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 did not mitigate C.I. 15985 web 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 Medical Molecular Hydrogen in 2012 and 2013. They proposed that hydrogen induces an adaptive response against oxidative stress, which is also called a hormesis impact. 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. An additional 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, evaluation of miRNA profiles of hippocampal neurons in the course of IR injury revealed that hydrogen inhibits IR-induced expression from the miR-200 family members by lowering ROS production, which has led to suppression of cell death [94]. Nevertheless, modulation of miRNA expression cannot solely clarify each of the biological effects mediated by hydrogen. In addition, mechanisms underlying modulated miRNA expressions remain to be elucidated. Matsumoto and colleagues reported that oral intake of hydrogen water enhanced 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 got shown that hydrogen water, but not hydrogen gas, prevented improvement of Parkinson’s disease in a rat model [11]. Prominent effect of oral hydrogen intake rather than hydrogen gas inhalation might be partly accounted for by gastric induction of ghrelin. Not too long ago, Ohta and colleagues showed at the 5th Symposium of Healthcare Molecular Hydrogen at Nagoya, Japan in 2015 that hydrogen influences a totally free radical chain reaction of unsaturated fatty acid on cell membrane and modifies its lipid peroxidation approach. In addition, they demonstrated that air-oxidized phospholipid that was produced either within the presence or absence of hydrogen in vitro, offers rise to unique 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 (at the very least 1.three ), suggesting that the biological effects of hydrogen may be explained by the aberrant oxidation of phospholipid beneath hydrogen exposure. Among the numerous molecules which might be altered by hydrogen, most are predicted to become passengers (downstream regulators) which can be modulated secondarily to a transform within a driver (master regulator). The best solution to determine the master regulator will be to prove the impact of hydrogen in an in vitro program. Despite the fact that, to our knowledge, the study on lipid peroxidation has not yet been published, the free of charge radical chain reaction for lipid peroxidation might be the second master regulator of hydrogen next to the radical scavenging impact. We’re also analyzing other novel molecules as you can master regulators of hydrogen (in preparation). Taken with each other, hydrogen is likely to have numerous master regulators, which drive a diverse array of downstreamIchihara et al. Health-related Gas Analysis (2015) five:Web page five ofTable two Illness model.