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Hydrogen therapy attenuates irradiation-induced lung damage by reducing oxidative stress

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Abstract

Molecular hydrogen (H(2)) is an efficient antioxidant that diffuses rapidly across cell membranes, reduces reactive oxygen species (ROS), such as hydroxyl radicals and peroxynitrite, and suppresses oxidative stress-induced injury in several organs. ROS have been implicated in radiation-induced damage to lungs. Because prompt elimination of irradiation-induced ROS should protect lung tissue from damaging effects of irradiation, we investigated the possibility that H(2) could serve as a radioprotector in the lung. Cells of the human lung epithelial cell line A549 received 10 Gy irradiation with or without H(2) treatment via H(2)-rich PBS or medium. We studied the possible radioprotective effects of H(2) by analyzing ROS and cell damage. Also, C57BL/6J female mice received 15 Gy irradiation to the thorax. Treatment groups inhaled 3% H(2) gas and drank H(2)-enriched water. We evaluated acute and late-irradiation lung damage after H(2) treatment. H(2) reduced the amount of irradiation-induced ROS in A549 cells, as shown by electron spin resonance and fluorescent indicator signals. H(2) also reduced cell damage, measured as levels of oxidative stress and apoptotic markers, and improved cell viability. Within 1 wk after whole thorax irradiation, immunohistochemistry and immunoblotting showed that H(2) treatment reduced oxidative stress and apoptosis, measures of acute damage, in the lungs of mice. At 5 mo after irradiation, chest computed tomography, Ashcroft scores, and type III collagen deposition demonstrated that H(2) treatment reduced lung fibrosis (late damage). This study thus demonstrated that H(2) treatment is valuable for protection against irradiation lung damage with no known toxicity.

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... A burst of inflammatory cytokines induced by IR stimulates the progression of RILF, and among these cytokines, transforming growth factor-β1 (TGF-β1) plays a critical role in the pathogenesis and development of RILF [8,9]. Excessive Reactive oxygen species (ROS), induced by IR, were reported to induce pulmonary injury, inflammation and fibrosis in RILF, and ROSinduced oxidative damage is considered to be a critical origin of inflammatory events involved in RILF [10,11]. ...
... ROS induced by IR were reported to induce pulmonary injury, inflammation and fibrosis in RILF [10,11]. ROS-induced oxidative damage is considered to be a critical origin of inflammatory events involved in RILF. ...
... The excessive accumulation of ROS induced by IR causes oxidative damage in lung tissues. ROS induced by IR were reported to induce pulmonary injury, inflammation and fibrosis in RILF [10,11]. ROS-induced oxidative damage is considered to be a critical origin of inflammatory events involved in RILF. ...
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Background: Radiation-induced lung fibrosis (RILF) is a severe and life-threatening complication of thoracic radiotherapy. Cell death is the key issue in RILF. Ferroptosis is a form programmed cell death implicated in the pathologies of inflammation. This study aimed to investigate the role of ferroptosis in RILF, and the effectiveness and the potential underlying mechanism of ferroptosis inhibitor on RILF. Methods: Immunofluorescence, western blot and RT-PCR assays were performed to examine the ferroptosis maker glutathione peroxidase 4 (GPX4) in a mice RILF model. The lung tissue sections were stained with hematoxylin and eosin (H&E), Masson trichrome staining and Sirius-Red staining to evaluate the histopathological changes in RILF mice. Reactive oxygen species (ROS) and hydroxyproline (HYP) in lungs were measured by the relevant kits. The serum levels of inflammatory cytokines (TNF-α, IL-6, IL-10, and TGF-β1) were measured with Elisa. The protein and mRNA levels of GPX4, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), hemeoxygenase-1 (HO1) and quinone oxidoreductase 1 (NQO1) in lungs were examined by western blot and RT-PCR. Results: GPX4 levels of the irradiated lungs were significantly down-regulated than the groups with no irradiation, and the ferroptosis inhibitor, liproxstatin-1, increased GPX4 levels significantly in RILF mice. Treatment with liproxstatin-1 lowered the Szapiel and Ashcroft scores significantly, down-regulated the levels of ROS and HYP in lungs and reduced the serum inflammatory cytokines levels in RILF mice. The protein and the mRNA levels of Nrf2, HO1 and NQO1 were up-regulated by liproxsratin-1 in RILF. Conclusions: Our data suggested that ferroptosis played a critical role in RILF, ferroptosis inhibitor liproxstatin-1 alleviated RILF via down-regulation of TGF-β1 by the activation of Nrf2 pathway. The effectiveness of ferroptosis inhibition on RILF provides a novel therapeutic target for RILF.
... As for the radioprotective effects of H 2 in animal models, protective effects on cognitive function, the immune system, lungs, heart, digestive organs, hematopoietic organs, testis, skin, and cartilage disorders have been reported [36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53]. An inhibitory effect on thymic lymphoma caused by radiation has also been reported [54]. ...
... [40] Lung damage A549 cells H 2 -rich PBS suppressed ROS production, and improved oxidative stress and apoptosis markers. [41] Mice H 2 gas inhibited not only acute lung damage, but also chronic lung damage. [41] Myocardial damage Mice H 2 -rich water protected against radiation-induced myocardium damage. ...
... [41] Mice H 2 gas inhibited not only acute lung damage, but also chronic lung damage. [41] Myocardial damage Mice H 2 -rich water protected against radiation-induced myocardium damage. [42] Rats H 2 -rich water protected against radiation-induced myocardium damage. ...
Article
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Although ionizing radiation (radiation) is commonly used for medical diagnosis and cancer treatment, radiation-induced damages cannot be avoided. Such damages can be classified into direct and indirect damages, caused by the direct absorption of radiation energy into DNA and by free radicals, such as hydroxyl radicals (�OH), generated in the process of water radiolysis. More specifically, radiation damage concerns not only direct damages to DNA, but also secondary damages to non-DNA targets, because low-dose radiation damage is mainly caused by these indirect effects. Molecular hydrogen (H2) has the potential to be a radioprotective agent because it can selectively scavenge �OH, a reactive oxygen species with strong oxidizing power. Animal experiments and clinical trials have reported that H2 exhibits a highly safe radioprotective effect. This paper reviews previously reported radioprotective effects of H2 and discusses the mechanisms of H2, not only as an antioxidant, but also in intracellular responses including anti-inflammation, anti-apoptosis, and the regulation of gene expression. In doing so, we demonstrate the prospects of H2 as a novel and clinically applicable radioprotective agent.
... Moreover, H 2 has antifibrosis effects. It was found that breathing 4% H 2 significantly delayed the progression of pulmonary fibrosis in a radiation induced pulmonary fibrosis model [19]. They confirmed that H 2 significantly reduced the fibrotic lesions in the lungs of mice. ...
... Oxidative Medicine and Cellular Longevity and improved the skin pathology of mice. Fibrosis has been proven playing an important role in the development of cGVHD disease [19]. Fibrosis leads to organ failure in patients with cGVHD, including scleroderma, bronchitis obliterans, and liver cirrhosis. ...
... In the current study, we found that in the skin tissues of mice, the expression levels of HO-1 and NQO1 proteins in the hydrogen group were significantly lower than those in the nonhydrogen cGVHD group. Many studies have confirmed that molecular hydrogen can directly react with oxygen free radicals such as hydroxyl radicals, thereby reducing oxidative damage [13,19]. We believed that molecular hydrogen may reduce the oxidative stress level in cGVHD mice, thereby reducing the expression levels of HO-1 and NQO1 proteins in cGVHD mice. ...
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Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important treatment option for various hematopoietic diseases and certain hereditary diseases. Chronic graft-versus-host disease (cGVHD) has become the main life-threatening complication and cause of death in later stage postallo-HSCT. Current treatment options for cGVHD are limited. Hydrogen gas (H2) has been demonstrated that has antioxidative, anti-inflammatory, and antifibrosis effects. The aim of this study was to confirm whether oral administration hydrogen-rich water exerted therapeutic effects on a scleroderma cGVHD mouse model and tried to explain the mechanism underly it. Methods: A mouse cGVHD model was established by haploidentical bone marrow transplantation. To evaluate therapeutic effects of H2 on cGVHD, survival rate, changes in clinical scores, and skin pathologic characteristics of cGVHD mice were observed. To evaluate its therapeutic mechanism, we detected the expression levels of antioxidative enzymes heme oxygenase-1(HO-1) and NAD (P)H: quinone acceptor oxidoreductase 1(NQO1) in skin homogenates. We also detected the expression level of the apoptotic protein caspase-3 in skin homogenates. Results: 1-month survival rate of cGVHD mice in the hydrogen group reached 93.3%, significantly higher than 66.7% in the nonhydrogen group (p < 0.05). Clinical score of cGVHD mice was improved by hydrogen-rich water at 96 days posttransplantation (2.2 versus 4.5, p < 0.05). The skin pathological condition of cGVHD mice was significantly improved by hydrogen-rich water. At 96 days posttransplantation, average skin pathological hematoxylin and eosin (HE) staining score in the hydrogen group was 1.05, which was significantly lower than 3.2 in the nonhydrogen group (p < 0.01). Average Masson staining score was 0.6 point in the hydrogen group, lower than 0.9 point in the nonhydrogen group (p < 0.05). Both the relative expression levels of HO-1 and NQO1 proteins in skin specimens of cGVHD mice in the hydrogen group were lower than that in the nonhydrogen group (2.47 versus 6.21 and 1.83 versus 3.59, p < 0.05). The relative expression level of caspase-3 protein in skin specimens of cGVHD mice increased to 7.17 on the 96th day after transplantation, significantly higher than 4.36 in the hydrogen group. Conclusion: In this study, we found that oral hydrogen-rich water improved the survival rate and clinical symptoms of cGVHD mice by antioxidant and antiapoptosis. This study would pave the way for further clinical study, which may provide a new treatment option for cGVHD.
... Inhaled H 2 suppresses oxidative stress-induced injury in several organs, such as ischaemia/reperfusion injury in the brain, 18 liver 19 and heart, 20 and irradiation-induced injury in the lungs. 21 Furthermore, continuous consumption of H 2 -rich water protects against oxidative damage, including manifestations of oxidative stress associated with diabetes in humans, 22 cisplatin-induced renal injury in mice, 23 naphthalene-evoked acute lung injury in mice 24 and non-alcoholic steatohepatitis 25,26 in animal models. ...
... H 2 -rich water was prepared using a previously described method. 21 Briefly, H 2 gas (purity > 99.999%; Iwatani) was dissolved in reverse osmosis water under high pressure (0.4 MPa) to a super-saturated level in a stainless steel tank (Unicontrols). During the preparation of H 2 -rich water, the H 2 concentration in the air was carefully monitored using a H 2 sensor with an alarm for safety. ...
... For lung analysis, we designated areas with intensities between −400 and −200 Hounsfield units as areas of abnormally high density. The ratioof an area of abnormally high density to the whole lung field was determined using LCT-200 system software and compared between control and bCII-injected mice with and without H 2 treatment.21 ...
Article
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Rheumatoid arthritis (RA)‐associated interstitial lung disease (ILD), a primary cause of mortality in patients with RA, has limited treatment options. A previously established RA model in D1CC transgenic mice aberrantly expressed major histocompatibility complex class II genes in joints, developing collagen II‐induced polyarthritis and anti‐cyclic citrullinated peptide antibodies and interstitial pneumonitis, similar to those in humans. Molecular hydrogen (H2) is an efficient antioxidant that permeates cell membranes and alleviates the reactive oxygen species‐induced injury implicated in RA pathogenesis. We used D1CC mice to analyse chronic lung fibrosis development and evaluate H2 treatment effects. We injected D1CC mice with type II collagen and supplied them with H2‐rich or control water until analysis. Increased serum surfactant protein D values and lung densities images were observed 10 months after injection. Inflammation was patchy within the perilymphatic stromal area, with increased 8‐hydroxy‐2ʹ‐deoxyguanosine‐positive cell numbers and tumour necrosis factor‐α, BAX, transforming growth factor‐β, interleukin‐6 and soluble collagen levels in the lungs. Inflammatory and fibrotic changes developed diffusely within the perilymphatic stromal area, as observed in humans. H2 treatment decreased these effects in the lungs. Thus, this model is valuable for studying the effects of H2 treatment and chronic interstitial pneumonia pathophysiology in humans. H2 appears to protect against RA‐ILD by alleviating oxidative stress.
... It means that low concentration hydrogen can be limited to deal with high reactive cytotoxic oxygen species and not to kill all the free radicals. Till now, hydrogen has been shown to have a therapeutic effect on over 170 different human diseases and animal models, including in antioxidant activity [1,[3][4][5][6][7][8][9], ischemia-reperfusion injury [2,[10][11][12][13][14], Parkinson's disease [15,16], cancer [17], retina [12], chondrocytes [7], diabetes disease [18], irradiation-induced lung damage [8], mitochondrial disease [9], and cardiac disease [13,19]. ...
... It means that low concentration hydrogen can be limited to deal with high reactive cytotoxic oxygen species and not to kill all the free radicals. Till now, hydrogen has been shown to have a therapeutic effect on over 170 different human diseases and animal models, including in antioxidant activity [1,[3][4][5][6][7][8][9], ischemia-reperfusion injury [2,[10][11][12][13][14], Parkinson's disease [15,16], cancer [17], retina [12], chondrocytes [7], diabetes disease [18], irradiation-induced lung damage [8], mitochondrial disease [9], and cardiac disease [13,19]. ...
... When hydrogen was focused on its biological effects in multiple diseases by scientists in recent years, the method of hydrogen applications is that we have to resolve it for adequately applying its antioxidant, anti-inflammatory, and antiapoptotic function for oxidative stress [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. This antioxidant effect of molecular hydrogen has been proved. ...
Chapter
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Oxygen sustains the lives of human a unique element. However, oxygen is unwanted and harmful when it is over tension to introduce oxygen-derived free radicals in the cells. Hydrogen and oxygen are both involved in the genesis of life that exists on Earth and metabolism in vivo, so it is not strange to exert a biological effect. Recently, scientists have found that hydrogen is an essential physiological regulatory function with antioxidant, anti-inflammatory, and antiapoptotic protective effects on cells. Using therapeutic hydrogen includes different delivery methods, such as inhalation of hydrogen gas, oral hydrogen water, and injection of hydrogen-saturated saline. In clinical applications, magnesium hydride hydrolysis instead of traditional metallic magnesium is effective in increasing the theoretical hydrogen storage capacity by two times. The hydrogen-water comes across as being an excellent choice to produce from magnesium hydride hydrolysis on-demand because its antioxidant activity cannot store.
... H 2 scavenged ·OH and protected against apoptotic damage related to oxidative stress induced by irradiation of cultured lung epithelial cells. In addition, inhalation of H 2 gas during irradiation and drinking H 2 -rich water after irradiation reduced lung tissue damage induced by oxidative stress in mice [16]. Moreover, oral intake of H 2 by drinking H 2 -rich water reduced tissue damage in animal models of cisplatin-induced toxicity in the kidney [17], anti-type II collagen antibody-induced arthritis [18], liver fibrogenesis [19], and lipopolysaccharide-induced sepsis [20]. ...
... Production of H 2 -rich water H 2 -rich water was prepared using a method described previously [16]. Briefly, H 2 gas (purity > 99.999%; Iwatani, Tokyo, Japan) was dissolved in reverse-osmosis water under high pressure (0.4 MPa) to a super-saturated level in a stainless steel tank (Unicontrols, Tokyo, Japan). ...
... The slices were analyzed with a microscope using an ×10 objective. Immunohistochemistry was performed using a previously described protocol (Histofine SAB-PO kit; Nichirei, Tokyo, Japan) [16]. Sections were stained with a rabbit polyclonal anti-CD3 antibody (1:200; Dako, Carpinteria, CA), a rat monoclonal anti-F4/80 antibody (clone CI-A3-1, 1:100; Novus Biologicals, Littleton, CO), a goat polyclonal anti-CCL2/MCP-1 antibody (1:50; Santa Cruz Biotechnology, Santa Cruz, CA), a rabbit polyclonal anti-Clara cell secretory protein (CCSP) antibody (1:500; EMD Millipore, Temecula, CA), a mouse monoclonal anti-IL-6 antibody (1:100; Leica, Wetzlar, Germany), or a mouse monoclonal anti-4-hydroxy-2-nonenal (4-HNE) antibody (1:20; Nikken SEIL, Shizuoka, Japan). ...
Article
Although inhibition of epidermal growth factor receptor (EGFR)-mediated cell signaling by the EGFR tyrosine kinase inhibitor gefitinib is highly effective against advanced non-small cell lung cancer, this drug might promote severe acute interstitial pneumonia. We previously reported that molecular hydrogen (H2) acts as a therapeutic and preventive anti-oxidant. Here, we show that treatment with H2 effectively protects the lungs of mice from severe damage caused by oral administration of gefitinib after intraperitoneal injection of naphthalene, the toxicity of which is related to oxidative stress. Drinking H2−rich water ad libitum mitigated naphthalene/gefitinib-induced weight loss and significantly improved survival, which was associated with a decrease in lung inflammation and inflammatory cytokines in the bronchoalveolar lavage fluid. Naphthalene decreased glutathione in the lung, increased malondialdehyde in the plasma, and increased 4-hydroxy-2-nonenal production in airway cells, all of which were mitigated by H2-rich water, indicating that the H2-rich water reverses cellular damage to the bronchial wall caused by oxidative stress. Finally, treatment with H2 did not interfere with the anti-tumor effects of gefitinib on a lung cancer cell line in vitro or on tumor-bearing mice in vivo. These results indicate that H2-rich water has the potential to improve quality of life during gefitinib therapy by mitigating lung injury without impairing anti-tumor activity.
... In vitro studies, Terasaki et al. [84] examined whether ·OH induced by IR can be mitigated by H 2 in living cells. For this purpose, they irradiated A549 cells and assessed cells for green fluorescence generated by oxidized HPF (a marker for oxidation by − ONOO and % OH) in PBS. ...
... In vivo studies, Terasaki et al. [84] used a mouse model with lung injury from irradiation to evaluate H 2 treatment through inhalation during the irradiation period; then drinking H 2 -enriched water after irradiation. During the acute phase of damage (within 1 week of the irradiation), mice with H 2 treatment showed significantly less amount of alveolar cells that were tested positive for TUNEL staining(markers of apoptosis) and 8-OH-dG. ...
Article
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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.
... upregulates the antiapoptotic factors B-cell lymphoma-2 (Bcl-2) and B-cell lymphoma-extra-large (Bcl-xl) [6]. Additionally, Terasaki and colleagues reported that H 2 can downregulate the gene expression of proapoptotic Bax and inhibit its translocation to mitochondria by an unknown mechanism [39]. H 2 can also inhibit apoptosis by activating the phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) and the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2-STAT3) signaling pathways in rats with myocardial ischemia-reperfusion injury (MIRI) [40,41], as well as downregulating the p38 MAPK signaling pathway in rat models with lipopolysaccharide-(LPS-) induced acute lung dysfunction [42] and cerebral ischemia-reperfusion injury (CIRI) [43]. ...
... In addition to treating atherosclerosis, H 2 reduces MIRI, which refers to a heart lesion that develops upon the resumption of the flow of oxygen-rich blood after a period of ischemia and which usually occurs during acute myocardial infarction or open-heart surgery [40,90]. A recent series of studies by Li et al. found that HW inhibited cardiomyocyte apoptosis by activating the PI3K/AKT and JAK2-STAT3 signaling pathways and can also reduce the level of oxidative stress in myocardial tissue by upregulating the expression of the nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway, which alleviated I/R injury in isolated rat hearts [39,40,91]. Other studies demonstrated that intraperitoneal injection of HW before reperfusion significantly decreased the concentration of malondialdehyde (MDA) and infarct size, as well as reducing myocardial 8-OHdG and the levels of TNF-α and IL-1β in an area at risk zones [92,93]. ...
Article
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H2 has shown anti-inflammatory and antioxidant ability in many clinical trials, and its application is recommended in the latest Chinese novel coronavirus pneumonia (NCP) treatment guidelines. Clinical experiments have revealed the surprising finding that H2 gas may protect the lungs and extrapulmonary organs from pathological stimuli in NCP patients. The potential mechanisms underlying the action of H2 gas are not clear. H2 gas may regulate the anti-inflammatory and antioxidant activity, mitochondrial energy metabolism, endoplasmic reticulum stress, the immune system, and cell death (apoptosis, autophagy, pyroptosis, ferroptosis, and circadian clock, among others) and has therapeutic potential for many systemic diseases. This paper reviews the basic research and the latest clinical applications of H2 gas in multiorgan system diseases to establish strategies for the clinical treatment for various diseases.
... Hydrogen inhalation therapy has been proven effective in mitigating in several animal models of lung injury including hyperoxic lung injury, hemorrhagic shock-induced lung injury, radiation-induced lung injury, and bronchial asthma [7,8,20,21]. Our study is the first to prove that hydrogen inhalation therapy effectively attenuates the decline of respiratory physiological function induced by bleomycin in a mouse model of persistent lung inflammation and fibrosis. ...
... In this study, we administered an air mixture with 3.2% hydrogen for 6 h daily beginning on the day of bleomycin administration and continuing for 21 days. Other investigations of inhaled hydrogen therapy have shown effective results with hydrogen concentrations of 2-4% [5,7,[20][21][22][23][24], and repeated inhalation was reported to be more effective than continuous inhalation in rat model of Parkinson's disease [25]. Because the endpoint of this study was to assess lung function during the fibrotic phase after lung injury, we targeted treatment during the proliferative phase of ARDS, which ordinary occurs 7 to 21 days after the onset of lung injury [1]. ...
Article
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Background Acute respiratory distress syndrome, which is caused by acute lung injury, is a destructive respiratory disorder caused by a systemic inflammatory response. Persistent inflammation results in irreversible alveolar fibrosis. Because hydrogen gas possesses anti-inflammatory properties, we hypothesized that daily repeated inhalation of hydrogen gas could suppress persistent lung inflammation by inducing functional changes in macrophages, and consequently inhibit lung fibrosis during late-phase lung injury. Methods To test this hypothesis, lung injury was induced in mice by intratracheal administration of bleomycin (1.0 mg/kg). Mice were exposed to control gas (air) or hydrogen (3.2% in air) for 6 h every day for 7 or 21 days. Respiratory physiology, tissue pathology, markers of inflammation, and macrophage phenotypes were examined. Results Mice with bleomycin-induced lung injury that received daily hydrogen therapy for 21 days (BH group) exhibited higher static compliance (0.056 mL/cmH 2 O, 95% CI 0.047–0.064) than mice with bleomycin-induced lung injury exposed only to air (BA group; 0.042 mL/cmH 2 O, 95% CI 0.031–0.053, p = 0.02) and lower static elastance (BH 18.8 cmH 2 O/mL, [95% CI 15.4–22.2] vs. BA 26.7 cmH 2 O/mL [95% CI 19.6–33.8], p = 0.02). When the mRNA levels of pro-inflammatory cytokines were examined 7 days after bleomycin administration, interleukin (IL)-6, IL-4 and IL-13 were significantly lower in the BH group than in the BA group. There were significantly fewer M2-biased macrophages in the alveolar interstitium of the BH group than in the BA group (3.1% [95% CI 1.6–4.5%] vs. 1.1% [95% CI 0.3–1.8%], p = 0.008). Conclusions The results suggest that hydrogen inhalation inhibits the deterioration of respiratory physiological function and alveolar fibrosis in this model of lung injury.
... The effective hydrogen concentration has been considered to be 2-4% (Terasaki et al., 2011). Hydrogen is neither inflammable nor explosive at a concentration < 4% when mixed with pure oxygen or atmospheric air (Huang et al., 2010). ...
... First, because DCD organs lacked blood supply, we were not able to accurately assess the DCD lung function using common diagnostic tools, such as arterial blood gas analysis, during the WIP before harvest. Second, Terasaki et al. (2011) demonstrated that the effective hydrogen concentration was 2-4%, different dosage effects of hydrogen were not investigated in our study. Therefore, the optimal hydrogen concentration still needs to be determined. ...
Article
Background: Successful amelioration of long-term warm ischemia lung injury in donors after cardiac death (DCDs) can remarkably improve outcomes. Hydrogen gas provides potent anti-inflammatory and antioxidant effects against ischemia-reperfusion injury (IRI). This study observed the effects of hydrogen inhalation on lung grafts during the warm ischemia phase in cardiac death donors. Methods: After cardiac death, rat donor lungs (n = 8) underwent mechanical ventilation with 40% oxygen plus 60% nitrogen (control group) or 3% hydrogen and 40% oxygen plus 57% nitrogen (hydrogen group) for 2 h during the warm ischemia phase in situ. Then, lung transplantation was performed after 2 h of cold storage and 3 h of recipient reperfusion prior to lung graft assessment. Rats that underwent left thoracotomy without transplantation served as the sham group (n = 8). The results of static compliance and arterial blood gas analysis were assessed in the recipients. The wet-to-dry weight ratio (W/D), inflammation, oxidative stress, cell apoptosis and histologic changes were evaluated after 3 h of reperfusion. Nuclear factor kappa B (NF-κB) protein expression in the graft was analyzed by Western blotting. Results: Compared with the sham group, lung function, W/D, inflammatory reaction, oxidative stress and histological changes were decreased in both transplant groups (control and hydrogen groups). However, compared with the control group, exposure to 3% hydrogen significantly improved lung graft static compliance and oxygenation and remarkably decreased the wet-to-dry weight ratio, inflammatory reactions, and lipid peroxidation. Furthermore, hydrogen improved the lung graft histological changes, decreased the lung injury score and apoptotic index and reduced NF-κB nuclear accumulation in the lung grafts. Conclusion: Lung inhalation with 3% hydrogen during the warm ischemia phase attenuated lung graft IRI via NF-κB-dependent anti-inflammatory and antioxidative effects in rat donors after cardiac death.
... Extensive studies have revealed that molecular hydrogen exerts radioprotective effects as an antioxidant and intracellular response modulator (Hirano et al. 2021). In the human lung epithelial cell line A549 undergoing irradiation, molecular hydrogen reduced the amount of radiation-induced ROS and apoptosis while enhancing cell viability (Terasaki et al. 2011). ...
... In an in vivo mouse model, molecular hydrogen similarly attenuated oxidative stress and apoptosis that act as measures of acute damage. It also reduced late damagepulmonary fibrosis as observed on alleviated chest computed tomography, Ashcroft score, and type III collagen deposition (Terasaki et al. 2011). ...
Article
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Acute lung injury (ALI) and acute respiratory distress syndrome, which is a more severe form of ALI, are life-threatening clinical syndromes observed in critically ill patients. Treatment methods to alleviate the pathogenesis of ALI have improved to a great extent at present. Although the efficacy of these therapies is limited, their relevance has increased remarkably with the ongoing pandemic caused by the novel coronavirus disease 2019 (COVID-19), which causes severe respiratory distress syndrome. Several studies have demonstrated the preventive and therapeutic effects of molecular hydrogen in the various diseases. The biological effects of molecular hydrogen mainly involve anti-inflammation, antioxidation, and autophagy and cell death modulation. This review focuses on the potential therapeutic effects of molecular hydrogen on ALI and its underlying mechanisms and aims to provide a theoretical basis for the clinical treatment of ALI and COVID-19.
... 123 It is now believed that both direct radiation damage to DNA and radiation-enhanced production of ROS cause cellular damage in RILF. [124][125][126] In addition, ROS caused by irradiation is closely related to inflammation and fibrosis. 125,126 Apart from apoptosis, several lines of evidence suggested that ferroptosis might play a critical role in the process of RILF. ...
... [124][125][126] In addition, ROS caused by irradiation is closely related to inflammation and fibrosis. 125,126 Apart from apoptosis, several lines of evidence suggested that ferroptosis might play a critical role in the process of RILF. Firstly, the expression level of GPX4 is obviously decreased in RILF mice. ...
Article
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Jian Zhou, Yuan Tan, Rurong Wang, Xuehan Li Department of Anesthesiology, Laboratory of Anesthesia and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, People’s Republic of ChinaCorrespondence: Xuehan Li, Department of Anesthesiology, Laboratory of Anesthesia and Critical Care Medicine, West China Hospital, Sichuan University, No. 37 Guoxue Xiang, Chengdu, Sichuan Province, 610041, People’s Republic of China, Tel +86 18980099133, Email xuehanli@scu.edu.cnAbstract: Ferroptosis is a unique and pervasive form of regulated cell death driven by iron-dependent phospholipid peroxidation. It results from disturbed cellular metabolism and imbalanced redox homeostasis and is regulated by various cellular metabolic pathways. Recent preclinical studies have revealed that ferroptosis may be an attractive therapeutic target in fibrotic diseases, such as liver fibrosis, pulmonary fibrosis, kidney fibrosis, and myocardial fibrosis. This review summarizes the latest knowledge on the regulatory mechanism of ferroptosis and its roles in fibrotic diseases. These updates may provide a novel perspective for the treatment of fibrotic diseases as well as future research.Keywords: ferroptosis, liver fibrosis, kidney fibrosis, myocardial fibrosis, pulmonary fibrosis
... The biological processes related to the 5 core target genes further support the results of our GO analysis. Noteworthy, these biological processes are also closely related to the occurrence and development of RILI (64,65). For example, hydrogen therapy was confirmed to attenuate irradiation-induced lung damage by reducing oxidative stress (64). ...
... Noteworthy, these biological processes are also closely related to the occurrence and development of RILI (64,65). For example, hydrogen therapy was confirmed to attenuate irradiation-induced lung damage by reducing oxidative stress (64). Isoflavone have showed radioprotective effects in irradiated lungs by limiting excessive immune cell homing via vascular endothelium into damaged lung tissue (65). ...
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Background Radiation-induced lung injury (RILI) is a severe side effect of radiotherapy for non-small cell lung cancer (NSCLC) ,and one of the major hindrances to improve the efficacy of radiotherapy. Previous studies have confirmed that sodium butyrate (NaB) has potential of anti-radiation toxicity. However, the mechanism of the protective effect of NaB against RILI has not yet been clarified. This study aimed to explore the underlying protective mechanisms of NaB against RILI in NSCLC through network pharmacology, molecular docking, molecular dynamic simulations and in vivo experiments. Methods The predictive target genes of NaB were obtained from the PharmMapper database and the literature review. The involved genes of RILI and NSCLC were predicted using OMIM and GeneCards database. The intersectional genes of drug and disease were identified using the Venny tool and uploaded to the Cytoscape software to identify 5 core target genes of NaB associated with RILI. The correlations between the 5 core target genes and EGFR, PD-L1, immune infiltrates, chemokines and chemokine receptors were analyzed using TIMER 2.0, TIMER and TISIDB databases. We constructed the mechanism maps of the 3 key signaling pathways using the KEGG database based on the results of GO and KEGG analyses from Metascape database. The 5 core target genes and drug were docked using the AutoDock Vina tool and visualized using PyMOL software. GROMACS software was used to perform 100 ns molecular dynamics simulation. Irradiation-induced lung injury model in mice were established to assess the therapeutic effects of NaB. Results A total of 51 intersectional genes involved in NaB against RILI in NSCLC were identified. The 5 core target genes were AKT1, TP53, NOTCH1, SIRT1, and PTEN. The expressions of the 5 core target genes were significantly associated with EGFR, PD-L1, immune infiltrates, chemokines and chemokine receptors, respectively. The results from GO analysis of the 51 intersectional genes revealed that the biological processes were focused on the regulation of smooth muscle cell proliferation, oxidative stress and cell death, while the three key KEGG pathways were enriched in PI3K-Akt signal pathway, p53 signal pathway, and FOXO signal pathway. The docking of NaB with the 5 core target genes showed affinity and stability, especially AKT1. In vivo experiments showed that NaB treatment significantly protected mice from RILI, with reduced lung histological damage. In addition, NaB treatment significantly inhibited the PI3K/Akt signaling pathway. Conclusions NaB may protect patients from RILI in NSCLC through multiple target genes including AKT1, TP53, NOTCH1, SIRT1 and PTEN, with multiple signaling pathways involving, including PI3K-Akt pathway, p53 pathway, and FOXO pathways. Our findings effectively provide a feasible theoretical basis to further elucidate the mechanism of NaB in the treatment of RILI.
... The two mechanisms involved in radiation injury to both tumor and normal cells are the direct and indirect DNA damage through the generation of reactive oxygen species and FRs that destroy protein, lipid, and nucleic acid molecules, thus causing ischemia and thrombosis through the secretion of cytokines and chemokines. [11,12] Khan et al. [13] in 2003 had described the potential role of reactive nitrogen species in causing radiation fibrosis in rats, but no such mechanism has been described in humans. ...
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Fibrosis is a descriptive appellation referring to the obliteration of normal tissue components replaced by matrix and disorganized and varied collagen fibrils that result in the loss of organ function and frequent tissue contraction leading to death or significant deterioration in the quality of life. Radiation fibrosis syndrome (RFS) is a progressive fibrotic tissue sclerosis with various clinical symptoms in the irradiation field. It is usually a late complication of radiation therapy and may occur weeks or even years after treatment. It may affect the musculoskeletal, soft tissue, neural tissue, and cardiopulmonary systems. RFS is a serious and lifelong disorder that, nevertheless, may often be prevented when identified and rehabilitated early. Genetic factors likely play a significant role in the development of chronic fibrotic response to radiation injury that persists even after the initial insult is no longer present. Management of this syndrome is a complex process comprising medication, education, rehabilitation, and physical and occupational therapy. A bibliographical search was carried out in PubMed using the following keywords: “radiation fibrosis,” “radiation fibrosis syndrome,” and “radiation‑induced fibrosis.” We also reviewed the most relevant and recent series on the current management of RFS, and the reviewed data are discussed in this article. This review discusses the pathophysiology, evaluation, and treatment of neuromuscular, musculoskeletal, and functional disorders as late effects of radiation treatment. Key words: Ionizing radiation, radiation fibrosis syndrome, radiotherapy
... High serum levels of inflammatory cytokines, such as interleukin-6 (IL-6), tumor necrosis factor-a (TNF-a), interleukin-10 (IL-10), and transforming growth factor-b1 (TGF-b1) are often recognized as the markers for RILI [5,6]. Reactive oxygen species (ROS) caused by irradiation induces cellular damage indirectly, and the lung injury, including the pulmonary inflammation and fibrosis are also related to ROS [7,8]. ROS-induced oxidative damage in lung tissues is a critical factor in the pathogenesis of RILI. ...
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Radiation-induced lung injury (RILI) is one of the most common and fatal complications of thoracic radiotherapy. Cell death is the critical point in RILI. Ferroptosis is discovered recently as a new type of cell death which is different from other forms. Our research investigated the role of ferroptosis in the process of acute RILI in mice. The levels of ROS in lungs and the inflammatory cytokine levels (TNF-α, IL-6, IL-10, and TGF-β1) in serum decreased significantly post ferroptosis inhibitor treatment in acute RILI. Ferroptotic characteristic changes of mitochondria in acute RILI was observed by transmission electron microscopy (TEM). Treatment with ferroptosis inhibitor significantly alleviated radiation-induced histopathological changes in mice lungs. Glutathione peroxidase 4 (GPX4), the key maker of the ferroptosis, was down-regulated in RILI. In summary, we observed that ferroptosis played a crucial role in acute RILI, and the ROS induced by irradaition might be the original trigger of ferroptosis in acute RILI. At the same time, ferroptosis may also affect the levels of inflammatory cytokines in acute RILI.
... Minutes after irradiation, the damage to DNA or cytoplasmic organelles triggers intracellular signaling, leading to altered gene expression and immediate release of growth factors such as transforming growth factor ß (TGF-ß), platelet-derived growth factor (PDGF), and interleukin 1 (IL-1) (4). Additionally, ionization of water molecules generates reactive oxygen species (ROS) such as superoxide, hydrogen peroxide, hydroxyl radicals and nitrogen species (NGS) (5) that account for 60% of the total damage inflicted (6,7). ROS can directly modify proteins and organelles but in an iron dependent manner (Fenton reaction) can produce hydroxyl radicals that cause DNA damage (8,9). ...
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Radiation pneumonitis (RP) and radiation fibrosis (RF) are two dose-limiting toxicities of radiotherapy (RT), especially for lung, and esophageal cancer. It occurs in 5–20% of patients and limits the maximum dose that can be delivered, reducing tumor control probability (TCP) and may lead to dyspnea, lung fibrosis, and impaired quality of life. Both physical and biological factors determine the normal tissue complication probability (NTCP) by Radiotherapy. A better understanding of the pathophysiological sequence of radiation-induced lung injury (RILI) and the intrinsic, environmental and treatment-related factors may aid in the prevention, and better management of radiation-induced lung damage. In this review, we summarize our current understanding of the pathological and molecular consequences of lung exposure to ionizing radiation, and pharmaceutical interventions that may be beneficial in the prevention or curtailment of RILI, and therefore enable a more durable therapeutic tumor response.
... SOD has also been used in a porcine animal model to successfully treat RIF [80]. Molecular hydrogen is an antioxidant that diffuses through cell membranes, reduces levels of ROS and decreases oxidative stressinduced injury in several organs [81]. The radioprotective drug Amifostine is used clinically for its properties of scavenging free radicals, DNA protection, and acceleration of repair and this drug has potential as a therapeutic for treatment of radiation-induced lung damage [82,83]. ...
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It is well-known that Radiation-induced fibrosis (RIF) is a late event occurring months to years after the initial radiation exposure. Fibrotic lesions have been shown to manifest in many tissues including the skin, heart, lung, liver and kidney. Fibrosis occurs due to abnormal accumulation of extracellular matrix (ECM) proteins that result in loss of normal tissue and organ function. The cell type involved in RIF is myofibroblasts, which do not undergo apoptosis after healing but instead continue to accumulate, producing excessive amounts of ECM proteins, thereby damaging the tissues and organs. Reactive oxygen species, generated in response to radiation, is one signal that helps maintain the myofibroblast phenotype. In this review, we discuss molecular mechanisms leading to this late radiation event, known biomarkers for prediction, preclinical animal models of radiation-induced toxicity and current clinical trials designed for mitigation and treatment of radiation-induced fibrosis. We also discuss other physical properties such as linear energy transfer (LET) than the ones used in the clinics today which may have the potential to change our understanding on this inevitable pathway from radiation treatment to organ fibrosis.
... The anti-inflammatory properties of ferroptosis inhibitors such as DFP also have reported benefits in neurodegenerative diseases [including Parkinson's disease (PD), motor neuron disease (MND) and Alzheimer's disease (AD)] [142], and iron chelation and anti-ferroptotic therapy for neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) are under investigation [143]. Similar to SBI, radiation-induced lung fibrosis (RILF) is also considered to involve excessive ROS-induced oxidative damage as the critical origin of inflammatory events [144,145]. As mentioned previously, one characteristic of ferroptosis is ROS accumulation by lipid peroxidation, so researchers have speculated that ferroptosis may occur in RILF; thus, inhibiting ferroptosis may alleviate RILF through the antiinflammatory and antioxidative effects. ...
Article
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Ferroptosis is a newly discovered type of cell death triggered by intracellular phospholipid peroxidation that is morphologically, biologically and genetically distinct from other types of cell death. Ferroptosis is classified as regulated necrosis and is more immunogenic than apoptosis. To date, compelling evidence indicates that ferroptosis plays an important role in inflammation, and several antioxidants functioning as ferroptosis inhibitors have been shown to exert anti-inflammatory effects in experimental models of certain diseases. Our review provides an overview of the link between ferroptosis and inflammation; a better understanding of the mechanisms underlying ferroptosis and inflammation may hasten the development of promising therapeutic strategies involving ferroptosis inhibitors to address inflammation.
... 23 Free radicals damage all components of cells, including proteins, nucleic acids, and lipids. 24 Superoxide dismutase, catalase, and glutathione peroxidase are responsible for controlling free radical damage. A deficiency in these enzymes leads to oxidative stress in tissues. ...
Article
Trismus refers to a person's inability to normally open his or her mouth. Trismus can occur as a symptom due to tumor ingrowth or it can occur postsurgical following the treatment for head and neck cancer. Radiation-induced trismus is also a relatively common oral complication. This review aimed at reviewing the etiopathogenesis of trismus in patients with head and neck cancer. Of the 16 publications included after final screening, of which one was a nonrandomized control trial, one a randomized control trial, 6 prospective cohort studies, and 8 retrospective cohort studies. Among them, 6 articles addressed the possible mechanism for trismus related to tumor ingrowth, 8 articles suggested the likely reason for trismus in patients who had undergone radiation therapy and 2 articles addressed the postsurgical cause for trismus. This review highlights the possible involvement of infratemporal fossa as a predetermining factor for developing trismus related to tumor extension. The molecular mechanism of radiation-induced fibrosis is well studied in the literature.
... Additionally, we believe that H 2 inhalation is an effective therapy that can be maintained until the complete recovery of the neuroinflammation and, consequently, cognitive/ memory loss observed in sepsis. Also, the frequency and the time inhaling H 2 can be increased dependent upon the patient recovery since H 2 is expired by the lungs at higher concentrations without causing any toxic effects (Terasaki, et al., 2011) The cellular mechanisms associated with cognitive damage in sepsis are not yet fully understood and there are no effective therapies available . For a long time, it was believed that the blood brain barrier (BBB) protected neurons and their synapses and the immune system did not influence the neural communication process (Sian-Marie et al., 2006). ...
Article
The central nervous system (CNS) is one of the first physiological systems to be affected in sepsis. During the exacerbated systemic inflammatory response at the early stage of sepsis, circulatory inflammatory mediators are able to reach the CNS leading to neuroinflammation and, consequently, long-term impairment in learning and memory formation is observed. The acute treatment with molecular hydrogen (H2) exerts important antioxidative, antiapoptotic, and anti-inflammatory effects in sepsis, but little is known about the mechanism itself and the efficacy of chronic H2 inhalation in sepsis treatment. Thus, we tested two hypotheses. We first hypothesized that chronic H2 inhalation is also an effective therapy to treat memory impairment induced by sepsis. The second hypothesis is that H2 treatment decreases sepsis-induced neuroinflammation in the hippocampus and prefrontal cortex, important areas related to short and long-term memory processing. Our results indicate that (1) chronic exposure of hydrogen gas is a simple, safe and promising therapeutic strategy to prevent memory loss in patients with sepsis and (2) acute H2 inhalation decreases neuroinflammation in memory-related areas and increases total nuclear factor E2-related factor 2 (Nrf2), a transcription factor that regulates a vast group of antioxidant and inflammatory agents expression in these areas of septic animals.
... 11 Hydrogen-rich solution may also work that Yasuhiro et al found hydrogen therapy could attenuate irradiation-induced lung damage. 35 Yong et al. demonstrated hydrogen-rich saline alleviated lipopolysaccharide-induced acute lung injury by inhibiting excessive autophagy activation via the ROS/AMPK/mTOR pathway in mice with lung histopathological changes. 36 As previous studies on hydrogen inhalation were based on model animals or healthy human groups, this study provides important findings that even single inhalation of hydrogen was effective in modulating airway inflammation in patients with asthma and COPD. ...
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Background: Hydrogen was proven to have anti-oxidative and anti-inflammation effects to various diseases. Aim: We wish to investigate the acute effects of inhaled hydrogen on airway inflammation in patients with asthma and chronic obstructive pulmonary disease (COPD). Design: Prospective study. Methods: 2.4% hydrogen containing steam mixed gas (XEN) was inhaled once for 45 minutes in 10 patients with asthma and 10 patients with COPD. The levels of granulocyte-macrophage colony stimulating factor (GM-CSF), interferon-γ (IFNγ), interleukin-1β (IL-1β), interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-6 (IL-6), et al. in peripheral blood and exhaled breath condensate (EBC) before and after "XEN" inhalation were measured. Results: 45 minutes "XEN" inhalation once decreased monocyte chemotactic protein 1 (MCP1) level in both COPD (564.70 to 451.51pg/mL, P = 0.019) and asthma (386.39 to 332.76 pg/mL, P = 0.033) group, while decreased IL-8 level only in asthma group (5.25 to 4.49pg/mL, P = 0.023). The level of EBC soluble cluster of differentiation-40 ligand (sCD40L) in COPD group increased after inhalation (1.07 to 1.16pg/mL, P = 0.031), while IL-4 and IL-6 levels in EBC were significantly lower after inhalation in the COPD (0.80 to 0.64pg/mL, P = 0.025) and asthma (0.06 to 0.05pg/mL, P = 0.007) group respectively. Conclusions: A single inhalation of hydrogen for 45 minitues attenuated inflammatory status in airways in patients with asthma and COPD.
... Although steroids had been used to treat RILI, severe side effects remain a huge challenge. IR induces cellular damage by direct deposit of energy and indirect oxidative damage via excessive reactive oxygen species (ROS), which were reported to be implicated in radiationinduced pulmonary injury, inflammation and fibrosis (6,7). IR induces the accumulation of ROS, including hydroxyl radicals, hydrogen peroxide, and superoxide. ...
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Radiation-induced lung injury (RILI) is one of the most common and fatal complications of thoracic radiotherapy. Inflammatory cell infiltration, imbalance of inflammatory cytokines, and oxidative damage were reported to be involved during RILI pathogenesis, especially in the early phase of RILI. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a key transcriptional regulator of antioxidative cascades, and regulates life span of mice after administration of thoracic irradiation. We investigated the effects of Nrf2 on RILI and inflammation using Nrf2-knockout, Nrf2-overexpression and wild-type mice with or without 15 Gy ionizing radiation to thorax. Our results showed that Nrf2 deficiency aggravated radiation-induced histopathological changes, macrophage and neutrophil infiltration, serum levels of pro-inflammatory cytokines (IL-6, MCP-1, IFN-γ, TNF, and IL-12p70), and the levels of peroxidation products in the mouse lung. Moreover, loss of Nrf2 reduced radiation-induced serum levels of anti-inflammatory cytokine, IL-10, and antioxidative proteins. Nrf2 overexpression significantly alleviated radiation-induced histopathological changes, macrophages and neutrophils infiltration, serum levels of pro-inflammatory cytokines, and the levels of peroxidation products in lung tissues. Nrf2 overexpression also increased the serum levels of IL-10 and antioxidative proteins. These results indicated that Nrf2 had a protective role against radiation-induced acute lung injury and inflammation, and that antioxidative therapy might be a promising treatment for RILI.
... Molecular hydrogen can penetrate the membrane structure of cell membrane and organelle and rapidly diffuse into tissues and cells without affecting the signal transduction process. When molecular hydrogen enters the subcellular structure, it can reduce the excessive ROS and reactive nitrogen produced under pathological conditions and plays a protective role on the subcellular structure [33]. Furthermore, our study indicated that molecular hydrogen could also alleviate the decreased SOD activity, increase the GSH-Px activity, and finally increase the T-AOC in organisms, exerting its protective effect on EMP exposure. ...
Article
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Infertility has got to be a broadly concerned social issue these days, in which the malefactor cannot be overlooked. Numerous studies have shown that electromagnetic pulse (EMP) radiation may have seriously damaging effects on reproductive health, through nonthermal effects and oxidative stress. Molecular hydrogen, a selective hydroxyl radical scavenger, explains the protective effects against many diseases closely associated with oxidative damage, such as ionizing radiation (IR). We sought to characterize the beneficial effects of molecular hydrogen on the male reproductive system in a rodent EMP exposure model. The 8-week-old male Sprague-Dawley rats were exposed to EMP (peak intensity 1000 kV/m, pulse edge 20 ns, pulse width 200 ns, 1 Hz, and 200 pulses), with or without hydrogen-rich water. The pathological structure of the testis, the rate of apoptosis of the testis, the serum testosterone level, the sperm parameters, and the activity of the antioxidant enzymes of the testis were measured. Then, transcriptomic and untargeted metabolomic analyses were applied to uncover the underlying mechanism. Exposure to EMP increased testicular apoptosis rate and apoptosis protein level, decreased sperm viability and motility, decreased serum testosterone levels, and diminished testicular antioxidant capacity. Molecular hydrogen-alleviated damage decreased the testicular apoptosis rate and apoptosis protein level, increased sperm motility, increased serum testosterone levels, and improved antioxidative capacity. Omics results showed that molecular hydrogen has a strong influence on metabolic pathways, and EMP affects mainly oxidative phosphorylation, TNF signaling pathways, and cytokine-receptor interactions. The mechanism of molecular hydrogen’s effect may be related to the reversal of some metabolite levels. These observations warrant molecular hydrogen as an innovative approach for potential protection against EMP.
... In addition, H 2 has also been proven to have a good anti-fibrotic effect. Terasaki Y et al. found in the mouse models of pulmonary fibrosis post radiation that breathing air containing 4% H 2 has a significant therapeutic effect on chronic pulmonary fibrosis, and can significantly delay the progress of pulmonary fibrosis (13). Although the current mechanism of cGVHD is not very clear, in the currently recognized pathogenesis of cGVHD, inflammatory factors imbalance and fibrosis occupy a dominant position (4,14). ...
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Chronic graft-versus-host-disease (cGVHD) is the leading cause of late non-relapse mortality after allogeneic hematopoietic stem cell transplantation(HSCT). There is no standard therapy for patients refractory or dependent to corticosteroid treatment. We hypothesized that hydrogen may exert therapeutic effects on cGVHD patients with few side effects. A prospective open-label phase 2 study of hydrogen was conducted. Patients received hydrogen-rich water 4ml/kg orally three times a day. Responses were graded in the skin, mouth, Gastrointestinal(GI), liver, eyes, lungs and joints and fascia every 3 months. A total of 24 patients (median age 27) were enrolled. Of the 24 patients, 18 (75%; 95% CI, 55.1% to 88%) had an objective response. No significant toxicity was observed. The estimated 4-year overall survival rate was 74.7%(95% CI, 54.9%–94.5%). The survival time was significantly prolonged in the response group. The survival rate at 4 years in the response group is significantly higher than the nonresponse group (86.6% vs 0%; p= 0.000132). Hydrogen showed great efficacy on cGVHD patients and long-term administration of hydrogen was not associated with significant toxic effects. The trial was registered at www.ClinicalTrials.Gov, NCT02918188.
... 28,56 Lungs are also radiosensitive to pneumonitis in acute and subacute settings and pulmonary fibrosis in chronic settings. 57 28,50 Due to their postmitotic state, cardiac myocytes are relatively resistant to radiation damage. 59 Endothelial cells are known to be sensitive to radiation, and their damage is associated with the pathophysiology of most forms of cardiac injuries, which may result from loss of alkaline phosphatase activity of capillary endothelial cells. ...
Article
ABSTRACT Overview: Nowadays, cancer presents a serious health problem worldwide. Oxidative stress has an important role in a variety of pathologies, and the search for an effective and well-tolerated antioxidant agent continues. Although cancer radiotherapy confers significant benefits, it causes remarkable tissue damage and subsequent apoptosis as a result of ionizing radiation by hydroxyl radicals (•OH) that follow the radiolysis of water. There is evidence, but inconclusive indicating that antioxidant capabilities of molecular hydrogen (H2) alleviate this oxidative stress and subsequent cancer complications and decrease death rates. Objectives: This article discusses current knowledge on the implications of H2 in the reduction of radiation therapy-induced adverse effects in cancer. It also highlights the outcomes of recent clinical trials. Methods: Relevant articles were identified through an up-to-date online search of PubMed, Medline, Scopus, Science Direct, PsycINFO, registered clinical trials, Google Scholar, and WHO database. Results: The available evidence shows that H2 as a therapeutic antioxidant selectively reduces the cytotoxic oxygen radicals, in particular, •OH, and may improve cancer conditions. Despite the non-specific mechanism of H2, researchers have reported several positive effects of H2 in cancer therapy, including delayed cancer progression, alleviation of radiotherapy and chemotherapy complications, and improved efficacy of conventional therapy when used in combination with H2. Conclusion: It seems that H2 has protective effects in the radiotherapy of many cancers. Nonetheless, there is a general scarcity of controlled human studies that investigate direct and longitudinal clinical and biochemical effects of H2 on key cancerous changes. Thus, further research is required. Keywords: antioxidants, carcinoma, hydrogen-rich water, radiation therapy, oxidative stress Running Title: Role of Molecular Hydrogen in Cancer Radiotherapy
... 85 However, ionizing radiation not only damages DNA but also induces the production of ROS, causing inflammation and fibrosis. 86,87 Therefore, other types of cell death in addition to apoptosis may occur in RILF. ROS accumulation is the main cause of ferroptosis and the major trigger of the inflammatory response in RILF. ...
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Wenting Xu,1,2,* Huimin Deng,2,* Song Hu,2,3,* Yiguo Zhang,2,3 Li Zheng,1,2 Meiyun Liu,2 Yuanli Chen,2 Juan Wei,2 Hao Yang,2 Xin Lv1– 3 1Department of Anesthesiology, Fuyang Hospital of Anhui Medical University, Fuyang, Anhui, 236000, People’s Republic of China; 2Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of China; 3Graduate School, Wannan Medical College, Wuhu, AnHui, 241002, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xin Lv; Hao YangDepartment of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, 507 Zhengmin Road, Shanghai, 200433, People’s Republic of ChinaEmail xinlvg@126.com; yanghaozunyi@sina.comAbstract: Ferroptosis is a new type of programmed cell death characterized by intracellular iron accumulation and lipid peroxidation that leads to oxidative stress and cell death. The metabolism of iron, lipids, and amino acids and multiple signalling pathways precisely regulate the process of ferroptosis. Emerging evidence has demonstrated that ferroptosis participates in the occurrence and progression of various pathological conditions and diseases, such as infections, neurodegeneration, tissue ischaemia-reperfusion injury and immune diseases. Recent studies have also indicated that ferroptosis plays a critical role in the pathogenesis of acute lung injury, chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary infection and asthma. Herein, we summarize the latest knowledge on the regulatory mechanism of ferroptosis and its association with iron, lipid and amino acid metabolism as well as several signalling pathways. Furthermore, we review the contribution of ferroptosis to the pathogenesis of lung diseases and discuss ferroptosis as a novel therapeutic target for various lung diseases.Keywords: ferroptosis, metabolic networks and pathways, signalling pathways, lung diseases
... Another indirect damage of DNA is activated by reactive oxygen species (ROS), which are primarily produced by mitochondrial oxidative metabolism to participate in the growth, differentiation, progression, and death of cells in the biological process (6). Furthermore, water molecules of irradiated cells are ionized to generate an excessive number of ROS, including superoxide, hydrogen peroxide, hydroxyl radicals, and nitrogen species (NGS), which indirectly cause DNA damage (7,8). Except for analogous nuclear DNA damage with direct impacts, ROS also induces mitochondrial DNA (mtDNA) damage, which leads to protein carbonylation, lipid peroxidation, increased oxidative metabolism, and enhanced rates of spontaneous gene mutations and neoplastic transformation. ...
Article
Background and objective: Radiation-induced lung injury (RILI) is often found in thoracic tumor patients after thoracic radiation therapy, and influences patient quality of life. However, systematic exploration of RILI, including its molecular biological mechanisms and standardized treatment, has not yet been fully elucidated. The main objective of the narrative review was to describe the available evidence concerning RILI, from the biological mechanism to the clinical management. The underlying causes of RILI are multifactorial, including gene-level changes, the influence of signaling pathways, the convergence of various cells, as well as the expression of cytokines and chemokines. Based on the various mechanisms of RILI, several novel treatment strategies have been proposed and gradually applied in clinical practice. Methods: PubMed was used to collect articles about RILI from 1995 to 2021. The papers included clinical trials, reviews, as well as systematic reviews and meta-analyses. Based on the mechanism, diagnosis, and treatment, we synthesized and analyzed these papers to form a clearly logical and normative suggestion to guide clinical application. Key content and findings: RILI is a constantly developing and changing process including radiation pneumonitis and radiation lung fibrosis. Different kinds of inflammatory and immune cells such as macrophages, fibroblasts, and T cells play key roles in the development of RILI, and transforming growth factor-β (TGF-β), interleukin-4 (IL-4), IL-13, and interferon-γ (IFN-γ) are also participants in this process. At present, glucocorticoids are mainly therapeutic drugs for the early stage of RILI, and drugs treatment should abide early period, sufficient doses, and the individual principles. Other novel drugs such as Azithromycin also have been tried in clinical application. radiation dose, combination therapy modality, the condition of the tumor, and the age and underlying conditions of patients all effect the occurrence of RILI. Importantly, RILI has a relatively higher incidence in patients who received radiotherapy combined with other treatments, especially immunotherapy. Conclusions: The occurrence of RILI after radiotherapy will greatly affect the prognosis and quality of life of patients. In clinical practice, early intervention, active treatment, and more effective therapeutic drugs should be found.
... In our study, we demonstrated that HRW administration was associated with a significant decrease in pathological collagen content equivalent to that of 5-FU. In contrast to previous reports demonstrating that molecular H 2 upregulates collagen biosynthesis and expression, and corresponding to the results of another study reporting that molecular H 2 significantly reduced type III collagen depositions as observed via staining [26][27][28]. Molecular H 2 has shown to both be able to promote and suppress outcomes, model dependent, for many biological processes, which may indicate that contradictory reports do not undermine our understanding of the mechanisms by which H 2 January 15, 2022 ...
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Background: Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the world. Tumor removal remains the preferred frontline treatment; however, effective non-surgical interventions remain a high priority. 5-fluorouracil (5-FU) is a widely used chemotherapy agent, and molecular hydrogen (H2) has been recognized for its antioxidant and anti-inflammatory effects, with research also suggesting its potential anti-tumor effects. Therefore, H2 dissolved in water [hydrogen-rich water (HRW)], with or without 5-FU, may present itself as a novel therapeutic for CRC. Aim: To investigate the effects of HRW, with or without 5-FU, as a novel therapeutic for CRC. Methods: CRC was induced in the left flank of inbred Balb/c mice. A total of 24 mice bearing tumors were randomly divided into four groups (n = 6 per group) and treated as follows: (1) Control group; (2) 5-FU group that received intraperitoneal injection of 5-FU (5 mg/kg) every other day; (3) H2 group that received HRW, created and delivered via dissolving the H2-generating tablet in the animals' drinking water, with 200 μL also delivered by oral gavage; and (4) The combination group, H2 (administered in same way as for group three) combined with 5-FU administered same way as group two. Results: Administration of HRW + 5-FU significantly improved tumor weight, tumor size, collagen content and fibrosis as compared to the CRC control group. Specifically, HRW attenuated oxidative stress (OS) and potentiated antioxidant activity (AA), whereas 5-FU treatment exacerbated OS and blunted AA. The combination of HRW + 5-FU significantly reduced tumor weight and size, as well as reduced collagen deposition and the degree of fibrosis, while further increasing OS and decreasing AA compared to administration of 5-FU alone. Conclusion: Administration of HRW, with or without 5-FU, may serve as a therapeutic for treating CRC.
... models of airway inflammation, intervention with different concentrations of H 2 could reduce oxidative stress markers MDA and improve antioxidant enzymes GSH in serum and lung tissue (Zhang N. et al., 2018;Huang et al., 2019). Importantly, it was reported that H 2 -rich medium intervention attenuates irradiation-induced human lung epithelial cell line A549 damage by decreasing the production of ROS (Terasaki et al., 2011). There are more studies showing that H 2 reduces ROS production in alveolar epithelial cells, attenuates the alveolar epithelial barrier damage, improves alveolar gas exchange, and reduces cell damage (Qiu et al., 2019). ...
Article
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Molecular hydrogen (H 2 ) is a colorless and odorless gas. Studies have shown that H 2 inhalation has the therapeutic effects in many animal studies and clinical trials, and its application is recommended in the novel coronavirus pneumonia treatment guidelines in China recently. H 2 has a relatively small molecular mass, which helps it quickly spread and penetrate cell membranes to exert a wide range of biological effects. It may play a role in the treatment and prevention of a variety of acute and chronic inflammatory diseases, such as acute pancreatitis, sepsis, respiratory disease, ischemia reperfusion injury diseases, autoimmunity diseases, etc.. H 2 is primarily administered via inhalation, drinking H 2 -rich water, or injection of H 2 saline. It may participate in the anti-inflammatory and antioxidant activity (mitochondrial energy metabolism), immune system regulation, and cell death (apoptosis, autophagy, and pyroptosis) through annihilating excess reactive oxygen species production and modulating nuclear transcription factor. However, the underlying mechanism of H 2 has not yet been fully revealed. Owing to its safety and potential efficacy, H 2 has a promising potential for clinical use against many diseases. This review will demonstrate the role of H 2 in antioxidative, anti-inflammatory, and antiapoptotic effects and its underlying mechanism, particularly in coronavirus disease-2019 (COVID-19), providing strategies for the medical application of H 2 for various diseases.
... However, the overproduction of ROS influences NO production and consequently leads to stress and inflammatory responses in the immune system [31,32]. Consistent with previous studies on H 2 and electrolysis-reduced water [33][34][35], our results revealed that HtRMS induced a decrease in ROS and NO levels in a concentration-dependent way ( Figure 2) after H 2 O 2 and LPS induction in murine macrophage cells. The present results suggest that HtRMS may be employed in therapeutic approaches to reduce the overproduction of harmful free radicals in murine macrophage cells. ...
Article
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Oxidative stress (OS) plays an important role in many diseases, and its excessive increase affects human health. Although the antioxidant effect of sea salt can be strengthened through special processing, it is scarcely studied. This study confirmed the antioxidative effect of high-temperature roasted mineral salt (HtRMS) produced through repeated roasting of sea salt at high temperature in a ceramic vessel. The dissolved HtRMS exhibited properties such as high alkalinity, rich mineral content, and a high concentration of hydrogen (H2). To detect the antioxidative effect of HtRMS, OS was induced in RAW 264.7 murine macrophage cells with hydrogen peroxide (H2O2) and lipopolysaccharide (LPS), and then treated with HtRMS solution at different concentrations (0.1, 1, and 10%). Cell viability, reactive oxygen species (ROS), nitric oxide (NO), and antioxidant enzymes such as catalase (CAT) and glutathione peroxidase (GPx), Ca2+, and mitogen-activated protein kinase (MAPK) pathway-related proteins (p-p38, p-JNK, and p-ERK) were measured. OS was significantly induced by treatment with H2O2 and LPS (p < 0.001). After treatment with HtRMS, cell viability and GPx activities significantly increased and ROS, NO, Ca2+, and CAT significantly decreased in a concentration-dependent manner compared to H2O2 and LPS-only groups, which was not observed in tap water (TW)-treated groups. Similarly, p-p38, p-JNK, and p-ERK levels significantly decreased in a concentration-dependent manner in HtRMS groups compared to both H2O2 and LPS-only groups; however, those in TW groups did not exhibit significant differences compared to H2O2 and LPS-only groups. In conclusion, our results suggest that HtRMS may have antioxidant potential by regulating the MAPK signaling pathway.
... Hydrogen is a novel therapeutic substance that is mainly administered in solution in water or gas. It has been shown to be effective against cancer, lung damage, skin tumors, and liver injury by inducing anti-inflammatory, antioxidative, and antiapoptotic effects [24][25][26][27]. Hydrogen treatment is beneficial since it is easy to apply and causes no harm or pain to patients. ...
Article
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Background: Cerebral ischemia and its reperfusion injury facilitate serious neurodegenerative diseases such as dementia due to cell death; however, there is currently no treatment for it. Reactive oxygen species is one of the many factors that induce and worsen the development of such diseases, and it can be targeted by hydrogen treatment. This study examined the effect of molecular hydrogen in cerebral ischemia-reperfusion injury, which is emerging as a novel therapeutic agent for various diseases. Methods: Ischemia-reperfusion injury was generated through bilateral common carotid artery occlusion in C57BL/6 mice. The test group received hydrogen-rich water orally during the test period. To confirm model establishment and the effect of hydrogen treatment, behavioural tests, biochemical assays, immunofluorescence microscopy, and cytokine assays were conducted. Results: Open field and novel object recognition tests revealed that the hydrogen-treated group had improved cognitive function and anxiety levels compared to the nontreated group, while hematoxylin and eosin stain showed abundant pyknotic cells in a model mouse brain, and this was attenuated in the hydrogen-treated mouse brain. Total antioxidant capacity and thiobarbituric acid reactive substance assays revealed that hydrogen treatment induced antioxidative effects in the mouse brain. Immunofluorescence microscopy revealed attenuated apoptosis in the striatum, cerebral cortex, and hippocampus of hydrogen-treated mice. Western blotting showed that hydrogen treatment reduced Bax and TNFα levels. Finally, cytokine assays showed that IL-2 and IL-10 levels significantly differed between the hydrogen-treated and nontreated groups. Conclusion: Hydrogen treatment could potentially be a future therapeutic strategy for ischemia and its derived neurodegenerative diseases by improving cognitive abilities and inducing antioxidative and antiapoptotic effects. Hydrogen treatment also decreased Bax and TNFα levels and induced an anti-inflammatory response via regulation of IL-2 and IL-10. These results will serve as a milestone for future studies intended to reveal the mechanism of action of molecular hydrogen in neurodegenerative diseases.
... Cancer therapy promotes reactive oxygen species (ROS) such as superoxide and hydrogen peroxide production [32], and these events account for most of the total tissue damage inflicted. ROS also causes mitochondrial DNA (mtDNA) and nuclear DNA damage. ...
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Advancements in cancer therapy increased the cancer free survival rates and reduced the malignant related deaths. Therapeutic options for patients with thoracic cancers include surgical intervention and the application of chemotherapy with ionizing radiation. Despite these advances, cancer therapy-related cardiopulmonary dysfunction (CTRCPD) is one of the most undesirable side effects of cancer therapy and leads to limitations to cancer treatment. Chemoradiation therapy or immunotherapy promote acute and chronic cardiopulmonary damage by inducing reactive oxygen species, DNA damage, inflammation, fibrosis, deregulation of cellular immunity, cardiopulmonary failure, and non-malignant related deaths among cancer-free patients who received cancer therapy. CTRCPD is a complex entity with multiple factors involved in this pathogenesis. Although the mechanisms of cancer therapy-induced toxicities are multifactorial, damage to the cardiac and pulmonary tissue as well as subsequent fibrosis and organ failure seem to be the underlying events. The available biomarkers and treatment options are not sufficient and efficient to detect cancer therapy-induced early asymptomatic cell fate cardiopulmonary toxicity. Therefore, application of cutting-edge multi-omics technology, such us whole-exome sequencing, DNA methylation, whole-genome sequencing, metabolomics, protein mass spectrometry and single cell transcriptomics, and 10 X spatial genomics, are warranted to identify early and late toxicity, inflammation-induced carcinogenesis response biomarkers, and cancer relapse response biomarkers. In this review, we summarize the current state of knowledge on cancer therapy-induced cardiopulmonary complications and our current understanding of the pathological and molecular consequences of cancer therapy-induced cardiopulmonary fibrosis, inflammation, immune suppression, and tumor recurrence, and possible treatment options for cancer therapy-induced cardiopulmonary toxicity.
... In the context of protecting the lung, aerosol delivery potentially allows the use of smaller doses that target more rapidly, and consequently avoid systemic side-effects. Despite these potential advantages there has, to our knowledge, been only one published report in which the mouse respiratory tract has been targeted by inhalation 75 . There has been no previous demonstration of radioprotection following aerosol delivery in a large animal model. ...
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Methods to protect against radiation-induced lung injury (RILI) will facilitate the development of more effective radio-therapeutic protocols for lung cancer and may provide the means to protect the wider population in the event of a deliberate or accidental nuclear or radiological event. We hypothesised that supplementing lipid membranes through nebulization of synthetic lamellar lipids would mitigate RILI. Following pre-treatment with either nebulised lamellar lipids or saline, anaesthetised sheep were prescribed fractionated radiotherapy (30 Gray (Gy) total dose in five 6 Gy fractions at 3-4 days intervals) to a defined unilateral lung volume. Gross pathology in radio-exposed lung 37 days after the first radiation treatment was consistent between treatment groups and consisted of deep red congestion evident on the pleural surface and firmness on palpation. Consistent histopathological features in radio-exposed lung were subpleural, periarteriolar and peribronchial intra-alveolar oedema, alveolar fibrosis, interstitial pneumonia and type II pneumocyte hyperplasia. The synthetic lamellar lipids abrogated radiation-induced alveolar fibrosis and reduced alpha-smooth muscle actin (ASMA) expression in radio-exposed lung compared to saline treated sheep. Administration of synthetic lamellar lipids was also associated with an increased number of cells expressing dendritic cell-lysosomal associated membrane protein throughout the lung.
... These mechanisms have been supported by many papers reporting the radioprotective effects of H 2 in animal experiments. 10,11,[17][18][19][20] In the present study, patients received the H 2 gas treatment after each time of IMRT. Previous studies reported the preventive (H 2 gas inhalation before radiation), but not therapeutic effects of this treatment. ...
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Although intensity-modulated radiation therapy (IMRT) has been developed as an alternative to conventional radiotherapy, reducing bone marrow damage is limited. Thus, a novel technology is needed to further mitigate IMRT-induced bone marrow damage. Molecular hydrogen (H2) was recently reported as a preventive and therapeutic antioxidant that selectively scavenges hydroxyl radical (·OH) and peroxynitrite (ONOO–). This observational study aimed to examine whether H2 gas treatment improves IMRT-induced bone marrow damage in cancer patients. The study was performed at Clinic C4 in Tokyo, Japan between May 2015 and November 2016. During this period, all enrolled patients received IMRT once per day for 1 to 4 weeks. After each time of IMRT, the patients of control group (n = 7, 3 men and 4 women, age range: 26–70 years) received mild hyperbaric oxygen therapy in health care chamber for 30 minutes, and the patients of H2 group (n = 16, 8 men and 8 women, age range: 35–82 years) received 5% H2 gas in health care chamber for 30 minutes once per day. Radiation-induced bone marrow damage was evaluated by hematological examination of peripheral blood obtained before and after IMRT, and the data were expressed by the ratio after to before treatment. The total number of radiation times and total exposure doses of radiation were similar between the control and H2 groups. IMRT with health care chamber therapy significantly reduced white blood cells and platelets, but not red blood cells, hemoglobin and hematocrit. In contrast, H2 gas treatment significantly alleviates the reducing effects of white blood cells and platelets (P = 0.0011 and P = 0.0275, respectively). Tumor responses to IMRT were similar between the two groups. The results obtained demonstrated that H2 gas inhalation therapy alleviated IMRT-induced bone marrow damage without compromising the anti-tumor effects of IMRT. The present study suggests that this novel approach of H2 gas inhalation therapy may be applicable to IMRT-induced bone marrow damage in cancer patients. The study protocol was approved by an Ethics Committee Review of Tokyo Clinic and Research Institute ICVS Incorporated (Tokyo, Japan) on February 1, 2019, and was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN ID: UMIN000035864) on February 20, 2019.
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.
Chapter
Radiation therapy is an essential treatment modality for the treatment of thoracic malignancies and plays a crucial role in the treatment of both non-small cell (NSCLC) and small cell lung cancer (SCLC). In lung cancer patients, radiation therapy is used as a curative-intent treatment for nonmetastatic disease, with or without other modalities such as surgery and systemic therapies. Radiation also plays a crucial role in the noncurative setting, improving quality of life and survival in the metastatic setting. The Cancer Treatment & Survivorship Facts & Figures (2019–2021) by the American Cancer Society has shown that 31% of patients with stage I–II non-small cell lung cancer, 53% of patients with stage III NSCLC, and 41% of patients with stage IV NSCLC receive radiation therapy to the chest either as a single modality or combined with surgery and/or systemic therapy (Miller et al. 2019).
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As research activities progressed, effects of molecular hydrogen (MH) proved to be more extended than previously expected. In parallel with exploratory experiments with animals, human clinical trials have also been performed and yielded positive results in most cases. Here I begin with animal experiments on ischemia-reperfusion injury, peritonitis to sepsis, wound healing, radiation injuries, organ transplantation, metabolic syndrome and lung diseases, and then proceed to describe clinical trials conducted in Japan including recovery from acute erythematous skin disease, cardiac arrest, stroke, brain disorder (Parkinson’s and Alzheimer’s diseases), diabetes, fatigue and aging, rheumatoid arthritis, blood dialysis, cataract surgery, periodontitis, and finally, recent results from other countries regarding radiation injuries and COVID-19 pneumonia. This is a main chapter of the book.
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Radiotherapy-related fibrosis remains one of the most challenging treatment related side effects encountered by patients with head and neck cancer. Several established and ongoing novel therapies have been studied with paucity of data in how to best treat these patients. This review aims to provide researchers and health care providers with a comprehensive review on the presentation, etiology, and therapeutic options for this serious condition.
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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.
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Oxidative stress (OS) and neuroinflammatory stress affect many neurological disorders. Despite the clinical significance of oxidative damage in neurological disorders, still, no effective and safe treatment methods for neuro diseases are available. With this, molecular hydrogen (H2) has been recently reported as an antioxidant and anti-inflammatory agent to treat several oxidative stress-related diseases. In animal and human clinical trials, the routes for H2 administration are mainly categorized into three types: H2 gas inhalation, H2 water dissolving, and H2-dissolved saline injection. This review explores some significant progress in research on H2 use in neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, neonatal disorders of the brain, and other NDs (retinal ischemia and traumatic brain injury). Even though most neurological problems are not currently curable, these studies have shown the therapeutic potential for prevention, treatment, and mitigation of H2 administration. Several possible H2-effectors, including cell signal-ing molecules and hormones, which prevent OS and inflammation, will also be addressed. However , more clinical and other related studies are required to evaluate the direct H2 target molecule.
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The aim of this study was to investigate the protective effect of hydrogen in a rat model of osteoradionecrosis of the jaw (ORNJ). The rats and bone marrow-derived mesenchymal stem cells (BMSCs) were pre-treated with hydrogen before receiving irradiation (7 Gy per fraction, five fractions in total once a day for rats, 4 Gy for BMSCs). Reactive oxygen species (ROS) and cell differentiation were measured in the BMSCs. Also, the radioprotective effect of hydrogen for ORNJ in Sprague-Dawley rats was examined by gross clinical manifestations, micro-computed tomography, and histology. Hydrogen significantly reduced the production of ROS in BMSCs after irradiation. The cell viability was significantly decreased after irradiation (P = 0.001), but pre-treatment with hydrogen before irradiation increased the cell viability (P = 0.025). Hydrogen considerably increased the cellular differentiation potential of the irradiated cells. Comparing with the rats underwent irradiaton only, those rats treated by hydrogen-rich saline significantly appeared improved occlusion, salivation, alopecia, oral ulcer, and less bone necrosis. Myofibroblasts accumulated overwhelmingly in the fibrosis medulla and around the sequestrum after irradiation, and this was decreased in the group pre-treated with hydrogen. Hydrogen may represent a strategy for the prevention and treatment of ORNJ. Its high efficacy and low toxicity suggest possible therapeutic application.
Head and neck cancer and its treatment result in soft tissue damage secondary to lymphedema and fibrosis. Lymphedema is the result of pathological accumulation of interstitial fluid in tissues. It is caused by the inability of the lymphatic system to transport lymph fluid from the tissues to the central circulatory system and is manifested clinically by tissue swelling. Fibrosis is defined as an overaccumulation of fibrotic tissues within the skin and soft tissues after a single or repetitive injury and is characterized by hardening of the soft tissues with associated loss of elasticity. Lymphedema and fibrosis are common yet overlooked late effects of head and neck cancer and its therapy. They may result in profound long-term symptom burden, loss of critical functions, and altered quality of life. The following review will discuss the current pathobiology, clinical manifestations, and future directions for research related to lymphedema and fibrosis.
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Purpose To determine the role of NLRP3 inflammasome activation in low-dose radiation-induced radiation pneumonitis (RP) and to assess whether the inhibition or deletion of the NLRP3 inflammasome is critical for conferring protection against RP. Materials and Methods THP-1 cells were treated with increasing doses of radiation to assess the activation of NLRP3 by Western blot and ELISA. Reactive oxygen species (ROS) production was measured by flow cytometry, with or without ROS inhibitor treatment. A mouse thoracic radiation model that received different doses of radiation was used, and the lung tissues of thoracic-irradiated nlrp3-/- and wild-type C57BL/6 mice were examined by H&E and immunofluorescence staining. The concentrations of cytokines in the bronchoalveolar lavage fluid (BALF) were measured by ELISA and Luminex multiplex assays. LPS was administered intranasally 28 days after thoracic irradiation, and MCC950 was administered intraperitoneally after irradiation at 2 different doses. Results 1. The NLRP3 inflammasome was activated in 2 Gy-irradiated THP-1 cells; NLRP3 and cleaved-caspase-1 levels were not associated with dose escalation. 2. Activation of the NLRP3 inflammasome was mediated by ROS, and ROS inhibitor treatment decreased the production of IL-1β and IL-18 in vitro. 3. NLRP3 was activated in mouse lungs by irradiation at 2 Gy, 4 Gy, and 16 Gy, and NLRP3 activation was continuous. 4. NLRP3 protects against LPS-mediated monocyte infiltration in the mouse lung. 5. The administration of MCC950 decreased the inflammation score of the mice irradiated with 2 Gy or 16 Gy in vivo. Conclusions Our results indicate that the NLRP3 inflammasome is activated by low-dose irradiation both in vitro and in vivo. The inhibition or deletion of NLRP3 can specifically alleviate the mouse lung inflammation caused by radiation and LPS treatment. This study reveals the mechanism of low-dose radiation therapy-induced RP; furthermore, it offers a possible treatment strategy for patients.
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Background: Previous studies have shown that hydrogen (H2) can antagonize the fibrosis of various organs. We investigated whether hydrogen-rich saline (HRS) can attenuate myocardial fibrosis in spontaneously hypertensive rats (SHR) and clarified the mechanisms involved. Methods: We examined the effect of HRS and pirfenidone (PFD) on myocardial fibrosis in SHR. Systolic blood pressure, left ventricular mass index (LVMI) and heart weight index (HWI) were measured, Masson trichrome staining was performed. We assessed the role of superoxide dismutase (SOD), malondialdehyde (MDA), Alpha-smooth muscle actin (α-SMA), collagen I, collagen III, and tissue inhibitors of metalloproteinases (TIMPs) in myocardium. We detected the concentrations of procollagen type-I C-terminal propeptide (PICP), procollagen type-III N-terminal propeptide (PIIINP), and angiotensin II (AngII) in rat serum. Furthermore, the relative protein levels of the TGFβ/Smad pathway were tested. Results: We discovered that HRS decreases LVMI (P<0.05) and HWI(P<0.05) in vivo. Compared to model group, HRS decreases the level of collagen volume fraction(P<0.0001), collagen I(P<0.001), and collagen III(P<0.001) in myocardium, and Ang II(P<0.05), PICP(P<0.001), and PIIINP(P<0.05) in serum. In addition, HRS down-regulates the expression of MDA(P<0.01), α-SMA(P<0.05), and TIMPs(P<0.05), and increased SOD(P<0.05). Furthermore, HRS down-regulated the expression levels of TGF-β1(P<0.0001), Smad3(P<0.0001), and Smad2/3(P<0.001), but had no effect on Smad7 expression(P>0.05). PFD had similar effect compared with HRS and control group. Conclusions: HRS reduced oxidative stress and improved myocardial collagen content, which may be related to inhibition of the TGF-β signaling pathway.This suggests that HRS is an effective therapeutic strategy for myocardial fibrosis.
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The small intestine is known to be particularly sensitive to radiation, and the major limiting factor of radiotherapy is the gastrointestinal syndrome that subsequently develops after its administration. The detrimental effects of radiation are mostly mediated via the overproduction of reactive oxygen species (ROS), especially the hydroxyl radical (·OH). Because hydrogen is a selective ·OH scavenger, we hypothesized that hydrogen might exert a protective effect against radiation-induced intestinal damage. Herein, radiation models were built both in mice and in an intestinal crypt epithelial cell (IEC-6) line. In the animal experiment, we demonstrated that hydrogen-rich saline significantly reduced radiation-induced intestinal mucosal damage, improved intestinal function, and increased the survival rate. In addition, radiation-induced oxidative stress damage and systemic inflammatory response were also mitigated by hydrogen treatment. Moreover, hydrogen treatment decreased cell apoptosis and maintained intestinal epithelial cell proliferation in mice. In vitro experiments using the IEC-6 cell line showed that hydrogen-rich medium significantly inhibited ROS formation, maintained cell viability, and inhibited cell apoptosis. Importantly, hydrogen treatment prevented mitochondrial depolarization, cytochrome c release, and activity of caspase-3, caspase-9, and PARP. Moreover, the decreased expression of Bcl-xl and Bcl-2 and the increased expression of Bax protein were also blocked by hydrogen treatment. In conclusion, our study concurrently demonstrated that hydrogen provides an obviously protective effect on radiation-induced intestinal and cell injuries. Our work demonstrated that this protective effect might be due to the blockage of the mitochondrial apoptotic pathway.
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Radiotherapy (RT) has become an indispensable part of oncologic treatment protocols for a range of malignancies. However, a serious adverse effect of RT is radiodermatitis; almost 95% of patients develop moderate to severe skin reactions following radiation treatment. In the acute setting, these can be erythema, desquamation, ulceration, and pain. Chronically, soft tissue atrophy, alopecia, and stiffness can be noted. Radiodermatitis can delay oncologic treatment protocols and significantly impair quality of life. There is currently a paucity of effective treatment options and prevention strategies for radiodermatitis. Importantly, recent preclinical and clinical studies have suggested that fat grafting may be of therapeutic benefit, reversing detrimental changes to soft tissue following RT. This review outlines the damaging effects of RT on the skin and soft tissue as well as discusses available treatment options for radiodermatitis. Emerging strategies to mitigate detrimental, chronic radiation-induced changes are also presented.
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The development and response to treatment of tumor are modulated by inflammation, and chronic inflammation promotes tumor progression and therapy resistance. This article summarizes the dynamic evolution of inflammation from acute to chronic in the process of tumor development, and its effect on T cells from activation to the promotion of exhaustion. We review the mechanisms by which inflammatory cells and inflammatory cytokines regulate T cell exhaustion and methods for targeting chronic inflammation to improve the efficacy of immunotherapy. It is great significance to refer to the specific state of inflammation and T cells at different stages of tumor development for accurate clinical decision-making of immunotherapy and improving the efficiency of tumor immunotherapy.
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Radiation‐induced lung injury (RILI) is a potentially fatal and dose-limiting complication of thoracic cancer radiotherapy. However, effective therapeutic agents for this condition are limited. Here, we describe a novel strategy to exert additive effects of a non-erythropoietic EPO derivative (ARA290), along with a free radical scavenger, superoxide dismutase (SOD), using a bioengineered nanoreactor ([email protected]). ARA290-chimeric nanoreactor makes SOD present in a confined reaction space by encapsulation into its interior to heighten stability against denaturing stimuli. In a RILI mouse model, intratracheal administration of [email protected] was shown to significantly ameliorate acute radiation pneumonitis and pulmonary fibrosis. Our investigations revealed that [email protected] performs its radioprotective effects by protecting against radiation induced alveolar epithelial cell apoptosis and ferroptosis, suppressing oxidative stress, inhibiting inflammation and by modulating the infiltrated macrophage phenotype, or through a combination of these mechanisms. In conclusion, [email protected] is a potential therapeutic agent for RILI, and given its multifaceted roles, it may be further developed as a translational nanomedicine for other related disorders.
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Background Acute respiratory distress syndrome, which is caused by acute lung injury, is a destructive respiratory disorder caused by a systemic inflammatory response. Persistent inflammation results in irreversible alveolar fibrosis due to excessive activation of M2 macrophages. Because hydrogen gas possesses anti-inflammatory properties, we hypothesized that daily intermittent inhalation of hydrogen gas could suppress persist acute inflammation by inducing functional changes in macrophages, and consequently inhibit lung fibrosis during late-phase lung injury. Methods To test this hypothesis, lung injury was induced in mice by intratracheal administration of bleomycin (1.0 mg/kg). Mice were exposed to control gas (air) or hydrogen (3.2% in air) for 6 hours every day for 7 or 21 days. Respiratory physiology, tissue pathology, markers of inflammation, and macrophage phenotypes were examined. Results Mice with bleomycin-induced lung injury who received daily hydrogen therapy for 21 days (BH group) exhibited higher static compliance (0.056 mL/cmH2O [95% CI:0.047–0.064] than mice with bleomycin-induced lung injury exposed only to air (BA group; 0.042 mL/cmH2O [95% CI:0.031–0.053], p = 0.02) and lower static elastance (BH 18.8 cmH2O/mL [95% CI:15.4–22.2] vs BA 26.7 cmH2O/mL [95% CI:19.6–33.8], p = 0.02). When the mRNA levels of pro-inflammatory cytokines were examined 7 days after bleomycin administration, interleukin (IL)-6, IL-4 and IL-13 were significantly lower in the BH group than in the BA group. There were significantly fewer M2 macrophages in the alveolar interstitium of the BH group than in the BA group (3.1% [95% CI: 1.6%-4.5%] vs 1.1% [95% CI: 0.3%-1.8%], p = 0.008). Conclusions The results suggest that hydrogen inhalation inhibits the deterioration of respiratory physiological function and alveolar fibrosis in this model of acute lung injury by suppressing differentiation of M2 macrophages in the alveolar interstitium.
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Radiation-induced fibrosis (RIF) is a severe long-term complication of the normal tissue following radiotherapy. Its prototypical characteristic is the persistent activation of myofibroblasts, resulting in proportion disorder and hyperplasia remodeling of the extracellular matrix comprising collagen. The continuous progress of RIF may contribute to multiple clinical manifestations such as hollow organ stenosis, impaired gaseous diffusion, and loss of tissue compliance significantly affecting the overall quality of daily life in patients with irradiated cancer. Traditionally, the potential mechanism of myofibroblast activation and differentiation has not been elucidated, and the process has been considered as static and irreversible. Recent studies have shown that RIF is a dynamic, multi-step process mediated by many regulated chemokines and cytokines. The RIF process includes release of reactive oxygen species (ROS), microvascular injury, recruitment of inflammatory cells, and activation of myofibroblasts. Numerous signaling pathways are involved in the initiation and progression of RIF, of which SMAD-regulated CTGF expression mediated by TGF-β1 is referred as the main axis. Current management strategies applied in clinical practice for patients with RIF are only supportive treatments, such as anti-inflammatory therapy using steroids; however, the efficacies achieved by these interventions are limited and unsatisfactory. Therefore, this review explores advances in RIF pathogenesis and anti-fibrosis therapy. We hope to provide clinicians with improved awareness and enormous promise in the management of RIF.
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The role of reactive oxygen species in ionizing radiation injury and the potential of antioxidants to reduce these deleterious effects have been studied in animal models for more than 50 years. This review focuses on the radioprotective efficacy and the toxicity in mice of phosphorothioates such as WR-2721 and WR-151327, other thiols, and examples of radioprotective antioxidants from other classes of agents. Naturally occurring antioxidants, such as vitamin E and selenium, are less effective radioprotectors than synthetic thiols but may provide a longer window of protection against lethality and other effects of low dose, low-dose rate exposures. Many natural antioxidants have antimutagenic properties that need further examination with respect to long-term radiation effects. Modulation of endogenous antioxidants, such as superoxide dismutase, may be useful in specific radiotherapy protocols. Other drugs, such as nimodipine, propranolol, and methylxanthines, have antioxidant properties in addition to their primary pharmacological activity and may have utility as radioprotectors when administered alone or in combination with phosphorothioates.
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Hydrogen has been reported to have neuron protective effects due to its antioxidant properties, but the effects of hydrogen on cognitive impairment due to senescence-related brain alterations and the underlying mechanisms have not been characterized. In this study, we investigated the efficacies of drinking hydrogen water for prevention of spatial memory decline and age-related brain alterations using senescence-accelerated prone mouse 8 (SAMP8), which exhibits early aging syndromes including declining learning ability and memory. However, treatment with hydrogen water for 30 days prevented age-related declines in cognitive ability seen in SAMP8 as assessed by a water maze test and was associated with increased brain serotonin levels and elevated serum antioxidant activity. In addition, drinking hydrogen water for 18 weeks inhibited neurodegeneration in hippocampus, while marked loss of neurons was noted in control, aged brains of mice receiving regular water. On the basis of our results, hydrogen water merits further investigation for possible therapeutic/preventative use for age-related cognitive disorders.
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Metabolic syndrome is characterized by cardiometabolic risk factors that include obesity, insulin resistance, hypertension and dyslipidemia. Oxidative stress is known to play a major role in the pathogenesis of metabolic syndrome. The objective of this study was to examine the effectiveness of hydrogen rich water (1.5-2 L/day) in an open label, 8-week study on 20 subjects with potential metabolic syndrome. Hydrogen rich water was produced, by placing a metallic magnesium stick into drinking water (hydrogen concentration; 0.55-0.65 mM), by the following chemical reaction; Mg + 2H(2)O --> Mg (OH)(2) + H(2). The consumption of hydrogen rich water for 8 weeks resulted in a 39% increase (p<0.05) in antioxidant enzyme superoxide dismutase (SOD) and a 43% decrease (p<0.05) in thiobarbituric acid reactive substances (TBARS) in urine. Further, subjects demonstrated an 8% increase in high density lipoprotein (HDL)-cholesterol and a 13% decrease in total cholesterol/HDL-cholesterol from baseline to week 4. There was no change in fasting glucose levels during the 8 week study. In conclusion, drinking hydrogen rich water represents a potentially novel therapeutic and preventive strategy for metabolic syndrome. The portable magnesium stick was a safe, easy and effective method of delivering hydrogen rich water for daily consumption by participants in the study.
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It has been demonstrated that hydrogen can selectively reduce hydroxyl and peroxynitrite in vitro. Since most of the ionizing radiation-induced cellular damage is caused by hydroxyl radicals, this study was designed to test the hypothesis that hydrogen may be an effective radioprotective agent. This paper demonstrates that treating cells with hydrogen before irradiation could significantly inhibit ionizing irradiation(IR)-induced Human Lymphocyte AHH-1 cells apoptosis and increase cells viability in vitro. This paper also shows that hydrogen can protect gastrointestinal endothelia from radiation-induced injury, decrease plasma malondialdehyde (MDA) intestinal 8-hydroxydeoxyguanosine (8-OHDG) levels and increase plasma endogenous antioxidants in vivo. It is suggested that hydrogen has a potential as an effective and safe radioprotective agent.
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Retinal ischemia-reperfusion (I/R) injury by transient elevation of intraocular pressure (IOP) is known to induce neuronal damage through the generation of reactive oxygen species. Study results have indicated that molecular hydrogen (H(2)) is an efficient antioxidant gas that selectively reduces the hydroxyl radical (*OH) and suppresses oxidative stress-induced injury in several organs. This study was conducted to explore the neuroprotective effect of H(2)-loaded eye drops on retinal I/R injury. Retinal ischemia was induced in rats by raising IOP for 60 minutes. H(2)-loaded eye drops were prepared by dissolving H(2) gas into a saline to saturated level and administered to the ocular surface continuously during the ischemia and/or reperfusion periods. One day after I/R injury, apoptotic cells in the retina were quantified, and oxidative stress was evaluated by markers such as 4-hydroxynonenal and 8-hydroxy-2-deoxyguanosine. Seven days after I/R injury, retinal damage was quantified by measuring the thickness of the retina. When H(2)-loaded eye drops were continuously administered, H(2) concentration in the vitreous body immediately increased and I/R-induced *OH level decreased. The drops reduced the number of retinal apoptotic and oxidative stress marker-positive cells and prevented retinal thinning with an accompanying activation of Müller glia, astrocytes, and microglia. The drops improved the recovery of retinal thickness by >70%. H(2) has no known toxic effects on the human body. Thus, the results suggest that H(2)-loaded eye drops are a highly useful neuroprotective and antioxidative therapeutic treatment for acute retinal I/R injury.
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Cisplatin is a widely used anti-cancer drug in the treatment of a wide range of tumors; however, its application is limited by nephrotoxicity, which is affected by oxidative stress. We have reported that molecular hydrogen (H(2)) acts as an efficient antioxidant (Ohsawa et al. in Nat Med 13:688-694, 2007). Here we show that hydrogen efficiently mitigates the side effects of cisplatin by reducing oxidative stress. Mice were administered cisplatin followed by inhaling hydrogen gas (1% H(2) in air). Furthermore, instead of inhaling hydrogen gas, we examined whether drinking water containing hydrogen (hydrogen water; 0.8 mM H(2) in water) is applicable by examining oxidative stress, mortality, and body-weight loss. Nephrotoxicity was assessed by morphological changes, serum creatinine and blood urea nitrogen (BUN) levels. Inhalation of hydrogen gas improved mortality and body-weight loss caused by cisplatin, and alleviated nephrotoxicity. Hydrogen was detected in blood when hydrogen water was placed in the stomach of a rat. Consuming hydrogen water ad libitum also reduced oxidative stress, mortality, and body-weight loss induced by cisplatin in mice. Hydrogen water improved metamorphosis accompanying decreased apoptosis in the kidney, and nephrotoxicity as assessed by serum creatinine and BUN levels. Despite its protective effects against cisplatin-induced toxicity, hydrogen did not impair anti-tumor activity of cisplatin against cancer cell lines in vitro and tumor-bearing mice in vivo. Hydrogen has potential for improving the quality of life of patients during chemotherapy by efficiently mitigating the side effects of cisplatin.
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The mouse has been used extensively to model radiation injury to the lung, a major dose-limiting organ for radiotherapy. Substantial differences in the timing and sensitivity of this tissue between mouse strains have been reported, with some strains, including C57BL/6, being designated as "fibrosis-prone". Pleural effusions have also been reported to be a prominent problem in many mouse strains, but it remains unclear how this affects the lung function and survival of the standard C57BL/6 mouse. The purpose of this investigation was to re-evaluate this strain in comparison with C57L and CBA mice after whole-thorax irradiation at doses ranging from 10 to 15 Gy. Breathing rate measurements, micro-computerized tomography, lung tissue weight, pleural fluid weight and histopathology showed that the most prominent features were an early phase of pneumonitis (C57L and CBA) followed by a late incidence of massive pleural effusions (CBA and C57BL/6). A remarkable difference was seen between the C57 strains: The C57L mice were exquisitely sensitive to early pneumonitis at 3 to 4 months while C57BL/6 mice showed a delayed response, with most mice presenting with large accumulations of pleural fluid at 6 to 9 months. These results therefore caution against the routine use of C57BL/6 mice in radiation lung experiments because pleural effusions are rarely observed in patients as a consequence of radiotherapy. Future experiments designed to investigate genetic determinants of radiation lung damage should focus on the high sensitivity of the C57L strain (in comparison with CBA or C3H mice) and the possibility that they are more susceptible to pulmonary fibrosis as well as pneumonitis.
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Reactive oxygen species (ROS) contribute to the development of interstitial fibrosis and tubular atrophy seen in chronic allograft nephropathy (CAN). As molecular hydrogen gas can act as a scavenger of ROS, we tested the effect of treatment with hydrogen water (HW) in a model of kidney transplantation, in which allografts from Lewis rats were orthotopically transplanted into Brown Norway recipients that had undergone bilateral nephrectomy. Molecular hydrogen was dissolved in water and recipients were given HW from day 0 until day 150. Rats that were treated with regular water (RW) gradually developed proteinuria and their creatinine clearance declined, ultimately leading to graft failure secondary to CAN. In contrast, treatment with HW improved allograft function, slowed the progression of CAN, reduced oxidant injury and inflammatory mediator production, and improved overall survival. Inflammatory signaling pathways, such as mitogen-activated protein kinases, were less activated in renal allografts from HW-treated rats as compared with RW-treated rats. Hence, oral HW is an effective antioxidant and antiinflammatory agent that prevented CAN, improved survival of rat renal allografts, and may be of therapeutic value in the setting of transplantation.
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Xerostomia frequently arises in patients with head and neck malignancies that are treated by radiation. However, the mechanisms responsible for the destruction of the salivary gland remain unknown. We previously established a xerostomia model of mice and identified the pathway through which nitric oxide (NO) affects the pathogenesis of radiation-induced salivary gland dysfunction. Although the toxicity of NO alone is modest, NO with superoxide anion (O2 ) rapidly forms peroxynitrite (ONOO-), a more powerful toxic oxidant. In this study, we used the experimental model to examine: 1) when NO and O2 production is maximum in the salivary gland after irradiation; 2) whether peroxynitrite, as assessed by nitrotyrosine production, is responsible for salivary gland dysfunction; and 3) the effect of the iNOS selective inhibitor, aminoguanidine (AG), on nitrotyrosine formation. The increases in production of NO and O2 in the salivary gland peaked on day 7 after irradiation. Nitrotyrosine detected immunohistochemically was significantly reduced by AG in the salivary gland. On the basis of these results, we concluded that NO together with O2 forms the more reactive ONOO- which might be an important pathogenic factor in radiation-induced salivary gland dysfunction.
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Ionizing radiation induces the production of reactive oxygen species (ROS), which play an important causative role in cell death. Therefore, compounds that control the level of ROS may confer radioprotective effects. Ebselen, a seleno-organic compound, has been shown to protect against cell injury caused by ROS. The objective of this study was to examine the effects of ebselen on radiation-dependent toxicity. We investigated the protective role of ebselen against ionizing radiation in U937 cells and mice. Upon exposure to 20 Gy of gamma-irradiation, there was a distinct difference between untreated cells and the cells pretreated with 5 microM ebselen for 2 h with respect to viability, cellular redox status, and oxidative damage to cells. When cells were exposed to 2 Gy of gamma-irradiation, there was a distinct difference between the untreated cells and the cells pretreated with ebselen with respect to apoptotic features and mitochondrial function. Ebselen administration for 14 days at a daily dosage of 10 mg/kg provided substantial protection against killing and oxidative damage to mice exposed to whole-body irradiation. These data indicate that ebselen may have great potential as a new class of in vivo, non-sulfur-containing radiation protector.
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This study investigated protection of lung injury by genistein following fractionated doses of radiation and its effect on tumor response. C3H/HeJ mice were irradiated (100 kVp X-rays) with 9 fractions of 3.1 Gy over 30 days (approximately equivalent to 10 Gy single dose) and were maintained on a genistein diet ( approximately 10mg/kg). Damage was assessed over 28 weeks in lung cells by a cytokinesis block micronucleus (MN) assay and by changes in breathing rate and histology. Tumor protection was assessed using a colony assay to determine cell survival following in situ irradiation of small lung nodules (KHT fibrosarcoma). Genistein caused about a 50% reduction in the MN damage observed during the fractionated radiation treatment and this damage continued to decrease at later times to background levels by 16 weeks. In mice not receiving Genistein MN levels remained well above background out to 28 weeks after irradiation. Genistein reduced macrophage accumulation by 22% and reduced collagen deposition by 28%. There was minimal protection against increases in breathing rate or severe morbidity during pneumonitis. No tumor protection by genistein treatment was observed. Genistein at the dose levels used in this study partially reduced the extent of fibrosis developing in mouse lung caused by irradiation but gave minimal protection against pneumonitis. There was no evidence that genistein caused protection of small tumors growing in the lung.