Intermittent hypoxia (IH) has been extensively studied during the last decade, primarily as a surrogate model of sleep apnea. However, IH is a much more pervasive phenomenon in human disease, is ...viewed as a potential therapeutic approach, and has also been used in other disciplines, such as in competitive sports. In this context, adverse outcomes involving cardiovascular, cognitive, metabolic, and cancer problems have emerged in obstructive sleep apnea-based studies, whereas beneficial effects of IH have also been identified. Those a priori contradictory findings may not be as contradictory as initially thought. Indeed, the opposite outcomes triggered by IH can be explained by the specific characteristics of the large diversity of IH patterns applied in each study. The balance between benefits and injury appears to primarily depend on the ability of the organism to respond and activate adaptive mechanisms to IH. In this context, the adaptive or maladaptive responses can be generally predicted by the frequency, severity, and duration of IH. However, the presence of underlying conditions such as hypertension or obesity, as well as age, sex, or genotypic variance, may be important factors tilting the balance between an appropriate homeostatic response and decompensation. Here, the two possible facets of IH as derived from human and experimental animal settings will be reviewed.
Chronic sleep fragmentation (SF) commonly occurs in human populations, and although it does not involve circadian shifts or sleep deprivation, it markedly alters feeding behaviors ultimately ...promoting obesity and insulin resistance. These symptoms are known to be related to the host gut microbiota. Mice were exposed to SF for 4 weeks and then allowed to recover for 2 weeks. Taxonomic profiles of fecal microbiota were obtained prospectively, and conventionalization experiments were performed in germ-free mice. Adipose tissue insulin sensitivity and inflammation, as well as circulating measures of inflammation, were assayed. Effect of fecal water on colonic epithelial permeability was also examined. Chronic SF-induced increased food intake and reversible gut microbiota changes characterized by the preferential growth of highly fermentative members of Lachnospiraceae and Ruminococcaceae and a decrease of Lactobacillaceae families. These lead to systemic and visceral white adipose tissue inflammation in addition to altered insulin sensitivity in mice, most likely via enhanced colonic epithelium barrier disruption. Conventionalization of germ-free mice with SF-derived microbiota confirmed these findings. Thus, SF-induced metabolic alterations may be mediated, in part, by concurrent changes in gut microbiota, thereby opening the way for gut microbiome-targeted therapeutics aimed at reducing the major end-organ morbidities of chronic SF.
Obesity, sleep apnea, and cancer Almendros, Isaac; Martinez-Garcia, Miguel A; Farré, Ramon ...
International Journal of Obesity,
08/2020, Letnik:
44, Številka:
8
Journal Article
Recenzirano
The interest on a potential association between cancer and sleep-disordered breathing (SDB) has clearly gained substantial traction over the last several years. This novel relationship was initially ...explored in experimental models of obstructive sleep apnea (OSA) and showed that both intermittent hypoxia and sleep fragmentation, the two main hallmarks of OSA, promoted alterations in both tumorigenesis and tumor malignant properties. In parallel, an intriguing role of obesity as a major interactive player in the relationship between cancer and OSA was postulated in the following contextual settings: (1) obesity (with or without OSA) is associated with increased risk of some types of cancer (both incidence and aggressiveness), whereas obesity could be protective for others ("obesity paradox"); (2) OSA has been associated with increased risk for some types of cancer (independent of obesity), but not with others; (3) More than 80% of adult patients with OSA are overweight and >50% are obese; (4) both OSA and obesity exhibit oscillations in tissue oxygen tensions in peripheral organs such as adipose tissues. Further understanding these complex relationships become all the more important considering that the prevalence of obesity, cancer and OSA are all increasing worldwide. In parallel, experimental models of OSA provide biological plausibility constructs to the clinical and epidemiological findings, suggesting that the metabolic and inflammatory changes induced by chronic intermittent hypoxia and sleep fragmentation may foster or exacerbate immune and biomechanical alterations of the tumor microenvironment, including the expression of extracellular matrix components facilitating tumor progression.
Cell response to force regulates essential processes in health and disease. However, the fundamental mechanical variables that cells sense and respond to remain unclear. Here we show that the rate of ...force application (loading rate) drives mechanosensing, as predicted by a molecular clutch model. By applying dynamic force regimes to cells through substrate stretching, optical tweezers, and atomic force microscopy, we find that increasing loading rates trigger talin-dependent mechanosensing, leading to adhesion growth and reinforcement, and YAP nuclear localization. However, above a given threshold the actin cytoskeleton softens, decreasing loading rates and preventing reinforcement. By stretching rat lungs in vivo, we show that a similar phenomenon may occur. Our results show that cell sensing of external forces and of passive mechanical parameters (like tissue stiffness) can be understood through the same mechanisms, driven by the properties under force of the mechanosensing molecules involved.
Obstructive sleep apnea (OSA) is a very prevalent breathing disorder (Peppard et al., 2013; Heinzeret al., 2015) characterized by recurrent obstructions of the upper airwayduring sleep.
Intermittent hypoxia is one of the major perturbations of sleep-disordered breathing and has been causally implicated in neurocognitive deficits. However, the reversibility of such deficits is ...unclear.Male C57BL/6J mice were exposed to either intermittent hypoxia or room air for 3-240 days, and then half were randomly selected and allowed to recover in normoxic conditions for the same duration of the previous exposure. A novel object recognition (NOR) test was performed.NOR performance was stable over time in room air. Intermittent hypoxia induced significant reductions in recognition index that progressed over the first 45 days and stabilised thereafter. Normoxic recovery of recognition index was essentially complete and indistinguishable from room air in mice exposed to shorter intermittent hypoxia times (<90 days). However, significant residual deficits emerged after normoxic recovery following prolonged intermittent hypoxia exposures (p<0.01). In addition, gradual attenuation of the magnitude of recovery in recognition index occurred with increasingly longer intermittent hypoxia exposures (MANOVA p<0.0001).Intermittent hypoxia during the resting period reduces NOR performance in a time-dependent fashion. Reversal of NOR performance deficits is unlikely after prolonged intermittent hypoxia duration. These findings suggest that early recognition of sleep apnoea and effective treatment are critical for restoration of the adverse cognitive effects of the disease.
Over the last few years, the relationship between obstructive sleep apnoea (OSA) and various metabolic disorders, especially type 2 diabetes (T2D), has emerged strongly. This circumstance is ...particularly relevant in terms of public healthcare, considering that 415 million people were affected by diabetes in 2015, with an expected prevalence of 642 million by 2040. To this, we must also add another 318 million individuals with features indicating future risk for developing T2D, including fasting hyperglycaemia, impaired glucose tolerance and insulin resistance 1. The healthcare expenditure for diabetes in Europe was about €75 billion in 2011, which is projected to increase to €90 billion by 2030 1, 2.
Obstructive sleep apnoea (OSA) is a very prevalent disorder with well proven mid- and long-term deleterious consequences, such as increased risk of cardiovascular, metabolic and neurocognitive ...diseases 1. Recently, considerable data from both animal models and patient studies also suggest that OSA increases the risk of cancer incidence and mortality 2. Some of these studies indicate that nocturnal hypoxic events experienced by OSA patients as a consequence of recurrent upper airway obstructions may be a main challenge driving tumour progression 3, 4. Although the clinical and experimental data available do not undoubtedly prove a relationship between cancer and OSA 5, its plausibility has raised the interest of basic and clinical researchers in the field, warranting further investigation 6.
Background Intermittent hypoxia (IH) is the principal injurious factor involved in the cardiovascular morbidity and mortality associated with OSA. The gold standard for treatment is CPAP, which ...eliminates IH and appears to reduce cardiovascular risk. There is no experimental evidence on the reversibility of cardiovascular remodeling after IH withdrawal. The objective of the present study is to assess the reversibility of early cardiovascular structural remodeling induced by IH after resumption of normoxic breathing in a novel recovery animal model mimicking OSA treatment. Methods We investigated cardiovascular remodeling in C57BL/6 mice exposed to IH for 6 weeks vs the normoxia group and its spontaneous recovery after 6 subsequent weeks under normoxia. Results Aortic expansive remodeling was induced by IH, with intima-media thickening and without lumen perimeter changes. Elastic fiber network disorganization, fragmentation, and estrangement between the end points of disrupted fibers were increased by IH. Extracellular matrix turnover was altered, as visualized by collagen and mucoid interlaminar accumulation. Furthermore, left ventricular perivascular fibrosis was increased by IH, whereas cardiomyocytes size was unaffected. These cardiovascular remodeling events induced by IH were normalized after recovery in normoxia, mimicking CPAP treatment. Conclusions The early structural cardiovascular remodeling induced by IH was normalized after IH removal, revealing a novel recovery model for studying the effects of OSA treatment. Our findings suggest the clinical relevance of early detection and effective treatment of OSA in patients to prevent the natural course of cardiovascular diseases.
Obstructive sleep apnea (OSA) affects 8-10% of the population, is characterized by chronic intermittent hypoxia (CIH), and causally associates with cardiovascular morbidities. In CIH-exposed mice, ...closely mimicking the chronicity of human OSA, increased accumulation and proliferation of pro-inflammatory metabolic M1-like macrophages highly expressing CD36, emerged in aorta. Transcriptomic and MeDIP-seq approaches identified activation of pro-atherogenic pathways involving a complex interplay of histone modifications in functionally-relevant biological pathways, such as inflammation and oxidative stress in aorta macrophages. Discontinuation of CIH did not elicit significant improvements in aorta wall macrophage phenotype. However, CIH-induced aorta changes were absent in CD36 knockout mice, Our results provide mechanistic insights showing that CIH exposures during sleep in absence of concurrent pro-atherogenic settings (i.e., genetic propensity or dietary manipulation) lead to the recruitment of CD36(+)
macrophages to the aortic wall and trigger atherogenesis. Furthermore, long-term CIH-induced changes may not be reversible with usual OSA treatment.
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