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Inflammation

First recorded some two thousand years ago and now is accredited with some 4 million modern research papers identifying the challenges that inflammation represents, inflammation is often referred to as the root cause of disease and ultimately results in trillions of dollars of economic and social losses each and every year around the world.

Inflammation is a generic response of body tissue following damage to our cells or detecting potential damage effectors. Both infectious and non-infectious agents, as well as cellular injury, can activate an inflammatory response. The response is generic because it doesn’t distinguish between the possible causes. The inflammatory response removes harmful stimuli and initiates the healing process while involving immune and circulatory systems, however, it is a balancing act that can go awry.

Molecular Hydrogen supplementation acts against inflammation in two synergistic ways. First, oxidative stress can initiate or sustain an inflammatory response. Since Molecular Hydrogen is a powerful antioxidant, it suppresses the oxidative stress signal and in turn, reduces the risk of unnecessarily triggering or over sustaining an inflammatory response. Second, all pathways to inflammation pass through the activation of the NF-kB pathway. It is true in oxidative stress, and it is also true in the case of infection or chronic inflammation. Molecular hydrogen dampens the NF-kB pathway, directly avoiding a highly detrimental runaway inflammatory response.

Mitochondrial defects characterized by cytoplasmic calcium elevation, increased reactive oxygen species (ROS) levels, and pronounced release of pro-apoptotic factors and mitochondrial DNA (mtDNA) for example, are key stimulators of inflammatory response pathways. There is accumulating evidence showing an interconnection between defective energy metabolism and inflammasome hyperstimulation. Mitophagy prevents the defective removal of damaged mitochondria that leads to abnormal exacerbation of inflammation via the activation of the NF-kB pathway. Interestingly, although a mild increase in ROS production promotes mitophagy of defective mitochondria, very large increases bypass their safe removal. The key signal that determines whether or not a mitochondrion is defective, is the absence of polarization of the mitochondrial inner membrane indicative of a failure of the respiratory chain.

Supplementation with molecular hydrogen, maintains or helps restore the inner membrane polarisation by enabling proton pumping in complex I, all the while decreasing ROS production by the same complex and increasing ATP production. Furthermore, molecular hydrogen supplementation, promotes the expression of superoxide dismutase and catalase further decreasing the ROS level, as well as upregulating the PINK1/parkin pathway that enables mitophagy.

  1. Niu, Y. et al. Hydrogen Attenuates Allergic Inflammation by Reversing Energy Metabolic Pathway Switch. Sci Rep-uk 10, 1962 (2020).
  2. Guan, W.-J. et al. Hydrogen/oxygen mixed gas inhalation improves disease severity and dyspnea in patients with Coronavirus disease 2019 in a recent multicenter, open-label clinical trial. J Thorac Dis 12, 3448–3452 (2020).
  3. Gkikas, I., Palikaras, K. & Tavernarakis, N. The Role of Mitophagy in Innate Immunity. Front Immunol 9, 1283 (2018).
  4. Sim, M. et al. Hydrogen-rich water reduces inflammatory responses and prevents apoptosis of peripheral blood cells in healthy adults: a randomized, double-blind, controlled trial. Sci Rep-uk 10, 12130 (2020).
  5. Chen, H. et al. Hydrogen alleviates mitochondrial dysfunction and organ damage via autophagymediated NLRP3 inflammasome inactivation in sepsis. Int J Mol Med 44, 1309-1324 (2019).
  6. Wu, X. et al. Hydrogen exerts neuroprotective effects on OGD/R damaged neurons in rat hippocampal by protecting mitochondrial function via regulating mitophagy mediated by PINK1/Parkin signaling pathway. Brain Res 1698, 89-98 (2018).
  7. Yao, L., Chen, H., Wu, Q. & Xie, K. Hydrogen-rich saline alleviates inflammation and apoptosis in myocardial I/R injury via PINK-mediated autophagy. Int J Mol Med 44, 1048-1062 (2019).

NF-kB Protein Complex

NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types.

It is involved in cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, ultraviolet irradiation and bacterial or viral antigens. In addition, NF-κB plays a crucial role in regulating the immune response to infection. Thus, incorrect regulation of NF-κB is linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development.

The triggers of an inflammatory response are very diverse, including oxidative stress, each using a different path that converges to the Nuclear Factor Kappa B family of transcription factors.

Although the inflammatory response is essential, it can become self-sustaining and become a problem in itself. For example, inflammation causes oxidative stress, which itself causes inflammation. Self-perpetuating inflammation can lead to cancer development or cause chronic inflammatory diseases, of which there are many.

  1. Pires, B. R. B., Silva, R. C. M. C., Ferreira, G. M. & Abdelhay, E. NF-kappaB: Two Sides of the Same Coin. Genes-basel 9, 24 (2018).
  2. Liu, T., Zhang, L., Joo, D. & Sun, S.-C. NF-κB signaling in inflammation. Signal Transduct Target Ther 2, 17023 (2017).
  3. Liu, S. F. & Malik, A. B. NF-κB activation as a pathological mechanism of septic shock and inflammation. Am J Physiol-lung C 290, L622–L645 (2006).
  4. Liu, T., Zhang, L., Joo, D. & Sun, S.-C. NF-κB signaling in inflammation. Signal Transduct Target Ther 2, 17023 (2017).

Immune Cells

Long-lasting immune challenges such as chronic inflammation or chronic illness such as cancer result in abnormally high exhaustion rates of immune cells that ultimately lead to their death. Recently, Scharping et al. (2021)1 demonstrated that immune cell exhaustion was caused by mitochondrial dysfunction associated with increased reactive oxygen species, such as the hydroxyl radical. Interestingly, Chen et al. (2020)2 demonstrated that just two weeks of molecular hydrogen inhalation could reactivate normal levels of exhausted immune cells in stage III and IV cancer patients.

At the start of the study, the patient presented with abnormally high levels of exhausted cytotoxic T cells, senescent cytotoxic T cells, and killer Vδ1 cells, and abnormally low level of functional helper and cytotoxic T cells, Th1, total natural killer T cells, natural killer, and Vδ2 cells.
After two weeks of molecular hydrogen inhalation, the number of exhausted and senescent cytotoxic T cells decreased to within the normal range, and there was an increase in killer Vδ1 cells.
All the while, T cells, Th1, total natural killer T cells, natural killer, and Vδ2 cells subsets increased to within the normal range.

Immune cell exhaustion is linked to a decrease in mitophagy and an accumulation of dysfunctional depolarised mitochondria. Yet again we see that supplementation with molecular hydrogen, maintains or helps restore the mitochondrial inner membrane polarisation by enabling proton pumping in complex I, all the while decreasing ROS production by the same complex and increasing ATP production. Furthermore, molecular hydrogen supplementation promotes the expression of superoxide dismutase and catalase further decreasing the ROS level, as well as upregulating the PINK1/parkin pathway that enables mitophagy.

  1. Scharping, N. E. et al. Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion. Nat Immunol 22, 205–215 (2021).
  2. Chen, J.-B. et al. Two weeks of hydrogen inhalation can significantly reverse adaptive and innate immune system senescence patients with advanced non-small cell lung cancer: a self-controlled study. Medical Gas Res 10, 149 (2020).
  3. Yu, Y. R. et al. Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion. Nat Immunol 21, 1540-1551 (2020).
  4. Li, W. & Zhang, L. Rewiring Mitochondrial Metabolism for CD8+ T Cell Memory Formation and Effective Cancer Immunotherapy. Front Immunol 11, 1834 (2020).
  5. Chen, H. et al. Hydrogen alleviates mitochondrial dysfunction and organ damage via autophagymediated NLRP3 inflammasome inactivation in sepsis. Int J Mol Med 44, 1309-1324 (2019).
  6. Li, W. & Zhang, L. Rewiring Mitochondrial Metabolism for CD8+ T Cell Memory Formation and Effective Cancer Immunotherapy. Front Immunol 11, 1834 (2020).
  7. Wu, X. et al. Hydrogen exerts neuroprotective effects on OGD/R damaged neurons in rat hippocampal by protecting mitochondrial function via regulating mitophagy mediated by PINK1/Parkin signaling pathway. Brain Res 1698, 89-98 (2018).
  8. Yao, L., Chen, H., Wu, Q. & Xie, K. Hydrogen-rich saline alleviates inflammation and apoptosis in myocardial I/R injury via PINK-mediated autophagy. Int J Mol Med 44, 1048-1062 (2019).
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