Simultaneous oral and inhalational intake of molecular hydrogen additively suppresses signaling pathways in rodents

Abstract

Molecular hydrogen (H2) is an agent with potential applications in oxidative stress-related and/or inflammatory disorders. H2 is usually administered by inhaling H2-containing air (HCA) or by oral intake of H2-rich water (HRW). Despite mounting evidence, the molecular mechanism underlying the therapeutic effects and the optimal method of H2 administration remain unclear. Here, we investigated whether H2 affects signaling pathways and gene expression in a dosage- or dose regimen-dependent manner. We first examined the H2 concentrations in blood and organs after its administration and found that oral intake of HRW rapidly but transiently increased H2 concentrations in the liver and atrial blood, while H2 concentrations in arterial blood and the kidney were one-tenth of those in the liver and atrial blood. In contrast, inhalation of HCA increased H2 equally in both atrial and arterial blood. We next examined whether H2 alters gene expression in normal mouse livers using DNA microarray analysis after administration of HCA and HRW. Ingenuity Pathway Analysis revealed that H2 suppressed the expression of nuclear factor-kappa B (NF-κB)-regulated genes. Western blot analysis showed that H2 attenuated ERK, p38 MAPK, and NF-κB signaling in mouse livers. Finally, we evaluated whether the changes in gene expression were influenced by the route of H2 administration and found that the combination of both HRW and HCA had the most potent effects on signaling pathways and gene expression in systemic organs, suggesting that H2 may act not only through a dose-dependent mechanism but also through a complex molecular network.

Molecular Hydrogen Alleviates Cellular Senescence in Endothelial Cells

“…In humans given H2-rich water orally, the H2 concentration in exhaled air reached a peak at approximately 10 min and returned to baseline 1 h after intake. 8,28, 29 In sum, past and present findings indicate that although the increase in H2 in the body is transient, its 24 h; that is, after H2 had disappeared from the medium. No significant difference was noted in Sirt1 activity between cells cultured in the presence and absence of H2 for 48 h, as was the case for the NAD + /NADH ratio.…”

Molecular hydrogen suppresses activated Wnt/β-catenin signaling

“…H 2 has been reported to inhibit mitogen-activated protein (MAP) kinase signaling in cell lines and rodent disease models345. A previous report shows that inhibition of JNK, but not of ERK or p38 MAP kinase, decreases Wnt3a-induced β-catenin accumulation18.…”

“…H 2 was first reported to be a selective scavenger of • OH and peroxynitrite2. Cumulative evidence, however, suggests that H 2 functions as a signaling modulator345. In this study, we dissected the effects of H 2 on Wnt/β-catenin signaling.…”

Effects of hydrogen-rich saline on early acute kidney injury in severely burned rats by suppressing oxidative stress induced apoptosis and inflammation

“…The data, obtained from human histocytic lymphoma U937 cells, indicated that H 2 O 2 and ·OH could activate PI3K-Akt and PLC-Ras-Raf-ERK signaling pathways [78], whereas Xu and Zhang discovered that saturated HS decreased LPS-induced ERK phosphorylation in a rat model of acute liver dysfunction [79]. Moreover, Sobue et al indicated that H 2 can attenuate ERK, p38 MAPK, and NF-κB activation in mouse livers [80]. Taken together, we suggested H 2 may inhibit NF-κB activation by reducing oxidative radicals-induced ERK phosphorylation, which allows degradation of IκBα from NF-κB.…”