Role of Oxidative Stress in the Neurocognitive Dysfunction of Obstructive Sleep Apnea Syndrome

Obstructive sleep apnea syndrome (OSAS) is characterized by chronic nocturnal intermittent hypoxia and sleep fragmentations. Neurocognitive dysfunction, a significant and extraordinary complication of OSAS, influences patients’ career, family, and social life and reduces quality of life to some extent. Previous researches revealed that repetitive hypoxia and reoxygenation caused mitochondria and endoplasmic reticulum dysfunction, overactivated NADPH oxidase, xanthine oxidase, and uncoupling nitric oxide synthase, induced an imbalance between prooxidants and antioxidants, and then got rise to a series of oxidative stress (OS) responses, such as protein oxidation, lipid peroxidation, and DNA oxidation along with inflammatory reaction. OS in brain could trigger neuron injury especially in the hippocampus and cerebral cortex regions. Those two regions are fairly susceptible to hypoxia and oxidative stress production which could consequently result in cognitive dysfunction. Apart from continuous positive airway pressure (CPAP), antioxidant may be a promising therapeutic method to improve partially reversible neurocognitive function. Understanding the role that OS played in the cognitive deficits is crucial for future research and therapeutic strategy development. In this paper, recent important literature concerning the relationship between oxidative stress and cognitive impairment in OSAS will be summarized and the results can provide a rewarding overview for future breakthrough in this field

Prevalence and characteristics of pain in moderate-to-severe obstructive sleep apnea patients and effect of CPAP treatment

Abstract Pain problems are common in patients with obstructive sleep apnea (OSA), but few studies have thoroughly evaluated pain in these patients. The objective of this study was to examine the prevalence and characteristics of pain in moderate-to-severe OSA patients and the effect of continuous positive airway pressure (CPAP) treatment. Moderate-to-severe OSA patients and healthy controls (HC) completed the Short Form McGill Pain Questionnaire (SF-MPQ) and a portion of the Brief Pain Inventory (BPI) Short Form to assess pain characteristics. The Epworth Sleepiness Scale (ESS), the Short Form-36 (SF-36), and the Hospital Anxiety and Depression Scale (HADS) were used to measure daytime sleepiness, health-related quality of life (HRQoL), and psychological status, respectively. The OSA patients with pain were divided into a CPAP-treated group and a CPAP-untreated group based on their adherence to CPAP. The subjects' pain intensity was reassessed after 3 months. The prevalence of pain was 57.5% in OSA versus 27.1% in HC (p < 0.001). Head (39.0%) accounted for the highest proportion of overall pain locations in subjects with OSA, with 28.8% of OSA patients experiencing headaches. Pain in OSA was associated with impaired HRQoL and psychological problems. Patients with very severe OSA had an increased risk for pain problems (OR: 7.000, p = 0.041). Associated factors for pain intensity in OSA included age, ESS ≥ 9.0, and lowest pulse oximetry (LSpO2) < 80.0%. Pain intensity in OSA decreased significantly after CPAP treatment (p < 0.001). Pain was prevalent among patients with moderate-to-severe OSA and was associated with depression, anxiety, and a lower HRQoL. Patients with very severe OSA had an increased risk for pain problems. The intensity of pain in OSA can be predicted by age, ESS ≥ 9.0, and LSpO2 < 80.0%, and it can be alleviated through CPAP treatment

Notch signaling in lung diseases: focus on Notch1 and Notch3

Notch signaling is an evolutionarily conserved cell–cell communication mechanism that plays a key role in lung homeostasis, injury and repair. The loss of regulation of Notch signaling, especially Notch1 and Notch3, has recently been linked to the pathogenesis of important lung diseases, in particular, chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis, pulmonary arterial hypertension (PAH), lung cancer and lung lesions in some congenital diseases. This review focuses on recent advances related to the mechanisms and the consequences of aberrant or absent Notch1/3 activity in the initiation and progression of lung diseases. Our increasing understanding of this signaling pathway offers great hope that manipulating Notch signaling may represent a promising alternative complementary therapeutic strategy in the future

Identification and functional characterization of a novel surfactant protein A2 mutation (p.N207Y) in a Chinese family with idiopathic pulmonary fibrosis

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a serious disorder with a high mortality rate worldwide. It is characterized by irreversible scarring of the lung parenchyma resulting from excessive collagen production by proliferating fibroblasts/myofibroblasts. Previous studies have revealed that mutations in surfactant protein‐related genes and telomerase complex genes are crucial underlying genetic factors. Methods In this study, we enrolled a family with IPF from the central southern region of China. Whole‐exome sequencing was employed to explore candidate genes in this family. Real‐time PCR and western blotting were used to study the functions of the identified mutations in vitro. Results A novel mutation (NM_001098668.4: c.619A>T; NP_001092138.1: p.N207Y) in surfactant protein A2 (SFTPA2,), having not been previously reported to be a mutation, was identified and co‐separated with all affected individuals in the IPF family. Functional research further revealed that the novel mutation affects the secretion of SFTPA2 protein and induces endoplasmic reticulum stress as well as apoptosis in A549 cells. Conclusion We are confident that this novel mutation (NM_001098668.4: c.619A>T; NP_001092138.1: p.N207Y) in SFTPA2 is the genetic mutation of the IPF family. Our study not only confirms the importance of SFTPA2 in IPF but also expands the spectrum of SFTPA2 mutations and contributes to the genetic diagnosis and counseling of IPF patients

Dysfunction of Nrf2-ARE Signaling Pathway: Potential Pathogenesis in the Development of Neurocognitive Impairment in Patients with Moderate to Severe Obstructive Sleep Apnea-Hypopnea Syndrome

The present study investigated the nuclear factor erythroid 2-related factor 2- (Nrf2-) antioxidant response element (ARE) signaling pathway in patients with moderate to severe obstructive sleep apnea-hypopnea syndrome (OSAHS). Their correlation with neurocognitive impairment metrics was investigated to explore potential pathogenesis in OSAHS. Forty-eight patients with OSAHS and 28 controls underwent testing with the Epworth Sleep Scale (ESS), MATRICS Consensus Cognitive Battery (MCCB), Stroop Color and Word Test, polysomnography (PSG), and measurements of the concentration of plasma superoxide dismutase (SOD) and thioredoxin (Trx). Further, 20 pairs of matched patients with OSAHS and controls were selected for measurement of the expression (protein and mRNA) of Nrf2 and of its downstream antioxidase, heme oxygenase-1 (HO-1), in peripheral mononuclear cells (PBMCs). Finally, correlations between neurocognitive impairment and the above metrics were analyzed. Expression of Nrf2 and HO-1 mRNA and protein in the PBMCs, as well as plasma SOD and Trx levels, were significantly reduced in patients with OSAHS. After adjusting for education, sex, age, and smoking index, the expression of Nrf2-ARE signaling pathway proteins (or mRNA) was closely correlated with sleep respiratory parameters. An inverse relationship was demonstrated between the expression of nuclear Nrf2 in PBMCs, concentration of plasma SOD and Trx, and apnea-hypopnea index (AHI) in patients with OSAHS. Trx, nuclear Nrf2 protein, and HO-1 protein were also negatively correlated with the percent of time that SaO2 was less than 90% (TSat90). Total Nrf2 protein level was positively correlated with AHI and TSat90 and negatively correlated with minimum SaO2 (LSaO2), while nuclear Nrf2 protein and HO-1 protein were positively correlated with LSaO2. Moreover, significant positive correlations were found between maze scores and expression of nuclear Nrf2 protein, HO-1 protein, and SOD and Trx levels. Furthermore, inverse relationships between total Nrf2 protein in PBMCs and HVLT-R and maze scores were found. Multiple linear regression showed plasma Trx concentration as a potential predictor of maze and BVMT-R scores. In conclusion, the expression of Nrf2-ARE molecules and related antioxidases is significantly decreased in patients with OSAHS and is correlated with neurocognitive dysfunction. The Nrf2-ARE signaling pathway may play a crucial role in neurocognitive impairment in patients with moderate to severe OSAHS. Further studies are needed to explore the exact mechanisms and potential treatment interventions

C-myc/miR-150/EPG5 axis mediated dysfunction of autophagy promotes development of non-small cell lung cancer.

Rationale: Lung cancer is the leading cause of cancer death worldwide, and treatment options are limited to mainly cytotoxic agents. Here we reveal a novel role of miR-150 in non-small cell lung cancer (NSCLC) development and seek potential new therapeutic targets. Methods: The miR-150-mediated autophagy dysfunction in NSCLC cells were examined using molecular methods in vitro and in vivo. The upstream regulatory element and downstream target of miR-150 were identified in vitro and validated in vivo. Potential therapeutic methods (anti-c-myc or anti-miR-150) were tested in vitro and in vivo. Clinical relevance of the c-myc/miR-150/EPG5 axis in NSCLC was validated in human clinical samples and large genomics database. Results: miR-150 blocked the fusion of autophagosomes and lysosomes through directly repressing EPG5. The miR-150-mediated autophagy defect induced ER stress and increased cellular ROS levels and DNA damage response, and promoted NSCLC cell proliferation and tumor growth. Knockdown of EPG5 promoted NSCLC cell proliferation, and attenuated the effects of miR-150. c-myc gene was identified as a miR-150 transcriptional factor which increased miR-150 accumulation, therefore pharmacologically or genetically inhibiting c-myc/miR-150 expression significantly inhibited NSCLC cell growth in vitro and in vivo. Both c-myc and miR-150 were significantly over-expressed in NSCLC, while EPG5 was down-regulated in NSCLC. Expression levels of these molecules were well correlated, and also well correlated with patient survival. Conclusions: Our findings suggest that c-myc/miR-150/EPG5 mediated dysfunction of autophagy contributes to NSCLC development, which may provide a potential new diagnostic and therapeutic target in NSCLC

Different clinical characteristics of current smokers and former smokers with asthma: a cross-sectional study of adult asthma patients in China

Abstract Smoking is a trigger for asthma, which has led to an increase in asthma incidence in China. In smokers, asthma management starts with smoking cessation. Data on predictors of smoking cessation in Chinese patients with asthma are scarce. The objective of this study was to find the differences in clinical characteristics between current smokers and former smokers with asthma in order to identify factors associated with smoking cessation. Eligible adults with diagnosed asthma and smoking from the hospital outpatient clinics (n = 2312) were enrolled and underwent a clinical evaluation, asthma control test (ACT), and pulmonary function test. Information on demographic and sociological data, lung function, laboratory tests, ACT and asthma control questionnaire (ACQ) scores was recorded. Patients were divided into a current smokers group and a former smokers group based on whether they had quit smoking. Logistic regression analysis was used to analyze the factors associated with smoking cessation. Of all patients with asthma, 34.6% were smokers and 65.4% were former smokers, and the mean age was 54.5 ± 11.5 years. Compared with current smokers, the former smokers were older, had longer duration of asthma, had higher ICS dose, had more partially controlled and uncontrolled asthma, had more pack-years, had smoked for longer, and had worse asthma control. The logistic regression model showed that smoking cessation was positively correlated with age, female sex, pack-years, years of smoking, partially controlled asthma, uncontrolled asthma, and body mass index (BMI), but was negatively correlated with ACT, FEV1, FEV1%predicted, and widowed status. More than 30% of asthma patients in the study were still smoking. Among those who quit smoking, many quit late, often not realizing they need to quit until they have significant breathing difficulties. The related factors of smoking cessation identified in this study indicate that there are still differences between continuing smokers and former smokers, and these factors should be focused on in asthma smoking cessation interventions to improve the prognosis of patients with asthma