Bone Marrow Mesenchymal Stem Cells (BMSCs) Restrain the Malignant Behaviors of A549 Lung Cancer Cells Under Hypoxia via miR-145

Deriving from bone marrow, the bone marrow mesenchymal stem cells (BMSCs) possess multipolar chemotaxis, proliferation potential, along with the capability to differentiate into various types of cells. Moreover, the hypoxic stimulation can effectively induce BMSCs differentiation. This study intends to explore the impediment of BMSCs on malignant behaviors of lung cancer stem cells under hypoxia. A co-culture system of BMSCs with A549 cells was established and then assigned into normoxia group, hypoxia group (50, 100, and 200 nmol/L) followed by analysis of cell viability by CCK-8 assay and miR-145 expression by qRT-PCR. In addition, A549 cells were grouped into NC group, miR-145-mimics group, and miR-145-inhibitors group followed by analysis of cell invasion and levels of miR-145 and Oct4. Hypoxia group exhibited a reduced cell viability and higher miR-145 expression (146.01±21.23%) compared to normoxia group (P < 0.05). Transfection of miR-145-mimic significantly upregulated miR-145 and decreased cell invasion (7.49±1.43%) compared with miR-145-inhibitors group or NC group (P < 0.05). Meanwhile, Oct4 level in miR-145-mimics group (0.934±2.98) was significantly decreased (P < 0.05). In conclusion, under hypoxia condition, the co-culture with BMSCs can upregulated miR-145 level, effectively reduce the viability of lung cancer stem cells and restrain proliferation capability.

Acute Exposure to Simulated High-altitude Hypoxia Alters Gut Microbiota in Mice

Gut microbiota bears adaptive potential to different environments, but little is known regarding its responses to acute high-altitude exposure. This study aimed to evaluate the microbial changes after acute exposure to simulated high-altitude hypoxia. C57BL/6J mice were divided into hypoxia and normoxia groups. The hypoxia group was exposed to a simulated altitude of 5500 m for 24 hours above sea level. The normoxia group was maintained in low-altitude of 10 m above sea level. Colonic microbiota was analyzed using 16S rRNA V4 gene sequencing. Compared with the normoxia group, shannon, simpson and Akkermansia were significantly increased, while Firmicutes to Bacteroidetes ratio and Bifidobacterium were significantly decreased in the hypoxia group. The hypoxia group exhibited lower mobile element containing and higher potentially pathogenic and stress tolerant phenotypes than those in the normoxia group. Functional analysis indicated that environmental information processing was significantly lower, metabolism, cellular processes and organismal systems were significantly higher in the hypoxia group than those in the normoxia group. In conclusion, acute exposure to simulated high-altitude hypoxia alters gut microbiota diversity and composition, which may provide a potential target to alleviate acute high-altitude diseases.

Continuous Infusion of Angiotensin IV Protects against Acute Myocardial Infarction via the Inhibition of Inflammation and Autophagy

Acute myocardial infarction (AMI) is a major cause of morbidity and mortality worldwide. Angiotensin (Ang) IV possesses many biological properties that are not yet completely understood. Therefore, we investigated the function and mechanism of Ang IV in AMI in in vivo and in vitro conditions. AMI was performed by ligation of the left anterior descending coronary artery (LAD) in male C57 mice. Ang IV was continuously infused by a minipump 3 d before AMI for 33 d. The neonatal rat ventricular myocytes (NRVCs) were stimulated with Ang IV and cultured under hypoxic conditions. In vivo, Ang IV infusion significantly reduced the mortality after AMI. By the 7th day after AMI, compared with the AMI group, Ang IV reduced the inflammatory cytokine expression. Moreover, terminal deoxyribonucleotidyl transferase- (TDT-) mediated dUTP nick-end labeling (TUNEL) assay showed that Ang IV infusion reduced AMI-induced cardiomyocyte apoptosis. Compared with AMI, Ang IV reduced autophagosomes in cardiomyocytes and improved mitochondrial swelling and disarrangement, as assessed by transmission electron microscopy. By 30th day after AMI, Ang IV significantly reduced the ratio of heart weight to body weight. Echocardiography showed that Ang IV improved impaired cardiac function. Hematoxylin and eosin (H&E) and Masson staining showed that Ang IV infusion reduced the infarction size and myocardial fibrosis. In vitro, dihydroethidium (DHE) staining and comet assay showed that, compared with the hypoxia group, Ang IV reduced oxidative stress and DNA damage. Enzyme-linked immunosorbent assay (ELISA) showed that Ang IV reduced hypoxia-induced secretion of the tumor necrosis factor- (TNF-) ɑ and interleukin- (IL-) 1β. In addition, compared with the hypoxia group, Ang IV reduced the transformation of light chain 3- (LC3-) I to LC3-II but increased p62 expression and decreased cardiomyocyte apoptosis. Overall, the present study showed that Ang IV reduced the inflammatory response, autophagy, and fibrosis after AMI, leading to reduced infarction size and improved cardiac function. Therefore, administration of Ang IV may be a feasible strategy for the treatment of AMI.

Combined Aerobic and Resistance Training Performed under Conditions of Normobaric Hypoxia and Normoxia Has the Same Impact on Metabolic Control in Men with Type 1 Diabetes

(1) Background: The aim was to assess whether combined aerobic and resistance training performed under hypoxic and normoxic conditions had an impact on diabetes control, VO2max (maximum oxygen consumption), and echocardiological and anthropometric parameters in men with long-term type 1 diabetes. (2) Methods: Sixteen male participants (mean age: 37 years, mean HbA1c (glycated hemoglobin): 7.0%) were randomly assigned to two groups: training in normoxic conditions or training in conditions of altitude hypoxia. All subjects participated in 60 min combined aerobic and resistance training sessions twice a week for 6 weeks. At baseline and in the 6th week, echocardiography, incremental exercise test, and anthropometric and diabetes control parameters were assessed. (3) Results: After 6 weeks, there was no significant change in HbA1c value in any group. We noted a more stable glycemia profile during training in the hypoxia group (p > 0.05). Patients in the hypoxia group required less carbohydrates during training than in the normoxia group. A comparable increase in VO2max was observed in both groups (p > 0.05). There were no significant differences in cardiological and anthropometric parameters. (4) Conclusions: Combined aerobic and resistance training improved VO2max after 6 weeks regardless of the conditions of the experiments. This exercise is safe in terms of glycemic control in patients with well-controlled diabetes.

Studies on the effects of hypothermia combined with hypoxia on rat skeletal muscle and lipid metabolism based on AMPK/PGC1α pathway

Aim To explore the effects of hypothermia and hypoxia on rat skeletal muscle and lipid metabolism. Method Forty male rats were randomly divided into blank group, low-temperature group, hypoxia group, and hypothermia combined with hypoxia group. The body weight of the rats was monitored. The changes of Irisin were detected by ELISA, and LDL, HDL, TC, and TG levels in serum were detected by blood biochemistry. Western blot was used to detect the changes of lipid metabolism-related proteins. CCK8 was used to verify the effect of AMPK/PGC1α on the proliferation of rat skeletal muscle cells. Result In the case of cold stimulation and hypoxia, the weight of the rats decreased significantly, and the levels of LDL, HDL, TC, and TG in the serum were abnormal. The activity of fatty acid metabolism factors Irisin, UCP-1, and FABP4 is down-regulated by hypothermia and hypoxia. The activity of fat metabolism-related enzymes, ATGL, HSL, and MGL increased under hypothermia and low oxygen conditions. Hypothermia and hypoxia affected the morphology of skeletal muscle, and AMPK/PGC-1α can regulate the proliferation of skeletal muscle cells. Conclusion Hypothermia and hypoxia can reduce the body weight of rats, and affect the structure of skeletal muscle to promote lipid metabolism through AMPK/PGC-1α signaling pathway.

Influencing Factors of Daytime Sleepiness in Patients with Obstructive Sleep Apnea Hypopnea Syndrome and Its Correlation with Pulse Oxygen Decline Rate

Objective. To explore the influencing factors of daytime sleepiness in patients with obstructive sleep apnea hypopnea syndrome (OSAHS) and the correlation between daytime sleepiness and pulse oxygen decline rate in patients with severe OSAHS. Methods. From January 2018 to April 2021, 246 consecutive patients with OSAHS diagnosed by polysomnography (PSG) in our hospital were selected. All patients were grouped according to the minimum nocturnal oxygen saturation and apnea hypopnea index (AHI). There were 33 cases in the no sleep hypoxia group, 34 cases in the mild hypoxia group, 119 cases in the moderate hypoxia group, and 60 cases in the severe hypoxia group. There were 30 cases in the simple snoring group, 55 cases in the mild OSAHS group, 48 cases in the moderate OSAHS group, and 113 cases in the severe OSAHS group. The Epworth Sleepiness Scale (ESS) scores of each group were compared. All patients were grouped according to ESS score. Those with score ≥9 were included in the lethargy group (n = 118), and those with score ≤10 were included in the no lethargy group (n = 128). Univariate and multivariate logistic regression analyses were used to explore the influencing factors of daytime sleepiness in OSAHS patients. Pearson correlation analysis showed the correlation between ESS score and pulse oxygen decline rate in patients with severe OSAHS. Results. The ESS score of the severe hypoxia group > the moderate hypoxia group > the mild hypoxia group > the no sleep hypoxia group. There was significant difference among the groups (F = 19.700, P < 0.0001 ). There were significant differences between the severe hypoxia group and other groups and between the moderate hypoxia group and the no sleep hypoxia group and the mild hypoxia group ( P < 0.05 ). The ESS score of the severe OSAHS group > the moderate OSAHS group > the mild OSAHS group > the simple snoring group. There was significant difference among the groups (F = 19.000, P < 0.0001 ). There were significant differences between the severe OSAHS group and other groups and between the moderate OSAHS group and the simple snoring group ( P < 0.05 ). Univariate analysis showed that BMI, neck circumference, snoring degree, total apnea hypopnea time, AHI, micro arousal index (MAI), oxygen saturation (CT90%), lowest oxygen saturation (LSaO2), and mean oxygen saturation (MSaO2) were the influencing factors of daytime sleepiness in OSAHS patients ( P < 0.05 ). Multiple logistic regression analysis showed that AHI and CT90% were independent risk factors for daytime sleepiness in OSAHS patients ( P < 0.05 ). Pearson correlation analysis showed that there was a positive correlation between ESS score and pulse oxygen decline rate in patients with severe OSAHS (r = 0.765, P < 0.0001 ). Conclusion. OSAHS patients may be accompanied by daytime sleepiness in varying degrees, which may be independently related to AHI and CT90%. The degree of daytime sleepiness in patients with severe OSAHS may be closely related to the decline rate of pulse oxygen, which should be paid great attention in clinic.

Role of Raphe Magnus 5-HT1A Receptor in Increased Ventilatory Responses Induced by Intermittent Hypoxia in Rats

Background: Intermittent hypoxia induces increased ventilatory responses in a 5-HT-dependent manner. This study aimed to explore that effect of raphe magnus serotonin 1A receptor (5-HT1A) receptor on the increased ventilatory responses induced by intermittent hypoxia.Methods: Stereotaxic surgery was performed in adult male rats, and acute and chronic intermittent hypoxia models were established after recovery from surgery. The experimental group received microinjections of 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) into the raphe magnus nucleus (RMg). Meanwhile, the control group received microinjections of artificial cerebrospinal fluid instead of 8-OH-DPAT. Whole-body plethysmography was performed, and ventilatory responses were compared among the different groups of oxygen status.Results: Compared with the normoxia group, the acute intermittent hypoxia group exhibited higher ventilatory responses (e.g., shorter inspiratory time and higher tidal volume, frequency of breathing, minute ventilation, and mean inspiratory flow) (P<0.05). 8-OH-DPAT microinjection partly weakened these changes in the acute intermittent hypoxia group. Further, compared with the acute intermittent hypoxia group, rats in chronic intermittent hypoxia group exhibited higher measures of ventilatory responses after 1 day of intermittent hypoxia (P<0.05). These effects peaked after 3 days of intermittent hypoxia treatment and then decreased gradually. Moreover, these changes were diminished and even disappeared in the experimental group.Conclusions: The results indicate that RMg 5-HT1A receptor is involved in the modulation of the increased ventilatory responses induced by intermittent hypoxia.

Glucocorticoid-Induced Osteocytic Cell Death in a Hypoxic Environment Is Associated with Necroptosis

Neither the underlying pathophysiology of nor prophylactic strategies for glucocorticoid-associated femoral head osteonecrosis have yet been established. In neurovascular and cardiac ischemic disorders, necroptosis has been reported as a new concept of cell death. Here we investigated the involvement of necroptosis in glucocorticoid-induced osteonecrosis in vitro, the putative cause of which is ischemia. Murine osteocytic cells (MLO-Y4) to which 1 µM dexamethasone (Dex) was added and were cultured in 1% O2 (hypoxia) are thought to resemble the in vivo environment in which glucocorticoid-induced osteonecrosis occurs (H-D stress environment). Using such cells cultured for 24 h (Dex(+)/hypoxia(+) group), immunofluorescent staining and Western blotting were performed with receptor-interacting protein (RIP) 1 and RIP3, which are necroptosis expression factors. In addition, the necroptosis inhibitor necrostatin-1 (Nec-1) was added to Dex(+)/hypoxia(+) and cultured for 12 h and 24 h. Then using an Apoptotic/Necrotic Cells Detection Kit the numbers of apoptotic and necrotic cells were counted and compared. In Dex(+)/hypoxia(+) group, expression of both RIP1 and RIP3 was found. Additionally, in Western blotting, the addition of Nec-1 attenuated their expression. A decrease in the number of cell deaths was also found following Nec-1 administration. Necroptosis has been implicated as a cause of death in osteocytic cell necrosis. Use of the necroptosis inhibitor, Nec-1, suggests a possible approach to preventing osteocytic cell necrosis even in an H-D stress environment when given within 12 h.

Effect of acute normobaric hypoxia on passively simulated illusions: A double-blind randomized study

Introduction: Number of accidents in the past four decades in rotary wing flying in high altitude areas in the Indian Air Force have been attributed to spatial disorientation (SD) or hypoxia or both. Although the two aviation stressors; hypoxia and SD, have been studied independently, literature is scant on the combined effects of the two notorious factors in military aviation. Material and Methods: In a double-blind randomized control design, 32 healthy volunteers divided into two groups (hypoxia group and normoxia group) of 16 subjects each, participated in the study. Subjects in the hypoxia group were exposed to normobaric hypoxia with pre-mixed gases in cylinders with nitrox gas (simulating altitude of 22,000 ft) and the normoxia group was exposed to normal air. Autokinesis time (AT) and vestibular adaptation time (VAT) during acceleration and deceleration, in both clockwise and counter-clockwise turns, were studied as surrogates for SD in both hypoxia group and normoxia group in Disorientation Simulator. Results: Mean AT showed a statistically significant decrease (t = −2.2, P = 0.039) in hypoxia group compared to normoxia group. Similarly, a statistically significant reduction (F = 5.989, P = 0.016) in mean VAT was observed in in hypoxia group compared to normoxia group. There was no significant difference in the VAT in clockwise and counter-clockwise yaw rotation in both the groups. Conclusion: A significant reduction in AT indicates that hypoxia may increase the onset of autokinesis early. The changes in VAT in hypoxic conditions bring out a possible effect of hypoxia on the adaptability of the vestibular system in the angular motion environment.

Transcriptional landscape in rat intestines under hypobaric hypoxia

Oxygen metabolism is closely related to the intestinal homeostasis environment, and the occurrence of many intestinal diseases is as a result of the destruction of oxygen gradients. The hypobaric hypoxic environment of the plateau can cause dysfunction of the intestine for humans, such as inflammation. The compensatory response of the small intestine cells to the harsh environment definitely changes their gene expression. How the small intestine cells response the hypobaric hypoxic environment is still unclear. We studied the rat small intestine under hypobaric hypoxic conditions to explore the transcriptional changes in rats under acute/chronic hypobaric hypoxic conditions. We randomly divided rats into three groups: normal control group (S), acute hypobaric hypoxia group, exposing to hypobaric hypoxic condition for 2 weeks (W2S) and chronic hypobaric hypoxia group, exposing to hypobaric hypoxic condition for 4 weeks (W4S). The RNA sequencing was performed on the small intestine tissues of the three groups of rats. The results of principal component analysis showed that the W4S and W2S groups were quite different from the control group. We identified a total of 636 differentially expressed genes, such as ATP binding cassette, Ace2 and Fabp. KEGG pathway analysis identified several metabolic and digestive pathways, such as PPAR signaling pathway, glycerolipid metabolism, fat metabolism, mineral absorption and vitamin metabolism. Cogena analysis found that up-regulation of digestive and metabolic functions began from the second week of high altitude exposure. Our study highlights the critical role of metabolic and digestive pathways of the intestine in response to the hypobaric hypoxic environment, provides new aspects for the molecular effects of hypobaric hypoxic environment on intestine, and raises further questions about between the lipid metabolism disorders and inflammation.