Intermittent Hypoxia Exposure Research Articles

Exosomes secreted by adipose mesenchymal stem cells overexpressing circPIP5K1C exert

BackgroundErectile dysfunction (ED) seriously affects men's normal life, and obstructive sleep apnoea (OSA) has been diagnosed as a causative factor. Currently, exosomes secreted by adipose mesenchymal stem cells (ADSC) have been used in the non-clinical experimental treatment of ED disease with prominent efficacy due to the advantages of high stability and no immune exclusion. MethodsIn this study, chronic intermittent hypoxia (CIH) exposure was used to induce ED-corresponding phenotypes in Sprague Dawley (SD) rats as well as in cavernous smooth muscle cells (CCSMCs). ED symptoms were treated using exosomes secreted by ADSCs overexpressing circPIP5K1C (EXO-circ) injected into the rat corpus cavernosum. ResultsEXO-circ has the effect of ameliorating ED induced by CIH exposure in rats, the mechanism of which is to promote the expression of the downstream target gene SMURF1 after adsorption of miR-153-3p through the sponge so that SMURF1 and PFKFB3 occur protein-protein binding and ubiquitination degradation of PFKFB3 appears to inhibit the occurrence of spongiotic smooth muscle cells glycolysis, and to restore the function of the smooth muscle. ConclusionsThese findings show that EXO-circ have a promising therapeutic potential in OSA-induced ED.

Hypoxic preacclimatization combining intermittent hypoxia exposure with physical exercise significantly promotes the tolerance to acute hypoxia.

Background: Both hypoxia exposure and physical exercise before ascending have been proved to promote high altitude acclimatization, whether the combination of these two methods can bring about a better effect remains uncertain. Therefore, we designed this study to evaluate the effect of hypoxic preacclimatization combining intermittent hypoxia exposure (IHE) and physical exercise on the tolerance to acute hypoxia and screen the optimal preacclimatization scheme among the lowlanders. Methods: A total of 120 Han Chinese young men were enrolled and randomly assigned into four groups, including the control group and three experimental groups with hypoxic preacclimatization of 5-day rest, 5-day exercise, and 3-day exercise in a hypobaric chamber, respectively. Main physical parameters for hypoxia acclimatization, AMS incidence, physical and mental capacity were measured for each participant in the hypobaric chamber simulated to the altitude of 4500m in the effect evaluation stage. The effect was compared between different schemes. Results: During the effect evaluation stage, SpO2 of the 5-day rest group and 5-day exercise group was significantly higher than that of the control group (p = 0.001 and p = 0.006, respectively). The participants with 5-day rest had significantly lower HR than the controls (p = 0.018). No significant differences of AMS incidence were found among the four groups, while the proportion of AMS headache symptom (moderate and severe vs. mild) was significantly lower in the 3-day exercise group than that in the control group (p = 0.002). The 5-day exercise group had significantly higher VO2max, than the other three groups (p = 0.033, p < 0.001, and p = 0.023, respectively). The 5-day exercise group also had significantly higher digital symbol and pursuit aiming test scores, while shorter color selection reaction time than the control group (p = 0.005, p = 0.005, and p = 0.004, respectively). Conclusion: Hypoxic preacclimatization combining IHE with physical exercise appears to be efficient in promoting the tolerance to acute hypoxia. Hypoxia duration and physical exercise of moderate intensity are helpful for improvement of SpO2 and HR, relief of AMS headache symptoms, and enhancement of mental and physical operation capacity.

Hypobaric hypoxia exposure regulates tissue distribution of nanomedicine for enhanced cancer therapy

BackgroundEffective drug delivery of nanomedicines to targeted sites remains challenging. Given that hypobaric hypoxia and hyperbaric oxygen exposure can significantly change pharmacokinetics of drugs, it is interesting to determine whether they can regulate tissue distribution of nanomedicine, especially in tumor, for enhanced cancer therapy.ResultsHypobaric hypoxia exposure improved the pharmacokinetics of paclitaxel-loaded liposomes and facilitated their distribution in the heart and liver, whereas hyperbaric oxygen exposure did not benefit and even impaired the pharmacokinetics and distribution. Particularly, both hypobaric hypoxia and hyperbaric oxygen exposure could not improve the distribution in subcutaneous tumor. Thus, we constructed orthotopic liver tumor model and discussed whether high distribution of the liposomal nanomedicine in the liver, facilitated by hypobaric hypoxia exposure, could ensure their effective accumulation in liver tumor for enhanced cancer therapy.ConclusionsThe liposomal nanomedicine with adjuvant hypobaric hypoxia exposure significantly inhibited the growth of orthotopic liver tumor for prolonged survival time, achieved by hypobaric hypoxia-promoted accumulation at tumor sites of the liver. It might be the first example of the application of adjuvant intermittent hypobaric hypoxia exposure in treating liver cancer.

Early Increase in Blood-Brain Barrier Permeability in a Murine Model Exposed to Fifteen Days of Intermittent Hypoxia.

Obstructive sleep apnea (OSA) is characterized by intermittent repeated episodes of hypoxia-reoxygenation. OSA is associated with cerebrovascular consequences. An enhanced blood-brain barrier (BBB) permeability has been proposed as a marker of those disorders. We studied in mice the effects of 1 day and 15 days intermittent hypoxia (IH) exposure on BBB function. We focused on the dorsal part of the hippocampus and attempted to identify the molecular mechanisms by combining in vivo BBB permeability (Evans blue tests) and mRNA expression of several junction proteins (zona occludens (ZO-1,2,3), VE-cadherin, claudins (1,5,12), cingulin) and of aquaporins (1,4,9) on hippocampal brain tissues. After 15 days of IH exposure we observed an increase in BBB permeability, associated with increased mRNA expressions of claudins 1 and 12, aquaporins 1 and 9. IH seemed to increase early for claudin-1 mRNA expression as it doubled with 1 day of exposure and returned near to its base level after 15 days. Claudin-1 overexpression may represent an immediate response to IH exposure. Then, after 15 days of exposure, an increase in functional BBB permeability was associated with enhanced expression of aquaporin. These BBB alterations are possibly associated with a vasogenic oedema that may affect brain functions and accelerate neurodegenerative processes.

Intermittent hypoxia exposure at sea level improves functional capacity (6MWT) at high altitude

Objectives: Our primary objective is to observe whether acclimatisation is elicited by the intermittent hypoxic exposure (IHE) protocol. For this, we have utilised performance in a 6-min walk test (6MWT) as a tool to assess physiological responses to high altitude (HA) both in control and IHE-exposed groups, respectively. Materials and Methods: The study was a prospective cohort study conducted on Indian army volunteers (n = 57) and they were divided into two groups, a control group (CG) and an experimental group (EG). At the sea level, a baseline study was carried out on barometric pressure. IHE was performed at sea level in the normobaric hypoxia chamber (low fraction of inspired oxygen [FiO2], at normal barometric pressure, 740 mmHg), in which the FiO2 of the chamber was artificially decreased using O2-filtering membranes. The oxygen percentage was constantly maintained at 12%-13%. After recording the baseline, the subjects were exposed to a normobaric hypoxia chamber at 12%-13% FiO2 (altitude – equivalent to 4350 m Approx). Heart rate and blood pressure (BP) were recorded with a battery-operated portable BP monitor (OMRON) at both locations. A finger pulse oximeter probe was set on the right index finger to measure the resting oxygen saturation (SpO2) level (Model MU 300). Incidence of acute mountain sickness (AMS) was scored with the help of the standard Lake Louise questionnaire (LLS). Total LLS scores more than &gt;3 (range 0–15) were considered AMS. Results: EG individuals that went through IHE performed better at 6MWT at Stage I (P = 0.03). EG also had better SpO2, levels as compared to CG (P = 0.00) at Stage II (P = 0.03). Furthermore, there was a significant difference in the Borg’s Scale between CG and EG. The Delta SpO2 of EG was better as compared to CG in all stages, albeit not significant (P = 0.07). There was a significant difference between IHE and CG groups, and CG was at an increased risk for lower SpO2 (8.00 [1.21–52.60], P = 0.03). Conclusion: The findings elucidate the benefits of IHE in rapid acclimatisation, and it contributed to better distance covered as shown by 6MWT as well and reduces hypoxic incidents in HA.

Senolytic-facilitated Reversal of End-Organ Dysfunction in a Murine Model of Obstructive Sleep Apnea.

Rationale: Obstructive sleep apnea (OSA) is a highly prevalent condition that is associated with accelerated biological aging and multiple end-organ morbidities. Current treatments, such as continuous positive airway pressure (CPAP), have shown limited cognitive, metabolic, and cardiovascular beneficial outcomes despite adherence. Thus, adjunct therapies aiming to reduce OSA burden, such as senolytics, could improve OSA outcomes.Objectives: To assess if targeting senescence in addition to partial normoxia mimicking "good" CPAP adherence can improve physiological outcomes in mice exposed to chronic intermittent hypoxia.Methods: We compared the effects of 6 weeks of therapy with either partial normoxic recovery alone or combined with the senolytic navitoclax after 16 weeks of intermittent hypoxia exposures, a hallmark of OSA, on multiphenotypic cardiometabolic and neurocognitive parameters.Measurements and Main Results: Our findings indicate that only when combined with navitoclax, partial normoxic recovery significantly improved sleepiness (sleep in the dark phase: 34% ± 4% vs. 26% ± 3%; P < 0.01), cognition (preference score: 51% ± 19% vs. 70% ± 11%; P = 0.048), coronary artery function (response to acetylcholine [vasodilation]: 56% ± 13% vs. 72% ± 10%; P < 0.001), glucose, and lipid metabolism and reduced intestinal permeability and senescence in multiple organs.Conclusions: These findings indicate that the reversibility of end-organ morbidities induced by OSA is not only contingent on restoration of normal oxygenation patterns but can be further enhanced by targeting other OSA-mediated detrimental cellular processes, such as accelerated senescence.

The transcriptomic and biochemical responses of blood clams (Tegillarca granosa) to prolonged intermittent hypoxia

The blood clam (Tegillarca granosa), a marine bivalve of ecological and economic significance, often encounters intermittent hypoxia in mudflats and aquatic environments. To study the response of blood clam foot to prolonged intermittent hypoxia, the clams were exposed to intermittent hypoxia conditions (0.5 mg/L dissolved oxygen, with a 12-h interval) for 31 days. Initially, transcriptomic analysis was performed, uncovering a total of 698 differentially expressed genes (DEGs), with 236 upregulated and 462 downregulated. These genes show enrichments in signaling pathways related to glucose metabolism, sugar synthesis and responses to oxidative stress. Furthermore, the activity of the enzyme glutathione peroxidase (GPx) and the levels of gpx1 mRNA showed gradual increases, reaching their peak on the 13th day of intermittent hypoxia exposure. This observation suggests an indirect protective role of GPx against oxidative stress. The results of this study make a significantly contribute to our broader comprehensive of the physiological, biochemical responses, and molecular reactions governing the organization of foot muscle tissue in marine bivalves exposed to prolonged intermittent hypoxic conditions.

Simulated Altitude Training and Sport Performance: Protocols and Physiological Effects

This article explores the physiological mechanisms and effects of simulated hypoxia environment training on sports performance. Different training protocols, including hypoxia high-intensity interval training (HHIIT), incremental hypoxia training, hypoxia submaximal exercise training and combined training, and hypoxia training in the recovery and sleep states, are discussed. HHIIT combines intermittent hypoxia exposure with high-intensity interval training, and has been shown to increase the maximum oxygen intake compare to the state of normoxia, improving cardiorespiratory fitness, skeletal muscle oxygen utilization, power performance, hematological adaptations, and sports performance. Incremental hypoxia training involves the gradual decrease in oxygen concentration while maintaining exercise intensity. It has been found to improve aerobic capacity; however, fewer effects were observed in hematological variables. Hypoxia submaximal exercise training and combined training in a hypoxia environment has shown to increase VO2 and VE, and only improve hemodynamic function in combined training with hypoxia. Hypoxia during the recovery state has been associated with improvements in maximum oxygen uptake, also providing benefits to sports performance. Overall, exposure to a hypoxia environment has been demonstrated to improve cardiorespiratory endurance, power performance, and specific physiological adaptations in training and resting states. However, the optimal training protocols and their effects on different sports and athlete proficiency require further research to optimize training and enhance athletic performance in hypoxia environments.

Gestational intermittent hypoxia induces endothelial dysfunction and hypertension in pregnant rats: role of endothelin type B receptor†.

Obstructive sleep apnea is a recognized risk factor for gestational hypertension, yet the exact mechanism behind this association remains unclear. Here, we tested the hypothesis that intermittent hypoxia, a hallmark of obstructive sleep apnea, induces gestational hypertension through perturbed endothelin-1 signaling. Pregnant Sprague-Dawley rats were subjected to normoxia (control), mild intermittent hypoxia (10.5% O2), or severe intermittent hypoxia (6.5% O2) from gestational days 10-21. Blood pressure was monitored. Plasma was collected and mesenteric arteries were isolated for myograph and protein analyses. The mild and severe intermittent hypoxia groups demonstrated elevated blood pressure, reduced plasma nitrate/nitrite, and unchanged endothelin-1 levels compared to the control group. Western blot analysis revealed decreased expression of endothelin type B receptor and phosphorylated endothelial nitric oxide synthase, while the levels of endothelin type A receptor and total endothelial nitric oxide synthase remained unchanged following intermittent hypoxia exposure. The contractile responses to potassium chloride, phenylephrine, and endothelin-1 were unaffected in endothelium-denuded arteries from mild and severe intermittent hypoxia rats. However, mild and severe intermittent hypoxia rats exhibited impaired endothelium-dependent vasorelaxation responses to endothelin type B receptor agonist IRL-1620 and acetylcholine compared to controls. Endothelium denudation abolished IRL-1620-induced vasorelaxation, supporting the involvement of endothelium in endothelin type B receptor-mediated relaxation. Treatment with IRL-1620 during intermittent hypoxia exposure significantly attenuated intermittent hypoxia-induced hypertension in pregnant rats. This was associated with elevated circulating nitrate/nitrite levels, enhanced endothelin type B receptor expression, increased endothelial nitric oxide synthase activation, and improved vasodilation responses. Our data suggested that intermittent hypoxia exposure during gestation increases blood pressure in pregnant rats by suppressing endothelin type B receptor-mediated signaling, providing a molecular mechanism linking intermittent hypoxia and gestational hypertension.

Intermittent hypoxia in neonatal rodents affects facial bone growth.

Preterm human infants often show periodic breathing (PB) or apnea of prematurity (AOP), breathing patterns which are accompanied by intermittent hypoxia (IH). We examined cause-effect relationships between transient IH and reduced facial bone growth using a rat model. Neonatal pups from 14 timed pregnant Sprague-Dawley rats were randomly assigned to an IH condition, with oxygen altering between 10% and 21% every 4 min for 1 h immediately after birth, or to a litter-matched control group. The IH pups were compared with their age- and sex-matched control groups in body weight (WT), size of facial bones and nor-epinephrine (NE) levels in blood at 3, 4, and 5-weeks. Markedly increased activity of osteoclasts in sub-condylar regions of 3-week-old IH-treated animals appeared, as well as increased numbers of sympathetic nerve endings in the same region of tissue sections. Male IH-pups showed significantly higher levels of NE levels in sera at 3, 4 as well as 5-week-old time points. NE levels in 4- and-5-week-old female pups did not differ significantly. Intercondylar Width, Mandible Length and Intermolar Width measures consistently declined after IH insults in 3- and 4-week-old male as well as female animals. Three-week-old male IH-pups only showed a significantly reduced (p < 0.05) body weight compared to those of 3-week controls. However, female IH-pups were heavier than age-matched controls at all 3 time-points. Trabecular bone configuration, size of facial bones, and metabolism are disturbed after an IH challenge 1 h immediately after birth. The findings raise the possibility that IH, introduced by breathing patterns such as PB or AOP, induce significantly impaired bone development and metabolic changes in human newborns. The enhanced NE outflow from IH exposure may serve a major role in deficient bone growth, and may affect bone and other tissue influenced by that elevation.

Antioxidative Parameters Improvements on Nutritional Approach: A Study on Hypoxic Multiple Organs of Sprague-Dawley

In various organs, such as the heart, kidneys, and colon, hypoxia enhances the generation of reactive oxygen species (ROS). However, the effects of reoxygenation, as occurs in intermittent hypoxia (IH) to achieve full recovery of hypoxic organs, are not yet clear. The acclimatization response can boost blood oxygen transport capacity, while hypoxia ROS can impact erythrocytes and plasma behavior, resulting in poor peripheral blood flow. This study aimed to study the antioxidant impact of puree Ficus carica (PFC) in rats with IH-induced oxidative stress. Twenty-nine Sprague-Dawley rats were randomly divided into five groups: group N (control, untreated and not exposed to IH, and Group HC was exposed to hypoxia and received distilled water. Group HPF-6.25, HPF-12.5, and HPF-25 (n = 6) received PFC with doses 6.25; 12.5; and 25 ml/kg/d, respectively for 4 weeks before IH exposure. At the end of 4 weeks, all animals except controls were exposed to IH (10% O2 and 90% N2; 4 hours/day for one week). Hematological parameters were measured with several oxidative stress indicators. Hypoxic rats exhibited substantially higher hemoglobin, hematocrit, and mean corpuscular hemoglobin concentrations. All groups exposed to IH showed increased malondialdehyde (MDA) and decreased superoxide dismutase (SOD) activity in the heart, kidneys, and colon. The increasing MDA and decreasing SOD compared to controls and pre-treatment using PFC had a dose-dependent protective effect on the heart, kidneys, and colon.

Intermittent hypoxia promotes largemouth bassheart adaptation through increasing angiogenesis, reprogramming calcium signaling, and upregulating mitochondrial turnover

Intermittent hypoxia (IH) is a common phenomenon in ecological environment. At present, researchers have shown that fish can adapt to hypoxia through various ways as improve respiratory efficiency, promote angiogenesis, and reduce metabolism, but different tissues have different coping strategies. The heart is the key organ for coping with environmental pressure such as hypoxia and has physiological plasticity. However, the changes in the fish heart under hypoxia are still opaque. Here we used multi-level techniques such as western blot, immunohistochemistry and transmission electron microscopy to explore the effects of IH on heart. First, we found that IH induced a significant increase in the ratios of heart weight/ body weight (the HW/BW of IH group is approximately 1.24 times that of C group at D16) and more collagen deposition, accompanied by higher levels of plasma catenine (CA), heart myoglobin (Mb), and nitric oxide (NO). Second, IH promoted angiogenesis through increasing the content of hemoglobin (Hb) and Erythropoietin (EPO), and the expression of related genes and protein that regulated angiogenesis, the EPO concentration increased 0.61-fold after IH. Third, IH exposure altered calcium signals, the content of cytoplasmic and mitochondrial Ca2+ increased 0.67-fold and 0.63 -fold respectively, the expression of calcium channels has also been altered. Finally, IH induced the enhancement of the mitochondrial function, the dynamic changes of fusion, division, biogenesis, and autophagy in mitochondria, and ultimately lead to the enhancement of the mitochondrial function. In conclusion, our study demonstrated that changing the structure, promoting angiogenesis, reprogramming Ca2+ signaling, and up-regulating mitochondrial turnover were the compensatory mechanisms of heart remodeling in the hypoxia adaptation of the largemouth bass.

Recovery Mimicking “Ideal” CPAP Adherence Does Not Improve Wakefulness or Cognition in Chronic Murine Models of OSA: Effect of Wake-Promoting Agents

IntroductionObstructive sleep apnea (OSA) is a chronic condition characterized by intermittent hypoxia (IH) and sleep fragmentation (SF). OSA can induce excessive daytime sleepiness (EDS) and is associated with impaired cognition and anxiety. Solriamfetol (SOL) and modafinil (MOD) are widely used wake-promoting agents in OSA patients with EDS. MethodsMale C57Bl/6J mice were exposed to SF along with sleep controls (SC) or to IH and room air (RA) controls during the light (inactive) phase for 4 and 16 weeks, respectively. Both IH and SF exposures were then discontinued to mimic “ideal” continuous positive airway pressure (CPAP) adherence. All groups were then randomly assigned to receive once daily intraperitoneal injections of SOL, MOD, or vehicle (VEH) for 6 days. Sleep/wake activity was assessed along with tests of explicit memory, anxiety and depression were performed before and after treatments. ResultsIH and SF exposures increased sleep percentage in the dark phase and reduced wake bouts lengths (i.e., EDS), and induced cognitive deficits and impulsivity in mice. Both SOL and MOD treatments effectively mitigated EDS when combined with recovery, while recovery alone did not improve EDS over the 6-day period. Furthermore, improvements explicit memory emerged only after SOL. ConclusionChronic IH and SF induce EDS in young adult mice that is not ameliorated by recovery except when combined with either SOL or MOD. SOL, but not MOD, significantly improves IH-induced cognitive deficits. Thus, SOL emerges as a viable adjuvant medication for residual EDS in OSA along with its positive impact on cognition.

Duration of intermittent hypoxia impacts metabolic outcomes and severity of murine NAFLD.

Obstructive sleep apnea (OSA) is associated with metabolic dysfunction, including progression of nonalcoholic fatty liver disease (NAFLD). Chronic intermittent hypoxia (IH) as a model of OSA worsens hepatic steatosis and fibrosis in rodents with diet induced obesity. However, IH also causes weight loss, thus complicating attempts to co-model OSA and NAFLD. We sought to determine the effect of various durations of IH exposure on metabolic and liver-related outcomes in a murine NAFLD model. We hypothesized that longer IH duration would worsen the NAFLD phenotype. Male C57BL/6J mice (n = 32) were fed a high trans-fat diet for 24 weeks, to induce NAFLD with severe steatohepatitis. Mice were exposed to an IH profile modeling severe OSA, for variable durations (0, 6, 12, or 18 weeks). Intraperitoneal glucose tolerance test was measured at baseline and at six-week intervals. Liver triglycerides, collagen and other markers of NAFLD were measured at sacrifice. Mice exposed to IH for 12 weeks gained less weight (p = 0.023), and had lower liver weight (p = 0.008) relative to room air controls. These effects were not observed in the other IH groups. IH of longer duration transiently worsened glucose tolerance, but this effect was not seen in the groups exposed to shorter durations of IH. IH exposure for 12 or 18 weeks exacerbated liver fibrosis, with the largest increase in hepatic collagen observed in mice exposed to IH for 12 weeks. Duration of IH significantly impacts clinically relevant outcomes in a NAFLD model, including body weight, fasting glucose, glucose tolerance, and liver fibrosis.

A randomized controlled crossover trial of acute intermittent and continuous hypoxia exposure in mild-moderate obstructive sleep apnea: A feasibility study.

In a prospective, randomized, controlled crossover study, we explored the effects of acute intermittent hypoxia and acute continuous hypoxia on patients with mild-moderate obstructive sleep apnea. Over three single-night sessions, subjects were alternately exposed to normoxia, acute continuous hypoxia and acute intermittent hypoxia before sleep. The apnea-hypopnea index and oxygen desaturation index were used to diagnose obstructive sleep apnea and evaluate efficacy. A responder was defined as a participant with a ≥ 50% reduction in apnea-hypopnea index between normoxia and hypoxia exposure. Sixteen participants with mild-moderate obstructive sleep apnea completed the study. Compared with normoxia, the mean apnea-hypopnea index decreased by 8.9 events per hr (95% confidence interval, 4.2-13.6, p = 0.001) with acute intermittent hypoxia and by 4.1 events per hr (95% confidence interval, 0.5-8.8, p = 0.082) with acute continuous hypoxia, equating to a mean decrease in apnea-hypopnea index of 4.8 events per hr (95% confidence interval, 0.1-9.5, p = 0.046) with acute intermittent hypoxia compared with acute continuous hypoxia. Compared with normoxia, the mean oxygen desaturation index decreased by 9.8 events per hr (95% confidence interval, 4.4-15.1, p = 0.001) with acute intermittent hypoxia but did not significantly decrease with acute continuous hypoxia; the mean oxygen desaturation index decreased by 7.2 events per hr (95% confidence interval, 1.8-12.6, p = 0.010) with acute intermittent hypoxia compared with acute continuous hypoxia. Of the 16 participants, 11 responded to acute intermittent hypoxia and four responded to acute continuous hypoxia (p = 0.032), of whom eight of 11 cases and all four cases had oxygen desaturation indexes <5 events per hr, respectively (p = 0.273). All participants tolerated acute intermittent hypoxia and there were no obvious adverse events during acute intermittent hypoxia exposure. In conclusion, acute intermittent hypoxia exposure improved apnea-hypopnea index and oxygen desaturation index in patients with mild-moderate obstructive sleep apnea, suggesting that further prospective validation of intermittent hypoxia exposure in patients with obstructive sleep apnea is needed to establish its clinical feasibility as a therapeutic modality.

The Effects of the Levels of Hypoxia in the Olfactory Nervous System in Mouse Model.

Intermittent hypoxia (IH) results in low-grade inflammation, sympathetic overactivity, and oxidative stress. However, the specific effects of IH on olfaction have not yet been directly assessed and remain unclear. Therefore, the purpose of this study was to investigate the cytotoxic effects of IH exposure on the mouse olfactory epithelium and the relationship between the concentration of hypoxia and the degree of destruction of the olfactory system. Thirty mice were randomly divided into six groups: control (room air for 4weeks), recovery control (room air for 5weeks), IH 5% oxygen concentration, IH 7% oxygen concentration, recovery 5% hypoxia, and recovery 7% hypoxia groups. Mice in the two hypoxia groups were exposed to 5% and 7% oxygen for 4weeks. Mice in the two recovery groups were exposed to room air for 1week after 4weeks of hypoxia period. Based on, the olfactory marker protein (OMP), Olfr1507, ADCY3, and GNAL were lower, whereas S100b and NGFRAP1 messenger RNA (mRNA) levels were higher in the 5% hypoxia group than those in the control group in the olfactory neuroepithelium. In the brain tissue, the changes in RNA analysis for Olfr 1507, OMP, ADCY, and GNAL mRNA were not typical. However, NeuN and GFAP levels were decreased under 5% hypoxia in the brain tissue. In the recovery state, CNPase, S100b and NeuN levels were increased significantly in both the olfactory neuroepithelium and brain tissue in the 5% hypoxia group. The change in RNA activity in PCR was much higher in the 5% hypoxia group than in the 7% hypoxia group. Our findings suggest that IH damages the olfactory neuroepithelium and brain tissue in mouse model. The activity of olfactory marker genes and neurogenesis in the olfactory neuroepithelium were decreased. The levels of oxygen may be affect changes in the olfactory neuroepithelium. The olfactory ensheathing cell may be a major factor in the recovery of the olfactory neuroepithelium.

Effect of Intermittent Hypobaric Hypoxia Exposure on HIF-1α, VEGF, and Angiogenesis in the Healing Process of Post-Tooth Extraction Sockets in Rats.

The aim of this study was to investigate the effect of intermittent hypobaric hypoxia (IHH) exposure on the expression of hypoxia-induced factor-1α (HIF-1α) messenger RNA (mRNA), vascular endothelial growth factor-a (VEGF-a) mRNA, and angiogenesis after tooth extraction in rats. On 45 male Sprague-Dawley rats were performed the removal of the maxillary left first molar, and then they were randomly divided into 9 groups, namely: 4 groups that were exposed to IHH for 30 minutes every day in the Hypobaric Chamber at an altitude of 18,000 feet, with 1 time hypobaric hypoxia (HH), 3 times HH, 5 times HH, and 7 times HH; 4 normoxia groups that were terminated on days 1, 3, 5, and 7 after tooth extraction; and the 1 control group. Real-time polymerase chain reaction measured the molecular changes in the socket tissue after tooth extraction in rats to evaluate the expression of HIF-1α mRNA and VEGF mRNA. Histological changes with hematoxylin and eosin staining were noted to evaluate the amount of angiogenesis in the socket after tooth extraction. Molecular and histological parameters were calculated at the end of each experiment on days 0, 1, 3, 5, and 7 after tooth extraction, which exhibited the improvement phase of the wound-healing process. Increases in the expression of HIF-1α mRNA, VEGF mRNA, and angiogenesis were found in the IHH group compared with the normoxia group and the control group. The expression of HIF-1α mRNA increased significantly (p < 0.05) in the group after one time HH exposure on day 1, then decreased in the IHH group (three times HH exposure, five times HH exposure, and seven times HH exposure) approaching the control group. The expression of VEGF mRNA and angiogenesis began to increase after one time HH exposure on day 1, and increased again after three times HH exposure on day 3, then increased even more after five times HH exposure on day 5, and increased very significantly (**p < 0.05) after seven times HH exposure on day 7. It showed that repeated or intermittent exposure to HH conditions induced a protective response that made cells adapt under hypoxia conditions. IHH exposure accelerates the socket healing of post-tooth extraction, which is proven by changes in HIF-1α mRNA expression and increase in VEGF mRNA expression as stimuli for angiogenesis in post-tooth extraction sockets under hypobaric hypoxic condition, which also stimulates the formation of new blood vessels, thereby increasing blood supply and accelerating wound healing.

Obstructive sleep apnea in a mouse model is associated with tissue-specific transcriptomic changes in circadian rhythmicity and mean 24-hour gene expression.

Intermittent hypoxia (IH) is a major clinical feature of obstructive sleep apnea (OSA). The mechanisms that become dysregulated after periods of exposure to IH are unclear, particularly in the early stages of disease. The circadian clock governs a wide array of biological functions and is intimately associated with stabilization of hypoxia-inducible factors (HIFs) under hypoxic conditions. In patients, IH occurs during the sleep phase of the 24-hour sleep-wake cycle, potentially affecting their circadian rhythms. Alterations in the circadian clock have the potential to accelerate pathological processes, including other comorbid conditions that can be associated with chronic, untreated OSA. We hypothesized that changes in the circadian clock would manifest differently in those organs and systems known to be impacted by OSA. Using an IH model to represent OSA, we evaluated circadian rhythmicity and mean 24-hour expression of the transcriptome in 6 different mouse tissues, including the liver, lung, kidney, muscle, heart, and cerebellum, after a 7-day exposure to IH. We found that transcriptomic changes within cardiopulmonary tissues were more affected by IH than other tissues. Also, IH exposure resulted in an overall increase in core body temperature. Our findings demonstrate a relationship between early exposure to IH and changes in specific physiological outcomes. This study provides insight into the early pathophysiological mechanisms associated with IH.

Chronic intermittent hypobaric hypoxia induces cardiovascular dysfunction in a high-altitude working shift model

AimsChronic intermittent hypobaric hypoxia (CIHH) exposure due to shift work occurs mainly in 4 × 4 or 7 × 7 days shifts in mining, astronomy, and customs activities, among other institutions. However, the long-lasting effects of CIHH on cardiovascular structure and function are not well characterized. We aimed to investigate the effects of CIHH on the cardiac and vascular response of adult rats simulating high-altitude (4600 m) x low-altitude (760 m) working shifts. Main methodsWe analyzed in vivo cardiac function through echocardiography, ex vivo vascular reactivity by wire myography, and in vitro cardiac morphology by histology and protein expression and immunolocalization by molecular biology and immunohistochemistry techniques in 12 rats, 6 exposed to CIHH in the hypoxic chamber, and respective normobaric normoxic controls (n = 6). Key findingsCIHH induced cardiac dysfunction with left and right ventricle remodeling, associated with an increased collagen content in the right ventricle. In addition, CIHH increased HIF-1α levels in both ventricles. These changes are associated with decreased antioxidant capacity in cardiac tissue. Conversely, CIHH decreased contractile capacity with a marked decreased in nitric oxide-dependent vasodilation in both, carotid and femoral arteries. SignificanceThese data suggest that CIHH induces cardiac and vascular dysfunction by ventricular remodeling and impaired vascular vasodilator function. Our findings highlight the impact of CIHH in cardiovascular function and the importance of a periodic cardiovascular evaluation in high-altitude workers.

TGF-β3 Protects Neurons Against Intermittent Hypoxia-Induced Oxidative Stress and Apoptosis Through Activation of the Nrf-2/KEAP1/HO-1 Pathway via Binding to TGF-βRI.

Intermittent hypoxia (IH) is the primary pathological manifestation of obstructive sleep apnea (OSA) and the main cause of OSA-induced cognitive impairment. Hippocampal neurons are considered to be critical cells affected by IH. Transforming growth factor-β3 (TGF-β3) is a cytokine with a neuroprotective effect, which plays a crucial role in resisting hypoxic brain injury, while its role in IH-induced neuronal injury is still unclear. Here, we aimed to clarify the mechanism of TGF-β3 protecting IH-exposed neurons by regulating oxidative stress and secondary apoptosis. Morris water maze results revealed that IH exposure was unable to affect the vision and motor ability of rats, but significantly affected their spatial cognition. Second-generation sequencing (RNA-seq) and subsequent experiments supported that IH decreased TGF-β3 expression and stimulated reactive oxygen species (ROS)-induced oxidative stress and apoptosis in rat hippocampus. In vitro, IH exposure significantly activated oxidative stress within HT-22 cells. Exogenous administration of Recombinant Human Transforming Growth Factor-β3 (rhTGF-β3) prevented ROS surge and secondary apoptosis in HT-22 cells caused by IH, while TGF-β type receptor I (TGF-βRI) inhibitor SB431542 blocked the neuroprotective effect of rhTGF-β3. Nuclear factor erythroid 2-related factor 2 (Nrf-2) is a transcription factor preserving intracellular redox homeostasis. rhTGF-β3 improved the nuclear translocation of Nrf-2 and activated downstream pathway. However, Nrf-2 inhibitor ML385 suppressed the activation of the Nrf-2 mechanism by rhTGF-3 and restored the effects of oxidative stress damage. These results indicate that TGF-β3 binding to TGF-βRI activates the intracellular Nrf-2/KEAP1/HO-1 pathway, reduces ROS creation, and attenuates oxidative stress and apoptosis in IH-exposed HT-22 cells.