:
Molecular hydrogen (H2
) was long regarded as non-functional in mammalian cells. We overturned the concept
by demonstrating that H2 exhibits antioxidant effects and protects cells against oxidative stress. Subsequently, it has been
revealed that H2 has multiple functions in addition to antioxidant effects, including ant-inflammatory, anti-allergic
functions, and as a cell death and autophagy regulation. Additionally, H2 stimulates energy metabolism. Because H2 does
not readily react with most biomolecules without a catalyst, it is essential to identify the primary targets with which H2
reacts or interacts directly. As a first event, H2 may react directly with strong oxidants such as hydroxyl radicals (•OH)
in vivo. This review addresses the key issues related to this in vivo reaction. •OH may have a physiological role because it
triggers a free radical chain reaction and may be involved in the regulation of Ca2+
- or mitochondrial ATP-dependent K+
-
channeling. In the subsequent pathway, H2 suppressed a free radical chain reaction, leading to decreases in lipid peroxide
and its end products. Derived from the peroxides, 4-hydroxy-2-nonenal functions as a mediator that up-regulates multiple
functional PGC-1α. As the other direct target in vitro and in vivo, H2
intervenes in the free radical chain reaction to
modify oxidized phospholipids, which may act as an antagonist of Ca2+
-channels. The resulting suppression of Ca2+
-
signaling inactivates multiple functional NFAT and CREB transcription factors, which may explain H2 multifunctionality. This review also addresses the involvement of NFAT in the beneficial role of H2
in COVID-19, Alzheimer’s
disease and advanced cancer. We discuss some unsolved issues of H2 action on lipopolysaccharide signaling, MAPK and
NF-κB pathways and the Nrf2 paradox. Finally, as a novel idea for the direct targeting of H2
, this review introduces the
possibility that H2 causes structural changes in proteins via hydrate water changes.
Molecular hydrogen regulates gene expression by modifying the free radical chain reaction-dependent generation of oxidized phospholipid mediators