Open AccessDirect Targets and Subsequent Pathways for Molecular Hydrogen to Exert Multiple Functions: Focusing on Interventions in Radical Reactions
Author(s) -
Shigeo Ohta
Publication year - 2021
Publication title -
current pharmaceutical design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.69
H-Index - 159
eISSN - 1873-4286
pISSN - 1381-6128
DOI - 10.2174/1381612826666200806101137
Subject(s) - chemistry , nfat , in vivo , radical , antioxidant , microbiology and biotechnology , oxidative stress , mitochondrion , hydrogen peroxide , mediator , hydroxyl radical , biochemistry , biophysics , transcription factor , biology , gene
Molecular hydrogen (H 2 ) was long regarded as non-functional in mammalian cells. We overturned theconcept by demonstrating that H 2 exhibits antioxidant effects and protects cells against oxidative stress. Subsequently,it has been revealed that H 2 has multiple functions in addition to antioxidant effects, including antiinflammatory,anti-allergic functions, and as cell death and autophagy regulation. Additionally, H 2 stimulatesenergy metabolism. As H 2 does not readily react with most biomolecules without a catalyst, it is essential to identifythe primary targets with which H 2 reacts or interacts directly. As a first event, H 2 may react directly withstrong oxidants, such as hydroxyl radicals (•OH) in vivo. This review addresses the key issues related to this invivo reaction. •OH may have a physiological role because it triggers a free radical chain reaction and may beinvolved in the regulation of Ca2+- or mitochondrial ATP-dependent K+-channeling. In the subsequent pathway,H 2 suppressed a free radical chain reaction, leading to decreases in lipid peroxide and its end products. Derivedfrom 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, H 2 intervenes in the free radical chain reaction to modify oxidizedphospholipids, which may act as an antagonist of Ca2+-channels. The resulting suppression of Ca2+-signalinginactivates multiple functional NFAT and CREB transcription factors, which may explain H 2 multi-functionality.This review also addresses the involvement of NFAT in the beneficial role of H 2 in COVID-19, Alzheimer’sdisease and advanced cancer. We discuss some unsolved issues of H 2 action on lipopolysaccharide signaling,MAPK and NF-κB pathways and the Nrf2 paradox. Finally, as a novel idea for the direct targeting of H2, thisreview introduces the possibility that H 2 causes structural changes in proteins via hydrate water changes.