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Hydrogen therapy attenuates irradiation-induced lung damage by reducing oxidative stress
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.
... Furthermore, many studies have reported the use of hydrogen therapy in different diseases, including those involving the nervous, digestive, cardiovascular and respiratory systems. The protective effects of hydrogen have also been confirmed in different animal models, including the ability to limit the infarct volume of the brain, heart, intestines and kidneys by reducing ischemiareperfusion injury without altering hemodynamic parameters and providing protection against multiple organ damage elicited by generalized inflammation [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] . These studies suggest that hydrogen plays a beneficial role in clinical applications in various organs. ...
... The mechanism of action of hydrogen in this model involves the ability of this compound to prevent oxidative damage, as indicated by decreased nucleic acid oxidation and lipid peroxidation 1,21 . Furthermore, many studies have provided evidence that hydrogen plays a protective role against acute and chronic injury in various organs [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] . According to the present data, the hydrogen concentrations in the animal tissues reached a maximum five minutes after oral and intraperitoneal treatment; therefore, the best time point for treatment with hydrogen, with respect to obtaining significant ROS scavenging effects, may be five minutes before the start of experiment. ...
... Based on these data, clinicians and researchers can choose the more efficient route of treatment and explore whether hydrogen inhibits inflammatory diseases in these organs. Hydrogen has not been reported to be toxic at effective doses, and overdoses are unlikely, as excess hydrogen is expired via the lungs 16 . This phenomenon contrasts with that of antioxidants, such as vitamins C and E, for which the effective dose in humans is higher than the upper limit of tolerated intake 13,17,23 . ...
Hydrogen exerts beneficial effects in disease animal models of ischemia-reperfusion injury as well as inflammatory and neurological disease. Additionally, molecular hydrogen is useful for various novel medical and therapeutic applications in the clinical setting. In the present study, the hydrogen concentration in rat blood and tissue was estimated. Wistar rats were orally administered hydrogen super-rich water (HSRW), intraperitoneal and intravenous administration of hydrogen super-rich saline (HSRS), and inhalation of hydrogen gas. A new method for determining the hydrogen concentration was then applied using high-quality sensor gas chromatography, after which the specimen was prepared via tissue homogenization in airtight tubes. This method allowed for the sensitive and stable determination of the hydrogen concentration. The hydrogen concentration reached a peak at 5 minutes after oral and intraperitoneal administration, compared to 1 minute after intravenous administration. Following inhalation of hydrogen gas, the hydrogen concentration was found to be significantly increased at 30 minutes and maintained the same level thereafter. These results demonstrate that accurately determining the hydrogen concentration in rat blood and organ tissue is very useful and important for the application of various novel medical and therapeutic therapies using molecular hydrogen. M olecular hydrogen, a potent free radical scavenger, selectively reduces the levels of hydroxyl radical and peroxynitrite, the most cytotoxic reactive oxygen species (ROS), thereby effectively protecting cells 1. Hydrogen is also beneficial for use in various novel medical therapeutic applications. Recently, hydrogen was reported to be helpful for treating schistosomiasis-associated chronic liver inflammation; these therapeutic properties are ascribed to the scavenging of hydroxyl radical 2. Furthermore, many studies have reported the use of hydrogen therapy in different diseases, including those involving the nervous, digestive, cardiovascular and respiratory systems. The protective effects of hydrogen have also been confirmed in different animal models, including the ability to limit the infarct volume of the brain, heart, intestines and kidneys by reducing ischemia-reperfusion injury without altering hemodynamic parameters and providing protection against multiple organ damage elicited by generalized inflammation 3-17. These studies suggest that hydrogen plays a beneficial role in clinical applications in various organs. However, it is difficult to accurately clarify the hydrogen concentrations in animal organs using different administration methods due to the sensitivity of the detectors and issues related to tissue processing. The present study therefore describes a feasible approach for precisely determining the hydrogen concentration in animal tissues. We modified a hydrogen detection method used in conventional gas chromatography in order to develop a more sensitive and accurate system. Using this novel method, we measured the hydrogen concentrations in the tissue following the administration of different concentrations of hydrogen super-rich water (HSRW) and hydrogen super-rich saline (HSRS) at different point times as well as the inhalation of hydrogen gas at different concentrations. Our results demonstrated the establishment of a method for accurately determining the hydrogen concentration in rat blood and organ tissues. Data regarding the hydrogen concentrations in vivo may be very useful and important for the application of various novel medical and therapeutic therapies using molecular hydrogen. OPEN SUBJECT AREAS: BIOCHEMICAL ASSAYS HOMEOSTASIS
... 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. ...
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.
... 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. ...
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.
... proteins, lipids) [20,21]. Generation of ROS are thought to account for more than 60% of the total radiation induced damage [22,23]. ...
... Radiotherapy improved the cancer-specific survival in patients with three nodes positive have a higher tumor burden and possibly higher risk of recurrence and metastasis than those of patients with one or two lymph nodes positive [6,23]. It is proven by a series of clinical studies that combined radiotherapy after mastectomy can improve the survival of patients with four or more positive lymph nodes [85][86][87][88]. ...
Breast cancer is the most common cancer among women worldwide. Breast cancer provides an excellent example of how multidisciplinary management has improved patient outcomes. This paper synthesizes the complex and evolving evidence regarding the role of radiation therapy after mastectomy. Although substantial evidence indicates that radiation therapy can reduce the risk of locoregional failure after mastectomy. This therapy is known as PMRT. Postmastectomy radiotherapy (PMRT) is an essential component of combined therapy for early‐stage, high‐risk breast cancer. Breast reconstruction (BR) is often considered for patients with breast cancer who have undergone mastectomy. There has been a considerable amount of discussion about the optimal approach to combining PMRT with BR in the treatment of breast cancer. PMRT may increase the risk of complications and prevent good aesthetic results after BR, while BR may increase the complexity of PMRT and the radiation dose to surrounding normal tissues. The goal of a PMRT plan is to achieve optimal coverage of the target volume while minimizing the irradiation dose to normal tissues. The purpose of this review is to give a broad overview and summary of the current topical fibronectin improves wound healing in postmastectomy breast cancer radiation therapy. In summary, Exogenous fibronectin diminishes wound progression, by increasing angiogenesis & cell proliferation. This suggests that enhances healing by stimulating the appearance of fibroblasts into the wound site and development of granulation tissue. This acceleration of the repair process may have an important application in the healing of skin chronic wounds.
... Hydrogen's anti-apoptotic functions have been proposed to occur via the inhibition of caspase-3 activation and the induction of anti-apoptotic gene B-cell lymphoma-2 (Bcl-2) [32]. Terasaki et al. reported that the activation of the pro-apoptotic gene Bax was reduced via hydrogen treatment [60]. The anti-apoptotic effects of hydrogen gas inhalation were partially mediated by the early activation of NF-κB during hydrogen treatment and correlated with decreased levels of Bax and elevated levels of the anti-apoptotic protein Bcl-2 [61]. ...
... Type III collagen plays a significant role in the interstitia of solid organs and in the formation of granulation tissue following ischemic tissue damage. Terasaki et al. conducted a study showing that both the inhalation of 3% hydrogen gas and the oral consumption of hydrogen-enriched water reduced oxidative stress and apoptosis, which are indicators of acute lung damage, in mice exposed to irradiation [60]. This led to a decrease in the deposition of type III collagen and the development of lung fibrosis, which is a manifestation of late-stage damage. ...
Hydrogen gas, renowned for its antioxidant properties, has emerged as a novel therapeutic agent with applications across various medical domains, positioning it as a potential adjunct therapy in transplantation. Beyond its antioxidative properties, hydrogen also exerts anti-inflammatory effects by modulating pro-inflammatory cytokines and signaling pathways. Furthermore, hydrogen’s capacity to activate cytoprotective pathways bolsters cellular resilience against stressors. In recent decades, significant advancements have been made in the critical medical procedure of transplantation. However, persistent challenges such as ischemia-reperfusion injury (IRI) and graft rejection continue to hinder transplant success rates. This comprehensive review explores the potential applications and therapeutic implications of hydrogen in transplantation, shedding light on its role in mitigating IRI, improving graft survival, and modulating immune responses. Through a meticulous analysis encompassing both preclinical and clinical studies, we aim to provide valuable insights into the promising utility of hydrogen as a complementary therapy in transplantation.
... 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). ...
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.
... 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. ...
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.
... 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). ...
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.
... 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]. ...
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.
... 8 Previous studies have found that hydrogen can improve the heart and lung fibrosis caused by radiation damage and liver fibrosis after infection. [9][10][11] Another recent study has shown that hydrogen can ameliorate cardiac hypertrophy in pressure-overload rats. 12 However, the molecular mechanism of the multiple organ protective effect of hydrogen has not been elucidated. ...
... Compared with hydrogen gas, HRS is safe, economical, easily available, and more convenient for long-term treatment. In the present study, we dissolved hydrogen in physiological saline for 4 hours under a pressure of 0.4 MPa, as described by Ohsawa et al. 10 We freshly prepared HRS every 3 days to ensure a constant concentration of more than 0.6 mM. ...
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.
... The indirect mechanism involves the ionization of water molecules within the cell, producing reactive oxygen species (ROS), including hydroxyl radical, superoxide, and hydrogen peroxide [35,38]. These ROS overwhelm the cell's natural antioxidant defenses and induce oxidative stress by attacking cellular components like lipids, proteins, and nucleic acids [39,40]. In cancer cells, such oxidative damage contributes to the formation of single-strand breaks (SSBs) and DSBs, driving cell death. ...
Surgical intervention utilizing various approaches is a cornerstone in the management of breast cancer. The surgical approaches include lumpectomy, mastectomy, axillary lymph node dissection, and primary or delayed reconstruction. Post-mastectomy radiotherapy is frequently recommended in cases of advanced tumors and extensive lymph node involvement. However, there are several adverse effects of radiotherapy. In this article, we critically reviewed the various complications. Additionally, we discussed the biological basis of radiation-induced tissue damage, the impact of implant-based and autologous tissue reconstruction, and the functional and aesthetic results of the reconstruction. Indeed, several radioprotective agents can attenuate the adverse effects of post-mastectomy radiotherapy while sustaining oncologic efficacy. Radioprotective agents, including free radical scavengers and antioxidants, offer promising strategies to protect tissues from the oxidative stress and inflammation induced by radiotherapy. The role of several radioprotective agents, including amifostine, N-acetylcysteine, tempol, manganese superoxide dismutase (MnSOD) plasmid liposomes, vitamin E, and beta-carotene has been analyzed with a focus on their logistical applications in breast reconstruction. Despite several challenges, the integration of radioprotective agents into post-mastectomy radiotherapy protocols offers significant potential to improve reconstructive outcomes. Development of novel radioprotective agents with improved selectivity and fewer side effects and large-scale clinical trials in diverse group of patients are warranted to determine long-term safety and efficacy.
... Inhaled hydrogen mitigates lung injury in various animal models, such as hemorrhagic shock (18), ventilator-induced lung injury (19), and radiationinduced lung injury (20). However, hydrogen + TTM32-TTM34 was not associated with improved oxygenation. ...
Objective
The Efficacy of Inhaled Hydrogen on Neurologic Outcome Following Brain Ischemia During Post-Cardiac Arrest Care (HYBRID) II trial (jRCTs031180352) suggested that hydrogen inhalation may reduce post-cardiac arrest brain injury (PCABI). However, the combination of hypothermic target temperature management (TTM) and hydrogen inhalation on outcomes is unclear. The aim of this study was to investigate the combined effect of hydrogen inhalation and hypothermic TTM on outcomes after out-of-hospital cardiac arrest (OHCA).
Design
Post hoc analysis of a multicenter, randomized, controlled trial.
Setting
Fifteen Japanese ICUs.
Patients
Cardiogenic OHCA enrolled in the HYBRID II trial.
Interventions
Hydrogen mixed oxygen (hydrogen group) versus oxygen alone (control group).
Measurements and Main Results
TTM was performed at a target temperature of 32–34°C (TTM32–TTM34) or 35–36°C (TTM35–TTM36) per the institutional protocol. The association between hydrogen + TTM32–TTM34 and 90-day good neurologic outcomes was analyzed using generalized estimating equations. The 90-day survival was compared between the hydrogen and control groups under TTM32–TTM34 and TTM35–TTM36, respectively. The analysis included 72 patients (hydrogen [ n = 39] and control [ n = 33] groups) with outcome data. TTM32–TTM34 was implemented in 25 (64%) and 24 (73%) patients in the hydrogen and control groups, respectively ( p = 0.46). Under TTM32–TTM34, 17 (68%) and 9 (38%) patients achieved good neurologic outcomes in the hydrogen and control groups, respectively (relative risk: 1.81 [95% CI, 1.05–3.66], p < 0.05). Hydrogen + TTM32–TTM34 was independently associated with good neurologic outcomes (adjusted odds ratio 16.10 [95% CI, 1.88–138.17], p = 0.01). However, hydrogen + TTM32–TTM34 did not improve survival compared with TTM32–TTM34 alone (adjusted hazard ratio: 0.22 [95% CI, 0.05–1.06], p = 0.06).
Conclusions
Hydrogen + TTM32–TTM34 was associated with improved neurologic outcomes after cardiogenic OHCA compared with TTM32–TTM34 monotherapy. Hydrogen inhalation is a promising treatment option for reducing PCABI when combined with TTM32–TTM34.
... ROS represent a subset of oxygen-containing free radicals, including superoxide, hydrogen peroxide, and the hydroxyl radical, with the latter being responsible for the majority of total damage in radiation exposure (60-70%). Free radicals are short-lived but highly unstable compounds characterized by unpaired electrons [44,45]. ...
Medical procedures, such as radiation therapy, are a vital element in treating many cancers, significantly contributing to improved survival rates. However, a common long-term complication of such exposure is radiation-induced skin fibrosis (RISF), a complex condition that poses substantial physical and psychological challenges. Notably, about 50% of patients undergoing radiation therapy may achieve long-term remission, resulting in a significant number of survivors managing the aftereffects of their treatment. This article delves into the intricate relationship between RISF, reactive oxygen species (ROS), and angiotensin II (Ang II) signaling. It proposes the underlying mechanisms and examines potential treatments for mitigating skin fibrosis. The primary goal is to offer essential insights in order to better care for and improve the quality of life of cancer survivors who face the risk of developing RISF.
... Molecular hydrogen significantly inhibits NF-κB activation to reduce inflammatory responses [26,27]. It has been reported that hydrogen plays a specific therapeutic role in RILI [28], and hydrogen therapy has a protective effect on acute and advanced radiation-induced lung injury in vivo. But the exact mechanism still needs to be clarified. ...
Background
Radiotherapy has become a standard treatment for chest tumors, but a common complication of radiotherapy is radiation lung injury. Currently, there is still a lack of effective treatment for radiation lung injury.
Methods
A mouse model of radioactive lung injury (RILI) was constructed and then treated with different cycles of hydrogen inhalation. Lung function tests were performed to detect changes in lung function.HE staining was used to detect pathological changes in lung tissue. Immunofluorescence staining was used to detect the polarization of macrophages in lung tissue. Immunohistochemistry was used to detect changes in cytokine expression in lung tissues. Western Blot was used to detect the expression of proteins related to the NF-κB signalling pathway.
Results
Lung function test results showed that lung function decreased in the model group and improved in the treatment group.HE staining showed that inflammatory response was evident in the model group and decreased in the treatment group. Immunohistochemistry results showed that the expression of pro-inflammatory factors was significantly higher in the model group, and the expression of pro-inflammatory factors was significantly higher in the treatment group. The expression of pro-inflammatory factors in the treatment group was significantly lower than that in the model group, and the expression of anti-inflammatory factors in the treatment group was higher than that in the model group. Immunofluorescence showed that the expression of M1 subtype macrophages was up-regulated in the model group and down-regulated in the treatment group. The expression of M2 subtype macrophages was up-regulated in the treatment group relative to the model group. Western Blot showed that P–NF-κB p65/NF-κB p65 was significantly increased in the model group, and P–NF-κB p65/NF-κB p65 was decreased in the treatment group.
Conclusion
Hydrogen therapy promotes macrophage polarization from M1 to M2 subtypes by inhibiting the NF-κB signalling pathway, thereby attenuating the inflammatory response to radiation lung injury.
... These studies have demonstrated hydrogen's efficacy in disease models where oxidative stress is a direct or indirect factor in nearly all organs. Additionally, hydrogen has been found to possess multiple functions, including anti-inflammatory [28], anti-apoptotic [29], and anti-allergic effects [9], and it stimulates energy metabolism [30,31]. Beyond model experiments, over 100 clinical trial papers have been published. ...
Molecular hydrogen, the smallest and lightest molecule, serves as an intense reducing agent. Its distinct characteristics, including minimal size and neutral charge, enhance bioavailability and facilitate significant biological effects. Previously considered physiologically inert, hydrogen has gained recognition as a powerful therapeutic agent, known for its antioxidative and anti-inflammatory properties. Electrolyzed hydrogen water (EHW), enriched with molecular hydrogen, demonstrates remarkable antioxidative capabilities, indicating potential benefits for various diseases. Inflammation-induced reactive oxygen species (ROS) amplify inflammation, leading to secondary oxidative stress and creating a crosstalk between ROS and inflammatory responses. This crosstalk contributes to the pathogenesis and progression of chronic diseases. EHW interrupts this crosstalk, reducing inflammatory cytokines and oxidative stress across various disease models, suggesting therapeutic potential. EHW is also known for its anti-inflammatory effects, extending to pain management, as evidenced in models like sciatic nerve ligation and inflammatory pain. In an inflammatory bowel disease (IBD) model, EHW effectively alleviates abdominal pain, mitigating 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced inflammation and oxidative stress, offering insights for clinical applications. Additionally, hydrogen selectively targets harmful radicals, and EHW intake helps balance stress-induced hormonal dysregulation, potentially easing disorders associated with chronic stress.
... Both vitamin C and hydrogen protect from radiation-induced damage [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] and function by removing ROS from the human body. They also reduce inflammation in tissues. ...
Radiation therapy is employed in treating various cancer types. However, depending on the type and stage of cancer, its benefits can be limited, and it may cause serious side effects that detrimentally affect the quality of life (QOL) for the patient. Preventing the side effects of radiation therapy can enhance the response to cancer treatment and improve the patient’s QOL. Independently, vitamin C and hydrogen have demonstrated potential in reducing the side effects of anticancer drugs and radiation therapy. Furthermore, both have been postulated to possess direct anticancer properties. However, the effects of their combined therapy remain underexplored. This study investigates the hypothesis that combining vitamin C and hydrogen efficiently prevents radiation-induced injuries. Survival rates were investigated in cancer cell lines (MDA-MB231 and GL261) and normal cells (HUVEC) treated with hydrogen, vitamin C and irradiation. Apoptosis was assessed using the FLICA test, and EMT gene expression was elucidated via the qPCR technique. In the normal cell line, the introduction of vitamin C and hydrogen to the culture medium boosted survival rates, exhibiting a radioprotective effect upon irradiation. In contrast, cancer cells showed a decreased survival rate with the introduction of vitamin C and hydrogen, which was further diminished with irradiation. Treated cancer cells showed signs of apoptosis. Caspase activity in viable cells was reduced by the combination treatment with vitamin C and hydrogen. Additionally, glioblastoma cells treated with this combination showed reduced EMT gene expression. This study reveals that a combined therapy of hydrogen and vitamin C offers radioprotective effects on normal cells and exerts direct anticancer effects on cancer cells, while also amplifying the anticancer effects of radiation. Importantly, this combined therapy attenuated the radiation-induced EMT signature in the GL261 murine glioma cell line, suggesting potential in diminishing treatment resistance and tumor invasion.
... H2 is considered as a potential radioprotective agent [75]. In radiation-injured lung epithelial cell line A549, H2 down-regulates the gene expression of pro-apoptotic Bax and inhibits its translocation to mitochondria through an unknown mechanism [76]. ...
The gas molecules O2, NO, H2S, CO, CH4 , have been increasingly used for medical purposes. Beside these gas molecules, H2, the smallest diatomic molecule in nature, has become a rising star in gas medicine in the past few decades. As a non-toxic and easily accessible gas, H2 has shown preventive and therapeutic effects on various diseases of the respiratory, cardiovascular, central nervous and other systems, but the mechanisms are still unclear and even controversial, especially the mechanism of H2 as a selective radical scavenger. Mitochondria are the main organelles regulating energy metabolism in living organisms, as well as the main organelle of reactive oxygen species generation and target. We propose that the protective role of H2 may be mainly dependent on its unique penetrating ability to everywhere of the cells to regulate mitochondrial homeostasis by activating the Keap1-Nrf2 phase II antioxidant system, rather than its direct free radical scavenging activity. In this review, we summarize the protective effects and focus on the mechanism of H2 as a mitochondria-targeting nutrient by activating the Keap1-Nrf2 system in different disease models, and wish to provide a more rational theoretical support for the medical applications of hydrogen.
... H 2 is considered to be a potential radioprotective agent [78]. In radiation-injured lung epithelial cell line A549, H 2 downregulates the gene expression of proapoptotic Bax and inhibits its translocation to mitochondria through an unknown mechanism [79]. ...
The gas molecules O2, NO, H2S, CO, and CH4, have been increasingly used for medical purposes. Other than these gas molecules, H2 is the smallest diatomic molecule in nature and has become a rising star in gas medicine in the past few decades. As a non-toxic and easily accessible gas, H2 has shown preventive and therapeutic effects on various diseases of the respiratory, cardiovascular, central nervous system, and other systems, but the mechanisms are still unclear and even controversial, especially the mechanism of H2 as a selective radical scavenger. Mitochondria are the main organelles regulating energy metabolism in living organisms as well as the main organelle of reactive oxygen species’ generation and targeting. We propose that the protective role of H2 may be mainly dependent on its unique ability to penetrate every aspect of cells to regulate mitochondrial homeostasis by activating the Keap1-Nrf2 phase II antioxidant system rather than its direct free radical scavenging activity. In this review, we summarize the protective effects and focus on the mechanism of H2 as a mitochondria-targeting nutrient by activating the Keap1-Nrf2 system in different disease models. In addition, we wish to provide a more rational theoretical support for the medical applications of hydrogen.
... Different H 2 dosages have been observed to reduce the oxidative stress biomarker MDA and raise the levels of antioxidant enzymes such as GSH in the blood and lung tissues of animal models of airway inflammation [86]. It has also been shown that H 2 -rich media intervention reduces damage in human cell lines (A549) of lung epithelial cells (irradiation-induced) by lowering ROS generation [98]. H 2 reduces cell damage, ROS production, alveolar epithelial barrier degradation, and gas exchange across the alveoli [99]. ...
Molecular hydrogen is renowned as an odorless and colorless gas. The recommendations developed by China suggest that the inhalation of hydrogen molecules is currently advised in COVID-19 pneumonia treatment. The therapeutic effects of molecular hydrogens have been confirmed after numerous clinical trials and animal-model-based experiments, which have expounded that the low molecular weight of hydrogen enables it to easily diffuse and permeate through the cell membranes to produce a variety of biological impacts. A wide range of both chronic and acute inflammatory diseases, which may include sepsis, pancreatitis, respiratory disorders, autoimmune diseases, ischemia-reperfusion damages, etc. may be treated and prevented by using it. H2 can primarily be inoculated through inhalation, by drinking water (which already contains H2), or by administrating the injection of saline H2 in the body. It may play a pivotal role as an antioxidant, in regulating the immune system, in anti-inflammatory activities (mitochondrial energy metabolism), and cell death (apoptosis, pyroptosis, and autophagy) by reducing the formation of excessive reactive O2 species and modifying the transcription factors in the nuclei of the cells. However, the fundamental process of molecular hydrogen is still not entirely understood. Molecular hydrogen H2 has a promising future in therapeutics based on its safety and possible usefulness. The current review emphasizes the antioxidative, anti-apoptotic, and anti-inflammatory effects of hydrogen molecules along with the underlying principle and fundamental mechanism involved, with a prime focus on the coronavirus disease of 2019 (COVID-19). This review will also provide strategies and recommendations for the therapeutic and medicinal applications of the hydrogen molecule.
... ROS radical generation by the interaction of ionizing radiation with water molecules plays a significant role in skin fibrosis progression [39]. Excessive ROS induce oxidative stress in tissues and the release of chemically induced molecules from damaged cells, triggering further inflammation [40,41]. ...
Radiation skin injury (RSI) is a frequent adverse effect of radiation therapy for malignant tumors. It often leads to problems such as decreased quality of life in patients and interferes with the normal course of radiation therapy (RT). With the rising incidence of tumors and the burgeoning number of patients undergoing RT, the care of RSI is of crucial importance in cancer patient treatment. Currently, drugs and biomaterials are widely used in the care of RSI. However, there is no international consensus on the current protocol for the therapeutic care of RSI. Many drugs and biomaterials cannot be applied to the appropriate type of radiation dermatitis, resulting in unfavorable results in the therapeutic care of RSI. The choice of appropriate drugs and biomaterials for the therapeutic care of the different types of RSI is essential to improving the quality of life of patients. This article first reviews the main mechanisms of acute and chronic RSI. Subsequently, the application of drugs and novel biomaterials in the preventive, acute, and chronic phases of the care of RSI is summarized. Finally, the suggestions and protocols for the application of novel biomaterials in the care of RSI are discussed, as are the current challenges and future prospects for the development of combined biomaterials and integrated care solutions.
... Hydrogen is a new type of therapeutic substance, used mainly in water or gaseous solutions. It has been shown to be effective against cancer, lung injury, skin tumors, and liver injury and it has anti-inflammatory, anti-oxidation, and anti-apoptotic effects [22][23][24][25]. However, the study of the action or mechanism of molecular hydrogen on IRI is still lacking, although some studies have revealed the molecular mechanism of hydrogen therapy [23,26,27]. ...
... 8 In 2012, Dixon et al 9 first proposed the concept of ferroptosis, a form of regulated cell death, is defined as an iron-catalyzed form of regulated necrosis that is characterized by mitochondrial atrophy and increased mitochondrial membrane density, the accumulation of iron and lipid reactive oxygen species and the involvement of a unique set of genes, which is under the constitutive control of glutathione peroxidase 4, ferroptosis through excessive peroxidation of polyunsaturated fatty acids. [10][11][12] In addition, the relationship between ferroptosis and inflammatory diseases has been investigated by some groups recently and they verified the positive anti-inflammatory effect of ferroptosis in inflammation, including nonalcoholic steatohepatitis, 13,14 lung fibrosis, 15 and ischemia-reperfusion injury. 16,17 The pathophysiological process of OM involves immune and inflammatory reactions, and ferroptosis with immunogenicity may play an active role in the pathogenesis and treatment of OM. 18,19 However, the mechanism of ferroptosis in SA-induced OM is still unclear. ...
Objective
Staphylococcus aureus (SA)-induced osteomyelitis (OM) is one of the most common refractory diseases in orthopedics. Early diagnosis is beneficial to improve the prognosis of patients. Ferroptosis plays a key role in inflammation and immune response, while the mechanism of ferroptosis-related genes (FRGs) in SA-induced OM is still unclear. The purpose of this study was to determine the role of ferroptosis-related genes in the diagnosis, molecular classification and immune infiltration of SA-induced OM by bioinformatics.
Methods
Datasets related to SA-induced OM and ferroptosis were collected from the Gene Expression Omnibus (GEO) and ferroptosis databases, respectively. The least absolute shrinkage and selection operator (LASSO) and support vector machine-recursive feature elimination (SVM-RFE) algorithms were combined to screen out differentially expressed-FRGs (DE-FRGs) with diagnostic characteristics, and gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were used to explore specific biological functions and pathways. Based on these key DE-FRGs, a diagnostic model was established, and molecular subtypes were divided to explore the changes in the immune microenvironment between molecular subtypes.
Results
A total of 41 DE-FRGs were identified. After screening and intersecting with LASSO and SVM-RFE algorithms, 8 key DE-FRGs with diagnostic characteristics were obtained, which may regulate the pathogenesis of OM through the immune response and amino acid metabolism. The ROC curve indicated that the 8 DE-FRGs had excellent diagnostic ability for SA-induced OM (AUC=0.993). Two different molecular subtypes (subtype 1 and subtype 2) were identified by unsupervised cluster analysis. The CIBERSORT analysis revealed that the subtype 1 OM had higher immune cell infiltration rates, mainly in T cells CD4 memory resting, macrophages M0, macrophages M2, dendritic cells resting, and dendritic cells activated.
Conclusion
We developed a diagnostic model related to ferroptosis and molecular subtypes significantly related to immune infiltration, which may provide a novel insight for exploring the pathogenesis and immunotherapy of SA-induced OM.
... Furthermore, H 2 has an anti-cell-death function by inhibiting ferroptosis through a decrease in peroxide [36], and by down-and up-regulating pro-and anti-death factors, respectively [37]. H 2 relieves inflammation by decreasing pro-inflammatory cytokines [38]. ...
(1) Background: Alzheimer’s disease (AD) is a progressive and fatal neurodegenerative disorder. Hydrogen gas (H2) is a therapeutic medical gas with multiple functions such as anti-oxidant, anti-inflammation, anti-cell death, and the stimulation of energy metabolism. To develop a disease-modifying treatment for AD through multifactorial mechanisms, an open label pilot study on H2 treatment was conducted. (2) Methods: Eight patients with AD inhaled 3% H2 gas for one hour twice daily for 6 months and then followed for 1 year without inhaling H2 gas. The patients were clinically assessed using the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog). To objectively assess the neuron integrity, diffusion tensor imaging (DTI) with advanced magnetic resonance imaging (MRI) was applied to neuron bundles passing through the hippocampus. (3) Results: The mean individual ADAS-cog change showed significant improvement after 6 months of H2 treatment (−4.1) vs. untreated patients (+2.6). As assessed by DTI, H2 treatment significantly improved the integrity of neurons passing through the hippocampus vs. the initial stage. The improvement by ADAS-cog and DTI assessments were maintained during the follow-up after 6 months (significantly) or 1 year (non-significantly). (4) Conclusions: This study suggests that H2 treatment not only relieves temporary symptoms, but also has disease-modifying effects, despite its limitations.
... The mechanisms of RILF have not been fully understood thus far. However, ROS-induced oxidative damage is considered the major factor that induces a cascade of inflammatory events in RILF, which is also the major trigger of ferroptosis [7,113]. Xuan et al. explored whether ferroptosis plays a critical role in RILF, and liproxstatin-1, a ferroptosis inhibitor, alleviated ferroptosis via downregulation of TGF-β1 by activation of the Nrf2 pathway [114]. ...
Since ferroptosis was first described as an iron-dependent cell death pattern in 2012, there has been increasing interest in ferroptosis research. In view of the immense potential of ferroptosis in treatment efficacy and its rapid development in recent years, it is essential to track and summarize the latest research in this field. However, few writers have been able to draw on any systematic investigation into this field based on human body organ systems. Hence, in this review, we provide a comprehensive description of the latest progress in unveiling the roles and functions, as well as the therapeutic potential of ferroptosis, in treating diseases from the aspects of 11 human body organ systems (including the nervous system, respiratory system, digestive system, urinary system, reproductive system, integumentary system, skeletal system, immune system, cardiovascular system, muscular system, and endocrine system) in the hope of providing references for further understanding the pathogenesis of related diseases and bringing an innovative train of thought for reformative clinical treatment.
... Recently, a preclinical study showed that administering neutral electrolyzed saline in a rheumatoid arthritis model reduced IL-6 levels in a dose-dependent manner [73]. Additionally, molecular hydrogen, which is a component of neutral electrolyzed saline, has previously been reported to reduce levels of malondialdehyde (a marker of lipid peroxidation) and TGF-β1 (a profibrotic cytokine) [22], which would generate a nephroprotective and antifibrotic effect [61,74,75]. ...
Background and Objectives: Gentamicin (GM) is a nephrotoxic aminoglycoside. Neutral electrolyzed saline (SES) is a compound with anti-inflammatory, antioxidant, and immunomodulatory properties. The objective of the present study was to evaluate whether kidney damage by GM can be prevented and/or reversed through the administration of SES. Materials and Methods: The study was carried out as a prospective, single-blind, five-arm, parallel-group, randomized, preclinical trial. The nephrotoxicity model was established in male BALB/c mice by administering GM at a dose of 100 mg/kg/day intraperitoneally for 30 days, concomitantly administering (+) SES or placebo (physiologic saline solution), and then administering SES for another 30 days after the initial 30 days of GM plus SES or placebo. At the end of the test, the mice were euthanized, and renal tissues were evaluated histopathologically. Results: The GM + placebo group showed significant tubular injury, interstitial fibrosis, and increased interstitial infiltrate of inflammatory cells compared with the group without GM. Tubular injury and interstitial fibrosis were lower in the groups that received concomitant GM + SES compared with the GM + placebo group. SES administration for 30 days after the GM administration periods (GM + placebo and GM + SES for 30 days) did not reduce nephrotoxicity. Conclusions: Intraperitoneal administration of SES prevents gentamicin-induced histologic nephrotoxicity when administered concomitantly, but it cannot reverse the damage when administered later.
... 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. ...
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.
... 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. ...
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 ...
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). ...
Molecular hydrogen (H2) is a colorless and odorless gas. Studies have shown that H2 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. H2 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.. H2 is primarily administered via inhalation, drinking H2-rich water, or injection of H2 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 H2 has not yet been fully revealed. Owing to its safety and potential efficacy, H2 has a promising potential for clinical use against many diseases. This review will demonstrate the role of H2 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 H2 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. ...
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. ...
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. ...
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.
... 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. ...
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.
... 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. ...
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.
Radiation represents an environmental factor that can adversely affect the heart and the vasculature. Depending on the dose and time, radiation-induced heart injury may evolve, as is well documented e. g. in long-term cancer survivors previously treated with radiotherapy. Oxidative stress induced by irradiation damages endothelial and myocardial cells. An inflammatory response is induced by cytokine release from dysfunctional endothelium and from injured irradiated cells which activate defense mechanisms. At later stages, the heart responds to radiation injury among others, by promoting cardiac hypertrophy and remodeling to compensate for impaired cardiac function, eventually leading to heart failure. MicroRNAs (miRNAs) are small non-coding RNA molecules participating in the regulation of different cellular processes. miRNAs dysregulation has been associated with various disease states, including adverse cardiac remodeling and toxicity. An increasing number of studies demonstrate the possible application of molecular hydrogen in various diseases. This small non-toxic molecule represents an effective antioxidant with anti-inflammatory, anti-apoptotic, and anti-fibrotic properties. However, the exact mechanisms of hydrogen action are still not fully clarified. Available literature points to the possible implication of miRNAs in the preventive effects of molecular hydrogen, including radiation-induced heart injury. To confirm these assumptions, further studies are needed, as the research in this area is still in its infancy.
We performed a comparative study of the effects of X-ray irradiation and bleomycin on the mRNA levels of E-cadherin and tight junction proteins (claudin-3, claudin-4, claudin-18, ZO-2, and occludin) in an alveolar epithelial cell line L2. Irradiation decreased claudin-4 levels and increased occludin levels, while the levels of other mRNAs remained unchanged. Bleomycin increased the expression levels of all proteins examined except claudin-3. Irradiation and bleomycin have different effects on the expression level of intercellular junction proteins, indicating different reactions triggered in alveolar epithelial cells and a great prospects of further comparative studies.
The pathophysiological mechanism behind complications associated with postmastectomy radiotherapy (PMRT) and subsequent implant-based breast reconstruction are not completely understood. The aim of this study was to examine if there is a relationship between PMRT and microvascular perfusion and saturation in the skin after mastectomy and assess if there is impaired responsiveness to a topically applied vasodilator (Methyl nicotinate – MN).
Skin microvascular perfusion and oxygenation >2 years after PMRT were measured using white light diffuse reflectance spectroscopy (DRS) and laser Doppler flowmetry (LDF) in the irradiated chest wall of 31 women with the contralateral breast as a control. In the non-irradiated breast, the perfusion after application of MN (median 0.84, 25th–75th centile 0.59–1.02 % RBC × mm/s) was higher compared to the irradiated chest wall (median 0.51, 25th–75th centile 0.21–0.68 % RBC × mm/s, p < 0.001). The same phenomenon was noted for saturation (median 91 %, 25th–75th centile 89–94 % compared to 89 % 25th–75th centile 77–93 %, p = 0.001). Eight of the women (26%) had a ≥10 % difference in skin oxygenation between the non-irradiated breast and the irradiated chest wall.
These results indicate that late microvascular changes caused by radiotherapy of the chest wall significantly affect skin perfusion and oxygenation.
Radiation-induced heart disease (RIHD) is a common complication of mediastinal radiotherapy. RIHD includes structural and functional abnormalities of the pericardium, coronary vessels, myocardium, valves, and conduction system. The underlying pathological mechanisms are complex, mainly related to endothelial cell injury, oxidative stress, and inflammation. Radiation can cause cardiomyocyte death, tissue fibrosis and ultimately may end up with heart failure. To overcome these complications, there is a need to look for specific therapeutic interventions, which are still missing. Molecular hydrogen (H2) has been recognized as a molecule with antioxidant, anti-inflammatory, and anti-apoptotic protective effects in different disease settings. In vitro as well as in vivo studies demonstrated that H2 exerted preventive or therapeutic effects on radiation-induced injury, including RIHD. H2 could be effective to mitigate RIHD through various mechanisms, e.g. selective neutralization of hydroxyl radicals, protection against inflammatory and apoptotic damage, anti-fibrotic and anti-hypertrophic effects, etc. More research is needed to elucidate further mechanisms of H2 action, and to verify the effectiveness of H2 therapy in clinical trials.
Nicaraven selectively protects normal tissue from radiation-induced injury. To further develop the clinical application of nicaraven for mitigating the side effects of cancer radiotherapy, we investigated the potential effect of nicaraven administration in radiation-induced inhibition of tumor growth. A subcutaneous tumor model was established in mice by the injection of Lewis lung cancer cells at the back of the chest. X-ray radiation was delivered to the thoracic area and different doses of nicaraven (0, 20, 50, 100 mg/kg) were administrated intraperitoneally pre- or post-irradiation. The tumor size was measured every other day. Mice were euthanized on day 30, and the tumor weight and the levels of cytokines in tumor tissue were measured. Pre- or post-irradiation administration of nicaraven up to a dose of 100 mg/kg did not significantly diminish the radiation-induced inhibition of tumor growth, but post-irradiation administration of 20 and 50 mg/kg nicaraven resulted in relatively lower tumor weight. The levels of IL-1β, IL-6, IL-10, MCP-1, MIP-2a, TGF-β1, VEGF, p53, p21, cyclin D1 and caspase-3 in tumor tissue did not change by nicaraven administration and were not significantly associated with the tumor weights. According to our experimental data, nicaraven will not significantly diminish the radiation-induced inhibition of tumor growth, even with pre-irradiation administration at a high dose.
Radiation-induced normal cell toxicity (RINCT) is a major factor to consider while treating any ailment with radiotherapy. Clinical irradiation of tumors necessitates an understanding of the potential efficacy of radiation protective agents in reducing radiation damage to healthy tissues and their effects on tumor tissue radiosensitivity. Ferroptosis is a relatively new form of iron-dependent cell death that has been linked to a variety of disease pathologies. The key mediators of ferroptosis have been identified as lipid peroxidation and iron metabolism. Lipid peroxidation is the result of a reaction between reactive oxygen (ROS) and reactive nitrogen species (RNS) with phosphatidylethanolamine-containing polyunsaturated fatty acids (PUFAs). Ferroptosis inhibitors have been demonstrated to have anti-inflammatory effects in animal models of disease. It was recently shown that ionizing radiation (IR) generates severe ferroptosis, a critical component of RT-mediated normal cell toxicity. These findings support the use of ferroptosis inhibitor treatments for the treatment of radiation normal cell toxicity. Targeting lipid metabolic substrates and controlling ferroptosis by radiation could reduce toxicity and improve clinical outcomes. In this study, we address the relationships between radiotherapy and various types of radiation-induced cell death, and we discuss the interactions between ferroptosis and other kinds of controlled cell death generated by radiotherapy, and we investigate combination treatment options targeting ferroptosis in radiotherapy. This review will be a foundation for future research on ferroptosis in radiotherapy. Additionally, the relevant patents on ferroptosis inhibitors with various therapeutic potentials have been discussed.
Oxidative stress injury and subsequent inflammatory response are considered to play critical roles in radiation-induced lung injury (RILI). Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor that regulates oxidative stress response and represses inflammation, but its therapeutic value in RILI remains elusive. Our previous studies have shown that the near-infrared (NIR) IR-61 dye evokes intracellular antioxidant defence by enhancing Nrf2 signalling and promoting anti-inflammatory effects. We established a model of RILI in mice exposed to whole-thoracic irradiation. The results showed that IR-61 treatment notably improved pulmonary functions by decreasing lung density and diminishing airway resistance. In addition, IR-61 significantly ameliorated radiation-induced inflammatory cell infiltration and proinflammatory cytokine (IL-1β, IL-6 and TNF-α) release, thereby mitigating inflammatory response. Furthermore, IR-61 mitigated radiation-induced lung fibrosis by decreasing the collagen deposition and the levels of fibrogenesis-related factors (collagen I, collagen III, α-SMA, and fibronectin). More importantly, IR-61 was found to accumulate in the mitochondria of macrophages in irradiated lung tissues. Therefore, the functions of IR-61 in macrophages were further studied in irradiated macrophage cell lines, MH-s and RAW 264.7 in vitro. The results indicated that IR-61 upregulated the expression of Nrf2 and haem oxygenase-1(HO-1) and decreased the levels of reactive oxygen species (ROS) and pro-inflammatory cytokines (IL-1β and IL-6) in macrophages after radiation. In summary, our study suggests that IR-61 effectively mitigates RILI by activating Nrf2 signalling in irradiated lung tissues. In particular, Nrf2-mediated anti-inflammatory and antioxidant effects in irradiated lung tissue macrophages play critical roles in protecting against RILI.
Background
Acute skeletal muscle injuries are common physical or sports traumas. Cellular therapy has excellent potential for regeneration after skeletal muscle injury. Adipose-derived stem cells (ADSCs) are a more accessible type of stem cell. However, it has a low survival rate and differentiation efficiency in the oxidative stress-rich microenvironment after transplantation. Although molecular hydrogen (H2) possesses anti-inflammatory and antioxidant biological properties, its utility in mitochondrial and stem cell research has not been adequately explored.
Objective
Revealing the role of H2 on Adipose-derived stem cells myogenic differentiation.
Methods
The protective effects of H2 in ADSCs were evaluated by MTT assay, live-dead cell staining, western blot analysis, immunofluorescence staining, confocal imaging, and transmission electron microscopy.
Results
An appropriate volume fraction of H2 significantly decreased mitochondrial reactive oxygen species (ROS) levels, increased the number of mitochondria, and promoted mitophagy, thus enhancing the survival and myogenic differentiation of ADSCs.
Conclusion
This study reveals the application potential of H2 in skeletal muscle diseases or other pathologies related to mitochondrial dysfunction.
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.
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).
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.
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.
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.
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.
Transient generation of reactive oxygen or nitrogen (ROS/RNS), de- tected with dihydrodichlorofluoroscein by fluorescence microscopy, oc- curs within minutes of exposing cells to ionizing radiation. In the 1-10 Gy dose range, the amount of ROS/RNS produced/cell is constant, but the percentage of producing cells increases with dose (20 to 80%). Reversible depolarization of the mitochondrial membrane potential (DC) and de- crease in fluorescence of a mitochondria-entrapped dye, calcein, are ob- served coincidentally. Radiation-induced ROS/RNS, DC depolarization, and calcein fluorescence decrease are inhibited by the mitochondrial permeability transition inhibitor, cyclosporin A, but not the structural analogue, cyclosporin H. Radiation-stimulated ROS/RNS is also inhibited by overexpressing the Ca21-binding protein, calbindin 28K, or treating cells with an intracellular Ca21 chelator. Radiation-induced ROS/RNS is observed in several cell types with the exception of ro cells deficient in mitochondrial electron transport. ro cells show neither radiation-induced ROS/RNS production nor DC depolarization. We propose that radiation damage in a few mitochondria is transmitted via a reversible, Ca21- dependent mitochondrial permeability transition to adjacent mitochon- dria with resulting enhanced ROS/RNS generation. Measurements of radiation-induced mitogen-activated protein kinase activity indicate that this sensing/amplification mechanism is necessary for activation of some cytoplasmic signaling pathways by low doses of radiation.
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.
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.
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.
It has been demonstrated that hydrogen can selectively reduce hydroxyl and peroxynitrite in vitro. Since most of the ionizing radiation-induced cellular damage is caused by hydroxyl radicals, this study was designed to test the hypothesis that hydrogen may be an effective radioprotective agent. This paper demonstrates that treating cells with hydrogen before irradiation could significantly inhibit ionizing irradiation(IR)-induced Human Lymphocyte AHH-1 cells apoptosis and increase cells viability in vitro. This paper also shows that hydrogen can protect gastrointestinal endothelia from radiation-induced injury, decrease plasma malondialdehyde (MDA) intestinal 8-hydroxydeoxyguanosine (8-OHDG) levels and increase plasma endogenous antioxidants in vivo. It is suggested that hydrogen has a potential as an effective and safe radioprotective agent.
Retinal ischemia-reperfusion (I/R) injury by transient elevation of intraocular pressure (IOP) is known to induce neuronal damage through the generation of reactive oxygen species. Study results have indicated that molecular hydrogen (H(2)) is an efficient antioxidant gas that selectively reduces the hydroxyl radical (*OH) and suppresses oxidative stress-induced injury in several organs. This study was conducted to explore the neuroprotective effect of H(2)-loaded eye drops on retinal I/R injury.
Retinal ischemia was induced in rats by raising IOP for 60 minutes. H(2)-loaded eye drops were prepared by dissolving H(2) gas into a saline to saturated level and administered to the ocular surface continuously during the ischemia and/or reperfusion periods. One day after I/R injury, apoptotic cells in the retina were quantified, and oxidative stress was evaluated by markers such as 4-hydroxynonenal and 8-hydroxy-2-deoxyguanosine. Seven days after I/R injury, retinal damage was quantified by measuring the thickness of the retina.
When H(2)-loaded eye drops were continuously administered, H(2) concentration in the vitreous body immediately increased and I/R-induced *OH level decreased. The drops reduced the number of retinal apoptotic and oxidative stress marker-positive cells and prevented retinal thinning with an accompanying activation of Müller glia, astrocytes, and microglia. The drops improved the recovery of retinal thickness by >70%.
H(2) has no known toxic effects on the human body. Thus, the results suggest that H(2)-loaded eye drops are a highly useful neuroprotective and antioxidative therapeutic treatment for acute retinal I/R injury.
Cell apoptosis induced by UV irradiation is a highly complex process in which different molecular signaling pathways are involved. p53 up-regulated modulator of apoptosis (PUMA) has been proposed as an important regulator in UV irradiation-induced apoptosis. However, the molecular mechanism through which PUMA regulates apoptosis, especially how PUMA activates Bcl-2-associated X protein (Bax) in response to UV irradiation is still controversial. In this study, by using real-time single-cell analysis and fluorescence resonance energy transfer, we investigated the tripartite nexus among PUMA, Bax, and Bcl-X(L) in living human lung adenocarcinoma cells (ASTC-a-1) to illustrate how PUMA promotes Bax translocation to initiate apoptosis. Our results show that the interaction between PUMA and Bax increased gradually, with Bax translocating to mitochondria and colocalizing with PUMA after UV irradiation, indicating PUMA promotes Bax translocation directly. Simultaneously, the interaction increased markedly between PUMA and Bcl-X(L) and decreased significantly between Bcl-X(L) and Bax after UV treatment, suggesting PUMA competitively binds to Bcl-X(L) to activate Bax indirectly. The above-mentioned results were further confirmed by coimmunoprecipitation experiments. In addition, pifithrin-alpha (a p53 inhibitor) and cycloheximide (a protein synthesis inhibitor) could inhibit PUMA-mediated Bax translocation and cell apoptosis. Together, these studies create an important conclusion that PUMA promotes Bax translocation by both by directly interacting with Bax and by competitive binding to Bcl-X(L) in UV-induced apoptosis.
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.
Flaxseed (FS) has high contents of omega-3 fatty acids and lignans with antioxidant properties. Its use in preventing thoracic X-ray radiation therapy (XRT)-induced pneumonopathy has never been evaluated. We evaluated FS supplementation given to mice given before and post-XRT. FS-derived lignans, known for their direct antioxidant properties, were evaluated in abrogating ROS generation in cultured endothelial cells following gamma radiation exposure. Mice were fed 10% FS or isocaloric control diet for three weeks and given 13.5 Gy thoracic XRT. Lungs were evaluated at 24 hours for markers of radiation-induced injury, three weeks for acute lung damage (lipid peroxidation, lung edema and inflammation), and at four months for late lung damage (inflammation and fibrosis). FS-Lignans blunted ROS generation in vitro, resulting from radiation in a dose-dependent manner. FS-fed mice had reduced expression of lung injury biomarkers (Bax, p21 and TGF-beta1) at 24 hours following XRT and reduced oxidative lung damage as measured by malondialdehyde (MDA) levels at 3 weeks following XRT. In addition, FS-fed mice had decreased lung fibrosis as determined by hydroxyproline content and decreased inflammatory cell influx into lungs at 4 months post XRT. Importantly, when Lewis lung carcinoma cells were injected systemically in mice, FS dietary supplementation did not appear to protect lung tumors from responding to thoracic XRT. Dietary FS is protective against pulmonary fibrosis, inflammation and oxidative lung damage in a murine model. Moreover, in this model, tumor radioprotection was not observed. FS lignans exhibited potent radiation-induced ROS scavenging action. Taken together, these data suggest that dietary flaxseed may be clinically useful as an agent to increase the therapeutic index of thoracic XRT by increasing the radiation tolerance of lung tissues.
Ischemia/reperfusion (I/R) injury during small intestinal transplantation (SITx) frequently causes complications including dysmotility, inflammation and organ failure. Recent evidence indicates hydrogen inhalation eliminates toxic hydroxyl radicals. Syngeneic, orthotopic SITx was performed in Lewis rats with 3 h of cold ischemic time. Both donor and recipient received perioperative air or 2% hydrogen inhalation. SITx caused a delay in gastrointestinal transit and decreased jejunal circular muscle contractile activity 24 h after surgery. Hydrogen treatment resulted in significantly improved gastrointestinal transit, as well as jejunal smooth muscle contractility in response to bethanechol. The transplant induced upregulation in the inflammatory mediators CCL2, IL-1 beta, IL-6 and TNF-alpha were mitigated by hydrogen. Hydrogen significantly diminished lipid peroxidation compared to elevated tissue malondialdehyde levels in air-treated grafts demonstrating an antioxidant effect. Histopathological mucosal erosion and increased gut permeability indicated a breakdown in posttransplant mucosal barrier function which was significantly attenuated by hydrogen treatment. In recipient lung, hydrogen treatment also resulted in a significant abatement in inflammatory mRNA induction and reduced neutrophil recruitment. Hydrogen inhalation significantly ameliorates intestinal transplant injury and prevents remote organ inflammation via its antioxidant effects. Administration of perioperative hydrogen gas may be a potent and clinically applicable therapeutic strategy for intestinal I/R injury.
The most important electron acceptor in the biosphere is molecular oxygen which, by virtue of its bi-radical nature, readily accepts unpaired electrons to give rise to a series of partially reduced species collectively known as reduced (or 'reactive') oxygen species (ROS). These include superoxide (O.2-), hydrogen peroxide (H2O2), hydroxyl radical (HO.) and peroxyl (ROO.) and alkoxyl (RO.) radicals which may be involved in the initiation and propagation of free radical chain reactions and which are potentially highly damaging to cells. Mechanisms have evolved to restrict and control such processes, partly by compartmentation, and partly by antioxidant defences such as chain-breaking antioxidant compounds capable forming stable free radicals (e.g. ascorbate, alpha-tocopherol) and the evolution of enzyme systems (e.g. superoxide dismutase, catalase, peroxidases) that diminish the intracellular concentration of the ROS. Although some ROS perform useful functions, the production of ROS exceeding the ability of the organism to mount an antioxidant defence results in oxidative stress and the ensuing tissue damage may be involved in certain disease processes. Evidence that ROS are involved in primary pathological mechanisms is a feature mainly of extraneous physical or chemical perturbations of which radiation is perhaps the major contributor. One of the important radiation-induced free-radical species is the hydroxyl radical which indiscriminately attacks neighbouring molecules often at near diffusion-controlled rates. Hydroxyl radicals are generated by ionizing radiation either directly by oxidation of water, or indirectly by the formation of secondary partially ROS. These may be subsequently converted to hydroxyl radicals by further reduction ('activation') by metabolic processes in the cell. Secondary radiation injury is therefore influenced by the cellular antioxidant status and the amount and availability of activating mechanisms. The biological response to radiation may be modulated by alterations in factors affecting these secondary mechanisms of cellular injury.
During the 7.1-MPa hydrogen-helium-oxygen record human dive, we tested the hypothesis that the increased ambient pressure would alter the maximal muscle performance, specifically that breathing dense gas would lead to fatigue of the respiratory muscle. A group of hand muscles (adductor pollicis, AP) and the inspiratory muscles (IM) were studied in three professional divers. Maximal voluntary contractions (MVC) of AP and maximal inspiratory pressure (P
imax) generated by IM were measured prior to the dive, during compression and decompression, and then 1 and 2 months after the dive. The decrease in MVC (−22%) was significant at 3.1 MPa, i.e. at the beginning of the introduction of hydrogen into the breathing mixture, whereas P
imax fell progressively during the dive and decompression (maximal ΔP
imax = −55%), a significant reduction still being measured 1 month after the dive. The altered IM function was attributed to the consequences of long-term ventilatory loading, a condition associated with breathing a dense gas. The transient decrease in MVC of the skeletal muscle would indicate a possible effect of the hyperbaric environment, possibly the high partial pressure of hydrogen, on neuromuscular drive.
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.
The potential of antioxidants to reduce the cellular damage induced by ionizing radiation has been studied in animal models for more than 50 years. The application of antioxidant radioprotectors to various human exposure situations has not been extensive although it is generally accepted that endogenous antioxidants, such as cellular non-protein thiols and antioxidant enzymes, provide some degree of protection. This review focuses on the radioprotective efficacy of naturally occurring antioxidants, specifically antioxidant nutrients and phytochemicals, and how they might influence various endpoints of radiation damage. Results from animal experiments indicate that antioxidant nutrients, such as vitamin E and selenium compounds, are protective against lethality and other radiation effects but to a lesser degree than most synthetic protectors. Some antioxidant nutrients and phytochemicals have the advantage of low toxicity although they are generally protective when administered at pharmacological doses. Naturally occurring antioxidants also may provide an extended window of protection against low-dose, low-dose-rate irradiation, including therapeutic potential when administered after irradiation. A number of phytochemicals, including caffeine, genistein, and melatonin, have multiple physiological effects, as well as antioxidant activity, which result in radioprotection in vivo. Many antioxidant nutrients and phytochemicals have antimutagenic properties, and their modulation of long-term radiation effects, such as cancer, needs further examination. In addition, further studies are required to determine the potential value of specific antioxidant nutrients and phytochemicals during radiotherapy for cancer.
The aim of this study is to evaluate the incidence of interstitial pneumonitis following fractionated total body irradiation conditioning for bone marrow transplantation with varying lung doses due to shielding technique and different dose-rates. Between 1987 and 2001, a total number of 105 patients have received total body irradiation conditioning for bone marrow transplantation for hematological malignancies at Gulhane Military Medical School. Twelve Gy fractionated total body irradiation was delivered in 6 fractions over 3 consecutive days with Co-60 teletherapy machine. Conditioning therapy included only cyclophosphamide (60 mg/ kg/day for two days) and total body irradiation. The median follow-up for patients was 12 months. Interstitial pneumonitis developed in 10 patients out of 105 patients (9.52%). The median total dose to lung was 9.60 Gy (8.88-10.90). The difference between total lung dose and interstitial pneumonitis was not significant. Pneumonitis development in the high dose-rate (>0.04 Gy/min) group versus low dose-rate (< or =0.04 Gy/min) group was statistically significant. Low dose-rate fractionated total body irradiation is a reliable conditioning program in bone marrow transplantation with effective lung sparing to avoid interstitial pneumonitis.
A review was undertaken of all patients treated at Royal Adelaide Hospital, South Australia with total body irradiation (TBI) for the purpose of assessing the incidence of interstitial pneumonitis (IP) and possible prognostic factors for its development. The aim was also to assess the impact of IP and other prognostic factors on long-term survival outcome following bone marrow transplantation. A total of 84 patients received TBI, with 12 Gy in six fractions delivered using two different instantaneous dose rates of 7.5 and 15 cGy min(-1). This series included 26 cases of acute lymphoblastic leukaemia, 26 of multiple myeloma and 15 of acute myelogenous leukaemia. On multivariate analysis, a higher dose rate was independently significant for an increased risk of IP.
Exposure of eukaryotic cells to ionizing radiation (IR) results in the immediate formation of free radicals that last a matter of milliseconds. It has been assumed that the subsequent alterations in multiple intracellular processes following irradiation is due to the initial oxidative damage caused by these free radicals. However, it is becoming increasingly clear that intracellular metabolic oxidation/reduction (redox) reactions can be affected by this initial IR-induced free radical insult and may remain perturbed for minutes, hours, or days. It would seem logical that these cellular redox reactions might contribute to the activation of protective or damaging processes that could impact upon the damaging effects of IR. These processes include redox sensitive signaling pathways, transcription factor activation, gene expression, and metabolic activities that govern the formation of intracellular oxidants and reductants. The physiological manifestations of these radiation-induced alterations in redox sensitive processes have been suggested to contribute to adaptive responses, bystander effects, cell cycle perturbations, cytotoxicity, heat-induced radiosensitization, genomic instability, inflammation, and fibrosis. While a great deal is known about the molecular changes associated with the initial production of free radicals at the time of irradiation, the contribution of perturbations in redox sensitive metabolic processes to biological outcomes following exposure to IR is only recently becoming established. This review will focus on evidence supporting the concept that perturbations in intracellular metabolic oxidation/reduction reactions contribute to the biological effects of radiation exposure as well as new concepts emerging from the field of free radical biology that may be relevant to future studies in radiobiology.
Acute oxidative stress induced by ischemia-reperfusion or inflammation causes serious damage to tissues, and persistent oxidative stress is accepted as one of the causes of many common diseases including cancer. We show here that hydrogen (H(2)) has potential as an antioxidant in preventive and therapeutic applications. We induced acute oxidative stress in cultured cells by three independent methods. H(2) selectively reduced the hydroxyl radical, the most cytotoxic of reactive oxygen species (ROS), and effectively protected cells; however, H(2) did not react with other ROS, which possess physiological roles. We used an acute rat model in which oxidative stress damage was induced in the brain by focal ischemia and reperfusion. The inhalation of H(2) gas markedly suppressed brain injury by buffering the effects of oxidative stress. Thus H(2) can be used as an effective antioxidant therapy; owing to its ability to rapidly diffuse across membranes, it can reach and react with cytotoxic ROS and thus protect against oxidative damage.
Data from 932 patients with leukemia who received bone marrow transplants were analyzed to determine factors associated with an increased risk of developing interstitial pneumonitis. Interstitial pneumonitis developed in 268 patients for a 2-year actuarial incidence of 35 +/- 4% (SD) and with a mortality rate of 24%. Six factors were associated with an increased risk: use of methotrexate rather than cyclosporine after transplantation (relative risk, 2.3; p less than 0.0002); older age (relative risk, 2.1; p less than 0.0001); presence of severe graft-versus-host disease (relative risk, 1.9; p less than 0.003); long interval from diagnosis to transplantation (relative risk, 1.6; p less than 0.002); performance ratings before transplantation of less than 100% (relative risk, 2.1; p less than 0.0001); and high dose-rates of irradiation in patients given methotrexate after transplantation (relative risk, 3.2; p less than 0.03). The risk of developing interstitial pneumonitis ranged from 8% in patients with none of these adverse risk factors to 94% in patients with all six. These findings may help to identify patients at high risk for this complication.
Total body irradiation is being used with increasing frequency for the treatment of lymphopoietic malignancies and in preparation for marrow transplantation. Acute toxicities include reversible gastroeneritis, mucositis, myelosuppression alopecia. As the success of treatment improves and more patients become long-term survivors, manifestations of delayed and chronic toxicity become evident. These include impairment of growth and development, gonadal failure and sterility, cataract formation and possibly secondary malignancies. The contribution of total body irradiation to the development of pneumonitis and pulmonary fibrosis is still poorly understood. Some of these changes are reversible or correctable, whereas others are permanent. Nevertheless, until equally effective but less toxic regimens become available, total body irradiation appears to be the treatment of choice to prepare patients with leukemia for marrow transplantation.
Oxidative stress is implicated in atherogenesis; however most clinical trials with dietary antioxidants failed to show marked success in preventing atherosclerotic diseases. We have found that hydrogen (dihydrogen; H2) acts as an effective antioxidant to reduce oxidative stress [I. Ohsawa, M. Ishikawa, K. Takahashi, M. Watanabe, K. Nishimaki, K. Yamagata, K. Katsura, Y. Katayama, S, Asoh, S. Ohta, Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals, Nat. Med. 13 (2007) 688–694]. Here, we investigated whether drinking H2-dissolved water at a saturated level (H2–water) ad libitum prevents arteriosclerosis using an apolipoprotein E knockout mouse (apoE−/−), a model of the spontaneous development of atherosclerosis. ApoE−/− mice drank H2–water ad libitum from 2 to 6 month old throughout the whole period. Atherosclerotic lesions were significantly reduced by ad libitum drinking of H2–water (p = 0.0069) as judged by Oil-Red-O staining series of sections of aorta. The oxidative stress level of aorta was decreased. Accumulation of macrophages in atherosclerotic lesions was confirmed. Thus, consumption of H2-dissolved water has the potential to prevent arteriosclerosis.
Development of new treatments is critical to effective protection against radiation-induced injury. We investigate the potential of developing small-molecule inhibitors of glycogen synthase kinase 3beta (GSK-3beta)-SB216763 or SB415286-as radioprotective agents to attenuate intestinal injury.
A survival study was done by use of C57BL/6J mice to evaluate the radioprotective effect of GSK-3beta inhibitors. Terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay and immunohistochemical staining for Bax and Bcl-2 were used to assess apoptosis in the small intestines of the treated mice. A clonogenic survival study, apoptosis assays (staining with annexin V or 4',6-diamidino-2-phenylindole), and immunoblot analysis of beta-catenin, Bcl-2, Bax, and caspase 3 were done by use of Rat intestinal epithelial cell line IEC-6 cells.
Pretreatment with SB415286 significantly improved survival of mice irradiated with 8 and 12 Gy. Mice pretreated with SB216763 or SB415286 showed a significant reduction in TUNEL- and Bax-positive cells and an increase in Bcl-2-positive cells in intestinal crypts at 4 and/or 12 h after radiation with 4 and/or 8 Gy compared with radiation alone. Pretreatment of irradiated IEC-6 cells with GSK-3beta inhibitors significantly increased clonogenic survival compared with cells treated with radiation alone. This increase was due to the attenuation of radiation-induced apoptosis, as shown by annexin V and 4',6-diamidino-2-phenylindole assays, as well as immunoblot analysis of Bcl-2, Bax, and caspase 3.
Glycogen synthase kinase 3beta small-molecule inhibitors protect mouse intestine from radiation-induced damage in cell culture and in vivo and improve survival of mice. Molecular mechanisms of this protection involve attenuated radiation-induced apoptosis regulated by Bcl-2, Bax, and caspase 3. Therefore GSK-3beta inhibitors reduce deleterious consequences of intestinal irradiation and thereby improve quality of life during radiation therapy.
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.
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.
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.
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.
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.