Molecular Hydrogen Therapy-A Review on Clinical Studies and Outcomes.

With its antioxidant properties, hydrogen gas (H2) has been evaluated in vitro, in animal studies and in human studies for a broad range of therapeutic indications. A simple search of "hydrogen gas" in various medical databases resulted in more than 2000 publications related to hydrogen gas as a potential new drug substance. A parallel search in clinical trial registers also generated many hits, reflecting the diversity in ongoing clinical trials involving hydrogen therapy. This review aims to assess and discuss the current findings about hydrogen therapy in the 81 identified clinical trials and 64 scientific publications on human studies. Positive indications have been found in major disease areas including cardiovascular diseases, cancer, respiratory diseases, central nervous system disorders, infections and many more. The available administration methods, which can pose challenges due to hydrogens' explosive hazards and low solubility, as well as possible future innovative technologies to mitigate these challenges, have been reviewed. Finally, an elaboration to discuss the findings is included with the aim of addressing the following questions: will hydrogen gas be a new drug substance in future clinical practice? If so, what might be the administration form and the clinical indications?

Hospital-oriented quad-generation (HOQG)-A combined cooling, heating, power and gas (CCHPG) system.

Along with the global spread of the COVID-19 pandemic, a number of hospitals are operating in the over-loaded state, which results in the ever-increasing requirements of cooling, heating, power, and medical gas supplies. This paper investigates a novel concept of hospital-oriented quad-generation (HOQG) to produce a combined cooling, heating, power and gas (CCHPG) system. Local renewable energy source (RES), high temperature superconducting (HTS) power cable and superconducting magnetic energy storage (SMES) device are used as the low-carbon electricity producer, carrier and regulator, respectively. Compared to the conventional copper cable and electrochemical battery, HTS terminal power units have superior advantages of high-efficiency power delivery and high-quality power compensation. To accommodate the surplus electricity from local RESs and guarantee emergency supply for the targeted hospital buildings, three cryogenic fluids of liquefied methane gas, liquefied oxygen and liquefied nitrogen are used as back-ups for both energy fuel and medical gas. By adopting a series of cascade energy utilization and thermally-activated energy conversion facilities, multiple clean energies of cooling, heating and power are produced to supply medical devices, and multiple medical gases of oxygen, nitrogen and carbon dioxide are delivered to hospitals for patient treatments. Compared to conventional diesel oil and compressed gas back-ups, these three cryogenic liquids have advantages of high-capacity, high-security storage and low-pollution utilization. Another possible benefit can be the low-temperature environment of these medical gases offers vaccines an appropriate delivering pathway against the COVID-19 pandemic. Therefore, the proposed HOQG can be expected to fulfill the demand of energy conservation and emission reduction simultaneously during the normal operation, as well as the demand of sustainable energy and medical gas supply under severe conditions such as natural and man-made disasters.

Carbon monoxide attenuates vasospasm and improves neurobehavioral function after subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is a devastating form of hemorrhagic stroke and is a serious medical condition caused by bleeding usually due to a ruptured aneurysm. Oxidative stress and inflammation from hemoglobin and heme released from lysed red blood cells are some postulated causes of vasospasm during SAH, which could lead to delayed cerebral ischemia. At low amounts, carbon monoxide (CO) gas may be neuroprotective through anti-inflammation, anti-cell death, and restoration of normal blood flow. Hence, this study focuses on a noninvasive strategy to treat SAH by using CO as a therapeutic medical gas. Mice were treated with 250 ppm CO or air for 1h started at 2h after SAH. Various anatomical and functional outcomes were monitored at 1 and 7d after SAH. CO decreased neurological deficit score (47.4 ±â€¯10.5%) and increased activity (30.0 ±â€¯9.1%) and stereotypic counts (261.5 ±â€¯62.1%) at 7d. There was a significant increase in lumen area/wall thickness ratio in the middle cerebral artery (173.5 ±â€¯19.3%), which tended to increase in the anterior cerebral artery (25.5 ±â€¯4.3%) at 7d. This is the first report to demonstrate that CO minimizes delayed SAH-induced neurobehavioral deficits, which suggests that post-treatment with CO gas or CO-donors can be further tested as a potential therapy against SAH.

The Biochemical and Pharmacological Properties of Ozone: The Smell of Protection in Acute and Chronic Diseases.

Ozone therapy has been widely used in everyday clinical practice over the last few years, leading to significant clinical results in the treatment of herniated discs and pain management. Nevertheless, further studies have demonstrated its potential efficacy and safety under other clinical and experimental conditions. However, some of these studies showed controversial results regarding the safety and efficacy of ozone therapy, thus mining its potential use in an everyday clinical practice. To this regard, it should be considered that extensive literature review reported the use of ozone in a significant different dose range and with different delivery systems. The aim of the present review is to describe the various pharmacological effects of ozone in different organs and clinical conditions and to provide possible biochemical and molecular insights for ozone biological properties, thus providing a possible explanation for various controversial clinical outcomes described in the scientific literature.

An In†Situ Depot for Continuous Evolution of Gaseous H2 Mediated by a Magnesium Passivation/Activation Cycle for Treating Osteoarthritis.

Inflammation is involved in many human pathologies, including osteoarthritis (OA). Hydrogen (H2 ) is known to have anti-inflammatory effects; however, the bioavailability of directly administered H2 gas is typically poor. Herein, a local delivery system that can provide a high therapeutic concentration of gaseous H2 at inflamed tissues is proposed. The delivery system comprises poly(lactic-co-glycolic acid) microparticles that contain magnesium powder (Mg@PLGA MPs). Mg@PLGA MPs that are intra-muscularly injected close to the OA knee in a mouse model can act as an in situ depot that can evolve gaseous H2 continuously, mediated by the cycle of passivation/activation of Mg in body fluids, at a concentration that exceeds its therapeutic threshold. The analytical data that are obtained in the biochemical and histological studies indicate that the proposed Mg@PLGA MPs can effectively mitigate tissue inflammation and prevent cartilage from destruction, arresting the progression of OA changes.

Cold Physical Plasma Reduces Motility of Various Bone Sarcoma Cells While Remodeling the Cytoskeleton.

BACKGROUND/AIM: Cold physical plasma (CPP) has emerged as an effective therapy in oncology by inducing cytotoxic effects in various cancer cells, including chondrosarcoma (CS), Ewing's sarcoma (ES), and osteosarcoma (OS). The current study investigated the impact of CPP on cell motility in CS (CAL-78), ES (A673), and OS (U2-OS) cell lines, focusing on the actin cytoskeleton. MATERIALS AND METHODS: The CASY Cell Counter and Analyzer was used to study cell proliferation and determine the optimal concentrations of fetal calf serum to maintain viability without stimulation of cell proliferation. CellTiter-BlueCell viability assay was used to determine the effects of CPP on the viability of bone sarcoma cells. The Radius assay was used to determine cell migration. Staining for Deoxyribonuclease I, G-actin, and F-actin was used to assay for the effects on the cytoskeleton. RESULTS: Reductions in cell viability and motility were observed across all cell lines following CPP treatment. CPP induced changes in the actin cytoskeleton, leading to decreased cell motility. CONCLUSION: CPP effectively reduces the motility of bone sarcoma cells by altering the actin cytoskeleton. These findings underscore CPP's potential as a therapeutic tool for bone sarcomas and highlight the need for further research in this area.

Hospital Oxygen Supply Overwhelmed Due to COVID-19: When Demand Exceeds Supply.

BACKGROUND: During the first wave of COVID-19, we experienced problems with our hospital oxygen supply system. This study aimed to analyze factors that stressed this system and rethink the design criteria of the gas pipeline system considering the varying oxygen demand. METHODS: A retrospective study was conducted to describe problems that occurred at different stages in the oxygen supply system at our hospital due to increases in oxygen use in general, and the creation of an intermediate respiratory care unit (IRCU) and use of high-flow nasal cannula (HFNC) in particular. Herein, the characteristics and design criteria of the medical gas pipeline system are analyzed, and the steps taken to avoid future problems are outlined. RESULTS: Increases in oxygen use were observed at times of maximum occupancy, and these created vulnerabilities in the oxygen supply due to insufficient capacity in terms of cryogenic tanks, evaporators, and the piping network. The peak consumption was 3 times higher than the peak in the preceding 4 years. The use of HFNC therapy aggravated the problem; IRCU use accounting for as much as two-fifths of the total across the hospital. Steps taken subsequently prevented the recurrence of vulnerabilities. CONCLUSIONS: The design criteria for storage and distribution networks of medical gases in hospitals need to be revised considering new parameters for their implementation and the use of HFNC therapy in an IRCU. In particular, the cryogenic tanks, evaporators, and piping network for hospital wards are critical.

Molecular Hydrogen: an Emerging Therapeutic Medical Gas for Brain Disorders.

Oxidative stress and neuroinflammation are the main physiopathological changes involved in the initiation and progression of various neurodegenerative disorders or brain injuries. Since the landmark finding reported in 2007 found that hydrogen reduced the levels of peroxynitrite anions and hydroxyl free radicals in ischemic stroke, molecular hydrogen's antioxidative and anti-inflammatory effects have aroused widespread interest. Due to its excellent antioxidant and anti-inflammatory properties, hydrogen therapy via different routes of administration exhibits great therapeutic potential for a wide range of brain disorders, including Alzheimer's disease, neonatal hypoxic-ischemic encephalopathy, depression, anxiety, traumatic brain injury, ischemic stroke, Parkinson's disease, and multiple sclerosis. This paper reviews the routes for hydrogen administration, the effects of hydrogen on the previously mentioned brain disorders, and the primary mechanism underlying hydrogen's neuroprotection. Finally, we discuss hydrogen therapy's remaining issues and challenges in brain disorders. We conclude that understanding the exact molecular target, finding novel routes, and determining the optimal dosage for hydrogen administration is critical for future studies and applications.

Medical Gas Therapy for Tissue, Organ, and CNS Protection: A Systematic Review of Effects, Mechanisms, and Challenges.

Gaseous molecules have been increasingly explored for therapeutic development. Here, following an analytical background introduction, a systematic review of medical gas research is presented, focusing on tissue protections, mechanisms, data tangibility, and translational challenges. The pharmacological efficacies of carbon monoxide (CO) and xenon (Xe) are further examined with emphasis on intracellular messengers associated with cytoprotection and functional improvement for the CNS, heart, retina, liver, kidneys, lungs, etc. Overall, the outcome supports the hypothesis that readily deliverable "biological gas" (CO, H2 , H2 S, NO, O2 , O3 , and N2 O) or "noble gas" (He, Ar, and Xe) treatment may preserve cells against common pathologies by regulating oxidative, inflammatory, apoptotic, survival, and/or repair processes. Specifically, CO, in safe dosages, elicits neurorestoration via igniting sGC/cGMP/MAPK signaling and crosstalk between HO-CO, HIF-1α/VEGF, and NOS pathways. Xe rescues neurons through NMDA antagonism and PI3K/Akt/HIF-1α/ERK activation. Primary findings also reveal that the need to utilize cutting-edge molecular and genetic tactics to validate mechanistic targets and optimize outcome consistency remains urgent; the number of neurotherapeutic investigations is limited, without published results from large in vivo models. Lastly, the broad-spectrum, concurrent multimodal homeostatic actions of medical gases may represent a novel pharmaceutical approach to treating critical organ failure and neurotrauma.

Hydrogen sulfide enhances adult neurogenesis in a mouse model of Parkinson's disease.

Hydrogen sulfide (H2S) is regarded to be a protectant against diseases of the central nervous system and cardiovascular system. However, the mechanism by which H2S elicits neuroprotective effects in the progression of Parkinson's disease (PD) remains unclear. To investigate the role of H2S in delaying the pathological process of PD, we used the most common sodium hydrosulfide (NaHS) as an H2S donor and established a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/p) in the present study. Our results show that H2S reduced neuronal loss during the progression of PD. Notably, we found that H2S exhibited protective effects on dopaminergic neurons. Excitingly, H2S also increased the proliferation of neural stem cells in the subventricular zone. Next, we evaluated whether the neuroprotective effects of H2S on dopaminergic neurons in PD are dependent on adult nerve regeneration by treating primary adult neural stem cells cultured ex vivo with 1-methyl-4-phenylpyridine. Our results show that H2S could prevent nerve injury induced by 1-methyl-4-phenylpyridine, promote the growth of neurospheres, and promote neurogenesis by regulating Akt/glycogen synthase kinase-3ß/ß-catenin pathways in adult neural stem cells. These findings confirm that H2S can increase neurogenesis in an adult mouse model of PD by regulating the Akt/glycogen synthase kinase-3ß/ß-catenin signaling pathway. This study was approved by the Animal Care and Use Committee of Nanjing Medical University, China (IACUC Approval No. 1601153-3).

Therapeutic ROS and Immunity in Cancer-The TRIC-21 Meeting.

The first Therapeutic ROS and Immunity in Cancer (TRIC) meeting was organized by the excellence research center ZIK plasmatis (with its previous Frontiers in Redox Biochemistry and Medicine (FiRBaM) and Young Professionals' Workshop in Plasma Medicine (YPWPM) workshop series in Northern Germany) and the excellence research program ONKOTHER-H (Rostock/Greifswald, Germany). The meeting showcased cutting-edge research and liberated discussions on the application of therapeutic ROS and immunology in cancer treatment, primarily focusing on gas plasma technology. The 2-day hybrid meeting took place in Greifswald and online from 15-16 July 2021, facilitating a wide range of participants totaling 66 scientists from 12 countries and 5 continents. The meeting aimed at bringing together researchers from a variety of disciplines, including chemists, biochemists, biologists, engineers, immunologists, physicists, and physicians for interdisciplinary discussions on using therapeutic ROS and medical gas plasma technology in cancer therapy with the four main sessions: "Plasma, Cancer, Immunity", "Plasma combination therapies", "Plasma risk assessment and patients studies", and "Plasma mechanisms and treated liquids in cancer". This conference report outlines the abstracts of attending scientists submitted to this meeting.

Recent advances in the protective role of hydrogen sulfide in myocardial ischemia/reperfusion injury: a narrative review.

Hydrogen sulfide (H2S) is recognized to be a novel mediator after carbon monoxide and nitric oxide in the organism. It can be produced in various mammalian tissues and exert many physiological effects in many systems including the cardiovascular system. A great amount of recent studies have demonstrated that endogenous H2S and exogenous H2S-releasing compounds (such as NaHS, Na2S, and GYY4137) provide protection in many cardiovascular diseases, such as ischemia/reperfusion injury, heart failure, cardiac hypertrophy, and atherosclerosis. In recent years, many mechanisms have been proposed and verified the protective role exhibited by H2S against myocardial ischemia/reperfusion injury, and this review is to demonstrate the protective role of exogenous and endogenous H2S on myocardial ischemia/reperfusion injury.

Hydrogen-induced Neuroprotection in Neonatal Hypoxic-ischemic Encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) remains to be a major cause of morbidity, mortality and severe neurodevelopmental disability in term neonates. Moderate whole body hypothermia is an established, effective neuroprotective therapy to reduce mortality and long-term disability associated with HIE, however, research for adjunct therapies is still warranted to complement the effect of hypothermia. In the last decade, molecular hydrogen emerged as a simple, available, inexpensive substance with advantageous pharmacokinetics to ameliorate hypoxic-ischemic cellular damage. The present review examines the preclinical studies employing hydrogen to combat the deleterious consequences of hypoxic-ischemic insults in rodent and piglet HIE models. Hydrogen exerted unequivocal neuroprotective actions shown by preserved neurovascular function, neuronal viability, and neurocognitive functions in virtually all model species and hypoxic-ischemic insult types tested. Administration of hydrogen started in most studies after the hypoxic-ischemic insult enhancing the translational value of the findings. Among the explored mechanisms of hydrogen-induced neuroprotection, antioxidant, anti- apoptotic and anti-inflammatory effects appeared to be dominant. Unfortunately, the additive neuroprotective effect of hydrogen and therapeutic hypothermia has not yet been demonstrated, thus such studies are warranted to promote the clinical testing of molecular hydrogen as an adjunct neuroprotective treatment of HIE.

A new mechanistic approach for the treatment of chronic neuropathic pain with nitrous oxide integrated from a systems biology narrative review.

The limitations of the currently available treatments for chronic neuropathic pain highlight the need for safer and more effective alternatives. The authors carried out a focused review using a systems biology approach to integrate the complex mechanisms of nociception and neuropathic pain, and to decipher the effects of nitrous oxide (N2O) on those pathways, beyond the known effect of N2O on N-methyl-D-aspartate receptors. This review identified a number of potential mechanisms by which N2O could impact the processes involved in peripheral and central sensitization. In the ascending pathway, the effects of N2O include activating TWIK-related K+ channel 1 potassium channels on first-order neurons, blocking voltage-dependent calcium channels to attenuate neuronal excitability, attenuating postsynaptic glutamatergic receptor activation, and possibly blocking voltage-dependent sodium channels. In the descending pathway, N2O induces the release of endogenous opioid ligands and stimulates norepinephrine release. In addition, N2O may mediate epigenetic changes by inhibiting methionine synthase, a key enzyme involved in DNA and RNA methylation. This could explain why this short-acting analgesic has shown long-lasting anti-pain sensitization effects in animal models of chronic pain. These new hypotheses support the rationale for investigating N2O, either alone or in combination with other analgesics, for the management of chronic neuropathic pain.

Therapeutic antioxidant medical gas.

Medical gases are pharmaceutical gaseous molecules which offer solutions to medical needs and include traditional gases, such as oxygen and nitrous oxide, as well as gases with recently discovered roles as biological messenger molecules, such as carbon monoxide, nitric oxide and hydrogen sulphide. Medical gas therapy is a relatively unexplored field of medicine; however, a recent increasing in the number of publications on medical gas therapies clearly indicate that there are significant opportunities for use of gases as therapeutic tools for a variety of disease conditions. In this article, we review the recent advances in research on medical gases with antioxidant properties and discuss their clinical applications and therapeutic properties.

The role of medical gas in stroke: an updated review.

Medical gas is a large class of bioactive gases used in clinical medicine and basic scientific research. At present, the role of medical gas in neuroprotection has received growing attention. Stroke is a leading cause of death and disability in adults worldwide, but current treatment is still very limited. The common pathological changes of these two types of stroke may include excitotoxicity, free radical release, inflammation, cell death, mitochondrial disorder, and blood-brain barrier disruption. In this review, we will discuss the pathological mechanisms of stroke and the role of two medical gases (hydrogen and hydrogen sulfide) in stroke, which may potentially provide a new insight into the treatment of stroke.

Combined application of hypothermia and medical gases in cerebrovascular diseases.

Cerebrovascular diseases have a heavy burden on society and the family. At present, in the treatment of cerebrovascular diseases, the recognized effective treatment method is a thrombolytic therapy after cerebral infarction, but limited to the time window problem, many patients cannot benefit. Other treatments for cerebrovascular disease are still in the exploration stage. The study found that medical gas and hypothermia have brain protection effects. Further research found that when the two are used in combination, the therapeutic effect has a superimposed effect. This article reviews the current research progress of hypothermia therapy combined with medical gas therapy for cerebrovascular disease.

A physiologically based model for denitrogenation kinetics.

Under normal conditions we continuously breathe 78% nitrogen (N2) such that the body tissues and fluids are saturated with dissolved N2. For normobaric medical gas administration at high concentrations, the N2 concentration must be less than that in the ambient atmosphere; therefore, nitrogen will begin to be released by the body tissues. There is a need to estimate the time needed for denitrogenation in the planning of surgical procedures. In this paper we will describe the application of a physiologically based pharmacokinetic model to denitrogenation kinetics. The results are compared to the data resulting from experiments in the literature that measured the end tidal N2 concentration while breathing 100% oxygen in the form of moderately rapid and slow compartment time constants. It is shown that the model is in general agreement with published experimental data. Correlations for denitrogenation as a function of subject weight are provided.

Failure of a "foolproof" pin-index medical pipeline system.

BACKGROUND: The pin-index medical gas pipeline system, which complies with Japan Industrial Standard (JIS), is considered to be "foolproof" and is widely used in Japan to avoid medical gas misconnections. CASE PRESENTATION: The wall-mounted gas outlet used in our hospital (NSV outlet, CENTRAL UNI, Co., Ltd., Tokyo, Japan) contains multiple sockets, which connect to hoses with gas-specific pins. Each socket is covered with a gas-specific plastic pin guide, which is considered to make the system foolproof; i.e., to prevent misconnections. However, while checking an anesthesia machine in accordance with the guidelines developed by the Japanese Society of Anesthesiologists, an anesthesiologist found that one of the gas-specific plastic pin guides covering the wall-mounted gas outlets had disappeared; and hence, the gas outlet system was no longer foolproof. A subsequent verification test performed by engineers of the system's manufacturer revealed that the plastic pin guides could be dislodged by applying 29.4 N of vertical force. CONCLUSIONS: It is important to check that gas outlet systems are functioning in a gas-specific manner when they are used for clinical purposes.