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 stress, which can be also known as a hormesis effect. These research indicate that the effectof hydrogen is mediated by Nrf2, but the mechanisms of how Nrf2 is activated by hydrogen remain to be solved. Another exciting mechanism is the fact 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 in the course of IR injury revealed that hydrogen inhibits IR-induced expression with the miR-200 family by lowering ROS production, which has led to suppression of cell death [94]. Nevertheless, modulation of miRNA expression can not solely explain all the biological effects mediated by hydrogen. In addition, mechanisms underlying modulated miRNA expressions stay to become 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’ve shown that hydrogen water, but not hydrogen gas, prevented development of Parkinson’s disease inside a rat model [11]. Prominent impact of oral hydrogen intake as an alternative to hydrogen gas inhalation may be partly accounted for by gastric induction of ghrelin. Recently, Ohta and colleagues showed in the 5th Symposium of Healthcare Molecular Hydrogen at Nagoya, Japan in 2015 that hydrogen influences a absolutely free radical chain reaction of unsaturated fatty acid on cell membrane and modifies its lipid peroxidation process. Additionally, they demonstrated that air-oxidized phospholipid that was created either inside the presence or absence of hydrogen in vitro, gives rise to distinct intracellular signaling and gene expression profiles when added for the culture medium. In addition they showed that this aberrant oxidization of phospholipid was observed using a low concentration of hydrogen (a minimum of 1.3 ), suggesting that the biological effects of hydrogen might be explained by the aberrant oxidation of phospholipid under hydrogen exposure. Among the many molecules that happen to be altered by hydrogen, most are predicted to be passengers (downstream regulators) which might be modulated secondarily to a change within a driver (master regulator). The very best method to identify the master regulator is to prove the impact of hydrogen in an in vitro system. order GSK583 Despite the fact that, to our information, the study on lipid peroxidation has not however been published, the totally free radical chain reaction for lipid peroxidation may be the second master regulator of hydrogen next to the radical scavenging effect. We’re also analyzing other novel molecules as you possibly can master regulators of hydrogen (in preparation). Taken with each other, hydrogen is likely to possess several master regulators, which drive a diverse array of downstreamIchihara et al. Health-related Gas Research (2015) 5:Web page 5 ofTable 2 Disease model.