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共44篇 平均IF=16.6 (2.9-98.4)更多分析
  • 1区Q1影响因子: 98.4
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    1. Adult obstructive sleep apnoea.
    作者:Jordan Amy S , McSharry David G , Malhotra Atul
    期刊:Lancet (London, England)
    日期:2013-08-02
    DOI :10.1016/S0140-6736(13)60734-5
    Obstructive sleep apnoea is an increasingly common disorder of repeated upper airway collapse during sleep, leading to oxygen desaturation and disrupted sleep. Features include snoring, witnessed apnoeas, and sleepiness. Pathogenesis varies; predisposing factors include small upper airway lumen, unstable respiratory control, low arousal threshold, small lung volume, and dysfunctional upper airway dilator muscles. Risk factors include obesity, male sex, age, menopause, fluid retention, adenotonsillar hypertrophy, and smoking. Obstructive sleep apnoea causes sleepiness, road traffic accidents, and probably systemic hypertension. It has also been linked to myocardial infarction, congestive heart failure, stroke, and diabetes mellitus though not definitively. Continuous positive airway pressure is the treatment of choice, with adherence of 60-70%. Bi-level positive airway pressure or adaptive servo-ventilation can be used for patients who are intolerant to continuous positive airway pressure. Other treatments include dental devices, surgery, and weight loss.
  • 1区Q1影响因子: 19.3
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    2. The Combination of Atomoxetine and Oxybutynin Greatly Reduces Obstructive Sleep Apnea Severity. A Randomized, Placebo-controlled, Double-Blind Crossover Trial.
    期刊:American journal of respiratory and critical care medicine
    日期:2019-05-15
    DOI :10.1164/rccm.201808-1493OC
    There is currently no effective pharmacological treatment for obstructive sleep apnea (OSA). Recent investigations indicate that drugs with noradrenergic and antimuscarinic effects improve genioglossus muscle activity and upper airway patency during sleep. We aimed to determine the effects of the combination of a norepinephrine reuptake inhibitor (atomoxetine) and an antimuscarinic (oxybutynin) on OSA severity (apnea-hypopnea index [AHI]; primary outcome) and genioglossus responsiveness (secondary outcome) in people with OSA. A total of 20 people completed a randomized, placebo-controlled, double-blind, crossover trial comparing 1 night of 80 mg atomoxetine plus 5 mg oxybutynin (ato-oxy) to placebo administered before sleep. The AHI and genioglossus muscle responsiveness to negative esophageal pressure swings were measured via in-laboratory polysomnography. In a subgroup of nine patients, the AHI was also measured when the drugs were administered separately. The participants' median (interquartile range) age was 53 (46-58) years and body mass index was 34.8 (30.0-40.2) kg/m. ato-oxy lowered AHI by 63% (34-86%), from 28.5 (10.9-51.6) events/h to 7.5 (2.4-18.6) events/h ( < 0.001). Of the 15/20 patients with OSA on placebo (AHI > 10 events/hr), AHI was lowered by 74% (62-88%) ( < 0.001) and all 15 patients exhibited a ≥50% reduction. Genioglossus responsiveness increased approximately threefold, from 2.2 (1.1-4.7)%/cm HO on placebo to 6.3 (3.0 to 18.3)%/cm HO on ato-oxy ( < 0.001). Neither atomoxetine nor oxybutynin reduced the AHI when administered separately. A combination of noradrenergic and antimuscarinic agents administered orally before bedtime on 1 night greatly reduced OSA severity. These findings open new possibilities for the pharmacologic treatment of OSA. Clinical trial registered with www.clinicaltrials.gov (NCT02908529).
  • 1区Q1影响因子: 19.3
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    3. Daily Exposure to Mild Intermittent Hypoxia Reduces Blood Pressure in Male Patients with Obstructive Sleep Apnea and Hypertension.
    期刊:American journal of respiratory and critical care medicine
    日期:2022-04-15
    DOI :10.1164/rccm.202108-1808OC
    Daily exposure to mild intermittent hypoxia (MIH) may elicit beneficial cardiovascular outcomes. To determine the effect of 15 days of MIH and in-home continuous positive airway pressure treatment on blood pressure in participants with obstructive sleep apnea and hypertension. We administered MIH during wakefulness 5 days/week for 3 weeks. The protocol consisted of twelve 2-minute bouts of hypoxia interspersed with 2 minutes of normoxia. End-tidal carbon dioxide was maintained 2 mm Hg above baseline values throughout the protocol. Control participants were exposed to a sham protocol (i.e., compressed air). All participants were treated with continuous positive airway pressure over the 3-week period. Results are mean ± SD. Sixteen male participants completed the study (experimental  = 10; control  = 6). Systolic blood pressure at rest during wakefulness over 24 hours was reduced after 15 days of MIH (142.9 ± 8.6 vs. 132.0 ± 10.7 mm Hg;  < 0.001), but not following the sham protocol (149.9 ± 8.6 vs. 149.7 ± 10.8 mm Hg;  = 0.915). Thus, the reduction in blood pressure from baseline was greater in the experimental group compared with control (-10.91 ± 4.1 vs. -0.17 ± 3.6 mm Hg;  = 0.003). Modifications in blood pressure were accompanied by increased parasympathetic and reduced sympathetic activity in the experimental group, as estimated by blood pressure and heart rate variability analysis. No detrimental neurocognitive and metabolic outcomes were evident following MIH. MIH elicits beneficial cardiovascular and autonomic outcomes in males with OSA and concurrent hypertension. Clinical trial registered with www.clinicaltrials.gov (NCT03736382).
  • 1区Q1影响因子: 19.3
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    4. Obstructive Sleep Apnea-induced Endothelial Dysfunction Is Mediated by miR-210.
    期刊:American journal of respiratory and critical care medicine
    日期:2023-02-01
    DOI :10.1164/rccm.202202-0394OC
    Obstructive sleep apnea (OSA)-induced endothelial cell (EC) dysfunction contributes to OSA-related cardiovascular sequelae. The mechanistic basis of endothelial impairment by OSA is unclear. The goals of this study were to identify the mechanism of OSA-induced EC dysfunction and explore the potential therapies for OSA-accelerated cardiovascular disease. The experimental methods include data mining, bioinformatics, EC functional analyses, OSA mouse models, and assessment of OSA human subjects. Using mined microRNA sequencing data, we found that microRNA 210 (miR-210) conferred the greatest induction by intermittent hypoxia in ECs. Consistently, the serum concentration of miR-210 was higher in individuals with OSA from two independent cohorts. Importantly, miR-210 concentration was positively correlated with the apnea-hypopnea index. RNA sequencing data collected from ECs transfected with miR-210 or treated with OSA serum showed a set of genes commonly altered by miR-210 and OSA serum, which are largely involved in mitochondrion-related pathways. ECs transfected with miR-210 or treated with OSA serum showed reduced [Formula: see text]o rate, mitochondrial membrane potential, and DNA abundance. Mechanistically, intermittent hypoxia-induced SREBP2 (sterol regulatory element-binding protein 2) bound to the promoter region of miR-210, which in turn inhibited the iron-sulfur cluster assembly enzyme and led to mitochondrial dysfunction. Moreover, the SREBP2 inhibitor betulin alleviated intermittent hypoxia-increased systolic blood pressure in the OSA mouse model. These results identify an axis involving SREBP2, miR-210, and mitochondrial dysfunction, representing a new mechanistic link between OSA and EC dysfunction that may have important implications for treating and preventing OSA-related cardiovascular sequelae.
  • 1区Q1影响因子: 6.4
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    5. Neuropeptide VF neurons promote sleep via the serotonergic raphe.
    作者:Lee Daniel A , Oikonomou Grigorios , Cammidge Tasha , Andreev Andrey , Hong Young , Hurley Hannah , Prober David A
    期刊:eLife
    日期:2020-12-18
    DOI :10.7554/eLife.54491
    Although several sleep-regulating neuronal populations have been identified, little is known about how they interact with each other to control sleep/wake states. We previously identified neuropeptide VF (NPVF) and the hypothalamic neurons that produce it as a sleep-promoting system (Lee et al., 2017). Here we show using zebrafish that -expressing neurons control sleep via the serotonergic raphe nuclei (RN), a hindbrain structure that is critical for sleep in both diurnal zebrafish and nocturnal mice. Using genetic labeling and calcium imaging, we show that -expressing neurons innervate and can activate serotonergic RN neurons. We also demonstrate that chemogenetic or optogenetic stimulation of expressing neurons induces sleep in a manner that requires NPVF and serotonin in the RN. Finally, we provide genetic evidence that NPVF acts upstream of serotonin in the RN to maintain normal sleep levels. These findings reveal a novel hypothalamic-hindbrain neuronal circuit for sleep/wake control.
  • 1区Q1影响因子: 6.4
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    6. Sleep homeostasis regulated by 5HT2b receptor in a small subset of neurons in the dorsal fan-shaped body of drosophila.
    作者:Qian Yongjun , Cao Yue , Deng Bowen , Yang Guang , Li Jiayun , Xu Rui , Zhang Dandan , Huang Juan , Rao Yi
    期刊:eLife
    日期:2017-10-06
    DOI :10.7554/eLife.26519
    Our understanding of the molecular mechanisms underlying sleep homeostasis is limited. We have taken a systematic approach to study neural signaling by the transmitter 5-hydroxytryptamine (5-HT) in drosophila. We have generated knockout and knockin lines for , the 5-HT synthesizing enzyme and all five 5-HT receptors, making it possible for us to determine their expression patterns and to investigate their functional roles. Loss of the , or gene decreased sleep time whereas loss of the or gene diminished sleep rebound after sleep deprivation. expression in a small subset of, probably a single pair of, neurons in the dorsal fan-shaped body (dFB) is functionally essential: elimination of the gene from these neurons led to loss of sleep homeostasis. Genetic ablation of 5HT2b neurons in the dFB decreased sleep and impaired sleep homeostasis. Our results have shown that serotonergic signaling in specific neurons is required for the regulation of sleep homeostasis.
  • 1区Q1影响因子: 14.7
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    7. Role of serotonergic dorsal raphe neurons in hypercapnia-induced arousals.
    作者:Kaur Satvinder , De Luca Roberto , Khanday Mudasir A , Bandaru Sathyajit S , Thomas Renner C , Broadhurst Rebecca Y , Venner Anne , Todd William D , Fuller Patrick M , Arrigoni Elda , Saper Clifford B
    期刊:Nature communications
    日期:2020-06-02
    DOI :10.1038/s41467-020-16518-9
    During obstructive sleep apnea, elevation of CO during apneas contributes to awakening and restoring airway patency. We previously found that glutamatergic neurons in the external lateral parabrachial nucleus (PBel) containing calcitonin gene related peptide (PBel neurons) are critical for causing arousal during hypercapnia. However, others found that genetic deletion of serotonin (5HT) neurons in the brainstem also prevented arousal from hypercapnia. To examine interactions between the two systems, we showed that dorsal raphe (DR) 5HT neurons selectively targeted the PBel. Either genetically directed deletion or acute optogenetic silencing of DR neurons dramatically increased the latency of mice to arouse during hypercapnia, as did silencing DR terminals in the PBel. This effect was mediated by 5HT receptors which are expressed by PBel neurons. Our results indicate that the serotonergic input from the DR to the PBel via 5HT receptors is critical for modulating the sensitivity of the PBel neurons that cause arousal to rising levels of blood CO.
  • 1区Q1影响因子: 50.5
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    8. Structural basis of ligand recognition at the human MT melatonin receptor.
    期刊:Nature
    日期:2019-04-24
    DOI :10.1038/s41586-019-1141-3
    Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone that maintains circadian rhythms by synchronization to environmental cues and is involved in diverse physiological processes such as the regulation of blood pressure and core body temperature, oncogenesis, and immune function. Melatonin is formed in the pineal gland in a light-regulated manner by enzymatic conversion from 5-hydroxytryptamine (5-HT or serotonin), and modulates sleep and wakefulness by activating two high-affinity G-protein-coupled receptors, type 1A (MT) and type 1B (MT). Shift work, travel, and ubiquitous artificial lighting can disrupt natural circadian rhythms; as a result, sleep disorders affect a substantial population in modern society and pose a considerable economic burden. Over-the-counter melatonin is widely used to alleviate jet lag and as a safer alternative to benzodiazepines and other sleeping aids, and is one of the most popular supplements in the United States. Here, we present high-resolution room-temperature X-ray free electron laser (XFEL) structures of MT in complex with four agonists: the insomnia drug ramelteon, two melatonin analogues, and the mixed melatonin-serotonin antidepressant agomelatine. The structure of MT is described in an accompanying paper. Although the MT and 5-HT receptors have similar endogenous ligands, and agomelatine acts on both receptors, the receptors differ markedly in the structure and composition of their ligand pockets; in MT, access to the ligand pocket is tightly sealed from solvent by extracellular loop 2, leaving only a narrow channel between transmembrane helices IV and V that connects it to the lipid bilayer. The binding site is extremely compact, and ligands interact with MT mainly by strong aromatic stacking with Phe179 and auxiliary hydrogen bonds with Asn162 and Gln181. Our structures provide an unexpected example of atypical ligand entry for a non-lipid receptor, lay the molecular foundation of ligand recognition by melatonin receptors, and will facilitate the design of future tool compounds and therapeutic agents, while their comparison to 5-HT receptors yields insights into the evolution and polypharmacology of G-protein-coupled receptors.
  • 1区Q1影响因子: 28.7
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    9. How (and why) the immune system makes us sleep.
    期刊:Nature reviews. Neuroscience
    日期:2009-02-11
    DOI :10.1038/nrn2576
    Good sleep is necessary for physical and mental health. For example, sleep loss impairs immune function, and sleep is altered during infection. Immune signalling molecules are present in the healthy brain, where they interact with neurochemical systems to contribute to the regulation of normal sleep. Animal studies have shown that interactions between immune signalling molecules (such as the cytokine interleukin 1) and brain neurochemical systems (such as the serotonin system) are amplified during infection, indicating that these interactions might underlie the changes in sleep that occur during infection. Why should the immune system cause us to sleep differently when we are sick? We propose that the alterations in sleep architecture during infection are exquisitely tailored to support the generation of fever, which in turn imparts survival value.
  • 1区Q1影响因子: 19.3
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    10. Serotonin. Culprit or promising therapy for obstructive sleep apnea?
    作者:Veasey S C
    期刊:American journal of respiratory and critical care medicine
    日期:2001-04-01
    DOI :10.1164/ajrccm.163.5.ed1101d
  • 1区Q1影响因子: 15
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    11. Sleep in Insects.
    作者:Helfrich-Förster Charlotte
    期刊:Annual review of entomology
    日期:2017-09-22
    DOI :10.1146/annurev-ento-020117-043201
    Sleep is essential for proper brain function in mammals and insects. During sleep, animals are disconnected from the external world; they show high arousal thresholds and changed brain activity. Sleep deprivation results in a sleep rebound. Research using the fruit fly, Drosophila melanogaster, has helped us understand the genetic and neuronal control of sleep. Genes involved in sleep control code for ion channels, factors influencing neurotransmission and neuromodulation, and proteins involved in the circadian clock. The neurotransmitters/neuromodulators involved in sleep control are GABA, dopamine, acetylcholine, serotonin, and several neuropeptides. Sleep is controlled by the interplay between sleep homeostasis and the circadian clock. Putative sleep-wake centers are located in higher-order brain centers that are indirectly connected to the circadian clock network. The primary function of sleep appears to be the downscaling of synapses that have been built up during wakefulness. Thus, brain homeostasis is maintained and learning and memory are assured.
  • 1区Q1影响因子: 14.7
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    12. The Serotonergic Raphe Promote Sleep in Zebrafish and Mice.
    作者:Oikonomou Grigorios , Altermatt Michael , Zhang Rong-Wei , Coughlin Gerard M , Montz Christin , Gradinaru Viviana , Prober David A
    期刊:Neuron
    日期:2019-06-24
    DOI :10.1016/j.neuron.2019.05.038
    The role of serotonin (5-HT) in sleep is controversial: early studies suggested a sleep-promoting role, but eventually the paradigm shifted toward a wake-promoting function for the serotonergic raphe. Here, we provide evidence from zebrafish and mice that the raphe are critical for the initiation and maintenance of sleep. In zebrafish, genetic ablation of 5-HT production by the raphe reduces sleep, sleep depth, and the homeostatic response to sleep deprivation. Pharmacological inhibition or ablation of the raphe reduces sleep, while optogenetic stimulation increases sleep. Similarly, in mice, ablation of the raphe increases wakefulness and impairs the homeostatic response to sleep deprivation, whereas tonic optogenetic stimulation at a rate similar to baseline activity induces sleep. Interestingly, burst optogenetic stimulation induces wakefulness in accordance with previously described burst activity of the raphe during arousing stimuli. These results indicate that the serotonergic system promotes sleep in both diurnal zebrafish and nocturnal rodents. VIDEO ABSTRACT.
  • 1区Q1影响因子: 13.8
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    13. Gut microbiota-derived metabolites mediate the neuroprotective effect of melatonin in cognitive impairment induced by sleep deprivation.
    期刊:Microbiome
    日期:2023-01-31
    DOI :10.1186/s40168-022-01452-3
    BACKGROUND:Sleep loss is a serious global health concern. Consequences include memory deficits and gastrointestinal dysfunction. Our previous research showed that melatonin can effectively improve cognitive impairment and intestinal microbiota disturbances caused by sleep deprivation (SD). The present study further explored the mechanism by which exogenous melatonin prevents SD-induced cognitive impairments. Here, we established fecal microbiota transplantation, Aeromonas colonization and LPS or butyrate supplementation tests to evaluate the role of the intestinal microbiota and its metabolites in melatonin in alleviating SD-induced memory impairment.  RESULTS: Transplantation of the SD-gut microbiota into normal mice induced microglia overactivation and neuronal apoptosis in the hippocampus, cognitive decline, and colonic microbiota disorder, manifesting as increased levels of Aeromonas and LPS and decreased levels of Lachnospiraceae_NK4A136 and butyrate. All these events were reversed with the transplantation of SD + melatonin-gut microbiota. Colonization with Aeromonas and the addition of LPS produced an inflammatory response in the hippocampus and spatial memory impairment in mice. These changes were reversed by supplementation with melatonin, accompanied by decreased levels of Aeromonas and LPS. Butyrate administration to sleep-deprived mice restored inflammatory responses and memory impairment. In vitro, LPS supplementation caused an inflammatory response in BV2 cells, which was improved by butyrate supplementation. This ameliorative effect of butyrate was blocked by pretreatment with MCT1 inhibitor and HDAC3 agonist but was mimicked by TLR4 and p-P65 antagonists.  CONCLUSIONS: Gut microbes and their metabolites mediate the ameliorative effects of melatonin on SD-induced cognitive impairment. A feasible mechanism is that melatonin downregulates the levels of Aeromonas and constituent LPS and upregulates the levels of Lachnospiraceae_NK4A136 and butyrate in the colon. These changes lessen the inflammatory response and neuronal apoptosis in the hippocampus through crosstalk between the TLR4/NF-κB and MCT1/ HDAC3 signaling pathways. Video Abstract.
  • 2区Q1影响因子: 4.6
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    14. Fibroblast growth factor 21 is an independent predictor of prevalent and incident obstructive sleep apnea.
    期刊:iScience
    日期:2023-01-14
    DOI :10.1016/j.isci.2023.105985
    Fibroblast growth factor 21 (FGF21) is a metabolic regulator and a potential biomarker of metabolic diseases. Limited data are available on the association between FGF21 and obstructive sleep apnea (OSA), which is considered as a manifestation of metabolic syndrome. In the present cross-sectional and longitudinal analyses, the FGF21 level was associated with OSA. This analysis of two clinical cohorts is the first to show that the FGF21 level increased significantly with OSA severity and was an independent predictor of incident OSA in Chinese adults. The circulating FGF21 level could serve as a potential serum biomarker of OSA and its comorbidities and thus aid risk evaluation and early intervention.
  • 3区Q1影响因子: 2.9
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    15. A systematic review and meta-analysis of the association between serotonergic gene polymorphisms and obstructive sleep apnea syndrome.
    作者:Xu Huajun , Guan Jian , Yi Hongliang , Yin Shankai
    期刊:PloS one
    日期:2014-01-27
    DOI :10.1371/journal.pone.0086460
    BACKGROUND:5-Hydroxytryptamine receptor (5-HTR) and 5-hydroxytryptamine transporter (5-HTT) gene polymorphisms have been reported to be associated with susceptibility to obstructive sleep apnea syndrome (OSAS). The associations, derived from sporadic, inconsistent, small-sample-size studies, need to be evaluated further in a meta-analysis. METHODS:Relevant studies were identified by searching PubMed, Embase, The Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, and Weipu. Eligible data were extracted from each included study. Odds ratios (ORs) were calculated using a fixed-effects or a random-effects model. The ORs and 95% confidence interval (CI) were used to assess the strength of the association between serotonergic gene polymorphisms and OSAS in the dominant and recessive models, as well as alleles. The Q statistic was used to evaluate homogeneity and Begg's test was used to assess publication bias. RESULTS:Eight studies were finally included in the meta-analysis of the association between 5-HTR2A gene variants (including 102T/C and 1438G/A), 5-HTT gene polymorphisms (including 5-HTT gene-linked promoter region (5-HTTLRP), and serotonin transporter intron 2 variable number tandem repeat (STin2VNTR) and OSAS risk. The G allele of 5-HTR2A 1438G/A, long 5-HTTLPR, and 10-tandem-repeats STin2VNTR were shown to increase OSAS susceptibility, with ORs of 2.33 (A vs. G, 95% CI 1.48-3.66), 1.24 (L vs. S, 95% CI: 1.04-1.49), and 2.87 (10 vs. 12, 95% CI: 1.38-5.97), respectively. These significant differences were determined in both dominant and recessive models. Of the 5-HTR2A 1438G/A gene polymorphism, the AA genotype increased the OSAS risk, with an OR of 4.21 (95% CI: 2.83-6.25) in a recessive model in male OSAS patients, but no significant association was found in females. CONCLUSIONS:Our meta-analysis demonstrated that polymorphisms in the 5-HTR2A 1438G/A and 5-HTT genes contributed to susceptibility to OSAS. The A allele of the 1438G/A gene polymorphism is predominantly distributed in males and increased the OSAS risk significantly.
  • 2区Q1影响因子: 6.1
    16. Melatonin attenuates chronic intermittent hypoxia-induced intestinal barrier dysfunction in mice.
    期刊:Microbiological research
    日期:2023-08-23
    DOI :10.1016/j.micres.2023.127480
    BACKGROUND AND PURPOSE:Chronic intermittent hypoxia (CIH) triggers subclinical intestinal barrier disruption prior to systemic low-grade inflammation. Increasing evidence suggests therapeutic effects of melatonin on systemic inflammation and gut microbiota remodelling. However, whether and how melatonin alleviates CIH-induced intestinal barrier dysfunction remains unclear. EXPERIMENTAL APPROACH:C57BL/6 J mice and Caco-2 cell line were treated. We evaluated gut barrier function spectrophotometrically using fluorescein isothiocyanate (FITC)-labelled dextran. Immunohistochemical and immunofluorescent staining were used to detect morphological changes in the mechanical barrier. Western blotting (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) revealed the expression of tight junctions, signal transducer and activator of transcription 3 (STAT3) levels. 16 S rRNA analysis of the colonic contents microflora. Flow cytometry was used to detect cytokines and Th17 cells with and without melatonin supplementation. KEY RESULTS:We found that CIH could induce colonic mucosal injury, including reduction in the number of goblet cells and decrease the expression of intestinal tight junction proteins. CIH could decrease the abundance of the beneficial genera Clostridium, Akkermansia, and Bacteroides, while increasing the abundance of the pathogenic genera Desulfovibrio and Bifidobacterium. Finally, CIH facilitated Th17 differentiation via the phosphorylation of signal transducer and activator of transcription 3 (STAT3) in vitro and elevated the circulating pro-inflammatory cytokine in vivo. Melatonin supplementation ameliorated CIH-induced intestinal mucosal injury, gut microbiota dysbiosis, enteric Th17 polarization, and systemic low-grade inflammation reactions mentioned-above. CONCLUSION AND IMPLICATIONS:Melatonin attenuated CIH-induced intestinal barrier dysfunction by regulating gut flora dysbiosis, mucosal epithelium integrity, and Th17 polarization via STAT3 signalling.
  • 1区Q1影响因子: 19.3
    17. Genome-Wide Association Study of Obstructive Sleep Apnea and Objective Sleep-related Traits Identifies Novel Risk Loci in Han Chinese Individuals.
    期刊:American journal of respiratory and critical care medicine
    日期:2022-12-15
    DOI :10.1164/rccm.202109-2044OC
    Previous genetic studies of obstructive sleep apnea (OSA) have limitations in terms of precise case definition, integrated quantitative traits, and interpretation of genetic functions; thus, the heritability of OSA remains poorly explained. To identify novel genetic variants associated with OSA and objective sleep-related traits and to explore their functional roles. A genome-wide association study was performed in 20,590 Han Chinese individuals (5,438 OSA and 15,152 control samples). Human samples and point mutation knockin mice were used for follow-up investigation of gene functions. Two characteristic study-wide significant loci ( < 2.63 × 10) for OSA were identified: the intronic variant rs6455893 on 6q26 (odds ratio [OR] = 1.62; 95% confidence interval [CI], 1.39-1.89;  = 6.98 × 10) and the missense variant rs3746804 (p.Pro267Leu) in the riboflavin transporter on 20p13 (OR = 0.83; 95% CI, 0.79-0.88;  = 7.57 × 10). In addition, 18 genome-wide significant loci associated with quantitative OSA and objective sleep-related traits were identified, 5 of which exceeded the study-wide significance threshold. Rs3746804 was associated with elevated serum riboflavin concentrations, and the corresponding mutation in mice increased riboflavin concentrations, suggesting that this variant may facilitate riboflavin uptake and riboflavin-dependent physiological activity. We identified several novel genome-wide significant loci associated with OSA and objective sleep-related traits. Our findings provide insight into the genetic architecture of OSA and suggest that might be a therapeutic target, whereas riboflavin might be a therapeutic agent.
  • 3区Q2影响因子: 3.9
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    18. Effects of Chronic Intermittent Hypoxia and Chronic Sleep Fragmentation on Gut Microbiome, Serum Metabolome, Liver and Adipose Tissue Morphology.
    作者:Wang Fan , Zou Juanjuan , Xu Huajun , Huang Weijun , Zhang Xiaoman , Wei Zhicheng , Li Xinyi , Liu Yupu , Zou Jianyin , Liu Feng , Zhu Huaming , Yi Hongliang , Guan Jian , Yin Shankai
    期刊:Frontiers in endocrinology
    日期:2022-02-01
    DOI :10.3389/fendo.2022.820939
    Chronic intermittent hypoxia (CIH) and chronic sleep fragmentation (CSF) are two cardinal pathological features of obstructive sleep apnea (OSA). Dietary obesity is a crucial risk intermediator for OSA and metabolic disorders. Gut microbiota affect hepatic and adipose tissue morphology under conditions of CIH or CSF through downstream metabolites. However, the exact relationship is unclear. Herein, chow and high-fat diet (HFD)-fed mice were subjected to CIH or CSF for 10 weeks each and compared to normoxia (NM) or normal sleep (NS) controls. 16S rRNA amplicon sequencing, untargeted liquid chromatography-tandem mass spectrometry, and histological assessment of liver and adipose tissues were used to investigate the correlations between the microbiome, metabolome, and lipid metabolism under CIH or CSF condition. Our results demonstrated that CIH and CSF regulate the abundance of intestinal microbes (such as , spp., spp., spp.) and functional metabolites, such as tryptophan, free fatty acids, branched amino acids, and bile acids, which influence adipose tissue and hepatic lipid metabolism, and the level of lipid deposition in tissues and peripheral blood. In conclusion, CIH and CSF adversely affect fecal microbiota composition and function, and host metabolism; these findings provide new insight into the independent and synergistic effects of CIH, CSF, and HFD on lipid disorders.
  • 1区Q1影响因子: 9
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    19. Metabolomics and microbiome profiling as biomarkers in obstructive sleep apnoea: a comprehensive review.
    期刊:European respiratory review : an official journal of the European Respiratory Society
    日期:2021-05-11
    DOI :10.1183/16000617.0220-2020
    INTRODUCTION:Obstructive sleep apnoea (OSA) is a common sleep disorder with a high social and economic burden. Thus, early prediction and diagnosis of OSA are important. Changes in metabolism and the microbiome may serve as biomarkers for OSA. Herein, we review the literature on the metabolomic and microbiome changes associated with OSA, and identify the metabolites and microorganisms involved. METHODS:We searched the PUBMED and EMBASE electronic databases using the following terms: "obstructive sleep apnea", "OSA", "sleep disordered breathing", "SDB", "intermittent hypoxia", "sleep fragmentation", and either "metabolomics" or "microbiome". In total, 273 papers were identified, of which 28 were included in our study. RESULTS:Changes in the levels of certain metabolites related to fatty acid, carbohydrate and amino acid metabolism were associated with the incidence of OSA. The diversity and abundance of microflora, particularly Firmicutes and Bacteroidetes, were altered in humans and rodents with OSA. CONCLUSIONS:Certain changes in metabolism and the microbiota play an integral role in the pathophysiology of OSA and OSA-induced cardiovascular complications. Metabolomic and microbiome biomarkers shed light on the pathogenesis of OSA, and facilitate early diagnosis and treatment.
  • 3区Q1影响因子: 3.8
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    20. Changes in cerebral metabolites in obstructive sleep apnea: a systemic review and meta-analysis.
    期刊:Scientific reports
    日期:2016-06-28
    DOI :10.1038/srep28712
    Cognitive impairment is associated with changes in cerebral metabolites in patients with obstructive sleep apnea (OSA). Several studies have used magnetic resonance spectroscopy (MRS) to detect variations in cerebral metabolites; however, the results have been inconsistent. This meta-analysis summarizes the differences in cerebral metabolites between patients with OSA and controls. Two electronic databases, PubMed and Embase, were searched for articles (published before March 31, 2016) describing studies that used MRS to evaluate the cerebral metabolite changes. The overall effects were measured using the weighted mean difference with a 95% confidence interval. Subgroup analysis and sensitivity analysis were used to explore the sources of between-study heterogeneity and the stability of the results. Publication bias was also evaluated. Thirteen studies were ultimately included. In the hippocampus, the N-acetylaspartate (NAA)/creatine ratio was lower in patients with OSA. In the frontal lobe, only the NAA/choline ratio was lower in patients with OSA. Cerebral metabolites are significantly altered in the hippocampus in patients with OSA. Further clinical studies are needed to explore the underlying mechanisms between OSA and the changes in cerebral metabolites in the brain.
  • 1区Q1影响因子: 19.3
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    21. Obstructive sleep apnea: brain structural changes and neurocognitive function before and after treatment.
    作者:Canessa Nicola , Castronovo Vincenza , Cappa Stefano F , Aloia Mark S , Marelli Sara , Falini Andrea , Alemanno Federica , Ferini-Strambi Luigi
    期刊:American journal of respiratory and critical care medicine
    日期:2010-10-29
    DOI :10.1164/rccm.201005-0693OC
    RATIONALE:Obstructive sleep apnea (OSA) is commonly associated with neurocognitive impairments that have not been consistently related to specific brain structure abnormalities. Knowledge of the brain structures involved in OSA and the corresponding functional implications could provide clues to the pathogenesis of cognitive impairment and its reversibility in this disorder. OBJECTIVES:To investigate the cognitive deficits and the corresponding brain morphology changes in OSA, and the modifications after treatment, using combined neuropsychologic testing and voxel-based morphometry. METHODS:A total of 17 patients treatment-naive to sleep apnea and 15 age-matched healthy control subjects underwent a sleep study, cognitive tests, and magnetic resonance imaging. After 3 months of treatment, cognitive and imaging data were collected to assess therapy efficacy. MEASUREMENTS AND MAIN RESULTS:Neuropsychologic results in pretreatment OSA showed impairments in most cognitive areas, and in mood and sleepiness. These impairments were associated with focal reductions of gray-matter volume in the left hippocampus (entorhinal cortex), left posterior parietal cortex, and right superior frontal gyrus. After treatment, we observed significant improvements involving memory, attention, and executive-functioning that paralleled gray-matter volume increases in hippocampal and frontal structures. CONCLUSIONS:The cognitive and structural deficits in OSA may be secondary to sleep deprivation and repetitive nocturnal intermittent hypoxemia. These negative effects may be recovered by consistent and thorough treatment. Our findings highlight the importance of early diagnosis and successful treatment of this disorder.
  • 1区Q1影响因子: 19.3
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    22. Ventilatory control and airway anatomy in obstructive sleep apnea.
    期刊:American journal of respiratory and critical care medicine
    日期:2004-08-18
    DOI :10.1164/rccm.200404-510OC
    Ventilatory instability may play an important role in the pathogenesis of obstructive sleep apnea. We hypothesized that the influence of ventilatory instability in this disorder would vary depending on the underlying collapsibility of the upper airway. To test this hypothesis, we correlated loop gain with apnea-hypopnea index during supine, nonrapid eye movement sleep in three groups of patients with obstructive sleep apnea based on pharyngeal closing pressure: negative pressure group (pharyngeal closing pressure less than -1 cm H(2)O), atmospheric pressure group (between -1 and +1 cm H(2)O), and positive pressure group (greater than +1 cm H(2)O). Loop gain was measured by sequentially increasing proportional assist ventilation until periodic breathing developed, which occurred in 24 of 25 subjects. Mean loop gain for all three groups was 0.37 +/- 0.11. A significant correlation was found between loop gain and apnea-hypopnea index in the atmospheric group only (r = 0.88, p = 0.0016). We conclude that loop gain has a substantial impact on apnea severity in certain patients with sleep apnea, particularly those with a pharyngeal closing pressure near atmospheric.
  • 1区Q1影响因子: 16.6
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    23. Intermittent hypoxia alters gut microbiota diversity in a mouse model of sleep apnoea.
    作者:Moreno-Indias Isabel , Torres Marta , Montserrat Josep M , Sanchez-Alcoholado Lidia , Cardona Fernando , Tinahones Francisco J , Gozal David , Poroyko Valeryi A , Navajas Daniel , Queipo-Ortuño Maria I , Farré Ramon
    期刊:The European respiratory journal
    日期:2014-12-23
    DOI :10.1183/09031936.00184314
    We assessed whether intermittent hypoxia, which emulates one of the hallmarks of obstructive sleep apnoea (OSA), leads to altered faecal microbiome in a murine model. In vivo partial pressure of oxygen was measured in colonic faeces during intermittent hypoxia in four anesthetised mice. 10 mice were subjected to a pattern of chronic intermittent hypoxia (20 s at 5% O2 and 40 s at room air for 6 h·day(-1)) for 6 weeks and 10 mice served as normoxic controls. Faecal samples were obtained and microbiome composition was determined by 16S rRNA pyrosequencing and bioinformatic analysis by Quantitative Insights into Microbial Ecology. Intermittent hypoxia exposures translated into hypoxia/re-oxygenation patterns in the faeces proximal to the bowel epithelium (<200 μm). A significant effect of intermittent hypoxia on global microbial community structure was found. Intermittent hypoxia increased the α-diversity (Shannon index, p<0.05) and induced a change in the gut microbiota (ANOSIM analysis of β-diversity, p<0.05). Specifically, intermittent hypoxia-exposed mice showed a higher abundance of Firmicutes and a smaller abundance of Bacteroidetes and Proteobacteria phyla than controls. Faecal microbiota composition and diversity are altered as a result of intermittent hypoxia realistically mimicking OSA, suggesting the possibility that physiological interplays between host and gut microbiota could be deregulated in OSA.
  • 1区Q1影响因子: 8.8
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    24. DNA binding protein HMGB1 secreted by activated microglia promotes the apoptosis of hippocampal neurons in diabetes complicated with OSA.
    期刊:Brain, behavior, and immunity
    日期:2018-06-18
    DOI :10.1016/j.bbi.2018.06.012
    Type 2 diabetes mellitus (T2DM) complicated with obstructive sleep apnea (OSA) may cause neuronal apoptosis and cognitive deficits, but the underlying mechanisms remain unclear. We aimed to determine the relationship between the activation of microglia and the apoptosis of hippocampal neurons, specifically in terms of high mobility group box-1 (HMGB1), after high glucose (HG) and intermittent hypoxia (IH) exposure. Diabetic KK-Ay mice and non-diabetic C57BL/6J mice (C57 mice) underwent IH or normoxia (control) exposure for 4 weeks. Cognitive function, microglial activation and hippocampal neuronal apoptosis were assessed after IH or normoxia exposure. Compared with C57 control mice, KK-Ay control mice exhibited increased cognitive dysfunction, microglial activation and hippocampal neuronal apoptosis. There were no differences between untreated KK-Ay control mice and C57 mice that had been exposed to IH. The abovementioned responses were aggravated in IH-exposed KK-Ay mice compared with control KK-Ay mice. In vitro, a cellular co-culture experiment showed that HG combined with IH could activate BV2 microglia, leading to the release of neuroinflammatory factors (ROS, TNF-α, IL-1β) and mediating the apoptosis of HT22 cells via the PI3K/Akt/GSK-3β signaling pathway. Meanwhile, HMGB1 was actively secreted into the extracellular environment from activated BV2 microglia. As a proinflammatory factor, it was able to sustain microglial activation by directly acting on those cells. The activation promoted positive feedback and aggravated neuronal damage further. In a cellular monoculture or co-culture system, HMGB1 siRNA was able to alleviate the activation of BV2 cells and the apoptosis of HT22 cells induced by HG combined with IH. Our object is to show that inhibition of HMGB1 may break the vicious cycle to prevent or treat neuroinflammation and hippocampal neuronal apoptosis caused by T2DM complicated with OSA.
  • 1区Q1影响因子: 38.7
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    25. Sleep apnoea and the brain: a complex relationship.
    期刊:The Lancet. Respiratory medicine
    日期:2015-04-14
    DOI :10.1016/S2213-2600(15)00090-9
    Intermittent hypoxia, reoxygenation, and hypercapnia or hypocapnia occur in both adults and children during untreated apnoea and hypopnoea, along with changes in cerebral blood flow and sleep fragmentation. These effects can result in cognitive deficits with functional effects on work and school efficiency. The assessment of how obstructive sleep apnoea affects cognition depends on the specificity and sensitivity of the tests, which are rarely developed specifically for obstructive sleep apnoea. In this Review, we discuss both the neural adaptive and maladaptive processes in response to hypoxaemia. The net result on cognitive and emotional performance depends on the stage of this dynamic process, effects on other body systems, cognitive reserve, and idiosyncratic susceptibility. We also explore the contribution of fragmented sleep, and the disruption of sleep structure, with focus on the effect at different times in the development of disease. This Review will address the gap in the underlying pathophysiology of new clinical and translational findings, and argue their contribution to the inherent complexity of the association between obstructive sleep apnoea and the brain.
  • 3区Q2影响因子: 4.2
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    26. Blocking the LncRNA MALAT1/miR-224-5p/NLRP3 Axis Inhibits the Hippocampal Inflammatory Response in T2DM With OSA.
    作者:Du Ping , Wang Jiahui , Han Yelei , Feng Jing
    期刊:Frontiers in cellular neuroscience
    日期:2020-05-12
    DOI :10.3389/fncel.2020.00097
    Studies have shown that diabetes can cause cognitive dysfunction, and cognitive dysfunction in patients with diabetes combined with obstructive sleep apnea (OSA) is more severe. LncRNAs are known to be associated with type 2 diabetes mellitus (T2DM) with OSA. This study aimed to investigate the role and underlying mechanism of the lncRNA MALAT1/miR-224-5p/NLRP3 axis in T2DM with OSA. qRT-PCR was used to quantify the expression of MALAT1, miR-224-5p, and NLRP3 in brain tissues. NLRP3 expression was assessed by immunohistochemistry (IHC) and immunofluorescent labeling. The interaction involving MALAT1, miR-224-5p, and NLRP3 was evaluated by transfection. Western blotting was utilized to evaluate the expression levels of the pathway-related proteins NLRP3, caspase 1, tumor necrosis factor-α (TNF-α) and interleukin-1 β (IL-1β) both and . qRT-PCR was used to assess the mRNA expression levels of NLRP3, caspase 1, TNF-α and IL-1β both and . In brain tissues of T2DM with OSA, MALAT1 and NLRP3 were overexpressed, while miR-224-5p was downregulated, which was consistent with subsequent cell experiments. We screened the miRNAs that could bind to MALAT1 and NLRP3 by the StarBase database and the TargetScanMouse7.2 website. Our research showed that among these miRNAs, the level of miR-224-5p was most significantly negatively correlated with the levels of MALAT1 and NLRP3. Also, a firefly luciferase assay showed that miR-224-5p, which is a target of MALAT1, directly reduced the expression of the downstream protein NLRP3. Overexpression of miR-224-5p significantly inhibited the expression levels of NLRP3, caspase 1, TNF-α and IL-1β . MALAT1 promoted NLRP3 expression by acting as a competing endogenous RNA and sponging miR-224-5p. MiR-224-5p reduces microglial inflammation activation through the regulation of NLRP3 expression, which ultimately affected the NLRP3/IL-1β pathway in the hippocampus. This suggests that miR-224-5p may serve as a potential target for T2DM and OSA therapy.
  • 2区Q1影响因子: 9.1
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    27. The role of short-chain fatty acids in intestinal barrier function, inflammation, oxidative stress, and colonic carcinogenesis.
    作者:Liu Pinyi , Wang Yanbing , Yang Ge , Zhang Qihe , Meng Lingbin , Xin Ying , Jiang Xin
    期刊:Pharmacological research
    日期:2021-01-09
    DOI :10.1016/j.phrs.2021.105420
    Short-chain fatty acids (SCFAs), mainly including acetate, propionate, and butyrate, are metabolites produced during the bacterial fermentation of dietary fiber in the intestinal tract. They are believed to be essential factors affecting host health. Most in vitro and ex vivo studies have shown that SCFAs affect the regulation of inflammation, carcinogenesis, intestinal barrier function, and oxidative stress, but convincing evidence in humans is still lacking. Two major SCFA signaling mechanisms have been identified: promotion of histone acetylation and activation of G-protein-coupled receptors. In this review, we introduce the production and metabolic characteristics of SCFAs, summarize the potential effects of SCFAs on the four aspects mentioned above and the possible mechanisms. SCFAs have been reported to exert a wide spectrum of positive effects and have a high potential for therapeutic use in human-related diseases.
  • 3区Q1影响因子: 3
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    28. I-FABP as a Potential Marker for Intestinal Barrier Loss in Porcine Polytrauma.
    期刊:Journal of clinical medicine
    日期:2022-08-07
    DOI :10.3390/jcm11154599
    Polytrauma and concomitant hemorrhagic shock can lead to intestinal damage and subsequent multiple organ dysfunction syndrome. The intestinal fatty acid-binding protein (I-FABP) is expressed in the intestine and appears quickly in the circulation after intestinal epithelial cell damage. This porcine animal study investigates the I-FABP dynamics in plasma and urine after polytrauma. Furthermore, it evaluates to what extent I-FABP can also act as a marker of intestinal damage in a porcine polytrauma model. Eight pigs (Sus scrofa) were subjected to polytrauma which consisted of lung contusion, tibial fracture, liver laceration, and hemorrhagic shock followed by blood and fluid resuscitation and fracture fixation with an external fixator. Eight sham animals were identically instrumented but not injured. Afterwards, intensive care treatment including mechanical ventilation for 72 h followed. I-FABP levels in blood and urine were determined by ELISA. In addition, immunohistological staining for I-FABP, active caspase-3 and myeloperoxidase were performed after 72 h. Plasma and urine I-FABP levels were significantly increased shortly after trauma. I-FABP expression in intestinal tissue showed significantly lower expression in polytraumatized animals vs. sham. Caspase-3 and myeloperoxidase expression in the immunohistological examination were significantly higher in the jejunum and ileum of polytraumatized animals compared to sham animals. This study confirms a loss of intestinal barrier after polytrauma which is indicated by increased I-FABP levels in plasma and urine as well as decreased I-FABP levels in immunohistological staining of the intestine.
  • 2区Q1影响因子: 4.7
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    29. Role of oxidative stress in intermittent hypoxia-induced immediate early gene activation in rat PC12 cells.
    作者:Yuan Guoxiang , Adhikary Gautam , McCormick Andrew A , Holcroft John J , Kumar Ganesh K , Prabhakar Nanduri R
    期刊:The Journal of physiology
    日期:2004-04-23
    DOI :10.1113/jphysiol.2003.058503
    Intermittent hypoxia (IH) occurs in many pathophysiological conditions. The molecular mechanisms associated with IH, however, have received little attention. Previous studies have reported that the c-fos gene via formation of activator protein-1 (AP-1) transcription factor contributes to adaptive responses to continuous hypoxia. In the present study, using a cell culture model we examined whether IH activates c-fos and AP-1 and if so, by what mechanisms. Experiments were performed on rat phaeochromocytoma cells exposed to 21% O(2) (normoxia) or 60 and 120 cycles of IH, each cycle consisting 15 s of hypoxia followed by 4 min of normoxia. IH resulted in a significant elevation of c-fos mRNA as well as transcriptional activation. IH was more potent and induced a longer lasting activation of c-fos than comparable cumulative duration of continuous hypoxia. IH increased AP-1 activity and tyrosine hydroxylase (TH) mRNA, an AP-1-regulated downstream gene, and these effects were prevented by antisense c-fos. Superoxide dismutase mimetic, a potent scavenger of superoxide anions, prevented IH-induced c-fos, AP-1 and TH activations. IH increased superoxide anion levels in mitochondria as evidenced by decreased aconitase enzyme activity and increased levels of hydrogen peroxide, a stable dismutated product of superoxide anions. Complex I of the mitochondrial electron transport chain was markedly inhibited in IH exposed cells. Pharmacological inhibitors of complex I mimicked the effects of IH during normoxia and occluded the effects of IH on c-fos activation, suggesting the involvement of the mitochondrial electron transport chain in the generation of superoxide anions during IH. These results suggest IH-induced c-fos-mediated transcriptional activation involves oxidative stress.
  • 1区Q1影响因子: 44.7
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    30. Hypoxia induces rapid changes to histone methylation and reprograms chromatin.
    作者:Batie Michael , Frost Julianty , Frost Mark , Wilson James W , Schofield Pieta , Rocha Sonia
    期刊:Science (New York, N.Y.)
    日期:2019-03-14
    DOI :10.1126/science.aau5870
    Oxygen is essential for the life of most multicellular organisms. Cells possess enzymes called molecular dioxygenases that depend on oxygen for activity. A subclass of molecular dioxygenases is the histone demethylase enzymes, which are characterized by the presence of a Jumanji-C (JmjC) domain. Hypoxia can alter chromatin, but whether this is a direct effect on JmjC-histone demethylases or due to other mechanisms is unknown. Here, we report that hypoxia induces a rapid and hypoxia-inducible factor-independent induction of histone methylation in a range of human cultured cells. Genomic locations of histone-3 lysine-4 trimethylation (H3K4me3) and H3K36me3 after a brief exposure of cultured cells to hypoxia predict the cell's transcriptional response several hours later. We show that inactivation of one of the JmjC-containing enzymes, lysine demethylase 5A (KDM5A), mimics hypoxia-induced cellular responses. These results demonstrate that oxygen sensing by chromatin occurs via JmjC-histone demethylase inhibition.
  • 2区Q2影响因子: 4
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    31. Intermittent hypoxia enhances the expression of hypoxia inducible factor HIF1A through histone demethylation.
    期刊:The Journal of biological chemistry
    日期:2022-09-27
    DOI :10.1016/j.jbc.2022.102536
    The cellular response to hypoxia is regulated through enzymatic oxygen sensors, including the prolyl hydroxylases, which control degradation of the well-known hypoxia inducible factors (HIFs). Other enzymatic oxygen sensors have been recently identified, including members of the KDM histone demethylase family. Little is known about how different oxygen-sensing pathways interact and if this varies depending on the form of hypoxia, such as chronic or intermittent. In this study, we investigated how two proposed cellular oxygen-sensing systems, HIF-1 and KDM4A, KDM4B, and KDM4C, respond in cells exposed to rapid forms of intermittent hypoxia (minutes) and compared to chronic hypoxia (hours). We found that intermittent hypoxia increases HIF-1α protein through a pathway distinct from chronic hypoxia, involving the KDM4A, KDM4B, and KDM4C histone lysine demethylases. Intermittent hypoxia increases the quantity and activity of KDM4A, KDM4B, and KDM4C, resulting in a decrease in histone 3 lysine 9 (H3K9) trimethylation near the HIF1A locus. We demonstrate that this contrasts with chronic hypoxia, which decreases KDM4A, KDM4B, and KDM4C activity, leading to hypertrimethylation of H3K9 globally and at the HIF1A locus. Altogether, we found that demethylation of histones bound to the HIF1A gene in intermittent hypoxia increases HIF1A mRNA expression, which has the downstream effect of increasing overall HIF-1 activity and expression of HIF target genes. This study highlights how multiple oxygen-sensing pathways can interact to regulate and fine tune the cellular hypoxic response depending on the period and length of hypoxia.
  • 1区Q1影响因子: 19.3
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    32. Pathogenesis of obstructive and central sleep apnea.
    作者:White David P
    期刊:American journal of respiratory and critical care medicine
    日期:2005-08-11
    DOI :10.1164/rccm.200412-1631SO
    Considerable progress has been made over the last several decades in our understanding of the pathophysiology of both central and obstructive sleep apnea. Central sleep apnea, in its various forms, is generally the product of an unstable ventilatory control system (high loop gain) with increased controller gain (high hypercapnic responsiveness) generally being the cause. High plant gain can contribute under certain circumstances (hypercapnic patients). On the other hand, obstructive sleep apnea can develop as the result of a variety of physiologic characteristics. The combinations of these may vary considerably between patients. Most obstructive apnea patients have an anatomically small upper airway with augmented pharyngeal dilator muscle activation maintaining airway patency awake, but not asleep. However, individual variability in several phenotypic characteristics may ultimately determine who develops apnea and how severe the apnea will be. These include: (1) upper airway anatomy, (2) the ability of upper airway dilator muscles to respond to rising intrapharyngeal negative pressure and increasing Co(2) during sleep, (3) arousal threshold in response to respiratory stimulation, and (4) loop gain (ventilatory control instability). As a result, patients may respond to different therapeutic approaches based on the predominant abnormality leading to the sleep-disordered breathing.
  • 1区Q1影响因子: 19.3
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    33. Loop gain in apnea: gaining control or controlling the gain?
    作者:Naughton Matthew T
    期刊:American journal of respiratory and critical care medicine
    日期:2010-01-15
    DOI :10.1164/rccm.200909-1449ED
  • 3区Q2影响因子: 3.3
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    34. Arousal from sleep: implications for obstructive sleep apnea pathogenesis and treatment.
    作者:Eckert Danny J , Younes Magdy K
    期刊:Journal of applied physiology (Bethesda, Md. : 1985)
    日期:2013-08-29
    DOI :10.1152/japplphysiol.00649.2013
    Historically, brief awakenings from sleep (cortical arousals) have been assumed to be vitally important in restoring airflow and blood-gas disturbances at the end of obstructive sleep apnea (OSA) breathing events. Indeed, in patients with blunted chemical drive (e.g., obesity hypoventilation syndrome) and in instances when other defensive mechanisms fail, cortical arousal likely serves an important protective role. However, recent insight into the pathogenesis of OSA indicates that a substantial proportion of respiratory events do not terminate with a cortical arousal from sleep. In many cases, cortical arousals may actually perpetuate blood-gas disturbances, breathing instability, and subsequent upper airway closure during sleep. This brief review summarizes the current understanding of the mechanisms mediating respiratory-induced cortical arousal, the physiological factors that influence the propensity for cortical arousal, and the potential dual roles that cortical arousal may play in OSA pathogenesis. Finally, the extent to which existing sedative agents decrease the propensity for cortical arousal and their potential to be therapeutically beneficial for certain OSA patients are highlighted.
  • 1区Q1影响因子: 19.3
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    35. Defining phenotypic causes of obstructive sleep apnea. Identification of novel therapeutic targets.
    期刊:American journal of respiratory and critical care medicine
    日期:2013-10-15
    DOI :10.1164/rccm.201303-0448OC
    RATIONALE:The pathophysiologic causes of obstructive sleep apnea (OSA) likely vary among patients but have not been well characterized. OBJECTIVES:To define carefully the proportion of key anatomic and nonanatomic contributions in a relatively large cohort of patients with OSA and control subjects to identify pathophysiologic targets for future novel therapies for OSA. METHODS:Seventy-five men and women with and without OSA aged 20-65 years were studied on three separate nights. Initially, the apnea-hypopnea index was determined by polysomnography followed by determination of anatomic (passive critical closing pressure of the upper airway [Pcrit]) and nonanatomic (genioglossus muscle responsiveness, arousal threshold, and respiratory control stability; loop gain) contributions to OSA. MEASUREMENTS AND MAIN RESULTS:Pathophysiologic traits varied substantially among participants. A total of 36% of patients with OSA had minimal genioglossus muscle responsiveness during sleep, 37% had a low arousal threshold, and 36% had high loop gain. A total of 28% had multiple nonanatomic features. Although overall the upper airway was more collapsible in patients with OSA (Pcrit, 0.3 [-1.5 to 1.9] vs. -6.2 [-12.4 to -3.6] cm H2O; P <0.01), 19% had a relatively noncollapsible upper airway similar to many of the control subjects (Pcrit, -2 to -5 cm H2O). In these patients, loop gain was almost twice as high as patients with a Pcrit greater than -2 cm H2O (-5.9 [-8.8 to -4.5] vs. -3.2 [-4.8 to -2.4] dimensionless; P = 0.01). A three-point scale for weighting the relative contribution of the traits is proposed. It suggests that nonanatomic features play an important role in 56% of patients with OSA. CONCLUSIONS:This study confirms that OSA is a heterogeneous disorder. Although Pcrit-anatomy is an important determinant, abnormalities in nonanatomic traits are also present in most patients with OSA.
  • 1区Q1影响因子: 38.7
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    36. Estimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis.
    作者:Benjafield Adam V , Ayas Najib T , Eastwood Peter R , Heinzer Raphael , Ip Mary S M , Morrell Mary J , Nunez Carlos M , Patel Sanjay R , Penzel Thomas , Pépin Jean-Louis , Peppard Paul E , Sinha Sanjeev , Tufik Sergio , Valentine Kate , Malhotra Atul
    期刊:The Lancet. Respiratory medicine
    日期:2019-07-09
    DOI :10.1016/S2213-2600(19)30198-5
    BACKGROUND:There is a scarcity of published data on the global prevalence of obstructive sleep apnoea, a disorder associated with major neurocognitive and cardiovascular sequelae. We used publicly available data and contacted key opinion leaders to estimate the global prevalence of obstructive sleep apnoea. METHODS:We searched PubMed and Embase to identify published studies reporting the prevalence of obstructive sleep apnoea based on objective testing methods. A conversion algorithm was created for studies that did not use the American Academy of Sleep Medicine (AASM) 2012 scoring criteria to identify obstructive sleep apnoea, allowing determination of an equivalent apnoea-hypopnoea index (AHI) for publications that used different criteria. The presence of symptoms was not specifically analysed because of scarce information about symptoms in the reference studies and population data. Prevalence estimates for obstructive sleep apnoea across studies using different diagnostic criteria were standardised with a newly developed algorithm. Countries without obstructive sleep apnoea prevalence data were matched to a similar country with available prevalence data; population similarity was based on the population body-mass index, race, and geographical proximity. The primary outcome was prevalence of obstructive sleep apnoea based on AASM 2012 diagnostic criteria in individuals aged 30-69 years (as this age group generally had available data in the published studies and related to information from the UN for all countries). FINDINGS:Reliable prevalence data for obstructive sleep apnoea were available for 16 countries, from 17 studies. Using AASM 2012 diagnostic criteria and AHI threshold values of five or more events per h and 15 or more events per h, we estimated that 936 million (95% CI 903-970) adults aged 30-69 years (men and women) have mild to severe obstructive sleep apnoea and 425 million (399-450) adults aged 30-69 years have moderate to severe obstructive sleep apnoea globally. The number of affected individuals was highest in China, followed by the USA, Brazil, and India. INTERPRETATION:To our knowledge, this is the first study to report global prevalence of obstructive sleep apnoea; with almost 1 billion people affected, and with prevalence exceeding 50% in some countries, effective diagnostic and treatment strategies are needed to minimise the negative health impacts and to maximise cost-effectiveness. FUNDING:ResMed.
  • 3区Q2影响因子: 3.3
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    37. Upper airway pressure-flow relationships in obstructive sleep apnea.
    作者:Smith P L , Wise R A , Gold A R , Schwartz A R , Permutt S
    期刊:Journal of applied physiology (Bethesda, Md. : 1985)
    日期:1988-02-01
    DOI :10.1152/jappl.1988.64.2.789
    We examined the pressure-flow relationships in patients with obstructive sleep apnea utilizing the concepts of a Starling resistor. In six patients with obstructive sleep apnea, we applied incremental levels of positive pressure through a nasal mask during non-rapid-eye-movement sleep. A positive critical opening pressure (Pcrit) of 3.3 +/- 3.3 (SD) cmH2O was demonstrated. As nasal pressure was raised above Pcrit, inspiratory airflow increased in proportion to the level of positive pressure applied until apneas were abolished (P less than 0.01). However, at pressures greater than Pcrit, esophageal pressures either did not correlate or correlated inversely with inspiratory airflow provided that esophageal pressure was less than Pcrit. When pressure was applied to a full face mask, inspiratory airflow did not occur and Pcrit could not be obtained at pressures well above Pcrit demonstrated with the nasal mask. These results are consistent with the view that the upper airway functions as a Starling resistor with a collapsible segment in the oropharynx. These findings offer a unifying construct for the association of sleep apnea, periodic hypopnea, and snoring.
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    38. Pharyngeal narrowing and closing pressures in patients with obstructive sleep apnea.
    作者:Morrison D L , Launois S H , Isono S , Feroah T R , Whitelaw W A , Remmers J E
    期刊:The American review of respiratory disease
    日期:1993-09-01
    DOI :10.1164/ajrccm/148.3.606
    Based on previous studies, we hypothesized that the pharynx collapses at multiple sites in most patients with obstructive sleep apnea (OSA). The purpose of this study was to document, in a population of apneic subjects, the site(s) of narrowing and closing pressure of the hypotonic pharynx. We endoscopically examined the pharynx in 45 OSA patients during sleep while they received nasal continuous positive airway pressure (CPAP), which produces hypotonia of pharyngeal muscles. Intrapharyngeal images and pressures were obtained at the end of expiration during single-breath tests (SBT). The fractional narrowing (FN) of each pharyngeal segment (nasopharynx, oropharynx, and hypopharynx) was calculated as the relative change in area when nasal airway pressure was reduced from a pressure that held the pharynx fully distended to the pressure at which the airway closed. The frequency distribution of FN for the nasopharynx was skewed toward larger values, and the frequency was relatively evenly distributed for the oropharynx and hypopharynx. A site having FN greater than 0.75 was defined as a site of primary narrowing, and a site showing FN 0.25 to 0.75 was defined as a site of secondary narrowing. The nasopharynx was a site of primary narrowing in 80% of patients, and two or more sites of narrowing were commonly observed (82%). Four categories of combined narrowing were identified: (1) primary narrowing only at the nasopharynx (18%); (2) primary narrowing at the nasopharynx plus other sites of secondary narrowing (40%); (3) primary narrowing at the nasopharynx plus other sites of primary narrowing (22%); and (4) other patterns (20%).(ABSTRACT TRUNCATED AT 250 WORDS)
  • 1区Q1影响因子: 16.6
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    39. Upper airway collapsibility, dilator muscle activation and resistance in sleep apnoea.
    期刊:The European respiratory journal
    日期:2007-04-25
    DOI :10.1183/09031936.00063406
    The calibre of the upper airway is thought to be dependant upon its passive anatomy/collapsibility and the activation of pharyngeal dilator muscles. During awake periods, the more collapsible upper airway in obstructive sleep apnoea (OSA) increases the dilator muscle activity through a negative-pressure reflex. A direct correlation between the critical closing pressure (P(crit)), as a measure of anatomy/collapsability and electromyogram (EMG) activity of genioglossus EMG (GG-EMG) and tensor palatini EMG (TP-EMG), was hypothesised. The relationship between these indices and pharyngeal resistance (R(phar)) was also examined. The study involved eight males with a mean age of 48 (interquartile range 46-52) yrs with OSA, and an apnoea/hypopnoea index of 75 (65-101).hr(-1) on two nights breathing normally and on nasal continuous positive airway pressure (nCPAP). The P(crit )was measured during nonrapid eye movement sleep on nCPAP using brief, incremental reductions in mask pressure. GG-EMG and TP-EMG were measured breath-by-breath, awake, during sleep onset and on nCPAP. R(phar) was measured using airway pressures and flow. Wakeful GG-EMG, early sleep TP-EMG and the sleep decrement in TP-EMG were directly related to P(crit). Muscle activation was negatively correlated with R(phar) for TP-EMG awake and GG-EMG early in sleep. In conclusion these results confirm that dilator muscle activation is directly related to airway narrowing and reduces resistance across patients with obstructive sleep apnoea.
  • 1区Q1影响因子: 11.2
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    40. Oxidative stress in obstructive sleep apnea and intermittent hypoxia--revisited--the bad ugly and good: implications to the heart and brain.
    作者:Lavie Lena
    期刊:Sleep medicine reviews
    日期:2014-07-24
    DOI :10.1016/j.smrv.2014.07.003
    Obstructive sleep apnea (OSA), characterized by intermittent hypoxia (IH), is linked with increased reactive oxygen species/reactive nitrogen species (ROS/RNS) and oxidative stress, which adversely affect the associated cardio-/cerebro-vascular disease in OSA. Yet, animal and a small number of human studies support activation of cardio-/cerebro-protective mechanisms as well. ROS/RNS are intricate and multifaceted molecules with multiple functions. At low-moderate concentrations ROS/RNS are considered "good", by regulating vital cellular functions. At higher levels, they are considered "bad" by promoting oxidative stress and damaging vital macromolecules through ischemia and reperfusion (I/R) injury. Subsequently, ROS/RNS can get "ugly" by eliciting sterile inflammation and a multitude of deadly pathologies. What makes ROS/RNS good, bad, or ugly? A dynamic interplay between a large number of factors determines the outcomes. These include the types of ROS/RNS produced, their quantity, duration, frequency, intracellular localization, micro-environmental antioxidants, as well as the genetic make-up and life style related variables. This review presents the currently available data on redox biology in physiological/pathophysiological conditions and in OSA/IH, in order to better understand the apparently contradictory findings on damage vs. repair. These findings are discussed within the context of the prevailing views on I/R associated ROS/RNS, and their potential implications to OSA.
  • 1区Q1影响因子: 76.9
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    41. Obstructive sleep apnoea syndrome.
    作者:Lévy Patrick , Kohler Malcolm , McNicholas Walter T , Barbé Ferran , McEvoy R Doug , Somers Virend K , Lavie Lena , Pépin Jean-Louis
    期刊:Nature reviews. Disease primers
    日期:2015-06-25
    DOI :10.1038/nrdp.2015.15
    Obstructive sleep apnoea syndrome (OSAS) is a common clinical condition in which the throat narrows or collapses repeatedly during sleep, causing obstructive sleep apnoea events. The syndrome is particularly prevalent in middle-aged and older adults. The mechanism by which the upper airway collapses is not fully understood but is multifactorial and includes obesity, craniofacial changes, alteration in upper airway muscle function, pharyngeal neuropathy and fluid shift towards the neck. The direct consequences of the collapse are intermittent hypoxia and hypercapnia, recurrent arousals and increase in respiratory efforts, leading to secondary sympathetic activation, oxidative stress and systemic inflammation. Excessive daytime sleepiness is a burden for the majority of patients. OSAS is also associated with cardiovascular co-morbidities, including hypertension, arrhythmias, stroke, coronary heart disease, atherosclerosis and overall increased cardiovascular mortality, as well as metabolic dysfunction. Whether treating sleep apnoea can fully reverse its chronic consequences remains to be established in adequately designed studies. Continuous positive airway pressure (CPAP) is the primary treatment modality in patients with severe OSAS, whereas oral appliances are also widely used in mild to moderate forms. Finally, combining different treatment modalities such as CPAP and weight control is beneficial, but need to be evaluated in randomized controlled trials. For an illustrated summary of this Primer, visit: http://go.nature.com/Lwc6te.
  • 1区Q1影响因子: 96.2
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    42. Obstructive Sleep Apnea in Adults.
    作者:Veasey Sigrid C , Rosen Ilene M
    期刊:The New England journal of medicine
    日期:2019-04-11
    DOI :10.1056/NEJMcp1816152
  • 1区Q1影响因子: 19.6
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    43. Obstructive Sleep Apnea.
    作者:Patel Sanjay R
    期刊:Annals of internal medicine
    日期:2019-12-03
    DOI :10.7326/AITC201912030
    Obstructive sleep apnea (OSA) is very common but is frequently undiagnosed. Symptoms include loud snoring, nocturnal awakening, and daytime sleepiness. Motor vehicle accidents due to drowsy driving are a particular concern. Evaluation and treatment should focus on symptomatic patients, both to alleviate symptoms and to potentially decrease cardiovascular risk. In recent years, a strategy of home sleep apnea testing followed by initiation of autotitrating continuous positive airway pressure therapy in the home has greatly reduced barriers to diagnosis and treatment and has also facilitated routine management of OSA by primary care providers.
  • 1区Q1影响因子: 40.8
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    44. Pathophysiological mechanisms and therapeutic approaches in obstructive sleep apnea syndrome.
    期刊:Signal transduction and targeted therapy
    日期:2023-05-25
    DOI :10.1038/s41392-023-01496-3
    Obstructive sleep apnea syndrome (OSAS) is a common breathing disorder in sleep in which the airways narrow or collapse during sleep, causing obstructive sleep apnea. The prevalence of OSAS continues to rise worldwide, particularly in middle-aged and elderly individuals. The mechanism of upper airway collapse is incompletely understood but is associated with several factors, including obesity, craniofacial changes, altered muscle function in the upper airway, pharyngeal neuropathy, and fluid shifts to the neck. The main characteristics of OSAS are recurrent pauses in respiration, which lead to intermittent hypoxia (IH) and hypercapnia, accompanied by blood oxygen desaturation and arousal during sleep, which sharply increases the risk of several diseases. This paper first briefly describes the epidemiology, incidence, and pathophysiological mechanisms of OSAS. Next, the alterations in relevant signaling pathways induced by IH are systematically reviewed and discussed. For example, IH can induce gut microbiota (GM) dysbiosis, impair the intestinal barrier, and alter intestinal metabolites. These mechanisms ultimately lead to secondary oxidative stress, systemic inflammation, and sympathetic activation. We then summarize the effects of IH on disease pathogenesis, including cardiocerebrovascular disorders, neurological disorders, metabolic diseases, cancer, reproductive disorders, and COVID-19. Finally, different therapeutic strategies for OSAS caused by different causes are proposed. Multidisciplinary approaches and shared decision-making are necessary for the successful treatment of OSAS in the future, but more randomized controlled trials are needed for further evaluation to define what treatments are best for specific OSAS patients.
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