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Intermittent hypoxia (IH) has been extensively studied in recent years, demonstrating adverse and beneficial effects on several physiological systems. However, the precise mechanism underlying its cardiac effects on the heart remains unclear. This study aims to explore the effect of treatment on atrial fibrillation under IH conditions, providing data that can potentially be used in the treatment of heart disease. An atrial fibrillation (AF) model was induced by injecting monocrotaline (MCT, 60 mg/kg) into rats. The study included 32 rats divided into four groups: Control, Control + IH, AF, and AF + IH. We evaluated molecular changes associated with AF using ELISA and Western blot and performed electrophysiological experiments to evaluate AF. Arrhythmia-related calcium and fibrosis markers were investigated. Phosphorylation levels of CaMKII, Phospholamban, and RyR2 all increased in the AF group but decreased in the IH-exposed group. Additionally, fibrosis marker expressions such as SMA, MMP2, MMP9, and TGF-β increased in the AF group but were significantly downregulated with IH treatment. Connexin 43 and AQP4 expression were restored in the IH-treated group. These findings suggest that IH may prevent AF by downregulating the expression of calcium-handling proteins and fibrosis-associated proteins in an AF-induced rat model. [ABSTRACT FROM AUTHOR]

Intermittent hypoxia in sleep apnea syndrome (SAS) patients increases the oxidative stress and can cause serious cardiovascular diseases such as hypertension or atherosclerotic diseases through endothelial dysfunction. The evaluation of risk caused by oxidative stress, however, is not easy in a clinical setting. Thus, we intended to evaluate the changes in oxidative stress by SAS treatment using a simple method that can be easily used in the clinical testing. We enrolled 42 consecutive newly diagnosed severe SAS patients (30 men). Reactive oxygen species metabolites (d-ROMs) for oxidative stress and biological antioxidant (BAP) in blood samples were estimated using FREE Carrio Duo® before and 3 months after continuous positive airway pressure (CPAP) treatment. SAS parameters were obtained by polysomnography before CPAP and endothelial function was measured twice as well. The body mass index and apnea hypopnea index (AHI) were 29.1 ± 5.3 and 57.9 ± 19.7/h. The d-ROMs and BAP were 317.4 ± 71.8 CARR U and 2121.2 ± 299.6 μmol/L. Although no significant correlation was found between hypoxia parameters and d-ROMs or BAP before CPAP treatment, we found a significant negative correlation between basal AHI or basal oxygen desaturation index representing intermittent hypoxia and the change in d-ROMs (r = − 0.31, p = 0.046/r = − 0.33, p = 0.03) and between the change in SpO2 < 90% duration (min) representing continuous hypoxia and the change in BAP (r = − 0.35, p = 0.03) after CPAP treatment. The changes in d-ROM and BAP might reflect the different kind of reduction of oxidative stress by CPAP treatment and, thus, can be used as handy indicators of the treatment effect. [ABSTRACT FROM AUTHOR]

Altered expressions of pro-/anti-oxidant genes are known to regulate the pathophysiology of obstructive sleep apnea (OSA).We aim to explore the role of a novel long non-coding (lnc) RNA FKSG29 in the development of intermittent hypoxia with re-oxygenation (IHR)-induced endothelial dysfunction in OSA. Gene expression levels of key pro-/anti-oxidant genes, vasoactive genes, and the FKSG29 were measured in peripheral blood mononuclear cells from 12 subjects with primary snoring (PS) and 36 OSA patients. Human monocytic THP-1 cells and human umbilical vein endothelial cells (HUVEC) were used for gene knockout and double luciferase under IHR exposure. Gene expression levels of the FKSG29 lncRNA, NOX2, NOX5, and VEGFA genes were increased in OSA patients versus PS subjects, while SOD2 and VEGFB gene expressions were decreased. Subgroup analysis showed that gene expression of the miR-23a-3p, an endogenous competitive microRNA of the FKSG29, was decreased in sleep-disordered breathing patients with hypertension versus those without hypertension. In vitro IHR experiments showed that knock-down of the FKSG29 reversed IHR-induced ROS overt production, early apoptosis, up-regulations of the HIF1A/HIF2A/NOX2/NOX4/NOX5/VEGFA/VEGFB genes, and down-regulations of the VEGFB/SOD2 genes, while the protective effects of FKSG29 knock-down were abolished by miR-23a-3p knock-down. Dual-luciferase reporter assays confirmed that FKSG29 was a sponge of miR-23a-3p, which regulated IL6R directly. Immunofluorescence stain further demonstrated that FKSGH29 knock-down decreased IHR-induced uptake of oxidized low density lipoprotein and reversed IHR-induced IL6R/STAT3/GATA6/ICAM1/VCAM1 up-regulations. The findings indicate that the combined RNA interference may be a novel therapy for OSA-related endothelial dysfunction via regulating pro-/anti-oxidant imbalance or targeting miR-23a-IL6R-ICAM1/VCAM1 signaling. [ABSTRACT FROM AUTHOR]

Generating highly organized skeletal muscle tissues that mimics the cellular alignment, maturation, and contraction of native skeletal muscle remains a challenge in disease modeling and regenerative therapies. Existing methodologies are constrained by complexity in fabrication and difficulty in achieving aligned 3D myofibers. Here, a functional skeletal muscle organoid‐on‐a‐chip (SMO) is engineered by establishing mechanical boundary constraints at either end of the cell‐laden extracellular matrix hydrogel within polydimethylsiloxane microstructures to promote the formation of an anisotropic biophysical microenvironment in tissues. The linearly aligned tissue, featuring multinucleated myofibers with distinct cross‐striations, exhibited a positive force‐frequency relationship and stable calcium transients under electrical stimulation. SMOs applicability is demonstrated by systematically evaluating muscle response to varying degrees of intermittent hypoxia. Murine‐ or human‐derived SMOs revealed that, with increasing hypoxia severity, muscles transitioned from a compensatory phase‐characterized by enhanced contractile function, vacuolation and hypertrophic‐like changes in myofibers, fiber type switching, and metabolic shift, to a decompensatory stage, paralleling in vivo muscle responses and highlighting interspecies differences. Human‐derived SMOs are also utilized to assess self‐repair capabilities and pharmaceuticals protective effects on damaged muscle. Together, the platform, with its simplicity of operation and reliable phenotypic readouts, demonstrates significant potential for future disease modeling and regenerative therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: Intermittent and chronic hypoxia are common and harmful to marine animals. The tiger puffer is a representative species of the family Tetraodontidae, which has only slit-like gill openings and is susceptible to hypoxia stress. Both intermittent and chronic hypoxia decrease the growth and visceral weight of tiger puffer but increase the feed conversion ratio and blood hemoglobin content. Chronic hypoxia but not intermittent hypoxia promoted protein synthesis and the glycolysis pathway. Intermittent hypoxia but not chronic hypoxia decreased lipid synthesis and monounsaturated fatty acids content but increased n-3 polyunsaturated fatty acids levels. These changes promoted the adaption of tiger puffer to intermittent and chronic hypoxia. Intermittent and chronic hypoxia are common stresses to marine fish, but the different responses of fish to intermittent and chronic hypoxia have not been well-known. In this study, tiger puffers were farmed in normoxia conditions (NO, 6.5 ± 0.5 mg/L), intermittent hypoxia (IH, 6.5 ± 0.5 mg/L in the day and 3.5 ± 0.5 mg/L in the night), or choric hypoxia (CH, 3.5 ± 0.5 mg/L) conditions for 4 weeks, after which the growth, nutrient metabolism and three hifα isoforms expression were measured. Both intermittent and chronic hypoxia decreased the fish growth and visceral weight but increased the feed conversion ratio and blood hemoglobin content. Chronic hypoxia but not intermittent hypoxia promoted protein synthesis and whole-fish protein content by activating mtor gene expression and promoted the glycolysis pathway by activating gene expression of hif1α and hif2α. Intermittent hypoxia but not chronic hypoxia decreased the hepatic lipid synthesis by inhibiting fasn and srebf1 gene expression. Meanwhile, intermittent hypoxia reduced the monounsaturated fatty acid content but increased the n-3 polyunsaturated fatty acids percentage. The results of this study clarified the adaptive mechanism of tiger puffer to intermittent and chronic hypoxia, which provides important information about mechanisms of hypoxia adaption in fish. [ABSTRACT FROM AUTHOR]

Background: The rise in the aging population highlights the need to address cognitive decline and neurodegenerative diseases. Intermittent hypoxia (IH) protocols show promise in enhancing cognitive abilities and brain health. Objective: This review evaluates IH protocols' benefits on cognition and brain health in older adults, regardless of cognitive status. Methods: A systematic search following PRISMA guidelines was conducted across four databases (PubMed, Scopus, Web of Science, and Cochrane Library) and two registers, covering records from inception to May 2024 (PROSPERO: CRD42023462177). Inclusion criteria were: 1) original research with quantitative details; 2) studies involving older adults, with or without cognitive impairment; 3) studies including IH protocols; 4) articles analyzing cognition and brain health in older adults. Results: Seven studies and five registered trials met the criteria. Findings indicate that Intermittent Hypoxia Training (IHT) and Intermittent Hypoxia-Hyperoxia Training (IHHT) improved cognitive functions and brain health. Intermittent Hypoxic Exposure (IHE) improved cerebral tissue oxygen saturation, middle cerebral arterial flow velocity, and cerebral vascular conductance, particularly in cognitively impaired populations. IHT and IHHT had no significant effect on BDNF levels. There is a lack of studies on IHHE in older adults with and without cognitive impairment. Conclusions: IH protocols may benefit cognition regardless of cognitive status. IHT and IHE positively affect cerebral outcomes, with all protocols having limited effects on BDNF levels. Future research should standardize IH protocols, investigate long-term cognitive effects, and explore neuroprotective biomarkers. Combining these protocols with physical exercise across diverse populations could refine interventions and guide targeted therapeutic strategies. [ABSTRACT FROM AUTHOR]

This systematic review and meta-analysis investigates the relationship between haemoglobin (Hb) concentrations and obstructive sleep apnea syndrome (OSAS). Following PRISMA guidelines, we searched PubMed, EMBASE, and Cochrane Library from inception to March 8, 2024. Eligible studies included cross-sectional, cohort, and case-control designs comparing Hb concentrations in OSAS patients and healthy controls. Two reviewers independently screened records and extracted data. The risk of bias was assessed using the Joanna Briggs Institute checklist. A total of 27 studies involving 6499 OSAS subjects and 5199 controls were included. Hb concentrations were significantly higher in OSAS patients compared to controls (SMD: 0.28; 95 % CI: 0.18 to 0.39; I2 = 84.4 %). Subgroup analysis by OSAS severity showed that severe OSAS patients had higher Hb concentrations than those with mild/moderate OSAS. Sensitivity analyses confirmed the robustness of the findings. However, 7 studies reported opposite results, indicating possible regional or methodological differences. Hb concentrations are elevated in OSAS patients, with higher levels observed in severe cases. The significant heterogeneity and the predominance of studies from Turkey highlight the need for further research in diverse populations. Limitations include potential publication bias and variability in study designs. • A systematic review and meta-analysis were conducted to investigate the relationship between Hb concentrations and OSAS. • A total of 27 studies with 6499 OSAS patients and 5199 controls were included. • Hb concentrations were significantly higher in OSAS compared to CTRL (SMD: 0.28; 95 % CI: 0.18 to 0.39; I2 = 84.4 %). • The results suggest that elevated Hb levels in OSAS patients may reflect an adaptive response to intermittent hypoxia. • The relationship between OSAS severity and Hb concentrations highlights the potential clinical significance. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea (OSA), characterized by episodes of intermittent hypoxia (IH), is highly prevalent in patients with abdominal aortic aneurysm (AAA). However, whether IH serves as an independent risk factor for AAA development remains to be investigated. Here, we determined the effects of chronic (6 mo) IH on angiotensin (Ang II)-induced AAA development in C57BL/6J male mice and investigated the underlying mechanisms of IH in cultured vascular smooth muscle cells (SMCs). IH increased the susceptibility of mice to develop AAA in response to Ang II infusion by facilitating the augmentation of the abdominal aorta's diameter as assessed by transabdominal ultrasound imaging. Importantly, IH with Ang II augmented aortic elastin degradation and the expression of matrix metalloproteinases (MMPs), mainly MMP8, MMP12, and a disintegrin and metalloproteinase-17 (ADAM17) as measured by histology and immunohistochemistry. Mechanistically, IH increased the activities of MMP2, MMP8, MMP9, MMP12, and ADAM17, while reducing the expression of the MMP regulator reversion-inducing cysteine-rich protein with Kazal motifs (RECK) in cultured SMCs. Aortic samples from human AAA were associated with decreased RECK and increased expression of ADAM17 and MMPs. These data suggest that IH facilitates AAA development when additional stressors are superimposed and that this occurs in association with an increased presence of aortic MMPs and ADAM17, potentially due to IH-induced modulation of RECK expression. These findings support a plausible synergistic link between OSA and AAA and provide a better understanding of the molecular mechanisms underlying the pathogenesis of AAA. NEW & NOTEWORTHY: IH facilitates Ang II-induced abdominal aortic diameter expansion and AAA development in C57BL/6J male mice. IH upregulates the expression of specific MMPs such as MMP8, MMP12, and ADAM17. IH directly suppresses RECK expression and increases MMPs activity in SMCs. Human AAA tissues exhibit a downregulation of RECK and an upregulation of ADAM17 and MMPs. [ABSTRACT FROM AUTHOR]

Background/Objectives: Mental disorders pose a significant public health challenge, affecting millions worldwide. Given the limitations of current therapies, many patients experience inadequate responses and adverse effects. Intermittent hypoxia (IH) has demonstrated anxiolytic, antidepressant, and neuroprotective properties in various protocols. This study investigated the effects of acute IH (13% O2, 1 h), fluoxetine (FLX) and their combination on depression-like behavior, serum corticosterone, and inflammatory cytokine levels induced by acute restraint stress in C57BL/6 female mice. Methods: Behavioral assessments included the tail suspension test, forced swim test, and open field test. Results: The combined IH + FLX treatment exhibited a synergistic effect, reducing immobility time and increasing latency time, respectively, in the tail suspension test (46%, p = 0.0014; 73%, p = 0.0033) and forced swim test (56%, p = 0.0082; 48%, p = 0.0322) compared to the ARS group. Biochemical analysis revealed that individual and combined treatments significantly reduced most inflammatory interleukins by up to 96%. Corticosterone levels were reduced by 30% only in the IH group. Conclusions: These findings highlight the potential of a one-hour IH session, particularly when combined with fluoxetine, to alleviate depressive-like behaviors and exert anti-inflammatory effects, suggesting a promising therapeutic approach for depression. [ABSTRACT FROM AUTHOR]

Caffeine is one of the most commonly used drugs in intensive care to stimulate the respiratory control mechanisms of very preterm infants. Respiratory instability, due to the degree of immaturity at birth, results in apnea of prematurity (AOP), hyperoxic, hypoxic, and intermittent hypoxic episodes. Oxidative stress cannot be avoided as a direct reaction and leads to neurological developmental deficits and even a higher prevalence of respiratory diseases in the further development of premature infants. Due to the proven antioxidant effect of caffeine in early use, largely protective effects on clinical outcomes can be observed. This is also impressively observed in experimental studies of caffeine application in oxidative stress-adapted rodent models of damage to the developing brain and lungs. However, caffeine shows undesirable effects outside these oxygen toxicity injury models. This review shows the effects of caffeine in hyperoxic, hypoxic/hypoxic-ischemic, and intermittent hypoxic rodent injury models, but also the negative effects on the rodent organism when caffeine is administered without exogenous oxidative stress. The narrative analysis of caffeine benefits in cerebral and pulmonary preterm infant models supports protective caffeine use but should be given critical consideration when considering caffeine treatment beyond the recommended corrected gestational age. [ABSTRACT FROM AUTHOR]

Wenbin Guo,1,&ast; Lin Sun,1,&ast; Huijun Yue,1,&ast; Xueqin Guo,1 Lin Chen,1 Jinhong Zhang,1 Zhuqi Chen,1 Yiming Wang,1 Jiao Wang,2 Wenbin Lei1 1Otorhinolaryngology Hospital, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People’s Republic of China; 2School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, 510080, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiao Wang, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, Guangdong, People’s Republic of China, Email wangj836@mail.sysu.edu.cn Wenbin Lei, Otorhinolaryngology Hospital, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, People’s Republic of China, Email leiwb@mail.sysu.edu.cnPurpose: Clinical studies focusing on the association between the gut microbiota and obstructive sleep apnea (OSA) are limited. This study aimed to explore the relationship between intermittent hypoxia and the composition of gut microbiota in adults by analyzing the differences in the characteristics and functional distribution of gut microbiota between patients with different severities of OSA and healthy individuals.Patients and Methods: A cohort of 113 individuals from the First Affiliated Hospital of Sun Yat-sen University underwent overnight polysomnography from July 2019 to August 2021. The individuals included 16 healthy controls and 97 patients with OSA, categorized by the apnea-hypopnea index into mild, moderate, and severe groups. Fecal samples were analyzed using high-throughput sequencing of the 16S rRNA V3–V4 region to assess gut microbiota composition and function. Correlation analysis was used to evaluate the association between clinical indicators and microbiota markers.Results: In patients with OSA, the gut microbiota diversity and the abundance of specific microbes that produce short-chain fatty acids decreased (P< 0.05). The phyla Verrucomicrobia and Candidatus Saccharibacteria, genera Gemmiger and Faecalibacterium, and the species Gemmiger formicilis exhibited decreasing abundance with increasing OSA severity. Correlation analysis revealed a robust association between the proportion of total sleep time, characterized by nighttime blood oxygen saturation below 90%, and the alterations in the gut microbiota, demonstrating that elevated levels of desaturation are correlated with pronounced microbiota dysbiosis (P< 0.05).Conclusion: Compared to the control group, the intermittent hypoxia exhibited by patients with OSA may be related to alterations in the composition and structure of the gut microbiota. Our results demonstrate the importance of monitoring hypoxia indicators in future clinical practice.Keywords: obstructive sleep apnea, gut microbiota, 16S rRNA, intermittent hypoxia

Background The body produces more hypoxia-inducible factor and reactive oxygen species in response to hypoxic situations because they cause unbalanced oxygen levels. Ficus carica provides numerous benefits because of its high antioxidant and mineral content. Nevertheless, the mechanism by which F. carica consumption confers this protective benefit remains incompletely understood. Aim This study aimed to evaluate how F. carica puree (FCP) can affect the antioxidant enzyme activity and malondialdehyde (MDA) levels in the lung by mitigating the effects of intermittent hypoxia (IH). Methods Thirty Sprague–Dawley rats were divided into five groups: negative control (NC), untreated; positive control (PC), treated with aquadest; FCP1; FCP2; and FCP3, which received FCP at doses of 1.25, 2.5, and 5 mL/200 g body weight. The treatment was administered for 4 weeks before inducing IH (10% O2 and 90% N2) into all groups (except NC) for 4 h for 7 days. Furthermore, hemoglobin (Hb) level, lung MDA level, and lung superoxide dismutase (SOD) enzyme activity were assessed. Results The Hb level did not exhibit a significant increase under IH conditions. Conversely, the PC group exhibited the least activity of lung antioxidant enzymes and the highest lung MDA levels. In addition, the FCP intervention group exhibited lower MDA levels than the PC group and ameliorated relative lung weight loss. Conclusion All FCP intervention groups showed lower MDA levels and higher SOD levels compared to the PC group, suggesting that FCP could mitigate the effects of hypoxia in rat lungs.

Lingling Wang,1 Huiguo Liu,1 Ling Zhou,1 Pengdou Zheng,1 Hai Li,2,3 Huojun Zhang,4,&ast; Wei Liu2,3,&ast; 1Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 3Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huojun Zhang, Email hjzhang@whu.edu.cn; Wei Liu, Email 404793938@tjh.tjmu.edu.cnAbstract: Obstructive sleep apnea (OSA), a common sleep-disordered breathing condition, is characterized by intermittent hypoxia (IH) and sleep fragmentation and has been implicated in the pathogenesis and severity of nonalcoholic fatty liver disease (NAFLD). Abnormal molecular changes mediated by IH, such as high expression of hypoxia-inducible factors, are reportedly involved in abnormal pathophysiological states, including insulin resistance, abnormal lipid metabolism, cell death, and inflammation, which mediate the development of NAFLD. However, the relationship between IH and NAFLD remains to be fully elucidated. In this review, we discuss the clinical correlation between OSA and NAFLD, focusing on the molecular mechanisms of IH in NAFLD progression. We meticulously summarize clinical studies evaluating the therapeutic efficacy of continuous positive airway pressure treatment for NAFLD in OSA. Additionally, we compile potential molecular biomarkers for the co-occurrence of OSA and NAFLD. Finally, we discuss the current research progress and challenges in the field of OSA and NAFLD and propose future directions and prospects.Keywords: intermittent hypoxia, hypoxia-inducible factor 1 alpha, nonalcoholic fatty liver disease, oxidative stress, dyslipidemia, leptin resistance

Periodic breathing (PB)-related intermittent hypoxia can have long-lasting deleterious consequences in preterm infants. Olfactory stimulation using vanilla odor is beneficial for apnea of prematurity in the first postnatal days/weeks. We aimed to determine for the first time whether vanilla odor can also decrease PB-related intermittent hypoxia. This pilot study was a balanced crossover clinical trial including 27 premature infants born between 30 and 33+6 weeks of gestation. We performed 12-h recordings on two nights separated by a 24-h period. All infants were randomly exposed to vanilla odor on the first or second study night. The primary outcome was the desaturation index, defined as the number per hour of pulse oximetry (SpO 2) values <90 % for at least 5 s, together with a drop of ≥5 % from the preceding value. Univariate mixed linear models were used for the statistical analysis. Overall, exposure to vanilla odor did not significantly decrease the desaturation index (52 ± 22 events/h [mean ± SD] on the intervention night vs. 57 ± 26, p = 0.2); furthermore, it did not significantly alter any secondary outcome. In a preliminary post hoc subgroup analysis, however, the effect of vanilla odor was statistically significant in infants with a desaturation index of ≥70/h (from 86 ± 12 to 65 ± 23, p = 0.04). In this pilot study, vanilla odor overall did not decrease PB-related intermittent hypoxia in infants born at 30–33+6 weeks of gestation, which is when they are close to term. Preliminary results suggesting a beneficial effect in infants with the highest desaturation index, however, justify further studies in the presence of PB-related intermittent hypoxia as well as in infants born more prematurely. [ABSTRACT FROM AUTHOR]

Intermittent hypoxia (IH) is the predominant pathophysiological disturbance in obstructive sleep apnea (OSA), characterized by neuronal cell death and neurocognitive impairment. We focus on the accumulated mitochondrial DNA (mtDNA) in the cytosol, which acts as a damage-associated molecular pattern (DAMP) and activates the cyclic GMP-AMP synthase (cGAS)—stimulator of interferon genes (STING) pathway, a known trigger for immune responses and neuronal death in degenerative diseases. However, the specific role and mechanism of the mtDNA-cGAS-STING axis in IH-induced neural damage remain largely unexplored. Here, we investigated the involvement of PANoptosis, a novel type of programmed cell death linked to cytosolic mtDNA accumulation and the cGAS-STING pathway activation, in neuronal cell death induced by IH. Our study found that PANoptosis occurred in primary cultures of hippocampal neurons and HT22 cell lines exposed to IH. In addition, we discovered that during IH, mtDNA released into the cytoplasm via the mitochondrial permeability transition pore (mPTP) activates the cGAS-STING pathway, exacerbating PANoptosis-associated neuronal death. Pharmacologically inhibiting mPTP opening or depleting mtDNA significantly reduced cGAS-STING pathway activation and PANoptosis in HT22 cells under IH. Moreover, our findings indicated that the cGAS-STING pathway primarily promotes PANoptosis by modulating endoplasmic reticulum (ER) stress. Inhibiting or silencing the cGAS-STING pathway substantially reduced ER stress-mediated neuronal death and PANoptosis, while lentivirus-mediated STING overexpression exacerbated these effects. In summary, our study elucidates that cytosolic escape of mtDNA triggers cGAS-STING pathway-dependent neuronal PANoptosis in response to IH, mainly through regulating ER stress. The discovery of the novel mechanism provides theoretical support for the prevention and treatment of neuronal damage and cognitive impairment in patients with OSA. [ABSTRACT FROM AUTHOR]

Structural neuroplasticity such as neurite extension and dendritic spine dynamics is enhanced by brain-derived neurotrophic factor (BDNF) and impaired by types of inhibitory molecules that induce growth cone collapse and actin depolymerization, for example, myelin-associated inhibitors, chondroitin sulfate proteoglycans, and negative guidance molecules. These inhibitory molecules can activate RhoA/rho-associated coiled-coil containing protein kinase (ROCK) signaling (known to restrict structural plasticity). Intermittent hypoxia (IH) and high-intensity interval training (HIIT) are known to upregulate BDNF that is associated with improvements in learning and memory and greater functional recovery following neural insults. We investigated whether the RhoA/ROCK signaling pathway is also modulated by IH and HIIT in the hippocampus, cortex, and lumbar spinal cord of male Wistar rats. The gene expression of 25 RhoA/ROCK signaling pathway components was determined following IH, HIIT, or IH combined with HIIT (30 min/day, 5 days/wk, 6 wk). IH included 10 3-min bouts that alternated between hypoxia (15% O2) and normoxia. HIIT included 10 3-min bouts alternating between treadmill speeds of 50 cm·s−1 and 15 cm·s−1. In the hippocampus, IH and HIIT significantly downregulated Acan and NgR2 mRNA that are involved in the inhibition of neuroplasticity. However, IH and IH + HIIT significantly upregulated Lingo-1 and NgR3 in the cortex. This is the first time IH and HIIT have been linked to the modulation of plasticity-inhibiting pathways. These results provide a fundamental step toward elucidating the interplay between the neurotrophic and inhibitory mechanisms involved in experience-driven neural plasticity that will aid in optimizing physiological interventions for the treatment of cognitive decline or neurorehabilitation. NEW & NOTEWORTHY: Intermittent hypoxia (IH) and high-intensity interval training (HIIT) enhance neuroplasticity and upregulate neurotrophic factors in the central nervous system (CNS). We provide evidence that IH and IH + HIIT also have the capacity to regulate genes involved in the RhoA/ROCK signaling pathway that is known to restrict structural plasticity in the CNS. This provides a new mechanistic insight into how these interventions may enhance hippocampal-related plasticity and facilitate learning, memory, and neuroregeneration. [ABSTRACT FROM AUTHOR]

Background: Obstructive sleep apnea (OSA) is associated with multiple comorbidities, including diabetes. Its development is preceded by alterations in the initial phase of carbohydrate metabolism characterized by insulin resistance. This study aims to evaluate the role of intermittent hypoxia and sleep fragmentation characteristic of OSA on the risk of insulin resistance among apneic patients without diabetes. Methodology: 92 consecutive patients with OSA without evidence of diabetes were recruited. Overnight video polysomnography was performed and, the following morning, fasting blood glucose, insulin and glycosylated hemoglobin were determined. Insulin resistance was measured using the HOMA-IR index. Results: Insulin resistance was present in 52.2% of OSA patients. In these subjects, insulin resistance was independently associated to the apnea index during REM sleep (adjusted odds ratio [aOR] 1.09; 95% CI, 1.03 to 1.16; p = 0.004), desaturation index (aOR 1.08; 95% CI: 1.04 to 1.13; p = 0.027), and sleep time with oxygen saturation below 90% (aOR 1.04; 95% CI 1.00 to 1.08; p = 0.049). Furthermore, the HOMA-IR level was also directly related to the desaturation index (standardized regression coefficient [B] = 0.514, p < 0.001) and to the apnea index during REM sleep (B = 0.344, p = 0.002). Conclusions: Intermittent hypoxia and disturbances in REM sleep emerge as main contributors to insulin resistance in OSA patients yet to experience diabetes onset. [ABSTRACT FROM AUTHOR]

Background: Obstructive sleep apnea (OSA) has been shown to be an important risk factor for cardiovascular disease (CVD), and intermittent hypoxia is an important pathogenetic factor for it. In the clinic, it was found that most CVD patients combined with OSA were also combined with solitary pulmonary nodules (SPN) or thyroid nodules (TN). Are these disorders related to intermittent hypoxia? One study showed that intermittent hypoxia is a pathogenic factor for lung cancer in mice, but there have been no clinical reports. So we conducted a retrospective study to explore whether intermittent hypoxia caused by OSA increases the incidence of SPN, TN, and other disorders. Methods: We selected 750 patients with cardiovascular disease (CVD), who were divided into the control group and the OSA group according to the result of portable sleep monitoring. Retrospectively analyzed the comorbidities that patients with OSA are prone to and explored the correlation between OSA and those comorbidities. Results: The incidence of SPN, TN, cervical spondylosis, and carotid-artery plaques was higher in the OSA group than in the control group. These diseases are significantly associated with OSA (p < 0.05), and their incidence increased with an elevated apnea–hypopnea index. After excluding interference from age, gender, BMI, smoking history, history of lung disease, and history of tumors, OSA showed a significant correlation with SPN. After excluding age, gender, BMI, and thyroid disease, OSA was associated with TN. Patients with comorbidities have lower nocturnal oxygen saturation and more extended periods of apnea. Logistic multiple regression results revealed that male, advanced age, obesity, CS, and nasal septum deviation were independent risk factors for OSA. Conclusions: Patients combined with OSA may further develop more comorbidities, such as SPN, TN, and carotid-artery plaques. It may be related to intermittent hypoxia caused by OSA. [ABSTRACT FROM AUTHOR]

Aging is associated with vascular endothelial dysfunction observed through a progressive loss of flow-mediated dilation caused partly by a decreased nitric oxide bioavailability. Intermittent hypoxia, consisting of alternating short bouts of breathing hypoxic and normoxic air, was reported to either maintain or improve vascular function in young adults. The aim of this study was to determine the impact of age on the vascular response to intermittent hypoxia. Twelve young adults and 11 older adults visited the laboratory on two occasions. Plasma nitrate concentrations and brachial artery flow-mediated dilation were assessed before and after exposure to either intermittent hypoxia or a sham protocol. Intermittent hypoxia consisted of eight 4-min hypoxic cycles at a targeted oxygen saturation of 80% interspersed with breathing room air to resaturation, and the sham protocol consisted of eight 4-min normoxic cycles interspersed with breathing room air. Vascular responses were assessed during intermittent hypoxia and the sham protocol. Intermittent hypoxia elicited a brachial artery vasodilation but did not change brachial artery shear rate in both young and older adults. Plasma nitrate concentrations were not significantly affected by intermittent hypoxia compared with the sham protocol in both groups. Brachial artery flow-mediated dilation was not acutely affected by intermittent hypoxia or the sham protocol in either young or older adults. In conclusion, the brachial artery vasodilatory response to intermittent hypoxia was not influenced by age. Intermittent hypoxia increased brachial artery diameter but did not acutely affect endothelium-dependent vasodilation in young or older adults. NEW & NOTEWORTHY: The objective of this study was to determine the impact of age on the vascular response to intermittent hypoxia. Eight 4-min bouts of hypoxia at a targeted oxygen saturation of 80% induced a brachial artery vasodilation in both young and older adults, indicating that age does not influence the vasodilatory response to intermittent hypoxia. Intermittent hypoxia did not acutely affect brachial artery flow-mediated dilation in young or older adults. [ABSTRACT FROM AUTHOR]

The increased incidence of hypertension associated with obstructive sleep apnea (OSA) presents significant physical, psychological, and economic challenges. Peroxisome proliferator-activated receptor gamma (PPARγ) plays a role in both OSA and hypertension, yet the therapeutic potential of PPARγ agonists and antagonists for OSA-related hypertension remains unexplored. Therefore, we constructed a chronic intermittent hypoxia (CIH)-induced hypertension rat model that mimics the pathogenesis of OSA-related hypertension in humans. The model involved administering PPARγ agonist rosiglitazone (RSG), PPARγ antagonist GW9662, or normal saline, followed by regular monitoring of blood pressure and thoracic aorta analysis using staining and electron microscopy. Intriguingly, our results indicated that both RSG and GW9662 appeared to potently counteract CIH-induced hypertension. In silico study suggested that GW9662's antihypertensive effect might mediated through angiotensin II receptor type 1 (AGTR1). Our findings provide insights into the mechanisms of OSA-related hypertension and propose novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea syndrome (OSAS) causes recurrent apnea and intermittent hypoxia at night, leading to several complications such as cognitive dysfunction. However, the molecular mechanisms underlying cognitive dysfunction in OSAS are unclear, and oxidative stress mediated by intermittent hypoxia is an important mechanism. In addition, the improvement of cognitive dysfunction in patients with OSAS varies by different treatment regimens; among them, continuous positive airway pressure therapy (CPAP) is mostly recognized for improving cognitive dysfunction. In this review, we discuss the potential mechanisms of oxidative stress in OSAS, the common factors of affecting oxidative stress and the Links between oxidative stress and inflammation in OSAS, focusing on the potential links between oxidative stress and cognitive dysfunction in OSAS and the potential therapies for neurocognitive dysfunction in patients with OSAS mediated by oxidative stress. Therefore, further analysis on the relationship between oxidative stress and cognitive dysfunction in patients with OSAS will help to clarify the etiology and discover new treatment options, which will be of great significance for early clinical intervention. [ABSTRACT FROM AUTHOR]

Intermittent hypoxia (IH) is an independent risk factor for metabolic dysfunction‐associated fatty liver disease (MAFLD). Copper deficiency can disrupt redox homeostasis, iron, and lipid metabolism. Here, we investigated whether hepatic copper deficiency plays a role in IH‐associated MAFLD and explored the underlying mechanism(s). Male C57BL/6 mice were fed a western‐type diet with adequate copper (CuA) or marginally deficient copper (CuD) and were exposed separately to room air (RA) or IH. Hepatic histology, plasma biomarkers, copper–iron status, and oxidative stress were assessed. An in vitro HepG2 cell lipotoxicity model and proteomic analysis were used to elucidate the specific targets involved. We observed that there were no differences in hepatic phenotypes between CuA‐fed and CuD‐fed mice under RA. However, in IH exposure, CuD‐fed mice showed more pronounced hepatic steatosis, liver injury, and oxidative stress than CuA‐fed mice. IH induced copper accumulation in the brain and heart and exacerbated hepatic copper deficiency and secondary iron deposition. In vitro, CuD‐treated cells with IH exposure showed elevated levels of lipid accumulation, oxidative stress, and ferroptosis susceptibility. Proteomic analysis identified 360 upregulated and 359 downregulated differentially expressed proteins between CuA and CuD groups under IH; these proteins were mainly enriched in citrate cycle, oxidative phosphorylation, fatty acid metabolism, the peroxisome proliferator‐activated receptor (PPAR)α pathway, and ferroptosis. In IH exposure, CuD significantly upregulated the ferroptosis‐promoting factor arachidonyl‐CoA synthetase long chain family member (ACSL)4. ACSL4 knockdown markedly eliminated CuD‐induced ferroptosis and lipid accumulation in IH exposure. In conculsion, IH can lead to reduced hepatic copper reserves and secondary iron deposition, thereby inducing ferroptosis and subsequent MAFLD progression. Insufficient dietary copper may worsen IH‐associated MAFLD. [ABSTRACT FROM AUTHOR]

Aims: Patients with type 2 diabetes have a 20% lower total blood volume than age- and weight-matched healthy adults, suggesting a reduced capacity to transport oxygen in this population. Intermittent hypoxia, consisting of alternating short bouts of breathing hypoxic and normoxic air, increases erythropoietin levels, the hormone regulating red blood cell production, in young and older adults. The objective of this study was to determine the effect of a single session of intermittent hypoxia on erythropoietin levels and hemoglobin mass, the absolute mass of hemoglobin contained in red blood cells, in patients with type 2 diabetes. Methods: Ten patients with type 2 diabetes were exposed to an intermittent hypoxia protocol consisting of eight 4-min cycles at a targeted oxygen saturation of 80% interspersed with normoxic cycles to resaturation. Erythropoietin and hemoglobin mass responses to intermittent hypoxia in patients with type 2 diabetes were compared to previously published data from an identical intermittent hypoxia protocol performed in age-matched older adults. Results: Intermittent hypoxia increased erythropoietin levels in older adults but did not induce any change in erythropoietin levels in patients with type 2 diabetes (3.2 ± 2.2 vs. 0.2 ± 2.7 mU/ml, p = 0.01). Hemoglobin mass indexed to body weight was 21% lower in patients with type 2 diabetes than in older adults (8.1 ± 1.7 vs. 10.2 ± 2.1 g/kg, p < 0.01). Conclusions: These findings suggest an impaired erythropoietin response to decreased oxygen levels in patients with type 2 diabetes, which may contribute to the reduced oxygen transport capacity observed in this population. [ABSTRACT FROM AUTHOR]

Experimental evidence suggests that chronic intermittent hypoxia (CIH), a major hallmark of obstructive sleep apnea (OSA), boosts carotid body (CB) responsiveness, thereby causing increased sympathetic activity, arterial and pulmonary hypertension, and cardiovascular disease. An enhanced circulatory chemoreflex, oxidative stress, and NO signaling appear to play important roles in these responses to CIH in rodents. Since the guinea pig has a hypofunctional CB (i.e., it is a natural CB knockout), in this study we used it as a model to investigate the CB dependence of the effects of CIH on pulmonary vascular responses, including those mediated by NO, by comparing them with those previously described in the rat. We have analyzed pulmonary artery pressure (PAP), the hypoxic pulmonary vasoconstriction (HPV) response, endothelial function both in vivo and in vitro, and vascular remodeling (intima–media thickness, collagen fiber content, and vessel lumen area). We demonstrate that 30 days of the exposure of guinea pigs to CIH (FiO2, 5% for 40 s, 30 cycles/h) induces pulmonary artery remodeling but does not alter endothelial function or the contractile response to phenylephrine (PE) in these arteries. In contrast, CIH exposure increased the systemic arterial pressure and enhanced the contractile response to PE while decreasing endothelium-dependent vasorelaxation to carbachol in the aorta without causing its remodeling. We conclude that since all of these effects are independent of CB sensitization, there must be other oxygen sensors, beyond the CB, with the capacity to alter the autonomic control of the heart and vascular function and structure in CIH. [ABSTRACT FROM AUTHOR]

Acute intermittent hypoxia (AIH) can induce sustained facilitation of motor output in people with spinal cord injury (SCI). Most studies of corticospinal tract excitability in humans have used 9% fraction inspired oxygen (F I O 2 ) AIH (AIH-9%), with inconsistent outcomes. We investigated the effect of single sessions of 9% F I O 2 and 12% F I O 2 AIH (AIH-12%) on corticospinal excitability of a hand and leg muscle in able-bodied adults. Ten naïve participants completed three sessions on separate days comprising 15 epochs of 1 min of AIH-9%, AIH-12%, or sham (SHAM-21%) followed by 1 min of room air (21% F I O 2 ) in a randomized crossover design. Motor-evoked potentials (MEPs; n = 30, ∼1 mV) elicited at rest by transcranial magnetic stimulation and maximal M-waves (Mmax) evoked by peripheral nerve stimulation were measured from the first dorsal interosseous (FDI) and tibialis anterior (TA) muscles at baseline and at ∼0, 20, 40, and 60 min post intervention. AIH-9% induced the greatest reduction in peripheral oxygen saturation (to 85% vs. 93% and 100% in AIH-12% and SHAM-21%, respectively; P < 0.001) and the greatest increase in ventilation [by 22% vs. 12% and −3% in AIH-9%, AIH-12%, and SHAM-21%, respectively (P < 0.001)]. There was no difference in MEP amplitudes (%Mmax) after any of the three conditions (AIH-9%, AIH-12%, SHAM-21%) for both the FDI (P = 0.399) and TA (P = 0.582). Despite greater cardiorespiratory changes during AIH-9%, there was no evidence of corticospinal facilitation (tested with MEPs) in this study. Further studies could explore variability in response to AIH between individuals and other methods to measure motor facilitation in people with and without spinal cord injuries. NEW & NOTEWORTHY: This is the first study that tests whether acute intermittent hypoxia (AIH) induces motor output facilitation in humans after two different doses of AIH (9% and 12% F I O 2 ) and the reproducibility of participant responses after a repeat AIH intervention at 9% AIH. There was no motor output facilitation in response to either dose of AIH. The results question the effectiveness of a single 30-min session of AIH in inducing motor output facilitation, tested in this way. [ABSTRACT FROM AUTHOR]

Introduction:Maternal obstructive sleep apnea (OSA) during pregnancy is the risk factor for impaired fetal growth with low birth weight in the offspring. However, it is unclear whether gestational intermittent hypoxia (IH, a hallmark of maternal OSA) has long-term detrimental consequences on the skeletal development of offspring. This study aimed to investigate postnatalmaxillofacial bone growth and cartilage metabolism in male and female offspring that were exposed to gestational IH. Methods: Mother rats underwent IH at 20 cycles/h (nadir, 4% O2; peak, 21% O2; 0% CO2) for 8 h per day during gestational days (GD) 7-20, and their male and female offspring were analyzed postnatally at 5 and 10 weeks of age. Allmale and female offspring were born and raised under normoxic conditions. Results: There was no significant difference in whole-body weight and tibial length between the IH male/female offspring and their control counterparts. In contrast, the mandibular condylar length was significantly shorter in the IH male offspring than in the control male offspring at 5 and 10 weeks of age, while there was no significant difference in the female offspring. Real-time polymerase chain reaction (PCR) showed that gestational IH significantly downregulated the mRNA level of SOX9 (a chondrogenesismarker) and upregulated themRNA level of HIF- 1α (a hypoxia-inducible factor marker) in the mandibular condylar cartilage of male offspring, but not in female offspring. Conclusion: Gestational IH induced underdeveloped mandibular ramus/condyles and reduced mRNA expression of SOX9, while enhancing mRNA expression of HIF-1α in a sex-dependent manner. [ABSTRACT FROM AUTHOR]

Summary Sympathetic overactivity caused by chronic intermittent hypoxia is a hallmark of obstructive sleep apnea. A high sympathetic tone elicits increases in plasma free fatty acid and insulin. Our objective was to assess the impact of 14 nights of chronic intermittent hypoxia exposure on sympathetic activity, glucose control, lipid profile and subcutaneous fat tissue remodelling in non‐obese healthy humans. In this prospective, double‐blinded crossover study, 12 healthy subjects were randomized, among them only nine underwent the two phases of exposures of 14 nights chronic intermittent hypoxia versus air. Sympathetic activity was measured by peroneal microneurography (muscle sympathetic nerve activity) before and after each exposure. Fasting glucose, insulin, C‐peptide and free fatty acid were assessed at rest and during a multisampling oral glucose tolerance test. We assessed histological remodelling, adrenergic receptors, lipolysis and lipogenesis genes expression and functional changes of the adipose tissue. Two weeks of exposure of chronic intermittent hypoxia versus ambient air significantly increased sympathetic activity (p = 0.04). Muscle sympathetic nerve activity increased from 24.5 [18.9; 26.8] before to 21.7 [13.8; 25.7] after ambient air exposure, and from 20.6 [17.4; 23.9] before to 28.0 [24.4; 31.5] bursts per min after exposure to chronic intermittent hypoxia. After chronic intermittent hypoxia, post‐oral glucose tolerance test circulating free fatty acid area under the curve increased (p = 0.05) and free fatty acid sensitivity to insulin decreased (p = 0.028). In adipocyte tissue, intermittent hypoxia increased expression of lipolysis genes (adipocyte triglyceride lipase and hormone‐sensitive lipase) and lipogenesis genes (fatty acid synthase; p < 0.05). In this unique experimental setting in healthy humans, chronic intermittent hypoxia induced high sympathetic tone, lipolysis and decreased free fatty acid sensitivity to insulin. This might participate in the trajectory to systemic insulin resistance and diabetes for patients with obstructive sleep apnea. [ABSTRACT FROM AUTHOR]

Aim: Preterm infants are at increased risk of Sudden Infant Death Syndrome (SIDS) and frequently experience short central apnoeas which can occur in isolation or a repetitive pattern (periodic breathing). We investigated the relationship between central apnoeas experienced before and over the 6 months after hospital discharge and cerebral oxygenation. Methods: Preterm infants born between 28 and 32 weeks gestational age (GA) were studied during supine daytime sleep at 32-36 weeks post menstrual age (PMA) (n = 40), 36-40 weeks PMA (n = 27), 3-months corrected age (CA) (n = 20) and 6-months CA (n = 26). Cerebral tissue oxygenation (TOI), peripheral oxygenation (SpO2) and heart rate were recorded continuously. The percentage total sleep time (%TST) spent having central apnoeas at each study and cerebral fractional oxygen extraction (SpO2-TOI/SpO2) were calculated. Results: %TST spent with central apnoeas decreased with increasing age in both active sleep (AS) and quiet sleep (QS). TOI tended to be lower and cerebral fractional oxygen extraction higher at 3 months compared to the other studies and this reached statistical significance compared to 32-36 weeks in QS. Conclusion: The nadir in cerebral tissue oxygenation at 3 months of age coincides with the peak risk period for SIDS and this may contribute to increased risk in these infants. [ABSTRACT FROM AUTHOR]

Purpose: Diaphragmatic impairment has been reported in obstructive sleep apnea–hypopnea syndrome (OSAHS) patients. However, the risk factors of diaphragmatic dysfunction are unclear. This study was conducted to evaluate the diaphragmatic function and to investigate impact factors of ultrasonographic changes of the diaphragm in OSAHS patients. Methods: This cross-sectional study recruited 150 snoring patients. All patients were divided into the control group (AHI < 5/h, n = 20), the mild-to-moderate OSAHS group (5/h ≤ AHI ≤ 30/h, n = 61), and the severe OSAHS group (AHI > 30/h, n = 69). Diaphragmatic thickness at function residual capacity (TFRC) and total lung capacity (TTLC) were measured by two-dimensional ultrasound, and the diaphragmatic excursion during tidal and deep breath was measured by M-mode ultrasound. The diaphragmatic thickening fraction (TF) was calculated. Spearman analysis and multiple linear stepwise regression analysis were conducted to analyze the impact factors of diaphragmatic function. Results: TFRC in the control group, mild-to-moderate OSAHS group, and severe OSAHS group was 1.23 (1.10, 1.39) mm, 1.60 (1.43, 1.85) mm, and 1.90 (1.70, 2.25) mm; TTLC was 2.75 (2.53, 2.93) mm, 3.25 (2.90, 3.55) mm, and 3.60 (3.33, 3.90) mm, and TF was 119.23% (102.94, 155.97), 96.55% (74.34, 119.11), and 85.29% (60.68,101.22). There were across-group significant differences in TFRC, TTLC, and TF (P < 0.05). The oxygen desaturation index was the influencing factor of TFRC, TTLC, and TF (P < 0.05). Conclusion: The diaphragm is thickened and diaphragmatic contractility is decreased in OSAHS patients. Nocturnal intermittent hypoxia is a risk factor for diaphragmatic hypertrophy and impaired diaphragmatic contractility. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea (OSA) is a common respiratory disorder. Multiple organs, especially the central nervous system (CNS), are damaged, and dysfunctional when intermittent hypoxia (IH) occurs during sleep for a long time. The quality of life of individuals with OSA is significantly impacted by cognitive decline, which also escalates the financial strain on their families. Consequently, the development of novel therapies becomes imperative. IH induces oxidative stress, endoplasmic reticulum stress, iron deposition, and neuroinflammation in neurons. Synaptic dysfunction, reactive gliosis, apoptosis, neuroinflammation, and inhibition of neurogenesis can lead to learning and long-term memory impairment. In addition to nerve injury, the role of IH in neuroprotection was also explored. While causing neuron damage, IH activates the neuronal self-repairing mechanism by regulating antioxidant capacity and preventing toxic protein deposition. By stimulating the proliferation and differentiation of neural stem cells (NSCs), IH has the potential to enhance the ratio of neonatal neurons and counteract the decline in neuron numbers. This review emphasizes the perspectives and opportunities for the neuroprotective effects of IH and informs novel insights and therapeutic strategies in OSA. [ABSTRACT FROM AUTHOR]

Background: Obstructive sleep apnea (OSA) is one of the risk factors for atrial fibrillation (AF). However, the mechanism underlying the atrial structural and electro-anatomical remodeling by OSA has not yet been clearly elucidated. Methods: This study was conducted in 83 patients who had undergone catheter ablation for AF (49 with OSA and 34 Controls without OSA). The left atrial (LA) maps were created in all the patients using a three-dimensional electro-anatomical mapping system. The LA with a bipolar voltage of

The article in the Journal of Physiology discusses the effects of intermittent hypoxia (IH) on motor learning and metabolic cost in healthy individuals. The study found that IH led to changes in motor function and metabolic cost, with potential implications for mitochondrial function and energy utilization. The authors suggest that further research is needed to understand the relationship between neural and mitochondrial adaptations post-IH, as well as the impact of carbon dioxide levels on motor plasticity. Overall, the study provides new insights into motor changes following IH and raises important questions for future research in the field. [Extracted from the article]

Menglu Dong,1 Xili Liang,1 Tian Zhu,1 Ting Xu,1 Liwei Xie,2,3 Yuan Feng1,4,5 1Sleep Medicine Center, Department of Psychiatric, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, People’s Republic of China; 3Department of Endocrinology and Metabolism, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 4Institute of Brain Disease, Nanfang Hospital of Southern Medical University, Guangzhou, People’s Republic of China; 5Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Science, Southern Medical University, Guangzhou, People’s Republic of ChinaCorrespondence: Liwei Xie, Email xielw@gdim.cn; Yuan Feng, Sleep Medicine Center, Department of Psychiatric, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Baiyun District, Guangzhou, 510515, People’s Republic of China, Email yuanstar@126.comBackground: Obstructive sleep apnea (OSA) is a prevalent sleep breathing disorder characterized by intermittent hypoxia (IH), with continuous positive airway pressure (CPAP) as its standard treatment. However, the effects of intermittent hypoxia/reoxygenation (IH/R) on weight regulation in obesity and its underlying mechanism remain unclear. Gut microbiota has gained attention for its strong association with various diseases. This study aims to explore the combined influence of IH and obesity on gut microbiota and to investigate the impact of reoxygenation on IH-induced alterations.Methods: Diet-induced obese (DIO) rats were created by 8-week high-fat diet (HFD) feeding and randomly assigned into three groups (n=15 per group): normoxia (NM), IH (6% O2, 30 cycles/h, 8 h/day, 4 weeks), or hypoxia/reoxygenation (HR, 2-week IH followed by 2-week reoxygenation) management. After modeling and exposure, body weight and biochemical indicators were measured, and fecal samples were collected for 16S rRNA sequencing.Results: DIO rats in the IH group showed increased weight gain (p=0.0016) and elevated systemic inflammation, including IL-6 (p=0.0070) and leptin (p=0.0004). Moreover, IH rats exhibited greater microbial diversity (p< 0.0167), and significant alterations in the microbial structure (p=0.014), notably the order Clostridiales, accompanied by an upregulation of bile acid metabolism predicted pathway (p=0.0043). Reoxygenation not only improved IH-exacerbated obesity, systemic inflammation, leptin resistance, and sympathetic activation, but also showed the potential to restore IH-induced microbial alterations. Elevated leptin levels were associated with Ruminococcaceae (p=0.0008) and Clostridiales (p=0.0019), while body weight was linked to Blautia producta (p=0.0377). Additionally, the abundance of Lactobacillus was negatively correlated with leptin levels (p=0.0006) and weight (p=0.0339).Conclusion: IH leads to gut dysbiosis and metabolic disorders, while reoxygenation therapy demonstrates a potentially protective effect by restoring gut homeostasis and mitigating inflammation. It highlights the potential benefits of CPAP in reducing metabolic risk among obese patients with OSA.Keywords: intermittent hypoxia, reoxygenation, high-fat diet-induced obese, gut microbiota, 16S rRNA

Abstract Obstructive sleep apnea (OSA) is a multifactorial sleep disorder with a high prevalence in the general population. OSA is associated with an increased risk of developing cardiovascular diseases (CVDs), particularly hypertension, and is linked to worse outcomes. Although the correlation between OSA and CVDs is firmly established, the mechanisms are poorly understood. Continuous positive airway pressure is primary treatment for OSA reducing cardiovascular risk effectively, while is limited by inadequate compliance. Moreover, alternative treatments for cardiovascular complications in OSA are currently not available. Recently, there has been considerable attention on the significant correlation between gut microbiome and pathophysiological changes in OSA. Furthermore, gut microbiome has a significant impact on the cardiovascular complications that arise from OSA. Nevertheless, a detailed understanding of this association is lacking. This review examines recent advancements to clarify the link between the gut microbiome, OSA, and OSA‐related CVDs, with a specific focus on hypertension, and also explores potential health advantages of adjuvant therapy that targets the gut microbiome in OSA.

Preterm infants often experience frequent intermittent hypoxia (IH) episodes which are associated with neuroinflammation. We tested the hypotheses that early caffeine and/or non‐steroidal inflammatory drugs (NSAIDs) confer superior therapeutic benefits for protection against IH‐induced neuroinflammation than late treatment. Newborn rats were exposed to IH or hyperoxia (50% O2) from birth (P0) to P14. For early treatment, the pups were administered: 1) daily caffeine (Caff) citrate (Cafcit, 20 mg/kg IP loading on P0, followed by 5 mg/kg from P1‐P14); 2) ketorolac (Keto) topical ocular solution in both eyes from P0 to P14; 3) ibuprofen (Ibu, Neoprofen, 10 mg/kg loading dose on P0 followed by 5 mg/kg/day on P1 and P2); 4) Caff+Keto co‐treatment; 5) Caff+Ibu co‐treatment; or 6) equivalent volume saline (Sal). On P14, animals were placed in room air (RA) with no further treatment until P21. For late treatment, pups were exposed from P0 to P14, then placed in RA during which they received similar treatments from P15‐P21 (Sal, Caff, and/or Keto), or P15‐P17 (Ibu). RA controls were similarly treated. At P21, whole brains were assessed for histopathology, apoptosis, myelination, and biomarkers of inflammation. IH caused significant brain injury and hemorrhage, inflammation, reduced myelination, and apoptosis. Early treatment with Caff alone or in combination with NSAIDs conferred better neuroprotection against IH‐induced damage than late treatment. Early postnatal treatment during a critical time of brain development, may be preferable for the prevention of IH‐induced brain injury in preterm infants. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the vascular networks of the retina and choroid using optical coherence tomography angiography (OCTA) to identify early biomarkers of obstructive sleep apnea (OSA) severity and to evaluate correlations with blood levels of oxidative stress. Study design: Patients with OSA were diagnosed based on video-polysomnography (PSG) and blood samples were collected to evaluate oxidative stress markers: total antioxidant status (TAS), biological antioxidant potential (BAP) test, Diacron reactive oxygen metabolites (d-ROMs) test. The eyes of children with OSA were evaluated and compared with eyes of healthy age-matched children. OCTA imaging was carried out to evaluate the choroidal and retinal vascular network density indices. Results: A total of 31 children with OSA were recruited and compared with 10 healthy children. Choriocapillaris flow area decreased (p = 0.006) and superficial capillary plexus vessel density increased (p=0.01) with increasing severity of OSA. Children with OSA showed significant differences in TAS and d-ROMs test when compared to normal pediatric values (p<0.05). In calculating the correlations between PSG, oxidative stress, and OCTA variables, there was a negative correlation between choriocapillaris flow area and apnea hypopnea index (AHI) (p = 0.02, r2 −0.5) and between choriocapillaris flow area and the d-ROMs test (p 0.03; r2 0.5). Conclusions: The severity of OSA was associated with the choroidal and retinal capillary vascular networks. The correlation of the choriocapillaris flow area with AHI and the d-ROMs test indicates the connection of the choroidal microvasculature with the number of obstructive apnea and hypopnea events and oxidative stress. [ABSTRACT FROM AUTHOR]

Purpose: Intermittent hypoxia (IH) is a hallmark of obstructive sleep apnea (OSA), which is related to tumorigenesis and progression. Although micro-ribonucleic acid-210-3p (miR-210-3p) is correlated with hypoxia-induced tumor development, its role in the relationship between IH and tumor function remains poorly understood. The present work focused on elucidating the molecular mechanism through which miR-210-3p drives tumor progression under IH. Methods: MiR-210-3p levels were quantified within tumor samples from patients with lung adenocarcinoma who had or did not have OSA. Correlations between miR-210-3p and polysomnographic variables were analyzed. For in vitro experiments, miR-210-3p was inhibited or overexpressed via transfection under IH conditions. Cell viability, growth, invasion and migration assays were carried out. For in vivo modeling of IH using mouse xenografts, a miR-210-3p antagomir was intratumorally injected, tumor biological behaviors were evaluated, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR), immunohistochemistry and western blot were carried out for detecting miR-210-3p and E2F transcription factor 3 (E2F3) expression. Results: For patients with lung adenocarcinoma and OSA, high miR-210-3p levels showed positive relation to polysomnographic variables, such as oxygen desaturation index, apnea–hypopnea index, and proportion of total sleep time with oxygen saturation in arterial blood < 90%. IH enhanced tumor viability, proliferation, migration, and invasion, downregulated E2F3 expression, and increased miR-210–3-p levels. miR-210-3p overexpression induced similar changes. These changes were reversed by miR-210-3p inhibition in vitro or miR-210-3p antagomir through intratumoral injection in vivo. Conclusions: IH-induced tumor development is driven through miR-210-3p by E2F3 suppression. MiR-210-3p represents a potential therapeutic target among patients with concomitant cancer and OSA. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Despite undeniable advances in modern medicine, lung cancer still has high morbidity and mortality rates. Lung cancer is preventable and treatable, and it is important to identify new risk factors for lung cancer, especially those that can be treated or reversed. Obstructive sleep apnea (OSA) is a very common sleepbreathing disorder that is grossly underestimated in clinical practice. It can cause, exacerbate, and worsen adverse outcomes, including death and various diseases, but its relationship with lung cancer is unclear. A possible causal relationship between OSA and the onset and progression of lung cancer has been established biologically. The pathophysiological processes associated with OSA, such as sleep fragmentation, intermittent hypoxia, and increased sympathetic nervous excitation, may affect normal neuroendocrine regulation, impair immune function (especially innate and cellular immunity), and ultimately contribute to the occurrence of lung cancer, accelerate progression, and induce treatment resistance. OSA may be a contributor to but a preventable cause of the progression of lung cancer. However, whether this effect exists independently of other risk factors is unclear. Therefore, by reviewing the literature on the epidemiology, pathogenesis, and treatment of lung cancer and OSA, we hope to understand the relationships between the two and promote the interdisciplinary exchange of ideas between basic medicine, clinical medicine, respiratory medicine, sleep medicine, and oncology. [ABSTRACT FROM AUTHOR]

Objective: Angiogenesis can be influenced by many factors. The main purpose of the present study was to explore the effect of aerobic training and intermittent hypoxia on angiogenic factors in the cardiac tissue of male Wistar rats. Methods: Thirty male Wistar rats were randomly divided into one of three groups; normal control (NC), hypoxia (H), and training (T). The Hypoxia group was exposed to chronic periodic and isobaric hypoxia (total pressure PiO2~760 mmHg, 14% oxygen) for 8 weeks. Animals in the training group ran on a motorized treadmill (22-26 meters per min) for 8 weeks, 5 sessions per week. At the end of the procedure, protein expression of Tie-1, HIF-1a, VEGF, and P-AKT were calculated by an immunoblotting technique in the cardiac tissue. Results: The findings indicated that periodic hypoxia and exercise training substantially raised the expression of the HIF-1a, VEGF, and P-AKT proteins as compared to the NC (p = 0.001). Moreover, chronic treadmill training significantly increased the phosphorylation of AKT as compared to the hypoxia group (p = 0.001), indicating that PI3K/Akt signalling pathway is influenced by exercise training rather than hypoxia. Conclusion: It seems that both hypoxia and exercise training are potent stimulators for the induction of angiogenesis signalling pathway. [ABSTRACT FROM AUTHOR]

Imaging tools are crucial for studying the vascular network and its barrier function in various physiopathological conditions. Shortwave infrared (SWIR) window optical imaging allows noninvasive, in-depth exploration. We applied SWIR imaging, combined with vessel segmentation and deep learning analyses, to study real-time dextran probe extravasation in mice experiencing intermittent hypoxia (IH)—a characteristic of obstructive sleep apnea associated with potential cardiovascular alterations due to early vascular permeability. Evidence for permeability in this context is limited, making our investigation significant. C57Bl/6 mice were exposed to normoxia or intermittent hypoxia for 14 days. Then SWIR imaging between 1,250 and 1,700 nm was performed on the saphenous artery and vein and on the surrounding tissue after intravenous injection of labeled dextrans of two different sizes (10 or 70 kDa). Postprocessing and segmentation of the SWIR images were conducted using deep learning treatment. We monitored high-resolution signals, distinguishing arteries, veins, and surrounding tissues. In the saphenous artery and vein, after 70-kD dextran injection, tissue/vessel ratio was higher after intermittent hypoxia (IH) than normoxia (N) over 500 seconds (P < 0.05). However, the ratio was similar in N and IH after 10-kD dextran injection. The SWIR imaging technique allows noninvasive, real-time monitoring of dextran extravasation in vivo. Dextran 70 extravasation is increased after exposure to IH, suggesting an increased vessel permeability in this mice model of obstructive sleep apnea. NEW & NOTEWORTHY: We demonstrate that SWIR imaging technique is a useful tool to monitor real-time dextran extravasation from vessels in vivo, with a high resolution. We report for the first time an increased real-time dextran (70 kD) extravasation in mice exposed to intermittent hypoxia for 14 days compared with normoxic controls. [ABSTRACT FROM AUTHOR]

Aim: We tested the hypothesis that low testosterone alters the effects of intermittent hypoxia (IH) on glucose homeostasis, hepatic oxidative stress, and transcriptomic profile in male mice. Methods: We used sham‐operated or orchiectomized (ORX) mice exposed to normoxia (Nx) or IH for 2 weeks. We performed fasting insulin and glucose tolerance tests and assessed fasting and postprandial insulin resistance with the HOMA‐IR. The activity of hepatic prooxidant (NADPH oxidase—NOX), antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase—SOD, Cat, GPx), lipid peroxidation (MDA concentration), and the total concentration of glutathione (GSH) were measured under postprandial conditions. mRNA sequencing and pathway enrichment analyses were used to identify hepatic genes underlying the interactions between IH and testosterone. Results: In Sham mice, IH improves fasting insulin sensitivity and glucose tolerance, while there are no effects of IH in ORX mice. In ORX mice, IH induces postprandial hyperinsulinemia, insulin resistance, and a prooxidant profile of enzyme activity (low SOD activity) without altering hepatic MDA and GSH content. ORX and IH altered the expression of genes involved in oxidoreductase activities, cytochromes‐dependent pathways, and glutathione metabolism. Among the genes upregulated in ORX‐IH mice, the flavin‐containing monooxygenases (FMO) are particularly relevant since these are potent hepatic antioxidants that could help prevent overt oxidative stress in ORX‐IH mice. Conclusion: Low levels of testosterone in male mice exposed to IH induce post‐prandial hyperinsulinemia and insulin resistance and determine the mechanisms by which the liver handles IH‐induced oxidative stress. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Intermittent hypoxia (IH) is emerging as a cost‐effective nonpharmacological method for vital organ protection. We aimed to assess the effects of a short‐term moderate intermittent hypoxia preconditioning protocol (four cycles of 13% hypoxia lasting for 10 min with 5‐min normoxia intervals) on acute hypoxic injury induced by sustained hypoxic exposure (oxygen concentration of 11.8% for 6 h). Methods: One hundred healthy volunteers were recruited and randomized to the IH group and the control group to receive IH or sham‐IH preconditioning for 5 days, respectively, and then were sent to a hypoxic chamber for simulated acute high‐altitude exposure (4500 m). Results: The overall incidence of acute mountain sickness was 27% (27/100), with 14% (7/50) in the IH group and 40% (20/50) in the control group (p = 0.003). After 6‐h simulated high‐altitude exposure, the mean Lake Louise Score was lower in the IH group as compared to controls (1.30 ± 1.27 vs. 2.04 ± 1.89, p = 0.024). Mean peripheral oxygen saturations (SpO2) and intracranial pressure (ICP) measures after acute hypoxic exposure exhibited significant differences, with the IH group showing significantly greater SpO2 values (85.47 ± 5.14 vs. 83.10 ± 5.15%, p = 0.026) and lower ICP levels than the control group (115.59 ± 32.15 vs. 130.36 ± 33.83 mmH2O, p = 0.028). IH preconditioning also showed greater effects on serum protein gene product 9.5 (3.89 vs. 29.16 pg/mL; p = 0.048) and C‐reactive protein (−0.28 vs. 0.41 mg/L; p = 0.023). Conclusion: The short‐term moderate IH improved the tolerance to hypoxia and exerted protection against acute hypoxic injury induced by exposure to sustained normobaric hypoxia, which provided a novel method and randomized controlled trial evidence to develop treatments for hypoxia‐related disease. [ABSTRACT FROM AUTHOR]

Background: Exosomes are involved in cell-to-cell communication in numerous diseases including cardiovascular diseases, neurological diseases. Little attention has been dedicated to exosomal circular RNAs in obstructive sleep apnea (OSA)-related cardiovascular diseases. The aim of this study was to explore the role of exosomal circular RNA ZNF292 (circZNF292) on AC16 cells exposure to intermittent hypoxia (IH). Methods: Exosome release inhibitor GW4869 was used to examine the effect of exosomes on IH-induced AC16 cells apoptosis. The expression of exosomal circZNF292 was detected by qRT-PCR in AC16 cells exposure to IH, and a luciferase reporter assay was conducted to confirm the connection between circZNF292 and miR-146a-5p. Exosomal circZNF292 was stably transfected with short hairpin RNAs (shRNAs) against circZNF292 and co-cultured with AC16 cells. The expression of miR-146a-5p and apoptosis-related protein was then measured to evaluate the effect of exosomal circZNF292. Results: We found that IH contributed to the AC16 cells apoptosis, and the administration of GW4869 increased the apoptosis of cardiomyocytes when exposed to IH. The expression of exosomal circZNF292 decreased and miR-146a-5p increased significantly in AC16 cells exposed to IH compared to normoxic conditions. Bioinformatics analysis predicted a circZNF292/miR-146a-5p axis in IH-induced cardiomyocytes apoptosis. The dual-luciferase reporter system validated the direct interaction of circZNF292 and miR-146a-5p. Knockdown of circZNF292 increased the expressions of miR-146a-5p and accelerated the AC16 cardiomyocytes apoptosis. Conclusions: The findings of this study suggested a novel mechanism by which exosomes transmit intrinsic regulatory signals to the myocardium through the exosomal circZNF292/miR-146a-5p axis. This finding highlights the potential of targeting this pathway as a therapeutic approach for treating cardiovascular diseases associated with OSA. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea (OSA) is characterized by intermittent hypoxia (IH) and is strongly associated with adverse cardiovascular outcomes. Myocardial injury and dysfunction have been commonly observed in clinical practice, particularly in patients with severe OSA. However, the underlying mechanisms remain obscure. In this review, we summarized the molecular mechanisms by which IH impact on myocardial injury and dysfunction. In brief, IH-induced cardiomyocyte death proceeds through the regulation of multiple biological processes, including differentially expressed transcription factors, alternative epigenetic programs, and altered post-translational modification. Besides cell death, various cardiomyocyte injuries, such as endoplasmic reticulum stress, occurs with IH. In addition to the direct effects on cardiomyocytes, IH has been found to deteriorate myocardial blood and energy supply by affecting the microvascular structure and disrupting glucose and lipid metabolism. For better diagnosis and treatment of OSA, further studies on the molecular mechanisms of IH-induced myocardial injury and dysfunction are essential. [ABSTRACT FROM AUTHOR]

Purpose: To investigate whether or not intermittent hypoxia (IH), the main characteristic of obstructive sleep apnea (OSA) may affect the myofibroblast differentiation and extracellular matrix (ECM) production of lung fibroblast through the HIF-1α-TGF-β/Smad pathway and assess the interventional role of a HIF-1α inhibitor, 2-methoxyestradiol (2-ME2). Method: The human lung fibroblast MRC5 cells were exposed to normoxia or IH conditions, and the expression of myofibroblast differentiation marker α-smooth muscle actin (α-SMA) and ECM protein collagen I were evaluated. To clarify the underlying mechanism, the expression level of HIF-1α, TGF-β, and p-Smads/Smads were measured and the effects of inhibiting HIF-1α with 2-ME2 on the α-SMA expression level and ECM production through the TGF-β/Smad pathway were assessed. Si HIF-1α was applied to genetically inhibit HIF-1α in MRC5 cells, and the related proteins were assessed. Results: IH increased the protein and mRNA expression of Collagen I and α-SMA of MRC5 cells in a time-dependent manner. IH activated the protein and mRNA level of HIF-1α and TGF-β and increased the phosphorylation of Smad2/Smad3 of MRC5 cells in a time-dependent manner. 2-ME2 inhibited the activation of HIF-1α induced by IH and decreased overexpression of TGF-β, p-Smad2/Smad2, and p-Smad3/Smad3, which in turn partially reversed the upregulation of α-SMA and Collagen I induced by IH in MRC5 cells. When HIF-1α was successfully silenced by si-HIF-1α, upregulation of TGF-β induced by intermittent hypoxia was partially decreased. Conclusions: This study showed that IH contributes to myofibroblast differentiation and excessive ECM production of MRC5 cells through activation of the HIF-1α-TGF-β/Smad pathway. 2-ME2 partially attenuated myofibroblast differentiation induced by IH by inhibiting the HIF-1α-TGF-β/Smad pathway. [ABSTRACT FROM AUTHOR]

Purpose: Metabolic-associated fatty liver disease (MAFLD) is an aging-related disease. Obstructive sleep apnea (OSA) may cause MAFLD. This study aimed to explore whether or not intermittent hypoxia (IH), the hallmark of OSA, induces liver aging through oxidative stress. Methods: C57BL/6J male mice were administered normal air (control), IH, or antioxidant tempol + IH daily for 6 weeks before the collection of serum and liver tissue samples. A histological examination was conducted to assess liver aging. ELISA was performed to measure liver function indicator levels in the serum and oxidative stress indicator activities in the liver. Western blot analysis was carried out to determine the protein expression of the markers related to oxidative stress, inflammation, and senescence. Results: Compared with control, IH resulted in significant increases in serum ALT, AST, and TG levels in mice (all P < 0.001), along with lobular inflammation and accumulation of collagen and fat in the liver. The protein levels of inflammatory factors and senescent markers were significantly increased in the IH mouse liver compared with those in the control mouse liver. Meanwhile, IH significantly reduced SOD and CAT activities while enhancing p22phox and Nrf2 protein expression in mouse liver compared with control. Importantly, antioxidant therapy with tempol effectively abrogated the effects of IH on oxidative stress response and aging-related liver injury. Conclusions: Our findings suggest that IH induces liver inflammation and aging through oxidative stress. OSA may exacerbate target organ aging and participate in target organ damage. Strategies targeting oxidative stress may prevent and treat OSA-related MAFLD. [ABSTRACT FROM AUTHOR]

Cellular magnetic field effects are assumed to base on coherent singlet-triplet interconversion of radical pairs that are sensitive to applied radiofrequency (RF) and weak magnetic fields (WEMFs), known as radical pair mechanism (RPM). As a leading model, the RPM explains how quantum effects can influence biochemical and cellular signalling. Consequently, radical pairs generate reactive oxygen species (ROS) that link the RPM to redox processes, such as the response to hypoxia and the circadian clock. Therapeutic nuclear magnetic resonance (tNMR) occupies a unique position in the RPM paradigm because of the used frequencies, which are far below the range of 0.1–100 MHz postulated for the RPM to occur. Nonetheless, tNMR was shown to induce RPM like effects, such as increased extracellular H2O2 levels and altered cellular bioenergetics. In this study we compared the impact of tNMR and intermittent hypoxia on the circadian clock, as well as the role of superoxide in tNMR induced ROS partitioning. We show that both, tNMR and intermittent hypoxia, exert on/off effects on cellular clocks that are dependent on the time of application (day versus night). In addition, our data provide further evidence that superoxide plays a central role in magnetic signal transduction. tNMR used in combination with scavengers, such as Vitamin C, led to strong ROS product redistributions. This discovery might represent the first indication of radical triads in biological systems.