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 Table of Contents  
Year : 2023  |  Volume : 13  |  Issue : 2  |  Page : 41-42

Discovery of a hydrogen molecular target

1 Department of Naval Medicine, Naval Medical University, Shanghai, China
2 Nippon Medical University, Tokyo, Japan; Department of Neurology Medicine, Juntendo University, Tokyo, Japan
3 Division of Physiology School of Medicine, Loma Linda University, Loma Linda, CA, USA

Date of Submission15-Aug-2022
Date of Decision09-Sep-2022
Date of Acceptance14-Sep-2022
Date of Web Publication28-Sep-2022

Correspondence Address:
Xuejun Sun
Department of Naval Medicine, Naval Medical University, Shanghai, China
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2045-9912.356472

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How to cite this article:
Sun X, Ohta S, Zhang JH. Discovery of a hydrogen molecular target. Med Gas Res 2023;13:41-2

How to cite this URL:
Sun X, Ohta S, Zhang JH. Discovery of a hydrogen molecular target. Med Gas Res [serial online] 2023 [cited 2022 Dec 5];13:41-2. Available from: https://www.medgasres.com/text.asp?2023/13/2/41/356472

Fe-porphyrin acts as a primary molecular target/biosensor of hydrogen (H2), which can catalyze H2 to reduce •OH and carbon dioxide (CO2) into H2O and carbon monoxide (CO), respectively, for downstream signaling.[1]

In 1975, Dole et al.[2] found that exposure to an H2/O2 (97.5%:2.5%) mixed gas at a pressure of 8 atm (1 atm = 101.325 kPa) for 2 weeks caused the marked regression of skin tumors in a skin tumor-bearing mouse model, which was speculated due to the •OH and O2- scavenging effect of H2. In 2007, Ohsawa et al.[3] found that H2 can selectively reduce •OH with high oxidability rather than other reactive oxygen species, but later research indicated that the probability/efficiency of the direct reduction of •OH by H2 is considerably low.[4] Increasing studies have suggested that H2can regulate the respiration of mitochondria,[5],[6],[7],[8],[9],[10] which is hardly explained by the direct •OH reduction by H2, especially in terms of anticancer. It seems that H2 might play a reducer or/and CO/ nitric oxide (NO)-like gasotransmitter, which was not confirmed previously with experimental evidence.

More encouragingly, Jin et al.[1] experimentally identified he- matin, a kind of Fe-phorphyrins, as a molecular target/biosensor of H2. They found that in both free and protein-confining states, Fe-porphyrin can self-catalyze hydrogenation by reacting with H2 to obtain high reducibility of Fe-coordinated hydrogen atoms, which subsequently can not only neutralize •OH into H2O but also reduce CO2 into CO in the hypoxic microenvironment.

Fe-porphyrin is mainly enriched in cellular mitochondria and in red blood cells, which are the two main workplaces of H2. At cellular mitochondria, H2 can efficiently reduce •OH under local catalysis of Fe-porphyrin to attenuate oxidative stress for anti­inflammation. Moreover, in the hypoxia microenvironment, such as solid tumor and heart ischemia, Fe-porphyrin-catalytically generated CO is locally coordinated with Fe-porphyrin to medi­ate the downstream CO signaling, inducing apoptosis in tumor cells and protecting myocardial cells via hypoxic alleviation. The therapeutic effects on many diseases may be related to the downstream CO signaling besides •OH scavenging. Since the other medical gasses, such as NO, CO, and hydrogen sulfide (H2S), target Fe-porphyrin (heme) to induce each signal transduction,[11] it is interesting that H2 commonly targets Fe-porphyrin (hematin) to exhibit its function.

Red blood cells containing plentiful amounts of Fe-porphyrin are a kind of natural H2 vehicle. In the ischemia\hypoxia mi­croenvironment, red blood cells can be a local capturer of H2 as well as a catalyst of hydrogenation for targeted H2 therapy. In the oxygen-rich blood circulation, oxygen molecules can impede the remote delivery of hydrogen to a certain extent by exhausting reactive hydrogen, but the sufficiently hydrided red blood cells can scavenge •OH in the blood circulation and even throughout the body by virtue of rapid blood flow, which implies the neces­sity of sustainable and plentiful hydrogen supply.

In plants, the drug/drought/salt/heavy metals-tolerating and anti-oxidative stress effects of H2[12],[13],[14],[15],[16] possibly derive from downstream CO. Noticeably, a moderate H2 concentration can maximize the therapeutic outcome of plant disease treatment, which may be due to CO poisoning at an excessively high con­centration of H2. Therefore, an especially high dosage of H2 will possibly cause cytotoxicity to animal cells, which can be used for anticancer and guide the exploration and avoidance of potential toxic side effects of H2.

Some diseases such as chronic liver diseases and neurodegen­erative diseases are highly related to free Fe-porphyrin, which can induce Fenton reaction-dependent ferroptosis. The therapeutic effect of H2 against these diseases might be owing to the intercep­tion of a Fenton-like reaction by H2 besides catalytic scavenging of generated •OH. It can provide great inspiration for H2-based drug discovery and development.

It is worth noting that Fe-porphyrin is identified as a hydro­genation biocatalyst that plays a role in hydrogen storage and transformation. As envisioned, transition metals-coordinated porphyrin and the molecules with a similar coordination structure are possibly valuable to hydrogen medicine/energy/agriculture for efficient hydrogen storage, safe/precision delivery, custom­ized transformation, and efficient utilization. Jin et al.[1] found that hydrogen can enhance the effect of CO, and heme protein has the potential to store and transport hydrogen, which is undoubtedly an important breakthrough in the field of hydrogen biomedicine and puts forward a new direction for future research on the medical mechanism of hydrogen. However, once these effects are identi­fied, there is cause for concern that hydrogen may potentially block oxygen transport and lead to hypoxia in aerobic organisms. In any case, this may be an important advance in the study of the biological effects of hydrogen, which provides important evidence for understanding and analyzing the effects of hydrogen.

  References Top

Jin Z, Zhao P, Gong W, Ding W, He Q. Fe-porphyrin: A redox-relat­ed biosensor of hydrogen molecule. Nano Res. 2022. doi: 10.1007/ s12274-022-4860-y.  Back to cited text no. 1
Dole M, Wilson FR, Fife WP Hyperbaric hydrogen therapy: a possible treatment for cancer. Science. 1975;190:152-154.  Back to cited text no. 2
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. 3
Ma XM, Zhang X, Xie F, et al. Bio-enzyme basis of hydrogen in bio­logical system. CurrBiotechnol. 2020;10:15-22.  Back to cited text no. 4
Yao X, Chen D, Zhao B, et al. Acid-degradable hydrogen-generating metal-organic framework for overcoming cancer resistance/metastasis and off-target side effects. Adv Sci (Weinh). 2022;9:e2101965.  Back to cited text no. 5
Zhao B, Wang Y, Yao X, et al. Photocatalysis-mediated drug- free sustainable cancer therapy using nanocatalyst. Nat Commun. 2021;12:1345.  Back to cited text no. 6
Zhao P, Jin Z, Chen Q, et al. Local generation of hydrogen for en­hanced photothermal therapy. Nat Commun. 2018;9:4241.  Back to cited text no. 7
Ostojic SM. Targeting molecular hydrogen to mitochondria: barriers and gateways. Pharmacol Res. 2015;94:51-53.  Back to cited text no. 8
Ostojic SM. Does H(2) alter mitochondrial bioenergetics via GHS-R1a activation? Theranostics. 2017;7:1330-1332.  Back to cited text no. 9
Ito M, Ibi T, Sahashi K, Ichihara M, Ito M, Ohno K. Open-label trial and randomized, double-blind, placebo-controlled, crossover trial of hydrogen-enriched water for mitochondrial and inflammatory myopa­thies. Med Gas Res. 2011;1:24.  Back to cited text no. 10
Kajimura M, Fukuda R, Bateman RM, Yamamoto T, Suematsu M. Interactions of multiple gas-transducing systems: hallmarks and un­certainties of CO, NO, and H2S gas biology. Antioxid Redox Signal. 2010;13:157-192.  Back to cited text no. 11
Zeng J, Ye Z, Sun X. Progress in the study of biological effects of hydrogen on higher plants and its promising application in agriculture. Med Gas Res. 2014;4:15.  Back to cited text no. 12
Dong Z, Wu L, Kettlewell B, Caldwell CD, Layzell DB. Hydrogen fertilization of soils - is this a benefit of legumes in rotation? Plant Cell Environ. 2003;26:1875-1879.  Back to cited text no. 13
Li C, Gong T, Bian B, Liao W. Roles of hydrogen gas in plants: a re­view. Funct Plant Biol. 2018;45:783-792.  Back to cited text no. 14
Wu M, Xie X, Wang Z, et al. Hydrogen-rich water alleviates pro­grammed cell death induced by GA in wheat aleurone layers by modu­lation of reactive oxygen species metabolism. Plant Physiol Biochem. 2021;163:317-326.  Back to cited text no. 15
Jin Q, Zhu K, Cui W, Li L, Shen W. Hydrogen-modulated stomatal sensitivity to abscisic acid and drought tolerance via the regulation of apoplastic pH in Medicago sativa. J Plant Growth Regul. 2016;35:565- 573.  Back to cited text no. 16


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