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1.  Stimulation of human damaged sperm motility with hydrogen molecule 
Background
Sperm motility is a critical factor in male fertility. Low motility can be caused by a variety factors including abnormal spermatogenesis, oxidative damage, or depletion of intracellular ATP. Recent findings indicate that hydrogen molecule (H2) selectively reduces toxic reactive oxygen species. In this study, we investigated the effects of H2 on human sperm motility in vitro.
Methods
Experimentally damaged sperm suspensions from patients left at room temperature for > 5 days or frozen immediately after ejaculation were used. After exposure with H2, their forward motility was measured with a counting chamber. A time-lapse movie was recorded to analyze sperm swimming speed. Mitochondria were stained with a membrane potential-sensitive dye.
Results
H2 treatment significantly improved the rate of forward motility, whereas treatment with nitrogen gas did not. While treatment for 30 min was sufficient to improve motility, it did not affect sperm swimming speed. After 24 h, retreatment with H2 increased the motility again. H2 treatment also increased mitochondrial membrane potential. Forward motility of low motile frozen-thawed sperm from patients significantly improved with cleavage medium containing H2.
Conclusions
Our results illustrated that H2 treatment stimulates low sperm motility. H2 is a new promising tool for male infertility treatments.
doi:10.1186/s13618-014-0023-x
PMCID: PMC4300028  PMID: 25649433
Frozen-thawed sperm; Hydrogen molecule; Male infertility; Mitochondria; Sperm motility
2.  Exogenous hydrogen sulfide mitigates the fatty liver in obese mice through improving lipid metabolism and antioxidant potential 
Background
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. Hydrogen sulfide (H2S) plays an important role in physiology and pathophysiology of liver. However, whether exogenous H2S could mitigate the hepatic steatosis in mice remains unclear. The aim of this study is to evaluate the effects of H2S on fatty liver.
Methods
C57BL/6 mice were fed with either a high-fat diet (HFD) or a normal fat diet (NFD) for 16 weeks. After 12 weeks of feeding, the HFD-fed mice were injected one time per day with NaHS or saline for the followed 4 weeks.
Results
Compared to NFD, HFD could induce an accumulation of lipids in liver and a damage of hepatic structure. Compared to saline treatment, in the liver of HFD fed mice H2S treatment could significantly (1) recover the structure; (2) decrease the accumulation of lipids including triglyceride (TG) and total cholesterol (TC); (3) decrease the expression of fatty acid synthase (FAS) and increase the expression of carnitine palmitoyltransferase-1 (CPT-1); (4) reduce malondialdehyde (MDA) levels; (5) increase the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx).
Conclusion
H2S could mitigate the fatty liver by improving lipid metabolism and antioxidant potential in HFD-induced obese mice.
doi:10.1186/s13618-014-0022-y
PMCID: PMC4299593  PMID: 25606341
Hydrogen sulfide; Fatty liver; Mitigation; Lipid metabolism; Antioxidant
3.  Argon prevents the development of locomotor sensitization to amphetamine and amphetamine-induced changes in mu opioid receptor in the nucleus accumbens 
Medical Gas Research  2014;4(1):21.
Systemic administration of γ-amino-butyric acid type A (GABA-A) and benzodiazepine receptor agonists has been reported to block the development of locomotor sensitization to amphetamine. Here, we investigated whether the non-anesthetic noble gas argon, shown to possess agonistic properties at these receptors, may block the acquisition of amphetamine-induced locomotor sensitization and mu opioid receptor activation in the nucleus accumbens. Rats were pretreated with saline solution or amphetamine (1 mg/kg) from day 1 to day 3 and then exposed, immediately after injection of amphetamine, to medicinal air or argon at 75 vol% (with the remainder being oxygen). After a 3-day period of withdrawal, rats were challenged with amphetamine on day 7. Rats pretreated with amphetamine and argon had lower locomotor activity (U = 5, P < 0.005) and mu opioid receptor activity in the nucleus accumbens (U = 0, P < 0.001) than rats pretreated with amphetamine and air. In contrast, argon had effect on locomotor and mu receptor activity neither in rats pretreated with saline and challenged with amphetamine (acute amphetamine) nor in rats pretreated and challenged with saline solution (controls). These results indicate that argon inhibits the development of both locomotor sensitization and mu opioid receptor activation induced by repeated administration of amphetamine.
doi:10.1186/s13618-014-0021-z
PMCID: PMC4299783  PMID: 25606340
Amphetamine; Locomotor sensitization; GABA; Benzodiazepine; Argon; Noble gases
4.  Hydrogen sulfide provides cardioprotection against myocardial/ischemia reperfusion injury in the diabetic state through the activation of the RISK pathway 
Medical Gas Research  2014;4(1):20.
Background
Coronary artery disease remains the principal cause of death in patients with diabetes mellitus. Diabetic mice display exacerbated injury following myocardial ischemia-reperfusion (MI/R) and are resistant to most therapeutic interventions. We have reported that sodium sulfide (Na2S) therapy confers cardioprotection during MI/R in non-diabetic mice. Here we tested the hypothesis that Na2S therapy would limit the extent of myocardial injury following MI/R when administered at the time of reperfusion.
Methods and results
Diabetic mice (db/db, 12 weeks of age) were subjected to transient myocardial ischemia for a period of 30 minutes followed by reperfusion up to 24 hours. Na2S (0.05 to 1 mg/kg) or saline (vehicle) was administered into the left ventricular lumen at the time of reperfusion. Na2S therapy significantly decreased myocardial injury in the db/db diabetic mouse, as evidenced by a reduction in infarct size and circulating troponin-I levels. The reduction in myocardial injury was also associated with a reduction in oxidative stress and a decrease in cleaved caspase-3 expression. In an effort to evaluate the signaling mechanism responsible for the observed cardioprotection, additional groups of mice were sacrificed during early reperfusion. Hearts were excised and processed for Western blot analysis. These studies revealed that Na2S therapy activated the Erk1/2 arm of the Reperfusion Injury Salvage Kinase (RISK) pathway.
Conclusion
These findings provide important information that myocardial Erk1/2 activation by Na2S therapy following MI/R sets into motion events, which ultimately lead to cardioprotection in the setting of diabetes.
doi:10.1186/s13618-014-0020-0
PMCID: PMC4269946  PMID: 25525500
Diabetes; Cardioprotection; Hydrogen sulfide; RISK pathway; Myocardial Ischemia-reperfusion injury
5.  Review and prospect of the biomedical effects of hydrogen 
Medical Gas Research  2014;4(1):19.
Hydrogen, the simplest gas in nature, was recently reported as a therapeutic antioxidant through selectively reducing cytotoxic oxygen radicals. Though hundreds of studies on curative effects of hydrogen were published and justified, the mechanism remains unclear. We proposed several promising directions in this area by relatively in-depth analysis. Firstly, the physiological function of hydrogen was regarded neutralizing free radicals at a low dose; however, physiological effects of an excessive dose of hydrogen were necessary for the comprehensive understanding. Secondly, the therapeutic effects and mechanisms were explained by anti-oxidative, anti-inflammatory and apoptosis ways, while the limitation was obvious and needed update. Thirdly, further studies might be focused on the possible networks including effecters and receptors of hydrogen, and the evolutionary perspective was a good point of view. In conclusion, this review might be a reference and guidance for relative scholars.
doi:10.1186/s13618-014-0019-6
PMCID: PMC4256831  PMID: 25485090
Hydrogen; Antioxidant; Reactive oxygen species; Inflammatory; Apoptosis; Necrosis; Physiological effect
6.  Progress in the study of biological effects of hydrogen on higher plants and its promising application in agriculture 
Medical Gas Research  2014;4:15.
While the medical effects of hydrogen have been broadly analyzed, research into the effects of hydrogen on higher plants has often been of lesser concern. Recent studies on the botanical effects of hydrogen have shown that it is involved in signal transduction pathways of plant hormones and can improve the resistance of plants to stressors, such as drought, salinity, cold and heavy metals. In addition, hydrogen could delay postharvest ripening and senescence of fruits. Observational evidence has also shown that hydrogen can regulate the flowering time of plants. These results indicate that hydrogen may have great potential applications within agricultural production, indicating that there may be a new ‘hydrogen agricultural era’ to come.
doi:10.1186/2045-9912-4-15
PMCID: PMC4177722  PMID: 25276344
7.  Extended normobaric hyperoxia therapy yields greater neuroprotection for focal transient ischemia-reperfusion in rats 
Medical Gas Research  2014;4:14.
Background
Normobaric hyperoxia (NBO) therapy is neuroprotective in acute ischemic stroke. However, how long the NBO should last to obtain optimal outcome is still unclear. Reports show that ischemic penumbra blood supply may remain compromised for a long period after ischemia-reperfusion, which would impair tissue oxygenation in ischemic penumbra. Therefore, we hypothesized that longer-lasting NBO may yield greater neuroprotection.
Methods
The relationship between treatment outcome and NBO duration was examined in this study. Rats were subjected to 90 min middle cerebral artery occlusion followed by reperfusion for 22.5 hours. NBO started at 30 min post ischemia and lasted for 2, 4 or 8 h. Treatment efficacy was evaluated by measuring infarction volume, oxidative stress and apoptosis.
Results
Among 2 h, 4 h and 8 h NBO, 8 h NBO offered the greatest efficacy in reducing 24-hour infarction volume, attenuating oxidative stress that was indicated by decreased production of 8-hydroxydeoxyguanosine and NADPH oxidase catalytic subunit gp91phox, and alleviating apoptosis that was associated with reduced production of DNA fragment and caspase-3 activity in cortex penumbra.
Conclusions
Under our experimental conditions, longer duration of NBO treatment produced greater benefits in focal transient cerebral ischemia-reperfusion rats.
doi:10.1186/2045-9912-4-14
PMCID: PMC4149308  PMID: 25177481
Apoptosis; Ischemic stroke; Normobaric hyperoxia; Oxidative stress; Tissue oxygenation
8.  Can carbon monoxide-poisoned victims be organ donors? 
Medical Gas Research  2014;4:13.
The increasing demand for organ allografts to treat end-stage organ failure has driven changes in traditional donor criteria. Patients who have succumbed to carbon monoxide (CO) poisoning, a common cause of toxicological mortality, are usually rejected as organ donors. To fulfill the increasing demand, selection criteria must be expanded to include CO-poisoned donors. However, the use of allografts exposed to high CO concentrations is still under debate. Basic research and literature review data suggest that patients with brain death caused by CO poisoning should be considered appropriate organ donors. Accepting organs from CO-poisoned victims could increase the number of potential donors and lower the death rate of patients on the waiting lists. This review and reported cases may increase awareness among emergency department physicians, as well as transplant teams, that patients dying of CO exposure may be acceptable organ donors.
doi:10.1186/2045-9912-4-13
PMCID: PMC4121619  PMID: 25097755
9.  Hyperbaric oxygen therapy fails to reduce hydrocephalus formation following subarachnoid hemorrhage in rats 
Medical Gas Research  2014;4:12.
Background & purpose
Approximately 40% of hemorrhagic stroke survivors develop hydrocephalus. Hyperbaric oxygen (HBO) has been shown to be anti-inflammation following experimental stroke; however, its effect upon post-hemorrhagic hydrocephalus formation is not known. The objective of this study is to investigate whether HBO therapy can effectively reduce hydrocephalus formation and improve neurobehavioral functions in a rat model of subarachnoid hemorrhage (SAH).
Method
Thirty-eight male Sprague–Dawley rats (300-320 g) rats survived for 21 days from SAH by endovascular perforation or sham surgery were used. At 24 hours after SAH, HBO (3 atmospheres absolute) or normobaric oxygen (NBO) administrated for 1 hour once daily for a total of 7 days. Wire hanging and rotarod testing were conducted at 14 days after SAH, and cognitive functions were evaluated via the Morris water maze, between day 17 to day 21 after surgery. At day 21, rats were sacrificed and cerebroventricular volumes were measured histologically.
Results
Hydrocephalus exacerbated neurological deficits after SAH, and HBO multiple treatment tendentially improved the neurobehavioral functions. Spatial learning and memory deficits were noticed after SAH, and rats with hydrocephalus showed worse learning and memory abilities and HBO treatment showed a minor improvement. In the SAH group (room air) 4 rats showed an increased ventricular volume at day 21 after SAH-induction (n = 10). HBO or NBO therapy did not alter the occurrence of hydrocephalus after SAH, as 4 rats in each of these groups showed an increased ventricular volume (n = 10 per group).
Conclusion
Multiple HBO therapy does not ameliorate hydrocephalus formation in a rat model of SAH; however, HBO tendentially improved the neurological functions and spatial learning and memory abilities in rats with hydrocephalus.
doi:10.1186/2045-9912-4-12
PMCID: PMC4134116  PMID: 25132956
Hyperbaric oxygen; Hydrocephalus; Neurobehavioral; Subarachnoid hemorrhage
10.  Expression analysis following argon treatment in an in vivo model of transient middle cerebral artery occlusion in rats 
Medical Gas Research  2014;4:11.
Background
Argon treatment following experimental neurotrauma has been found neuroprotective in an array of in vivo and in vitro models. The inherent cellular and molecular mechanisms are still unknown. We seeked to shed light on these processes by examinig the cellular distribution and the expression of inflammatory markers and growth factors in argon treated brain tissue.
Methods
Male adult Sprague-Dawley rats were randomly assigned to one of the study groups: sham surgery + placebo, sham surgery + argon, tMCAO + placebo, and tMCAO + argon. Animals underwent 2 h-transient middle cerebral artery occlusion (tMCAO) using the endoluminal thread model or sham surgery without tMCAO. After the first hour of tMCAO or sham surgery a 1 h inhalative argon (50% argon/50% O2) or placebo (50% N2/50% O2) treatment was performed. Brains were removed and evaluated after 24 h. RealTime-PCR was performed from biopsies of the penumbra and contralateral corresponding regions. Paraffin sections were immunostained with antibodies against GFAP, NeuN, and Iba1. Cell counts of astrocytes, neurons and microglia in different cortical regions were performed in a double-blinded manner.
Results
Fifteen animals per tMCAO group and twelve sham + placebo respectively eleven sham + argon animals completed the interventional procedure. We identified several genes (IL-1β, IL-6, iNOS, TGF-β, and NGF) whose transcription was elevated 24 h after the study intervention, and whose expression levels significantly differed between argon treatment and placebo following tMCAO. Except for the core region of ischemia, cell numbers were comparable between different treatment groups.
Conclusion
In our study, we found an elevated expression of several inflammatory markers and growth factors following tMCAO + argon compared to tMCAO + placebo. Although conflicting the previously described neuroprotective effects of argon following experimental ischemia, these findings might still be associated with each other. Further studies will have to evaluate their relevance and potential relationship.
doi:10.1186/2045-9912-4-11
PMCID: PMC4322493  PMID: 25671080
Argon; Noble gas; MCAO; Ischemia; Neuroprotection
11.  A systematic review of neuroprotective strategies after cardiac arrest: from bench to bedside (part II-comprehensive protection) 
Medical Gas Research  2014;4:10.
Neurocognitive deficits remain a significant source of morbidity in survivors of cardiac arrest. We conducted a literature review of treatment protocols designed to evaluate neurologic outcome and survival following global cerebral ischemia associated with cardiac arrest. The search was limited to investigational therapies that were implemented either during cardiopulmonary resuscitation or after return of spontaneous circulation in studies that included assessment of impact on neurologic outcome. Given that complex pathophysiology underlies global brain hypoxic ischemia following cardiac arrest, neuroprotective strategies targeting multiple stages of neuropathologic cascades should promise to improve survival and neurologic outcomes in cardiac arrest victims. In Part II of this review, we discuss several approaches that can provide comprehensive protection against global brain injury associated with cardiac arrest, by modulating multiple targets of neuropathologic cascades. Pharmaceutical approaches include adenosine and growth factors/hormones including brain-derived neurotrophic factor, insulin-like growth factor-1 and glycine-proline-glutamate, granulocyte colony stimulating factor and estrogen. Preclinical studies of these showed some benefit but were inconclusive in models of global brain injury involving systemic ischemia. Several medical gases that can mediate neuroprotection have been evaluated in experimental settings. These include hydrogen sulfide, hyperbaric oxygen and molecular hydrogen. Hyperbaric oxygen and molecular hydrogen showed promising results; however, further investigation is required prior to clinical application of these agents in cardiac arrest patients.
doi:10.1186/2045-9912-4-10
PMCID: PMC4322492  PMID: 25671079
Cardiac arrest; Global brain injury; Comprehensive neuroprotection; Model; Pharmaceutical; Hyperbaric oxygen; Hydrogen sulfide; Hydrogen gas
12.  A systematic review of neuroprotective strategies after cardiac arrest: from bench to bedside (Part I – Protection via specific pathways) 
Neurocognitive deficits are a major source of morbidity in survivors of cardiac arrest. Treatment options that could be implemented either during cardiopulmonary resuscitation or after return of spontaneous circulation to improve these neurological deficits are limited. We conducted a literature review of treatment protocols designed to evaluate neurologic outcome and survival following cardiac arrest with associated global cerebral ischemia. The search was limited to investigational therapies that were utilized to treat global cerebral ischemia associated with cardiac arrest. In this review we discuss potential mechanisms of neurologic protection following cardiac arrest including actions of several medical gases such as xenon, argon, and nitric oxide. The 3 included mechanisms are: 1. Modulation of neuronal cell death; 2. Alteration of oxygen free radicals; and 3. Improving cerebral hemodynamics. Only a few approaches have been evaluated in limited fashion in cardiac arrest patients and results show inconclusive neuroprotective effects. Future research focusing on combined neuroprotective strategies that target multiple pathways are compelling in the setting of global brain ischemia resulting from cardiac arrest.
doi:10.1186/2045-9912-4-9
PMCID: PMC4012247  PMID: 24808942
Cardiac arrest; Global brain ischemia; Neuronal death; Neuroprotection; Resuscitation; Argon; Xenon; Nitric oxide
13.  Hyperbaric oxygen therapy for chronic post-concussive syndrome 
In this editorial, the value of hyperbaric oxygen therapy in the management of chronic post-concussive syndrome following mild traumatic brain injury is discussed.
doi:10.1186/2045-9912-4-8
PMCID: PMC3984490  PMID: 24717073
Hyperbaric oxygen; Traumatic brain injury; Outcome
14.  The development of hyperbaric oxygen therapy for skin rejuvenation and treatment of photoaging 
Hyperbaric oxygen therapy (HBOT), a therapy that have patients breath in pure oxygen in a pressurized chamber, has been long used as a treatment for conditions such as decompression sickness and carbon monoxide poisoning. Oxygen recently has been found to be an important component in skin rejuvenation, treatment of photoaging skin, and improvement in skin complexions. The interest in the use of HBOT for this purpose is continually growing and becoming more widespread. In addition to aging and genetic makeup, chronic UV radiation due to everyday exposure, especially UV-B, can greatly increase the rate of wrinkle formation through increasing skin angiogenesis and degradation of extracellular matrix molecules. The use of HBOT and hyperoxia conditions has been found to attenuate the formation of wrinkles from UV irradiation. It accomplishes the task by possibly inhibiting various processes and pathways involved such as the HIF1-α, VEGF, neutrophil infiltrations, and MMP-2 & MMP-9, which are directly involved with promoting skin angiogenesis in its active state. There are currently medical aesthetic clinics that are using oxygen therapy under high pressure applied directly to skin to reduce visible wrinkles but this procedure is not widespread yet due to more research that needs to be done on this topic. However, this treatment for wrinkles is definitely growing due to recent studies done showing the effectiveness of oxygen therapy on wrinkles. This review article will explore and summarize researches done on possible mechanisms dealing with the use of oxygen therapy for reduction of UVB-caused wrinkles, its side effects, and its possible future improvement and use in medicine.
doi:10.1186/2045-9912-4-7
PMCID: PMC3977684  PMID: 24690202
Hyperbaric oxygen therapy; Wrinkles; Mechanisms; Photoaging; Angiogenesis; UVB
15.  Cognitive dysfunction following desflurane versus sevoflurane general anesthesia in elderly patients: a randomized controlled trial 
As life expectancy increases, more patients ≥65 years undergo general anesthesia. Anesthetic agents may contribute to postoperative cognitive dysfunction, and incidence may differ with anesthetic agents or intraoperative anesthesia depth. Responses to anesthetic adjuvants vary among elderly patients. Processed electroencephalography guidance of anesthetic may better ensure equivalent cerebral suppression. This study investigates postoperative cognitive dysfunction differences in elderly patients given desflurane or sevoflurane using processed electroencephalography guidance.
IRB approved, randomized trial enrolled consenting patients ≥65 years scheduled for elective surgery requiring general anesthesia ≥120 minute duration. After written informed consent, patients were randomly assigned to sevoflurane or desflurane. No perioperative benzodiazepines were administered. Cognitive impairment was measured by an investigator blinded to group assignment using mini-Mental Status Examination (MMSE) at baseline; 1, 6, and 24 hours after the end of anesthesia. Mean arterial pressure was maintained within 20% of baseline. Anesthetic dose was adjusted to maintain moderate general anesthesia per processed electroencephalograpy (Patient State Index 25 to 50). The primary outcome measure was intergroup difference in MMSE change 1 hour after anesthesia (median; 95% confidence interval).
110 patients consented; 26 were not included for analysis (no general anesthesia; withdrew consent; baseline MMSE abnormality; inability to perform postoperative MMSE; data capture failure); 47 sevoflurane and 37 desflurane were analyzed. There were no significant differences in patient characteristics; intraoperative mean blood pressure (desflurane 86.4; 81.3 to 89.6 versus sevoflurane 82.5; 80.2 to 86.1 mmHg; p = 0.42) or Patient State Index (desflurane 41.9; 39.0 to 44.0 versus sevoflurane 41.0; 37.5 to 44.0; p = 0.60) despite a lower MAC fraction in desflurane (0.82; 0.77 to 0.86) versus sevoflurane (0.96; 0.91 to 1.03; p < 0.001). MMSE decreased 1 hour after anesthesia (p < 0.001). The decrease at one hour was larger in sevoflurane (−2.5; −3.3 to −1.8) than desflurane (−1.3; −2.2 to −0.5; p = 0.03). MMSE returned to baseline by 6 hours after anesthesia.
Conclusions
For elderly patients in whom depth of anesthesia is maintained in the moderate range, both desflurane and sevoflurane are associated with transient decreases in cognitive function as measured by MMSE after anesthesia, with clinically insignificant differences between them in this setting.
Trial registry
ClinicalTrials.gov NCT01199913
doi:10.1186/2045-9912-4-6
PMCID: PMC3976084  PMID: 24666542
General anesthesia; Postoperative cognitive decline; Geriatric patient
16.  The potential dual effects of sevoflurane on AKT/GSK3β signaling pathway 
Background
Anesthesia with multiple exposures of commonly used inhalation anesthetic sevoflurane induces neuroinflammation and cognitive impairment in young mice, but anesthesia with a single exposure to sevoflurane does not. AKT/glycogen synthase kinase 3β (GSK3β) signaling pathway is involved in neurotoxicity and neurobehavioral deficits. However, whether sevoflurane can induce a dual effect (increase versus decrease) on the activation of AKT/GSK3β signaling pathway remains to be determined. We therefore set out to assess the effects of sevoflurane on AKT/GSK3β signaling pathway in vivo and in vitro.
Methods
Six day-old wild-type mice were exposed to 3% sevoflurane two hours daily for one or three days. In the in vitro studies, H4 human neuroglioma cells were treated with 4% sevoflurane for two or six hours. We then determined the effects of different sevoflurane treatments on the levels of phosphorylated (P)-GSK3β(ser9) and P-AKT(ser473) by using Western blot analysis.
Results
Here we show that anesthesia with 3% sevoflurane two hours daily for one day increased the levels of P-GSK3β(ser9) and P-AKT(ser473), but the anesthesia with 3% sevoflurane daily for three days decreased them in the mice. The treatment with 4% sevoflurane for two hours increased, but the treatment with 4% sevoflurane for six hours decreased, the levels of P-GSK3β(ser9) and P-AKT(ser473) in the H4 human neuroglioma cells.
Conclusions
Anesthetic sevoflurane might induce a dual effect (increase versus decrease) on the activation of the AKT/GSK3β signaling pathway. These studies have established a system to perform further studies to determine the effects of sevoflurane on brain function.
doi:10.1186/2045-9912-4-5
PMCID: PMC3996018  PMID: 24580743
Anesthetic; Sevoflurane; Phosphorylation; AKT/GSK3β signaling pathway
17.  In vitro Activation of heme oxygenase-2 by menadione and its analogs 
Background
Previously, we reported that menadione activated rat, native heme oxygenase-2 (HO-2) and human recombinant heme oxygenase-2 selectively; it did not activate spleen, microsomal heme oxygenase-1. The purpose of this study was to explore some structure–activity relationships of this activation and the idea that redox properties may be an important aspect of menadione efficacy.
Methods
Heme oxygenase activity was determined in vitro using rat spleen and brain microsomes as the sources of heme oxygenase-1 and −2, respectively, as well as recombinant, human heme oxygenase-2.
Results
Menadione analogs with bulky aliphatic groups at position-3, namely vitamins K1 and K2, were not able to activate HO-2. In contrast, several compounds with similar bulky but less lipophilic moieties at position-2 (and −3) were able to activate HO-2 many fold; these compounds included polar, rigid, furan-containing naphthoquinones, furan-benzoxazine naphthoquinones, 2-(aminophenylphenyl)-3-piperidin-1-yl naphthoquinones. To explore the idea that redox properties might be involved in menadione efficacy, we tested analogs such as 1,4-dimethoxy-2-methylnaphthalene, pentafluoromenadione, monohalogenated naphthoquinones, α-tetralone and 1,4-naphthoquinone. All of these compounds were inactive except for 1,4-naphthoquinone. Menadione activated full-length recombinant human heme oxygenase-2 (FL-hHO-2) as effectively as rat brain enzyme, but it did not activate rat spleen heme oxygenase.
Conclusions
These observations are consistent with the idea that naphthoquinones such as menadione bind to a receptor in HO-2 and activate the enzyme through a mechanism that may involve redox properties.
doi:10.1186/2045-9912-4-4
PMCID: PMC3942077  PMID: 24533775
Heme oxygenase; Enzyme activator; Menadione; Agonist; In vitro; Redox properties
18.  Argon gas: a potential neuroprotectant and promising medical therapy 
Argon is a noble gas element that has demonstrated narcotic and protective abilities that may prove useful in the medical field. The earliest records of argon gas have exposed its ability to exhibit narcotic symptoms at hyperbaric pressures greater than 10 atmospheres with more recent evidence seeking to display argon as a potential neuroprotective agent. The high availability and low cost of argon provide a distinct advantage over using similarly acting treatments such as xenon gas. Argon gas treatments in models of brain injury such as in vitro Oxygen-Glucose-Deprivation (OGD) and Traumatic Brain Injury (TBI), as well as in vivo Middle Cerebral Artery Occlusion (MCAO) have largely demonstrated positive neuroprotective behavior. On the other hand, some warning has been made to potential negative effects of argon treatments in cases of ischemic brain injury, where increases of damage in the sub-cortical region of the brain have been uncovered. Further support for argon use in the medical field has been demonstrated in its use in combination with tPA, its ability as an organoprotectant, and its surgical applications. This review seeks to summarize the history and development of argon gas use in medical research as mainly a neuroprotective agent, to summarize the mechanisms associated with its biological effects, and to elucidate its future potential.
doi:10.1186/2045-9912-4-3
PMCID: PMC3996095  PMID: 24533741
Argon; Xenon; Noble gas; Inert gas; Narcosis; Anesthesia; Neuroprotection; Organoprotection; Ischemia; Brain injury; Oxygen-Glucose deprivation; Traumatic brain injury; Middle cerebral artery occlusion; Tissue plasminogen activation; Argon plasma coagulation
19.  Adverse effect of inhalational anesthetics on the developing brain 
We did a PubMed search and summarized studies on the potential adverse effect of anesthetics especially neurotoxicity in the developing brain, so named anesthesia-induced developmental neurotoxicity. Even though many experimental studies using animal models indicated some adverse effect of anesthetics, more evidence is needed before a recommendation can be made to change the way those anesthetics are used in the pediatric population. Two large clinical trials are underway and may provide insight to the potential human neurotoxic effect of anesthetics.
doi:10.1186/2045-9912-4-2
PMCID: PMC3926857  PMID: 24528992
Anesthetics; Developing brain; Neurotoxicity
20.  Variability in uptake efficiency for pulsed versus constant concentration delivery of inhaled nitric oxide 
Background
Nitric oxide (NO) is currently administered using devices that maintain constant inspired NO concentrations. Alternatively, devices that deliver a pulse of NO during the early phase of inspiration may have use in optimizing NO dosing efficiency and in extending application of NO to long-term use by ambulatory, spontaneously breathing patients. The extent to which the amount of NO delivered for a given pulse sequence determines alveolar concentrations and uptake, and the extent to which this relationship varies with breathing pattern, physiological, and pathophysiological parameters, warrants investigation.
Methods
A mathematical model was used to analyze inhaled nitric oxide (NO) transport through the conducting airways, and to predict uptake from the alveolar region of the lung. Pulsed delivery was compared with delivery of a constant concentration of NO in the inhaled gas.
Results
Pulsed delivery was predicted to offer significant improvement in uptake efficiency compared with constant concentration delivery. Uptake from the alveolar region depended on pulse timing, tidal volume, respiratory rate, lung and dead space volume, and the diffusing capacity of the lung for NO (DLNO). It was predicted that variation in uptake efficiency with breathing pattern can be limited using a pulse time of less than 100 ms, with a delay of less than 50 ms between the onset of inhalation and pulse delivery. Nonlinear variation in uptake efficiency with DLNO was predicted, with uptake efficiency falling off sharply as DLNO decreased below ~50-60 ml/min/mm Hg. Gas mixing in the conducting airways played an important role in determining uptake, such that consideration of bulk convection alone would lead to errors in assessing efficiency of pulsed delivery systems.
Conclusions
Pulsed NO delivery improves uptake efficiency compared with constant concentration delivery. Optimization of pulse timing is critical in limiting intra- and inter-subject variability in dosing.
doi:10.1186/2045-9912-4-1
PMCID: PMC3914359  PMID: 24450473
Lung model; Trumpet model; Medical gas; Nitric oxide; Gas transport; Conducting airways; Mixing; Dispersion; Bolus; Pulse
21.  Amelioration of cardio-renal injury with aging in dahl salt-sensitive rats by H2-enriched electrolyzed water 
Medical Gas Research  2013;3:26.
Abstract
Recent studies have revealed the biological effects of H2 in suppressing organ injuries due to acute inflammation and oxidative stress. Dahl salt-sensitive (SS) rats naturally develop elevated blood pressure (BP) and kidney injury with aging. The present study examined the effect of long-term supplementation of H2 in drinking water on age-related changes.
Four-week-old male Dahl SS rats were fed 3 types of water (n = 30 each) for up to 48 weeks: filtered water (FW), water with a high H2 content (492.5 ppb) obtained with water electrolysis (EW), or dehydrogenated EW (DW). Animals were subjected to histological analysis at 16, 24, and 48 weeks.
The FW group showed progressive BP elevation and increases in albuminuria and cardiac remodeling during the course of treatment. Histologically, there were significant changes as a function of aging, i.e., glomerular sclerosis with tubulointerstitial fibrosis in the kidney, and increased cardiomyocyte diameter with interstitial fibrosis in the heart at 48 weeks. These changes were related to the enhanced inflammation and oxidative stress in the respective organs. However, there were no striking differences in BP among the groups, despite histological alterations in the EW group being significantly decreased when compared to FW and DW in both organs, with concurrently lower oxidative stress and inflammatory markers at 48 weeks.
Conclusion
Long-term ad libitum consumption of H2-enriched electrolyzed water can ameliorate the processes of kidney injury and cardiac remodeling with aging in Dahl SS rats by suppressing, at least partly, elevated inflammation and oxidative stress.
doi:10.1186/2045-9912-3-26
PMCID: PMC3866609  PMID: 24289332
Aging; Cardiac remodeling; Chronic kidney disease; Hydrogen molecule; Electrolyzed water
22.  Hypocapnia as a poor prognostic factor in aneurysmal subarachnoid hemorrhage 
Medical Gas Research  2013;3:25.
In this editorial, the issues of hypocapnia and its relation to symptomatic vasospasm, prognosis, and outcome among patients with aneurysmal subarachnoid hemorrhage is discussed. Potential directions for future studies are provided.
doi:10.1186/2045-9912-3-25
PMCID: PMC4177388  PMID: 24274339
Hypocapnia; CO2; Cerebral vasospasm; Subarachnoid hemorrhage; Outcome
23.  A comparative study on the anti-inflammatory effects of single oral doses of naproxen and its hydrogen sulfide (H2S)-releasing derivative ATB-346 in rats with carrageenan-induced synovitis 
Medical Gas Research  2013;3:24.
Background
Non-steroidal antiinflammatory drugs (NSAIDs) are the most commonly prescribed agents for arthritic patients, although gastric effects limit their long-term use. Considering the reported gastric safety of hydrogen sulfide (H2S)-releasing NSAIDs, in addition to the anti-inflammatory effects of H2S administration to rats with synovitis, we decided to evaluate the effects of the H2S-releasing naproxen derivative ATB-346 in this animal model.
Methods
Male Wistar rats were anesthetized with inhalatory halothane and pre-treated with equimolar oral doses of either naproxen (0.3, 1, 3 or 10 mg/kg) or ATB-346 (0.48, 1.6, 4.8, or 16 mg/kg) 30 min before the i.art. injection of 7.5 mg of carrageenan (CGN) into the right knee joint cavity. Joint swelling and pain score were assessed after 1, 3 and 5 h, and tactile allodynia after 2 and 4 h. After the last measurement, the joint cavity lavages were performed for counting of the recruited leukocytes. The drugs (at the highest doses) were also tested for their gastric effects by evaluating macroscopical damage score and neutrophil recruitment (measured as myeloperoxidase – MPO activity) in the stomachs 5 h after administration of the drugs. In addition, the serum naproxen pharmacokinetic profiles of both compounds, administered at the highest equimolar doses, were obtained during the first 6 h after dosing.
Results
At the two highest tested doses, both naproxen and ATB-346 reduced edema and pain score (measured 3 and 5 h after CGN; P < 0.001). Tactile allodynia was similarly inhibited by ~45% 4 h after CGN by both naproxen (at 1, 3 and 10 mg/kg) and ATB-346 (at 1.6 and 4.8 mg/kg; P < 0.001), as well as leukocyte infiltration. Naproxen (but not ATB-346) induced significant gastric damage and, despite the increased gastric MPO activity by ~130% in the naproxen-, but not in the ATB-346-treated rats, this effect was of no statistical significance.
Conclusion
The presence of a H2S-releasing moiety in the ATB-346 structure does not impair the antiinflammatory activity of the parent compound in rats with CGN-induced synovitis. In addition, released H2S may account for the absence of deleterious gastric effects, thus making of ATB-346 a potentially useful therapeutic alternative to traditional naproxen for treatment of patients with arthritis.
doi:10.1186/2045-9912-3-24
PMCID: PMC3843537  PMID: 24237604
Hydrogen sulfide; NSAID; ATB-346; Synovitis; Joint; Inflammation; Rat
24.  Hypercapnia: is it protective in lung injury? 
Medical Gas Research  2013;3:23.
Hypercapnic acidosis has been regarded as a tolerated side effect of protective lung ventilation strategies. Various in vivo and ex vivo animal studies have shown beneficial effects in acute lung injury setting, but some recent work raised concerns about its anti-inflammatory properties. This mini-review article aims to expand the potential clinical spectrum of hypercapnic acidosis in critically ill patients with lung injury. Despite the proven benefits of hypercapnic acidosis, further safety studies including dose-effect, level-and-onset of anti-inflammatory effect, and safe applicability period need to be performed in various models of lung injury in animals and humans to further elucidate its protective role.
doi:10.1186/2045-9912-3-23
PMCID: PMC3833649  PMID: 24209944
Hypercapnia; Hypercarbia; Carbon Dioxide; Oxygenation; Acute Lung Injury (ALI); Ventilator Associated Lung Injury (VALI); Pneumonia; Sepsis; Acute Respiratory Distress Syndrome (ARDS); Ventilator-induced diaphragmatic dysfunction (VIDD)
25.  Bustling argon: biological effect 
Medical Gas Research  2013;3:22.
Argon is a noble gas in group 18 of the periodic table. Certificated to exist in air atmosphere merely one century ago, discovery of argon shows interesting stories of researching and exploring. It was assumed to have no chemical activity. However, argon indeed present its biological effect on mammals. Narcotic effect of argon in diving operation and neur-protective function of argon in cerebral injury demonstrate that argon has crucial effect and be concentrated on is necessary. Furthermore, consider to be harmless to human, argon clinical application in therapy would be another option.
doi:10.1186/2045-9912-3-22
PMCID: PMC3850710  PMID: 24088583

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