. We also identified 4399 potential target genes for 285 of the miRNAs. The differential expression data and the mRNA-miRNA interaction network described here provide new insights into the molecular mechanisms that determine the performance of PEMs exposed to H2 during somatic embryogenesis.
... H 2 acts as a gaseous-signaling molecule, similar to nitric oxide (127). Several studies have demonstrated that molecular hydrogen improves mitochondrial function through preserving the mitochondrial membrane potential and alleviating mitochondrial swelling (128). ...
... H 2 also exerts anti-inflammatory effects by regulating Toll-like receptor 4 (TLR4) signaling (126) and anti-apoptotic effects through Ras-ERK1/2-MEK1/2 and Akt pathway inactivation (54). H 2 may also protect against allergic reactions by directly modulating the high-affinity IgE receptor (FcεRI)-related signaling, rather than through radical-scavenging activity (127). ...
Article
There are many situations of excessive production of reactive oxygen species (ROS) such as radiation, ischemia/reperfusion (I/R), and inflammation. ROS contribute to and arises from numerous cellular pathologies, diseases, and aging. ROS can cause direct deleterious effects by damaging proteins, lipids, and nucleic acids as well as exert detrimental effects on several cell signaling pathways. However, ROS are important in many cellular functions. The injurious effect of excessive ROS can hypothetically be mitigated by exogenous antioxidants, but clinically this intervention is often not favorable. In contrast, molecular hydrogen provides a variety of advantages for mitigating oxidative stress due to its unique physical and chemical properties. H2 may be superior to conventional antioxidants, since it can selectively reduce ●OH radicals while preserving important ROS that are otherwise used for normal cellular signaling. Additionally, H2 exerts many biological effects, including anti-oxidation, anti-inflammation, anti-apoptosis, and anti-shock. H2 accomplishes these effects by indirectly regulating signal transduction and gene expression, each of which involve multiple signaling pathways and crosstalk. The Keap1-Nrf2-ARE signaling pathway, which can be activated by H2 , plays a critical role in regulating cellular redox balance, metabolism, and inducing adaptive responses against cellular stress. H2 also influences the crosstalk among the regulatory mechanisms of autophagy and apoptosis, which involve MAPKs, p53, Nrf2, NF-κB, p38 MAPK, mTOR, etc. The pleiotropic effects of molecular hydrogen on various proteins, molecules and signaling pathways can at least partly explain its almost universal pluripotent therapeutic potential.
... Specific scavenging activities of hydroxyl radical and peroxynitrite, however, cannot fully explain the anti-inflammatory and anti-apoptotic effects, which should involve a number of fine-tuned signaling pathways. It was shown that hydrogen suppresses signaling pathways in allergies ( Itoh et al. 2009) and inflammation ( Itoh et al. 2011) without directly scavenging reactive oxygen/nitrogen species. Signaling molecules that are modulated by hydrogen include RAS ( Chen et al. 2013). ...
... Administration of hydrogen downregulated pro-inflammatory cytokines including tumor necrosis-factor-(TNF-), interleukin-(IL-) 1β, IL-6, IL-12, interferon-(IFN-), and high mobility group box 1 (HMGB1) ( Buchholz et al. 2008, 2011, Kajiya et al. 2009a,b, Mao et al. 2009, Hayashi et al. 2011, Yoon et al. 2011, 2011, Ji et al. 2011, Shen et al. 2011, Yang et al. 2011). Hydrogen also downregulated nuclear factors including nuclear factor kappa B, JNK, and proliferation cell nuclear antigen and caspases ( Itoh et al. 2009). Other important molecules including vascular endothelial growth factor ( Ye et al. 2008), MMP2 and MMP9 ( Chen et al. 2010), brain natriuretic peptide, intercellular-adhesion-molecule-1 and myeloperoxidase, B-cell lymphoma 2 and Bcl-2-associated X protein, MMP3 and MMP13, cyclooxygenase 2, neuronal nitric oxide synthase, connexins ( Hugyecz et al. 2011), and others were studied as well ( Sun et al. 2011). ...
Article
Full-text available
Excessive production of oxygen free radicals has been regarded as a causative common denominator of many pathological processes in the animal kingdom. Hydroxyl and nitrosyl radicals represent the major cause of the destruction of biomolecules either by a direct reaction or by triggering a chain reaction of free radicals. Scavenging of free radicals may act preventively or therapeutically. A number of substances that preferentially react with free radicals can serve as scavengers, thus increasing the internal capacity/activity of endogenous antioxidants and protecting cells and tissues against oxidative damage. Molecular hydrogen (H(2)) reacts with strong oxidants, such as hydroxyl and nitrosyl radicals, in the cells, that enables utilization of its potential for preventive and therapeutic applications. H(2) rapidly diffuses into tissues and cells without affecting metabolic redox reactions and signaling reactive species. H(2) reduces oxidative stress also by regulating gene expression, and functions as an anti-inflammatory and anti-apoptotic agent. There is a growing body of evidence based on the results of animal experiments and clinical observations that H(2) may represent an effective antioxidant for the prevention of oxidative stress-related diseases. Application of molecular hydrogen in situations with excessive production of free radicals, in particular, hydroxyl and nitrosyl radicals is relatively simple and effective, therefore, it deserves special attention.
... Molecular hydrogen is a natural antioxidant that antagonizes oxidative stress in several ways ( Fig. 3): (1) by neutralizing ·OH [54], (2) reducing ·ONOO-and its gene expression directly [55], and inhibiting the production of nitro-tyrosine indirectly, which is an indicator of ·ONOO-generation [13], (3) by inducing antioxidant gene expression and increasing antioxidant enzyme activity, including superoxide dismutase (SOD), HO-1, catalase (CAT), and myeloperoxidase (MPO) [56], (4) by reducing the levels of oxidative stress indicators, such as 8-iso-prostaglandin F2α [57], and the lipid peroxidation marker malondialdehyde (MDA) [13], (5) by reducing ·NO production through inhibiting inducible nitric oxide synthase (iNOS) [29,58] and endothelial nitric oxide synthase (eNOS) [59], and (6) by inhibiting NADPH oxidase activity, which is the main source of free radicals in sepsis [59][60][61]. ...
... Studies have demonstrated that HRS reduces ROS production and attenuates mitochondrial dysfunction by inhibiting NADPH oxidase activity in rat cardiomyocytes [59,61]. In addition, researchers have found that molecular hydrogen reduces the levels of the p40 phox, p47 phox, and p67 phox subunits of NADPH oxidase in the cell membrane, while increasing their levels in the cytoplasm, suggesting that molecular hydrogen reduces NADPH oxidase activity by limiting the translocation of these molecules to the cell membrane [60]. ...
Article
Sepsis is a syndrome comprised of a series of life-threatening organ dysfunctions caused by a maladjusted body response to infection with no effective treatment. Molecular hydrogen is a new type of antioxidant with strong free radical scavenging ability, which has been demonstrated to be effective for treating various diseases, such as infection, trauma, poisoning, organ ischemia-reperfusion, metabolic diseases, and tumors. Molecular hydrogen exerts multiple biological effects involving anti-inflammation, anti-oxidation, anti-apoptosis, anti-shock, and autophagy regulation, which may attenuate the organ and barrier damage caused by sepsis. However, the underlying molecular mechanisms remain elusive, but are likely related to the signaling pathways involved. This review focuses on the research progress and potential mechanisms of molecular hydrogen against sepsis to provide a theoretical basis for clinical treatment.
... Inhaled hydrogen gas has shown beneficial effects in lung transplantation, e.g., in a rat model of IRI, lung graft injury in a brain-dead donor, pulmonary microvascular endothelial cells during cold storage, and a pig model of ex vivo donor lung perfusion [5][6][7][8][9][10][11][12]. Molecular hydrogen can be easily administered through the oral route using a special apparatus in both clinical and experimental settings [13][14][15][16][17][18][19][20][21]. ...
... Molecular hydrogen can be added not just to water but also to other beverages (tea, sports drinks, etc.) using this apparatus [13], with no adverse effects on animals or humans. We previously reported the beneficial effects of hydrogen-saturated water in pulmonary and neurodegenerative disease, fetal hippocampal IRI, and allergic reaction [14][15][16][17][18][19][20][21]. Molecular hydrogen can be internalized through consumption of hydrogen-saturated water, inhalation of hydrogen gas, or by intravenous or intraperitoneal injection. ...
Article
Full-text available
Objective Bronchiolitis obliterans syndrome arising from chronic airway inflammation is a leading cause of death following lung transplantation. Several studies have suggested that inhaled hydrogen can protect lung grafts from ischemia–reperfusion injury via anti-inflammatory and -oxidative mechanisms. We investigated whether molecular hydrogen-saturated water can preserve lung allograft function in a heterotopic tracheal allograft mouse model of obliterative airway disease Methods Obliterative airway disease was induced by heterotopically transplanting tracheal allografts from BALB/c donor mice into C57BL/6 recipient mice, which were subsequently administered hydrogen water (10 ppm) or tap water (control group) (n = 6 each) daily without any immunosuppressive treatment. Histological and immunohistochemical analyses were performed on days 7, 14, and 21. Results Hydrogen water decreased airway occlusion on day 14. No significant histological differences were observed on days 7 or 21. The cluster of differentiation 4/cluster of differentiation 3 ratio in tracheal allografts on day 14 was higher in the hydrogen water group than in control mice. Enzyme-linked immunosorbent assay performed on day 7 revealed that hydrogen water reduced the level of the pro-inflammatory cytokine interleukin-6 and increased that of forkhead box P3 transcription factor, suggesting an enhancement of regulatory T cell activity. Conclusions Hydrogen water suppressed the development of mid-term obliterative airway disease in a mouse tracheal allograft model via anti-oxidant and -inflammatory mechanisms and through the activation of Tregs. Thus, hydrogen water is a potential treatment strategy for BOS that can improve the outcome of lung transplant patients.
... 3 Ischemia injury, inflammation, cancer and allergy have been reported to be alleviated to some extent by H 2 . [4][5][6][7] Specifically, H 2 could mitigate inflammation in lung, liver and other organs. [8][9][10] The mechanism by which H 2 alleviates inflammation may be that it directly reduces the amount of media accounting for incurring inflammation, 11 or it directly combines with cytotoxic reactive oxygen species (ROS), such as the ·OH and ONOOradicals, to ameliorate the oxidative stress, which is deemed to initiate and promote inflammation. ...
Article
Full-text available
The therapeutic effects of hydrogen-rich saline (HRS) have been reported for a wide range of diseases mainly via selectively reducing the amount of reactive oxygen species. Oxidative stress plays an important role in the pathogenesis of uveitis and endotoxin-induced uveitis (EIU). In this study, we investigated whether HRS can mitigate EIU in rats. Sprague-Dawley rats were randomly divided into Norm group, Model group, HRS group, dexamethasone (DEX) group, and rats in the latter three groups were injected with equal amount of lipopolysaccharide (LPS) to induce EIU of different severities (by 1 mg/kg of LPS, or 1/8 mg/kg of LPS). Rats in HRS group were injected with HRS intraperitoneally at three different modes to purse an ameliorating effect of EIU (10 mL/kg of HRS immediately after injection of 1 mg/kg of LPS, 20 mL/kg of HRS once a day for 1 week before injection of 1 mg/kg of LPS and at 0, 0.5, 1, 2, 6, 8, 12 hours after LPS administration, or 20 mL/kg of HRS once a day for 1 week before injection of 1/8 mg/kg of LPS, and at 0, 0.5, 1, 2, 6, 8, 12, 24 hours and once a day for 3 weeks after LPS administration). Rats of DEX group were injected with 1 mL/kg of DEX solution intraperitoneally immediately after LPS administration. Rats in Norm and Model groups did not receive any treatment. All rats were examined under slit lamp microscope and graded according to the clinical signs of uveitis. Electroretinogram, quantitative analysis of protein in aqueous humor (AqH) and histological examination of iris and ciliary body were also carried out. Our results showed that HRS did not obviously ameliorate the signs of uveitis under slit lamp examination and the inflammatory cells infiltration around iris and cilliary body of EIU induced by 1 mg/kg or 1/8 mg/kg of LPS (P > 0.05), while DEX significantly reduced the inflammation reflected by the above two indicators (P < 0.05). The impaired retinal function of mild EIU induced by 1/8 mg/kg of LPS, showed by delay of peak time of b-wave of Dark adapted 3.0 electroretinogram, was not significantly restored by HRS (P > 0.05), while DEX had an obvious therapeutic effect (P < 0.05). However, HRS exerted an inhibition trend on elevation of protein in AqH of EIU induced by 1 mg/kg of LPS, and significantly reduced the increasing amount of protein in AqH of mild EIU induced by 1/8 mg/kg of LPS (P < 0.05). In conclusion, HRS could not obviously mitigate EIU in rats, while it could inhibit the elevation of AqH protein.
... Therefore, it was concluded that probably hydrogen acts as a gaseous signal in the control of inflammatory reactions. (Itoh, et al. 2009) Atopic dermatitis or eczema is a type of allergic inflammation that intensifies with oxidative stress. In a study the effect of hydrogen-rich water was investigated on dermatitis in experimental mouse and demonstrated that serum level of inflammatory cytokines such as IL-10, TNF-α, IL-12p70 and GM-CSF of mouse treated with HW significantly reduced in relation to the control group. ...
Conference Paper
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Antioxidant substances have the ability to bind free radicals, caused by oxidative stress, and may have significance in prevention and/or therapy of various skin diseases, as well as in slowing the skin aging process. Previous studies have shown that hydrogen exerts antioxidant, anti-apoptotic and anti-inflammatory properties that are beneficial to the cell. Alkaline water stick is a portable filter whenever placed in a half liter bottle of water after 1-2 hours, give alkali metal ions such as Magnesium and Calcium to the water and making hydrogen rich water (HRW). Many articles demonstrate positive effect of hydrogen on the complications of dermatitis, skin aging, photo-damage and wound healing due to reduce free radicals, that's required daily use it to enhance the skin health in the society.
... Ohsawa et al. first reported that hydrogen has a selective antioxidant effect and can alleviate cerebral ischemia reperfusion injury [11]. Following this study, other researchers have found that hydrogen not only has antioxidant effects, but also has anti-inflammatory [12], anti-apoptosis [13] and anti-allergic effects [14]. The main methods of hydrogen application include inhalation of hydrogen, drinking hydrogen rich water and injection of hydrogen rich saline (HRS) [15]. ...
Article
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Aim: To compare and evaluate the hepatoprotective effect of liver parenchyma injection of ADSCs and portal vein injection of HRS in laparoscopic hepatic ischemia reperfusion combined with hepatectomy injury in miniature pigs. Methods: Eighteen miniature pigs were randomly assigned to IRI group, HRS group and ADSCs group. HRS was injected through the portal vein 10 min before reperfusion, 1 d, 2 d, and 3 d after surgery. ADSCs were injected into liver parenchyma after hepatectomy. The serum and liver tissue samples were collected at different time points (preoperative, and postoperative at 1 d, 3 d and 7 d). Results: Compared with the IRI group, both ADSCs and HRS groups can promote liver function recovery, reduce oxidative stress, reduce inflammation, and promote liver regeneration. Compared with HRS, ALT and TBIL in ADSCs group were significantly decreased at 3 d, and AST was significantly reduced at 1 d. The activities of SOD and GSH-Px in ADSCs group were significantly higher than that in HRS group, but the MDA level in HRS group was markedly lower than that in ADSCs group at 1 d. IL-1β was significantly lower in the ADSCs group than in the HRS group at 1 day after operation. The expressions of HGF and PCNA were significantly higher than that in the HRS group at 3 day after surgery. Conclusion: Our study has demonstrated that HRS and ADSCs have significant hepatoprotective effects in miniature pigs after HIRI and hepatectomy injury. However, liver parenchyma injection of ADSCs is more beneficial to the recovery of liver function than portal vein injection of HRS.
... 3. It appears that molecular hydrogen may be considered to be a new signaling molecule, which may modify the systems of cell signaling, cellular metabolism, and gene expression [14,15,19]. ...
... This histamine will affect the hyperreactivity of bronchial smooth muscle. The alkaline administration of histamine is then expected to reduce bronchial muscle hyperactivity and mucin secretion in the pathophysiology of asthma attacks [20]. Thus, this combination therapy has an effect on improving pulmonary function, especially peak expiratory flow rate value. ...
Article
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Background: Asthma is an abnormality in the form of chronic airway inflammation which can be reduced by providing asthma-induced gymnastics and healthy lifestyle such as consuming alkaline water.Aims: The objective of this study is to examine a combination of alkaline water provision and asthma-induced gymnastics towards peak expiratory flow rate of asthma patients at Surakarta Lung Clinic, IndonesiaMethods: This research was a quasi-experimental pre-test-post-test design with control group. The number of respondents in this study was 30 respondents, divided equally into intervention group and control group. The control group was given asthma-induced gymnastics twice a week for 14 days with duration of 60 minutes, while the intervention group was provided with a combination of alkaline water pH9+ for 14 days as much as 1,200 ml/day and asthma-induced gymnastics 4 times a week for 14 days with a duration of 60 minutes.Results: There was a significant difference in the value of peak expiratory flow for 14 days in the intervention group and the control group (p < 0.001). There was an improvement in the average of peak expiratory flow rate values for each measurement in both groups, however, this study orchestrates that the intervention group has a higher improvement than the control group. The combination of alkaline water and asthma-induced gymnastics effectively and significantly improves the peak expiratory flow rate values at the Day 8 (p = 0.039) and the Day 14 (p = 0.012).Conclusion: The combination of alkaline water and asthma-induced gymnastics can be applied in nursing care management in patients with intermittent and persistent asthma. Keywords: Alkaline Water, Asthma Gymnastics, Peak Expiratory Flow Rate, Asthma.
... H 2 gas inhalation therapy was neuroprotective in preclinical cellular and in vivo models of brain ischemia and ICH [107,157,158], as well as in clinical studies of brain ischemia [159][160][161]. The neuroprotective effects promoted by H 2 can be mediated also by a modulatory action on MCs, since the gas inhalation can reduce mastocytic activation through the inhibition of the FcεR-mediated signal transduction [109,162]. ...
Article
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Mast cells (MCs) are densely granulated perivascular resident cells of hematopoietic origin. Through the release of preformed mediators stored in their granules and newly synthesized molecules, they are able to initiate, modulate, and prolong the immune response upon activation. Their presence in the central nervous system (CNS) has been documented for more than a century. Over the years, MCs have been associated with various neuroinflammatory conditions of CNS, including stroke. They can exacerbate CNS damage in models of ischemic and hemorrhagic stroke by amplifying the inflammatory responses and promoting brain–blood barrier disruption, brain edema, extravasation, and hemorrhage. Here, we review the role of these peculiar cells in the pathophysiology of stroke, in both immature and adult brain. Further, we discuss the role of MCs as potential targets for the treatment of stroke and the compounds potentially active as MCs modulators.
... Additional studies confirmed that H 2 could exert anti-inflammatory effects by regulating Tolllike receptor 4 (TLR4) signaling [48], and anti-apoptotic effects through Ras-ERK1/2-MEK1/2 and Akt pathway inactivation [49]. H 2 may also protect against allergic reactions by directly modulating FcεRI-related signaling, rather than through radical-scavenging activity [50]. ...
Article
Full-text available
Since the 2007 discovery that molecular hydrogen (H2) has selective antioxidant properties, multiple studies have shown that H2 has beneficial effects in diverse animal models and human disease. This review discusses H2 biological effects and potential mechanisms of action in various diseases, including metabolic syndrome, organ injury, and cancer; describes effective H2 delivery approaches; and summarizes recent progress toward H2 applications in human medicine. We also discuss remaining questions in H2 therapy, and conclude with an appeal for a greater role for H2 in the prevention and treatment of human ailments that are currently major global health burdens. This review makes a case for supporting hydrogen medicine in human disease prevention and therapy.
... Hydrogen gas acts as an antioxidant by scavenging hydroxyl radicals, decreasing the activity of NADPH oxidase and reducing H 2 O 2 production (180,181). Hydrogen gas inhalation therapy was neuroprotective against ICH by reducing MC-mediated oxidative stress in mice (135,176). Hydrogen gas inhalation was able to inhibit FcεR-signal transduction and degranulation of MCs (180) through the phosphorylation of Lyn kinase in MCs (135,176,182). ...
Article
Background: Mast cells (MCs) are perivascularly located immune cells of haematopoietic origin. Emerging evidences suggest that the activation of MCs play important roles in the pathogenesis of blood brain barrier disruption, neuroinflammation, and neurodegeneration. Objectives: In this review, we aimed to discuss the detrimental effects of MCs in response to various types of brain injury, as well as the therapeutic potential and neuroprotective effects of targeting the activation and degranulation of MCs, particularly in the management of the acute phase. Methods: An extensive online literature search was conducted through Pubmed/Central on March 2018. Then, we comprehensively summarized the effects of the activation of brain MCs in acute brain injury along with current pharmacological strategies targeting at the activation of MCs. Results: The review of the current literature indicated that the activation and degranulation of brain MCs significantly contribute to the acute pathological process following different types of brain injury including focal and global cerebral ischaemia, intracerebral haemorrhage, subarachnoid haemorrhage, and traumatic brain injury. Conclusions: Brain MCs significantly contribute to the acute pathological processes following brain injury. In that regard, targeting brain MCs may provide a novel strategy for neuroprotection.
... Numerous studies have consistently shown that the contributors were significantly down regulated after applying hydrogen medicine therapy [10, 14,26,27,41]. Besides, with the deepening biological mechanism of hydrogen research being developed, scientists gradually found that hydrogen therapy can significantly suppress many pathological signal transduction channels such as NF-κβ, MAPK, Lyn-P, and MEK-1 as well as ERK1/2 pathways and ultimately achieve the goal of recovery from many diseases [44,45,[49][50][51][52][53]. In addition, it is worth noting that as H2 is moderate enough, it can selectively react with only hydroxyl radicals (•OH) and peroxynitrite(ONOO-), the main contributors of oxidative stress in vitro and in vivo without disturbing metabolic redox reactions ...
... 3. It appears that molecular hydrogen may be considered to be a new signaling molecule, which may modify the systems of cell signaling, cellular metabolism, and gene expression [14,15,19]. ...
... However, a short dwell time of exogenously administered hydrogen in our bodies and production of a large amount of hydrogen in our intestine make the radical-scavenging effects of hydrogen unlikely to be the primary mechanism. We have shown that molecular hydrogen inhibits signalling pathways in allergies [10], inflammation [11], and Wnt/b-catenin [12], which require no radical-scavenging effects. Many signalling molecules (for example, Lyn, Ras, , and NF-jB to name a few) are modulated by molecular hydrogen [2,3]. ...
Article
Background: Molecular hydrogen exerts its effect on multiple pathologies, including oxidative stress, inflammation, and apoptosis. However, its molecular mechanisms have not been fully elucidated. In order to explore the effects of molecular hydrogen, we meta-analyzed gene expression profiles modulated by molecular hydrogen. Methods: We performed microarray analysis of the mouse liver with or without drinking hydrogen water. We also integrated two previously reported microarray datasets of the rat liver into meta-analyses. We used two categories of meta-analysis methods: the cross-platform method and the conventional meta-analysis method (Fisher’s method). For each method, hydrogen-modulated pathways were analyzed by (i) the hypergeometric test (HGT) in the class of over-representation analysis (ORA), (ii) the gene set enrichment analysis (GSEA) in the class of functional class scoring (FCS), and (iii) the signaling pathway impact analysis (SPIA), pathway regulation score (PRS), and others in the class of pathway topology-based approach (PTA). Results: Pathways in the collagen biosynthesis and the heat shock response were upregulated according to (a) ORA with the cross-platform method, (b) GSEA with the cross-platform method, and (c) PRS with the cross-platform method. Pathways in cell cycles were downregulated a ORA with the cross-platform method, (b) GSEA with the cross-platform method, and (d) GSEA with the conventional meta-analysis method. Discussion: Because the heat shock response leads to upregulation of collagen biosynthesis and a transient arrest of cell cycles, induction of the heat shock response is likely to be a primary event induced by molecular hydrogen in the liver of wild-type rodents.
... However, a short dwell time of exogenously administered hydrogen in our bodies and production of a large amount of hydrogen in our intestine make the radical-scavenging effects of hydrogen unlikely to be the primary mechanism. We have shown that molecular hydrogen inhibits signalling pathways in allergies [10], inflammation [11], and Wnt/b-catenin [12], which require no radical-scavenging effects. Many signalling molecules (for example, Lyn, Ras, , and NF-jB to name a few) are modulated by molecular hydrogen [2,3]. ...
... However, radical scavenging effects of H 2 cannot fully explain the anti-inflammatory and anti-apoptotic effects, which should involve a number of fine-tuned signaling pathways. Studies also have shown that H 2 suppresses signaling pathways in allergies 37 and inflammation 38 without directly scavenging reactive oxygen/nitrogen species. ...
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Psoriasis and parapsoriasis en plaques are chronic inflammatory skin diseases, both representing therapeutic challenge in daily practice and adversely affecting the quality of life. Reactive oxygen species (ROS) has been evidenced to be involved in the pathogenesis of the chronic inflammatory diseases. We now report that hydrogen water, an effective ROS scavenger, has significant and rapid improvement in disease severity and quality of life for patients with psoriasis and parapsoriasis en plaques. At week 8, our parallel-controlled trial revealed 24.4% of patients (10/41) receiving hydrogen-water bathing achieved at least 75% improvement in Psoriasis Area Severity Index (PASI) score compared with 2.9% of patients (1/34) of the control group (Pc = 0.022, OR = 0.094, 95%CI = [0.011, 0.777]). Of patients, 56.1% (23/41) who received bathing achieved at least 50% improvement in PASI score compared with only 17.7%(6/34) of the control group (P = 0.001, OR = 0.168, 95%CI = [0.057, 0.492]). The significant improvement of pruritus was also observed (P = 3.94 × 10⁻⁴). Besides, complete response was observed in 33.3% of patients (2/6) of parapsoriasis en plaques and partial response in 66.7% (4/6) at week 8. Our findings suggested that hydrogen-water bathing therapy could fulfill the unmet need for these chronic inflammatory skin diseases.
... These studies have confirmed the data reported in 2007 [28] that H 2 acts directly on • OH and ONOO _ to decrease oxidative stress. Furthermore, recent studies have added other ways in which H 2 may reduce oxidative stress such as (i) regulating antioxidant gene expression and rising antioxidant enzyme activity such as SOD, CAT, myeloperoxidase (MPO) and heme oxygenase-1(HO-1) [32]; (ii) decreasing oxidative stress status such as 8-iso-prostaglandin-F2α (8-iso-PGF2α) [33], thiobarbituric acid reactive substances (TBARS) [34] and malondialdehyde (MDA) [35]; (iv) reducing nitric oxide (NO) production [33,36,37]; and (v) inhibiting nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity [37][38][39]. The potential effects of H 2 are summarized in Fig. (1). ...
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Physical exercise-induced oxidative stress and inflammation may be beneficial when exercise is a regular activity, but it is rather harmful when exercise is exhaustive and performed by unaccustomed organisms. Molecular hydrogen (H2 ) has recently appeared as a potent antioxidant and anti-inflammatory molecule in numerous pathological conditions. However, its role is relatively unknown under physiological conditions such as physical exercise. Therefore, this review summarizes the current knowledge of the H2 reducing oxidative stress and inflammation in physical exercise, reporting data from both animal and human studies.
... Researchers have found that hydrogen molecule not only has anti-oxidation effect but also has anti-inflammatory, antiapoptotic and anti-allergic effects [5][6][7]. More importantly, several studies have suggested that H 2 is a kind of endogenous signaling molecules [8,9]. Therefore, H 2 therapy is considered a promising strategy for the treatment of various diseases. ...
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Hydrogen therapy has recently attracted increasing attention as an emerging and promising therapeutic technology due to its selective antioxidant properties and regulatory capacities in vivo. To effectively solve the low solubility issue of hydrogen, a variety of nanomaterials and devices for hydrogen supply have recently been developed, aiming to increase the concentration of hydrogen in specific disease location and realize controlled hydrogen release and combined treatment. In this review, we mainly focus on the latest advances in using hydrogen-generating devices and nanomaterials for hydrogen therapy. These developments include the sustained release of H2 , controlled release of H2 , and versatile modalities of synergistic therapy, etc. Also, bio-safety issues and challenges are discussed to further promote the clinical applications of hydrogen therapy and the development of hydrogen medicine.
... It has also been demonstrated that oral HRW abolishes the immediate-type allergic reaction in mice, and prevents degranulation of mast cells by suppressing NADPH oxidase activity [15]. The researchers subsequently reported that HRW reduced LPS/interferon gammainduced NO • production in macrophages, which form a molecular basis for the functional interaction between these two gaseoussignaling molecules [16]. ...
... The effect of molecular hydrogen was initially attributed to its specific scavenging activity of hydroxyl radicals and peroxynitrite. 36 We and others later reported additional mechanisms of molecular hydrogen on the signal transduction pathways 37,38 and on secretion of ghrelin. 39 We also demonstrated that pulsative administration of hydrogen either by consumption of hydrogen water or intermittent inhalation of hydrogen gas suppresses development of Parkinson's disease in rats. ...
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Objective: Duchenne muscular dystrophy (DMD) is a devastating muscle disease caused by a mutation in DMD encoding dystrophin. Oxidative stress accounts for dystrophic muscle pathologies in DMD. We examined the effects of molecular hydrogen in mdx mice, a model animal for DMD. Methods: The pregnant mother started to take supersaturated hydrogen water (>5 ppm) ad libitum from E15.5 up to weaning of the offspring. The mdx mice took supersaturated hydrogen water from weaning until age 10 or 24 weeks when they were sacrificed. Results: Hydrogen water prevented abnormal body mass gain that is commonly observed in mdx mice. Hydrogen improved the spontaneous running distance that was estimated by a counter-equipped running-wheel, and extended the duration on the rota-rod. Plasma creatine kinase activities were decreased by hydrogen at ages 10 and 24 weeks. Hydrogen also decreased the number of central nuclei of muscle fibers at ages 10 and 24 weeks, and immunostaining for nitrotyrosine in gastrocnemius muscle at age 24 weeks. Additionally, hydrogen tended to increase protein expressions of antioxidant glutathione peroxidase 1, as well as anti-apoptotic Bcl-2, in skeletal muscle at age 10 weeks. Discussion: Although molecular mechanisms of the diverse effects of hydrogen remain to be elucidated, hydrogen potentially improves muscular dystrophy in DMD patients.
... Other scholars have proposed that H 2 has a signaling effect. 16 However, the evidence that H 2 is a signal molecule was not sufficient. For example, there was no evidence to suggest that animal cells have the ability to synthesize H 2 . ...
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Gas medicine, including O 2 , NO, H 2 S, CO, CH 4 , has played important roles in prevention and treatment of diseases for a long time. Molecular hydrogen (H 2 ), the smallest diatomic molecule in nature, has become a rising star in gas medicine in the past decades. Many studies have shown that H 2 has preventive and therapeutic effects on various diseases through its selective antioxidant activity. H 2 , as a non-toxic gas for the human body and convenience to obtain, has provided a great possibility to be used widely. Currently, the main difficulties in hydrogen medicine are lack of definitive clinical evidence and the molecular basis of hydrogen effects. In this paper, the authors have conducted a comprehensive review and analysis of these issues, and also proposed the possibility of developing Hydrogen Biology and Hydrogen Medicine as new disciplines of biology and medicine.
... 2 Oxidative Medicine and Cellular Longevity study has shown that H 2 decreased the levels of NADPH oxidase subunits, including p40 phox, p47 phox, and p67 phox in the cell membrane, but increased their levels in the cytoplasm. By limiting the translocation of these molecules to the cell membrane, H 2 reduces the NADPH oxidase activity [39]. ...
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Ageing is a physiological process of progressive decline in the organism function over time. It affects every organ in the body and is a significant risk for chronic diseases. Molecular hydrogen has therapeutic and preventive effects on various organs. It has antioxidative properties as it directly neutralizes hydroxyl radicals and reduces peroxynitrite level. It also activates Nrf2 and HO-1, which regulate many antioxidant enzymes and proteasomes. Through its antioxidative effect, hydrogen maintains genomic stability, mitigates cellular senescence, and takes part in histone modification, telomere maintenance, and proteostasis. In addition, hydrogen may prevent inflammation and regulate the nutrient-sensing mTOR system, autophagy, apoptosis, and mitochondria, which are all factors related to ageing. Hydrogen can also be used for prevention and treatment of various ageing-related diseases, such as neurodegenerative disorders, cardiovascular disease, pulmonary disease, diabetes, and cancer. This paper reviews the basic research and recent application of hydrogen in order to support hydrogen use in medicine for ageing prevention and ageing-related disease therapy.
... 15 Soon afterward, hydrogen therapy quickly gained attention in the fields of inflammation and allergy. [16][17][18] Previous studies have demonstrated that H2 dissolved in saline to generate a hydrogen-rich saline (HRS) solution was effective in relieving AR symptoms and reducing inflammatory mediators such as IL-1β, IL-4, IL-5, IL-6, IL-13, and TNFα. [19][20][21][22] Additional studies have confirmed that HRS could induce an increase in CD4+CD25+ FoxP3+Treg levels in AR guinea pigs and promote IL-10 and TGF-B secretion. ...
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Purpose: Chronic rhinitis (CR) is a common chronic inflammation of the nasal mucosa. Nasal saline irrigation has been demonstrated to be an effective treatment for CR. In this study, we investigated the beneficial effects of hydrogen-rich saline irrigation as an anti-inflammatory irrigation therapy for CR and compared its effectiveness over saline irrigation. Hydrogen-rich saline (HRS) was investigated due to its antioxidant and anti-inflammatory properties. Methods: A total of 120 patients with CR were randomly divided into two groups, patients irrigated with HR (HRS group) and the control group irrigated with saline (NS group). A randomized, double-blind control study was performed. The main observation index in this study was the total score of nasal symptoms (TNSS). In addition, eosinophilic protein (ECP) of the nasal secretions, nasal nitric oxide (nNO) levels, and levels of regulatory T cells (Treg) and regulatory B cells (Breg) were also compared between the two groups. Furthermore, patients with allergic rhinitis (AR) and non-allergic rhinitis (NAR) were also evaluated based on serum-specific IgE positivity. Results: After treatment, TNSS and nasal ECP in the two groups decreased significantly (P<0.05), with patients in the HRS group showing significantly lower levels compared to the NS group (P<0.05). There were no significant differences in Treg and Breg levels between the two groups. Subgroup analysis showed that TNSS in the AR-HRS group showed a more significant reduction compared to the AR-NS group (P<0.05); however, there were no significant differences for the other inflammatory biomarkers (P>0.05). ECP levels were reduced significantly in the NAR subgroup compared to NS irrigation (P<0.05). There were no obvious adverse events observed in patients during the entire treatment period. Conclusion: Compared to saline irrigation, HRS nasal irrigation was found to improve CR clinical symptoms, especially in patients with AR. HRS could effectively be used for the clinical treatment of patients with CR.
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Recently, molecular hydrogen has been reported to have a suppressive effect on inflammation in human and rodent models. The aim of this study was to evaluate the preventive effects of hydrogen-rich water (HRW) on zebrafish challenged by A. hydrophila. We have found an increased survival rate of bacteria-challenged zebrafish subjected to the HRW immersion treatment. Furthermore, we have revealed that HRW was able to block multiplication of A. hydrophila in zebrafish. In addition, treatment of zebrafish infected by A. hydrophila with effective concentrations of HRW strongly affected the expression of genes mediating pro-inflammatory and anti-inflammatory cytokines. There were down-regulation of selected pro-inflammatory immune response genes (IL-1β, IL-6, and NF-κB), and up-regulation of the anti-inflammatory cytokine gene (IL-10) in the spleen, kidney, and liver. This study is the first one to investigate the effects of HRW on fish infected with bacteria, and might shed new light on hydrogen's antimicrobial effects and further application in aquaculture fish species.
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Background: Substantial evidence indicates that molecular hydrogen (H2) has beneficial vascular effects because of its antioxidant and/or anti-inflammatory effects. Thus, hydrogen-rich water may prove to be an effective anti-aging drink. This study examined the effects of H2on endothelial senescence and clarified the mechanisms involved.Methods and Results:Hydrogen-rich medium was produced by a high-purity hydrogen gas generator. Human umbilical vein endothelial cells (HUVECs) were incubated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for various time periods in normal or hydrogen-rich medium. The baseline H2concentration in hydrogen-rich medium was 0.55±0.07 mmol/L. This concentration gradually decreased, and H2was almost undetectable in medium after 12 h. At 24 h after TCDD exposure, HUVECs treated with TCDD exhibited increased 8OHdG and acetyl-p53 expression, decreased nicotinamide adenine dinucleotide (NAD(+))/NADH ratio, impaired Sirt1 activity, and enhanced senescence-associated β-galactosidase. However, HUVECs incubated in hydrogen-rich medium did not exhibit these TCDD-induced changes accompanying Nrf2 activation, which was observed even after H2was undetectable in the medium. Chrysin, an inhibitor of Nrf2, abolished the protective effects of H2on HUVECs. Conclusions: H2has long-lasting antioxidant and anti-aging effects on vascular endothelial cells through the Nrf2 pathway, even after transient exposure to H2. Hydrogen-rich water may thus be a functional drink that increases longevity.
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Cardiac fibrosis induced by sustained pressure overload contributes to heart failure. Oxidative stress serves an important role in cardiac remodeling and heart failure independent of etiological factors. The application of hydrogen as an antioxidant is a novel concept in disease treatment, however no studies as present have investigated the effects of hydrogen on cardiac fibrosis. In the present study, the effects of hydrogen on pressure overload‑induced cardiac fibrosis and heart failure were investigated in abdominal aortic‑constricted rats. Masson's trichrome staining and echocardiography were used to evaluate the fibrotic area and cardiac function, respectively. Reactive oxygen species (ROS) content was detected by immunofluorescence. Malondialdehyde (MDA) concentration, the activity of superoxide dismutase (SOD) and hydroxyproline content were measured by spectrophotometry. Western blot analysis was used to detect the protein levels of transforming growth factor (TGF)‑β1, connective tissue growth factor (CTGF), NADPH oxidases (NOX)2, NOX4, p38 mitogen‑activated protein kinase (MAPK) and Smad2/3. Reverse transcription‑quantitative polymerase chain reaction was performed to detect the mRNA expression of collagen I (Col I) and fibronectin 1 (FN1). Hydrogen-containing saline (HCS) treatment was observed to improve interstitial fibrosis and cardiac function and to decrease the level of ROS, the oxidative‑stress marker MDA and expression of NOXs, while increasing the activity of the anti‑oxidant enzyme SOD. HCS treatment also decreased the phosphorylation of p38 MAPK and Smad2/3, and the expression of TGF‑β1 and CTGF, which were accompanied by reduced hydroxyproline content, Col I and FN1 mRNA levels. These results indicate that HCS treatment can improve cardiac function by reducing interstitial fibrosis in pressure‑overloaded rats through its anti‑oxidative properties and via suppression of TGF-β1 signaling.
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Hydrogen gas (H2) was recently suggested to perform multiple roles during plant response to abiotic stresses. However, physiological mechanisms and downstream targets remain elusive. Here, we showed that osmotic stress triggered by polyethylene glycol (PEG) could enhance hydrogenase-like activity and H2 production in alfalfa seedlings. After the administration of H2, the enhanced tolerance to PEG stress was confirmed, as evidence by the observation of the alleviation of root inhibition and the decrease in lipid peroxidation. H2 also rapidly elevated hydrogen peroxide (H2O2) levels, peaking at 5 h. When supplemented with exogenous H2O2, a heme oxygenase-1 (HO-1; a novel antioxidant enzyme) inducer hemin, and one of HO-1 catalytic products, carbon monoxide (CO), antioxidant enzymes and subsequent PEG tolerance were induced. The inhibition of NADPH oxidase and chemical scavenging of H2O2 could block H2-induced HO-1 expression and PEG tolerance. Simultaneously, a HO-1 inhibitor counteracted the effects of H2 except H2-induced H2O2 production. In summary, these results suggested that H2O2 might play a significant role in HO-1-dependent induction of plant osmotic stress tolerance triggered by H2.
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Background: Periodontal disease is a progressive destructive change that causes loss of bone and periodontal ligaments around the teeth that can eventually lead to its loss. The main bacteria in chronic periodontitis is Porphyromonas gingivalis. Aggregatibacter actinomycetemcomitans, a pathogen associated with aggressive periodontitis, initiates a proinflammatory response that causes tissue destruction of periodontal, alveolar bone resorption and subsequent tooth loss. Electrolyzed reduced water (ERW) is an alkaline water, ERW not only has a high pH and low oxidation reduction potential (ORP), but also contains several magnesium ions. Magnesium ions proven effective for the prevention of various diseases. Purpose: To analyze the level of malondialdehyde (MDA) in Wistar rats with cases of chronic and aggressive periodontitis that consumed ERW. Method: Wistar rats were divided into four groups, each group with 10 rats. The first and second group were Wistar rat with chronic periodontitis and consume drinking water and ERW. The third and fourth group were Wistar rat with aggressive periodontitis and consume drinking water and ERW. This experiment is done by calculating the levels of MDA. The calculation of the levels of MDA is done with spectrophotometric assay for MDA. Result: The results of this experiment show that the level of MDA in serum in group that consume ERW had decreased significantly different with thegroup that consume drinking water with the statistical test. Conclusion: It can be concluded that ERW can decrease the MDA level in Wistar rat with chronic and aggressive periodontitis case.
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Mast cells are a heterogeneous multifunctional cellular population that promotes connective tissue homeostasis by slow release of biologically active substances, affecting primarily the permeability of vessels and vascular tone, maintenance of electrolyte and water balance, and composition of the extracellular matrix. Along with this, they can rapidly release inflammatory mediators and chemotactic factors that ensure the mobilization of effector innate immune cells to fight against a variety of pathogens. Furthermore, they play a key role in initiation of allergic reactions. Aggregation of high affinity receptors to IgE (FcεRI) results in rapid degranulation and release of inflammatory mediators. It is known that reactive oxygen species (ROS) participate in intracellular signaling and, in particular, stimulate production of several proinflammatory cytokines that regulate the innate immune response. In this review, we focus on known molecular mechanisms of FcεRI-dependent activation of mast cells and discuss the role of ROS in the regulation of this pathway.
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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.
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Molecular hydrogen is reported to be used medically to ameliorate various systemic pathological conditions. This study aimed to investigate the effect of hydrogen (H2) gas on hypertension induced by intermittent hypoxia in rats. The adult rats were exposed to chronic intermittent hypoxia (CIH) 8 hours/day for 5 weeks and/or H 2 gas 2 hours/day. We found that the systolic and diastolic blood pressure (BP) increased significantly in rats exposed to intermittent hypoxia, both of which were markedly attenuated after H treatment. Furthermore, intermittent hypoxia exposure elevated renal sympathetic nerve activity, consistent with plasma norepinephrine. Additionally, H 2 gas significantly improved CIH‐induced abnormal vascular relaxation. Nevertheless, inhalation of H 2 gas alone did not cause such changes. Moreover, H 2 gas‐treated rats exposed to CIH showed a significant reduction in 8‐hydroxy‐2 deoxyguanosine content and increases in superoxide dismutase activity, indicating improved oxidative stress. Taken together, these results indicate that H 2 gas has significant effects on the reduction of BP without any side effects. Mechanistically, inhibition of sympathetic activity and reduction of systemic vascular resistance may participate in this process via the antioxidant activity of H 2. Hydrogen (H2) is effective in preventing hypertension with no significant adverse effects via antioxidation. H2 downregulated sympathetic activity in rats with chronic intermittent hypoxia (CIH). H2 reduced the resistance of mesenteric artery in rats with CIH.
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Allergic rhinitis (AR) is a common chronic inflammatory condition. It has been previously indicated that oxidative stress may contribute to allergic inflammation, including AR. Although molecular hydrogen (H2), an anti-oxidative agent, has been effective in treatment of numerous oxidative stress-associated diseases, the effect of inhalation of a high concentration of H2 on AR remains unknown. In the current study, female BALB/c mice were sensitized with ovalbumin (OVA) followed by intranasal OVA challenge to establish an animal model of AR. Mice were subjected to exposure to H2 and the inert gas helium at different frequencies and durations. The frequencies of sneezing/scratching and the body weights of mice were recorded. Histological analysis and multiplex cytokine assays were performed to evaluate the effects of H2 on AR. Challenge with OVA induced significant nasal mucosa inflammation. H2 inhalation reduced the infiltration of inflammatory cells into mucosa and lowered the levels of interleukin (IL)-5, IL-13 and monocyte chemoattractant protein-1 in serum. H2 inhalation slightly increased the level of interferon-γ, however the difference was not statistically significant. Treatment with H2 limited the weight increase in healthy mice and reversed the weight loss in mice with AR. Furthermore, H2 inhalation induced a therapeutic effect on AR in a dose.dependent manner. The current results demonstrate that H2 may demonstrate a therapeutic value for allergic diseases.
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Hydrogen has therapeutic and preventive effects against various diseases. Although animal and clinical studies have reported promising results, hydrogen distribution in organs after administration remains unclear. Herein, the sequential changes in hydrogen concentration in tissues over time were monitored using a highly sensitive glass microsensor and continuous inhalation of 3% hydrogen gas. The hydrogen concentration was measured in the brain, liver, kidney, mesentery fat and thigh muscle of rats. The maximum concentration, time to saturation, and other measurements representing the dynamics of distribution were obtained from the concentration curves, and the results obtained for different organs were compared. The time to saturation was significantly longer (20.2 vs 6.3–9.4 min. P = 0.004 in all cases) and increased more gradually in muscle than in the other organs. The maximum concentration was the highest in liver and the lowest in the kidney (29.0 ± 2.6 vs 18.0 ± 2.2 μmol/L; P = 0.03 in all cases). The concentration varied significantly depending on the organ (P = 0.03). These results provide the fundamentals for elucidating the mechanisms underlying the in vivo favourable effects of hydrogen gas in mammalian systems.
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Recently, molecular hydrogen (H 2 )has become known as a new class of antioxidants and redox-modulating interventions. Effects of H 2 have been documented for many acute and chronic pathological conditions. The present study was aimed at determining the effect of hydrogen on the physiology and longevity of Drosophila. The flies were given a patented food supplement consisting of a mixture of inert salts with metallic magnesium, which reacted with acidic aqueous solutions, thereby releasing hydrogen gas. The supplementation with hydrogen-rich food prolonged the life span of the wild-type strain. To gain insights into the effect of hydrogen, we used previously generated mutant under-expressing redox-regulating enzymes, peroxiredoxins, in mitochondria. The hydrogen-releasing material lessened the severe shortening of life span of the mutant. Hydrogen also delayed the development of intestinal dysfunction caused by under-expression of peroxiredoxins in the intestinal epithelium. Hydrogen also averted a significant decrease in the mobility of mutant flies that under-expressed peroxiredoxins globally or in specific tissues. Together, the results showed that the introduction of hydrogen to aging or short-lived flies could increase their survival, delay the development of the intestinal barrier dysfunction and significantly improve physical activity.
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The molecular footprints of COVID-19 occur everywhere, even reaching the family of biologically active gases and gasotransmitters. Besides nitric oxide and hydrogen sulfide, COVID-19 might also alter the homeostasis of dihydrogen (H2), another gaseous bioactive molecule produced endogenously by the human gut bacteria. Many studies have shown various alterations of the gut microbiota in patients with coronavirus disease 2019, including the lower abundance of hydrogen-producing bacteria that could instigate the shortage of hydrogen output. Since dihydrogen has many important bioactivities, including cytoprotective, antioxidant, anti-inflammatory, and antiapoptotic, its malproduction in COVID-19 might contribute to the disease progression and severity. On the other hand, replenishing dihydrogen by exogenous administration could be beneficial in COVID-19 for both patient- and clinical-reported outcomes. Assessing low dihydrogen along with H2 supplementation to restore normal levels could be thus combined via theranostic approaches to aid COVID-19 diagnosis and treatment.
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Ever since molecular hydrogen was first reported as a hydroxyl radical scavenger in 2007, the beneficial effect of hydrogen was documented in more than 170 disease models and human diseases including ischemia/reperfusion injury, metabolic syndrome, inflammation, and cancer. All these pathological damages are concomitant with overproduction of reactive oxygen species (ROS) where molecular hydrogen has been widely demonstrated as a selective antioxidant. Although it is difficult to construe the molecular mechanism of hydrogen's biomedical effect, an increasing number of studies have been helping us draw the picture clearer with days passing by. In this review, we summarized the current knowledge on systemic and cellular modulation by hydrogen treatment. We discussed the antioxidative, anti-inflammatory, and anti-apoptosis effects of hydrogen, as well as its protection on mitochondria and the endoplasmic reticulum, regulation of intracellular signaling pathways, and balancing of the immune cell subtypes. We hope that this review will provide organized information that prompts further investigation for in-depth studies of hydrogen effect.
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Key message: H2 prolonged the vase life and improved the vase quality of cut roses through repressing endogenous ethylene production and alleviating ethylene signal transduction during the entire senescing period. Recently, the application of hydrogen gas (H2) was shown to improve postharvest quality and longevity in perishable horticultural products, but the specific regulation mechanism remains obscure. Here, endogenous ethylene production and the expression of genes in ethylene biosynthesis and signalling pathway were investigated to explore the crosstalk between H2 and ethylene during the senescence of cut roses. Our results revealed that addition of exogenous ethylene by ethephon accelerated the senescence of cut roses, in which 100 mg L-1 ethephon displayed the most obvious senescent phenotype. While the applied different concentrations (1%, 10%, 50% and 100%) of hydrogen-rich water (HRW) conducted different affects in alleviating the senescence of cut roses, and 1% HRW displayed the best ornamental quality and the longest vase life by reducing ethylene production, supported by the decrease of 1-aminocyclopropene-1-carboxylate (ACC) accumulation, ACC synthase (ACS) and ACC oxidase (ACO) activities, and Rh-ACS3 and Rh-ACO1 expressions in ethylene biosynthesis. In addition, HRW increased the transcripts of ethylene receptor genes Rh-ETR1 at blooming period from day 4 to day 6 and suppressed Rh-ETR3 at senescence phase at day 8 after harvest. Furthermore, the relevant affection of HRW on Rh-ETR1 and Rh-ETR3 expressions still existed when the ethylene production was compromised by adequate addition of exogenous ethylene in HRW-treated cut rose petals, and HRW directly repressed the protein level of Rh-ETR3 in a transient expression assay. Overall, the results suggested that H2 is involved in neutralizing ethylene-mediated postharvest in cut flowers.
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In recent years, many studies have shown that hydrogen has therapeutic and preventive effects on various diseases. Its selective antioxidant properties were well noticed. Most of the ionizing radiation-induced damage is caused by hydroxyl radicals (% OH) from radiolysis of H O 2. Since hydrogen can mitigate such damage through multiple mechanisms, it presents noteworthy potential as a novel radio-protective agent. This review analyses possible mechanisms for hydrogen's radioprotective properties and effective delivery methods. We also look into details of vitro and vivo studies for hydrogen's radioprotective effects, and clinical practices. We conclude that hydrogen has good potential in radio-protection, with evidence that warrants greater research efforts in this field.
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Molecular hydrogen (H2 ) was long regarded as non-functional in mammalian cells. We overturned the concept by demonstrating that H2 exhibits antioxidant effects and protects cells against oxidative stress. Subsequently, it has been revealed that H2 has multiple functions in addition to antioxidant effects, including ant-inflammatory, anti-allergic functions, and as a cell death and autophagy regulation. Additionally, H2 stimulates energy metabolism. Because H2 does not readily react with most biomolecules without a catalyst, it is essential to identify the primary targets with which H2 reacts or interacts directly. As a first event, H2 may react directly with strong oxidants such as hydroxyl radicals (•OH) in vivo. This review addresses the key issues related to this in vivo reaction. •OH may have a physiological role because it triggers a free radical chain reaction and may be involved in the regulation of Ca2+ - or mitochondrial ATP-dependent K+ - channeling. In the subsequent pathway, H2 suppressed a free radical chain reaction, leading to decreases in lipid peroxide and its end products. Derived from the peroxides, 4-hydroxy-2-nonenal functions as a mediator that up-regulates multiple functional PGC-1α. As the other direct target in vitro and in vivo, H2 intervenes in the free radical chain reaction to modify oxidized phospholipids, which may act as an antagonist of Ca2+ -channels. The resulting suppression of Ca2+ - signaling inactivates multiple functional NFAT and CREB transcription factors, which may explain H2 multifunctionality. This review also addresses the involvement of NFAT in the beneficial role of H2 in COVID-19, Alzheimer’s disease and advanced cancer. We discuss some unsolved issues of H2 action on lipopolysaccharide signaling, MAPK and NF-κB pathways and the Nrf2 paradox. Finally, as a novel idea for the direct targeting of H2 , this review introduces the possibility that H2 causes structural changes in proteins via hydrate water changes.
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Stroke is a major cause of mortality and morbidity worldwide. Effective treatments are limited. Molecular hydrogen is emerging as a novel medical gas with therapeutic potential for various neurological diseases, including stroke. We reviewed the experimental and clinical findings of the effects of molecular hydrogen therapy in stroke patients and models. The underlying neuroprotective mechanisms aganist stroke pathology were also discussed.
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Aberrant redox-sensitive reactions and accumulation of oxidative damage can impair body functions and contribute to the development of various pathologies and aging. Although antioxidant substances have long been recognized as a measure of alleviating oxidative stress and restoring redox balance, the arsenal of effective means of preventing the development of various disorders is still limited. There is an emerging field that utilizes molecular hydrogen (H2 ) as a scavenger of free radicals and reactive oxygen species (ROS). Among the remarkable characteristics of H2 is its ability to counteract harmful effects of hydroxyl radical and peroxynitrite without affecting activity of functionally important ROS, such as hydrogen peroxide and nitric oxide. The beneficial effects of H2 have been documented in numerous clinical studies and studies on animal models and cell cultures. However, the established scavenging activity of H2 can only partially explain its beneficial effects, because the effects are achieved at very low concentrations of H2 . Given the rate of H2 diffusion, such low concentrations may not be sufficient to scavenge continuously generated ROS. H2 can also act as a signaling molecule and induce defense responses. However, the exact targets and mechanism(s) by which H2 exerts these effects are unknown. Here we analyzed both positive and negative effects of the endogenous H2 , identified the redox-sensitive components of the pathways affected by molecular hydrogen, and also discussed a potential role of molecular hydrogen in regulating cellular redox.
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Radiation-induced lung injury is characterized by an acute pneumonia phase followed by a fibrotic phase. At the time of irradiation, a rapid, short-lived burst of reactive oxygen species (ROS) such as hydroxyl radicals (•OH) occurs, but chronic radiation-induced lung injury may occur due to excess ROS such as H2O2 , O2•− , ONOO− , and •OH. Molecular hydrogen (H2 ) is an efficient antioxidant that quickly diffuses cell membranes, reduces ROS such as •OH and ONOO− , and suppresses damage caused by oxidative stress in various organs. In 2011, through the evaluation of electron-spin resonance and fluorescent indicator signals, we had reported that H2 can eliminate •OH and can protect against oxidative stress-related apoptotic damage induced by irradiation of cultured lung epithelial cells. We had explored for the first time the radioprotective effects of H2 treatment on acute and chronic radiation-induced lung damage in mice by inhaled H2 gas (for acute) and imbibed H2 -enriched water (for chronic). Thus, we had proposed that H2 be considered a potential radioprotective agent. Recent publications have shown that H2 directly neutralizes highly reactive oxidants and indirectly reduces oxidative stress by regulating the expression of various genes. By regulating gene expression, H2 functions as an anti-inflammatory and anti-apoptotic molecule and promotes energy metabolism. The increased evidence obtained from cultured cells or animal experiments reveal a putative place for H2 treatment and its radioprotective effect clinically. This review focuses on major scientific advances of in the treatment of H2 as a new class of radioprotective agents.
Chapter
Hydrogen-rich water (HRW) supresses the development of the diseases caused by oxidative stress such as diabetes, cancer, arteriosclerosis, and neurodegenerative diseases. It also prevents the side effects caused by hemodialysis and anti-cancer drugs. The active species in this water are hydrogen molecules and atoms. The antioxidant, antiapoptic, and anti-inflammatory properties of HRW come from the presence of the active hydrogen atoms. They scavenge for reactive oxygen species (ROS), which cause oxidative stress-related diseases. The mechanism through which the scavenging of ROS occurs is not yet fully understood. Therefore, it is advisable to be cautious when administering HRW to patients.
Article
Bronchopulmonary dysplasia (BPD) is characterized by developmental arrest of the alveolar tissue. Oxidative stress is causally associated with development of BPD. The effects of hydrogen have been reported in a wide range of disease models and human diseases especially caused by oxidative stress. We made a rat model of BPD by injecting lipopolysaccharide (LPS) into the amniotic fluid at E16.5. The mother started drinking hydrogen-rich water from E9.5 and also while feeding milk. Hydrogen normalized LPS-induced abnormal enlargement of alveoli at P7 and P14. LPS increased staining for nitrotyrosine and 8-OHdG of the lungs, and hydrogen attenuated the staining. At P1, LPS treatment decreased expressions of genes for FGFR4, VEGFR2, and HO-1 in the lungs, and hydrogen increased expressions of these genes. In contrast, LPS treatment and hydrogen treatment had no essential effect on the expression of SOD1. Inflammatory marker proteins of TNFα and IL-6 were increased by LPS treatment, and hydrogen suppressed them. Treatment of A549 human lung adenocarcinoma epithelial cells with 10% hydrogen gas for 24 hr decreased production of reactive oxygen species in both LPS-treated and untreated cells. Lack of any known adverse effects of hydrogen makes hydrogen a promising therapeutic modality for BPD. Pediatr Pulmonol. © 2016 Wiley Periodicals, Inc.
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The small GTPase Rac functions as a molecular switch in several important cellular events including cytoskeletal reorganization and activation of the phagocyte NADPH oxidase, the latter of which leads to production of superoxide, a precursor of microbicidal oxidants. During formation of the active oxidase complex at the membrane, the GTP-bound Rac appears to interact with the N-terminal region of p67(phox), another indispensable activator that translocates from the cytosol upon phagocyte stimulation. Here we show that the p67(phox) N terminus lacks the CRIB motif, a well known Rac target, but contains four tetratricopeptide repeat (TPR) motifs with highly alpha-helical structure. Disruption of any of the N-terminal three TPRs, but the last one, results in defective interaction with Rac, while all the four are required for the NADPH oxidase activation. We also find that Arg-102 in the third repeat is likely involved in binding to Rac via an ionic interaction, and that replacement of this residue with Glu completely abrogates the capability of activating the oxidase both in vivo and in vitro. Thus the TPR motifs of p67(phox) are packed to function as a Rac target, thereby playing a crucial role in the active oxidase complex formation.
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The Fc epsilonRI complex forms a high-affinity cell-surface receptor for the Fc region of antigen-specific immunoglobulin E (IgE) molecules. Fc epsilonRI is multimeric and is a member of a family of related antigen/Fc receptors which have conserved structural features and similar roles in initiating intracellular signalling cascades. In humans, Fc epsilonRI controls the activation of mast cells and basophils, and participates in IgE-mediated antigen presentation. Multivalent antigens bind and crosslink IgE molecules held at the cell surface by Fc epsilonRI. Receptor aggregation induces multiple signalling pathways that control diverse effector responses. These include the secretion of allergic mediators and induction of cytokine gene transcription, resulting in secretion of molecules such as interleukin-4, interleukin-6, tumour-necrosis factor-alpha and granulocyte-macrophage colony-stimulating factor. Fc epsilonRI is therefore central to the induction and maintenance of an allergic response and may confer physiological protection in parasitic infections.
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FcepsilonRI signaling in rat basophilic leukemia cells depends on phosphatidylinositol 3-kinase (PI3-kinase) and the small GTPase Rac. Here, we studied the functional relationship among PI3-kinase, its effector protein kinase B (PKB), and Rac using inhibitors of PI3-kinase and toxins inhibiting Rac. Wortmannin, an inhibitor of PI3-kinase, blocked FcepsilonRI-mediated tyrosine phosphorylation of phospholipase Cgamma, inositol phosphate formation, calcium mobilization, and secretion of hexosaminidase. Similarly, Clostridium difficile toxin B, which inactivates all Rho GTPases including Rho, Rac and Cdc42, and Clostridium sordellii lethal toxin, which inhibits Rac (possibly Cdc42) but not Rho, blocked these responses. Stimulation of the FcepsilonRI receptor induced a rapid increase in the GTP-bound form of Rac. Whereas toxin B inhibited the Rac activation, PI3-kinase inhibitors (wortmannin and LY294002) had no effect on activation of Rac. In line with this, wortmannin had no effect on tyrosine phosphorylation of the guanine nucleotide exchange factor Vav. Wortmannin, toxin B, and lethal toxin inhibited phosphorylation of PKB on Ser(473). Similarly, translocation of the pleckstrin homology domain of PKB tagged with the green fluorescent protein to the membrane, which was induced by activation of the FcepsilonRI receptor, was blocked by inhibitors of PI3-kinase and Rac inactivation. Our results indicate that in rat basophilic leukemia cells Rac and PI3-kinase regulate PKB and suggest that Rac is functionally located upstream and/or parallel of PI3-kinase/PKB in FcepsilonRI signaling.
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Activation of the superoxide-producing phagocyte NADPH oxidase, crucial in host defense, requires the cytosolic proteins p67(phox) and p47(phox). They translocate to the membrane upon cell stimulation and activate flavocytochrome b(558), the membrane-integrated catalytic core of this enzyme system. The activators p67(phox) and p47(phox) form a ternary complex together with p40(phox), an adaptor protein with unknown function, comprising the PX/PB2, SH3 and PC motif- containing domains: p40(phox) associates with p67(phox) via binding of the p40(phox) PC motif to the p67(phox) PB1 domain, while p47(phox) directly interacts with p67(phox) but not with p40(phox). Here we show that p40(phox) enhances membrane translocation of p67(phox) and p47(phox) in stimulated cells, which leads to facilitated production of superoxide. The enhancement cannot be elicited by a mutant p40(phox) carrying the D289A substitution in PC or a p67(phox) with the K355A substitution in PB1, each being defective in binding to its respective partner. Thus p40(phox) participates in activation of the phagocyte oxidase by regulating membrane recruitment of p67(phox) and p47(phox) via the PB1-PC interaction with p67(phox).
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Protein-phosphoinositide interaction participates in targeting proteins to membranes where they function correctly and is often modulated by phosphorylation of lipids. Here we show that protein phosphorylation of p47(phox), a cytoplasmic activator of the microbicidal phagocyte oxidase (phox), elicits interaction of p47(phox) with phosphoinositides. Although the isolated phox homology (PX) domain of p47(phox) can interact directly with phosphoinositides, the lipid-binding activity of this protein is normally suppressed by intramolecular interaction of the PX domain with the C-terminal Src homology 3 (SH3) domain, and hence the wild-type full-length p47(phox) is incapable of binding to the lipids. The W263R substitution in this SH3 domain, abrogating the interaction with the PX domain, leads to a binding of p47(phox) to phosphoinositides. The findings indicate that disruption of the intramolecular interaction renders the PX domain accessible to the lipids. This conformational change is likely induced by phosphorylation of p47(phox), because protein kinase C treatment of the wild-type p47(phox) but not of a mutant protein with the S303304328A substitution culminates in an interaction with phosphoinositides. Furthermore, although the wild-type p47(phox) translocates upon cell stimulation to membranes to activate the oxidase, neither the kinase-insensitive p47(phox) nor lipid-binding-defective proteins, one lacking the PX domain and the other carrying the R90K substitution in this domain, migrates. Thus the protein phosphorylation-driven conformational change of p47(phox) enables its PX domain to bind to phosphoinositides, the interaction of which plays a crucial role in recruitment of p47(phox) from the cytoplasm to membranes and subsequent activation of the phagocyte oxidase.
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Earlier studies, including our own, revealed that activation of mast cells is accompanied by production of reactive oxygen species (ROS) that help to mediate the release of the inflammatory mediators, including histamine and eicosanoids. However, little is known about the mechanisms of ROS production, including the species of oxidants produced. In this study we show that in both the RBL-2H3 mast cell line and bone marrow-derived mast cells, FcepsilonRI cross-linking stimulates intracellular oxidative burst, including hydrogen peroxide (H(2)O(2)) production, as defined with the oxidant-sensitive dyes dichlorofluorescein and scopoletin and the selective scavenger ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one). The oxidative burst was observed immediately after stimulation and was most likely due to an NAD(P)H oxidase. Experiments using selective pharmacological inhibitors demonstrated that activation of tyrosine kinases and phosphatidylinositol-3-kinase is required for induction of the oxidative burst. Blockade of the oxidative burst by diphenyleneiodonium impaired the release of preformed granular mediators, such as histamine and beta-hexosaminidase, and the secretion of newly synthesized leukotriene C(4), whereas selective scavenging H(2)O(2) by ebselen impaired leukotriene C(4) secretion, but not degranulation. Sustained elevation of cytosolic calcium through store-operated calcium entry was totally abolished when ROS production was blocked. In contrast, selective depletion of H(2)O(2) caused a considerable decrease and delay of the calcium response. Finally, tyrosine phosphorylation of phospholipase Cgamma and the linker for activation of T cells, an event required for calcium influx, was suppressed by diphenyleneiodonium and ebselen. These studies demonstrate that activation of the intracellular oxidative burst is an important regulatory mechanism of mast cell responses.
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Acute oxidative stress induced by ischemia-reperfusion or inflammation causes serious damage to tissues, and persistent oxidative stress is accepted as one of the causes of many common diseases including cancer. We show here that hydrogen (H(2)) has potential as an antioxidant in preventive and therapeutic applications. We induced acute oxidative stress in cultured cells by three independent methods. H(2) selectively reduced the hydroxyl radical, the most cytotoxic of reactive oxygen species (ROS), and effectively protected cells; however, H(2) did not react with other ROS, which possess physiological roles. We used an acute rat model in which oxidative stress damage was induced in the brain by focal ischemia and reperfusion. The inhalation of H(2) gas markedly suppressed brain injury by buffering the effects of oxidative stress. Thus H(2) can be used as an effective antioxidant therapy; owing to its ability to rapidly diffuse across membranes, it can reach and react with cytotoxic ROS and thus protect against oxidative damage.
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We have reported that hydrogen (H(2)) acts as an efficient antioxidant by gaseous rapid diffusion. When water saturated with hydrogen (hydrogen water) was placed into the stomach of a rat, hydrogen was detected at several microM level in blood. Because hydrogen gas is unsuitable for continuous consumption, we investigated using mice whether drinking hydrogen water ad libitum, instead of inhaling hydrogen gas, prevents cognitive impairment by reducing oxidative stress. Chronic physical restraint stress to mice enhanced levels of oxidative stress markers, malondialdehyde and 4-hydroxy-2-nonenal, in the brain, and impaired learning and memory, as judged by three different methods: passive avoidance learning, object recognition task, and the Morris water maze. Consumption of hydrogen water ad libitum throughout the whole period suppressed the increase in the oxidative stress markers and prevented cognitive impairment, as judged by all three methods, whereas hydrogen water did not improve cognitive ability when no stress was provided. Neural proliferation in the dentate gyrus of the hippocampus was suppressed by restraint stress, as observed by 5-bromo-2'-deoxyuridine incorporation and Ki-67 immunostaining, proliferation markers. The consumption of hydrogen water ameliorated the reduced proliferation although the mechanistic link between the hydrogen-dependent changes in neurogenesis and cognitive impairments remains unclear. Thus, continuous consumption of hydrogen water reduces oxidative stress in the brain, and prevents the stress-induced decline in learning and memory caused by chronic physical restraint. Hydrogen water may be applicable for preventive use in cognitive or other neuronal disorders.
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Kinetic data for the radicals H⋅ and ⋅OH in aqueous solution,and the corresponding radical anions, ⋅O− and eaq−, have been critically pulse radiolysis, flash photolysis and other methods. Rate constants for over 3500 reaction are tabulated, including reaction with molecules, ions and other radicals derived from inorganic and organic solutes.
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The FcɛRI complex forms a high-affinity cell-surface receptor for the Fc region of antigen-specific immunoglobulin E (IgE) molecules. FcɛRI is multimeric and is a member of a family of related antigen/Fc receptors which have conserved structural features and similar roles in initiating intracellular signalling cascades. In humans, FcɛRI controls the activation of mast cells and basophils, and participates in IgE-mediated antigen presentation. Multivalent antigens bind and crosslink IgE molecules held at the cell surface by FcɛRI. Receptor aggregation induces multiple signalling pathways that control diverse effector responses. These include the secretion of allergic mediators and induction of cytokine gene transcription, resulting in secretion of molecules such as interleukin-4, interleukin-6, tumour-necrosis factor-α and granulocyte-macrophage colony-stimulating factor. FcɛRI is therefore central to the induction and maintenance of an allergic response and may confer physiological protection in parasitic infections.
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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.
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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.
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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.
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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.
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The major side-effect of treatment with alpha-glucosidase inhibitors, flatulence, occurs when undigested carbohydrates are fermented by colonic bacteria, resulting in gas formation. We propose that the cardiovascular benefits of alpha-glucosidase inhibitors are partly attributable to their ability to neutralise oxidative stress via increased production of H(2) in the gastrointestinal tract. Acarbose, which is an alpha-glucosidase inhibitor, markedly increased H(2) production, with a weaker effect on methane production. Our hypothesis is based on our recent discovery that H(2) acts as a unique antioxidant, and that when inhaled or taken orally as H(2)-dissolved water it ameliorates ischaemia-reperfusion injury and atherosclerosis development.
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Molecular hydrogen serves as an antioxidant that reduces hydroxyl radicals, but not the other reactive oxygen and nitrogen species. In the past year, molecular hydrogen has been reported to prevent or ameliorate eight diseases in rodents and one in human associated with oxidative stress. In Parkinson's disease, mitochondrial dysfunction and the associated oxidative stress are major causes of dopaminergic cell loss in the substantia nigra. We examined effects of approximately 50%-saturated molecular hydrogen in drinking water before or after the stereotactic surgery on 6-hydroxydopamine-induced nigrostrital degeneration in a rat model of Parkinson's disease. Methamphetamine-induced behavioral analysis showed that molecular hydrogen prevented both the development and progression of the nigrostrital degeneration. Tyrosine hydroxylase staining of the substantia nigra and striatum also demonstrated that pre- and post-treatment with hydrogen prevented the dopaminergic cell loss. Our studies suggest that hydrogen water is likely able to retard the development and progression of Parkinson's disease.
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Oxidative stress is recognized widely as being associated with various disorders including diabetes, hypertension, and atherosclerosis. It is well established that hydrogen has a reducing action. We therefore investigated the effects of hydrogen-rich water intake on lipid and glucose metabolism in patients with either type 2 diabetes mellitus (T2DM) or impaired glucose tolerance (IGT). We performed a randomized, double-blind, placebo-controlled, crossover study in 30 patients with T2DM controlled by diet and exercise therapy and 6 patients with IGT. The patients consumed either 900 mL/d of hydrogen-rich pure water or 900 mL of placebo pure water for 8 weeks, with a 12-week washout period. Several biomarkers of oxidative stress, insulin resistance, and glucose metabolism, assessed by an oral glucose tolerance test, were evaluated at baseline and at 8 weeks. Intake of hydrogen-rich water was associated with significant decreases in the levels of modified low-density lipoprotein (LDL) cholesterol (ie, modifications that increase the net negative charge of LDL), small dense LDL, and urinary 8-isoprostanes by 15.5% (P < .01), 5.7% (P < .05), and 6.6% (P < .05), respectively. Hydrogen-rich water intake was also associated with a trend of decreased serum concentrations of oxidized LDL and free fatty acids, and increased plasma levels of adiponectin and extracellular-superoxide dismutase. In 4 of 6 patients with IGT, intake of hydrogen-rich water normalized the oral glucose tolerance test. In conclusion, these results suggest that supplementation with hydrogen-rich water may have a beneficial role in prevention of T2DM and insulin resistance.
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Mast cells can function as effector and immunoregulatory cells in immunoglobulin E-associated allergic disorders, as well as in certain innate and adaptive immune responses. This review focuses on exciting new developments in the field of mast cell biology published in the past year. We highlight advances in the understanding of FcvarepsilonRI-mediated signaling and mast cell-activation events, as well as in the use of genetic models to study mast cell function in vivo. Finally, we discuss newly identified functions for mast cells or individual mast cell products, such as proteases and interleukin 10, in host defense, cardiovascular disease and tumor biology and in settings in which mast cells have anti-inflammatory or immunosuppressive functions.
Article
Ischemia/reperfusion (I/R) injury during small intestinal transplantation (SITx) frequently causes complications including dysmotility, inflammation and organ failure. Recent evidence indicates hydrogen inhalation eliminates toxic hydroxyl radicals. Syngeneic, orthotopic SITx was performed in Lewis rats with 3 h of cold ischemic time. Both donor and recipient received perioperative air or 2% hydrogen inhalation. SITx caused a delay in gastrointestinal transit and decreased jejunal circular muscle contractile activity 24 h after surgery. Hydrogen treatment resulted in significantly improved gastrointestinal transit, as well as jejunal smooth muscle contractility in response to bethanechol. The transplant induced upregulation in the inflammatory mediators CCL2, IL-1 beta, IL-6 and TNF-alpha were mitigated by hydrogen. Hydrogen significantly diminished lipid peroxidation compared to elevated tissue malondialdehyde levels in air-treated grafts demonstrating an antioxidant effect. Histopathological mucosal erosion and increased gut permeability indicated a breakdown in posttransplant mucosal barrier function which was significantly attenuated by hydrogen treatment. In recipient lung, hydrogen treatment also resulted in a significant abatement in inflammatory mRNA induction and reduced neutrophil recruitment. Hydrogen inhalation significantly ameliorates intestinal transplant injury and prevents remote organ inflammation via its antioxidant effects. Administration of perioperative hydrogen gas may be a potent and clinically applicable therapeutic strategy for intestinal I/R injury.
Article
The novel data indicating the role of carbon monoxide as an eventual putative neurotransmitter are discussed. The perspectives of further studies are delineated. Actually following scarce points suggest that carbon monoxide (CO) my be eventually neurotransmitter: an uneven distribution in the nervous system of heme oxygenase, which produces CO; the generation of long term potentiation in hippocampus; possible mediation of release of hypothalamic factors; eventual signalling role of CO in immune system.
Article
In this study, we measured the antiallergic activities of ginsenosides isolated from the root of Panax ginseng ( Araliaceae), and of their metabolites, as produced by human intestinal bacteria. Compound K, which was identified as a main metabolite, had the most potent inhibitory activity on β-hexosaminidase release from RBL-2H3 cells and on the PCA reaction. The inhibitory activity of compound K was more potent than that of disodium cromoglycate, one of the commercial anti-allergic drugs. This compound demonstrated a membrane stabilizing action on differential scanning calorimetry. However, compound K did not inhibit the activation of hyaluronidase and did not scavenge active oxygen. These results suggest that the antiallergic action of compound K originates from its cell membrane stabilizing activity and that the ginsenosides of ginseng are prodrugs with extensive antiallergic properties. Abbreviations compound K:20-O-β-D-glucopyranosyl-20(S)-protopanaxadiol DNP:dinitrophenol DSCG:disodium cromoglycate DPPC:dipalmitoylphosphatidylcholine DPPH:1,1-diphenyl-2-picrylhydrazyl HSA:human serum albumin IC50:50% inhibitory concentration EC50:50% effective concentration XOD:xanthine oxidase ICR:Institute of Cancer Research PBS:phosphate buffered saline PCA:passive cutaneous anaphylaxis RAW264.7:mouse monocyte leukemiaRBL-2H3: rat basophil leukemia SD:Sprague-Dawley
Article
All cells seem to produce oxygen radicals. Recent results suggest that small nontoxic amounts of these radicals are released by various cell types in response to stimulation with tumour necrosis factor (TNF), interleukin 1 (IL-1) and phorbol esters, all of which activate a cytoplasmic form of the transcription factor NF-kappa B by releasing an inhibitory protein subunit. Activation is inhibited by agents that remove oxygen radicals, and mimicked by exposure to mild oxidant stress. This article proposes that oxygen radicals act as second messengers for a variety of agents, including the immunomodulatory cytokines TNF and IL-1, in at least one type of regulatory pathway activating NF-kappa B.
Article
Nitric oxide (NO) and carbon monoxide (CO) synthesized from L-arginine by NO synthase and from heme by heme oxygenase, respectively, are the well-known neurotransmitters and are also involved in the regulation of vascular tone. Recent studies suggest that hydrogen sulfide (H(2)S) is the third gaseous mediator in mammals. H(2)S is synthesized from L-cysteine by either cystathionine beta-synthase (CBS) or cystathionine gamma-lyase (CSE), both using pyridoxal 5'-phosphate (vitamin B(6)) as a cofactor. H(2)S stimulates ATP-sensitive potassium channels (K(ATP)) in the vascular smooth muscle cells, neurons, cardiomyocytes and pancreatic beta-cells. In addition, H(2)S may react with reactive oxygen and/or nitrogen species limiting their toxic effects but also, attenuating their physiological functions, like nitric oxide does. In contrast to NO and CO, H(2)S does not stimulate soluble guanylate cyclase. H(2)S is involved in the regulation of vascular tone, myocardial contractility, neurotransmission, and insulin secretion. H(2)S deficiency was observed in various animal models of arterial and pulmonary hypertension, Alzheimer's disease, gastric mucosal injury and liver cirrhosis. Exogenous H(2)S ameliorates myocardial dysfunction associated with the ischemia/reperfusion injury and reduces the damage of gastric mucosa induced by anti-inflammatory drugs. On the other hand, excessive production of H(2)S may contribute to the pathogenesis of inflammatory diseases, septic shock, cerebral stroke and mental retardation in patients with Down syndrome, and reduction of its production may be of potential therapeutic value in these states.
Article
We have recently showed that molecular hydrogen has great potential for selectively reducing cytotoxic reactive oxygen species, such as hydroxyl radicals, and that inhalation of hydrogen gas decreases cerebral infarction volume by reducing oxidative stress [I. Ohsawa, M. Ishikawa, K. Takahashi, M. Watanabe, K. Nishimaki, K. Yamagata, K.-I. 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 show that the inhalation of hydrogen gas is applicable for hepatic injury caused by ischemia/reperfusion, using mice. The portal triad to the left lobe and the left middle lobe of the liver were completely occluded for 90min, followed by reperfusion for 180min. Inhalation of hydrogen gas (1-4%) during the last 190min suppressed hepatic cell death, and reduced levels of serum alanine aminotransferase and hepatic malondialdehyde. In contrast, helium gas showed no protective effect, suggesting that the protective effect by hydrogen gas is specific. Thus, we propose that inhalation of hydrogen gas is a widely applicable method to reduce oxidative stress.
Article
Nitric oxide (NO) has earned the reputation of being a signaling mediator with many diverse and often opposing biological activities. The diversity in response to this simple diatomic molecule comes from the enormous variety of chemical reactions and biological properties associated with it. In the past few years, the importance of steady-state NO concentrations has emerged as a key determinant of its biological function. Precise cellular responses are differentially regulated by specific NO concentration. We propose five basic distinct concentration levels of NO activity: cGMP-mediated processes ([NO]<1-30 nM), Akt phosphorylation ([NO] = 30-100 nM), stabilization of HIF-1alpha ([NO] = 100-300 nM), phosphorylation of p53 ([NO]>400 nM), and nitrosative stress (1 microM). In general, lower NO concentrations promote cell survival and proliferation, whereas higher levels favor cell cycle arrest, apoptosis, and senescence. Free radical interactions will also influence NO signaling. One of the consequences of reactive oxygen species generation is to reduce NO concentrations. This antagonizes the signaling of nitric oxide and in some cases results in converting a cell-cycle arrest profile to a cell survival profile. The resulting reactive nitrogen species that are generated from these reactions can also have biological effects and increase oxidative and nitrosative stress responses. A number of factors determine the formation of NO and its concentration, such as diffusion, consumption, and substrate availability, which are referred to as kinetic determinants for molecular target interactions. These are the chemical and biochemical parameters that shape cellular responses to NO. Herein we discuss signal transduction and the chemical biology of NO in terms of the direct and indirect reactions.
Article
Inhalation of hydrogen (H(2)) gas has been demonstrated to limit the infarct volume of brain and liver by reducing ischemia-reperfusion injury in rodents. When translated into clinical practice, this therapy must be most frequently applied in the treatment of patients with acute myocardial infarction, since angioplastic recanalization of infarct-related occluded coronary artery is routinely performed. Therefore, we investigate whether H(2) gas confers cardioprotection against ischemia-reperfusion injury in rats. In isolated perfused hearts, H(2) gas enhances the recovery of left ventricular function following anoxia-reoxygenation. Inhaled H(2) gas is rapidly transported and can reach 'at risk' ischemic myocardium before coronary blood flow of the occluded infarct-related artery is reestablished. Inhalation of H(2) gas at incombustible levels during ischemia and reperfusion reduces infarct size without altering hemodynamic parameters, thereby preventing deleterious left ventricular remodeling. Thus, inhalation of H(2) gas is promising strategy to alleviate ischemia-reperfusion injury coincident with recanalization of coronary artery.
Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals Inhalation of hydrogen gas suppresses hepatic injury caused by ischemia/reperfusion through reducing oxidative stress
  • K Yamagata
  • Y Katsura
  • S Katayama
  • S Asoh
  • S Ohta Fukuda
  • M Asoh
  • Y Ishikawa
  • I Yamamoto
  • S Ohsawa
  • Ohta
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. [4] K. Fukuda, S. Asoh, M. Ishikawa, Y. Yamamoto, I. Ohsawa, S. Ohta, Inhalation of hydrogen gas suppresses hepatic injury caused by ischemia/reperfusion through reducing oxidative stress, Biochem Biophys Res Commun 361 (2007) 670-674. [5] K. Hayashida, M. Sano, I. Ohsawa, K. Shinmura, K. Tamaki, K. Kimura, J.
New developments in mast cell biology
  • Kalesnikoff
J. Kalesnikoff, S.J. Galli, New developments in mast cell biology, Nat Immunol 9 (2008) 1215-1223.
hippocampus-dependent learning tasks during chronic physical restraint in mice
  • J Cai
  • Z Kang
  • W W Liu
  • X Luo
  • S Qiang
  • J H Zhang
  • S Ohta
  • X Sun
J. Cai, Z. Kang, W.W. Liu, X. Luo, S. Qiang, J.H. Zhang, S. Ohta, X. Sun, W. hippocampus-dependent learning tasks during chronic physical restraint in mice, Neuropsychopharmacology 34 (2009) 501-508.