Anticancer effect of exogenous hydrogen sulfide in cisplatinresistant A549/DDP cells. 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). Sci Rep. (2017) 7:6889. doi: 10.1038/s41598-017-05930-9, 9. Theranostics. Importantly, scores of quality of life during radiotherapy were significantly improved in hydrogen-rich water group compared to the placebo water group. Cao X, Ding L, Xie ZZ, Yang Y, Whiteman M, Moore PK, et al. Nita M, Grzybowski A. 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. Cheung YT, Ng T, Shwe M, Ho HK, Foo KM, Cham MT, et al. (2011) 29:50312. Int J Mol Sci. (2013) 12:93147. Modulation of oxidative stress as an anticancer strategy. Estimation of the hydrogen concentration in rat tissue using an airtight tube following the administration of hydrogen via various routes. doi: 10.1371/journal.pone.0173645, 47. Med Sci Monit. Ohta S. Recent progress toward hydrogen medicine: potential of molecular hydrogen for preventive and therapeutic applications. (2019) 53:30913. The concentration order of hydrogen gas, when reached saturated status, was liver, brain, mesentery, muscle, kidney, indicating various distributions among organs in rats. (2018) 61:114655. Drug Resist Updat. doi: 10.1111/febs.14209, 96. Dual-targeted and pH-sensitive doxorubicin prodrug-microbubble complex with ultrasound for tumor treatment. The combination of PdH0.2 nanocrystals with NIR irradiation significantly enhanced the anticancer efficacies of thermal therapy, achieving a synergetic anticancer effect. (2016) 139:263545. (2019) 120:42532. Liu C, Kurokawa R, Fujino M, Hirano S, Sato B, Li XK. Verheij M, Vens C, van Triest B. However, cancer patients receiving these treatments often experience fatigue and impaired quality of life (7577). doi: 10.7150/thno.16677, 82. Paardekooper LM, van den Bogaart G, Kox M, Dingjan I, Neerincx AH, Bendix MB, et al. (2014) 7:101523. 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. (2017) 7:7685. (2017) 11:1284962. (2019) 99:793806. Hydrogen gas may act as a ROS modulator. Subcutaneous injection of hydrogen gas is a novel effective treatment for type 2 diabetes. 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. 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. (2019) 11:3236. (2010) 12:55461. 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. Wardill HR, Mander KA, Van Sebille YZ, Gibson RJ, Logan RM, Bowen JM, et al. A possible prevention strategy of radiation pneumonitis: combine radiotherapy with aerosol inhalation of hydrogen-rich solution. 29. Copyright 2019 Li, Liao, Sheng, Luo, Zhang, Wen, Zhou and Peng. However, regarding its medicinal properties, such as dosage and administration, or possible adverse reactions and use in specific populations, less information is available. Med Gas Res. Recently, hydrogen gas (formula: H2) emerges as another GSM which possesses multiple bioactivities, including anti-inflammation, anti-reactive oxygen species, and anti-cancer. (2012) 13:3099102. Stuehr DJ, Vasquez-Vivar J. Nitric oxide synthases-from genes to function. Modulating ROS to overcome multidrug resistance in cancer. 77. Susanne K, Michael F, Thomas S, Peter E, Andreas H. Predictors of fatigue in cancer patients: a longitudinal study. 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. 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. (2016) 17:266. doi: 10.3390/ijms17030266, 6. (2012) 24:98190. Qiao L, Wong BC. Oliveira C, Benfeito S, Fernandes C, Cagide F, Silva T, Borges F. NO and HNO donors, nitrones, and nitroxides: past, present, and future. By regulating inflammation, hydrogen gas can prevent tumor formation, progression, as well as reduce the side effects caused by chemotherapy/radiotherapy (66).
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'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).
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). Kumari S, Badana AK, G MM, G S, Malla R. Reactive oxygen species: a key constituent in cancer survival. doi: 10.1038/nrc2745, 71. Cell Signal. Cui Q, Yang Y, Ji N, Wang JQ, Ren L, Yang DH, et al. (2018) 8:1549. Hydrogen-rich water also showed renal protective effect against cisplatin-induced nephrotoxicity in rats. (2004) 7:97110. Furthermore, hydrogen-rich water shortened the healing time and increased the healing rate of skin injury (48). doi: 10.1093/jrr/rry074, 49. Li Q, Tanaka Y, Miwa N. Influence of hydrogen-occluding-silica on migration and apoptosis in human esophageal cells in vitro.
Acs Nano. SL, XW, JZ, and KP: conceptualization. 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). doi: 10.1038/nrc3613, 54. doi: 10.3390/biom5032073, 56. doi: 10.1016/j.drup.2010.01.002, 75. 
SL, RL, and XS: revising. Cytokine-mediated blood brain barrier disruption as a conduit for cancer/chemotherapy-associated neurotoxicity and cognitive dysfunction. 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). 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. Hydrogen gas alleviates chronic intermittent hypoxia-induced renal injury through reducing iron overload. (2017) 12:e173645. The presence of ROS can produce cellular stress and damage that may produce cell death, via a mechanism known as oxidative stress (39, 40). Ann Oncol. Clin Transl Oncol. A phase II study of 5-fluorouracil/L-leucovorin/oxaliplatin. (2008) 7:1041. doi: 10.1038/nrd2765, 68. Zhao Y, Hu X, Liu Y, Dong S, Wen Z, He W, et al. Pfeffer CM, Singh A. Apoptosis: a target for anticancer therapy. 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. Ma C, Zhang Q, Greten TF. Li et al. designed a solidified hydrogen-occluding-silica (H2-silica) that could stably release molecular hydrogen into cell culture medium. doi: 10.1007/s10147-017-1138-6, 89. Chromosomes 3 (SMC3), a complex required for chromosome cohesion during the cell cycle (97), was suppressed by hydrogen gas via ubiquitinating effects. Fukuda K, Asoh S, Ishikawa M, Yamamoto Y, Ohsawa I, Ohta S. Inhalation of hydrogen gas suppresses hepatic injury caused by ischemia/reperfusion through reducing oxidative stress. doi: 10.1038/s41401-018-0158-8, 83. 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. doi: 10.1038/emm.2017.246, 93. Yu J, Yu Q, Liu Y, Zhang R, Xue L. Hydrogen gas alleviates oxygen toxicity by reducing hydroxyl radical levels in PC12 cells. (2018) 104:78897. PLoS ONE. 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. doi: 10.1080/19490976.2018.1546522, 22. Zhang JY, Liu C, Zhou L, Qu K, Wang R, Tai MH, et al. Li Y, Li Q, Chen H, Wang T, Liu L, Wang G, et al. Molecules. Jpn J Radiol. Curr Pharm Des. Non-alcoholic fatty liver disease promotes hepatocellular carcinoma through direct and indirect effects on hepatocytes. Chen J, Luo H, Liu Y, Zhang W, Li H, Luo T, et al. 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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. Chemotherapy and radiotherapy remain the leading strategies to treat cancer (73, 74). (summarized in Table 1). SL, RL, XS, XL, XZ, JZ, and KP: writing. Huang D, Ichikawa K. Drug discovery targeting apoptosis. 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). 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. J Med Chem. Non-alcoholic steatohepatitis (NASH) due to oxidative stress induced by various stimuli, is one of the reasons that cause hepatocarcinogenesis (94, 95). Asthma Res Pract. doi: 10.1097/DCR.0000000000001207, 88. *Correspondence: Jin Zhou, zhou-jin-2008@163.com; Kang Peng, kds978@163.com, Hydrogen Gas Selectively Scavenges Hydroxyl Radical and Peroxynitrite, and Regulates Certain Antioxidant Enzymes, Hydrogen Gas Suppresses Inflammatory Cytokines, Hydrogen Gas Exhibits Potential in Cancer Treatment, Creative Commons Attribution License (CC BY). Rodriguez ML, Martin MM, Padellano LC, Palomo AM, Puebla YI. 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 (1619). Under treatment of epidermal growth factor receptor inhibitor gefitinib, patients with non-small cell lung cancer often suffer with severe acute interstitial pneumonia (79). Kang KM, Kang YN, Choi IB, Gu Y, Kawamura T, Toyoda Y, et al. Except the thigh muscle required a longer time to saturate, the other organs need 510 min to reach Cmax (maximum hydrogen concentration). doi: 10.1002/hep.25782, 97. Cell Physiol Biochem. Int J Mol Sci. In the study, cisplatin treatment induced higher level of oxidation products, suppressed the antioxidant enzyme activity. The combination of radiotherapy with certain forms of hydrogen gas may be beneficial to alleviate these side effects (89). Dong A, Yu Y, Wang Y, Li C, Chen H, Bian Y, et al. Marco MR, Zhou L, Patil S, Marcet JE, Varma MG, Oommen S, et al. 
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Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome. 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. Drug Resist Updat. Zhao et al. (2001) 4:31421. Zha J, Chen F, Dong H, Shi P, Yao Y, Zhang Y, et al. Meng J, Yu P, Jiang H, Yuan T, Liu N, Tong J, et al. (2018) 29:2868. Li Z, Huang Y, Du J, Liu AD, Tang C, Qi Y, et al. Biochem Biophys Res Commun. Hydrogen-rich water prevents progression of non-alcoholic steatohepatitis and accompanying hepatocarcinogenesis in mice. 1. doi: 10.2174/1381612821666150514105413, 5. Food Chem Toxicol. Smith NW, Shorten PR, Altermann EH, Roy NC, McNabb WC. Hepatogastroenterology. Int J Cancer. Shakola F, Suri P, Ruggiu M. Splicing regulation of pro-inflammatory cytokines and chemokines: at the interface of the neuroendocrine and immune systems. Sci Rep. 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Typically, hydrogen gas may exert its bio-functions via regulating ROS, inflammation and apoptosis events. Febs J. Received: 02 May 2019; Accepted: 15 July 2019; Published: 06 August 2019. doi: 10.21037/tcr.2018.07.09, 100. 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. 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). Science. Cancer Cell. Horimatsu T, Nakayama N, Moriwaki T, Hirashima Y, Fujita M, Asayama M, et al. Ning K, Liu WW, Huang JL, Lu HT, Sun XJ. No use, distribution or reproduction is permitted which does not comply with these terms. 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. Mol Clin Oncol. In the current review, we take a spot on its application in cancer treatment. (2011) 17:Y14. J Dermatolog Treat. Kawai D, Takaki A, Nakatsuka A, Wada J, Tamaki N, Yasunaka T, et al. 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). doi: 10.1038/nm1577, 27. These data suggested that hydrogen gas could serve as a new method for the treatment of lung cancer (98). Wang FH, Shen L, Li J, Zhou ZW, Liang H, Zhang XT, et al. Chuai Y, Zhao L, Ni J, Sun D, Cui J, Li B, et al. doi: 10.4103/2045-9912.248264. Front Oncol. 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. Dig Liver Dis. Zheng DW, Li B, Li CX, Xu L, Fan JX, Lei Q, et al. Gaseous signaling molecules and their application in resistant cancer treatment: from invisible to visible. Med Gas Res. doi: 10.1016/S0140-6736(03)12190-3, 80. (2012) 56:91221. doi: 10.1097/SHK.0000000000000810, 50.
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). Nat Commun. Molecular hydrogen suppresses glioblastoma growth via inducing the glioma stem-like cell differentiation. (2010) 83:50914. Shang L, Xie F, Li J, Zhang Y, Liu M, Zhao P, et al. Interestingly, through various administrations, these molecules also exhibit potential in cancer treatment. Its mechanism, target, indications are also not clear, further study are warranted. One clinical trials (NCT03818347) is now undergoing to study the hydrogen gas in cancer rehabilitation in China. A review of hydrogen sulfide synthesis, metabolism, and measurement: is modulation of hydrogen sulfide a novel therapeutic for cancer? J Radiat Res. Nat Immunol. (2009) 9:897903. 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). doi: 10.3892/etm.2015.2787, 87. 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. doi: 10.1259/bjr/25604811, 85. Shen BY, Chen C, Xu YF, Shen JJ, Guo HM, Li HF, et al. Mol Neurobiol. Lancet. Zitvogel L, Pietrocola F, Kroemer G. Nutrition, inflammation, and cancer. Ann Med. Dozen M, Enosawa S, Tada Y, Hirasawa K. Inhibition of hepatic ischemic reperfusion injury using saline exposed to electron discharge in a rat model. Ge L, Yang M, Yang NN, Yin XX, Song WG. Drug Resist Updat. (2019) 20:E676. Effects of hydrogen on polarization of macrophages and microglia in a stroke model. In vivo safety evaluation showed that the injection dose of 10 mg kg1 PdH0.2 nanocrystals caused no death, no changes of several blood indicators, and no affected functions of liver and kidney. (2014) 25:1828. (2010) 44:47996. 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). Sci Rep. (2019) 9:1255. doi: 10.1038/s41598-018-38180-4, 25. Effects of drinking hydrogen-rich water on the quality of life of patients treated with radiotherapy for liver tumors. This work suggested that hydrogen-rich water was a promising regimen to attenuate Fe-NTA-induced renal injury and suppress early tumor events (66). Hydrogen gas can regulate intracellular apoptosis by impacting the expression of apoptosis-related enzymes. Protective effects of hydrogen gas against sepsis-induced acute lung injury via regulation of mitochondrial function and dynamics. Drug Resist Updat. doi: 10.1007/s00520-019-04780-7. The information may direct the future clinical application of hydrogen gas. Nitric Oxide. Free Radic Res. doi: 10.1097/MCG.0000000000001062, 95. doi: 10.1007/s12094-010-0553-1, 92.