(2018) 40:7482. (2010) 83:50914.

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(2018) 40:7482. (2010) 83:50914.

(2018) 40:7482. (2010) 83:50914. Hydrogen-rich saline attenuated subarachnoid hemorrhage-induced early brain injury in rats by suppressing inflammatory response: possible involvement of NF-kappaB pathway and NLRP3 inflammasome. Hydrogen gas attenuates myocardial ischemia reperfusion injury independent of postconditioning in rats by attenuating endoplasmic reticulum stress-induced autophagy. doi: 10.1016/j.juro.2012.12.001, 34. doi: 10.1073/pnas.97.26.14478, 98. 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). doi: 10.2147/OTT.S60114, 65. Food Chem Toxicol. LeBaron TW, Laher I, Kura B, Slezak J. Hydrogen gas: from clinical medicine to an emerging ergogenic molecule for sports athletes. 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. J Med Chem. Zhao P, Jin Z, Chen Q, Yang T, Chen D, Meng J, et al. oxygen photosynthesis glucose diabetestalk Med Gas Res.

(2019) 24: 24:E1184. doi: 10.3390/molecules24061184, 20. doi: 10.1097/SHK.0000000000000810, 50. (2018) 31:138. Circ J. (2010) 13:2943. (2015) 26:144651. 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 TNF in the bronchoalveolar lavage fluid, leading to a relieve of lung inflammation. (2012) 56:91221. ROS signaling under metabolic stress: cross-talk between AMPK and AKT pathway. 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. 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). Cell Physiol Biochem. Support Care Cancer. This study suggested that hydrogen-rich saline treatment exerted its protective effects via inhibiting the inflammatory TNF-/IL-6 pathway, increasing the cleaved C8 expression and Bcl-2/Bax ratio, and attenuating cell apoptosis in both heart and liver tissue (71). (2018) 65:36672. 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). 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 (913). Nat Immunol. Med Gas Res. Protective effects of hydrogen-rich saline against erectile dysfunction in a streptozotocin induced diabetic rat model. PLoS ONE. Sci Rep. (2019) 9:1255. doi: 10.1038/s41598-018-38180-4, 25. Clin Transl Oncol. doi: 10.1002/med.21461, 3. Shock. Modulation of oxidative stress as an anticancer strategy. (2019) 10:145. doi: 10.1186/s13287-019-1241-x, 101. Drug Resist Updat. 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). (2019) 60:1722. 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. Reactive oxygen species in cancer cells: live by the sword, die by the sword. (2012) 59:102632. doi: 10.1016/j.drup.2018.11.001, 43. Gao Y, Yang H, Fan Y, Li L, Fang J, Yang W. Hydrogen-rich saline attenuates cardiac and hepatic injury in doxorubicin rat model by inhibiting inflammation and apoptosis. doi: 10.1016/j.ccr.2006.08.015, 79. In the study, cisplatin treatment induced higher level of oxidation products, suppressed the antioxidant enzyme activity. doi: 10.4155/fmc-2018-0403, 10. More important, inhalation of hydrogen gas inhibited the tumor volume significantly as shown in the Hs38.T xenografted BALB/c nude mice model (99). doi: 10.1259/bjr/25604811, 85. Ann Med. Antiproliferative effects of carbon monoxide on pancreatic cancer. (2011) 17:Y14.

Zitvogel L, Pietrocola F, Kroemer G. Nutrition, inflammation, and cancer. Nat Rev Cancer. 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. Dual-targeted and pH-sensitive doxorubicin prodrug-microbubble complex with ultrasound for tumor treatment. (2010) 44:47996. Smith NW, Shorten PR, Altermann EH, Roy NC, McNabb WC. Most of the ionizing radiation-induced adverse effects to normal cells are induced by hydroxyl radicals. Vitek L, Gbelcova H, Muchova L, Vanova K, Zelenka J, Konickova R, 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). Int J Mol Sci. 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). (2017) 7:7685. 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. The presence of ROS can produce cellular stress and damage that may produce cell death, via a mechanism known as oxidative stress (39, 40). Meanwhile, the liver had the highest Cmax (24). Gastrointestinal toxicity associated to radiation therapy. (2018) 19:E448. doi: 10.3727/215517913X666486, 33. doi: 10.1016/j.drup.2004.01.004, 41. Biomed Pharmacother.

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. Nat Med. Targeting apoptosis as an approach for gastrointestinal cancer therapy. (2000) 97:1447883. doi: 10.1016/j.dld.2013.12.007, 4. Nakashima-Kamimura N, Mori T, Ohsawa I, Asoh S, Ohta S. Molecular hydrogen alleviates nephrotoxicity induced by an anti-cancer drug cisplatin without compromising anti-tumor activity in mice. Ohta S. Recent progress toward hydrogen medicine: potential of molecular hydrogen for preventive and therapeutic applications. 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. doi: 10.1021/acs.jmedchem.6b01672, 11. doi: 10.5754/hge11883, 102. 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. Shao A, Wu H, Hong Y, Tu S, Sun X, Wu Q, et al. Zhou P, Lin B, Wang P, Pan T, Wang S, Chen W, et al. Chuai Y, Zhao L, Ni J, Sun D, Cui J, Li B, et al. (2006) 10:1756. 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. No use, distribution or reproduction is permitted which does not comply with these terms. Mediators Inflamm. 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 combination of PdH0.2 nanocrystals with NIR irradiation significantly enhanced the anticancer efficacies of thermal therapy, achieving a synergetic anticancer effect. code states united primary law sources hydrogen peroxide drugs drug chapter title (2016) 2016:3164734. doi: 10.1155/2016/3164734, 40. Recently, hydrogen gas was found to inhibit cancer stem cells (CSCs). A possible prevention strategy of radiation pneumonitis: combine radiotherapy with aerosol inhalation of hydrogen-rich solution. Under treatment of epidermal growth factor receptor inhibitor gefitinib, patients with non-small cell lung cancer often suffer with severe acute interstitial pneumonia (79). Int J Cancer. Zheng DW, Li B, Li CX, Xu L, Fan JX, Lei Q, et al. (2016) 80:18703. (2013) 5:837.

Liu MY, Xie F, Zhang Y, Wang TT, Ma SN, Zhao PX, et al. J Dermatolog Treat. doi: 10.1093/annonc/mdv206, 64.

(2016) 139:263545. doi: 10.1054/drup.2001.0219, 55. Acs Nano. 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. One in vivo study showed that intraperitoneal injection of hydrogen-rich saline ameliorated the mortality, and cardiac dysfunction caused by doxorubicin. Int J Mol Sci. Ostojic SM. Wardill HR, Mander KA, Van Sebille YZ, Gibson RJ, Logan RM, Bowen JM, et al. (2019) 53:30913. Except the thigh muscle required a longer time to saturate, the other organs need 510 min to reach Cmax (maximum hydrogen concentration). Ma Y, Yan Z, Deng X, Guo J, Hu J, Yu Y, et al. Inadequate production of H2 by gut microbiota and Parkinson disease. doi: 10.18632/oncotarget.21130, 37. Gao Y, Yang H, Chi J, Xu Q, Zhao L, Yang W, 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). We thank Miss Ryma Iftikhar, Dhiviya Samuel, Mahnoor Shamsi (St. John's University), and Mr. Muaz Sadeia for editing and revising the manuscript. 1. Cancer Chemother Pharmacol. doi: 10.12659/MSM.881698, 90. SL, RL, and XS: revising. (2016) 53:346276. Cheung YT, Ng T, Shwe M, Ho HK, Foo KM, Cham MT, et al. The role of the reactive oxygen species and oxidative stress in the pathomechanism of the age-related ocular diseases and other pathologies of the anterior and posterior eye segments in adults. doi: 10.1002/hep.25782, 97. (2017) 11:1284962. (2019) 120:42532. Future Med Chem. (2015) 10:227782. Disulfiram targeting lymphoid malignant cell lines via ROS-JNK activation as well as Nrf2 and NF-kB pathway inhibition. (2017) 63:29. doi: 10.1016/j.niox.2017.01.005, 15. 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). doi: 10.1007/s00520-019-04780-7. (2017) 29:1703822. doi: 10.1002/adma.201703822, 13. Similar results were also observed in Meng et al. doi: 10.1038/emm.2017.246, 93. Gorrini C, Harris IS, Mak TW. (2015) 47:3014. Cao X, Ding L, Xie ZZ, Yang Y, Whiteman M, Moore PK, et al. Review and prospect of the biomedical effects of hydrogen. More importantly, hydrogen didn't impair the anti-tumor activity of cisplatin against cancer cell lines in vitro and in tumor-bearing mice (85). Chemotherapy-enhanced inflammation may lead to the failure of therapy and metastasis. Can J Physiol Pharmacol. Antioxid Redox Signal. Li FY, Zhu SX, Wang ZP, Wang H, Zhao Y, Chen GP. Free Radic Res.

Hydrogen gas alleviates chronic intermittent hypoxia-induced renal injury through reducing iron overload. (2017) 7:45265.

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). The role of sulfur dioxide in the regulation of mitochondrion-related cardiomyocyte apoptosis in rats with isopropylarterenol-induced myocardial injury. Zhai X, Chen X, Ohta S, Sun X. (2009) 12:5564. Another study also confirmed that hydrogen gas might reduce the oxygen toxicity resulted from hyperbaric oxygen via effectively reducing OH (46). (2011) 76:46770. Therapeutic potential of molecular hydrogen in ovarian cancer. Exp Mol Med. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. In a mouse model, hydrogen-rich water administration lowered the hepatic cholesterol, peroxisome proliferator-activated receptor- (PPAR) expression, and increased the anti-oxidative effects in the liver when compared with control and pioglitazone treated group (96). This effect was further confirmed by apoptosis and cell migration assay in these two cell lines. (2017) 22:90512. 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. Nat Commun. Ethylene, an early marker of systemic inflammation in humans.

doi: 10.1253/circj.CJ-16-0127, 36. Subcutaneous injection of hydrogen gas is a novel effective treatment for type 2 diabetes. 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). Mager LF, Wasmer MH, Rau TT, Krebs P. Cytokine-induced modulation of colorectal cancer. doi: 10.1016/j.intimp.2018.10.012, 51. The Summary of various formulation, application, mechanisms of H2 in cancer treatment. (2018) 7:98895. Int J Clin Oncol. These data suggested that hydrogen gas could serve as a new method for the treatment of lung cancer (98). Local generation of hydrogen for enhanced photothermal therapy. Meng J, Yu P, Jiang H, Yuan T, Liu N, Tong J, et al. Dermond O, Ruegg C. Inhibition of tumor angiogenesis by non-steroidal anti-inflammatory drugs: emerging mechanisms and therapeutic perspectives. The editor and reviewer's affiliations are the latest provided on their Loop research profiles and may not reflect their situation at the time of review. Molecular hydrogen: an inert gas turns clinically effective. Hydrogen-rich water treatment could significantly reverse the toxic effects, and it showed much higher transverse relaxation rate by eliminating oxygen radicals (83, 84). Gastrointestinal toxicity is a common side effect induced by radiotherapy, which impairs the life quality of cancer patients (91). Pfeffer CM, Singh A. Apoptosis: a target for anticancer therapy. (2016) 6:96. doi: 10.3389/fonc.2016.00096, 60. Cell Med. Guan P, Sun ZM, Luo LF, Zhao YS, Yang SC, Yu FY, et al. Furthermore, hydrogen-rich saline stimulated the Nrf2 pathway in rats with ovarian damage (86). 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. water plates ionizer alkaline mesh kyk comparison plate As the lightest molecule in natural, hydrogen gas exhibits appealing penetration property, as it can rapidly diffuse through cell membranes (22, 23). doi: 10.1016/j.smim.2018.10.011, 57. 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. Hydrogen sulfide-based anti-inflammatory and chemopreventive therapies: an experimental approach. 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). The evolution of molecular hydrogen: a noteworthy potential therapy with clinical significance. One clinical trials (NCT03818347) is now undergoing to study the hydrogen gas in cancer rehabilitation in China. 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). 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. J Clin Gastroenterol. Dixon BJ, Tang J, Zhang JH. Anticancer effect of exogenous hydrogen sulfide in cisplatinresistant A549/DDP cells. Interestingly, through various administrations, these molecules also exhibit potential in cancer treatment. 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. Its mechanism, target, indications are also not clear, further study are warranted. Biochem Biophys Res Commun. Increase in breath hydrogen concentration was correlated with the main pancreatic duct stenosis. 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. First, as shown in Ohsawa et al. Flannigan KL, Wallace JL. Bottazzi B, Riboli E, Mantovani A.

doi: 10.2174/138161211797052664, 103. doi: 10.1038/ni.3754, 58. (2017) 8:10265373.

These gaseous molecules possess multiple critical functions in regulating cell biology in vivo via signal transduction (9). Consolidation mFOLFOX6 chemotherapy after chemoradiotherapy improves survival in patients with locally advanced rectal cancer: final results of a multicenter phase II trial. (2018) 4:3. doi: 10.1186/s40733-018-0040-y, 62. doi: 10.1038/s41374-019-0187-z, 81. doi: 10.1007/s00520-019-4660-4. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Int J Mol Sci. 77. Front. Table 1. Meng X, Chen H, Wang G, Yu Y, Xie K. Hydrogen-rich saline attenuates chemotherapy-induced ovarian injury via regulation of oxidative stress. Wang D, Wang L, Zhang Y, Zhao Y, Chen G. Hydrogen gas inhibits lung cancer progression through targeting SMC3. Meanwhile, the combination group showed no visible damage to heart, liver, spleen, lung, and kidney, indicating suitable tissue safety and compatibility (52). ph balance cancer every too acidic easiest single person check way