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The hypoxia‐inducible factor HIF‐1 is essential for oxygen homeostasis. Despite its well‐understood oxygen‐dependent expression, regulation of its transcriptional activity remains unclear. We show that phosphorylation by extracellular signal‐regulated kinases1/2 (ERK1/2), in addition to promoting HIF‐1α nuclear accumulation, also enhances its interaction with chromatin and stimulates direct binding to nucleophosmin (NPM1), a histone chaperone and chromatin remodeler. NPM1 is required for phosphorylation‐dependent recruitment of HIF‐1 to hypoxia response elements, its interaction with acetylated histones, and high expression of HIF‐1 target genes under hypoxia. Transcriptome analysis revealed a significant number of hypoxia‐related genes commonly regulated by NPM1 and HIF‐1. These NPM1/HIF‐1α co‐upregulated genes are enriched in three different cancer types, and their expression correlates with hypoxic tumor status and worse patient prognosis. In concert, silencing of NPM1 expression or disruption of its association with HIF‐1α inhibits metabolic adaptation of cancer cells and triggers apoptotic death upon hypoxia. We suggest that ERK‐mediated phosphorylation of HIF‐1α regulates its physical interaction with NPM1, which is essential for the productive association of HIF‐1 with hypoxia target genes and their optimal transcriptional activation, required for survival under low oxygen or tumor growth., NPM1 marks and may organize hypoxia‐inducible promoters. Upper panel: In the absence of ERK‐mediated phosphorylation HIF‐1α binding to HRE is weak resulting in basal levels of transcriptional activity. Bottom panel: In cells with elevated ERK1/2 activity phosphorylated HIF‐1α can then bind to NPM1 and mediate stable association of HIF‐1 with a neighboring HRE resulting in maximal activation of transcription.

Oxygen homeostasis disturbances play a critical role in the pathogenesis of acute kidney injury (AKI). The transcription factor hypoxia-inducible factor-1 (HIF-1) is a master regulator of adaptive responses to hypoxia. Aside from posttranslational hydroxylation, the mechanism of HIF-1 regulation in AKI remains largely unclear. In this study, the mechanism of HIF-α regulation in AKI was investigated. We found that tubular HIF-1α expression significantly increased at the transcriptional level in ischemia-reperfusion-, unilateral ureteral obstruction-, and sepsis-induced AKI models, which was closely associated with macrophage-dependent inflammation. Meanwhile, NF-κB, which plays a central role in the inflammation response, was involved in the increasing expression of HIF-1α in AKI, as evidenced by pharmacological modulation (NF-κB inhibitor BAY11-7082). Mechanistically, NF-κB directly bound to the HIF-1α promoter and enhanced its transcription, which occurred not only under hypoxic conditions but also under normoxic conditions. Moreover, the induced HIF-1α by inflammation protected against tubular injury in AKI. Thus, our findings not only provide novel insights into HIF-1 regulation in AKI but also offer to understand the pathophysiology of kidney diseases.NEW & NOTEWORTHY Here, the mechanism of hypoxia-inducible factor-α (HIF-α) regulation in acute kidney injury (AKI) was investigated. We found that tubular HIF-1α expression significantly increased at the transcriptional level, which was closely associated with macrophage-dependent inflammation. Meanwhile, NF-κB was involved in the increasing expression of HIF-1α in AKI. Mechanistically, NF-κB directly bound to the HIF-1α promoter and enhanced its transcription. Our findings not only provide novel insights into HIF-1 regulation in AKI but also offer to understand the pathophysiology of kidney diseases.

Anaemia is one of the leading causes of disability in young adults and is associated with increased morbidity and mortality in elderly. With a global target to reduce the disease burden of anaemia, recent researches focus on novel compounds with the ability to induce erythropoiesis and regulate iron homeostasis. We aimed to explore the biological events and potential polypharmacological effects of water‐extracted olive leaf (WOL) on human bone marrow–derived haematopoietic stem cells (hHSCs) using a comprehensive gene expression analysis. HPLC analysis identifies six bioactive polyphenols in the WOL. Treatment with WOL for 12 days regulated gene expressions related to erythroid differentiation, oxygen homeostasis, iron homeostasis, haem metabolism and Hb biosynthesis in hHSCs. Functional clustering analysis reveals several major functions of WOL such as ribosomal biogenesis and mitochondrial translation machinery, glycolytic process, ATP biosynthesis and immune response. Additionally, the colonies of both primitive and mature erythroid progenitors, CFU‐E and BFU‐E, were significantly increased in WOL‐treated hHSCs. The expressions of erythroid markers, CD47, glycophorin A (GYPA), and transferrin receptor (TFRC) and adult Hb subunits‐HBA and HBB were also confirmed in immunofluorescent staining and flow cytometer analysis in WOL‐treated hHSCs. It is well known that induction of lineage‐specific differentiation, as well as the maturation of early haematopoietic precursors into fully mature erythrocytes, involves multiple simultaneous biological events and complex signalling networks. In this regard, our genome‐wide transcriptome profiling with microarray study on WOL‐treated hHSCs provides general insights into the multitarget prophylactic and/or therapeutic potential of WOL in anaemia and other haematological disorders.

Introduction.Reperfusion-reoxygenation syndrome (RRS) after revascularization of the lower limbs in obliterating atherosclerosis of the arteries is accompanied by a violation of the oxygen transport function of the blood (OTFB) and the content of gas transmitters (GTs). Reperfusion injury affects not only the tissues of the lower limbs, but also of anatomically distant organs, which supposes that effective RRS correction is required. Aim. To study the effect of Corvitin on the OTFB parameters and the content of GT of nitrogen monoxide (NO) and hydrogen sulfide (H2S) in the venous blood of the forearm after revascularization of the lower limb in chronic atherosclerotic occlusion of the superficial femoral artery (SFA).Materials and methods.The study included 118 male patients. Revascularization of the lower limb was carried out by the method of loop endaterectomy from the SFA. Patients of group I (n=52) received traditional medication, 51 patients of group II additionally received Corvitin. In the blood from the vein of the elbow bend before the operation, on the 3rdand 8thdays after it, the indices of OTFB and GTs were determined.Results.In group I, on the 3rdday after surgery, pO2increased in relation to healthy individuals by 5.2–18.5%, while pCO2decreased by 4.8–6.7%, depending on the stage of initial ischemia. The concentrations of NO and H2S increased by 9.2–50.1% and 9.2–21.1%, respectively. The increase in the parameters of hyperoxemia, hypocapnemia and GT after the return of blood circulation decreases with the use of Corvitin (p˂0.05). By the end of the early postoperative period, the indicators of OTFB and GT not only return to their initial values, but also do not significantly differ from the group of healthy individuals (p˃0.05).Conclusion.The use of Corvitin effectively corrects violations of OTFB and GT during ischemia-reperfusion of the lower limbs, which prevents tissue reperfusion damage.

This study involving ten apparently healthy male volunteers aged 19 to 31 years was aimed at establishing possible effects of a three-week course of normobaric intermittent hypoxic trainings (IHTs) on the state of endothelial function (EF). IHTs were performed on a daily basis with each training session lasting 60 min and the FIO2 operating level equal to 9% in the 5-min hypoxia/5-min normoxia cyclic mode. The EF state and the pulse wave velocity (PWV, ΔPWV) were evaluated using a Tonocard device by a noninvasive method based on the capacity of the endothelium to release nitric oxide (NO) during reactive hyperemia. The adaptation to intermittent hypoxia was accompanied by a significant (p < 0.05) 34.3% increase in the erythropoietin (Epo) concentration, a larger than twofold increase in the reticulocyte count, a 6.4% increase in the erythrocyte count, and a 4.1% increase in the hemoglobin content. After the course of IHTs, the value of EF used to increase significantly by 38.9% (p < 0.05), which could be caused by a higher level of endothelium-dependent relaxation in muscular arteries. At the same time, the PWV and ΔPWV values reflecting the elastic–viscous characteristics of vascular wall remained at the prior-to-the study level. The data obtained in the study are discussed in this article from the position of possible trigger effects of the hypoxia-inducible transcription factors (HIF-1 and HIF-2), which create a broad molecular basis for the activation of endothelial cells and the increase in the NO production. Apart from increasing the erythrocyte production, which is greatly important for maintaining oxygen homeostasis under reduced PO2, Epo can participate in the complicated mechanisms of ventilatory response, activation of NO production by endothelial cells, and angiogenesis during the adaptation of the body to hypoxia.

An analysis of modern concepts of the mechanism of the antiradiation effect of alpha1-adrenergic agonists, which are of great interest in clinical practice of radiochemotherapy in cancer patients, has been carried out. The first explanation of their mechanism of action is based on the role of circulatory hypoxia in radiosensitive tissues due to the vasoconstrictor effect of alpha1-adrenergic agonists. During further study of the real decrease in oxygen tension in tissue under circulatory hypoxia, it was found that it is insufficient to fully provide the observed increase in the body’s radioresistance under their influence. The second important fact is that in the course of a decrease in the baseline oxygen consumption per unit of body weight when passing from small to large animals, the antiradiation effect of circulatory and hypoxic hypoxia decreases due to the great adaptive abilities in maintaining oxygen homeostasis of the cell under these conditions. This point is directly related to humans. To explain the high radiation protection in large animals under the influence of alpha1-adrenergic agonists, a hypothesis on the development of acute tissue hypoxia due to the intensification of oxygen consumption under alpha1-adrenergic receptor stimulation has been proposed. The third thesis is that alpha1-adrenergic agonists can stabilize mitochondrial homeostasis under exposure to radiation, thereby reducing the probability of radiation apoptosis of cells and maintaining optimal tissue functioning. All three noted components of the mechanism of the antiradiation effect of alpha1-adrenergic agonists can interact with each other, leading to high protection. The role of each component can change and dominate for each specific scenario of their practical application.

To investigate the heterogeneity of decidual stromal cells (DSCs) and their functional alterations during delivery, we conducted single-cell RNA sequencing analysis to characterize the transcriptomic profiles of DSCs before and after labor onset. According to their transcriptomic profiles, DSCs (6382 cells) were clustered into five subgroups with different functions. Similar to stromal cells, cells in cluster 1 were involved in cell substrate adhesion. On the other hand, cells in clusters 2 and 3 were enriched in signal transduction-related genes. Labor onset led to significant alterations in many pathways, including the activator protein 1 pathway (all clusters), as well as in the response to lipopolysaccharide (clusters 1-3). The downregulated genes were involved in coagulation, ATP synthesis, and oxygen homeostasis, possibly reflecting the oxygen and energy balance during delivery. Our findings highlight that peripartum DSCs are heterogeneous and play multiple roles in labor.

Neuroglobin is a representative of the globin group, an oxygen-binding protein which is predominantly expressed in the nervous system. Despite the large amount of conducted research, its role is still poorly understood. It’s assumed that neuroglobin is able to regulate cell activity in health and disease:in health it provides oxygen homeostasis of neurons, and in pathology it binds free radicals and nitrogen monoxide, blocks mitochondrial factors of apoptosis and suppresses oxidative stress. A clearer understanding of the role of neuroglobin in pathology can offer new approaches in the treatment of neurodegenerative diseases. Special attention in the literature is paid to the role of neuroglobin in cerebral ischemia, which among other cerebrovascular diseases is the cause of disability and mortality of the population all over the world. In the present article an overview of the literature data available to date on the study of the neuroprotective effect of neuroglobin in hypoxia/ischemia is provided: models used to study function in vitro and in vivo, the effects of its increased or decreased expression, neuroglobin-mediated neuroprotective action of hemin, estimated pathways of the induction of neuroglobin and views on the mechanisms of neuroprotection.

We identified the main changes in serum metabolites associated with severe (n = 46) and mild (n = 19) COVID-19 patients by gas chromatography coupled to mass spectrometry. The modified metabolic profiles were associated to an altered amino acid catabolism in hypoxic conditions. Noteworthy, three α-hydroxyl acids of amino acid origin increased with disease severity and correlated with altered oxygen saturation levels and clinical markers of lung damage. We hypothesize that the enzymatic conversion of α-keto-acids to α- hydroxyl-acids helps to maintain NAD recycling in patients with altered oxygen levels, highlighting the potential relevance of amino acid supplementation during SARS-CoV-2 infection.

Over one billion adults worldwide are estimated to suffer from sleep apnea, a condition with wide-reaching effects on brain health. Sleep apnea causes cognitive decline and is a risk factor for neurodegenerative conditions such as Alzheimer’s disease. Rodents exposed to intermittent hypoxia (IH), a hallmark of sleep apnea, exhibit spatial memory deficits associated with impaired hippocampal neurophysiology and dysregulated adult neurogenesis. We demonstrate that IH creates a pro-oxidant condition that reduces the Tbr2+ neural progenitor pool early in the process, while also suppressing terminal differentiation of adult born neurons during late adult neurogenesis. We further show that IH-dependent cell-autonomous hypoxia inducible factor 1-alpha (HIF1a) signaling is activated in early neuroprogenitors and enhances the generation of adult born neurons upon termination of IH. Our findings indicate that oscillations in oxygen homeostasis, such as those found in sleep apnea, have complex stage-dependent influence over hippocampal adult neurogenesis.

Aim: Hypoxia-inducible factor 1 (HIF-1α) is responsible in regulating oxygen homeostasis in tissues and is a central effector of the hypoxic response besides its protein overexpression has been shown to have prognostic relevance in several cancers including breast cancer. Several reports indicated that HIF-1α gene variation C1772T (Pro582Ser) is associated with increased breast susceptibility but results remained controversial. Therefore, we performed the molecular evaluation of HIF-1α gene variation and determined its frequency and association with Breast Cancer susceptibility in Saudi Arabia. Methods: This study was conducted on histologically confirmed Breast cancer patients and gender matched healthy women. HIF-1α C1772T (Pro582Ser) genotyping was done by Amplification refractory mutation system PCR method. The HIF-1α gene genotypes were correlated with different clinicopathological characteristics of breast cancer patients. Results: A significant difference was observed in genotype distribution of HIF-1α gene variation C1772T (Pro582Ser) between breast cancer cases and gender matched healthy controls (P=0.010). Our findings showed that the HIF- 1α variant was associated with an increased risk of Breast cancer for HIF-1α CC vs CT genotype OR = 2.20, 95% CI = (1.28 -3.77), P = 0.004) in codominant inheritance model. The significant association was reported for HIF1A for genotypes CC vs (CT+ TT) OR = 1.98, 95% CI = (1.17-3.34), P = 0.010) in dominant inheritance model tested. In case of recessive inheritance model, a non-significant association of HIF-1 alpha gene variants was reported for (CC+ CT) vs TT) OR = 1.03, 95% CI = (0. 064-16.79), P = 0.97). During the allelic comparison, a non-significant association was reported between A vs C allele among Breast cancer patients. A significant association of HIF- 1α polymorphism was reported with stage as well as distant metastasis of the disease. Conclusion: A significant difference was observed in genotype distribution of HIF-1α gene variation C1772T (Pro>Ser) between breast cancer cases and gene matched healthy controls (P=0.010). HIF-1α- CT heterozygosity and CC genotype increased the susceptibility .The HIF-1α polymorphism was reported to be significantly associated with the distant metastasis of Breast cancer. Further studies with larger data set and well-designed models are required to validate our findings.

Human life on Earth depends on the continuous availability of oxygen. Conditions for the entry of oxygen into the body’s cells change in time and space, are easily broken, thus causing the possibility of development of hypoxia - a condition of oxygen starvation of tissues. The second part of the review is devoted to information about the successful use of oxygen-rich water in domestic therapeutic and surgical practice in complex treatment to reduce the negative effect of hypoxia in patients with chronic heart failure and generalized peritonitis complicated by intestinal insufficiency syndrome. Authors consider a common method for improving the supply of oxygen to the body using enteral oxygen therapy - oxygen cocktails in diseases of the cardiovascular system, lungs, bronchi and gastrointestinal tract, atopic dermatitis, placental insufficiency, as well as to improve physical performance, reduce the level of neuroticism and normalize the psychoemotional status. The first part of the review provides data on the modern understanding processes providing oxygen homeostasis in cells, on the critical component responsible for regulating the molecular response to hypoxia - the Hypoxia-Inducible Factors (HIFs) of the family of transcription factors. The possibility to compensate for the lack of oxygen in the body by delivering it to cells and tissues was indicated to consider water and various oxygen cocktails. Data from experimental studies of the biological effect of oxygenated drinking water are analyzed, as well as the results of studying the effects of oxygen-enriched drinking water with the participation of volunteers. The issue of the formation of oxygen (free) radicals when drinking oxygen-enriched drinking water is considered. The review draws specialist’s attention to the problem of the biological effect of oxygen-enriched drinking water, its insufficient knowledge and the possible yet unrealized potential in terms of preventing various diseases and maintaining optimal human health.

Atrial fibrillation (AF) is a common arrhythmia that has major morbidity and mortality. Hypoxia plays an important role in AF initiation and maintenance. Hypoxia-inducible factor (HIF), the master regulator of oxygen homeostasis in cells, plays a fundamental role in the regulation of multiple chemokines and cytokines that are involved in different physiological and pathophysiological pathways. HIF is also involved in the pathophysiology of AF induction and propagation mostly through structural remodeling such as fibrosis; however, some of the cytokines discussed have even been implicated in electrical remodeling of the atria. In this article, we highlight the association between HIF and some of its related cytokines with AF. Additionally, we provide an overview of the potential diagnostic benefits of using the mentioned cytokines as AF biomarkers. Research discussed in this review suggests that the expression of these cytokines may correlate with patients who are at an increased risk of developing AF. Furthermore, cytokines that are elevated in patients with AF can assist clinicians in the diagnosis of suspect paroxysmal AF patients. Interestingly, some of the cytokines have been elevated specifically when AF is associated with a hypercoagulable state, suggesting that they could be helpful in the clinician's and patient's decision to begin anticoagulation. Finally, more recent research has demonstrated the promise of targeting these cytokines for the treatment of AF. While still in its early stages, tools such as neutralizing antibodies have proved to be efficacious in targeting the HIF pathway and treating or preventing AF.

IOX-2 is a potent inhibitor of enzyme prolyl hydroxylases-2 (PHD) that plays a critical role in regulating hypoxia inducible factor (HIF) abundance and oxygen homeostasis. Federation for Equestrian Sports has listed HIF activators as prohibited substances to prevent their usage in doping. Consequently, it became essential to develop adequate knowledge and testing methods to detect it in equine sports drug testing samples. The validated method utilizes ultra-high-performance liquid chromatography coupled to high-resolution mass spectrometry in order to detect extremely low concentration of the analyte present in both matrices. Confirmation for the presence of the analyte was achieved by comparing ion ratios, retention time, and accurate mass. Method linear range for plasma was between 0.25 to 100 ng/ml, and limit of detection (LOD) was 0.075 ng/ml. The linear range for urine was 0.125 to 100 ng/ml, and LOD was 0.025 ng/ml. Intraday precision at 0.5, 10, and 50 ng/ml was between 4.0% and 9.7% for plasma and 4.2% and 10.4% for urine. Accuracy at 0.5, 10, and 50 ng/ml was between 91% and 94% for plasma and 99% and 103% for urine. Elimination profile of IOX-2 in equine plasma and urine was carried out using the developed method in which two horses were intravenously administered IOX-2 and samples were collected. Metabolic profile in plasma and urine was investigated. IOX-2 was detected for a minimum of 54 and 151 h of post administration in plasma and urine, respectively, thereby providing a valuable tool for evaluating its misuse in equine racing.

Highlights • HPC triggers hormetic mechanisms that improve and maintain tissue oxygenation • HIF-1 regulates cell responses to hypoxia leading to cell survival and regeneration • We propose HPC as a preventitive therapy on healthy contacts of COVID-19 patients • Monitoring responses to HPC can predict cases likely to develop severe COVID-19 ARDS, Hypoxia is defined by low oxygen concentration in organs, tissues and cells. Maintaining oxygen homeostasis represents the essential cellular metabolic process for the structural integrity of tissues in different pathological conditions, including SARS-CoV-2 infection. Considering the role of hypoxia–inducible factor-1 (HIF-1) as regulator of cellular response to hypoxia and its involvement in angiogenesis, erythropoiesis, glucose metabolism, inflammation, we propose hypoxic preconditiong (HPC) as a novel prevention therapeutic approach on healthy contacts of COVID-19 patients. To date, several studies revealed the benefic effects of hypoxic preconditioning in ischemia, kidney failure and in pulmonary function recovery of lung surgery patients. HPC increases the expression of factors that promote cell survival and angiogenesis, induces an anti-inflammatory outcome, triggers coordinated hypoxia responses that promote erythropoiesis, and mobilizes the circulating progenitor cells. Futhermore, the mesenchymal stem cells (MSC) exposed to HPC show improvement of their regenerative capacities, and increases the effectiveness of stem cell therapy in different pathologies, including COVID-19. In conclusion, HPC should be considered an approach with beneficial outcomes and without significant side effects when the organism is severely exposed to the same stressor. HPC appears as a trigger to mechanisms that improve and maintain tissue oxygenation and repair, a main goal in different pathologies, including COVID-19 or other respiratory conditions.

Ferroptosis is an iron‐dependent mode of non‐apoptotic cell death characterized by accumulation of lipid reactive oxygen species (ROS). As a regulator of ROS, cytoglobin (CYGB) plays an important role in oxygen homeostasis and acts as a tumour suppressor. However, the mechanism by which CYGB regulates cell death is largely unknown. Here, we show that CYGB overexpression increased ROS accumulation and disrupted mitochondrial function as determined by the oxygen consumption rate and membrane potential. Importantly, ferroptotic features with accumulated lipid ROS and malondialdehyde were observed in CYGB‐overexpressing colorectal cancer cells. Moreover, CYGB significantly increased the sensitivity of cancer cells to RSL3‐ and erastin‐induced ferroptotic cell death. Mechanically, both YAP1 and p53 were significantly increased based on the RNA sequencing. The knock‐down of YAP1 alleviated production of lipid ROS and sensitivity to ferroptosis in CYGB overexpressed cells. Furthermore, YAP1 was identified to be inhibited by p53 knock‐down. Finally, high expression level of CYGB had the close correlation with key genes YAP1 and ACSL4 in ferroptosis pathway in colon cancer based on analysis from TCGA data. Collectively, our results demonstrated a novel tumour suppressor role of CYGB through p53‐YAP1 axis in regulating ferroptosis and suggested a potential therapeutic approach for colon cancer.

Introduction: Hypoxia-inducible factor (HIF) is a master regulator of oxygen homeostasis. The increased expression of genes targeted by HIF is associated with many human diseases, including ischemi...

There is accumulating evidence that the subfamily of large-conductance potassium (“big”, “BK”) channels are involved in diverse, and perhaps coordinated, protective or counteractive responses to local or generalized ischemia and hypoxia. Although widely distributed, the physiological differences among BK channels which results from posttranslational modification (alternative splicing) and co-assembly with auxiliary modulatory subunits (β1-4 and γ1-4), bestows localized differences in subunit composition, distribution, 2nd-messenger coupling, and pharmacologic properties. Due to the ubiquitous nature of BK channels and the multiplicity of subtypes, they have many potential therapeutic applications in the maintenance of oxygen homeostasis, cerebro- and cardio-protection, and stimulation of respiration in response to drug-induced respiratory depression. BK channels may also offer other potentially broad and underrecognized promising targets for novel pharmaceutical development.

Stimulus-responsive polymer materials have attracted much attention as drug carriers because of the ability to deliver drugs to the active site. Reactive oxygen species (ROS) play crucial roles in cellular signaling and regulation of oxygen homeostasis. However, ROS are present in abnormally high levels in many pathological environments. Based on the above points, three-arm poly(lactic-co-glycolic acid)-PO-poly(ethylene glycol) (3s-PLGA-PO-PEG or simply PP) was synthesized by using peroxalate esters (PO) as hydrogen peroxide-responsive linkages. PP was used to deliver promote hematopoietic recovery drugs erythropoietin (EPO) and EPO nanoparticles (EPO NPs) were prepared. We established a hematopoietic system injury model by ionizing radiation (IR) and unexpectedly found the good therapeutic effect of blank PP. Moreover, the administration of EPO NPs obviously decreased IR-induced ROS in bone marrow cells (BMCs) and reconstituted hematopoietic stem cells in BMCs. This study reveals a novel ROS-responsive polymer material that could be employed to remove excess ROS in the lesion and promote the efficacy of drug therapy.

Disorders of the oxygen transport play an important role in the development of multiple organ disfunction syndrome and are a marker of tissue hypoxia and ischemia. Disorders of the oxygen transport could be use for predicting patient survival and as criteria for the severity of the pathological process. The aim of this study was to explore the indicators of systemic oxygen transport in the perioperative period in patients with traumatic deases in multi-stage surgical correction at polytrauma in terms of standard and advanced intensive care. Materials and methods. A prospective study of 88 patients with traumatic deases was conducted. The dynamics of indices of oxygen delivery (iDО2) and oxygen consumption (iVO2), oxygen extraction coefficient (KEO2) at different variants of intensive care was studied. Results. The patients in both groups was noted iDO2 decline, which was due to massive blood loss and decreased cardiac output on admission to the operation room. Despite the fact that during the acute period was held stop bleeding, correction of hypovolemia and posthemorrhagic anemia, the average level of iDО2 was quite low. iDO2 was multidirectional nature of the changes in the studied groups at the second and third stages of the study. In turn, the average values KEO2 characterized the degree of tension compensatory mechanisms and metabolic changes caused by hypoxia and hypoperfusion. Normalization of oxygen homeostasis parameters was achieved in the fourth stage of the study. Conclusions. The maximal intensity of development of compensatory mechanisms and changes of oxygen transport occurs within the first 5 days after the injury. The optimized intensive care which has been used in the treatment patients of Group II, has positive effect on the ability to potentiate adaptive defense mechanisms and reduce oxygen debt.

Sirtuins are deacetylases dependent on nicotine adenine dinucleotide (NAD) and take an important role in metabolism and aging. In mammals, there are seven sirtuins (SlRTl-7), and only SIRT2 is predominantly localized in cytoplasm. Under hypoxic environments, metazoan organisms must maintain oxygen homeostasis to survive. Hypoxia conditions induce reduction the ratio of NAD+/NADH, and aberrant increases or decreases in cellular O2 concentration induced excessive reactive oxygen species generation. Here, we report that inhibition of SIRT2 stabilizes hypoxia-inducible factor 1α (HIF-1α) protein levels and enhances hypoxia-responsive element-containing gene expression. We also show that the SIRT2 inhibitor AGK2 induces VEGF and HO-1 gene expression and protects neuronal viability from oxidative stress. Our findings suggest that SIRT2 negatively regulates HIF-1α signaling, indicating that SIRT2 inhibition may be a useful treatment strategy following ischemic injury.

During adaptation to a semi-aquatic lifestyle, the muskrat (Ondatra zibethicus) developed numerous biochemical adaptations to maintain oxygen homeostasis. The aim of the study was to explore age-related and seasonal changes in muscle tissue antioxidant defenses and erythrocyte morphometric parameters in the muskrat. Animals were captured in autumn (juveniles and adults) and spring (adults) in the North-West of Russia (Republic of Karelia). Some physiological and biochemical parameters of “autumn” animals showed an age-related variability: in adult muskrats (most adapted to diving), as compared to juveniles, catalase activity in skeletal muscles was lower, while the respiratory function of blood was higher (due to a lower total surface area of erythrocytes). Adult muskrats demonstrated seasonal changes in some parameters: in “spring” animals, activities of catalase in the heart and superoxide dismutase in skeletal muscles were higher, while levels of low-molecular-weight antioxidants (α-tocopherol and glutathione) both in cardiac and skeletal muscles were lower compared to “autumn” animals. After a long winter (ice-fishing) season, the blood of “spring” animals contained mainly mature erythrocyte forms (normocytes), with their average diameter and surface area being larger than in adult “autumn” muskrats. Our findings, as well as data obtained on other species, support the involvement of the antioxidant system and erythrocytes in the mechanisms that maintain oxygen homeostasis in diving mammals.

The critical roles of oxygen homeostasis in metabolism are indisputable and hypoxic responses are correlated with the pathogenesis of gastrointestinal, pulmonary, renal diseases and cancers. Evaluating tissue hypoxia to predict treatment outcome is challenging, however, due to the lack of rapid, accurate and non-invasive methods. Hypoxia enhances prolyl-4-hydroxylase α1 (P4HA1) expression, which can convert bradykinin (BK) to hydroxyprolyl-BK (Hyp-BK), leading us to hypothesize that circulating Hyp-BK/BK ratios may reflect tissue hypoxia and predict treatment outcomes. Direct quantification of Hyp-BK peptides in serum or plasma by conventional MALDI-TOF MS analysis is technically challenging. In our study, a nanopore-based fractionation and enrichment protocol was utilized to allow the simple workflow for circulating Hyp-BK/BK analysis. Hypoxia is linked to poor prognosis due to its role in promoting pancreatic cancer progression and metastasis. Here we show that P4HA1 expression was increased in pancreatic tumors versus adjacent tissue, associated with poor survival, and corresponded with tumor expression of the hypoxia inducible factor 1α (HIF-1α) and carbonic anhydrase 9 (CA9). Hypoxia-induced P4HA1 expression and BK conversion to Hyp-BK were found to be HIF-1α dependent, pre-treatment serum Hyp-BK/BK ratios corresponded with tissue HIF-1α and P4HA1 expression, and high Hyp-BK/BK levels corresponded with poor response to therapy. These results suggest that pre-treatment circulating Hyp-BK/BK ratios may have value as a non-invasive, surrogate indicator of tissue hypoxia and tumor responses to therapy.

Human survival is dependent upon the continuous delivery of O2 to each cell in the body in sufficient amounts to meet metabolic requirements, primarily for ATP generation by oxidative phosphorylation. Hypoxia-inducible factors (HIFs) regulate the transcription of thousands of genes to balance O2 supply and demand. The HIFs are negatively regulated by O2-dependent hydrox-ylation and ubiquitination by prolyl hydroxylase domain (PHD) proteins and the von Hippel–Lindau (VHL) protein. Germline mutations in the genes encoding VHL, HIF-2α, and PHD2 cause hereditary erythrocytosis, which is characterized by polycythemia and pulmonary hypertension and is caused by increased HIF activity. Evolutionary adaptation to life at high altitude is associated with unique genetic variants in the genes encoding HIF-2α and PHD2 that blunt the erythropoietic and pulmonary vascular responses to hypoxia.

Summary There has been being a growing research interest in the biological and medical significance of oxygen and associated oxygenic species in terms of homeostasis and pathologies. As dominant media to interact with oxygen molecules and the related oxygenic species, oxygen-functional materials (OFMs) have attracted broad attention for investigations, especially of biomedical applications. Here, we overview different types of typical OFMs, their material fundamentals, and biomedical functions in diverse oxygen-relevant physical-chemical processes, i.e., oxygen production, activation, and reduction, in a comprehensive manner. Furthermore, the therapeutic applications of OFMs through different material-oxygen interactions are extensively discussed. Finally, on the way to the clinical translations of these theranostic OFMs, prospects, challenges, and possible research progress in the future are outlined, aiming to deliver sophisticated ideas to the design, mechanistic exploration, and biomedical applications of OFMs.

At high altitude, hypobaric hypoxia is a significant stress for humans and other animals, challenging oxygen homeostasis and therefore tissue metabolism. Genetic signals of physiological adaptation have been identified in human populations and nonhuman species with long-term residence at high altitude. In Tibetans, some genetic signals are linked to altered metabolic function, for example, variants in EPAS1 are associated with increased glycolysis, whilst variants in PPARA are associated with a decreased capacity for fatty acid oxidation. A number of other genetic signals that may impact on metabolism have been identified in Tibetans and other populations, although the downstream consequences are not well defined. Use of high-throughput technologies to comprehensively profile metabolic phenotype could advance understanding of the evolutionary processes conferring hypoxia tolerance at high altitude.

Molecular oxygen (O2) sustains intracellular bioenergetics and is consumed by numerous biochemical reactions, making it essential for most species on Earth. Accordingly, decreased oxygen concentration (hypoxia) is a major stressor that generally subverts life of aerobic species and is a prominent feature of pathological states encountered in bacterial infection, inflammation, wounds, cardiovascular defects and cancer. Therefore, key adaptive mechanisms to cope with hypoxia have evolved in mammals. Systemically, these adaptations include increased ventilation, cardiac output, blood vessel growth and circulating red blood cell numbers. On a cellular level, ATP-consuming reactions are suppressed, and metabolism is altered until oxygen homeostasis is restored. A critical question is how mammalian cells sense oxygen levels to coordinate diverse biological outputs during hypoxia. The best-studied mechanism of response to hypoxia involves hypoxia inducible factors (HIFs), which are stabilized by low oxygen availability and control the expression of a multitude of genes, including those involved in cell survival, angiogenesis, glycolysis and invasion/metastasis. Importantly, changes in oxygen can also be sensed via other stress pathways as well as changes in metabolite levels and the generation of reactive oxygen species by mitochondria. Collectively, this leads to cellular adaptations of protein synthesis, energy metabolism, mitochondrial respiration, lipid and carbon metabolism as well as nutrient acquisition. These mechanisms are integral inputs into fine-tuning the responses to hypoxic stress.

Significance: The skin undergoes an inevitable degeneration as an individual ages. As intrinsic and extrinsic factors degrade the structural integrity of the skin, it experiences a critical loss of function and homeostatic stability. Thus, aged skin becomes increasingly susceptible to injury and displays a prolonged healing process. Recent Advances: Several studies have found significant differences during wound healing between younger and older individuals. The hypoxia-inducible factor 1-alpha (HIF-1α) signaling pathway has recently been identified as a major player in wound healing. Hypoxia-inducible factors (HIFs) are pleiotropic key regulators of oxygen homeostasis. HIF-1α is essential to neovascularization through its regulation of cytokines, such as SDF-1α (stromal cell-derived factor 1-alpha) and has been shown to upregulate the expression of genes important for a hypoxic response. Prolyl hydroxylase domain proteins (PHDs) and factor inhibiting HIF effectively block HIF-1α signaling in normoxia through hydroxylation, preventing the signaling cascade from activating, leading to impaired tissue survival. Critical Issues: Aged wounds are a major clinical burden, resisting modern treatment and costing millions in health care each year. At the molecular level, aging has been shown to interfere with PHD regulation, which in turn prevents HIF-1α from activating gene expression, ultimately leading to impaired healing. Other studies have identified loss of function in cells during aging, impeding processes such as angiogenesis. Future Directions: An improved understanding of the regulation of molecular mediators, such as HIF-1α and PHD, will allow for manipulation of the various factors underlying delayed wound healing in the aged. The findings highlighted in this may facilitate the development of potential therapeutic approaches involved in the alteration of cellular dynamics and aging.

During adaptation to a semi-aquatic mode of life, the muskrat (Ondatra zibethicus) developed numerous biochemical adaptations to maintain homeostasis. The aim of the study was to explore age-related and seasonal changes in muscle tissue antioxidant defenses and erythrocyte morphometric parameters in the muskrat. Animals were caught in autumn (juveniles and adults) and spring (adults) in the North-West of Russia (Republic of Karelia). Some physiological and biochemical parameters of animals caught in autumn showed an age-related variability: in adult animals (most adapted to diving), as compared to juveniles, catalase activity in skeletal muscles was lower, while the respiratory function of blood was higher (due to a lower total surface area of erythrocytes). Adult muskrats demonstrated seasonal changes in some parameters studied: in spring, activities of catalase in the heart and superoxide dismutase in skeletal muscles were higher, while levels of low-molecular-weight antioxidants ( α -tocopherol and glutathione) both in cardiac and skeletal muscles were lower, compared to animals caught in autumn. After a long winter (ice-fishing) season, the blood of animals caught in spring contained mainly mature erythrocyte forms (normocytes), with their average diameter and surface area being larger than in adult muskrats caught in autumn. Our findings, as well as data obtained on other species, support the involvement of the antioxidant system and erythrocytes in the mechanisms that maintain oxygen homeostasis in diving mammals.

Heat stress (HS) is devastating to poultry production sustainability due its detrimental effects on performance, welfare, meat quality, and profitability. One of the most known negative effects of HS is feed intake depression, which is more pronounced in modern high-performing broilers compared to their ancestor unselected birds, yet the underlying molecular mechanisms are not fully defined. The present study aimed, therefore, to determine the hypothalamic expression of a newly involved pathway, hypoxia/oxygen homeostasis, in heat-stressed broiler-based research lines and jungle fowl. Three populations of broilers (slow growing ACRB developed in 1956, moderate growing 95RB from broilers available in 1995, and modern fast growing MRB from 2015) and unselected Jungle fowl birds were exposed to cyclic heat stress (36°C, 9 h/day for 4 weeks) in a 2 × 4 factorial experimental design. Total RNAs and proteins were extracted from the hypothalamic tissues and the expression of target genes and proteins was determined by real-time quantitative PCR and Western blot, respectively. It has been previously shown that HS increased core body temperature and decreased feed intake in 95RB and MRB, but not in ACRB or JF. HS exposure did not affect the hypothalamic expression of HIF complex, however there was a line effect for HIF-1α (P = 0.02) with higher expression in JF under heat stress. HS significantly up regulated the hypothalamic expression of hemoglobin subunits (HBA1, HBBR, HBE, HBZ), and HJV in ACRB, HBA1 and HJV in 95RB and MRB, and HJV in JF, but it down regulated FPN1 in JF. Additionally, HS altered the hypothalamic expression of oxygen homeostasis- up and down-stream signaling cascades. Phospho-AMPKThr172 was activated by HS in JF hypothalamus, but it decreased in that of the broiler-based research lines. Under thermoneutral conditions, p-AMPKThr172 was higher in broiler-based research lines compared to JF. Ribosomal protein S6K1, however, was significantly upregulated in 95RB and MRB under both environmental conditions. HS significantly upregulated the hypothalamic expression of NF-κB2 in MRB, RelB, and TNFα in ACRB, abut it down regulated RelA in 95RB. The regulation of HSPs by HS seems to be family- and line-dependent. HS upregulated the hypothalamic expression of HSP60 in ACRB and 95RB, down regulated HSP90 in JF only, and decreased HSP70 in all studied lines. Taken together, this is the first report showing that HS modulated the hypothalamic expression of hypoxia- and oxygen homeostasis-associated genes as well as their up- and down-stream mediators in chickens, and suggests that hypoxia, thermotolerance, and feed intake are interconnected, which merit further in-depth investigations.

Hypoxia-inducible factors (HIFs) induce numerous genes regulating oxygen homeostasis. As oxygen sensors of the cells, the HIF prolyl 4-hydroxylases (HIF-P4Hs) regulate the stability of HIFs in an oxygen-dependent manner. During hair follicle (HF) morphogenesis and cycling, the location of dermal papilla (DP) alternates between the dermis and hypodermis and results in varying oxygen levels for the DP cells. These cells are known to express hypoxia-inducible genes, but the role of the hypoxia response pathway in HF development and homeostasis has not been studied. Using conditional gene targeting and analysis of hair morphogenesis, we show here that lack of Hif-p4h-2 in Forkhead box D1 (FoxD1)-lineage mesodermal cells interferes with the normal HF development in mice. FoxD1-lineage cells were found to be mainly mesenchymal cells located in the dermis of truncal skin, including those cells composing the DP of HFs. We found that upon Hif-p4h-2 inactivation, HF development was disturbed during the first catagen leading to formation of epithelial-lined HF cysts filled by unorganized keratins, which eventually manifested as truncal alopecia. Furthermore, the depletion of Hif-p4h-2 led to HIF stabilization and dysregulation of multiple genes involved in keratin formation, HF differentiation, and HIF, transforming growth factor β (TGF-β), and Notch signaling. We hypothesize that the failure of HF cycling is likely to be mechanistically caused by disruption of the interplay of the HIF, TGF-β, and Notch pathways. In summary, we show here for the first time that HIF-P4H-2 function in FoxD1-lineage cells is essential for the normal development and homeostasis of HFs.

Endothelial PAS domain-containing protein 1 (EPAS1), also HIF2α, is an alpha subunit of hypoxia-inducible transcription factor (HIF), which mediates cellular and systemic response to hypoxia. EPAS1 has an important role in the transcription of many hypoxia-responsive genes, however, it has been less researched than HIF1α. The aim of this study was to integrate an increasing number of data on EPAS1 into a map of diverse OMICs elements. Publications, databases, and bioinformatics tools were examined, including Ensembl, MethPrimer, STRING, miRTarBase, COSMIC, and LOVD. The EPAS1 expression, stability, and activity are tightly regulated on several OMICs levels to maintain complex oxygen homeostasis. In the integrative EPAS1 map we included: 31 promoter-binding proteins, 13 interacting miRNAs and one lncRNA, and 16 post-translational modifications regulating EPAS1 protein abundance. EPAS1 has been associated with various cancer types and other diseases. The development of neuroendocrine tumors and erythrocytosis was shown to be associated with 11 somatic and 20 germline variants. The integrative map also includes 12 EPAS1 target genes and 27 interacting proteins. The study introduced the first integrative map of diverse genomics, transcriptomics, proteomics, regulomics, and interactomics data associated with EPAS1, to enable a better understanding of EPAS1 activity and regulation and support future research.

Living at high altitudes and living with prostatic illness are two different conditions closely related to a hypoxic environment. People at high altitudes exposed to acute, chronic or intermittent hypobaric hypoxia turn on several mechanisms at the system, cellular, and molecular level to cope with oxygen atmosphere scarcity maintaining the oxygen homeostasis. This exposure affects the whole organism and function of many systems, such as cardiovascular, respiratory, and reproductive. On the other hand, malignant prostate is related to the scarcity of oxygen in the tissue microenvironment due to its low availability and high consumption due to the swift cell proliferation rates. Based on the literature, this similarity in the oxygen scarcity suggests that hypobaric hypoxia, and other common factors between these two conditions, could be involved in the aggravation of the pathological prostatic status. However, there is still a lack of evidence in the association of this disease in males at high altitudes. This review aims to examine the possible mechanisms that hypobaric hypoxia might negatively add to the pathological prostate function in males who live and work at high altitudes. More profound investigations of hypobaric hypoxia’s direct action on the prostate could help understand this exposure’s effect and prevent worse prostate illness impact in males at high altitudes.

Variations in dissolved oxygen levels are common in the Amazonian aquatic environments and the aquatic organisms that inhabit these environments developed a variety of adaptive responses to deal with such conditions. Some Amazonian fish species are tolerant to low oxygen levels and the cichlid Astronotus ocellatus is one of the most hypoxia-tolerant species. Herein, we aimed to unveil the biochemical and molecular responses that A. ocellatus presents when submitted to hypoxia. Hypoxia indicators were measured, such as plasma glucose, plasma lactate, hepatic glycogen and relative transcript levels of prolyl hydroxylase 2 (phd2) and hypoxia-inducible factor-1α (hif-1α) in juveniles of approximately 50 g exposed to 1, 3, and 5 hours of hypoxia (0.7 mg O2.L-1), followed by 3 hours of recovery in normoxia (6 mg O2.L-1). Fish exposed to hypoxia reduced liver glycogen levels within 3 hours of hypoxia, when comparing with 1 hour, and increased plasma glucose and lactate. Under the same condition, phd2 transcripts levels increased in gills, but decreased in liver. In contrast, hypoxia did not affect relative gene expression of hif-1α in both tissues. Based on the transcription pattern of phd2, these results showed that liver and gills of A. ocellatus have different molecular strategies to cope with environmental hypoxia.