(This blog is for my fellow science nerds)
Neutralization of ROS
The disequilibrium between ROS and the antioxidant system causes oxidative stress which is considered as a common initial step for many pathological processes.
These ROS include superoxide anion, hydroxyl (•OH), peroxyl (RO2•), alkoxyl (RO•) radicals, and nitric oxide (NO•), and they primarily come from mitochondrial respiration, NADH/NADPH oxidase. When cell damage occurs, oxidative phosphorylation and electron transport in mitochondria are obstructed, and electrons are leaked to produce excess ROS. On the one hand, the overproduction of ROS causes damage of cell membrane or organelle membrane. Then the lipids are detached from the membrane and further peroxide to generate arachidonic acid and leukotrienes, which contribute to inflammatory pain.
Furthermore, ROS produced by neutrophils and macrophages could attack pathogens, which may damage the structure of mitochondria and nucleus of normal cells and subsequently lead to the initiation of apoptosis. There is no known enzyme specifically to deal with •OH, since the •OH non-selectively reacts instantaneously with the nearest nucleophilic biomolecules. H2 is a new type of reductant that can penetrate the cell membrane and neutralize particles that damage the body, •OH and ONOO− in cellular structure, and almost no effects of and H2O2 which maintains physiological function and internal environment stability. The direct scavenging of the hydroxyl radical according to the chemical reaction of H2 + OH → H2O + H• followed by H• + → was considered as a potential mode of action. As early as 2001, they found that H2 could increase superoxide dismutase (SOD) activity and reduce lipid peroxide malondialdehyde (MDA) level in schistosomiasis-associated liver inflammation model.
In 2007, Ohsawa described its protective benefit against reperfusion oxidative injury in vitro and in vivo. They demonstrated the protective potential of H2 against I/R injury, where H2 reduced oxidative stress and scavenged ·OH and ONOO−, acting as an electron donor for ROS molecules, but the direct ROS scavenging effect of H2 is only confirmed in the acellular experiment. By regulating their concentration, they also prevent the production of hydroxyl radicals as they can be converted to •OH radicals via the Haber-Weiss and Fenton reaction in the presence of catalytically active metals such as Fe2+ and Cu+.
Furthermore, the biological and antioxidant effects of H2 remain even after H2 has been cleared from the body, especially at a low concentration, which suggests that the mechanism may have more to do with antioxidant signal modulation than direct free radical scavenging. Nuclear factor erythroid-2 related factor 2 (Nrf2) shifting into the nucleus could lead to the regulation of gene expression involved in defense systems against oxidative stress. Studies have shown that H2 can improve the symptoms of experimental autoimmune encephalomyelitis (EAE) by activating the Nrf2-ARE signaling pathway.
In addition, H2 significantly reduces intracellular ROS by upregulating Nrf2 transcription to promote the expression of SOD and glutathione (GSH) and downregulating the expression of NADPH oxidase. H2 could protect cells against cell death by blocking the abnormal oxidation of phospholipids, reducing the increase in the cell membrane permeability, and thus blocking lipid peroxidation may be another important mechanism of H2 antioxidation. Unexpectedly, recent notable studies have suggested that excessive antioxidants increased mortality rates of cancer and cardiovascular diseases. An ideal antioxidant is expected to mitigate excess oxidative stress, but not to disturb redox homeostasis. H2 might be the ideal antioxidant via the rapid diffusion into cells by blood circulation.
Regulation of Mitochondria
In addition to focusing on H2 neutralizing oxidative stress, the processes upstream of the dysfunction of electron transport chain were focused, which is the first step during mitochondrial oxidative stress. Mitochondria are generally termed the powerhouses of the cell as they produce the 90% of energy in the form of ATP. This process relies on oxidative phosphorylation and accompanies the generation of ROS by forward and reverse electron transfer. H2 improves mitochondrial dysfunction by preventing the uncontrolled electron leakage from the electron transport chain and is predicted to have the potential ability to regenerate the dysfunction of the cells.
ATP-sensitive K+ channel, which is an important energy regulation participant, is located on the mitochondria. For acute myocardial infarction, H2 gas could activate mKATP and regulate mitochondrial membrane potential to equilibrize the level of myocardial NAD+ (the precursor of ATP synthesis) and the production of mitochondrial ATP, thus alleviating myocardial I/R injury.
Coenzyme Q (CoQ) is a key component of the mitochondrial electron transfer chain. The dominant form is CoQ10 in human, while it is CoQ9 in rats. CoQ accepts electrons from Complex I and Complex II and transfers to Complex III, which contributes to the generation of NAD+, the precursor to ATP production and the proton motive force for ATP production. After H2 application, CoQ9 concentrations in plasma and myocardium tissue were significantly increased. In addition, increased CoQ9 improves ATP production via mitochondrial oxidative phosphorylation. H2 gas has been suggested to enhance the clinical efficacy of nivolumab by increasing CoQ10 of mitochondria to restore exhausted CD8+ T cells.
Therefore, they believe that H2 can protect against cell damage by improving mitochondrial function. Improvement of mitochondrial dysfunction is also expected to improve the disordered signal transduction that affects cellular death process, such as Bax and caspase activities.
Mitophagy plays an important role in maintaining mitochondria homeostasis by eliminating damaged or dysfunctional mitochondria. Fun 14 domain-containing protein 1 (Fundc1) is one of mitophagy receptors localized on the outer membrane of the mitochondrion, which can maintain mitochondrial ATP balance by regulating the mitophagy and interacting with LC3 II. Administration with 2% H2 for 3 h promoted Fundc1-induced mitophagy and protected mice from the sepsis-induced liver injury. In addition, H2 exerts neuroprotective effect on oxygen/glucose deprivation neuronal damage in rats, and the increasing expression of mitophagy-related factors, PINK1 and Parkin, indicated that H2 is beneficial for ATP generation by promoting mitochondrial autophagy. Animal studies of sepsis have identified the mitochondrial dysfunction may reduce the cellular energy level, resulting in sepsis-related multiple organ failure. For example, in myocardial tissues, H2 treatment scavenged ROS by upregulating the heme oxygenase-1 (HO-1, known as heat shock protein 32) to protect sepsis-related multiple organ injury in HO-1/Nrf2 dependent manner (Zhang et al., 2020).
Mitochondrial damage induced by excessive ROS is an important cause of many neurodegenerative diseases. Antioxidant effects of H2 intervention on Parkinson's disease or Alzheimer's disease models have been shown in previous studies.
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