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Review

Hydrogen Therapy and Its Future Prospects for Ameliorating COVID-19: Clinical Applications, Efficacy, and Modality

by
Ishrat Perveen
1,
Bakhtawar Bukhari
1,
Mahwish Najeeb
2,
Sumbal Nazir
3,
Tallat Anwar Faridi
2,
Muhammad Farooq
1,
Qurat-ul-Ain Ahmad
4,
Manal Abdel Haleem A. Abusalah
5,
Thana’ Y. ALjaraedah
6,
Wesal Yousef Alraei
6,
Ali A. Rabaan
7,
Kirnpal Kaur Banga Singh
5,* and
Mai Abdel Haleem A. Abusalah
8,*
1
Food and Biotechnology Research Centre, Pakistan Council of Scientific and Industrial Research Centre, Lahore 54590, Pakistan
2
University Institute of Public Health, The University of Lahore, Lahore 54590, Pakistan
3
School of Zoology, Minhaj University Lahore, Lahore 54770, Pakistan
4
Division of Science and Technology, University of Education, Township Lahore, Lahore 54770, Pakistan
5
Department of Medical Microbiology and Parasitology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Malaysia
6
Department of Diet Therapy Technology & Dietetics, Faculty of Allied Medical Sciences, Zarqa University, Al-Zarqa 13132, Jordan
7
Molecular Diagnostic Laboratory, Johns Hopkins Aramco Healthcare, Dhahran 31311, Saudi Arabia
8
Department of Medical Laboratory Sciences, Faculty of Allied Medical Sciences, Zarqa University, Al-Zarqa 13132, Jordan
*
Authors to whom correspondence should be addressed.
Biomedicines 2023, 11(7), 1892; https://doi.org/10.3390/biomedicines11071892
Submission received: 14 May 2023 / Revised: 9 June 2023 / Accepted: 13 June 2023 / Published: 4 July 2023
(This article belongs to the Special Issue Oxidative Stress and Inflammation: From Mechanisms to Therapeutic Approaches 4.0)
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Review Reports Versions Notes

Abstract

:
Molecular hydrogen is renowned as an odorless and colorless gas. The recommendations developed by China suggest that the inhalation of hydrogen molecules is currently advised in COVID-19 pneumonia treatment. The therapeutic effects of molecular hydrogens have been confirmed after numerous clinical trials and animal-model-based experiments, which have expounded that the low molecular weight of hydrogen enables it to easily diffuse and permeate through the cell membranes to produce a variety of biological impacts. A wide range of both chronic and acute inflammatory diseases, which may include sepsis, pancreatitis, respiratory disorders, autoimmune diseases, ischemia-reperfusion damages, etc. may be treated and prevented by using it. H2 can primarily be inoculated through inhalation, by drinking water (which already contains H2), or by administrating the injection of saline H2 in the body. It may play a pivotal role as an antioxidant, in regulating the immune system, in anti-inflammatory activities (mitochondrial energy metabolism), and cell death (apoptosis, pyroptosis, and autophagy) by reducing the formation of excessive reactive O2 species and modifying the transcription factors in the nuclei of the cells. However, the fundamental process of molecular hydrogen is still not entirely understood. Molecular hydrogen H2 has a promising future in therapeutics based on its safety and possible usefulness. The current review emphasizes the antioxidative, anti-apoptotic, and anti-inflammatory effects of hydrogen molecules along with the underlying principle and fundamental mechanism involved, with a prime focus on the coronavirus disease of 2019 (COVID-19). This review will also provide strategies and recommendations for the therapeutic and medicinal applications of the hydrogen molecule.

1. Introduction

The hydrogen (H2) molecule is widely known as the most prevalent and lightest element found in the atmosphere of the earth. It has, however, also been regarded as a novel naturally occurring antioxidant molecule having some propensity for interaction with many biomolecules and possible medicinal and therapeutic purposes. Hydreliox, known as the breathing gas, which is a mixture of H2, oxygen [1], and helium (He) gases, was widely recommended and administered as a source of H2 for therapeutic purposes, i.e., to avoid nitrogen narcosis and decompression sickness during extremely deep technical diving in humans. The first instance of H2 being utilized therapeutically took place in the late twentieth century when research on mice with cutaneous squamous carcinoma revealed that hyperbaric H2 significantly reduced tumor growth. The inhalation of the modest concentrations of H2 reduced the risk of ischemia-reperfusion (I/R), dramatic cerebral damage, and other cerebral strokes in mice by regulating oxidative stress [2].
Numerous cellular, animal, and clinical studies have found the biological effects of hydrogen (H2) molecules, focusing mostly on its anti-inflammatory, antiapoptotic, and antioxidative properties. It has been reported that the selective free radical and inflammatory scavenging ability of H2 is still widely acknowledged to be its mechanism, despite numerous errors. According to a prior study, the inhalation of H2 has been found to prevent acute pancreatitis in rats, which was reported to be induced by caerulein. This could happen by preventing oxidative stress and premature inflammation [3]. Patients suffering from various chronic pulmonary diseases have been reported to respond well to H2 treatment in clinical trials. This has confirmed that the therapeutic application of H2 is both safe and effective [4] Moreover, the therapeutic and medicinal applications of H2 have also been demonstrated in patients suffering from cardiac-arrest-related diseases due to oxidative stress and sports-related disorders [5,6]. Some of the therapeutic applications of hydrogen molecules have been given in Figure 1. It has been recommended to breathe H2 gas (66.6% H2) mixed with O2 (33.3% O2), since H2 plays a vital role in preventing lung function loss and emphysema and other lung conditions, according to a publication issued about the prevention of COVID-19 by the Health Commission of China of Clinical Guidance for Pneumonia Treatment [7].
H2 is portable, safe, and easy to supply, therefore drinking it may be better. H2 may dissolve in water at 1.6 mg/L (0.8 mM), without changing pH, at ambient temperature and atmospheric pressure. However, because H2 is poorly soluble in water, its low bioavailability may not give enough H2 in certain local injury conditions. H2 water injections help extend the half-life. H2-rich water retained 41% of H2 consumed by the body [8]. After drinking H2 water, typical H2 sensors may not detect enough H2 in rats’ brains [9]. H2 intervention works best when administered at high payloads to targeted areas. It was found that the microbubble (MB) delivery method places H2 gas on the MB shell and transports it through blood flow. H2 MBs had a higher H2 content/volume than H2-saturated saline, suggesting they may be better at preventing myocardial damage in mice [10]. Hydrogen baths have enhanced therapeutic implications because hydrogen may diffuse through the cell membrane. H2 water baths can heal skin disorders [11,12]. Hydrogen also preserves graft organs. Removed grafted organs were cold-preserved in H2-rich saturated water to minimize chronic graft-vs.-host disease and cold I/R graft injury [13,14].
Post-COVID-19 syndrome’s symptoms are characterized by ongoing, disappearing, recurring or relapsing symptoms, developed over more than twenty days, followed by the development of infection. It can, however, manifest as severe, moderate or mild symptoms [15,16,17]. Individuals are likely to be predisposed to post-COVID-19 syndrome due to a combination of factors, including an overactive immune system, chronic inflammation, tissue damage brought on by infection, and stress resulting from the pandemic’s concurrent socioeconomic effects [18,19]. An accurate diagnosis of this condition is challenging, however, because of the viral infection’s resolution and the absence of serological antibodies [16,20]. Chronic fatigue, which has been reported in more than fifty percent (58%) of cases, cognitive deficits, myalgia, and dyspnea are among the common symptomatic manifestations [21]. The currently available data indicate that symptoms that make it difficult for patients to carry out daily tasks can affect up to 63% of individuals in post-COVID-19, of which 17.8% of patients were working before developing COVID-19 [7]. It was found that nosocomial patients tend to perform routine tasks less efficiently than outpatients [22]. Despite the initial appearance of mild symptoms, post-COVID-19 syndrome symptoms develop in children. According to compiled research, 10% of children aged 2 to 11 have one or more COVID-19-related persistent symptoms, and this number rises to 13% for adolescents aged 12 to 16 years old [7]. COVID-19 may be a factor in the post-COVID-19 syndrome’s persistent immune dysregulation and major organ dysfunction, because of the systemic inflammation and hyperactive immunological responses. Chronic fatigue, cognitive deficits, and cardio-respiratory dysfunction are the most common symptoms of post-COVID-19 syndrome. More than fifty percent of the reported cases indicate chronic fatigue, exertional fatigue, and OxS as the most prevalent symptoms. Research suggests that this condition is also characterized by persistent mitochondrial dysfunction, OxS, and inflammation. The symptoms of myalgic encephalomyelitis (ME) and chronic fatigue (CFS) syndrome, which is a highly individualized disorder, can include cardiovascular distress (such as palpitations and irregular heartbeat), cognitive dysfunction (such as anxiety, confusion, decreased cognitive function, and forgetfulness), dizziness, and extreme fatigue. Since research on the long-term implications of H2 on COVID-19 and/or SARS-CoV-2 infections is still in its early stages, this review analyses the recent studies and proposes its positive future prospects. Furthermore, the current review emphasizes the anti-apoptotic, antioxidative, and anti-inflammatory properties of hydrogen (H2) molecules, as well as the underlying principle and fundamental mechanisms involved, with a prime focus on the coronavirus outbreak of 2019. This review will also provide strategies and recommendations for the therapeutic and medicinal applications of the hydrogen molecule.

2. Biological Effects of Microbial Hydrogen

2.1. Role of Physiology of H2 Molecule in Therapeutic Applications

Natural molecular hydrogen is tiny, inert, and colorless. Airborne H2 gas burns at 4–75% concentrations. It quickly diffuses into the blood via alveoli during breathing and distributes throughout the body. H2 molecules penetrate through the cellular membrane quickly and distribute to organelles including the cytoplasm, nucleus, and others to perform biological tasks due to their molecular weight, and non-polar nature. H2 molecules can easily cross most of the barriers (i.e., blood–brain) which is not possible for most antioxidant molecules. H2 has no known cytotoxicity. Hydrogen molecules do not affect blood pressure, pH, or body temperature [23]. Mammalian cells, however, lack hydrogenases, which prevents them from producing molecular hydrogen. It has been reported that acute pulmonary injuries and distress syndromes may include respiratory distress and lung injury, i.e., ARDS and ALI, respectively. These may exhibit the characteristics of alveolar proteinaceous exudate, pulmonary edema, dysregulated inflammation-induced endothelium and epithelial damages, and alveolar/capillary barrier breakdown. The interstitium and bronchoalveolar area receive neutrophils, as given in Figure 2. The 2012 Berlin Conference classified ARDS as mild, moderate, or severe based on hypoxemia severity. Many lung insults can cause ALI. Dysregulated oxidative stress, apoptosis, and autophagy also cause ALI [24]. This is illustrated in Figure 2.

2.2. Administration Routes and Exposure to Hydrogen Molecules

The administration of H2, and the delivery procedures that are typically used in animal models and human research studies, may include the inhaling of H2 gas, the consumption of hydrogen-dissolved H2O molecules, and the inoculation of H2 saline in the body. Systems for delivering nanomaterials have also been created recently. However, the effects of all distribution methods depend on how well H2 dissolves in liquids such as water, saline, or blood. The various administration routes for molecular hydrogen to combat various body infections and/or diseases, along with their respective management strategies, are given in Table 1. H2 gas inhalation is the simplest therapeutic and has been utilized extensively since the first report. H2 inhalation guarantees the dose and retention time in the body. H2 that has been inhaled can travel throughout the body via the circulatory system and may diffuse into the plasma through the alveoli. Clinical testing revealed that 72 h of exposure to 2.4% H2 gas had no negative impacts on any physiological measures, which indicates that the H2 molecule does not have any negative effects on the human body [25]. The chemical components and features of the H2 molecule, however, indicate that it reacts with oxygen to generate water when it burns. According to research, H2 does not explode when mixed with air or oxygen if the concentration is less than 10%, even if it may be explosive and deadly when it is higher than 4% in the air [26]. Additionally, the research has demonstrated that the H2 concentration in both tissues and blood depends on the intensity and time of inhalation. Moreover, the antioxidant action of H2 was also found to be dose-dependent [27]. Recently, it has become more and more popular to provide a gaseous mixture (i.e., H2:O2; 66:33%) produced through the electrolysis of H2O, which has found practical implications in both clinical and research evaluations [28]. High concentrations of H2 gases may be used to provide more beneficial effects. High-pressure gas cylinders can be safely and conveniently replaced with a generator that does not need to be restocked [29].
When retinal damage (I/R) showed a transient rise in intraocular pressure and reactive oxygen species (ROS), the prolonged administration of H2-saturated eye drops prevented apoptosis in animal models [39]. The saline injection of molecular hydrogen is a well-known method that directly applies H2 to the affected area and quickly delivers a large amount of H2. H2 injections can be harmful. H2 was delivered orally, intravenously, intraperitoneally, or inhaled in mice. Gas chromatography, with high-quality sensors, measured H2 in various tissues. Thus, molecular H2 can independently reach most human organs or blood via these three methods [9].
In pigs, hydrogen gas inhalation and its pharmacokinetics showed that the peak of molecular H2 saturation was lower in venous blood than arterial blood, indicating the diffusion of H2 molecules during bloodstream transport [40]. Mitochondrial respiration, xanthine oxidoreductase, and NADH/NADPH oxidase produce ROS, such as hydroxyl (•OH), superoxide anion (O2•), peroxyl (RO2•), nitric oxide (NO•), and alkoxyl radicals [41]. Cell injury hinders electron transport and mitochondrial oxidative phosphorylation, leaking electrons to produce excess ROS. ROS damage cellular or organelle membranes. Figure 3 shows how lipid peroxidation after membrane release produces leukotrienes and arachidonic acid, which tend to produce inflammation. Neutrophils and macrophages may produce ROS to destroy infections, damaging healthy cells’ mitochondria and nuclei and killing them [42].
For many pathogenic processes, hydrogen peaks in the oral and inhalation administration steps, but the duration of drinking H2 water was longer [43]. These ROS comprise hydroxyl (•OH), superoxide anion (O2•), peroxyl (RO2•), nitric oxide (NO•), and alkoxyl (RO•) radicals, and are generally formed by NADH/NADPH oxidase, mitochondrial respiration, and/or xanthine oxidoreductase [41]. Electron transport and mitochondrial oxidative phosphorylation are hampered by cell damage, and electrons leak out to produce an excessive amount of ROS. On the one hand, cell or organelle membranes are harmed by excessive ROS production. Leukotrienes and arachidonic acid, which have been reported to support inflammatory pain, are created by the lipids’ subsequent peroxidation after they have been released from the membrane. Furthermore, neutrophils and macrophages may create ROS to kill infections, which may damage healthy cells’ mitochondria and nuclei and ultimately lead to death [42].

3. Biological Effects of Hydrogen

3.1. Antioxidant Effect

3.1.1. ROS Neutralization

Oxidative stress is the common first step in many processes implicated in many illnesses and it is reportedly caused by a disparity between the antioxidant system and ROS [43]. These ROS comprise hydroxyl (•OH), alkoxyl (RO•), nitric oxide (NO•), superoxide anion (O2•−), and peroxyl (RO2•) radicals. It has been found that they are typically produced by NADH/NADPH oxidase, xanthine oxidoreductase, and/or mitochondrial respiration. When cells are damaged, electron transport and oxidative phosphorylation in the mitochondria are hampered, and electrons leak to form excessive ROS. This excessive ROS generation damages cellular or organelle membranes. The lipids are then separated from the membrane and peroxidized, producing arachidonic acid and leukotrienes, both of which contribute to ameliorating inflammatory pain. Additionally, ROS which have been generated by macrophages and neutrophils may tend to attack pathogens. This would further cause severe damages to the cellular organelles, including nuclei and mitochondria, and may subsequently initiate cellular apoptosis. H2 as a reductant can permeate and neutralize the cellular membrane against harmful substances and particles which may be found in the cellular structure (•OH and ONOO) and essentially negates the impacts of O2 and H2O2 in maintaining the internal environment stability and various physiological functions. A proposed method of action was the scavenging of (•OH) radical by the chemical fusion of the hydrogen molecule with the hydroxyl ion and ultimately producing a water molecule and hydrogen ion, which was later followed by the fusion of the hydrogen ion with the oxygen molecule leading to the production of HO2 [44].
Molecular hydrogen can protect against I/R damage by lowering the scavenging of ONOO and OH and oxidative stress, which function as ROS’ electron donor molecules, but only in acellular tests. After two weeks of breathing 1.3% H2 gas, vasculitis mice had less OH and ONOO, reducing tissue damage. It also prevents hydroxyl radicals from undergoing the Haber–Weiss and Fenton reaction to create •OH radicals [45].
The antioxidant potential and biological benefits of H2 persist after elimination, especially at lower levels [46]. This suggests that the process involves regulating antioxidant signals rather than scavenging free radicals. H2-rich saline administration stimulates the Nrf2-ARE signaling pathway, reducing experimental autoimmune encephalomyelitis (EAE) symptoms in mice [47].
The Alternaria alternata tangerine pathotype illustrates ROS detoxification signaling mechanisms. ROS resistance genes are activated by H2O2 from the membrane-bound NADPH oxidase (NOX) complex. When exposed to ROS, YAP1 conformationally changes, forms disulfide bonds with two conserved cysteine residues, and enters the nucleus to regulate environmental stress genes. ROS detoxification requires the YAP1 and HOG1 MAP kinase, SKN7 redox-responsive regulators, NOX complex, Siderophores, and NPS6-mediated siderophore synthesis, which absorbs iron from the environment and requires NPS6’s non-ribosomal peptide synthetase [48]. This is illustrated in Figure 4.
In addition, intracellular ROS is significantly reduced by the activation of Nrf2 transcription which increases the SOD glutathione synthesis and downregulates the expression of NADPH oxidase [49]. Hydrogen may prevent cell death by preventing aberrant phospholipid oxidation, and lipid peroxidation, as well as by limiting the rise in cell membrane permeability, which is yet another crucial mechanism of H2 antioxidation [50]. Interestingly, significant recent studies have shown that high antioxidant levels increased the mortality rates from cardiovascular disease and cancer. An ideal antioxidant should reduce oxidative stress without disrupting redox equilibrium [51]. Due to its fast diffusion into cells through blood circulation, H2 may serve as the optimal antioxidant [52,53].

3.1.2. Regulation of Mitochondria

Along with the methods by which H2 neutralizes oxidative stress, the mechanisms leading up to the malfunction of the electron transport chain—the first step of mitochondrial oxidative stress—were emphasized. As they generate 90% of a cell’s energy in the form of ATP, mitochondria are sometimes referred to as the powerhouses of the cell. The production of ROS via forward and reverse electron transfer is accompanied by this mechanism, which depends on oxidative phosphorylation [54]. By limiting excessive hydrogen production, H2 reduces mitochondrial dysfunction. It is believed that the leakage of electrons from the electron chain transport may be able to repair the cells’ malfunctioning.
The mitochondria are where the ATP-sensitive K+ channel (mKATP), a crucial player in energy control, is present. To balance the amount of cardiac NAD+ and the generation of ATP (mitochondrial), which would lessen myocardial I/R damage, H2 gas might activate mKATP and control mitochondrial membrane potential [55]. One of the most important elements of the mitochondrial sequence of electron transfers is Coenzyme-Q [56]. In humans, CoQ10 predominates, but in rats, CoQ9 does. CoQ helps in the formation of NAD+, and proton motive force, both of which function as the ATP precursors by accepting electrons from Complex I and Complex II and transferring them to Complex III [57]. Nivolumab’s clinical effectiveness may be improved by H2 gas by boosting the amount of CoQ10 in mitochondria and replenishing worn-out CD8+ T cells’ action. Thus, it has been presumed that, through enhancing mitochondrial activity, H2 can prevent cell damage. The correction of mitochondrial dysfunction is anticipated to also enhance the disorganized signal transmission that influences the process of cellular death, for instance, in Caspase and Bax actions [58].
Mitophagy is essential for maintaining homeostasis in mitochondria [59]. The homeostasis is maintained by removing malfunctioning and damaged mitochondria. A mitophagy receptor named Fundc1 (protein 1), that controls mitophagy and interacts with LC3 II to support the maintenance of ATP balance in the mitochondria, is found on the cellular surface of mitochondria. The administration of H2 (2%) for three hours, was found to increase Fundc1-induced mitophagy. This resulted in rescuing the mice against liver damage, which was induced by sepsis. Moreover, H2 has a neuroprotective impact on glucose/oxygen-deprivation-induced brain injury in mice, which was found to increase in the expression of the mitophagy-associated genes, Parkin and PINK1 [60]. This further suggests that the advantageous role of hydrogen in ATP production could be due to the stimulation of mitochondrial autophagy. The mitochondrial malfunctioning, as reported by various sepsis-based animal studies, may diminish cellular energy which may further cause the failure of multiple organs.
H2 treatment, for instance, upregulated heat shock protein 32 (HO-1; heme oxygenase-1) in cardiac tissues, scavenging ROS and preventing sepsis-related damage to multiple organs in a HO-1/Nrf2 dependent pathway [61]. Many neurodegenerative diseases are primarily brought about by excessive ROS-induced mitochondrial damage [62]. Previous research has demonstrated that H2 intervention has antioxidative effects on animals suffering from Parkinson’s and Alzheimer’s disease [63].
This is despite the fact that the breathing of 6.5% H2 gas at 2 L/min twice daily for an hour had no positive effects on those with Parkinson’s disease. It was postulated that this is related to H2 concentration and treatment duration and concluded by the speculation that H2 may balance mitochondrial electron transport, which would account for its ability to improve mitochondrial energy metabolism and scavenge ROS [64].

3.2. Anti-Inflammatory Effect

External pathogenic infection or tissue damage is considered to trigger inflammation, which is the body’s adaptive response [65]. Inflammation may lead to an increase in monocytes, neutrophil, as well as other immune cells, in addition to the generation of inflammatory cytokines. Mononuclear phagocytes and lymphocytes may travel from veins to the region of injured tissue, where they can develop and activate into macrophages. The primary source of cytokines and growth factors in this mechanism is phagocytes [21]. Inflammatory transcription factors such as nuclear, hypoxia-inducible, matrix metalloproteinases, nitrosyl radicals, and apoptotic factors (e.g., NF-B, HIF-1, and p53) may all be triggered by excessive intracellular ROS [66,67,68]. As a consequence, several reciprocal effects of cellular damage, inflammation, and apoptosis might coexist throughout the pathogenic phase of oxidative stress. By inhibiting the production of intercellular adhesion and chemokine molecules, hydrogen may prevent neutrophil and macrophage invasion during the initial stages of inflammation [69], for instance, by inhibiting the production of IL-1β and TNF-α (inflammatory cytokines), which tends to subsequently reduce inflammatory cytokines such as IFN-γ and IL-6 [70].
H2-rich serum l levels of IL-6, TNF, and IL-1 blocked the activation of the critical inflammatory signaling pathway NF-B, which, in turn, reduced the airway and pulmonary inflammatory response which is caused by any burn in mice [71]. Additionally, H2 has been shown to significantly lower NF-B expression in a variety of injury models, including acute sports injuries to skeletal muscle injury [22], liver injury, and hematencephalon [22]. This implies that H2 molecules can influence the inflammation process through the various regulating and modulating factors which are involved in nuclear transcription and proinflammatory cytokines. Additionally, it is important to highlight the balance between pro- and anti-inflammation while treating disorders caused by dysfunctional inflammation. The anti-inflammatory effects of H2 can also be observed in the animals suffering from cerebral injury (I/R) and allergic rhinitis by regulating Tregs (T-cells), which cause a reduction in the NF-B expression along with having an immunosuppressive effect [28,34].
Heme oxygenase-1 has been reported as a microsomal enzyme (rate limiting) and heat-shock protein that is involved in heme catabolism. Bilirubin, a powerful endogenous antioxidant, is produced when biliverdin is rapidly reduced. It may lower NF-B and IL-1 expression, hence reducing septic damage [72]. H2 infusion enhanced the synthesis of anti-inflammatory cytokine (i.e., IL-10) and HO-1 in mouse lung tissue and endothelial cells from human umbilical veins that had been activated by LPS [73]. It has also been demonstrated that pre-inhaling H2 gas can effectively prevent the onset of acute forms of pancreatitis by promoting the early expression and production of a heat stress protein (Hsp60) in mice, which promotes synthesis in response to high temperatures in order to defend and protect itself [3]. Due to this, it is thought that hydrogen may boost the body’s defenses and significantly aid in the anti-inflammatory process.

4. Hydrogen (H2) and Cell Death Regulation

4.1. Apoptosis

Cell shrinkage, the formation of apoptotic bodies, and the condensation of chromatin are all characteristics of a type of planned cell death known as apoptosis. As a result, cells are cleared from the body while causing little injury to neighboring tissues, which is critical for tissue homeostasis and regulating cellular turnover [22]. Both internal and extrinsic cues can cause apoptosis. The cell surface’s death receptors activate the extrinsic apoptotic cascade by interacting with the Fas and tumor necrosis receptor factors, resulting in the caspase-8 being activated and, eventually, apoptosis. The antiapoptotic proteins, B-cell-lymphoma-2, and proapoptotic Bax were all found to be associated with the intrinsic apoptotic pathway [41].
Both apoptotic routes meet at a similar location, resulting in DNA fragmentation and caspase-3 activation [74]. H2 may have an antiapoptotic impact via scavenging ROS or regulating gene transcription, and both of these may influence endogenous apoptosis. In the in vitro investigation carried out in the epithelial cells of the intestine, it has reportedly been found that caspase-9 and 3 were suppressed but that cell viability was retained, and ROS production was dramatically reduced by H2-rich media. Moreover, H2 reversed the overexpression of Bcl-2 and Bax [75].
This impact of hydrogen-enriched water can be accomplished by preventing the mitochondrial translocation of apoptotic markers Bax and caspase-3. H2-rich water may potentially have an antiapoptotic effect by increasing the production of Bcl-2, a key factor (antiapoptotic), as shown in Figure 5. Furthermore, by stimulating the mitogen-activated protein kinase (MAPK)/HO-1 pathway, H2 can reduce ischemic brain damage in newborn mice and decrease neuronal death [76]. Alternatively, by stimulating the PI3K/Akt signaling pathway, alveolar epithelium (protect type II) cells protect against hyperoxia-induced apoptosis [77].
By stimulating the production of cleaved caspase-3, H2 has been demonstrated to increase cell death and inhibit the growth and migration of lung and esophageal cancer cells, which indicates a possible use of H2 in tumor therapy [78]. Hence, it has been proposed, through recent research, that H2 may serve numerous roles, including shielding normal cells from harm and limiting cancer cell growth.

4.2. Autophagy

By digesting macromolecules, autophagy can support, but it can also exacerbate, tissues and organ’s damage and inflammation, as seen in sepsis. Beclin-1 and LC3 protein are two autophagy-related proteins that play critical roles in autophagy detection. It has been demonstrated that H2 protected cardiomyocytes from isoproterenol-induced damage by suppressing autophagy [79]. In LPS-induced lung damage, H2-saturated water dramatically decreased the indication of LC3 and Beclin-1 (autophagy proteins) which indicates that tissues are sheltered by H2, preventing excessive autophagy [80]. H2 might, however, relieve LPS-induced neuroinflammation by lowering mTOR expression in glial cells, inducing autophagy and raising the ratio of LC3 II with LC3 I. This may be because of the varying intensity of the models occupying LPS-induced inflammation [22]. By adjusting mitophagy, mitochondrial ATP balance can be maintained with the help of a receptor such as Fundc-l. A three-hour treatment with 2% H2 protected mice against sepsis-induced liver damage and increased Fundc1-induced mitophagy [81]. This is shown in Figure 6.
Moreover, it has been demonstrated by investigations that there is an increasing trend in the Beclin-1 voicing of impaired cardiomyocytes and ratio of LC3 I/LC3II when H2-rich water was present, showing that H2 was involved in the breakdown of flawed mitochondria to maintain intracellular homeostasis [30]. By inhibiting the p38 and JNK/MAPK stress pathways, H2 can also promote autophagy [7]. Cell apoptosis and autophagy were also considerably increased in the cell lines of H1975 and A549 of lung cancer cured by using various doses of H2 gas [82].
Thus, it has been concluded that H2 followed a bidirectional regulating influence for autophagy hyperactivated during inflammation and/or can provide immense protection to tissues and cells from any harm.

4.3. Pyrolysis

Pyrolysis is a kind of controlled cell death which protects monocytes, microphages, and various pathogens. Caspase-1 is required for pyrolysis activation, and the primary downstream inflammatory agents in the pyrolytic pathway are cytokines, IL-1 and IL-18. H2 has been shown to have antibacterial properties in septic mice [83,84]. Saline enriched with H2 can substantially reduce the expression of caspase-1, which subsequently reduces the inflammatory response in early subarachnoid hemorrhage brain damage models [85]. Additionally, in models of organ damage due to sepsis, H2 therapy dramatically decreased caspase-1 expression in the injured organ as well as IL-18 and IL-1 cytokine levels. We already knew that H2 lung expansion is a good means of preventing I/R damage to donor lungs. However, H2 could have a specific regulatory function in malignancies [86].
Although there has been no direct evidence which may tend to explain the process of hydrogen involved in cell pyroptosis, it is likely that the H2 modulation of various nuclear and inflammatory components will interfere with pyroptosis progression. The actions of H2 on the pyrolysis route may suppress the production of tumor cells and/or provide protection for normal cells and tissues from harm, which is analogous to apoptosis.

5. Therapeutic Administration of H2 Molecules and Its Application in COVID-19

Pneumonia, pulmonary fibrosis, severe bronchitis, and COVID-19 have been widely known as severe pulmonary syndromes. COVID-19, however, has reportedly been found to rapidly spread all over the world. It is currently responsible for almost 185 million verified cases. The majority of COVID-19 patients show as having just a respiratory infection, beginning with a dry cough and fever and progressing to breathing difficulties and respiratory failures. Around 80% of ailed persons recover without hospitalization, whereas the other 20% suffer pneumonia, and approximately 5% develop acute ARDS [87]. Presently, only a few of medicines have been shown to promptly alleviate respiratory signs and limit disease development.
Mobilization in infiltrating immune cells and alveolar macrophages is increased with the rise in infections, causing prion inflammatory cytokines to be released into the alveoli and bronchioles. Alveolar hypoxia activates inflammatory pathways, resulting in the production of ROS and stimulation of hypoxia inducible and nuclear (NF-B) and (HIF-1) factors [88].
Mitochondrial ROS production typically initiates when cellular injury takes place, which can result in the destruction of the alveolar epithelial cell membrane and the surface deactivation, increasing membrane permeability and resulting in increased protein leakage in alveoli in the time of lung injury [89,90]. While high-speed oxygen breathing is possible, airway inflammation and exudation of viscous mucus in alveoli and bronchioles may render blood oxygenation in severe COVID-19 ineffective, because O2 cannot easily permeate in mucus plugs. Due to its low molecular weight, H2 has the potential to increase forced vital capacity while decreasing overall respiratory system resistance [91]. Moreover, H2 gas may improve dyspnea in COPD patients by decreasing bronchiole mucus buildup and hyperplasia in goblet cells [92].
Furthermore, in individuals with low SpO2 levels, the breathing of high concentrations of oxygen may cause damaging superoxide free radicals, which may lead to paralyzing lung function. As a result, for patients of COVID-19, inhaling H2 may be an effective way to combat both oxidative stress and hypoxia, lowering downstream cytokine release. Antioxidants such as Vitamin-E and co-enzyme Q-10, i.e., coenzyme Q-10, have been recommended to prevent lung surfactants from lipid peroxidation [93]. SARS-CoV-2 in the bronchus activates the immune system. Monocytes and lymphocytes enter the alveoli through small capillaries and release excessive cytokines, i.e., IL-6 and TNF-, triggering cytokine storms and damaging the alveolar epithelial cells. However, when NF-B transcription is inhibited, it reduces the activation of immune cells which may subsequently reduce hydrogen-induced inflammation. Hydrogen protects the epithelial cells of alveoli from apoptosis and oxidative stress by regulating Nrf2 transcription. Oxygen delivery and bronchial mucus production can also reduce dyspnea by using hydrogen [94]. This is shown in Figure 7.
H2 therapeutics have gained popularity in the last two decades of objective analysis due to their simple and diverse application methods. Recent studies demonstrate the therapeutic, i.e., anti-inflammatory and antioxidant, characterization of molecular hydrogen. H2 therapeutics, such as oxy-hydrogen inhalation, can improve post-COVID parameters such as mild cognitive impairment, chronic fatigue, and cardiovascular function inhibition [87]. However, if H2 therapies are recommended as alternative or ancillary COVID-19 treatments, a comprehensive strategy including clinical evidence, cost-benefit analysis, dosage concentrations and durations, and further mechanistic studies will be needed. It has been found that the unique characteristics of molecular H2 i.e., its lessened molecular weight, electrochemical neutrality, and gaseous and non-polar nature, prevents electrochemical gradients, hydrophilic, and hydrophobic forces from affecting H2 distribution across phospholipid membranes [89,90]. H2 has a significant impact on processes occurring in the specific cellular structures, including organelles such as mitochondria [95]. H2-inclusive interventions, for a wide range of are both infectious and non-infectious purposes, are being studied in labs and clinics. H2 can be administered by inhalation, infusion, ingestion, or topical application [96].
Severe COVID-19 infections require anti-inflammatory and antioxidant therapy. An overloaded immune system can cause catastrophic inflammatory cytokine storms that damage the lungs. In COVID-19 patients, serum levels of IL-6 and IL-10 are also highly linked with disease severity, which indicates that inflammatory cytokines could be potential biomarkers. In an animal model, inhaling 2% H2 greatly decreased the number of cells which cause inflammation and TNF, IL-23, IL-6, and IL-17 gene levels in the broncho alveolar lavage fluid [97]. It has also been found that 45 min of H2 gas inhalation reduced airway and pulmonary inflammation in chronic obstructive pulmonary disease (COPD) and asthma patients by reducing MCP-1, IL-6, and IL-4 levels. Hence, it has been reported that the administration of H2 in COVID-19 patients might positively decrease cytokine hailstorms and, as a result, may reduce acute lung damage [4].
Different H2 dosages have been observed to reduce the oxidative stress biomarker MDA and raise the levels of antioxidant enzymes such as GSH in the blood and lung tissues of animal models of airway inflammation [86]. It has also been shown that H2-rich media intervention reduces damage in human cell lines (A549) of lung epithelial cells (irradiation-induced) by lowering ROS generation [98]. H2 reduces cell damage, ROS production, alveolar epithelial barrier degradation, and gas exchange across the alveoli [99]. As a result, we have grounds to think that, by neutralizing oxidative stress, H2 can effectively mitigate COVID-19 pneumonia. We noted that in a few recently reported multicenter clinical studies, the researchers employed a combination of H2 and oxygen [1] gas (66% H2; 33% O2), produced by electrolyzed water and supplied to patients with COVID-19. Even though randomization was not used because of the importance of dealing with the outbreak, a considerably larger proportion of patients in the therapy group were reported to inhale a mixture of H2 and O2, and showed improved clinical symptoms, than control group patients, who received traditional oxygen treatment [38].
Similarly, using H2 increases the O2 utilization rate, decreases O2 intake, as well as the negative impacts on exercise in healthy adults [97]. Inhaling an O2 and H2 mixture can enlarge the bronchioles and minimize inspiratory work, promoting O2 absorption through alveoli [23]. SARS-CoV-2 may cause lymphopenia by stimulating the p53 apoptotic signaling pathway in lymphocytes. H2 may prevent apoptosis in peripheral blood cells which could potentially assist in COVID-19 [33]. To reduce lung damage, surfactant proteins can be enhanced by H2 [100]. In combination with the preceding studies, we propose that H2 inhalation may be a potential treatment for COVID-19 by decreasing inflammation, apoptosis, hypoxia, and oxidative stress to some extent.

6. Effects on Human Immune System

The overactivation of immune system cells and prion inflammatory chemicals plays a significant role in the development of inflammation in many inflammatory disorders. The traditional animal model for multiple sclerosis in humans is EAE. H2-rich water intervention may improve EAE symptoms by reducing CD4+T cell infiltration and suppressing Th17 cell growth in the spinal cord [35]. Different H2 concentrations for immune paucity can enhance the immune deficiency condition and antitumor immunological activity by increasing the percentage of CD8+ T-cells [101].
The most frequent side effect in many people receiving radiation is immunological dysfunction. According to studies, pretreatment with H2-enhanced CD8+ and CD4+ T cells prevented radiation-induced splenocyte death in mice, which prevented immunological dysfunction [102]. In addition, healthy adult peripheral blood cells showed a considerable downregulation of inflammation and apoptotic signaling following four weeks of H2-water intake. When eosinophils and mast cells are activated, type I hypersensitivity reactions, that result in allergic rhinitis, produce tissue congestion and edema. Around a 67% concentration of hydrogen molecules can alleviate it by preventing Th2 cells from responding in an inflammatory response [103]. Moreover, it has been found that H2-rich saline reduces allergic rhinitis by rectifying the Th1/Th1 polarity. Many inflammatory disorders have pathogenic characteristics of macrophage circulation and M1/M2 disproportion [104].
Acute kidney damage [105], ischemic stroke [106], and rheumatoid arthritis [107] are only a few conditions for which high concentrations of H2 have been shown to significantly enhance IL-4 via controlling the M1/M2 balance. In a chronic pancreatitis rat model, H2 was first shown to reverse Treg loss, demonstrating that H2 also controls inflammation through mediating Treg [34]. By encouraging Treg proliferation and preventing immunological overactivation, a low dosage H2 intervention decreased inflammation [108]. As a result, the various H2 dosages may regulate the proliferation of immune cells to balance immunological overactivation or immunodeficiency.
Recent studies have shown that H2 inhalation has a negative impact on the process number, duration, and immunohistochemical signals of microglia in rats with chronic L-DOPA-induced striatal lesions. Reactive microglia produce a variety of cytokines and chemokines inflammatory compounds, as well as cell surface molecules, that are primarily responsible for macrophagic and antigen-cell function [34,108]. Some findings explicitly demonstrate that inhaling H2 was unable to bring astrocyte levels down to normal levels. It is critical to note that astrogliosis’ effects on adjacent non-neural and neural cells may be both positive and negative [34,108]. Findings from some other studies, however, suggest that regarding the impact of hydrogen on inflammatory conditions in conjunction with its impact on the microglial (striatal) reactivity may generally support the reduction in LID [34,108]. However, these findings could not prevent scientists from perpetually speculating about the other mechanisms involved in the significant anti-dyskinetic effect of molecular hydrogen.
The current study details how the numerous effects of H2 on the treatment and prevention of various diseases is still in the initial phases. Clinical trials and efficacy evaluation on animals and cell cultures differ significantly, so further investigation is required. Evidently, it has been observed that every research investigation has yielded inconsistent results. However, the administration of hydrogen in the human body, and the various subsequent associated factors, such as excessive accumulation, reduction potential, dose duration, dosage quantity, and antioxidant safety, should be included in forthcoming clinical research.

7. Conclusions and Future Prospects

Hydrogen controls gene expression and the phenotypes that ameliorate ailing situations. It has been concluded that H2 intervention can control the production of inflammatory cytokines, reduce or prevent both in vitro and in vivo cellular apoptotic damages, and scavenge free radicals, demonstrating the therapeutic benefit of H2. We conclude that H2 diffuses into cells and reduces mitochondrial free radicals via transporting electrons from damaged mitochondrial membranes. It also influences oxidative stress, hypoxia, and Nrf2 transcription. H2 has also been reportedly found to inhibit the nucleus transcription of anti-inflammatory NF-B and Foxp3. However, this could directly affect how Caspase3 and Bax are assembled, blocking apoptosis. This review has also found that molecular hydrogen therapies effectively remediated the life-threatening consequences of SARS-CoV-2 infection. In patients with mild-to-moderate disease symptoms, H2 administration has been reported to improve recovery through the abatement of the hyperinflammatory cytokine cascade and a reduction in inhalation resistance, as it functions as an effective anti-inflammatory and antioxidative agent. In essence, molecular hydrogen’s antioxidant capacity and respiratory disease studies suggest that inhaling it may also help in mitigating COVID-19. Despite its potency, molecular hydrogen needs to be further identified, characterized, described, and verified through pragmatic human and animal experiments, which may quadruple its significance as a novel and potential antioxidant agent.
Hence, this study details the current and plausible future prospective advancements in the field, based on the numerous therapeutic, nutraceutical, and pharmaceutical effects of H2 on the treatment and prevention of various diseases. Further studies are, however, required, since there are critical differences and clear disparities between clinical trials and efficacy testing conducted on animals and/or in cell cultures. Evidently, it has been found that not every study produced corroborating results. It is, however, recommended that clinical research should include data on the excess accumulation, reduction potential, dose duration, dosage quantity, and antioxidant safety of H2.

Author Contributions

Conceptualization, I.P., M.A.H.A.A. (Mai Abdel Haleem A. Abusalah) and K.K.B.S.; software, B.B., M.N. and S.N.; validation, Q.-u.-A.A., T.A.F., M.F. and M.A.H.A.A. (Manal Abdel Haleem A. Abusalah); resources, T.Y.A., W.Y.A. and K.K.B.S.; data curation, I.P., M.A.H.A.A. (Mai Abdel Haleem A. Abusalah) and K.K.B.S.; writing—original draft preparation, A.A.R., T.A.F., M.F., S.N., T.A.F. and M.F.; writing—review and editing, Q.-u.-A.A., M.A.H.A.A. (Manal Abdel Haleem A. Abusalah), M.A.H.A.A. (Mai Abdel Haleem A. Abusalah) and K.K.B.S.; visualization, M.A.H.A.A. (Manal Abdel Haleem A. Abusalah); supervision, M.A.H.A.A. (Mai Abdel Haleem A. Abusalah) and K.K.B.S.; project administration, I.P. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Acknowledgments

Authors would like to acknowledge PCSIR, Punjab, for providing the facilities to write this review.

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. Therapeutic applications of hydrogen molecules (H2) in human beings.
Figure 1. Therapeutic applications of hydrogen molecules (H2) in human beings.
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Figure 2. Dysregulated inflammation and malfunctioning of the alveolar and endothelial barriers involved in the pathophysiology of acute lung damage [24].
Figure 2. Dysregulated inflammation and malfunctioning of the alveolar and endothelial barriers involved in the pathophysiology of acute lung damage [24].
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Figure 3. Production routes, sources, and effects of over-production of ROS (reactive oxygen species).
Figure 3. Production routes, sources, and effects of over-production of ROS (reactive oxygen species).
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Figure 4. ROS Detoxification Pathway [48].
Figure 4. ROS Detoxification Pathway [48].
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Figure 5. Induction of apoptosis through apoptotic pathways (i.e., intrinsic, and extrinsic) and subsequent activation of Caspase-3 and -7.
Figure 5. Induction of apoptosis through apoptotic pathways (i.e., intrinsic, and extrinsic) and subsequent activation of Caspase-3 and -7.
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Figure 6. Bi-directional regulatory effect of hydrogen molecule on autophagy. Pictorial representation of inhibitory role of H2 in protecting the lung tissues from excessive autophagy; its role in promoting autophagy and mitophagy to protect the glial cells, injured liver cells, and damaged cardiomyocytes.
Figure 6. Bi-directional regulatory effect of hydrogen molecule on autophagy. Pictorial representation of inhibitory role of H2 in protecting the lung tissues from excessive autophagy; its role in promoting autophagy and mitophagy to protect the glial cells, injured liver cells, and damaged cardiomyocytes.
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Figure 7. Hypothetical schematic illustration of hydrogen therapy for COVID-19 [94].
Figure 7. Hypothetical schematic illustration of hydrogen therapy for COVID-19 [94].
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Table
Table 1. Administration routes of molecular hydrogen in human bodies to combat various infections and/or diseases, along with the respective management strategies.
Table 1. Administration routes of molecular hydrogen in human bodies to combat various infections and/or diseases, along with the respective management strategies.
Administrative Routes in the BodySubject/s (Time Taken to Initiate an Action)Human Body Response/sEffects on Target Organ or at Injury SiteAdministration ProtocolAdvantagesProspective Risks AssociatedRef.
Dissolved H2 SalineRats (24 h)Anti-inflammatory and anti-apoptotic effect Myocardial I/R injury 10 mL/kg, 0.6 mmol/L,Direct exposure or inoculation of dose at the target siteCross-infection, Invasive[30]
Mice (12 h)Anti-inflammatory response, reduces sepsis associated diseasesEncephalopathy5 mL/kg, 0.6 mmol/LDirect exposure or inoculation of dose at the target siteCross-infection, Invasive[31]
Drinking of dissolved H2 water Human (2 weeks) Alleviates InjuriesInjured soft tissues (sports-related)2 g/day, H2-rich tabletsSafe and portableDose intake limitations[32]
Human (4 weeks)Reduction in inflammation and anti-apoptoticPeripheral blood vessels and blood cells1500 mL/day, 0.753 mg/LSafe and portableDose intake limitations[33]
Human (8 weeks)Improves parapsoriasisPlaques10–15 min bathing with H2 water (two times a week)Safe and portableDose intake limitations[11]
Guinea Pig (10 days)Immunoregulation and improves allergic rhinitisAllergic rhinitis0.6 mmol/L, 20 μL/day
Inoculated through nasal passage		Safe and portableDose intake limitations[34]
Mice (10 days)Anti-inflammatory responseEAE 1 symptoms;0.89 mM/0.36 Twice/daySafe and portableDose intake limitations[35]
H2 gas inhalation through nasal routes Rats (120 min)Antioxidant, protects from cerebral injuryCerebral injury (I/R)4, 1, or 2% H2Dose and intake time can be ensuredIf concentration rises above 4%, it may be explosive[2]
Rats (4 months)Anti-inflammatory, ameliorates COPDCOPD 2 symptoms2, 22 or 41.6% H2
For 2 h (Once/day)		Dose and intake time can be ensuredIf concentration rises above 4%, it may be explosive[36]
Human (7 days)Anti-inflammatory, ameliorates COPDCOPD symptoms6 to 8 h/d, 66.6% H2Dose and intake time can be ensuredIf concentration rises above 4%, it may be explosive[37]
Human (daily till discharge)Ameliorates COVID-19COVID-1966.6% H2
33.3% O2		Dose and intake time can be ensuredIf concentration rises above 4%, it may be explosive[38]
H2 administration into the body via nanoparticlesRats (3/24 h)Antioxidant, anti-inflammatory, ameliorates lung and myocardial injuriesMyocardial injury (I/R), lung injury4 × 109 or 2 × 1010
bubbles		Safe to use, high H2 content/unit volumeExpensive[10]
1 EAE: experimental autoimmune encephalomyelitis; 2 COPD: chronic obstructive pulmonary disease.
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Perveen, I.; Bukhari, B.; Najeeb, M.; Nazir, S.; Faridi, T.A.; Farooq, M.; Ahmad, Q.-u.-A.; Abusalah, M.A.H.A.; ALjaraedah, T.Y.; Alraei, W.Y.; et al. Hydrogen Therapy and Its Future Prospects for Ameliorating COVID-19: Clinical Applications, Efficacy, and Modality. Biomedicines 2023, 11, 1892. https://doi.org/10.3390/biomedicines11071892

AMA Style

Perveen I, Bukhari B, Najeeb M, Nazir S, Faridi TA, Farooq M, Ahmad Q-u-A, Abusalah MAHA, ALjaraedah TY, Alraei WY, et al. Hydrogen Therapy and Its Future Prospects for Ameliorating COVID-19: Clinical Applications, Efficacy, and Modality. Biomedicines. 2023; 11(7):1892. https://doi.org/10.3390/biomedicines11071892

Chicago/Turabian Style

Perveen, Ishrat, Bakhtawar Bukhari, Mahwish Najeeb, Sumbal Nazir, Tallat Anwar Faridi, Muhammad Farooq, Qurat-ul-Ain Ahmad, Manal Abdel Haleem A. Abusalah, Thana’ Y. ALjaraedah, Wesal Yousef Alraei, and et al. 2023. "Hydrogen Therapy and Its Future Prospects for Ameliorating COVID-19: Clinical Applications, Efficacy, and Modality" Biomedicines 11, no. 7: 1892. https://doi.org/10.3390/biomedicines11071892

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