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RESEARCH ARTICLE
Ahead of print publication  

Conventional drug acts as a “rifle gun” while hydrogen as a “machine gun”


1 Department of Research and Development, MiZ Company Limited, Kamakura, Japan
2 Keio University; Faculty of Data Science, Musashino University, Tokyo, Japan

Date of Submission20-Dec-2020
Date of Decision18-Jan-2021
Date of Acceptance25-Feb-2021
Date of Web Publication12-May-2022

Correspondence Address:
Shin-ichi Hirano,
Department of Research and Development, MiZ Company Limited, Kamakura
Japan
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2045-9912.344982

  Abstract 


Most of the drugs used in modern medical treatments are symptomatic treatments and are far from being a cure for the diseases. The adverse effects are unavoidable in the drugs in modern medical treatments. Molecular hydrogen (H2) has a remarkable therapeutic effect on various diseases, and many clinical studies have reported that H2 has no adverse effects. Therefore, H2 is a novel medical gas that is outside the concept of modern medical treatment. H2, unlike drugs, works on the root of many diseases by scavenging the two kinds of strong reactive oxygen species, hydroxyl radical (·OH) and peroxynitrite (ONOO-). Since the H2 alleviates the root of diseases and can treat many diseases at the same time, the medical application of H2 may be called “machine gun therapy.” In this review, we demonstrated that the root of many diseases is based on ·OH-induced oxidative stress in the mitochondria, and at the same time, the root of chronic inflammation is also attributed to ·OH.

Keywords: chronic inflammation; elemental reductionist approach; hydroxyl radical; machine gun therapy; mitochondria; modern medicine; molecular hydrogen; NLRP3; reactive oxygen species



How to cite this URL:
Hirano Si, Ichikawa Y, Sato B, Takefuji Y, Satoh F. Conventional drug acts as a “rifle gun” while hydrogen as a “machine gun”. Med Gas Res [Epub ahead of print] [cited 2022 Aug 9]. Available from: https://www.medgasres.com/preprintarticle.asp?id=344982




  Introduction Top


Most conventional drugs used in modern medicine act on each target. The drugs are symptomatic treatments and are far from being a cure for the diseases. Modern medical treatment can control acute inflammatory diseases, but not chronic inflammatory diseases. In contrast, molecular hydrogen (H2) acts on the root of many diseases and has various therapeutic and preventive effects. H2 taken into the body is distributed throughout the body by its diffusing effect. And since H2, unlike drugs, has no adverse effects, the dosage of H2 can be increased. Recently, we demonstrated that H2 is promising for medical applications.[1]

Jones[2] has demonstrated that H2 is the safest reducing agent and that it could be a promising anti-inflammatory agent. In this review, expanding on the hypothesis of Jones’ paper,[2] we present the perspective for H2 medicine by discussing why H2 is effective against many diseases.


  Problems in Modern Medicine Top


Based on the World Health Organization’s Statistical Classification and Related Health Problems, the number of diseases should be from 30,000 to 40,000.[3] However, pharmacopeia such as U.S. and British Pharmacopeia illustrates approximately 20,000 drugs registered.[4],[5] The registered drugs with a variety of dosages are duplicated so that only several thousand drugs exist in our society. Modern medicine views the human body as an aggregation of organs and conducts a microscopic analysis of organs as objects. These methods of modern medicine are called the “elemental reductionist approach.”[1],[6],[7] It subdivides the object of study from organ to cell, then to molecule, and finally to gene to identify the factors that most affect diseases. Drugs are designed to act on a single factor (e.g., enzymes, receptors, and genes) in order to ameliorate the diseases.[1],[6],[7] In modern medicine, it is also said that there is a “one-to-one relationship” between the cause of a disease and its treatment.[1],[6],[7] However, many diseases are not caused by a single factor alone, but by multiple factors and a wide variety of mechanisms.[1],[6],[7] Therefore, modern medicine may be called “rifle gun therapy” because it can target a single shot.


  Hydroxy Radical as a Root of Many Diseases Top


The human adult consumes large amounts of oxygen per day at rest. However, various reactive oxygen species (ROS) are formed by an imbalance between free radical and reactive metabolic production. ROS are products of oxygen-derived small molecules involved in normal cellular metabolism, including superoxide anion (O2), hydrogen peroxide (H2O2), and hydroxyl radical (-OH).[8] Among the ROS, the -OH has greater oxidation power than O2- and oxidizes intranuclear DNA, while O2- and H2O2 do not have sufficient oxidation power to oxidize the DNA directly. In addition, mitochondria, the source of these ROS, are constantly exposed to high levels of -OH, which cause mitochondrial DNA damage and cellular apoptosis.[8]

Therapeutic applications of H2 were first described in 1975.[9] Dole et al.[9] reported that hyperbaric hydrogen showed marked antitumor effects in mice. However, the potential of H2 in medical applications has not been widely reported. In 2007, H2 was indicated by Ohsawa et al.[8] as a therapeutic antioxidant that could selectively scavenge two kinds of strong ROS, -OH and peroxynitrite (ONOO).

H2 diffuses into the cytosol, mitochondria, and nucleus in relation to its distribution characteristics.[8] H2 is an inactive molecule that has no metabolic system in mammalian cells and does not interact with biological substances, but it is a molecule that reacts with ·OH, which occurs inside mitochondria.[6] In addition, because the reaction product of H2 and ·OH is a water molecule, and the production of H2 in the intestine,[6] adverse effects caused by H2 have not been observed in many clinical studies. Indeed, the clinical efficacy and safety of H2 were reported in more than 100 papers.[10],[11],[12],[13] H2 has become a novel antioxidant due to its antiapoptotic, antioxidant, and anti-inflammatory effects.


  Involvement of Hydroxyl Radical in Chronic Inflammation Top


Chronic inflammation is the root cause of many diseases. It is no exaggeration to say that “chronic inflammation is the treatment source of all disease”. Modern medical treatment can control acute inflammatory diseases, but it cannot control chronic inflammatory diseases. Inflammation is induced by releasing inflammatory cytokines produced by macrophages and neutrophils. Minor but prolonged inflammation can damage the living body and induce chronic inflammation. Recent studies have shown that mitochondria play an important role in producing cytokines.[7],[14],[15],[16] It has also been reported that mitochondria-related ROS activates the nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, and its stimulation triggers producing inflammatory cytokines.[17],[18],[19]

In a normal condition, the NLRP3 activity is tightly restrained by ubiquitination. However, stimulation of cells with lipopolysaccharide and adenosine triphosphate can trigger NLRP3 deubiquitination and can abolish this constraint, resulting in the activation of NLRP3 inflammasome.[20] Lipopolysaccharide and adenosine triphosphate can elicit vigorous production of proinflammatory cytokines via the transmem-brane Toll-like receptor 4 and P2X purinoceptor 7 receptors, respectively. This process is dependent on mitochondrial ROS production. In addition, oxidized mitochondrial DNA, the ROS-oxidized product released from mitochondria, is capable of binding and activating NLRP3.[21] NLRP3 inflammasome activation by inhibiting mitochondrial ROS-dependent NLRP3 deubiquitination and by suppressing the generation of oxidized mitochondrial DNA may be blocked by mitochondria-targeted antioxidants such as H2.

It has been shown by some literature that H2 in the various animal models of inflammation could be based on the mechanisms by inhibitions of mitochondrial oxidation and NLRP3 inflammasome activation.[22],[23],[24],[25],[26],[27],[28],[29],[30] Therefore, the mitochondrial selective ·OH scavenger such as H2 can block the cascade leading to the activation of the NLRP3 inflammasome. H2 may be able to aim for “machine gun therapy” because it works on the root of many diseases including chronic inflammatory diseases by scavenging ·OH and ONOO-. H2 is a novel medical gas that is outside the concept of modern medical treatment.

Non-steroidal anti-inflammatory drugs, steroids, and biological products such as anti-interleukin-6 monoclonal antibody and antitumor necrosis factor-amonoclonal antibody have been applied clinically as anti-inflammatory drugs. However, these drugs have less effects and adverse effects, indicating that H2 is an ideal antioxidant with potent anti-inflammatory effects and without adverse effects.

In Japan, although H2 gas has been approved by the Ministry of Health, Labor, and Welfare as an advanced medical treatment B, the pharmaceutical approval of H2 as a medical gas is not obtained. Therefore, clinicians have used the H2 at their own discretion or in clinical research. We are trying to develop an H2 gas inhaler as a medical device. The day will come when H2 gas inhalers will be used in the market as a medical device in the near future.

[TAG:2]Conclusion[TAG:2]

In this paper, we demonstrate that the root of many diseases is based on ·OH-induced oxidative stress in the mitochondria, and at the same time, the root of chronic inflammation is also attributed to ·OH. And we have also shown that H2 medicine is a new treatment that can be replaced by modern medicine. Since the H2 alleviates the root of disease and subsequently treats many diseases, the medical application of H2 truly may be called “machine gun therapy.”

Author contributions

SH collected the literature and drafted the initial manuscript. SH, IY, SB, TY, and SF revised the manuscript and edited the language. All authors read and approved the final manuscript.

Conflicts of interest

HS, IY, SB, SF are employees of MiZ Company Limited, Japan.

Open access statement

This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.



 
  References Top

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Hirano SI, Ichikawa Y, Sato B, Satoh F, Takefuji Y. Hydrogen is promising for medical applications. Clean Technol. 2020;2:529-541.  Back to cited text no. 1
    
2.
Jones D. Gas therapy. Nature. 1996;383:676-676.  Back to cited text no. 2
    
3.
International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10)-WHO Version for 2016. http://apps.who.int/classifications/icd10/browse/2016/en#/U00-U49. Assessed by January 20, 2021.  Back to cited text no. 3
    
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United States Pharmacopeia. http://www.usp.org/. Assessed by January 20, 2021  Back to cited text no. 4
    
5.
Medicines & Healthcare Products Regulatory Agency. British Pharmacopeia. https://www.pharmacopoeia.com. Assessed January 20, 2021.  Back to cited text no. 5
    
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Hirano SI, Ichikawa Y, Kurokawa R, Takefuji Y, Satoh F. A “philosophical molecule,” hydrogen may overcome senescence and intractable diseases. Med Gas Res. 2020;10:47-49.  Back to cited text no. 6
    
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Hirano SI, Ichikawa Y, Sato B, Yamamoto H, Takefuji Y, Satoh F. Potential therapeutic applications of hydrogen in chronic inflammatory diseases: possible inhibiting role on mitochondrial stress. Int J Mol Sci. 2021;22:2549.  Back to cited text no. 7
    
8.
Ohsawa I, Ishikawa M, Takahashi K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 2007;13:688-694.  Back to cited text no. 8
    
9.
Dole M, Wilson FR, Fife WP. Hyperbaric hydrogen therapy: a possible treatment for cancer. Science. 1975;190:152-154.  Back to cited text no. 9
    
10.
Yoritaka A, Takanashi M, Hirayama M, Nakahara T, Ohta S, Hattori N. Pilot study of H therapy in Parkinson’s disease: a randomized double-blind placebo-controlled trial. Mov Disord. 2013;28:836-839.  Back to cited text no. 10
    
11.
Ishibashi T, Sato B, Shibata S, et al. Therapeutic efficacy of infused molecular hydrogen in saline on rheumatoid arthritis: a randomized, double-blind, placebo-controlled pilot study. Int Immunopharmacol. 2014;21:468-473.  Back to cited text no. 11
    
12.
Nishimaki K, Asada T, Ohsawa I, et al. Effects of molecular hydrogen assessed by an animal model and a randomized clinical study on mild cognitive impairment. Curr Alzheimer Res. 2018;15:482-492.  Back to cited text no. 12
    
13.
Ono H, Nishijima Y, Adachi N, et al. A basic study on molecular hydrogen (H2) inhalation in acute cerebral ischemia patients for safety check with physiological parameters and measurement of blood H2 level. Med Gas Res. 2012;2:21.  Back to cited text no. 13
    
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Man SM, Kanneganti TD. Regulation of inflammasome activation. Immunol Rev. 2015;265:6-21.  Back to cited text no. 14
    
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Elliott EI, Sutterwala FS. Initiation and perpetuation of NLRP3 inflammasome activation and assembly. Immunol Rev. 2015;265:35-52.  Back to cited text no. 15
    
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Mason DR, Beck PL, Muruve DA. Nucleotide-binding oligomerization domain-like receptors and inflammasomes in the pathogenesis of non-microbial inflammation and diseases. J Innate Immun. 2012;4:16-30.  Back to cited text no. 16
    
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Mangan MSJ, Olhava EJ, Roush WR, Seidel HM, Glick GD, Latz E. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat Rev Drug Discov. 2018;17:588-606.  Back to cited text no. 17
    
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Swanson KV, Deng M, Ting JP. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol. 2019;19:477-489.  Back to cited text no. 18
    
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Guo H, Callaway JB, Ting JP. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med. 2015;21:677-687.  Back to cited text no. 19
    
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Juliana C, Fernandes-Alnemri T, Kang S, Farias A, Qin F, Alnemri ES. Non-transcriptional priming and deubiquitination regulate NLRP3 inflammasome activation. J Biol Chem. 2012;287:36617-36622.  Back to cited text no. 20
    
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Shimada K, Crother TR, Karlin J, et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity. 2012;36:401-414.  Back to cited text no. 21
    
22.
Ren JD, Ma J, Hou J, et al. Hydrogen-rich saline inhibits NLRP3 inflammasome activation and attenuates experimental acute pancreatitis in mice. Mediators Inflamm. 2014;2014:930894.  Back to cited text no. 22
    
23.
Xie K, Zhang Y, Wang Y, et al. Hydrogen attenuates sepsis-associated encephalopathy by NRF2 mediated NLRP3 pathway inactivation. Inflamm Res. 2020;69:697-710.  Back to cited text no. 23
    
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Chen H, Zhou C, Xie K, Meng X, Wang Y, Yu Y. Hydrogen-rich saline alleviated the hyperpathia and microglia activation via autophagy mediated inflammasome inactivation in neuropathic pain rats. Neuroscience. 2019;421:17-30.  Back to cited text no. 24
    
25.
Ren JD, Wu XB, Jiang R, Hao DP, Liu Y. Molecular hydrogen inhibits lipopolysaccharide-triggered NLRP3 inflammasome activation in macrophages by targeting the mitochondrial reactive oxygen species. Biochim Biophys Acta. 2016;1863:50-55.  Back to cited text no. 25
    
26.
Yang L, Guo Y, Fan X, et al. Amelioration of coagulation disorders and inflammation by hydrogen-rich solution reduces intestinal ischemia/reperfusion injury in rats through NF-κB/NLRP3 pathway. Mediators Inflamm. 2020;2020:4359305.  Back to cited text no. 26
    
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Zou R, Wang MH, Chen Y, et al. Hydrogen-rich saline attenuates acute lung injury induced by limb ischemia/reperfusion via down-regulating chemerin and NLRP3 in rats. Shock. 2019;52:134-141.  Back to cited text no. 27
    
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Shao A, Wu H, Hong Y, et al. Hydrogen-rich saline attenuated subarachnoid hemorrhage-induced early brain injury in rats by suppressing inflammatory response: possible involvement of NF-κB pathway and NLRP3 inflammasome. Mol Neurobiol. 2016;53:3462-3476.  Back to cited text no. 28
    
29.
Zhuang K, Zuo YC, Sherchan P, Wang JK, Yan XX, Liu F. Hydrogen inhalation attenuates oxidative stress related endothelial cells injury after subarachnoid hemorrhage in rats. Front Neurosci. 2019;13:1441.  Back to cited text no. 29
    
30.
Chen H, Mao X, Meng X, et al. Hydrogen alleviates mitochondrial dysfunction and organ damage via autophagy-mediated NLRP3 inflammasome inactivation in sepsis. Int J Mol Med. 2019;44:1309-1324.  Back to cited text no. 30
    




 

 
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