The use of ozone (O₃) gas as a therapy in alternative medicine has attracted skepticism due to its unstable molecular structure. However, copious volumes of research have provided evidence that O₃'s dynamic resonance structures facilitate physiological interactions useful in treating a myriad of pathologies. Specifically, O₃ therapy induces moderate oxidative stress when interacting with lipids. This interaction increases endogenous production of antioxidants, local perfusion, and oxygen delivery, as well as enhances immune responses. We have conducted a comprehensive review of O₃ therapy, investigating its contraindications, routes and concentrations of administration, mechanisms of action, disinfectant properties in various microorganisms, and its medicinal use in different pathologies. We explore the therapeutic value of O₃ in pathologies of the cardiovascular system, gastrointestinal tract, genitourinary system, central nervous system, head and neck, musculoskeletal, subcutaneous tissue, and peripheral vascular disease. Despite compelling evidence, further studies are essential to mark it as a viable and quintessential treatment option in medicine.

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Stroke is considered to be an acute cerebrovascular disease, including ischemic stroke and hemorrhagic stroke. The high incidence and poor prognosis of stroke suggest that it is a highly disabling and highly lethal disease which can pose a serious threat to human health. Nitric oxide (NO), a common gas in nature, which is often thought as a toxic gas, because of its intimate relationship with the pathological processes of many diseases, especially in the regulation of blood flow and cell inflammation. However, recent years have witnessed an increased interest that NO plays a significant and positive role in stroke as an essential gas signal molecule. In view of the fact that the neuroprotective effect of NO is closely related to its concentration, cell type and time, only in the appropriate circumstances can NO play a protective effect. The purpose of this review is to summarize the roles of NO in ischemic stroke and hemorrhagic stroke.

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Hydrogen sulfide (H₂S) has been recognized and studied for nearly 300 years, but past researches mainly focus on its toxicity effect. During the past two decades, the majority of researches have reported that H₂S is a novel endogenous gaseous signal molecule in organisms, and play an important role in various systems and diseases. H₂S is mainly produced by three enzymes, including cystathionine β-synthase, cystathionine γ-lyase and 3-mercaptopyruvate sulfurtransferase along with cysteine aminotransferase. H₂S had been firstly reported as a neuromodulator in the brain, because of its essential role in the facilitating hippocampal long-term potentiation at physiological concentration. It is subsequently reported that H₂S may have relevance to neurologic disorders through antioxidative, anti-inflammatory, anti-apoptotic and additional effects. Recent basic medical studies and preclinical studies on neurologic diseases have demonstrated that the administration of H₂S at physiological or pharmacological levels attenuates brain injury. However, the neuroprotective effect of H₂S is concentration-dependent, only a comparatively low dose of H₂S can provide beneficial effect. Herein, we review the neuroprotevtive role of H₂S therapy in brain diseases from its mechanism to clinical application in animal and human subjects, and therefore provide the potential strategies for further clinical treatment.

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Molecular hydrogen (H₂ ) medicine research has flourished since a landmark publication in Nature Medicine that revealed the antioxidant and cytoprotective effects of hydrogen gas in a focal stroke model. Emerging evidence has consistently demonstrated that molecular hydrogen is a promising therapeutic option for a variety of diseases and the underlying comprehensive mechanisms is beyond pure hydroxyl radicals scavenging. The non-toxicity at high concentrations and rapid cellular diffusion features of molecular hydrogen ensure the feasibility and readiness of its clinical translation to human patients.

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Isoflurane, a volatile and inhalational anesthetic, has been extensively used in perioperative period for several decades. A large amount of experimental studies have indicated that isoflurane exhibits neuroprotective properties when it is administrated before or after (pre-conditioning and post-conditioning) neurodegenerative diseases (e.g., hypoxic ischemia, stroke and trauma). Multiple mechanisms are involved in isoflurane induced neuroprotection, including activation of glycine and γ-aminobutyric acid receptors, antagonism of ionic channels and alteration of the function and activity of other cellular proteins. Although neuroprotection provided by isoflurane is observed in many animal studies, convincing evidence is lacking in human trials. Therefore, there is still a long way to go before translating its neuroprotective properties into clinical practice.

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Spinal cord injury (SCI) is a complex disease process that involves both primary and secondary mechanisms of injury and can leave patients with devastating functional impairment as well as psychological debilitation. While no curative treatment is available for spinal cord injury, current therapeutic approaches focus on reducing the secondary injury that follows SCI. Hyperbaric oxygen (HBO) therapy has shown promising neuroprotective effects in several experimental studies, but the limited number of clinical reports have shown mixed findings. This review will provide an overview of the potential mechanisms by which HBO therapy may exert neuroprotection, provide a summary of the clinical application of HBO therapy in patients with SCI, and discuss avenues for future studies.

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Stroke, which is defined as a neurologic deficit caused by sudden impaired blood supply, has been considered as a common cause of death and disability for decades. The World Health Organization has declared that almost every 5 seconds a new stroke occurs, placing immense socioeconomic burdens. However, the effective and available treatment strategies are still limited. Additionally, the most effective therapy, such as thrombolysis and stenting for ischemic stroke, generally requires a narrow therapeutic time window after the event. A large majority of patients cannot be admitted to hospital and receive these effective treatments for reperfusion timely. Hyperbaric oxygen therapy (HBOT) has been frequently applied and investigated in stroke since 1960s. Numerous basic and clinical studies have shown the beneficial efficacy for neurological outcome after stroke, and meanwhile many underlying mechanisms associated with neuroprotection have been illustrated, such as cerebral oxygenation promotion and metabolic improvement, blood-brain barrier protection, anti-inflammation and cerebral edema, intracranial pressure modulation, decreased oxidative-stress and apoptosis, increased vascular and neural regeneration. However, HBOT in human stroke is still not sufficiently evidence-based, due to the insufficient randomized double-blind controlled clinical studies. To date, there are no uniform criteria for the dose and session duration of HBOT in different strokes. Furthermore, the additional effect of HBOT combined with drugs and other treatment strategies are being investigated recently. Therefore, more experimental and clinical research is imperative to identify the mechanisms more clearly and to explore the best protocol of HBOT in stroke treatment.

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Oxygen-ozone (O₃) therapy serves as an alternative medical technique that increases the oxygen in the body along with the introduction of O₃. O₃ therapy has finally reached a level where the biological mechanisms of action have been understood, showing that they are in the domain of physiology, biochemistry, and pharmacology. Few clinical applications have been reviewed here as well as exemplifying that O₃ therapy is particularly useful in musculoskeletal disorders. In the therapeutic range, O₃ can be used as a more effective and safe substitute of standard medications. O₃ therapy has been used for many years for its ability to inactivate various viruses, cancer, and acquired immune deficiency syndrome but is now making strides in the treatment of musculoskeletal disorders such as rheumatoid arthritis, lumbar facet joint syndrome, subacromial bursitis, carpal tunnel syndrome, osteoarthritis, hip bursitis, shoulder adhesive capsulitis, herniated disc, and temporomandibular joint disorder.

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Traumatic brain injury (TBI) is a serious public health problem in the United States. Survivors of TBI are often left with significant cognitive, behavioral, and communicative disabilities. So far there is no effective treatment/intervention in the daily clinical practice for TBI patients. The protective effects of hyperbaric oxygen therapy (HBOT) have been proved in stroke; however, its efficiency in TBI remains controversial. In this review, we will summarize the results of HBOT in experimental and clinical TBI, elaborate the mechanisms, and bring out our current understanding and opinions for future studies.

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Ozone is a highly reactive compound composed of three oxygen atoms that acts as an oxidant and oxidizer. It exists at the ground level as an air pollutant and a constituent of urban smog, as well as in the Earth’s upper atmosphere as a protective layer from ultraviolet rays. Healthy cells contain antioxidants such as vitamins C and E to protect against ozone oxidization. However, pathogens such as bacteria contain very trace amounts of antioxidants in their membranes, which make them susceptible to ozone and destroy the cell membrane. This review explores the history, composition, and use of ozone worldwide in dentistry. Ozone therapy has thus far been utilized with wound healing, dental caries, oral lichen planus, gingivitis and periodontitis, halitosis, osteonecrosis of the jaw, post-surgical pain, plaque and biofilms, root canals, dentin hypersensitivity, temporomandibular joint disorders, and teeth whitening. The utility of ozone will undoubtedly grow if studies continue to show positive outcomes in an increasing number of dental conditions.

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Hyposmia is one of the earliest and the most common symptoms in Parkinson’s disease (PD). The benefits of hydrogen water on motor deficits have been reported in animal PD models and PD patients, but the effects of hydrogen gas on PD patients have not been studied. We evaluated the effect of inhalation of hydrogen gas on olfactory function, non-motor symptoms, activities of daily living, and urinary 8-hydroxy-2′-deoxyguanine (8-OHdG) levels by a randomized, double-blinded, placebo-controlled, crossover trial with an 8-week washout period in 20 patients with PD. Patients inhaled either ~1.2–1.4% hydrogen-air mixture or placebo for 10 minutes twice a day for 4 weeks. Inhalation of low dose hydrogen did not significantly influence the PD clinical parameters, but it did increase urinary 8-OHdG levels by 16%. This increase in 8-OHdG is markedly less than the over 300% increase in diabetes, and is more comparable to the increase after a bout of strenuous exercise. Although increased reactive oxygen species is often associated with toxicity and disease, they also play essential roles in mediating cytoprotective cellular adaptations in a process known as hormesis. Increases of oxidative stress by hydrogen have been previously reported, along with its ability to activate the Nrf2, NF-κB pathways, and heat shock responses. Although we did not observe any beneficial effect of hydrogen in our short trial, we propose that the increased 8-OHdG and other reported stress responses from hydrogen may indicate that its beneficial effects are partly or largely mediated by hormetic mechanisms. The study was approved by the ethics review committee of Nagoya University Graduate School of Medicine (approval number 2015-0295). The clinical trial was registered at the University Hospital Medical Information Network (identifier UMIN000019082).

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Cerebral ischemic stroke is a leading cause of serious long-term disability and cognitive dysfunction. The high mortality and disability of cerebral ischemic stroke is urging the health providers, including anesthesiologists and other perioperative professioners, to seek effective protective strategies, which are extremely limited, especially for those perioperative patients. Intriguingly, several commonly used inhalational anesthetics are recently suggested to possess neuroprotective effects against cerebral ischemia. This review introduces multiple paradigms of inhalational anesthetic treatments that have been investigated in the setting of cerebral ischemia, such as preconditioning, proconditioning and postconditioning with a variety of inhalational anesthetics. The pleiotropic mechanisms underlying these inhalational anesthetics-afforded neuroprotection against stroke are also discussed in detail, including the common pathways shared by most of the inhalational anesthetic paradigms, such as anti-excitotoxicity, anti-apoptosis and anti-inflammation. There are also distinct mechanisms involved in specific paradigms, such as preserving blood brain barrier integrity, regulating cerebral blood flow and catecholamine release. The ready availability of these inhalational anesthetics bedside and renders them a potentially translatable stroke therapy attracting great efforts for understanding of the underlying mechanisms.

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Glioblastoma multiforme (GBM) is the most common type of malignant intracranial tumor in adults. Tumor tissue hypoxia, high mitotic rate, and rapid tumor spread account for its poor prognosis. Hyperbaric oxygen therapy (HBOT) may improve the sensitivity of radio-chemotherapy by increasing oxygen tension within the hypoxic regions of the neoplastic tissue. This review summarizes the research of HBOT applications within the context of experimental and clinical GBM. Limited clinical trials and preclinical studies suggest that radiotherapy immediately after HBOT enhances the effects of radiotherapy in some aspects. HBOT also is able to strengthen the anti-tumor effect of chemotherapy when applied together. Overall, HBOT is well tolerated in the GBM patients and does not significantly increase toxicity. However, HBOT applied by itself as curative strategy against GBM is controversial in preclinical studies and has not been evaluated rigorously in GBM patients. In addition to HBOT favorably managing the therapeutic resistance of GBM, future research needs to focus on the multimodal or cocktail approaches to treatment, as well as molecular strategies targeting GBM stem cells.

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Health and a vibrant life are sought by everyone. To improve quality of life (QOL), maintain a healthy state, and prevent various diseases, evaluations of the effects of potentially QOL-increasing factors are important. Chronic oxidative stress and inflammation cause deteriorations in central nervous system function, leading to low QOL. In healthy individuals, aging, job stress, and cognitive load over several hours also induce increases in oxidative stress, suggesting that preventing the accumulation of oxidative stress caused by daily stress and daily work contributes to maintaining QOL and ameliorating the effects of aging. Hydrogen has anti-oxidant activity and can prevent inflammation, and may thus contribute to improve QOL. The present study aimed to investigate the effects of drinking hydrogen-rich water (HRW) on the QOL of adult volunteers using psychophysiological tests, including questionnaires and tests of autonomic nerve function and cognitive function. In this double-blinded, placebo-controlled study with a two-way crossover design, 26 volunteers (13 females, 13 males; mean age, 34.4 ± 9.9 years) were randomized to either a group administered oral HRW (600 mL/d) or placebo water (PLW, 600 mL/d) for 4 weeks. Change ratios (post-treatment/pre-treatment) for K6 score and sympathetic nerve activity during the resting state were significantly lower after HRW administration than after PLW administration. These results suggest that HRW may reinforce QOL through effects that increase central nervous system functions involving mood, anxiety, and autonomic nerve function.

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Acute ischemic stroke is a common and serious neurological disease. Oxygen therapy has been shown to increase oxygen supply to ischemic tissues and improve outcomes after cerebral ischemia/reperfusion. Normobaric hyperoxia (NBO), an easily applicable and non-invasive method, shows protective effects on acute ischemic stroke animals and patients in pilot studies. However, many critical scientific questions are still unclear, such as the therapeutic time window of NBO, the long-term effects and the benefits of NBO in large clinic trials. In this article, we review the current literatures on NBO treatment of acute ischemic stroke in preclinical and clinical studies and try to analyze and identify the key gaps or unknowns in our understanding about NBO. Based on these analyses, we provide suggestions for future studies.

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Clinical and pre-clinical studies have reported a broad range of applications for hydrogen gas therapy. Classically, conventional antioxidant therapy is limited because it neutralizes both the detrimental and protective effects of reactive oxygen species. As a weak reducing agent, hydrogen gas avoids this paradox by reacting with strong oxidants while leaving other beneficial oxidants reactive. This review gathers a promising list of hydrogen gas applications that merit further mechanistic investigation and additional therapeutic trials. Reports support the ability of hydrogen gas to downregulate the expression of pro-inflammatory cytokines and pro-apoptotic factors. Mechanistically, hydrogen gas has been shown to downregulate miR-9 and miR-21, while upregulating miR-199 to reduce inflammatory injury. In angiogenic pathways, hydrogen’s inhibition of cyclic guanosine monophosphate-degrading phosphodiesterase led to higher levels of cyclic guanosine monophosphate, activation of protein kinase, and angiogenesis; next, as hydrogen gas increased the levels of intracellular calcium, stimulated vascular endothelial growth factor increased nitric oxide production. In conjunction, hydrogen gas opened adenosine triphosphate-sensitive potassium channel channels, which activate downstream mitogen-activated protein kinase pathways. Growing molecular mechanisms have discovered a plethora of downstream targets for hydrogen gas therapy that include autophagy (via the adenosine 5’-monophosphate-activated protein kinase/mammalian target of rapamycin pathway), histone modification, mitochondrial unfolded protein response, acute oxidative stress after exercise, and oxidative stress secondary to aging. In conclusion, evolving research has discovered novel molecular connections that will continue to widen applications for hydrogen therapy.

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Mild traumatic brain injury (TBI) persistent post-concussion syndrome (PPCS) and post-traumatic stress disorder (PTSD) are epidemic in United States Iraq and Afghanistan War veterans. Treatment of the combined diagnoses is limited. The aim of this study is to assess safety, feasibility, and effectiveness of hyperbaric oxygen treatments (HBOT) for mild TBI PPCS and PTSD. Thirty military subjects aged 18–65 with PPCS with or without PTSD and from one or more blast-induced mild-moderate traumatic brain injuries that were a minimum of 1 year old and occurred after 9/11/2001 were studied. The measures included symptom lists, physical exam, neuropsychological and psychological testing on 29 subjects (1 dropout) and SPECT brain imaging pre and post HBOT. Comparison was made using SPECT imaging on 29 matched Controls. Side effects (30 subjects) experienced due to the HBOT: reversible middle ear barotrauma (n = 6), transient deterioration in symptoms (n = 7), reversible bronchospasm (n = 1), and increased anxiety (n = 2; not related to confinement); unrelated to HBOT: ureterolithiasis (n = 1), chest pain (n = 2). Significant improvement (29 subjects) was seen in neurological exam, symptoms, intelligence quotient, memory, measures of attention, dominant hand motor speed and dexterity, quality of life, general anxiety, PTSD, depression (including reduction in suicidal ideation), and reduced psychoactive medication usage. At 6-month follow-up subjects reported further symptomatic improvement. Compared to Controls the subjects' SPECT was significantly abnormal, significantly improved after 1 and 40 treatments, and became statistically indistinguishable from Controls in 75% of abnormal areas. HBOT was found to be safe and significantly effective for veterans with mild to moderate TBI PPCS with PTSD in all four outcome domains: clinical medicine, neuropsychology, psychology, and SPECT imaging. Veterans also experienced a significant reduction in suicidal ideation and reduction in psychoactive medication use.

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A 58-year-old female was diagnosed with Alzheimer’s dementia (AD) which was rapidly progressive in the 8 months prior to initiation of hyperbaric oxygen therapy (HBOT). ¹⁸Fluorodeoxyglucose (¹⁸FDG) positron emission tomography (PET) brain imaging demonstrated global and typical metabolic deficits in AD (posterior temporal-parietal watershed and cingulate areas). An 8-week course of HBOT reversed the patient’s symptomatic decline. Repeat PET imaging demonstrated a corresponding 6.5–38% regional and global increase in brain metabolism, including increased metabolism in the typical AD diagnostic areas of the brain. Continued HBOT in conjunction with standard pharmacotherapy maintained the patient’s symptomatic level of function over an ensuing 22 months. This is the first reported case of simultaneous HBOT-induced symptomatic and ¹⁸FDG PET documented improvement of brain metabolism in AD and suggests an effect on global pathology in AD.

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Mitochondrial dysfunctions are characteristic features of numerous diseases and play a critical role in disease pathogenesis. Despite intensive research in this area, there are no approved therapies that directly target mitochondria. Recently a study by Jain et al. from Massachusetts General Hospital, USA reported the effectiveness of hypoxia for treatment of mitochondrial disease in mice. In this commentary, we summarized the potential mechanisms underlying the therapeutic effects of hypoxia on mitochondrial dysfunction, and clinical limitations of hypoxia as a therapy for human patients. We hope that our concerns will be helpful for further clinical studies addressing moderate hypoxia in mitochondrial dysfunction.

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This study aimed to investigate the protective effects of hydrogen rich water on the intestinal ischemia/reperfusion (I/R) injury in a rat intestinal intussusception (II) model. Ninety Sprague-Dawley rats were randomly assigned into three groups (n = 30 per group). In sham group, rats received laparotomy, and the intestine was exposed for 15 minutes without II. In I/R + saline group and I/R + hydrogen group, rats received II after laparotomy and then intestine was relocated 8 hours later, followed by immediately intraperitoneal injection of normal saline and hydrogen rich water (HRW) (5 mL/kg), respectively. One hour later, the intestine was collected for hematoxylin-eosin staining and immunohistochemistry for apoptotic cells and 8-oxo-deoxyguanosine, and blood was harvested for detection of tumor necrosis factor-a, malondialdehyde and superoxide dismutase. Hematoxylin-eosin staining showed the intestinal mucosa was significantly damaged in I/R + saline group, which was markedly attenuated after HRW treatment. The serum tumor necrosis factor-α content increased significantly in I/R + saline group, but HRW treatment reduced serum tumor necrosis factor-α content as compared to I/R + saline group (P < 0.05). Serum malondialdehyde content and 8-oxo-deoxyguanosine positive cells in the intestine increased dramatically after II, but HRW significantly reduced them in I/R+hydrogen group (P < 0.05). In addition, superoxide dismutase activity reduced markedly and apoptotic cells increased in I/R + saline group as compared to sham group, but they HRW increased superoxide dismutase activity and reduced apoptotic cells significantly in I/R + hydrogen group (P < 0.05). Our results indicate hydrogen rich water is able to attenuate II induced intestinal I/R injury via inhibiting intestinal inflammation, attenuating intestinal/serum oxidative stress and reducing apoptotic intestinal cells.

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Increasing evidence indicates that molecular hydrogen-dissolved alkaline electrolyzed water (AEW) has various physiological activities such as antioxidative activity. Gut microbiota are deeply associated with our health through a symbiotic relationship. Recent reports have described that most gastrointestinal microbial species encode the genetic capacity to metabolize molecular hydrogen, meaning that molecular hydrogen might affect the gut microbial composition. Nevertheless, AEW effects on gut microbiota remain unknown. This study investigated AEW effects on the intestinal environment in mice, including microbial composition and short-chain fatty acid contents. After mice were administered AEW for 4 weeks, 16S rRNA gene sequencing analyses revealed their fecal microbiota profiles. Organic acid concentrations in cecal contents were measured using an HPLC system. Compared to the control group, AEW administration mice had significantly lower serum low-density lipoprotein cholesterol level and alanine aminotransferase activity. Organic acid concentrations of propionic, isobutyric, and isovaleric acids were higher in AEW-administered mice. Results of 16S rRNA gene sequencing analyses showed that the relative abundances of 20 taxa differed significantly in AEW-administered mice. Although the definitive role of gut microbes of AEW-administered mice remains unknown, our data demonstrate the possibility that AEW administration affects the gut microbial composition and that it has beneficial health effects in terms of cholesterol metabolism and liver protection.

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Globins are globular proteins for either transport or storage of oxygen which are critical for cellular metabolism. Four globins have been identified in rodent and human brains. Among them, neuroglobin, cytoglobin and hemoglobin chains are constitutively expressed in normal brain, while myoglobin is only expressed in some neurological disorders. Studies on the molecular structure, expression and functional features of these brain globins indicated that they may play crucial roles in maintenance of neural cell survival and activity, including neurons and astrocytes. Their regulation in neurological disorders may help thoroughly understand initiation and progression of ischemia, Alzheimer's disease and glioma, etc. Elucidation of the brain globin functions might remarkably improve medical strategies that sustain neurological homeostasis and treat neurological diseases. Here the expression pattern and functions of brain globins and their involvement in neurological disorders are reviewed.

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Because inhaled carbon monoxide (CO) provides potent anti-inflammatory and antioxidant effects against ischemia reperfusion injury, we hypothesized that treatment of organ donors with inhaled CO would decrease graft injury after heart transplantation. Hearts were heterotopically transplanted into syngeneic Lewis rats after 8 hours of cold preservation in University of Wisconsin solution. Donor rats were exposed to CO at a concentration of 250 parts per million for 24 hours via a gas-exposure chamber. Severity of myocardial injury was determined by total serum creatine phosphokinase and troponin I levels at three hours after reperfusion. In addition, Affymetrix gene array analysis of mRNA transcripts was performed on the heart graft tissue prior to implantation. Recipients of grafts from CO-exposed donors had lower levels of serum troponin I and creatine phosphokinase; less upregulation of mRNA for interleukin-6, intercellular adhesion molecule-1, and tumor necrosis factor-α; and fewer infiltrating cells. Although donor pretreatment with CO altered the expression of 49 genes expressly represented on the array, we could not obtain meaningful data to explain the mechanisms by which CO potentiated the protective effects.Pretreatment with CO gas before organ procurement effectively protected cardiac grafts from ischemia reperfusion-induced injury in a rat heterotopic cardiac transplant model. A clinical report review indicated that CO-poisoned organ donors may be comparable to non-poisoned donors.

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It has been confirmed that inflammation plays an important role in the pathogenesis of ischemic stroke. The polarization of microglia as an important participant in the inflammation following stroke is also found to be involved in stroke. This study aimed to investigate the effects of hydrogen gas on the polarization of macrophages/microglia in vitro. Raw264.7 cells were treated with lipopolysaccharides and then exposed to hydrogen. The microglia were treated with the supernatant from oxygen and glucose deprivation-treated neurons and then exposed to hydrogen. The phenotypes of Raw 264.7 cells and microglia were determined by flow cytometry, and cell morphology was observed. Results showed lipopolysaccharides significantly increased the M1 macrophages, and the supernatant from oxygen and glucose deprivation-treated neurons dramatically elevated the proportion of M1 microglia, but both treatments had little influence on the M2 cells. In addition, hydrogen treatment significantly inhibited the increase in M1 cells, but had no influence on M2 ones. Our findings suggest that the neuroprotection of hydrogen may be related to its regulation of microglia in the nervous system after stroke.

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