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Pharmaceuticals
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Therapeutic Potential of Molecular Hydrogen
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Therapeutic Potential of Molecular Hydrogen

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (25 January 2024) | Viewed by 55885

Special Issue Editors

Dr. Tyler W. LeBaron

E-Mail Website
Guest Editor
1. Department of Kinesiology and Outdoor Recreation, Southern Utah University, Cedar City, UT 84720, USA
2. Molecular Hydrogen Institute, Cedar City, UT 84720, USA
Interests: molecular hydrogen; reactive oxygen species; nitric oxide; inflammation; cardiovascular disease
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Jan Slezak

E-Mail Website
Guest Editor
Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovakia
Interests: heart transplantation; ischemia/reperfusion injury; oxidative stress; molecular hydrogen; inflammation

Special Issue Information

Dear Colleagues,

Molecular hydrogen (H2 gas) can easily penetrate biomembranes and reach subcellular compartments. Over the past 15 years, H2 has been demonstrated to have a wide range of therapeutic effects, including through antioxidant, anti-inflammatory, and antiapoptotic activities. Furthermore, it modulates microRNA expression and protein phosphorylation cascades and influences many signal transduction pathways. Hydrogen’s therapeutic potential has been demonstrated in over 170 different animal disease models that are applicable to every human system. However, details of the mechanistic actions of molecular hydrogen, its true clinical viability, and the optimal dose, frequency, and duration remain elusive.

This Special Issue seeks contributions that further elucidate the potential therapeutic use of molecular hydrogen. Both in vitro cellular mechanistic studies and in vivo animal and human clinical studies are of interest. Authors are invited to submit original research articles, reviews, perspectives, and short communications that advance understanding of the pharmacokinetics, pharmacodynamics, and therapeutic potential of molecular hydrogen.

Dr. Tyler W. LeBaron
Prof. Dr. Jan Slezak
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • molecular hydrogen
  • oxidative stress
  • reactive oxygen species
  • inflammation
  • apoptosis
  • microRNA
  • protein phosphorylation
  • signal transduction
  • gaseous signaling molecules

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Published Papers (10 papers)

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Research

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12 pages, 3146 KiB  
Article
Therapeutic Potential of Hydrogen-Rich Water on Muscle Atrophy Caused by Immobilization in a Mouse Model
by Seyedeh Elnaz Nazari, Alex Tarnava, Nima Khalili-Tanha, Mahdieh Darroudi, Ghazaleh Khalili-Tanha, Amir Avan, Majid Khazaei and Tyler W. LeBaron
Pharmaceuticals 2023, 16(10), 1436; https://doi.org/10.3390/ph16101436 - 10 Oct 2023
Viewed by 2853
Abstract
Skeletal muscle atrophy is associated with poor quality of life and disability. Thus, finding a new strategy for the prevention and treatment of skeletal muscle atrophy is very crucial. This study aimed to investigate the therapeutic potential of hydrogen-rich water (HRW) on muscle [...] Read more.
Skeletal muscle atrophy is associated with poor quality of life and disability. Thus, finding a new strategy for the prevention and treatment of skeletal muscle atrophy is very crucial. This study aimed to investigate the therapeutic potential of hydrogen-rich water (HRW) on muscle atrophy in a unilateral hind limb immobilization model. Thirty-six male Balb/C mice were divided into control (without immobilization), atrophy, and atrophy + hydrogen-rich water (HRW). Unilateral hind limb immobilization was induced using a splint for 7 days (atrophy) and removed for 10 days (recovery). At the end of each phase, gastrocnemius and soleus muscle weight, limb grip strength, skeletal muscle histopathology, muscle fiber size, cross-section area (CSA), serum troponin I and skeletal muscle IL-6, TNF-α and Malondialdehyde (MDA), and mRNA expression of NF-κB, BAX and Beclin-1 were evaluated. Muscle weight and limb grip strength in the H2-treated group were significantly improved during the atrophy phase, and this improvement continued during the recovery period. Treatment by HRW increased CSA and muscle fiber size and reduced muscle fibrosis, serum troponin I, IL-6, TNF-α and MDA which was more prominent in the atrophy phase. These data suggest that HRW could improve muscle atrophy in an immobilized condition and could be considered a new strategy during rehabilitation. Full article
(This article belongs to the Special Issue Therapeutic Potential of Molecular Hydrogen)
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17 pages, 12533 KiB  
Article
Hydrogen Attenuates Inflammation by Inducing Early M2 Macrophage Polarization in Skin Wound Healing
by Pengxiang Zhao, Zisong Cai, Xujuan Zhang, Mengyu Liu, Fei Xie, Ziyi Liu, Shidong Lu and Xuemei Ma
Pharmaceuticals 2023, 16(6), 885; https://doi.org/10.3390/ph16060885 - 15 Jun 2023
Cited by 5 | Viewed by 2326
Abstract
The heterogeneous and highly plastic cell populations of macrophages are important mediators of cellular responses during all stages of wound healing, especially in the inflammatory stage. Molecular hydrogen (H2), which has potent antioxidant and anti-inflammatory effects, has been shown to promote [...] Read more.
The heterogeneous and highly plastic cell populations of macrophages are important mediators of cellular responses during all stages of wound healing, especially in the inflammatory stage. Molecular hydrogen (H2), which has potent antioxidant and anti-inflammatory effects, has been shown to promote M2 polarization in injury and disease. However, more in vivo time series studies of the role of M1-to-M2 polarization in wound healing are needed. In the current study, we performed time series experiments on a dorsal full-thickness skin defect mouse model in the inflammatory stage to examine the effects of H2 inhalation. Our results revealed that H2 could promote very early M1-to-M2 polarization (on days 2–3 post wounding, 2–3 days earlier than in conventional wound healing), without disturbing the functions of the M1 phenotype. Time series analysis of the transcriptome, blood cell counts, and multiple cytokines further indicated that peripheral blood monocytes were a source of H2-induced M2 macrophages and that the functions of H2 in macrophage polarization were not only dependent on its antioxidant effects. Therefore, we believe that H2 could reduce inflammation in wound care by shifting early macrophage polarization in clinical settings. Full article
(This article belongs to the Special Issue Therapeutic Potential of Molecular Hydrogen)
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17 pages, 3833 KiB  
Article
Effects of Coenzyme Q10 on the Biomarkers (Hydrogen, Methane, SCFA and TMA) and Composition of the Gut Microbiome in Rats
by Anastasiia Yu. Ivanova, Ivan V. Shirokov, Stepan V. Toshchakov, Aleksandra D. Kozlova, Olga N. Obolenskaya, Sofia S. Mariasina, Vasily A. Ivlev, Ilya B. Gartseev and Oleg S. Medvedev
Pharmaceuticals 2023, 16(5), 686; https://doi.org/10.3390/ph16050686 - 2 May 2023
Cited by 6 | Viewed by 5203
Abstract
The predominant route of administration of drugs with coenzyme Q10 (CoQ10) is administration per os. The bioavailability of CoQ10 is about 2–3%. Prolonged use of CoQ10 to achieve pharmacological effects contributes to the creation of elevated concentrations of CoQ10 in the intestinal [...] Read more.
The predominant route of administration of drugs with coenzyme Q10 (CoQ10) is administration per os. The bioavailability of CoQ10 is about 2–3%. Prolonged use of CoQ10 to achieve pharmacological effects contributes to the creation of elevated concentrations of CoQ10 in the intestinal lumen. CoQ10 can have an effect on the gut microbiota and the levels of biomarkers it produces. CoQ10 at a dose of 30 mg/kg/day was administered per os to Wistar rats for 21 days. The levels of gut microbiota biomarkers (hydrogen, methane, short-chain fatty acids (SCFA), and trimethylamine (TMA)) and taxonomic composition were measured twice: before the administration of CoQ10 and at the end of the experiment. Hydrogen and methane levels were measured using the fasting lactulose breath test, fecal and blood SCFA and fecal TMA concentrations were determined by NMR, and 16S sequencing was used to analyze the taxonomic composition. Administration of CoQ10 for 21 days resulted in a 1.83-fold (p = 0.02) increase in hydrogen concentration in the total air sample (exhaled air + flatus), a 63% (p = 0.02) increase in the total concentration of SCFA (acetate, propionate, butyrate) in feces, a 126% increase in butyrate (p = 0.04), a 6.56-fold (p = 0.03) decrease in TMA levels, a 2.4-fold increase in relative abundance of Ruminococcus and Lachnospiraceae AC 2044 group by 7.5 times and a 2.8-fold decrease in relative representation of Helicobacter. The mechanism of antioxidant effect of orally administered CoQ10 can include modification of the taxonomic composition of the gut microbiota and increased generation of molecular hydrogen, which is antioxidant by itself. The evoked increase in the level of butyric acid can be followed by protection of the gut barrier function. Full article
(This article belongs to the Special Issue Therapeutic Potential of Molecular Hydrogen)
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12 pages, 2806 KiB  
Article
Protective Effect of Hydrogen-Rich Saline on Spinal Cord Damage in Rats
by Murat Kayabaş, Levent Şahin, Mustafa Makav, Duried Alwazeer, Levent Aras, Serdar Yiğit and Tyler W. LeBaron
Pharmaceuticals 2023, 16(4), 527; https://doi.org/10.3390/ph16040527 - 1 Apr 2023
Cited by 5 | Viewed by 2451
Abstract
The anti-inflammatory and anti-apoptotic effects of molecular hydrogen, delivered as hydrogen-rich saline (HRS), on spinal cord injury was investigated. Four-month-old male Sprague Dawley rats (n = 24) were classified into four groups: (1) control—laminectomy only at T7-T10; (2) spinal injury—dura left intact, [...] Read more.
The anti-inflammatory and anti-apoptotic effects of molecular hydrogen, delivered as hydrogen-rich saline (HRS), on spinal cord injury was investigated. Four-month-old male Sprague Dawley rats (n = 24) were classified into four groups: (1) control—laminectomy only at T7-T10; (2) spinal injury—dura left intact, Tator and Rivlin clip compression model applied to the spinal cord for 1 min, no treatment given; (3) HRS group—applied intraperitoneally (i.p.) for seven days; and (4) spinal injury—HRS administered i.p. for seven days after laminectomy at T7–T10 level, leaving the dura intact and applying the Tator and Rivlin clip compression model to the spinal cord for 1 min. Levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were measured in blood taken at day seven from all groups, and hematoxylin–eosin (H & E) and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) were used to stain the tissue samples. IL-6 and TNF-α levels were significantly lower in the group treated with HRS following the spinal cord injury compared to the group whose spinal cord was damaged. A decrease in apoptosis was also observed. The anti-inflammatory and anti-apoptotic effect of IL-6 may be a clinically useful adjuvant therapy after spinal cord injury. Full article
(This article belongs to the Special Issue Therapeutic Potential of Molecular Hydrogen)
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13 pages, 2136 KiB  
Article
Therapeutic Inhalation of Hydrogen Gas for Alzheimer’s Disease Patients and Subsequent Long-Term Follow-Up as a Disease-Modifying Treatment: An Open Label Pilot Study
by Hirohisa Ono, Yoji Nishijima and Shigeo Ohta
Pharmaceuticals 2023, 16(3), 434; https://doi.org/10.3390/ph16030434 - 13 Mar 2023
Cited by 8 | Viewed by 8524
Abstract
(1) Background: Alzheimer’s disease (AD) is a progressive and fatal neurodegenerative disorder. Hydrogen gas (H2) is a therapeutic medical gas with multiple functions such as anti-oxidant, anti-inflammation, anti-cell death, and the stimulation of energy metabolism. To develop a disease-modifying treatment for [...] Read more.
(1) Background: Alzheimer’s disease (AD) is a progressive and fatal neurodegenerative disorder. Hydrogen gas (H2) is a therapeutic medical gas with multiple functions such as anti-oxidant, anti-inflammation, anti-cell death, and the stimulation of energy metabolism. To develop a disease-modifying treatment for AD through multifactorial mechanisms, an open label pilot study on H2 treatment was conducted. (2) Methods: Eight patients with AD inhaled 3% H2 gas for one hour twice daily for 6 months and then followed for 1 year without inhaling H2 gas. The patients were clinically assessed using the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog). To objectively assess the neuron integrity, diffusion tensor imaging (DTI) with advanced magnetic resonance imaging (MRI) was applied to neuron bundles passing through the hippocampus. (3) Results: The mean individual ADAS-cog change showed significant improvement after 6 months of H2 treatment (−4.1) vs. untreated patients (+2.6). As assessed by DTI, H2 treatment significantly improved the integrity of neurons passing through the hippocampus vs. the initial stage. The improvement by ADAS-cog and DTI assessments were maintained during the follow-up after 6 months (significantly) or 1 year (non-significantly). (4) Conclusions: This study suggests that H2 treatment not only relieves temporary symptoms, but also has disease-modifying effects, despite its limitations. Full article
(This article belongs to the Special Issue Therapeutic Potential of Molecular Hydrogen)
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16 pages, 8830 KiB  
Article
Mast Cells in Regeneration of the Skin in Burn Wound with Special Emphasis on Molecular Hydrogen Effect
by Dmitri Atiakshin, Mariya Soboleva, Dmitry Nikityuk, Nataliya Alexeeva, Svetlana Klochkova, Andrey Kostin, Viktoriya Shishkina, Igor Buchwalow and Markus Tiemann
Pharmaceuticals 2023, 16(3), 348; https://doi.org/10.3390/ph16030348 - 24 Feb 2023
Cited by 8 | Viewed by 2371
Abstract
The mechanisms of regeneration for the fibrous component of the connective tissue of the dermis are still insufficiently studied. The aim of this study was to evaluate the effectiveness of the use of molecular hydrogen on the local therapy of a II degree [...] Read more.
The mechanisms of regeneration for the fibrous component of the connective tissue of the dermis are still insufficiently studied. The aim of this study was to evaluate the effectiveness of the use of molecular hydrogen on the local therapy of a II degree burn wound with the intensification of collagen fibrillogenesis in the skin. We analyzed the involvement of mast cells (MCs) in the regeneration of the collagen fibers of the connective tissue using water with a high content of molecular hydrogen and in a therapeutic ointment for the cell wounds. Thermal burns led to an increase in the skin MC population, accompanied by a systemic rearrangement of the extracellular matrix. The use of molecular hydrogen for the treatment of burn wounds stimulated the regeneration processes by activating the formation of the fibrous component of the dermis, accelerating wound healing. Thus, the intensification of collagen fibrillogenesis was comparable to the effects of a therapeutic ointment. The remodeling of the extracellular matrix correlated with a decrease in the area of damaged skin. Skin regeneration induced by the activation of the secretory activity of MCs may be one of the possible points of implementation of the biological effects of molecular hydrogen in the treatment of burn wounds. Thus, the positive effects of molecular hydrogen on skin repair can be used in clinical practice to increase the effectiveness of therapy after thermal exposure. Full article
(This article belongs to the Special Issue Therapeutic Potential of Molecular Hydrogen)
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Review

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24 pages, 3590 KiB  
Review
Novel Role of Molecular Hydrogen: The End of Ophthalmic Diseases?
by Si-Yu Li, Rong-Yue Xue, Hao Wu, Ning Pu, Dong Wei, Na Zhao, Zong-Ming Song and Ye Tao
Pharmaceuticals 2023, 16(11), 1567; https://doi.org/10.3390/ph16111567 - 7 Nov 2023
Cited by 5 | Viewed by 7716
Abstract
Molecular hydrogen (H2) is a colorless, odorless, and tasteless gas which displays non-toxic features at high concentrations. H2 can alleviate oxidative damage, reduce inflammatory reactions and inhibit apoptosis cascades, thereby inducing protective and repairing effects on cells. H2 can [...] Read more.
Molecular hydrogen (H2) is a colorless, odorless, and tasteless gas which displays non-toxic features at high concentrations. H2 can alleviate oxidative damage, reduce inflammatory reactions and inhibit apoptosis cascades, thereby inducing protective and repairing effects on cells. H2 can be transported into the body in the form of H2 gas, hydrogen-rich water (HRW), hydrogen-rich saline (HRS) or H2 produced by intestinal bacteria. Accumulating evidence suggest that H2 is protective against multiple ophthalmic diseases, including cataracts, dry eye disease, diabetic retinopathy (DR) and other fields. In particular, H2 has been tested in the treatment of dry eye disease and corneal endothelial injury in clinical practice. This medical gas has brought hope to patients suffering from blindness. Although H2 has demonstrated promising therapeutic potentials and broad application prospects, further large-scale studies involving more patients are still needed to determine its optimal application mode and dosage. In this paper, we have reviewed the basic characteristics of H2, and its therapeutic effects in ophthalmic diseases. We also focus on the latest progress in the administration approaches and mechanisms underlying these benefits. Full article
(This article belongs to the Special Issue Therapeutic Potential of Molecular Hydrogen)
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19 pages, 1781 KiB  
Review
Mast Cells as a Potential Target of Molecular Hydrogen in Regulating the Local Tissue Microenvironment
by Dmitri Atiakshin, Andrey Kostin, Artem Volodkin, Anna Nazarova, Viktoriya Shishkina, Dmitry Esaulenko, Igor Buchwalow, Markus Tiemann and Mami Noda
Pharmaceuticals 2023, 16(6), 817; https://doi.org/10.3390/ph16060817 - 30 May 2023
Cited by 8 | Viewed by 2236
Abstract
Knowledge of the biological effects of molecular hydrogen (H2), hydrogen gas, is constantly advancing, giving a reason for the optimism in several healthcare practitioners regarding the management of multiple diseases, including socially significant ones (malignant neoplasms, diabetes mellitus, viral hepatitis, mental [...] Read more.
Knowledge of the biological effects of molecular hydrogen (H2), hydrogen gas, is constantly advancing, giving a reason for the optimism in several healthcare practitioners regarding the management of multiple diseases, including socially significant ones (malignant neoplasms, diabetes mellitus, viral hepatitis, mental and behavioral disorders). However, mechanisms underlying the biological effects of H2 are still being actively debated. In this review, we focus on mast cells as a potential target for H2 at the specific tissue microenvironment level. H2 regulates the processing of pro-inflammatory components of the mast cell secretome and their entry into the extracellular matrix; this can significantly affect the capacity of the integrated-buffer metabolism and the structure of the immune landscape of the local tissue microenvironment. The analysis performed highlights several potential mechanisms for developing the biological effects of H2 and offers great opportunities for translating the obtained findings into clinical practice. Full article
(This article belongs to the Special Issue Therapeutic Potential of Molecular Hydrogen)
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27 pages, 1387 KiB  
Review
Therapeutic Potential of Molecular Hydrogen in Metabolic Diseases from Bench to Bedside
by Fei Xie, Yifei Song, Yang Yi, Xue Jiang, Shiwen Ma, Chen Ma, Junyu Li, Ziyi Zhanghuang, Mengyu Liu, Pengxiang Zhao and Xuemei Ma
Pharmaceuticals 2023, 16(4), 541; https://doi.org/10.3390/ph16040541 - 4 Apr 2023
Cited by 11 | Viewed by 6388
Abstract
Oxidative stress and chronic inflammation have been implicated in the pathophysiology of metabolic diseases, including diabetes mellitus (DM), metabolic syndrome (MS), fatty liver (FL), atherosclerosis (AS), and obesity. Molecular hydrogen (H2) has long been considered a physiologically inert gas. In the [...] Read more.
Oxidative stress and chronic inflammation have been implicated in the pathophysiology of metabolic diseases, including diabetes mellitus (DM), metabolic syndrome (MS), fatty liver (FL), atherosclerosis (AS), and obesity. Molecular hydrogen (H2) has long been considered a physiologically inert gas. In the last two decades, accumulating evidence from pre-clinical and clinical studies has indicated that H2 may act as an antioxidant to exert therapeutic and preventive effects on various disorders, including metabolic diseases. However, the mechanisms underlying the action of H2 remain unclear. The purpose of this review was to (1) provide an overview of the current research on the potential effects of H2 on metabolic diseases; (2) discuss the possible mechanisms underlying these effects, including the canonical anti-oxidative, anti-inflammatory, and anti-apoptotic effects, as well as suppression of ER stress, activation of autophagy, improvement of mitochondrial function, regulation of gut microbiota, and other possible mechanisms. The potential target molecules of H2 will also be discussed. With more high-quality clinical trials and in-depth mechanism research, it is believed that H2 will eventually be applied to clinical practice in the future, to benefit more patients with metabolic disease. Full article
(This article belongs to the Special Issue Therapeutic Potential of Molecular Hydrogen)
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Other

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14 pages, 2681 KiB  
Systematic Review
The Effects of Hydrogen-Rich Water on Blood Lipid Profiles in Clinical Populations: A Systematic Review and Meta-Analysis
by Nikola Todorovic, Julen Fernández-Landa, Asier Santibañez, Branislav Kura, Valdemar Stajer, Darinka Korovljev and Sergej M. Ostojic
Pharmaceuticals 2023, 16(2), 142; https://doi.org/10.3390/ph16020142 - 18 Jan 2023
Cited by 6 | Viewed by 13228
Abstract
Over the last two decades, a plethora of disease models and human studies have confirmed the beneficial effects of molecular hydrogen (H2), a simple biotherapeutic gas. Recent small-scale studies evaluating the effects of hydrogen-rich water (HRW) on various metabolic conditions pointed [...] Read more.
Over the last two decades, a plethora of disease models and human studies have confirmed the beneficial effects of molecular hydrogen (H2), a simple biotherapeutic gas. Recent small-scale studies evaluating the effects of hydrogen-rich water (HRW) on various metabolic conditions pointed to advantageous effects of HRW in regulating blood lipid profiles. However, to the best of the authors’ knowledge, no systematic review and/or meta-analysis (SRMA) were published considering HRW consumption and lipid/lipoprotein status. Therefore, the aim of this SRMA was to assess the effects of HRW consumption on blood lipid panel in clinical populations. The search strategy was designed using PRISMA guidelines, and the databases PubMed/Medline, Web of Science, and Scopus were explored from inception until 4 October 2022. A total of seven studies satisfied all the eligibility criteria and were included in SRMA. The results for the pooled meta-analysis showed a significant reduction in total cholesterol, low-density lipoprotein, and triglycerides after HRW intake (p = 0.01), with small to moderate effects (pooled SMD = −0.23 (from −0.40 to 0.05); pooled SMD = −0.22 (from −0.39 to 0.04); pooled SMD = −0.38 (from −0.59 to 0.18), respectively). Our findings indicate that drinking HRW can significantly improve lipid status in the clinical populations. Additional studies are warranted to further validate this connection. Full article
(This article belongs to the Special Issue Therapeutic Potential of Molecular Hydrogen)
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