Effect of continuous positive airway pressure treatment on Th17/Treg imbalance in patients with obstructive sleep apnea and a preliminary study on its mechanism.

BACKGROUND: Obstructive sleep apnea (OSA) can be considered a chronic inflammatory disease that impacts all bodily systems, including the immune system. This study aims to assess the Th17/Treg pattern in patients with OSA and the effect of continuous positive airway pressure (CPAP) treatment. METHODS: OSA patients and healthy controls were recruited. OSA patients recommended for CPAP treatment were followed up for three months. Flow cytometry was employed to determine the proportion of Th17 and Treg cells. Real-time quantitative polymerase chain reaction (PCR) and western blotting were utilized to detect the mRNA and protein levels of receptor-related orphan receptor γt (RORγt) and forkhead/winged helix transcription factor (Foxp3), respectively, in peripheral blood mononuclear cells (PBMCs). Enzyme-linked immunosorbent assay (ELISA) was performed to measure the serum levels of interleukin-17 (IL-17), IL-6, transforming growth factor-ß1 (TGF-ß1), and hypoxia-induced factor-1α (HIF-1α). RESULTS: A total of 56 OSA patients and 40 healthy controls were recruited. The proportion of Th17 cells, Th17/Treg ratio, mRNA and protein levels of RORγt, and serum IL-17, IL-6, and HIF-1α levels were higher in OSA patients. Conversely, the proportion of Treg cells, mRNA and protein levels of Foxp3, and serum TGF-ß1 levels were decreased in OSA patients. The proportion of Th17 and Treg cells in OSA can be predicted by the apnea hypopnea index (AHI), IL-6, TGF-ß1 and, HIF-1α. 30 moderate-to-severe OSA patients were adherent to three-month CPAP treatment, with improved Th17/Treg imbalance, IL-17, IL-6, TGF-ß1, and HIF-1α levels compared to pre-treatment values. CONCLUSION: There was a Th17/Treg imbalance in OSA patients. The prediction of Th17 and Treg cell proportions in OSA can be facilitated by AHI, as well as serum IL-6, TGF-ß1, and HIF-1α levels. Furthermore, CPAP treatment can potentially improve the Th17/Treg imbalance and reduce proinflammatory cytokines in OSA patients.

SPRi Biosensor for Simultaneous Determination of HIF-1α, Angiopoietin-2, and Interleukin-1ß in Blood Plasma.

A new analytical method, based on SPRi biosensors, has been developed for the simultaneous determination of the pro-angiogenic factors HIF-1α, angiopoietin-2 (ANG-2), and interleukin-1ß (IL-1ß) in biological fluids. These proteins take part in the process of angiogenesis, i.e., the creation of new blood vessels, which is a key stage of cancer development and metastasis. A separate validation process was carried out for each individual compound, indicating that the method can also be used to study one selected protein. Low values of the limit of detection (LOD) and quantification (LOQ) indicate that the developed method enables the determination of very low concentrations, in the order of pg/mL. The LOD values obtained for HIF-1α, ANG-2, and IL-1ß were 0.09, 0.01, and 0.01 pg/mL, respectively. The LOQ values were 0.27, 0.039, and 0.02 pg/mL, and the response ranges of the biosensor were 5.00-100.00, 1.00-20.00, and 1.00-15.00 pg/mL. Moreover, determining the appropriate validation parameters confirmed that the design offers high precision, accuracy, and sensitivity. To prove the usefulness of the biosensor in practice, determinations were made in plasma samples from a control group and from a study group consisting of patients with diagnosed bladder cancer. The preliminary results obtained indicate that this biosensor can be used for broader analyses of bladder cancer. Each of the potential biomarkers, HIF-1α, ANG-2, and IL-1ß, produced higher concentrations in the study group than in the control group. These are preliminary studies that serve to develop hypotheses, and their confirmation requires the analysis of a larger number of samples. However, the constructed biosensor is characterized by its ease and speed of measurement, and the method does not require special preparation of samples. SPRi biosensors can be used as a sensitive and highly selective method for determining potential blood biomarkers, which in the future may become part of the routine diagnosis of cancers.

[Expression and significance of hypoxia-inducible factor 1α and Bcl-2/adenovirus E1B19kDa-interacting protein 3 in children with traumatic brain injury]. / ç¼ºæ°§è¯±å¯¼å› å­1α、Bcl-2/è ºç— æ¯’E1B19kDa相互作用蛋白3在儿童创伤性脑损伤中的表达及意义.

OBJECTIVES: To dynamically observe the changes in hypoxia-inducible factor 1α (HIF-1α) and Bcl-2/adenovirus E1B19kDa-interacting protein 3 (BNIP3) in children with traumatic brain injury (TBI) and evaluate their clinical value in predicting the severity and prognosis of pediatric TBI. METHODS: A prospective study included 47 children with moderate to severe TBI from January 2021 to July 2023, categorized into moderate (scores 9-12) and severe (scores 3-8) subgroups based on the Glasgow Coma Scale. A control group consisted of 30 children diagnosed and treated for inguinal hernia during the same period, with no underlying diseases. The levels of HIF-1α, BNIP3, autophagy-related protein Beclin-1, and S100B were compared among groups. The predictive value of HIF-1α, BNIP3, Beclin-1, and S100B for the severity and prognosis of TBI was assessed using receiver operating characteristic (ROC) curves. RESULTS: Serum levels of HIF-1α, BNIP3, Beclin-1, and S100B in the TBI group were higher than those in the control group (P<0.05). Among the TBI patients, the severe subgroup had higher levels of HIF-1α, BNIP3, Beclin-1, and S100B than the moderate subgroup (P<0.05). Correlation analysis showed that the serum levels of HIF-1α, BNIP3, Beclin-1, and S100B were negatively correlated with the Glasgow Coma Scale scores (P<0.05). After 7 days of treatment, serum levels of HIF-1α, BNIP3, Beclin-1, and S100B in both non-surgical and surgical TBI patients decreased compared to before treatment (P<0.05). ROC curve analysis indicated that the areas under the curve for predicting severe TBI based on serum levels of HIF-1α, BNIP3, Beclin-1, and S100B were 0.782, 0.835, 0.872, and 0.880, respectively (P<0.05), and for predicting poor prognosis of TBI were 0.749, 0.775, 0.814, and 0.751, respectively (P<0.05). CONCLUSIONS: Serum levels of HIF-1α, BNIP3, and Beclin-1 are significantly elevated in children with TBI, and their measurement can aid in the clinical assessment of the severity and prognosis of pediatric TBI.

Metabolic reprograming shapes neutrophil functions in severe COVID-19.

To better understand the mechanisms at the basis of neutrophil functions during SARS-CoV-2, we studied patients with severe COVID-19 pneumonia. They had high blood proportion of degranulated neutrophils and elevated plasma levels of myeloperoxidase (MPO), elastase, and MPO-DNA complexes, which are typical markers of neutrophil extracellular traps (NET). Their neutrophils display dysfunctional mitochondria, defective oxidative burst, increased glycolysis, glycogen accumulation in the cytoplasm, and increase glycogenolysis. Hypoxia-inducible factor 1α (ΗΙF-1α) is stabilized in such cells, and it controls the level of glycogen phosphorylase L (PYGL), a key enzyme in glycogenolysis. Inhibiting PYGL abolishes the ability of neutrophils to produce NET. Patients displayed significant increases of plasma levels of molecules involved in the regulation of neutrophils' function including CCL2, CXCL10, CCL20, IL-18, IL-3, IL-6, G-CSF, GM-CSF, IFN-γ. Our data suggest that metabolic remodelling is vital for the formation of NET and for boosting neutrophil inflammatory response, thus, suggesting that modulating ΗΙF-1α or PYGL could represent a novel approach for innovative therapies.

Clotting disorder in severe acute respiratory syndrome coronavirus 2.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel human respiratory viral infection that has rapidly progressed into a pandemic, causing significant morbidity and mortality. Blood clotting disorders and acute respiratory failure have surfaced as the major complications among the severe cases of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection. Remarkably, more than 70% of deaths related to COVID-19 are attributed to clotting-associated complications such as pulmonary embolism, strokes and multi-organ failure. These vascular complications have been confirmed by autopsy. This study summarizes the current understanding and explains the possible mechanisms of the blood clotting disorder, emphasizing the role of (1) hypoxia-related activation of coagulation factors like tissue factor, a significant player in triggering coagulation cascade, (2) cytokine storm and activation of neutrophils and the release of neutrophil extracellular traps and (3) immobility and ICU related risk factors.

Vitamin D and Hypoxia-Inducible Factor (HIF-1α) Serum Levels as Markers for Progression of Nephropathy in Type 2 Diabetic Patients.

BACKGROUND: Vitamin D is a locally acting hormone, which plays a major role in skeletal health. Previous studies reported an important role of vitamin D in modulation of inflammatory response. We aimed to investigate the role of vitamin D deficiency and hypoxia-inducible factor (HIF-1α) as markers for the progression of diabetic nephropathy in Saudi patients with type 2 diabetes mellitus (T2DM). METHODS: We included 174 Saudi patients with T2DM in addition to 60 healthy control subjects. Patients were classified according to urinary Albumin to Creatinine Ratio (ACR) into three groups: Group AI: ACR < 30 µg/mg, Group AII: ACR levels of 30 - 300 µg/mg and Group AIII: ACR > 300 µg/mg. We estimated fasting blood glucose, HbA1c, lipid profile, serum creatinine, hemoglobin concentration (Hb), estimated glomerular filtration rate (eGFR), urine albumin/creatinine ratio, serum 25 hydroxyvitamin D, calcium, parathyroid hormone (PTH), tumor necrosis factor (TNF-α), C- reactive protein (CRP), and hypoxia-inducible factor (HIF-1α). RESULTS: There was a significant difference among studied groups regarding serum levels of vitamin D, calcium, PTH, TNF-α, CRP, and HIF-1α levels. The level of vitamin D was lower in diabetic patients in comparison to the controls and was significantly related to the severity of renal nephropathy as indicated by the level of albumin in urine. Moreover, vitamin D levels showed significant negative correlation with the inflammatory markers: TNF-α, CRP, and HIF-1α levels. CONCLUSIONS: Vitamin D deficiency and elevated HIF-1α serum levels showed a significant correlation to progression of nephropathy in Saudi patients with T2DM.

Repeated sprint training under hypoxia improves aerobic performance and repeated sprint ability by enhancing muscle deoxygenation and markers of angiogenesis in rugby sevens.

OBJECTIVE: To evaluate the effects of repeated sprint (RS) training in hypoxia on aerobic performance, repeated sprint ability (RSA), and muscle oxygenation in Rugby Sevens. METHODS: Fourteen Rugby Sevens players were randomly allocated into hypoxic (RSH, FIO2 = 14.5%, n = 7) or normoxic (RSN, FIO2 = 20.9%, n = 7) groups. Both groups underwent RS training consisting of 3 sets of 6-s × 10 sprints at 140% of velocity at peak oxygen uptake ([Formula: see text]) on a motorized treadmill, 3 days/week for 6 weeks in addition to usual training. Hematological variables, hypoxia-inducible factor-1 alpha (HIF-1α), and vascular endothelial growth factor (VEGF) concentrations were measured. Aerobic performance, RSA, and muscle oxygenation during the running-based anaerobic sprint (RAS) test were analyzed. RESULTS: RSH caused no changes in hemoglobin concentration and hematocrit but significant improvements in [Formula: see text] (7.5%, p = 0.03, ES = 1.07), time to exhaustion (17.6%, p = 0.05, ES = 0.92), and fatigue index (FI, - 12.3%, p = 0.01, ES = 1.39) during the RSA test compared to baseline but not RSN. While ∆deoxygenated hemoglobin was significantly increased both after RSH and RSN (p < 0.05), ∆tissue saturation index (- 56.1%, p = 0.01, ES = 1.35) and ∆oxygenated hemoglobin (- 54.7%, p = 0.04, ES = 0.97) were significantly decreased after RSH. These changes were concomitant with increased levels of HIF-1α and VEGF in serum after RSH with a strong negative correlation between ∆FI and ∆deoxygenated hemoglobin after RSH (r = - 0.81, p = 0.03). CONCLUSION: There was minimal benefit from adding RSH to standard Rugby Sevens training, in eliciting improvements in aerobic performance and resistance to fatigue, possibly by enhanced muscle deoxygenation and increased serum HIF-1α and VEGF concentrations.

Effects of Spironolactone on Hypoxia-Inducible Factor-1α in the Patients Receiving Coronary Artery Bypass Grafting.

ABSTRACT: We explored the protective effect of spironolactone on cardiac function in the patients undergoing coronary artery bypass grafting (CABG) by determining serum hypoxia-inducible factor-1α (HIF-1α) before and after CABG. We used the propensity score matching method retrospectively to select 174 patients undergoing CABG in our hospital from March 2018 to December 2019. Of the 174 patients, 87 patients taking spironolactone for more than 3 months before CABG were used as a test group and other 87 patients who were not taking spironolactone as a control group. In all patients, serum HIF-1α and troponin I levels were determined before as well as 24 hours and 7 days after CABG, serum N-terminal probrain natriuretic peptide (NT-proBNP) level was determined before as well as 12, 24, and 36 hours after CABG, and electrocardiographic monitoring was performed within 36 hours after CABG. The results indicated that there were no significant differences in the HIF-1α level between the test group and the control group before and 7 days after CABG, but the HIF-1α level was significantly lower in the test group than that in the control group 24 hours after CABG (P < 0.01). The 2 groups were not significantly different in the troponin I level at any time point. There was no significant difference in the serum NT-proBNP level between the test group and the control group before CABG, but NT-proBNP (BNP) levels were all significantly lower in the test group than those in the control group at postoperative 12, 24, and 36 hour time points (all P <0.05). The incidence of postoperative atrial fibrillation was also significantly lower in the test group than that in the control group (P = 0.035). Spironolactone protects cardiac function probably by improving myocardial hypoxia and inhibiting myocardial remodeling.

The lower expression of circulating miR-210 and elevated serum levels of HIF-1α in ischemic stroke; Possible markers for diagnosis and disease prediction.

BACKGROUND: Stroke, either due to ischemia or hemorrhage, causes acute neurological damages to the brain. There is shortage of reliable biomarkers for ischemic stroke (IS), and we therefore investigated the serum concentrations of microRNA-210 (miR-210) and hypoxia inducible factor-1α (HIF-1α), as possible diagnostic and/or prognostic markers for IS. METHODS: Serum samples were acquired from 52 IS patients and their healthy counterparts at five time points: upon admission, 24 and 48 h after admission, upon discharge and 3 months later. Serum levels of miR-210 and HIF-1α were respectively analyzed using real time RT-PCR and ELISA. Diagnostic and prognostic accuracy tests were performed to assess the value of suggested biomarkers. RESULTS: IS patients demonstrated higher levels of serum HIF-1α and lower miR-210 in comparison to the healthy subjects. MiR-210 was suggested to be a weak diagnostic biomarker at the time of admission (AUC = 0.61; p = 0.05), while HIF-1α was an acceptable diagnostic marker for IS (AUC = 0.73; p < 0.0001). The higher expression of miR-210 and lower levels of HIF-1α were associated with better survivals in IS patients. CONCLUSIONS: Serum miR-210 is a weak diagnostic marker of IS. Serum HIF-1α is a better biomarker in diagnosing IS patients but further work in larger groups, including those with hemorrhagic stroke is necessary to confirm its diagnostic utility. Similarly, the prognostic potentiality of miR-210 and HIF-1α was acceptable but needs bigger sample size and longer follow-up to be statistically confirmed.

HIF1A: A Putative Modifier of Hemochromatosis.

HFE-related hereditary hemochromatosis (HH) is characterized by marked phenotypic heterogeneity. Homozygosity for p.C282Y is a low penetrance genotype suggesting that the HFE-HH is a multifactorial disease resulting from a complex interaction involving a major gene defect, genetic background and environmental factors. We performed a targeted NGS-based gene panel to identify new candidate modifiers by using an extreme phenotype sampling study based on serum ferritin and iron removed/age ratio. We found an increased prevalence of the HIF1A p.Phe582Ser and p.Ala588Thr variants in patients with a severe iron and clinical phenotype. Accordingly, Huh-7 cells transfected with both variants showed significantly lower HAMP promoter activity by luciferase assay. The qRT-PCR assays showed a downregulation of hepcidin and an upregulation of the HIF1A target genes (VEGF, HMOX, FUR, TMPRSS6) in cells transfected with the HIF1A-P582S vector. We identified mutations in other genes (e.g., Serpina1) that might have some relevance in single cases in aggravating or mitigating disease manifestation. In conclusion, the present study identified HIF1A as a possible modifier of the HFE-HH phenotype cooperating with the genetic defect in downregulating hepcidin synthesis. In addition, this study highlights that an NGS-based approach could broaden our knowledge and help in characterizing the genetic complexity of HFE-HH patients with a severe phenotype expression.

Effect of vitamin B12 supplementation on retinal lesions in diabetic rats.

Purpose: Diabetic retinopathy (DR) is the most common complication of diabetes involving microvasculature and neuronal alterations in the retina. Previously, we reported that vitamin B12 deficiency could be an independent risk factor for DR in humans. However, the effect of vitamin B12 supplementation in experimental DR is unknown. Thus, in this study, we investigated the impact of dietary supplementation of vitamin B12 on retinal changes in diabetic rats. Methods: Diabetes was induced in 2-month-old Sprague-Dawley rats and maintained for 4 months. One group of diabetic rats were fed normal levels of vitamin B12, and one group double the quantity of vitamin B12 (50 µg/kg diet). Vitamin B12 and homocysteine levels in the plasma were analyzed with radioimmunoassay (RIA) and high-performance liquid chromatography (HPLC), respectively. At the end of 4 months of experimentation, the eyeballs were collected. Retinal changes were analyzed with hematoxylin and eosin (H&E) staining, immunoblotting, and immunofluorescence methods. Results: Dietary supplementation of vitamin B12 had no effect on food intake, bodyweight, fasting blood glucose, and plasma homocysteine levels in the diabetic rats. However, vitamin B12 supplementation prevented loss of rhodopsin, and overexpression of VEGF, and completely prevented overexpression of HIF1α, GFAP, and endoplasmic reticulum (ER) stress markers (GRP78, ATF6α, XBP1, CHOP, and caspase 12) in the diabetic rat retina. Further, vitamin B12 ameliorated apoptosis in the retina as shown with terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) and prevented retinal thinning. Conclusions: Vitamin B12 supplementation of diabetic rats appeared to be beneficial by circumventing retinal hypoxia, VEGF overexpression, and ER stress-mediated cell death in the retina. The present study adds another potential therapeutic strategy of vitamin B12 in diabetes.

Plasma angiogenesis and oxidative stress markers in patients with diabetic retinopathy.

Background: Neovascularization in the retina and hyperglycaemia-induced oxidative stress are implicated in the pathogenesis of diabetic retinopathy (DR). In this study, we hypothesized that the plasma angiogenic and oxidative stress markers associated with these derangements could aid in the screening of diabetic patients who are at an increased risk of developing retinopathy.Methods: This study included normal (n = 148), type2 diabetes without retinopathy (DNR; n = 148), proliferative DR (PDR; n = 74) and non-PDR (NPDR; n = 148) subjects. Plasma concentrations of vascular endothelial growth factor-A (VEGF-A), hypoxia-inducible factor-1α (HIF-1α), matrix metalloproteinase-9 (MMP-9), pigment epithelium-derived factor (PEDF), nitric oxide (NO), soluble receptors for advanced glycation end products (sRAGE), malondialdehyde (MDA) and protein thiols were estimated.Results: A statistically significant increase was observed in the plasma concentrations of pro-angiogenic factors and markers of oxidative stress in both retinopathy groups. By contrast, the concentrations of anti-angiogenic factors and antioxidants were decreased significantly in these groups. Receiver operating characteristic analysis indicated that the plasma thresholds of HIF-1α and PEDF can be suitable markers in case of NPDR. However, in PDR, HIF-1α, NO, MMP-9 and PEDF showed high sensitivity and specificity.Conclusions: The factors associated with hypoxia, matrix degradation and angiogenic inhibition play a crucial role in predicting DR.

Limb Ischemic Conditioning Induces Oxidative Stress Followed by a Correlated Increase of HIF-1α in Healthy Volunteers.

BACKGROUND: Local and remote ischemic preconditioning has been used as a protective intervention against ischemia/reperfusion (I/R) damage in several preclinical and clinical studies. However, its physiological mechanisms are not completely known. I/R increases the production of reactive oxygen species, which also serve as messengers for a variety of functions. Hypoxia-inducible factor 1 alpha (HIF-1α) is probably the most important transcription factor mediator of hypoxic signaling. OBJECTIVE: We hypothesized that limb ischemic conditioning (LIC) induces a local oxidative/nitrosative stress and a correlated increase of HIF-1α plasma levels. METHODS: An observational, prospective, and single-center study has been conducted in 27 healthy volunteers. LIC was applied: three cycles (5 min of ischemia followed by 5 min of reperfusion) using an ischemia cuff placed on the upper left arm. Time course of 8-isoprostane, nitrite, and HIF-1α levels was measured in blood plasma. Venous blood was sampled from the left arm before tourniquet inflation (basal) and after LIC: 1 min and 2 hr for 8-isoprostane and nitrite; and 1 min, 2 hr, 8 hr, 24 hr, and 48 hr for HIF-1α. RESULTS: After LIC, we have found an early increase of 8-isoprostane and nitrite. HIF-1α increased at 2 and 8 hr after LIC. We found a direct correlation between HIF-1α and 8-isoprostane and nitrite plasma levels. CONCLUSIONS: We concluded that LIC induces an early oxidative/nitrosative stress in the arm followed by an increase of HIF-1α plasma levels correlated with 8-isoprostane and nitrite levels, possibly as a local response.

Therapeutic effect of high-frequency ultrasound-assisted dye laser on hemangioma and its influence on serum HIF-1α in patients.

BACKGROUND: To analyze the therapeutic effect of high-frequency ultrasound (HFU)-assisted dye laser on hemangioma patients and changes in serum hypoxia-inducible factor-1α (HIF-1α). METHODS: A total of 20 patients diagnosed with hemangioma in our hospital from January 2013 to March 2018 were selected, including 12 males and eight females. All patients were treated with HFU-assisted dye laser. The site and type of hemangioma and age distribution of patients were collected, and changes in data and area of hemangioma and serum HIF-1α before and after treatment were analyzed. RESULTS: The vascular condition of hemangioma in all patients was significantly improved at 7, 14, and 30 days after treatment. Gray-scale ultrasound displayed that the tumor area was reduced by more than 50%. After treatment, the serum HIF-1α level declined obviously after treatment compared with that before treatment, showing a statistically significant difference (P < 0.05). CONCLUSION: HFU-assisted dye laser can effectively reduce the tumor area, decrease the serum HIF-1α level, and improve the prognosis in the treatment of hemangioma.

Plasma expression of HIF-1α as novel biomarker for the diagnosis of obstructive sleep apnea-hypopnea syndrome.

BACKGROUND: Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a common breathing disorder during sleep with potential lethality and multi-complications. Polysomnography (PSG) is now the golden standard for the diagnosis obstructive sleep apnea-hypopnea syndrome. However, PSG is expensive and time-consuming. Therefore, it is important to find inexpensive and convenient biomarkers for the diagnosis of OSAHS. OBJECTIVE: The present study aimed to explore the potential diagnostic value of HIF-1α for OSAHS and its clinical significance. METHODS: This study consisted of 368 patients admitted to the sleep laboratory. The patients were classified according to their apnea-hypopnea index (AHI) scores as OSA negative (AHI < 5), mild-moderate (AHI:5-30), and severe OSA (AHI > 30), and severe OSA treated with continuous positive airway pressure (CPAP). qRT-PCR was used to detect mRNA levels in the plasma; Pearson's correlation analysis was performed to analyze the correlation of HIF-1α mRNA level and the clinicopathological factors of OSAHS; ROC curve was constructed to evaluate the diagnostic value of HIF-1α mRNA. RESULTS: HIF-1α mRNA was significantly up-regulated in the plasma of OSAHS patients, especially patients with severe OSAHS. HIF-1α mRNA was positively correlated with the AHI and ODI but negatively correlated with the mean oxygen saturation in patients with OSAHS. Results of ROC curve showed that HIF-1α is a sensitive biomarker for the diagnosis of OSAHS, especially severe OSAHS. CONCLUSIONS: HIF-1α mRNA might be used as s a convenient and inexpensive method for triaging OSAHS patients PSG assessment in the hospital and evaluate the curative effect.

Hypoxia-inducible factor-1α, hepcidin and interleukin-6 levels in pregnancies with preterm labour.

The aim of the study was to investigate whether serum hypoxia-inducible factor-1alpha (HIF-1α), hepcidin and interleukin-6 (IL-6) concentrations differed between threatened preterm labour (TPL) and uncomplicated pregnancies. This study was conducted on 54 women with TDL pregnancies and 26 healthy pregnant women. The TPL group was further divided into two subgroups according to the gestational age at delivery. Patients who gave birth within 48-72 h after the hospitalisation were referred to as preterm delivery (PD) and who gave birth at ≥37 weeks were referred to as term delivery (TD). Maternal levels of serum HIF-1α, hepcidin and IL-6 were measured with the use of enzyme-linked immunosorbent assay kits. The mean maternal serum HIF-1α, hepcidin and IL-6 levels of PD were significantly higher than TD (p < .001*) and control group (p < .001*). The mean maternal serum HIF-1α and hepcidin levels of TD were no significantly higher than the control group (p=.058, p = .064). The mean maternal serum IL-6 level of TD was significantly higher than the control group (p < .001*). A negative correlation was found between serum concentration of HIF1α, hepcidin, IL-6 with the gestational week of delivery (r = -0.421, p < .01* for HIF-1α; r = -0.578, p < .01* for hepcidin and r = -0.435, p < .01* for IL-6). High levels of HIF-1α, hepcidin and IL-6 may have potential to be used as biomarkers for the differentiation of PD and TD.Impact statementWhat is already known on this subject? It is known that hypoxia-inducible factor-1alpha (HIF-1α) is a hypoxia marker and hepcidin and interleukin-6 (IL-6) increase in inflammation. Our study is the comparison of maternal serum HIF-1α, hepcidin and IL-6 levels between the TPL group (TD and PD) and healthy control group.What the results of this study add? The present study demonstrates that serum HIF-1α, hepcidin and IL-6 levels were significantly higher in TPD group than uncomplicated group. The mean maternal serum HIF-1α and hepcidin levels of TD were no significantly higher than the control group.What the implications are of these findings for clinical practice and/or further research? High levels of HIF-1α, hepcidin and IL-6 may be biomarkers in the determination of true preterm labour within the TPL group.

Could HIF-1α be a novel biomarker for the clinical course and treatment of pulmonary embolism?

Background/aim: Pulmonary embolism (PE) is associated with high morbidity and mortality rates if not diagnosed and treated rapidly. The aim of our study was to investigate the relationship between levels of hypoxia-induced factor-1 alpha (HIF-1α) and clinical course and prognosis in patients with intermediate low-risk, intermediate high-risk, and high-risk PE. Materials and methods: The study included 240 subjects in 4 groups: a healthy control group (n = 60, mean age = 60 ± 15.2, female/male = 30/30 ), intermediate low-risk PE group (n = 60, mean age = 60 ± 12,5, female/male = 27/33), intermediate high-risk PE group (n = 60, mean age = 61,4 ± 14,8, female/male = 36/24), and high-risk PE group (n = 60, mean age = 62,3 ± 15, female/male = 33/27). Plasma HIF-1α levels were measured using commercial enzyme-linked immunosorbent assay (ELISA) kit. Results: Comparison of HIF-1α levels revealed a statistically significant difference between the groups in proportion to clinical scoring (P = 0.001 for all). Comparison of initial HIF-1α and troponin levels in intermediate high-risk PE patients given thrombolytic therapy and those treated with enoxaparin sodium showed that HIF-1α levels were significantly higher in the group that received thrombolytic therapy (P = 0.001), while there was no difference in troponin levels (P = 0.146). Conclusion: HIF-1α can be used in the PE clinical risk stratification and monitoring of PE and may also serve as a valuable early indicator in intermediate high-risk PE, for which early reperfusion therapy is important.

Role of miRNA-210, miRNA-21 and miRNA-126 as diagnostic biomarkers in colorectal carcinoma: impact of HIF-1α-VEGF signaling pathway.

Colorectal cancer (CRC) is a major cause of death worldwide. Novel non-invasive, high diagnostic value screening test is urgently needed to improve survival rate, treatment and prognosis. Stable, small, circulating microRNA (miRNA) offers unique opportunities for the early diagnosis of several diseases. It acts as tumor oncogenes or suppressors and involve in cell death, survival, and metastasis. Communication between miRNA and carcinogenesis is critical but it still not clear and needs further investigation. The aim of our study is to evaluate the role of miR-210, miR-21, miR-126, as non-invasive diagnostic biomarkers for screening, early detection of CRC, studying their correlation with prognostic variables, and clarifying the roles of miRNAs on HIF-1α-VEGF signaling pathway. The expression of miR-210, miR-21 and miR-126 was performed using qRT-PCR in adenocarcinoma (no = 35), adenomas (no = 51), and neoplasm free controls (no = 101). Serum levels of VEGF and HIF-1α was determined by ELISA Kit. The results show that the expression of miR-210, miR-21, VEGF, HIF-1α was significantly up-regulated while that miRNA-126 was down-regulated in both adenocarcinoma and adenomas compared with controls (p < 0.001 for each). No significant difference was noted comparing patients with adenocarcinoma and adenomas. The three miRNAs correlated with VEGF, HIF-α. The miR-210 and miR-21 associated with TNM classification and clinical staging of adenocarcinoma (p < 0.001) and they show high diagnostic value with sensitivity and specificity 88.6%, 90.1% and 91.4%, 95.0% respectively. Our study revealed that circulating miR-210, miR-21 were up-regulated while miR-126 was down-regulated in CRC and adenomas patients, they all correlated with TNM staging and they had high diagnostic value. HIF-1α VEGF signaling pathways regulated by miRNAs played a role in colon cancer initiation. To the best of our knowledge, this is the first study of this miRNAs panel in CRC in our community. These data suggested that these biomarkers could be a potential novel, non-invasive marker for early diagnosis, screening and predicting prognosis of CRC. Understanding the molecular functions by which miRNAs affect cancer and understanding its roles in modulating the signaling output of VEGF might be fruitful in reducing the incidence and slowing the progression of this dark malignancy.

Age-dependent hypoxia-induced PD-L1 upregulation in patients with obstructive sleep apnoea.

BACKGROUND AND OBJECTIVE: In obstructive sleep apnoea (OSA), intermittent hypoxia (IH) compromises immune surveillance through the upregulation of the programmed cell death-1 (PD-1) receptor and its ligand (PD-L1). Because the risk of OSA-related cancer depends on age, we assessed PD-L1/PD-1 expression in middle-aged and older patients with OSA as well as in a murine model. METHODS: PD-L1 expression was studied in 41 patients with severe OSA and 40 healthy volunteers (HV), divided into two groups (≤55 and >55 years of age). We used flow cytometry, quantitative PCR (qPCR) and ELISA to determine PD-L1 expression on monocytes and plasma PD-L1 protein levels. Moreover, we analysed PD-L1 expression on an in vivo IH model with old and young mice. RESULTS: In subjects up to 55 years of age, severe OSA increased PD-L1 surface protein and mRNA level expression on monocytes and soluble-PD-L1 protein concentration in plasma compared to HV. PD-L1 and hypoxia-induced factor (HIF)-1α expression correlated with age in HV, whereas in patients with OSA there was a negative relationship. In the mice exposed to IH, PD-L1 expression on F4/80+ splenocytes was also only increased in young animals. HIF-1α expression was significantly higher in patients with OSA than in HV in subjects up to 55 years of age, while PD-L1 expression in monocytes was related to HIF-1α expression in young patients with OSA. CONCLUSION: PD-L1 upregulation in patients with OSA as a consequence of HIF-1α activation occurs mainly in young patients. In older patients with OSA, upregulation was not detected, possibly due to impaired oxygen sensitivity.

Modulating effects of preconditioning exercise in the expression of ET-1 and BNP via HIF-1α in ischemically injured brain.

It is well-known that in ischemia-induced hypoxia, hypoxia-inducible factor -1α (HIF-1α) is critical in triggering expression of its downstream target genes to produce several products, such as erythropoietin (EPO), vascular endothelial growth factor (VEGF), nitric oxide synthesis (NOS), glucose transportor-1 (GLUT-1), insulin-like growth factor (IGF), which further promote erythropoiesis, angiogenesis, vasodilation and capitalization of glucose to overcome hypoxia. Meanwhile, as the factors with opposite effects on blood vessels, endothelin-1 (ET-1) and brain natriuretic peptide (BNP) also stand out strikingly in ischemic pathophysiology. To this day, several preconditioning manners have been used to induce tolerance to ischemia. During our research, exercise preconditioning was applied and it was demonstrated that HIF-1α triggered expression of ET-1 and BNP, which confirmed their downstream target genes for HIF-1α. And ET-1 may influcence expression of BNP to some degree but not the only factor which regulates BNP expression. Therefore, our findings suggest exercise preconditioning may provide protection to the ischemic brain tissue via HIF-1α which in turn increases expression of BNP to cause vasodilation in cooperation with some other factors, such as VEGF and EPO, to increase the blood flow in the ischemic area and then relieve the injuries induced by ischemia.