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Sleep apnea syndrome (SAS) exposes cells throughout the body to intermittent hypoxia (IH). Intermittent hypoxia is a risk factor not only for hypertension and insulin resistance but also for vascular dysfunction. We have reported correlations between IH, insulin resistance and hypertension. However, the details of why IH leads to vascular dysfunction remain unclear. In this study, we investigated inflammation-related transcripts in vascular endothelial cells (human HUEhT-1 and mouse UV2) exposed to IH by real-time RT-PCR and found that intercellular adhesion molecule-1 (ICAM-1) and endothelial cell-specific molecule-1 (ESM1) mRNAs were significantly increased. ELISA confirmed that, in the UV2 cell medium, ICAM-1 and ESM1 were significantly increased by IH. However, the promoter activities of ICAM-1 and ESM1 were not upregulated. On the other hand, IH treatment significantly decreased microRNA (miR)-181a1 in IH-treated cells. The introduction of miR-181a1 mimic but not miR-181a1 mimic NC abolished the IH-induced upregulation of Ican-1 and ESM1. These results indicated that ICAM-1 and ESM1 were upregulated by IH via the IH-induced downregulation of miR-181a1 in vascular endothelial cells and suggested that SAS patients developed atherosclerosis via the IH-induced upregulation of ICAM-1 and ESM1., (© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

The coexistence of multiple autoantibodies associated with autoimmune encephalitis (AE) is rare. A 63-year-old woman developed psychosis and consciousness disorder. Her cerebrospinal fluid was positive for anti-N-methyl-D-aspartate receptor antibodies, and her serum was positive for anti-Hu antibodies. Enhanced computed tomography revealed a mass in the right pulmonary hilum. AE complicated with small-cell lung cancer was diagnosed. Immunotherapy (steroid therapy and intravenous immunoglobulin) and four courses of carboplatin-etoposide chemotherapy were required to improve her neurological symptoms. When the coexistence of multiple antibodies is detected, despite its rarity, aggressive detection and treatment of any underlying malignancy may be recommended.

Sleep apnoea syndrome is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]) and is a risk factor for insulin resistance/Type 2 diabetes. The induction of insulin resistance in skeletal muscle is a key phenomenon to develop diabetes. However, the mechanisms linking IH stress and insulin resistance remain elusive. We exposed human RD and mouse C2C12 muscle cells to normoxia or IH and measured their mRNA levels by real-time RT-PCR. We found that IH significantly increased the mRNA and protein levels of muscle-derived insulin resistance-factors (myokines) such as IL-8, osteonectin (ON), and myonectin (MN) in muscle cells. We further analysed the IH-induced expression mechanisms of IL-8, ON, and MN genes in muscle cells. Deletion analyses of the human myokine promoter(s) revealed that the regions -152 to -151 in IL-8, -105 to -99 in ON, and - 3741 to -3738 in MN promoters were responsible for the activation by IH in RD cells. The promoters contain consensus transcription factor binding sequences for OCT1 in IL-8 and MN promoters, and for NRF2 in ON promoter, respectively. The introduction of siRNA for OCT1 abolished the IH-induced expression(s) of IL-8 and MN and siRNA for NRF2 abolished the IH-induced expression of ON., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Introduction: Understanding the composition of stroke thrombi retrieved by mechanical thrombectomy is essential to clarify the pathogenesis of stroke. However, it is difficult to evaluate thrombus composition precisely and objectively. Immunohistochemical staining was used to evaluate thrombus composition and age., Materials and Methods: Consecutive thrombi (n = 108) retrieved from patients who underwent mechanical thrombectomy for acute large-vessel ischemic stroke were retrospectively analyzed. Lytic features of granulocytes and CD163 were estimated as indicators of the age of the cardioembolic (CE) thrombus., Results: The stroke subtypes were as follows: CE, 74 cases; large artery atherosclerosis, 11; undetermined etiology, 12; and other determined etiology, 11. There were no statistical differences in thrombi composition according to stroke subtypes. The fibrin area was positively correlated with the red blood cell (RBC) and platelet areas. The following analysis was performed using CE only. Regarding age, the thrombus was judged as fresh in 30.0 % and older in 70.0 % based on the lytic features. The RBC areas of older thrombi were smaller than those of fresh thrombi. The puncture-to-reperfusion time of older thrombi was longer than that of fresh thrombi. Platelet-rich thrombi were associated with a greater number of maneuvers, a smaller prevalence of TICI 3, and unfavorable functional outcomes compared to platelet-poor thrombi. The number of CD163 positive cells in thrombi with anticoagulants was higher than in those without anticoagulants., Conclusion: Thrombus composition correlated with revascularization and clinical outcomes. The composition of an acute ischemic thrombus may reflect the pathophysiology of stroke and influence treatment efficacy., Competing Interests: Declaration of competing interest All authors state that there are no conflicts of interest to declare., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Intermittent hypoxia (IH), one of the primary pathologies of sleep apnea syndrome (SAS), exposes cells throughout the body to repeated cycles of hypoxia/normoxia that result in oxidative stress and systemic inflammation. Since SAS is epidemiologically strongly correlated with type 2 diabetes/insulin resistance, obesity, hypertension, and dyslipidemia included in metabolic syndrome, the effects of IH on gene expression in the corresponding cells of each organ have been studied intensively to clarify the molecular mechanism of the association between SAS and metabolic syndrome. Dementia has recently been recognized as a serious health problem due to its increasing incidence, and a large body of evidence has shown its strong correlation with SAS and metabolic disorders. In this narrative review, we first outline the effects of IH on the expression of genes related to metabolism in neuronal cells, pancreatic β cells, hepatocytes, adipocytes, myocytes, and renal cells (mainly based on the results of our experiments). Next, we discuss the literature regarding the mechanisms by which metabolic disorders and IH develop dementia to understand how IH directly and indirectly leads to the development of dementia.

Sleep apnea syndrome (SAS) is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]), and is a risk factor for cardiovascular disease (CVD) and insulin resistance/Type 2 diabetes. However, the mechanisms linking IH stress and CVD remain elusive. We exposed rat H9c2 and mouse P19.CL6 cardiomyocytes to experimental IH or normoxia for 24 h to analyze the mRNA expression of several cardiomyokines. We found that the mRNA levels of regenerating gene IV ( Reg IV ) and hepatocyte growth factor ( Hgf ) in H9c2 and P19.CL6 cardiomyocytes were significantly increased by IH, whereas the promoter activities of the genes were not increased. A target mRNA search of microRNA (miR)s revealed that rat and mouse mRNAs have a potential target sequence for miR-499. The miR-499 level of IH-treated cells was significantly decreased compared to normoxia-treated cells. MiR-499 mimic and non-specific control RNA (miR-499 mimic NC) were introduced into P19.CL6 cells, and the IH-induced upregulation of the genes was abolished by introduction of the miR-499 mimic, but not by the miR-499 mimic NC. These results indicate that IH stress downregulates the miR-499 in cardiomyocytes, resulting in increased levels of Reg IV and Hgf mRNAs, leading to the protection of cardiomyocytes in SAS patients.

Sleep apnea syndrome (SAS) is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia, IH), and it is a risk factor for cardiovascular disease (CVD) and insulin resistance/type 2 diabetes. However, the mechanisms linking IH stress and CVD remain elusive. We exposed rat H9c2 and mouse P19.CL6 cardiomyocytes to experimental IH or normoxia for 24 h to analyze the mRNA expression of the components of Cd38-cyclic ADP-ribose (cADPR) signaling. We found that the mRNA levels of cluster of differentiation 38 ( Cd38 ), type 2 ryanodine receptor ( Ryr2 ), and FK506-binding protein 12.6 ( Fkbp12.6 ) in H9c2 and P19.CL6 cardiomyocytes were significantly decreased by IH, whereas the promoter activities of these genes were not decreased. By contrast, the expression of phosphatase and tensin homolog deleted from chromosome 10 (Pten) was upregulated in IH-treated cells. The small interfering RNA for Pten (siPten) and a non-specific control RNA were introduced into the H9c2 cells. The IH-induced downregulation of Cd38 , Ryr2 , and Fkbp12.6 was abolished by the introduction of the siPten, but not by the control RNA. These results indicate that IH stress upregulated the Pten in cardiomyocytes, resulting in the decreased mRNA levels of Cd38 , Ryr2 , and Fkbp12.6 , leading to the inhibition of cardiomyocyte functions in SAS patients.

Sleep apnea syndrome (SAS), characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia (IH)), is a risk factor for hypertension and insulin resistance. We report a correlation between IH and insulin resistance/diabetes. However, the reason why hypertension is induced by IH is elusive. Here, we investigated the effect of IH on the expression of catecholamine-metabolizing enzymes using an in vitro IH system. Human and mouse neuroblastoma cells (NB-1 and Neuro-2a) were exposed to IH or normoxia for 24 h. Real-time RT-PCR revealed that IH significantly increased the mRNA levels of dopamine β-hydroxylase ( DBH ) and phenylethanolamine N-methyltransferase ( PNMT ) in both NB-1 and Neuro-2a. Western blot showed that the expression of DBH and PNMT in the NB-1 cells was significantly increased by IH. Reporter assays revealed that promoter activities of DBH and PNMT were not increased by IH. The miR-375 level of IH-treated cells was significantly decreased relative to that of normoxia-treated cells. The IH-induced up-regulation of DBH and PNMT was abolished by the introduction of the miR-375 mimic, but not by the control RNA. These results indicate that IH stress increases levels of DBH and PNMT via the inhibition of miR-375-mediated mRNA degradation, potentially playing a role in the emergence of hypertension in SAS patients.

Sleep apnea syndrome (SAS) is a breathing disorder characterized by recurrent episodes of upper-airway collapse, resulting in intermittent hypoxia (IH) during sleep. Experimental studies with animals and cellular models have indicated that IH leads to attenuation of glucose-induced insulin secretion from pancreatic β cells and to enhancement of insulin resistance in peripheral tissues and cells, such as the liver (hepatocytes), adipose tissue (adipocytes), and skeletal muscles (myocytes), both of which could lead to obesity. Although obesity is widely recognized as a major factor in SAS, it is controversial whether the development of SAS could contribute directly to obesity, and the effect of IH on the expression of appetite regulatory genes remains elusive. Appetite is regulated appropriately by both the hypothalamus and the gut as a gut-brain axis driven by differential neural and hormonal signals. In this review, we summarized the recent epidemiological findings on the relationship between SAS and feeding behavior and focused on the anorexigenic effects of IH on the gut-brain axis by the IH-induced up-regulation of proopiomelanocortin and cocaine- and amphetamine-regulated transcript in neuronal cells and the IH-induced up-regulation of peptide YY, glucagon-like peptide-1 and neurotensin in enteroendocrine cells and their molecular mechanisms.