Gen activates Nrf2 [36, 817] and its downstream heme oxygenase-1 (HO-1) [36, 51, 52, 65, 71, 81, 82, 843]. Kawamura and colleagues reported that hydrogen didn’t mitigate hyperoxic lung injury in Nrf2knockout mice [82]. Similarly, Ohsawa and colleagues reported that hydrogen enhanced mitochondrial functions and induced nuclear translocation of Nrf2 at the Symposium of Healthcare Molecular Hydrogen in 2012 and 2013. They proposed that hydrogen induces an adaptive response against oxidative anxiety, that is also called a hormesis impact. These H 4065 studies indicate that the effectof hydrogen is mediated by Nrf2, however the mechanisms of how Nrf2 is activated by hydrogen stay to be solved. A different intriguing mechanism is that hydrogen modulates miRNA expressions [64, 94]. Hydrogen regulates expressions of miR-9, PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/21300292 miR-21, and miR-199, and modifies expressions of IKK-, NF-B, and PDCD4 in LPSactivated retinal microglia cells [64]. Similarly, analysis of miRNA profiles of hippocampal neurons throughout IR injury revealed that hydrogen inhibits IR-induced expression from the miR-200 family by decreasing ROS production, which has led to suppression of cell death [94]. Having said that, modulation of miRNA expression can not solely clarify all of the biological effects mediated by hydrogen. Also, mechanisms underlying modulated miRNA expressions stay to be elucidated. Matsumoto and colleagues reported that oral intake of hydrogen water increased gastric expression and secretion of ghrelin and that the neuroprotective effect of hydrogen water was abolished by the ghrelin receptorantagonist and by the ghrelin secretion-antagonist [95]. As stated above, we have shown that hydrogen water, but not hydrogen gas, prevented improvement of Parkinson’s illness within a rat model [11]. Prominent effect of oral hydrogen intake rather than hydrogen gas inhalation may be partly accounted for by gastric induction of ghrelin. Lately, Ohta and colleagues showed at the 5th Symposium of Medical Molecular Hydrogen at Nagoya, Japan in 2015 that hydrogen influences a free of charge radical chain reaction of unsaturated fatty acid on cell membrane and modifies its lipid peroxidation approach. Furthermore, they demonstrated that air-oxidized phospholipid that was created either in the presence or absence of hydrogen in vitro, offers rise to various intracellular signaling and gene expression profiles when added for the culture medium. In addition they showed that this aberrant oxidization of phospholipid was observed with a low concentration of hydrogen (no less than 1.3 ), suggesting that the biological effects of hydrogen may very well be explained by the aberrant oxidation of phospholipid under hydrogen exposure. Amongst the many molecules which are altered by hydrogen, most are predicted to be passengers (downstream regulators) which can be modulated secondarily to a modify within a driver (master regulator). The very best technique to determine the master regulator is usually to prove the impact of hydrogen in an in vitro system. Even though, to our expertise, the study on lipid peroxidation has not however been published, the absolutely free radical chain reaction for lipid peroxidation might be the second master regulator of hydrogen next towards the radical scavenging impact. We are also analyzing other novel molecules as you can master regulators of hydrogen (in preparation). Taken collectively, hydrogen is probably to possess several master regulators, which drive a diverse array of downstreamIchihara et al. Healthcare Gas Analysis (2015) 5:Web page 5 ofTable 2 Disease model.