UltraWater Testing expanded by 45% to 249 Contaminants, including “Forever Chemicals”!
UltraWater Testing expanded by 45% to 249 Contaminants, including “Forever Chemicals”!
We present the case of a lung cancer patient with multiple metastases (diagnosis established in 2015) who, after the failure of the targeted oral drugs (chemotherapy), multiple cerebral , bone , adrenal gland and liver metastases have reappeared .
4 months after molecular gas-hydrogen therapy as a UNIQUE TREATMENT, the size of brain metastases / tumors was significantly reduced, and the amount of intracranial fluid was significantly reduced.
12 months of SOLE treatment with molecular hydrogen, ALL brain tumors entered FULL REMISSION and the liver and lung metastases remained stable and the survival time was prolonged.
For copyright reasons I will not reproduce the entire article but I invite you to your read it here
A comparative review conducted on the consumption of molecular hydrogen H 2 -rich water, ip or intravenous administration of molecular hydrogen H 2 -rich saline, and inhalation of molecular hydrogen H 2 gas in regards to Molecular hydrogen (water) in the treatment of Conditions of acute and chronic neurological (Alzheimer’s, Parkinson’s, etc.) .
The results Showed That although molecular hydrogen H 2 Concentrations in the brain either tilt to be high after inhalation or intravenous administration, have not been Observed Significant differences in comparison with the Concentrations after the consumption of molecular hydrogen H 2 -rich water and ip administration of molecular hydrogen H 2 -rich brine. Thus, although variations There have been based on the administration method, all Methods have been found to result in the presence of molecular hydrogen H 2 in the serum and brain tissue .
Liu et al. ( 39 ) Measured molecular hydrogen H 2 levels in the arteries, veins, and brain tissues after the inhalation of 2% molecular hydrogen H 2 gas. They found That arterial molecular hydrogen H 2 peaked at 30 min after administration, whereas brain tissue and venous molecular hydrogen H 2 peaked at 45 min after administration. They Reported That molecular hydrogen H 2 levels in arteries and similar Were brain tissues.
This demonstrated That molecular hydrogen H 2 migrates to the brain tissue Regardless of the method of administration ( Thus, the studies have been Might well as molecular hydrogen Performed Using INSTEAD of molecular hydrogen gas water or saline molecular hydrogen ).
Furthermore, keep in mind That crossing the blood-brain barrier ( BBB ) is a very difficult task to Achieve for many Substances, thus the FACT That molecular hydrogen H 2 Crosses the BBB and migrates to the brain tissue Regardless of the method of administration ( Including molecular hydrogen by drinking water – Which is the easiest method of administration molecular hydrogen ) That is a strong indicator of can benefit from one molecular hydrogen drinking water just as much as from any other method of administration molecular hydrogen
However, when molecular hydrogen Concentrations in drinking water in the inhaled gas and is compared, dose-response There is no effect.
Molecular hydrogen-rich water shows generally the more prominent effect than molecular hydrogen gas, although the amount of hydrogen Taken up by hydrogen water is ~ 100 times less than that given by hydrogen gas [ 11 ] .
I invite you to read and yet this article to a better understanding of molecular hydrogen administration and related effects
Gas signaling molecules (GSMs), composed of oxygen, carbon monoxide, nitric oxide, hydrogen sulfide, etc., play critical roles in regulating signal transduction and cellular homeostasis. Interestingly, through various administrations, these molecules also exhibit potential in cancer treatment. Recently, hydrogen gas (formula: H2) emerges as another GSM which possesses multiple bioactivities, including anti-inflammation, anti-reactive oxygen species, and anti-cancer. Growing evidence has shown that hydrogen gas can either alleviate the side effects caused by conventional chemotherapeutics, or suppress the growth of cancer cells and xenograft tumor, suggesting its broad potent application in clinical therapy. In the current review, we summarize these studies and discuss the underlying mechanisms. The application of hydrogen gas in cancer treatment is still in its nascent stage, further mechanistic study and the development of portable instruments are warranted.
Gaseous signaling molecules (GSMs) refer to a group of gaseous molecules, such as oxygen (1), nitric oxide (2), carbon monoxide (3), hydrogen sulfide (4), sulfur dioxide (5, 6), ethylene (7, 8), etc. These gaseous molecules possess multiple critical functions in regulating cell biology in vivo via signal transduction (9). More importantly, certain GSMs could serve as therapeutic agents in primary cancer, as well as in multidrug-resistant cancer treatment when used by directly or certain pharmaceutical formulations (9–13). In addition, some of these GSMs can be generated in body via different bacteria or enzymes, such as nitric oxide, hydrogen sulfide, indicating that they are more compatible molecules that may exhibit less adverse effects compared with conventional chemotherapeutics (9, 14, 15). Recently, hydrogen gas has been recognized as another important GSM in biology, exhibiting appealing potential in health care for its role in preventing cell injury from various attacking (16–19).
With the formula of H2, hydrogen gas is the lightest molecule in the nature which only accounts for about 0.5 parts per million (ppm) of all the gas. Naturally, hydrogen gas is a colorless, odorless, tasteless, non-toxic, highly combustible gas which may form explosive mixtures with air in concentrations from 4 to 74% that can be triggered by spark, heat, or sunlight. Hydrogen gas can be generated in small amount by hydrogenase of certain members of the human gastrointestinal tract microbiota from unabsorbed carbohydrates in the intestine through degradation and metabolism (20, 21), which then is partially diffused into blood flow and released and detected in exhaled breath (20), indicating its potential to serve as a biomarker.
As the lightest molecule in natural, hydrogen gas exhibits appealing penetration property, as it can rapidly diffuse through cell membranes (22, 23). Study in animal model showed that, after orally administration of hydrogen super-rich water (HSRW) and intra-peritoneal administration of hydrogen super-rich saline (HSRS), the hydrogen concentration reached the peak at 5 min; while it took 1 min by intravenous administration of HSRS (23). Another in vivo study tested the distribution of hydrogen in brain, liver, kidney, mesentery fat, and thigh muscle in rat upon inhalation of 3% hydrogen gas (24). The concentration order of hydrogen gas, when reached saturated status, was liver, brain, mesentery, muscle, kidney, indicating various distributions among organs in rats. Except the thigh muscle required a longer time to saturate, the other organs need 5–10 min to reach Cmax (maximum hydrogen concentration). Meanwhile, the liver had the highest Cmax (24). The information may direct the future clinical application of hydrogen gas.
Although hydrogen gas was studied as a therapy in a skin squamous carcinoma mouse model back in 1975 (25), its potential in medical application has not been vastly explored until 2007, when Oshawa et al. reported that hydrogen could ameliorate cerebral ischemia-reperfusion injury by selectively reducing cytotoxic reactive oxygen species (ROS), including hydroxyl radical (•OH) and peroxynitrite (ONOO-) (26), which then provoked a worldwide attention. Upon various administrative formulations, hydrogen gas has been served as a therapeutic agent for a variety of illnesses, such as Parkinson’s disease (27, 28), rheumatoid arthritis (29), brain injury (30), ischemic reperfusion injury (31, 32), and diabetes (33, 34), etc.
More importantly, hydrogen has been shown to improve clinical end-points and surrogate markers, from metabolic diseases to chronic systemic inflammatory disorders to cancer (17). A clinical study in 2016 showed that inhalation of hydrogen gas was safe in patients with post-cardiac arrest syndrome (35), its further therapeutic application in other diseases became even more appealing.
In the current review, we take a spot on its application in cancer treatment. Typically, hydrogen gas may exert its bio-functions via regulating ROS, inflammation and apoptosis events.
By far, many studies have indicated that hydrogen gas doesn’t target specific proteins, but regulate several key players in cancer, including ROS, and certain antioxidant enzymes (36).
ROS refers to a series of unstable molecules that contain oxygen, including singlet oxygen (O2•), hydrogen peroxide (H2O2), hydroxyl radical (•OH), superoxide (37, 38). Once generated in vivo, due to their high reactivity, ROS may attack proteins, DNA/RNA and lipids in cells, eliciting distinct damage that may lead to apoptosis. The presence of ROS can produce cellular stress and damage that may produce cell death, via a mechanism known as oxidative stress (39, 40). Normally, under physical condition, cells including cancer cells maintain a balance between generation and elimination of ROS, which is of paramount importance for their survival (41, 42). The over-produced ROS, resulted from imbalance regulatory system or outer chemical attack (including chemotherapy/radiotherapy), may initiate inner apoptosis cascade, causing severely toxic effects (43–45).), nitric oxide (NO•), and peroxynitrite (ONOO−), etc. (
Hydrogen gas may act as a ROS modulator. First, as shown in Ohsawa et al.’s study, hydrogen gas could selectively scavenge the most cytotoxic ROS, •OH, as tested in an acute rat model of cerebral ischemia and reperfusion (26). Another study also confirmed that hydrogen gas might reduce the oxygen toxicity resulted from hyperbaric oxygen via effectively reducing •OH (46).
Second, hydrogen may induce the expression of some antioxidant enzymes that can eliminate ROS, and it plays key roles in regulating redox homeostasis of cancer cells (42, 47). Studies have indicated that upon hydrogen gas treatment, the expression of superoxide dismutase (SOD) (48), heme oxyganase-1 (HO-1) (49), as well as nuclear factor erythroid 2-related factor 2 (Nrf2) (50), increased significantly, strengthening its potential in eliminating ROS.
By regulating ROS, hydrogen gas may act as an adjuvant regimen to reduce the adverse effects in cancer treatment while at the same time doesn’t abrogate the cytotoxicity of other therapy, such as radiotherapy and chemotherapy (48, 51). Interestingly, due the over-produced ROS in cancer cells (38), the administration of hydrogen gas may lower the ROS level at the beginning, but it provokes much more ROS production as a result of compensation effect, leading to the killing of cancer cells (52).
Inflammatory cytokines are a series of signal molecules that mediate the innate immune response, whose dys-regulation may contribute in many diseases, including cancer (53–55). Typical inflammatory cytokines include interleukins (ILs) excreted by white blood cells, tumor necrosis factors (TNFs) excreted by macrophages, both of which have shown close linkage to cancer initiation and progression (56–59), and both of ILs and TNFs can be suppressed by hydrogen gas (60, 61).
Inflammation induced by chemotherapy in cancer patients not only causes severely adverse effects (62, 63), but also leads to cancer metastasis, and treatment failure (64, 65). By regulating inflammation, hydrogen gas can prevent tumor formation, progression, as well as reduce the side effects caused by chemotherapy/radiotherapy (66).
Apoptosis, also termed as programed cell death, can be triggered by extrinsic or intrinsic signals and executed by different molecular pathways, which serve as one efficient strategy for cancer treatment (67, 68). Generally, apoptosis can be induced by (1) provoking the death receptors of cell surface (such as Fas, TNF receptors, or TNF-related apoptosis-inducing ligand), (2) suppressing the survival signaling (such as epidermal growth factor receptor, mitogen-activated protein kinase, or phosphoinositide 3-kinases), and (3) activating the pro-apoptotic B-cell lymphoma-2 (Bcl-2) family proteins, or down-regulating anti-apoptosis proteins (such as X-linked inhibitor of apoptosis protein, surviving, and the inhibitor of apoptosis) (69, 70).
Hydrogen gas can regulate intracellular apoptosis by impacting the expression of apoptosis-related enzymes. At certain concentration, it can either serve as apoptosis-inhibiting agent via inhibiting the pro-apoptotic B-cell lymphoma-2-associated X protein (Bax), caspase-3, 8, 12, and enhancing the anti-apoptotic B-cell lymphoma-2 (Bcl-2) (71), or as apoptosis-inducing agent via the contrast mechanisms (72), suggesting its potential in protecting normal cells from anti-cancer drugs or in suppressing cancer cells.
Chemotherapy and radiotherapy remain the leading strategies to treat cancer (73, 74). However, cancer patients receiving these treatments often experience fatigue and impaired quality of life (75–77). The skyrocketed generation of ROS during the treatment is believed to contribute in the adverse effects, resulting in remarkable oxidative stress, and inflammation (41, 42, 78). Therefore, benefited from its anti-oxidant and anti-inflammatory and other cell protective properties, hydrogen gas can be adopted as an adjuvant therapeutic regimen to suppress these adverse effects.
Under treatment of epidermal growth factor receptor inhibitor gefitinib, patients with non-small cell lung cancer often suffer with severe acute interstitial pneumonia (79). In a mice model treated with oral administration of gefitinib and intraperitoneal injection of naphthalene which induced severely lung injury due to oxidative stress, hydrogen-rich water treatment significantly reduced the inflammatory cytokines, such as IL-6 and TNFα in the bronchoalveolar lavage fluid, leading to a relieve of lung inflammation. More importantly, hydrogen-rich water didn’t impair the overall anti-tumor effects of gefitinib both in vitro and in vivo, while in contrast, it antagonized the weight loss induced by gefitinib and naphthalene, and enhanced the overall survival rate, suggesting hydrogen gas to be a promising adjuvant agent that has potential to be applied in clinical practice to improve quality of life of cancer patients (80).
Doxorubicin, an anthracycline antibiotic, is an effective anticancer agent in the treatment of various cancers, but its application is limited for the fatal dilated cardiomyopathy and hepatotoxicity (81, 82). One in vivo study showed that intraperitoneal injection of hydrogen-rich saline ameliorated the mortality, and cardiac dysfunction caused by doxorubicin. This treatment also attenuated histopathological changes in serum of rats, such as the serum brain natriuretic peptide (BNP), aspartate transaminase (AST), alanine transaminase (ALT), albumin and malondialdehyde (MDA) levels. Mechanistically, hydrogen-rich saline significantly lowered the ROS level, as well as inflammatory cytokines TNF-α, IL-1β, and IL-6 in cardiac and hepatic tissue. Hydrogen-rich saline also induced less expression of apoptotic Bax, cleaved caspase-3, and higher anti-apoptotic Bcl-2, resulting in less apoptosis in both tissues (71). This study suggested that hydrogen-rich saline treatment exerted its protective effects via inhibiting the inflammatory TNF-α/IL-6 pathway, increasing the cleaved C8 expression and Bcl-2/Bax ratio, and attenuating cell apoptosis in both heart and liver tissue (71).
Hydrogen-rich water also showed renal protective effect against cisplatin-induced nephrotoxicity in rats. In the studies, blood oxygenation level-dependent (BOLD) contrast magnetic resonance images (MRI) acquired in different treated group showed that the creatinine and blood urea nitrogen (BUN) levels, two parameters that related to nephrotoxicity, were significantly higher in cisplatin treated group than those in the control group. Hydrogen-rich water treatment could significantly reverse the toxic effects, and it showed much higher transverse relaxation rate by eliminating oxygen radicals (83, 84).
Another study showed that both inhaling hydrogen gas (1% hydrogen in air) and drinking hydrogen-rich water (0.8 mM hydrogen in water) could reverse the mortality, and body-weight loss caused by cisplatin via its anti-oxidant property. Both treatments improved the metamorphosis, accompanied with decreased apoptosis in the kidney, and nephrotoxicity as assessed by serum creatinine and BUN levels. More importantly, hydrogen didn’t impair the anti-tumor activity of cisplatin against cancer cell lines in vitro and in tumor-bearing mice (85). Similar results were also observed in Meng et al.’s study, as they showed that hydrogen-rich saline could attenuate the follicle-stimulating hormone release, elevate the level of estrogen, improve the development of follicles, and reduce the damage to the ovarian cortex induced by cisplatin. In the study, cisplatin treatment induced higher level of oxidation products, suppressed the antioxidant enzyme activity. The hydrogen-rich saline administration could reverse these toxic effects by reducing MDA and restoring the activity of superoxide dismutase (SOD), catalase (CAT), two important anti-oxidant enzymes. Furthermore, hydrogen-rich saline stimulated the Nrf2 pathway in rats with ovarian damage (86).
The mFOLFOX6 regimen, composed with folinic acid, 5-fluorouracil, and oxaliplatin, is used as first-line treatment for metastatic colorectal cancer, but it also confers toxic effects to liver, leading to bad quality of life of patient (87, 88). A clinical study was conducted in China by investing the protective effect of hydrogen-rich water on hepatic function of colorectal cancer patients (144 patients were enrolled and 136 of them were include in the final analysis) treated with mFOLFOX6 chemotherapy. The results showed that the placebo group exhibited damaging effects caused by mFOLFOX6 chemotherapy as measured by the elevated levels of ALT, AST and indirect bilirubin (IBIL), while the hydrogen-rich water combinational treatment group exhibited no differences in liver function during the treatment, probably due to its antioxidant activity, indicating it a promising protective agent to alleviate the mFOLFOX6-related liver injury (51).
Most of the ionizing radiation-induced adverse effects to normal cells are induced by hydroxyl radicals. The combination of radiotherapy with certain forms of hydrogen gas may be beneficial to alleviate these side effects (89). Indeed, several studies found that hydrogen could protect cells and mice from radiation (48, 90).
As tested in a rat model of skin damage established by using a 44 Gy electronic beam, the treated group by hydrogen-rich water exhibited higher lever of SOD activity and lower MDA and IL-6 in the wounded tissues than the control group and the distilled water group. Furthermore, hydrogen-rich water shortened the healing time and increased the healing rate of skin injury (48).
Gastrointestinal toxicity is a common side effect induced by radiotherapy, which impairs the life quality of cancer patients (91). As shown in Xiao et al.’s study in mice model, hydrogen-water administration via oral gavage increased the survival rate and body weight of mice which were exposed to total abdominal irradiation, accompanied with an improvement in gastrointestinal tract function and the epithelial integrity of the small intestine. Further microarray analysis revealed that hydrogen-water treatment up-regulated miR-1968-5p, which then up-regulated its target myeloid differentiation primary response gene 88 (MyD88, a mediator in immunopathology, and gut microbiota dynamics of certain intestinal diseases involving toll-like receptors 9) expression in the small intestine after total abdominal irradiation (92).
Another study conducted in clinical patients with malignant liver tumors showed that the consumption of hydrogen-rich water for 6 weeks reduced the level of reactive oxygen metabolite, hydroperoxide, and maintained the biologic antioxidant activity in the blood. Importantly, scores of quality of life during radiotherapy were significantly improved in hydrogen-rich water group compared to the placebo water group. Both groups exhibited similar tumor response to radiotherapy, indicating that the consumption of hydrogen-rich water reduced the radiation-induced oxidative stress while at the same time didn’t compromise anti-tumor effect of radiotherapy (93).
Recently, one study found that hydrogen might enhance the effect of photothermal therapy. Zhao et al. designed the hydrogenated Pd nanocrystals (named as PdH0.2) as multifunctional hydrogen carrier to allow the tumor-targeted delivery (due to 30 nm cubic Pd nanocrystal) and controlled release of bio-reductive hydrogen (due to the hydrogen incorporated into the lattice of Pd). As shown in this study, hydrogen release could be adjusted by the power and duration of near-infrared (NIR) irradiation. Treatment of PdH0.2 nanocrystals plus NIR irradiation lead to higher initial ROS loss in cancer cells, and the subsequent ROS rebound was also much higher than that in normal cells, resulting in more apoptosis, and severely mitochondrial metabolism inhibition in cancer cells but not in normal cells. The combination of PdH0.2 nanocrystals with NIR irradiation significantly enhanced the anticancer efficacies of thermal therapy, achieving a synergetic anticancer effect. In vivo safety evaluation showed that the injection dose of 10 mg kg−1 PdH0.2 nanocrystals caused no death, no changes of several blood indicators, and no affected functions of liver and kidney. In 4T1 murine breast cancer tumor model and B16-F10 melanoma tumor model, the combined PdH0.2 nanocrystals and NIR irradiation therapy exhibited a synergetic anticancer effect, leading to remarkable tumor inhibition when compared with thermal therapy. Meanwhile, the combination group showed no visible damage to heart, liver, spleen, lung, and kidney, indicating suitable tissue safety and compatibility (52).
Li et al. reported that the consumption of hydrogen-rich water alleviated renal injury caused by Ferric nitrilotriacetate (Fe-NTA) in rats, evidenced by decreased levels of serum creatinine and BUN. Hydrogen-rich water suppressed the Fe-NTA-induced oxidative stress by lowering lipid peroxidation, ONOO−, and inhibiting the activities of NADPH oxidase and xanthine oxidase, as well as by up-regulating antioxidant catalase, and restoring mitochondrial function in kidneys. Consequently, Fe-NTA-induced inflammatory cytokines, such as NF-κB, IL-6, and monocyte chemoattractant protein-1 were significantly alleviated by hydrogen treatment. More importantly, hydrogen-rich water consumption inhibited several cancer-related proteins expression, including vascular endothelial growth factor (VEGF), signal transducer and activator of transcription 3 (STAT3) phosphorylation, and proliferating cell nuclear antigen (PCNA) in rats, resulting in lower incidence of renal cell carcinoma and the suppression of tumor growth. This work suggested that hydrogen-rich water was a promising regimen to attenuate Fe-NTA-induced renal injury and suppress early tumor events (66).
Non-alcoholic steatohepatitis (NASH) due to oxidative stress induced by various stimuli, is one of the reasons that cause hepatocarcinogenesis (94, 95). In a mouse model, hydrogen-rich water administration lowered the hepatic cholesterol, peroxisome proliferator-activated receptor-α (PPARα) expression, and increased the anti-oxidative effects in the liver when compared with control and pioglitazone treated group (96). Hydrogen-rich water exhibited strong inhibitory effects to inflammatory cytokines TNF-α and IL-6, oxidative stress and apoptosis biomarker. As shown in NASH-related hepatocarcinogenesis model, in the group of hydrogen-rich water treatment, tumor incidence was lower and the tumor volumes were smaller than control and pioglitazone treated group. The above findings indicated that hydrogen-rich water had potential in liver protection and liver cancer treatment (96).
Not only working as an adjuvant therapy, hydrogen gas can also suppress tumor and tumor cells growth.
As shown in Wang et al.’s study, on lung cancer cell lines A549 and H1975 cells, hydrogen gas inhibited the cell proliferation, migration, and invasion, and induced remarkable apoptosis as tested by CCK-8, wound healing, transwell assays and flow cytometry. Hydrogen gas arrested the cell cycle at G2/M stage on both cell lines via inhibiting the expression of several cell cycle regulating proteins, including Cyclin D1, CDK4, and CDK6. Chromosomes 3 (SMC3), a complex required for chromosome cohesion during the cell cycle (97), was suppressed by hydrogen gas via ubiquitinating effects. Importantly, in vivo study showed that under hydrogen gas treatment, tumor growth was significantly inhibited, as well as the expression of Ki-67, VEGF and SMC3. These data suggested that hydrogen gas could serve as a new method for the treatment of lung cancer (98).
Due to its physicochemical characteristics, the use of hydrogen gas has been strictly limited in hospital and medical facilities and laboratories. Li et al. designed a solidified hydrogen-occluding-silica (H2-silica) that could stably release molecular hydrogen into cell culture medium. H2-silica could concentration-dependently inhibit the cell viability of human esophageal squamous cell carcinoma (KYSE-70) cells, while it need higher dose to suppress normal human esophageal epithelial cells (HEEpiCs), indicating its selective profile. This effect was further confirmed by apoptosis and cell migration assay in these two cell lines. Mechanistic study revealed that H2-silica exerted its anticancer via inducing H2O2 accumulation, cell cycle arrest, and apoptosis induction mediated by mitochondrial apoptotic pathways (72).
Recently, hydrogen gas was found to inhibit cancer stem cells (CSCs). Hydrogen gas reduced the colony formation and sphere formation of human ovarian cancer cell lines Hs38.T and PA-1 cells via inhibiting the proliferation marker Ki67, stem cell markers CD34, and angiogenesis. Hydrogen gas treatment significantly inhibited the proliferation, invasion, migration of both Hs38.T and PA-1 cells. More important, inhalation of hydrogen gas inhibited the tumor volume significantly as shown in the Hs38.T xenografted BALB/c nude mice model (99).
Another recent study also confirmed the effects of hydrogen gas in suppressing glioblastoma (GBM), the most common malignant brain tumor. In vitro study indicated that hydrogen gas inhibited several markers involved in stemness, resulting in the suppression of sphere formation, cell migration, invasion, and colony formation of glioma cells. By inhaling hydrogen gas (67%) 1 h, 2 times per day, the GBM growth was significantly inhibited, and the survival rate was improved in a rat orthotopic glioma model, suggesting that hydrogen might be a promising agent in the treatment of GBM (100).
Hydrogen gas has been recognized as one medical gas that has potential in the treatment of cardiovascular disease, inflammatory disease, neurodegenerative disorders, and cancer (17, 60). As a hydroxyl radical and peroxynitrite scavenger, and due to its anti-inflammatory effects, hydrogen gas may work to prevent/relieve the adverse effects caused by chemotherapy and radiotherapy without compromise their anti-cancer potential (as summarized in Table 1 and Figure 1). Hydrogen gas may also work alone or synergistically with other therapy to suppress tumor growth via inducing apoptosis, inhibiting CSCs-related and cell cycle-related factors, etc. (summarized in Table 1).
More importantly, in most of the research, hydrogen gas has demonstrated safety profile and certain selectivity property to cancer cells over normal cells, which is quite pivotal to clinical trials. One clinical trials (NCT03818347) is now undergoing to study the hydrogen gas in cancer rehabilitation in China.
By far, several delivery methods have proved to be available and convenient, including inhalation, drinking hydrogen-dissolved water, injection with hydrogen-saturated saline and taking a hydrogen bath (101). Hydrogen-rich water is non-toxic, inexpensive, easily administered, and can readily diffuse into tissues and cells (102), cross the blood-brain barrier (103), suggesting its potential in the treatment of brain tumor. Further portable devices that are well-designed and safe enough will be needed.
However, regarding its medicinal properties, such as dosage and administration, or possible adverse reactions and use in specific populations, less information is available. Its mechanism, target, indications are also not clear, further study are warranted.
Molecular hydrogen-rich water generally shows a more prominent effect than molecular hydrogen gas, although the amount of hydrogen taken up by hydrogen water is ~100 times less than that given by hydrogen gas .
We have showed that drinking molecular hydrogen water, but not continuous molecular hydrogen gas exposure, prevented development of 6-hydorxydopamine-induced Parkinson’s disease in rats .
SL, XW, JZ, and KP: conceptualization. SL, RL, XS, XL, XZ, JZ, and KP: writing. SL, RL, and XS: revising.
This work was supported in part by grants from the Natural Science Foundation of Guangdong Province (2018A030313987) and Traditional Chinese Medicine Bureau of Guangdong Province (20164015 and 20183009) and Science and Technology Planning Project of Guangdong Province (2016ZC0059).
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We thank Miss Ryma Iftikhar, Dhiviya Samuel, Mahnoor Shamsi (St. John’s University), and Mr. Muaz Sadeia for editing and revising the manuscript.
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Received: 02 May 2019; Accepted: 15 July 2019;
Published: 06 August 2019.
Nelson Shu-Sang Yee, Penn State Milton S. Hershey Medical Center, United States
Copyright © 2019 Li, Liao, Sheng, Luo, Zhang, Wen, Zhou and Peng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
†These authors share co-first authorship
The study published in 2017 was conducted to investigate the protective effect of hydrogen-rich water on the liver function of colorectal cancer (CRC) patients treated with mFOLFOX6 chemotherapy.
A controlled, randomized, single-blind clinical trial was designed.
A total of 152 patients with colorectal cancer were recruited by the Department of Oncology of Taishan Hospital (Taian, China) between June 2010 and February 2016, among whom 146 met the inclusion criteria. Subsequently, 144 patients were randomized into the treatment with hydrogen water(n=80) and placebo (n=64) groups. At the end of the study, 76 patients in the hydrogen water treatment group and 60 patients in the placebo group were included in the final analysis.
The 80 patients group started drinking hydrogen-rich water 1 day prior to chemotherapy until the end of the cycle, for a total of 4 days, with a total intake of 1,000 ml hydrogen-rich water per day in 4 doses (250 ml hydrogen-rich water each). Hydrogen-rich water was consumed 0.5 h after a meal and before bedtime.
The patients did not discontinue consuming hydrogen-rich water during the entire course of chemotherapy.
The other 64 placebo patients consumed distilled water, with a daily intake of 1,000 ml in 4 doses (250 ml each).
The changes in liver function after the chemotherapy, such as altered levels of alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase, indirect bilirubin (IBIL) and direct bilirubin, were observed. The damaging effects of the mFOLFOX6 chemotherapy on liver function were mainly represented by increased ALT, AST and IBIL levels. The hydrogen-rich water group exhibited no significant differences in liver function before and after treatment, whereas the placebo group exhibited significantly elevated levels of ALT, AST and IBIL. Thus, hydrogen-rich water appeared to alleviate the mFOLFOX6-related liver injury
Acute physical exercise increases reactive oxygen species in skeletal muscle, leading to tissue damage and fatigue. Molecular hydrogen (H2) acts as a therapeutic antioxidant directly or indirectly by inducing antioxidative enzymes.
Here, we examined the effects of drinking hydrogen H2 water (H2-infused water) on psychometric fatigue and endurance capacity in a randomized, double-blind, placebo-controlled fashion.
In Experiment 1, all participants(humans) drank only placebo water in the first cycle ergometer exercise session, and for comparison they drank either hydrogen H2 water or placebo water 30 min before exercise in the second examination.In these healthy non-trained participants (n = 99), psychometric fatigue judged by visual analogue scales was significantly decreased in the hydrogen H2 water group after mild exercise. When each group was divided into 2 subgroups, the subgroup with higher visual analogue scale values was more sensitive to the effect of hydrogen water H2.
In Experiment 2, trained participants (n = 60) were subjected to moderate exercise by cycle ergometer in a similar way as in Experiment 1, but exercise was performed 10 min after drinking hydrogen H2 water. Endurance/fatigue were significantly improved/relieved in the hydrogen water H2 group as judged by maximal oxygen consumption and Borg’s scale, respectively.
Taken together, drinking hydrogen H2 water just before exercise exhibited anti-fatigue and improved endurance effects.
Possible appliance of effective and safe alkalizing agent in the treatment of metabolic acidosis could be of particular interest to humans experiencing an increase in plasma acidity, such as exercise-induced acidosis.
In the present study we tested the hypothesis that the daily oral intake of 2L of hydrogen-rich water (HRW) for 14 days would increase arterial blood alkalinity at baseline and post-exercise as compared with the placebo.
This study was a randomized, double blind, placebo-controlled trial involving 52 presumably healthy physically active male volunteers. Twenty-six participants received hydrogen-rich water HRW and 26 a placebo (tap water) for 14 days.
Arterial blood pH, partial pressure for carbon dioxide (pCO2), and bicarbonates were measured at baseline and postexercise at the start (day 0) and at the end of the intervention period (day 14).
Intake of hydrogen-rich water HRW significantly increased fasting arterial blood pH by 0.04 (95% confidence interval; 0.01 – 0.08; p < 0.001), and postexercise pH by 0.07 (95% confidence interval; 0.01 – 0.10; p = 0.03) after 14 days of intervention.
Fasting bicarbonates were significantly higher in the hydrogen-rich water HRW trial after the administration regimen as compared with the preadministration (30.5 ± 1.9 mEq/L vs. 28.3 ± 2.3 mEq/L; p < 0.0001).
No volunteers withdrew before the end of the study, and no participant reported any vexatious side effects of supplementation.
These results support the hypothesis that hydrogen-rich water HRW administration is safe and may have an alkalizing effect in young physically active men.
Objective: This study aims to investigate the selective protective effect of hydrogen water on the free radical injury of athletes after high-intensity exercise and to provide a reliable method for reducing oxidative stress injury of athletes.
Methods: A total of 60 athletes from the swimming team in our city were selected as the research subjects. They were divided into the control group and hydrogen water group according to different intervention methods. The athletes in the control group were treated with placebo, and the athletes in the hydrogen water group were supplemented with hydrogen water. The serum superoxide anions, Serum Superoxide Dismutase (SOD) activities, and total antioxidant capacities of athletes were compared between the two groups.
Results: The serum superoxide anions, serum SOD activities, and total antioxidant capacities of athletes during and after training were significantly superior to those of the control group (P<0.05), and the difference was statistically significant.
Conclusion: Hydrogen water supplement could effectively reduce the oxidized substances in athletes before, during, and after exercise and could prevent the free radical injury caused by high-intensity exercise.
Hydrogen water is one of the antioxidants. Its low price, nontoxic side effects, being non-stimulant, and other benefits provide a decisive advantage in clinical application . Clinical study indicated that injection or drinking of hydrogen water in the human body or animals or breathing hydrogen has a therapeutic effect for periodontitis, foot swelling, traumatic pancreatitis, intestinal ischemia reperfusion injury, brain injury, and other diseases caused by oxidative stress . One-time injection of hydrogen water had a protective effect on the biological membrane damage of free radical after acute exhaustive exercise in rat. Meanwhile, they first proved the collective selective oxidation of hydrogen water . However, previous research on hydrogen water used animal experiments, and research in the field of sport medicine is still in the initial exploratory stage. The systematic analysis of athletes undergoing professional high-intensity exercise is yet to be conducted . In this study, 60 athletes from our swimming team in our city were selected as the research subjects. They were supplemented with hydrogen water at different time phases. The antioxidant effects were compared, and the detailed discussion of the research follows.
A total of 60 athletes from the swimming team in our city were selected as the research subjects. They were divided into the control group and hydrogen water group according to the different intervention methods. The athletes in the control group were treated with placebo, and the athletes in the hydrogen water group were supplemented with hydrogen water. Every group had 30 male athletes. In the control group, the athletes were aged 14-22 years old with average of (18.1 ± 1.3) years old and had the following characteristics: height 172-196 cm, average (180.2 ± 6.3) cm; body weight 62-78 kg, average (68.2 ± 4.5) kg; and exercise duration 1-7 years, average (4.1 ± 0.5) years. In the hydrogen water group, the athletes were aged 15-22 years old, average (17.9 ± 1.5) years old, and had the following characteristics: height 174-192 cm, average (179.8 ± 6.5) cm; body weight 65-76 kg, average (68.0 ± 4.3) kg; exercise duration 2-7 years, average (3.7 ± 0.7) years. No statistical difference in athlete age, height, weight, and exercise duration (P>0.05) was noted between the two groups.
The hydrogen water in this study was purchased from Japan. It was authenticated as neither stimulant nor banned substance by the analeptic inspection center. All athletes were in good health during the intervention period and did not take any antioxidants, including vitamins C and E. The heart rates of athletes in the two groups were monitored. Meanwhile, the blood lactic acid of athletes was measured after exercise to ensure that exercise intensity was adequate. The study lasted for 8 d. A total of 5 ml fasting venous blood was drawn in the morning of the first day. The athletes were treated with the placebo (mineral water) and hydrogen water before, during, and after high-intensity exercise, tid, 200 ml each time. Venous blood was drawn after 2 h exercise. The intensities and amounts of training of all athletes were consistent in the study. The venous blood was labelled, naturally coagulated, and centrifuged by 3000 r/min in the refrigerated centrifuge. The separated serum was preserved in the refrigerator. The athletes were instructed to be mindful of their diet, and antioxidant nourishment was prohibited.
The selective antioxidant indexes (superoxide anion (O2-)), antioxidant defense system indexes (Superoxide Dismutase (SOD)), and serum Total Antioxidant Capacity (T-AOC) of athletes were monitored in the two groups.
The activity of resisting superoxide anion was measured through colorimetric method. The operation was in accordance with the kit instruction of Nanjing Bioengineering Institute, and the OD value of each tube was measured. The formula was as follows: anti O2- activity (U/L)=(OD value of the control tube-OD value of the measured tube)/(OD value of the control tube-OD value of the standard tube) × 1000 ml × concentration of standard sample × diluted times of the sample before test.
The SOD level in vivo was tested through biotin doubleantibody sandwich Enzyme-Linked Immunosorbent Assay (ELISA). The operation was in accordance with the kit instruction of human SOD from Shanghai Lianshuo Biological Technology Co., Ltd. SOD concentration was positively correlated with the color.
The T-AOC in vivo was determined through biotin doubleantibody sandwich ELISA. The operation was in accordance with the kit instruction of human SOD from Shanghai Lianshuo Biological Technology Co., Ltd. T-AOC concentration was positively correlated with the color.
In this study, all the data were imputed into the Excel table and analysed using the SPSS19.0 statistical software. The measurement data were expressed with (χ ± s) and compared using t test. P<0.05 showed that the difference was statistically significant.
Comparison of serum superoxide anion activities of athletes between the two groups
The serum antisuperoxide anion activities of athletes were not different between the two groups before exercise. Meanwhile, the serum antisuperoxide anion activities of athletes in the two groups decreased after exercise. However, the serum antisuperoxide anion activity of athletes in the hydrogen water group was decreased compared with that of the control group during and after exercise, as shown in Table 1.
|Group||N||Before exercise||During exercise||After exercise||P value|
|Blank group||30||146.60 ± 9.31||139.67 ± 9.07||117.17 ± 15.27||<0.05|
|Hydrogen water group||30||143.18 ± 7.88||95.86 ± 12.85||98.86 ± 8.30||<0.05|
Table 1: Comparison of serum antisuperoxide anion activities of athletes in the two groups (χ ± s; U/ml).
Comparison of serum superoxide dismutase activities of athletes between the two groups
The SOD activities of athletes were not different between the two groups before exercise. Meanwhile, the SOD of athletes in the blank group was decreased after exercise. However, the SOD activity of athletes in the hydrogen water group during and after exercise was significantly higher than that of the control group and higher than that before and during exercise, as shown in Table 2.
|Group||N||Before the training||During the training||After the training||P value|
|Blank group||30||57.07 ± 7.08||47.86 ± 7.31||45.65 ± 7.63||<0.05|
|Hydrogen water group||30||55.79 ± 9.20||56.88 ± 4.83||66.92 ± 6.70||<0.05|
Table 2: Comparison of serum superoxide dismutase activities of athletes between the two groups (χ ± s; U/L).
Comparison of serum total antioxidant capacities of athletes between the two groups at different time phases
The serum total antioxidant capacities of athletes was not different between the two groups before exercise. Meanwhile, the serum T-AOC of athletes in the blank group fluctuated after exercise. However, the serum T-AOC of athletes in the hydrogen water group during and after exercise was significantly higher than that of the control group and higher than that before and during exercise, as shown in Table 3.
|Group||N||Before exercise||During exercise||After exercise||P value|
|Blank group||30||2.48 ± 0.11||2.28 ± 0.16||2.35 ± 0.11||<0.05|
|Hydrogen water group||30||2.46 ± 0.13||2.52 ± 0.19||3.36 ± 0.12||<0.05|
Table 3: Comparison of serum total antioxidant capacities of athletes between the two groups at different time points (χ ± s; U/ml).
Free radicals are a kind of substance produced by the normal metabolism in the human body. They do not contain paired electrons, so its nature is lively. Free radicals will offensively target all cells and induce injury. The free radical has two types, and 95% of free radicals belong to oxygen free radicals . It has normal biological functions, such as sterilization, playing an important role in embryonic development, regulating angiotensin, and involvement in the biological initiation of various biological factors as a second messenger. However, the free radical is also cytotoxic. A large number of research  have reported that the free radical is closely related to cancer, inflammation, Alzheimer’s disease, depression, protein oxidative pyrolysis, and lipid peroxidation. Therefore, the free radical is regarded as a “double-edged sword,” and too much or too little will cause adverse effects or even damage. Superoxide anion free radical is a source of various free radicals. Free radicals will absorb the electrons in the endoplasmic reticulum, mitochondria, and nucleus through both non-enzymatic and enzymatic reaction; produce all kinds of oxygen free radicals; and cause damage . Under normal circumstances, the content of plasma Hb is little. However, after high-intensity exercise, a large number of free radicals generate in the body, and the erythrocyte membrane permeability is increased, resulting in the release of Hb into the blood. After drinking the hydrogen water, the antisuperoxide anion activity of athletes was significantly lower than that of the control group (P<0.01), suggesting that hydrogen water could inhibit the antisuperoxide anion activity to a certain extent and reduce the oxidative stress injury.
SOD is an important substance of antioxidant system in body. It can effectively eliminate the superoxide anion during metabolism; prevent lipid peroxidation, aging, fatigue, and injury; and improve athletic ability. Monitoring SOD activity can effectively investigate the quantity of free radicals in vivo . The study found that the SOD activity of athletes in the blank group was decreased after exercise. However, the SOD activities of athletes in the hydrogen water group during and after exercise were significantly higher than those of the control group and also higher than those before and during exercise (P<0.01). T-AOC is a comprehensive index. It can measure the intergraded function of the antioxidant system in body. Its value is closely related to the body’s defense system and can directly reflect the health of the body . At present, reports on SOD activity after exercise are inconsistent. Compared with before exercise and other periods, the serum SOD activity was significantly increased. Meanwhile, the serum SOD activities were not significantly different among other time phases. The serum SOD activities were significantly decreased after anaerobic and aerobic exercises. The study found that in the blank group, serum T-AOC of athletes fluctuated after exercise . However, the serum T-AOC of athletes in the hydrogen group was significantly higher than that of the control group and higher than that before and during exercise (P<0.05).
Hydrogen water supplement can effectively reduce the oxidizing substance before, during, and after exercise, preventing free radical damage caused by high-intensity exercise. Whether or not it can be generally used in athletes still requires further research with a large sample size.
Biomedical Research (2017) Volume 28, Issue 10
Accepted date: March 14, 2017
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Volatile Organic Compounds