Moderate Hypoxia Research Articles

Feed supplementation with winery by-products improves the physiological status of juvenile Liza aurata during a short-term feeding trial and hypoxic challenge

The search of bioactive compounds obtained from natural sources with beneficial effects in growth and health is an increasing trend in aquaculture. Wine by-products are an excellent source of such compounds, mostly phenolics, with demonstrated antioxidant and immunostimulant activities in vertebrates. The present study evaluated the effects of dietary inclusion (100 g/kg) of two wine by-products (grape pomace and lees) on growth, immune status and metabolism of juvenile golden gray mullet (Liza aurata), as well as the potential protective effect of compounds present in the two by products against induced stress produced by moderate hypoxia. Results evidenced a significant positive effect of grape pomace on feed efficiency, as well as in different indicators of metabolic and immunological status of the fish. Also, a significant negative effect of wine lees on the functional diversity of intestinal microbiota was evidenced. Fish fed on diets containing any of the two by-products evidenced significantly lower levels of cortisol when challenged by hypoxia, this pointing to a protective effect mediated by their contents in phenolic compounds and suggesting an interesting and practical application for these agricultural by-products.

Gamified assessment of cognitive performance during moderate hypoxia.

There is a need for rapid and objective assessment tools to identify people at risk of impaired cognitive function during hypoxia. To test the hypotheses that performance on gamified cognitive tests examining the cognitive domains of executive function (Gridshot), working memory (Capacity) and spatial tracking (Multitracker) will be reduced during normobaric exposure to moderate normobaric hypoxia. Following three consecutive days of practice, twenty-one healthy adults (27 ± 5 y, 9 females) completed five 1-min rounds of the tablet-based games Gridshot, Capacity, and Multitracker (Statespace Labs, Inc.) at Baseline and 60 and 90 min after exposure to 14.0 ± 0.2% (hypoxia) and 20.6 ± 0.3% (normoxia) oxygen. Both conditions were completed on the same day and were administered in a single-blind, block randomized manner. Arterial oxyhemoglobin saturation was estimated via forehead pulse oximetry (SpO2). Data were analyzed using ANCOVA with a covariate of Baseline. Compared to normoxia (98 ± 1%), SpO2 was lower (p < 0.001) at 60 (91 ± 3%) and 90 (91 ± 2%) min of hypoxia. No condition x time interaction effects were identified for any gamified cognitive tests (p ≥ 0.32). A main effect of condition was identified for Capacity (p = 0.05) and Multitracker (p = 0.04), but not Gridshot (p = 0.33). Post hoc analyses of the composite scores for both Capacity (p = 0.11) and Multitracker (p = 0.73) demonstrated no difference between conditions. Performance on gamified cognitive tests was not consistently affected by acute normobaric moderate hypoxic exposure.

Moderate hypoxia induces metabolic divergence in circulating monocytes and tissue resident macrophages from Berkeley sickle cell anemia mice.

Human and murine sickle cell disease (SCD) associated pulmonary hypertension (PH) is defined by hemolysis, nitric oxide depletion, inflammation, and thrombosis. Further, hemoglobin (Hb), heme, and iron accumulation are consistently observed in pulmonary adventitial macrophages at autopsy and in hypoxia driven rodent models of SCD, which show distribution of ferric and ferrous Hb as well as HO-1 and ferritin heavy chain. The anatomic localization of these macrophages is consistent with areas of significant vascular remodeling. However, their contributions toward progressive disease may include unique, but also common mechanisms, that overlap with idiopathic and other forms of pulmonary hypertension. These processes likely extend to the vasculature of other organs that are consistently impaired in advanced SCD. To date, limited information is available on the metabolism of macrophages or monocytes isolated from lung, spleen, and peripheral blood in humans or murine models of SCD. Here we hypothesize that metabolism of macrophages and monocytes isolated from this triad of tissue differs between Berkley SCD mice exposed for ten weeks to moderate hypobaric hypoxia (simulated 8,000 ft, 15.4% O2) or normoxia (Denver altitude, 5000 ft) with normoxia exposed wild type mice evaluated as controls. This study represents an initial set of data that describes the metabolism in monocytes and macrophages isolated from moderately hypoxic SCD mice peripheral lung, spleen, and blood mononuclear cells.

Ductus venosus opens in high-risk pregnancies without signs of increased central venous pressure.

It has been belived that changes in diastolic blood velocities in the fetal ductus venosus were due to increased central venous pressure secondary to increased fetal heart strain during hypoxia or heart failure. There have been recent reports of changes in ductus venosus blood velocity without signs of increased fetal heart strain. The aim of this evaluation was to compare blood velocity in the right hepatic vein as a marker of increased central venous pressure in relationship to changes in ductus venosus blood velocity. Fifty pregnancies suspected of fetal growth resitriction were evaluated by Doppler ultrasound. Blood velocity was recorded in the right hepatic vein, ducus venosus and in the umbilical vein. Placental blood flow was also recorded in the uterine and umbilical arteries as well as the fetal middle cerebral artery. Increased umbilical artery pulsatility index was recorded in 19 fetuses and 20 has signes of brain sparing according to recordings in the middle cerebral artery. Abnormal blood velocity in the ductus venosus was recorded in 5 fetuses, none of these fetuses had an abnormal pulsatility in the right hepatic vein. Opening of the ductus venosus is not only related to fetal cardiac strain. This might indicate that the ductus venosus does not primarily open due to increased central venous pressure in moderate fetal hypoxia. Increased fetal cardiac strain might be a late event in the process of chronic fetal hypoxia.

The Impact of Acute Mild Normobaric Hypoxia and a Single Bout of Exercise to Volitional Exhaustion on Cognitive Performance in Endurance and Strength-Trained Athletes: The role of BDNF, EP-1, Catecholamines and Lactate.

The aim of the study was to examine whether a single bout of exercise to volitional exhaustion, performed under moderate normobaric hypoxia (H), would affect psychomotor performance (PP) in differently trained athletes. For this purpose, ten strength-trained (S) athletes, ten endurance-trained (E) athletes and ten healthy men leading a sedentary lifestyle as a control (C) group performed voluntarily two graded exercise tests until volitional exhaustion (EVE) under normoxia (N) and H (FiO2 = 14.7%). We measured the peripheral level of the brain derived neurotrophic factor (BDNF), choice reaction time (CRT) and the number of correct reactions (NCR) as indices of PP. Psychomotor tests were performed at rest, immediately after the EVE and 3 minutes after the EVE. Venous blood samples were collected at rest, immediately after cessation of each EVE, and 1 h after each EVE. The results showed that the EVE significantly (p < 0.05) impaired CRT under N and H, and NCR under H only in the E group. The higher WRmax in the E compared to the S and C groups was associated with a significant (p < 0.005) increase in adrenaline (A) and noradrenaline (NA). There were no significant differences between conditions (N vs. H) in the BDNF at rest and after exercise. The EVE impaired cognitive function only in the E group; higher involvement of the sympathetic nervous system, A and NA may also play a role in this phenomenon. Therefore, it can be concluded that exposure to H did not have a negative impact on CRT or NCR. Moreover, BDNF did not improve cognitive function.

Mechanical Asymmetries during Treadmill Running: Effects of Running Velocity and Hypoxic Exposure

Studies evaluating mechanical asymmetry across a range of running velocities during treadmill runs have yielded inconsistent findings, while the impact of additional hypoxic exposure has never been investigated. The aim of this study was to characterize the effects of manipulating running velocity and hypoxic exposure on gait asymmetry during treadmill running. Eleven trained individuals performed seven runs at different velocities (8, 10, 12, 14, 16, 18, and 20 km·h−1) in a randomized order, each lasting 45 s. The running took place on an instrumented treadmill for normoxia (FiO2 = 20.9%), moderate hypoxia (FiO2 = 16.1%), high hypoxia (FiO2 = 14.1%), and severe hypoxia (FiO2 = 13.0%). Vertical and antero-posterior ground reaction force recordings over 20 consecutive steps (i.e., after running ∼25 s) allowed the measurement of running mechanics. Lower-limb asymmetry was assessed from the ‘symmetry angle’ (SA) score. Two-way repeated-measures ANOVA (seven velocities × four conditions) was used. There was no significant difference in SA scores for any of the biomechanical variables for velocity (except contact time and braking phase duration; p = 0.003 and p = 0.002, respectively), condition, or interaction. Mean SA scores varied between ∼1% and 2% for contact time (1.5 ± 0.8%), flight time (1.6 ± 0.6%), step length (0.8 ± 0.2%), peak vertical force (1.2 ± 0.5%), and mean vertical loading rate (2.1 ± 1.0%). Mean SA scores ranged from ∼2% to 5% for duration of braking (1.6 ± 0.7%) and push-off phases (1.9 ± 0.6%), as well as peak braking (5.0 ± 1.9%) and push-off forces (4.8 ± 1.7%). In conclusion, the trained runners exhibited relatively even strides, with mechanical asymmetries remaining low-to-moderate across a range of submaximal, constant running velocities (ranging from 8 to 20 km·h−1) and varying levels of hypoxia severity (between normoxia and severe hypoxia).

Adverse Effects of Topiramate in Neonate with Moderate to Severe Perinatal Asphyxia: A Randomized Controlled Trial

Introduction: A harmful pregnancy condition that harms both the mother and the fetus is perinatal asphyxia. It frequently happens as a result of challenges during labour, including protracted or challenging delivery, concerns with the umbilical cord, placental abnormalities, or maternal health conditions. Topiramate, an anticonvulsant, works through a variety of different methods. Topiramate looks to be effective as a neuroprotective agent as well as an anti-seizure medication in animal models of newborn brain injury. Angiogenesis, neurogenesis, and neuronal anti-apoptotic pathways are all stimulated and regulated by topiramate. In light of this, this observational study was conducted to ascertain Topiramate's negative consequences in kids with mild to moderate neonatal hypoxia. Methods: This observational case-control study was carried out in the Neonatal ward and ICU of Dhaka Shishu Hospital from April 2015 to March 2016. A total of 64 neonates were enrolled in this study and were assigned Group A -the interventional group (n=32) received topiramate and standard treatment protocol, and Group B or the control group (n=32) received only standard treatment protocol. The data were analyzed according to standard procedure. Results: Among the study neonates, based on sex in case and control groups, respectively, seventeen (17,53%) and twenty-one (21,66%) neonates were male, and fifteen (15,47%) and eleven (11,44%) neonates were female. Statistically, the sex distribution between groups was not significant (p=0.44). USG finding of the neonates after treatment was normal in 12 (48%) and 13(41%), and abnormal in 20(32%) and 19 (59%) neonates in the control and case groups, respectively. Out of 27 neonates in the control group, 11 (41%) were neurologically normal, and 16 (59%) had abnormal neurological findings. Out of 29 neonates in the case group, 24 (73%) were neurologically normal, and 5(17%) showed abnormal neurological findings. Statistically, significant variation ..

DIPG-31. HIF-1A AND HIF-2A COMBINATORIAL TARGETING OR HOW TO REVERSE THEIR BALANCED ONCOGENIC IMPACT

Abstract HIF-1a and HIF-2a are master regulators operating during tumor hypoxia. Few data are available on their role in pediatric high-grade gliomas (pHGGs), in which recent insights on metabolism and immunotolerance induction through hypoxia-driven mechanisms might opening the path to study further this process and their molecular actors. Our study investigated and confirmed the balanced dependency of both transcription factors in pHGGs at protein levels, but not in their transcriptional reprogramming. We also examined how HIF-1a and HIF-2a are operating during acute and chronic hypoxia in a spatiotemporal cell setting. HIF-1a was clearly correlated within pHGGs samples and models to acute and moderate hypoxia, whereas HIF-2a was associated to H3.3K27M mutant DIPG and chronic hypoxia. The impact of targeting both transcription factors in pHGG-derived models was on cell proliferative and invasive mechanisms, especially when studying this drug testing in engineered neural tissues. We might position those new targets as an innovative way to counterpart their hyperactivation in tumor core hypoxia and to propose them as an innovative approach interfering with cell-to-cell adhesion and synaptic interactions with normal brain cells.

Long-Term Effect of Moderate Hypoxia and Chronic Administration of Fluoxetine during the Neonatal Period on Cognitive and Stress-Hormonal Functions in Adult Male Rats.

We studied the effect of moderate neonatal normobaric hypoxia on the indicators of spatial learning, memory, and reactivity of the hypothalamic-pituitary-adrenocortical system in adult male Wistar rats. The pharmacological effect of chronic injections of the serotonin reuptake inhibitor fluoxetine during the neonatal period on the studied behavioral and the physiological indices was evaluated. Hypoxia impaired spatial training, increased the short-term memory performance, but did not change long-term memory and stress indicator in response to its testing. The use of fluoxetine normalized learning, but did not change memory indicators and the stress-induced level of corticosterone in blood plasma in the hypoxic rats and control animals. New results indicate a protective effect of fluoxetine in the neonatal period under conditions of moderate normobaric hypoxia.

Altitude-induced effects on neuromuscular, metabolic and perceptual responses before, during and after a high-intensity resistance training session.

We tested if an acute ascending to 2320m above sea level (asl) affects corticospinal excitability (CSE) and intracortical inhibition (SICI) measured with transcranial magnetic stimulation (TMS) at rest, before, during and after a traditional hypertrophy-oriented resistance training (RT) session. We also explored whether blood lactate concentration (BLa), ratings of perceived exertion (RPE), perceived muscular pain and total training volume differed when the RT session was performed at hypoxia (H) or normoxia (N). Twelve resistance-trained men performed eight sets of 10 repetitions at 70% of one repetition maximum of a bar biceps curl at N (SpO2 = 98.0 ± 0.9%) and H (at 2320 asl, SpO2 = 94.0 ± 1.9%) in random order. Before each session, a subjective well-being questionnaire, the resting motor threshold (rMT) and a single pulse recruitment curve were measured. Before, during and after the RT session, BLa, RPE, muscle pain, CSE and SICI were measured. Before the RT session only the rMT differed between H (- 5.3%) and N (ES = 0.38). RPE, muscle pain and BLa increased through the RT session and were greater at H than N (12%, 54% and 15%, respectively) despite a similar training volume (1618 ± 468kg vs. 1638 ± 509kg). CSE was reduced during the RT session (~ 27%) but recovered ten minutes after, regardless of the environmental condition. SICI did not change after any RT session. The data suggest that acute exposure to moderate hypoxia slightly increased the excitability of the most excitable structures of the corticospinal tract but did not influence intracortical or corticospinal responses to a single RT session.

Increased spinal adenosine impairs phrenic long-term facilitation in aging rats.

Moderate acute intermittent hypoxia (mAIH) elicits a form of spinal, respiratory motor plasticity known as phrenic long-term facilitation (pLTF). In middle-aged male and geriatric female rats, mAIH-induced pLTF is attenuated through unknown mechanisms. In young adults, mAIH activates competing intracellular signaling cascades, initiated by serotonin 2 and adenosine 2A (A2A) receptors, respectively. Spinal A2A receptor inhibition enhances mAIH-induced pLTF, meaning, serotonin dominates, and adenosine constrains mAIH-induced plasticity in the daily rest phase. Thus, we hypothesized elevated basal adenosine levels in the ventral cervical spinal cord of aged rats shifts this balance, undermining mAIH-induced pLTF. A selective A2A receptor antagonist (MSX-3) or vehicle was delivered intrathecally at C4 in anesthetized young (3-6 mo) and aged (20-22 mo) Sprague-Dawley rats before mAIH (3,5-min episodes; arterial Po2 = 45-55 mmHg). In young males, spinal A2A receptor inhibition enhanced pLTF (119 ± 5%) vs. vehicle (55 ± 9%), consistent with prior reports. In old males, pLTF was reduced to 25 ± 11%, but A2A receptor inhibition increased pLTF to levels greater than in young males (186 ± 19%). Basal adenosine levels in ventral C3-C5 homogenates are elevated two- to threefold in old vs. young males. These findings advance our understanding of age as a biological variable in phrenic motor plasticity and will help guide translation of mAIH as a therapeutic modality to restore respiratory and nonrespiratory movements in older populations afflicted with clinical disorders that compromise movement.NEW & NOTEWORTHY Advanced age undermines respiratory motor plasticity, specifically phrenic long-term facilitation (pLTF) following moderate acute intermittent hypoxia (mAIH). We report that spinal adenosine increases in aged male rats, undermining mAIH-induced pLTF via adenosine 2A (A2A) receptor activation, an effect reversed by selective spinal adenosine 2A receptor inhibition. These findings advance our understanding of mechanisms that impair neuroplasticity, and the ability to compensate for the onset of lung or neural injury with age, and may guide efforts to harness mAIH as a treatment for clinical disorders that compromise breathing and other movements.

Implementing an Awake Proning Protocol for COVID-19 Patients with Moderate Hypoxia in the Emergency Department

Background: New York City emergency departments (EDs) faced a sudden influx of critically ill patients during the initial wave of COVID-19, leading to a shortage of resources to care for patients experiencing hypoxia. This study describes the development and implementation of an awake proning protocol in which conscious patients with suspected or confirmed COVID-19 moderate hypoxia were assisted to a prone position to improve oxygenation. Methods: This one-week project took place in a single New York City ED. An interdisciplinary team of nursing and medical leadership reviewed the literature on the safety and effectiveness of awake proning and developed a treatment protocol and seven-member interdisciplinary proning team. Oxygenation (SpO2), heart rate (HR), and respiration rate (RR) were recorded at baseline and 10-minutes post-proning. Results: Thirty patients were included. Mean age was 60.8 and a majority were male (n = 25; 83%). Significant differences between pre- and post-proning measures were found for SpO2 (p &lt; 0.000), HR (p &lt; 0.028), and RR (p &lt; 0.025) after 10 minutes of awake proning. Conclusion: Awake proning is a promising technique for improving outcomes in patients with respiratory distress and can be implemented effectively in an ED setting.

EFFECTS OF NEONATAL HYPOXIA AND ANTIDEPRESSANT FLUOXETINE ON COGNITIVE AND STRESS-HORMONAL FUNCTIONS IN ADULT RATS

The ability to spatial learning and the functionality of the spatial memory, and also the stressful reactivity of the hypothalamus-pituitary-adrenocortical axis (the HPA axis) were investigated in adult male and female rats, subjected to moderate acute hypoxia on the 2nd day of life, and then to chronic administration of the serotonin reuptake inhibitor fluoxetine. When testing the ability to spatial training in adult rats subjected to neonatal hypoxia, an increase in the latent period of reaching the platform in the Morris water maze in the first try in the first of five days of training was found. The results of memory analysis in the novel object recognition test and in the Morris water maze testify that hypoxia did not cause memory deficiency in adult animals. Moreover, hypoxia improved the memory indices on the first day in males and on the fourth day in females after removing the platform from the pool compared to the corresponding control values. The content of corticosterone in blood plasma of males in response to memory testing did not differ between control and experimental groups and was characterized by higher rates than in females of corresponding groups. Hypoxia increased the HPA axis reactivity in females, which was combined with a longer memory storage. Fluoxetine normalized the indicator of spatial learning, did not cause changes in control animals and did not change the identified improvement of memory in hypoxic rats without administration of this drug. The new data obtained expand the idea of the long-term effect of neonatal normobaric moderate hypoxia on the spatial memory and the HPA axis reactivity depending on sex and emphasize the absence of the harmful effect of fluoxetine on spatial memory in both control rats and in rats with the effects of hypoxia.

Spinal adenosine 2A receptor inhibition restores phrenic long-term facilitation during mild systemic inflammation

Inflammation undermines several forms of neuroplasticity, including phrenic long-term facilitation (pLTF), a form of respiratory motor plasticity elicited by moderate acute intermittent hypoxia (mAIH; 3, 5-min episodes, 5 min intervals; arterial PO2 ~ 40–50 mmHg). Mild inflammation elicited by a low dose of the TLR-4 receptor agonist lipopolysaccharide (LPS; 100 mg/kg, i.p.) abolishes mAIH-induced pLTF by a mechanism that requires spinal p38 MAP kinase and protein phosphatase activity. Neuroinflammation activates microglia and other cells in the CNS, elevating extracellular levels of adenosine—a purine nucleoside known to suppress mAIH-induced pLTF. We hypothesized basal adenosine levels in ventral spinal C 3 -C 5 segments are increased in adult male Sprague-Dawley rats 24 hours post-LPS administration, thereby undermining mAIH-induced pLTF via adenosine 2A receptor (A 2A ) activation. Thus, we predicted that cervical intrathecal administration of the A 2A receptor inhibitor MSX-3 (10 μM, 12 μL) would rescue mAIH-induced pLTF in rats pre-treated with LPS. As predicted, LPS significantly increased basal ventral C 3 -C 5 adenosine levels (p=0.010 vs controls; n=7 per group). In control rats (saline injection, i.p.), MSX-3 enhanced pLTF versus vehicle controls (LPS: 110 ± 16% baseline; controls: 53 ± 6%; p=0.002; each n=6). As expected, mAIH-induced pLTF was abolished in LPS-treated rats (4 ± 6% baseline; n=6). MSX-3 restored mAIH-induced pLTF to levels equivalent to MSX-3 treated control rats (120 ± 14%; p&lt;0.001; n=6; versus LPS controls with MSX-3: p=0.539). Thus, mild LPS-induced inflammation abolishes mAIH-induced pLTF by a mechanism associated with increased spinal adenosine levels and A 2A receptor activation. As we move mAIH forward as a therapeutic modality to improve breathing and non-respiratory movements in people with spinal cord injury or ALS, pretreatment with A 2A receptor inhibitors may offset the undermining effects of systemic inflammation associated with these severe neuromuscular disorders. NIH HL147554, HL148030, T32HL134621 (ABM) and the UF McKnight Brain Institute This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Physiological Responses of Anemic Women to Exercise under Hypoxic Conditions

When combining two conditions of reduced oxygen availability, anemia and hypoxia, human physiological responses are highly challenged to maintain arterial oxygen delivery, especially during whole-body exercise. The aim of this study was to compare the cardiorespiratory responses of mildly anemic women with those of healthy controls, while cycling in normobaric hypoxia. Two groups of young females were matched for age, weight, height, and involvement in physical activity, one with normal hemoglobin, hematocrit, and ferritin levels and another suffering from mild iron deficiency anemia (10 &lt; (Hb) &lt; 12 g/dL, 34 &lt; Hct &lt; 37%, ferritin &lt; 15 μg/L). They cycled to exhaustion under normoxia and hypoxia (FIO2 0.21 and 0.14), and their physiological responses were compared at 40, 80, and 100% VO2max of the specific condition. The two groups differed (p &lt; 0.05) mainly at the higher exercise intensities; the anemic participants exhibited similar heart rate but lower oxygen pulse than their control counterparts, as well as a larger drop in maximal oxygen uptake. However, they sustained maximal effort by employing the anaerobic metabolism to a larger extent, which stimulated a greater ventilatory response. It appears that iron deficiency anemia of mild severity, which is commonly observed in young athletic females, impacts physiological responses during whole-body exercise in the presence of moderate hypoxia.

Expression of the hypoxia-inducible factor as a predictor of the resistance of the organism of laboratory animals to hypoxia

BACKGROUND:One of the key transcriptional regulators that determine the bodys resistance to hypoxia is the hypoxia-inducible factorHIF-1, the study of the role of which in the bodys resistance to extreme influences can justify new directions in medical technologies for its increase.&#x0D; AIM:To evaluate the quantitative contribution of the level of expression of the hypoxia-inducible factorHIF-1in various tissues of laboratory animals to the increase in the resistance of animals to the effects of hypoxic hypoxia.&#x0D; MATERIALS AND METHODS:The study was carried out on outbred white laboratory rats obtained from the Rappolovo nursery weighing 180220 g. To conduct the study, animals were previously tested for an individual level of resistance to hypoxia, which made it possible to form experimental groups from highly resistant and low resistant animals. Biological material was taken from all animals (whole blood, plasma, tissues of the heart, liver, kidneys, brain), in which the expression of theHIF-1andTSPOgenes (housekeeping gene) was determined by the Real-Time-PCR method. Total RNA was isolated from the test material by affinity sorption,synthesis of the first strand of cDNA, amplification, followed by determination of the expression level of theHIF-1gene in rats was carried out according to the instructions and the manufacturers protocol by PCR with detection of the accumulation of reaction products in real time (Real-Time PCR) using a CFX-96 detecting amplifier (Bio-Rad, USA) and specific primers and probes for theHIF-1gene in rats (DNK-Sintez, Russia). Statistical processing of the obtained data was carried out using the ANOVA analysis of variance.&#x0D; RESULTS:It has been established that the level of resistance of animals to hypoxia is largely determined by their genetic characteristics. Even under normoxic conditions, the expression of theTSPOhousekeeping gene in animals with a high level of resistance to hypoxia differed with a high degree of reliability from low-resistance animals (in the kidneys, liver, and brain, on average, by 4060%; in the heart, by 25%). The values of the expression of this gene, determined in whole blood or plasma, make it possible to differentiate groups of animals according to the level of resistance to hypoxia. A similar ratio between animals with high and low resistance is also observed in tissues obtained immediately after hypoxic exposure. An analysis of the reaction of the genomic regulation system to extreme exposure showed that it increased the expression of the TSPO gene by 1.62 times equally in all tissues, regardless of the level of animal resistance. For theHIF-1gene, similar patterns were found, but the severity of their manifestations is more and significant.&#x0D; CONCLUSIONS:The main organ that provides a high level of resistance to hypoxia associated with the basic (under normoxic conditions) expression ofHIF-1is the brain. The expression of the hypoxia-inducible factor in it is more than 300 times higher than the expression of the housekeeping genes. The second most important organ is the liver, in whichHIF-1expression activity is more than 15 times higher than the expression of housekeeping genes. Under conditions of moderate hypoxia, a compensatory-adaptive reaction is noted, associated with the activation of hypoxic defense mechanisms in blood and liver cells, and in low-resistant animals, also in the brain tissue. In the myocardium, such a compensatory-adaptive reaction is activated only in the group of highly resistant animals. A high level of basal expression of theHIF-1transcription factor under daily (normoxic) conditions may be a predictor of a high level of resistance to hypoxia in a given animal.

Impact of hypoxia conditions on the Mnemiopsis leidyi A. Agassiz, 1865 bioluminescence.

The findings of the study on the impact of hypoxia on the glow of the Black Sea ctenophore Mnemiopsis leidyi A. Agassiz, 1865 of three size groups (20-30, 30-45, and 45-60 mm) were obtained under experimental conditions. Peculiarities of ctenophore bioluminescence were studied during mechanical and chemical stimulation under the conditions of normoxia (at an oxygen concentration of 5.6-6.7 mg O2 ·L-1 ), moderate hypoxia (2.5-2.8 mg O2 ·L-1 ), and acute hypoxia (1.2-1.5 mg O2 ·L-1 ). An increase in the amplitude and energy of luminescence of the ctenophores mechanically and chemically stimulated was observed at an oxygen concentration of 1.2-1.5 mg O2 ·L-1 (acute hypoxia) in two size groups in the lobate form (30-45 and 45-60 mm). The inhibition of amplitude, energy, and duration of the signal was registered in M. leidyi ctenophores at the transitional stage from larva to the lobate form under conditions of acute hypoxia. It was noted that in normoxia, the values of the amplitude and energy of the bioluminescent signal of M. leidyi increase along with a size growth of an individual. This phenomenon was observed both during mechanical and chemical stimulations. Under conditions of acute hypoxia, this trend was mainly preserved. The universality of the relation between the bioluminescence of the organisms and their bioenergetics is obvious. The bioluminescent system of ctenophores has the role of an antioxidant system and is engaged in the neutralization of reactive oxygen species, that is the process during which photons are emitted. The response of the bioluminescent system to a decrease in О2 concentration can be associated with an increase in the production of ROS that provides high values of the ctenophore luminescence under hypoxic conditions.

Combined effects of exercise and different levels of acute hypoxic severity: A randomized crossover study on glucose regulation in adults with overweight.

Purpose: The aim of this study was to investigate the influence of manipulating hypoxic severity with low-intensity exercise on glucose regulation in healthy overweight adults. Methods: In a randomized crossover design, 14 males with overweight (age: 27 ± 5years; body mass index (BMI) 27.1 ± 1.8kg⋅m2) completed three exercise trials involving 60min aerobic exercise cycling at 90% lactate threshold in normoxia (NM, FiO2 = 20.9%), moderate hypoxia (MH, FiO2 = 16.5%) and high hypoxia (HH, FiO2 = 14.8%). A post-exercise oral glucose tolerance test (OGTT) was performed. Venous blood samples were analyzed for incremental area under the curve (iAUC), plasma glucose and insulin, as well as exerkine concentrations (plasma apelin and fibroblast growth factor 21 [FGF-21]) pre- and post-exercise. A 24-h continuous glucose monitoring (CGM) was used to determine interstitial glucose concentrations. Heart rate, oxygen saturation (SpO2) and perceptual measures were recorded during exercise. Results: Post-exercise OGTT iAUC for plasma glucose and insulin concentrations were lower in MH vs. control (p = 0.02). Post-exercise interstitial glucose iAUC, plasma apelin and FGF-21 were not different between conditions. Heart rate was higher in HH vs. NM and MH, and MH vs. NM (p < 0.001), while SpO2 was lower in HH vs. NM and MH, and MH vs. NM (p < 0.001). Overall perceived discomfort and leg discomfort were higher in HH vs. NM and MH (p < 0.05), while perceived breathing difficulty was higher in HH vs. NM only (p = 0.003). Conclusion: Compared to higher hypoxic conditions, performing acute aerobic-based exercise under moderate hypoxia provided a more effective stimulus for improving post-exercise glucose regulation while concomitantly preventing excessive physiological and perceptual stress in healthy overweight adults.

Abstract 1263: Hypoxia induces down-regulation of stimulator of interferon genes (STING) that is synergized with oncometabolites

Abstract The cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway, a component of the innate immune system, functions to detect the presence of cytosolic DNA, and STING signaling is necessary for the anti-cancer immune response. However, STING expression is suppressed or lost in the majority of cancers, which correlates with poor survival in cancer patients. Hypoxia is a key feature of solid tumors that adversely affects prognosis by altering gene expression, creating an immunosuppressive tumor microenvironment, promoting genome instability, and hampering therapy responses. In this study, we found that that prolonged moderate hypoxia induces downregulation of STING expression in multiple cancer cell lines, causing decreased STING pathway activation after treatment with a STING agonist, or with DNA damaging chemotherapy. Mechanically, we found that hypoxia suppressed histone 3 lysine 4 (H3K4) methylation at the STING promoter based on chromatin immunoprecipitation (ChIP) assays in H1975 cells, a non-small cell lung cancer cell line, and knockdown of the H3K4 demethylases, KDM5A or KDM1A, prior to hypoxic exposure prevented hypoxia-induced down-regulation of STING expression. Moreover, decreased STING expression in hypoxic cells was reversed by treatment with the DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine. Next, we found that prolonged hypoxia increased both D-2-hydroxyglutarate (D-2-HG) and L-2-HG levels in H1975 cells, and that 2-HG treatment, by itself, decreased STING expression under normoxic conditions in H1975 cells. These findings are consistent with analysis of TCGA data showing that STING expression at the mRNA level is reduced in malignancies with mutations in isocitrate dehydrogenase 1 (IDH1) which causes elevated D-2-HG. Furthermore, we found that hypoxia increased Branched Chain Amino Acid Transaminase 1 (BCAT1) expression, and overexpression of BCAT1 accelerated STING downregulation in hypoxic condition. Functionally, expression of interferon (IFN)-stimulated genes (ISGs), CCL5 and interferon-β, was low in hypoxic H1975 cells compared to normoxic cells after treatment with poly(dA:dT), a small molecule STING agonist, and doxorubicin. Immunogenic cell death (ICD) was also reduced in hypoxic H1975 cells. In summary, the results suggest that hypoxia suppresses STING expression through epigenetic regulation, leading to STING silencing, and that this process synergizes with oncometabolites. The decreased STING caused by hypoxia further causes reduction of innate immune responses in cancer cells. Our study provides new understanding of the underlying mechanisms for STING silencing, which will help not only to study cancer immunity but also to develop novel therapeutic strategies. Citation Format: Yuhong Lu, Annali Yurkevicz, Yanfeng Liu, Jonathan Dow, Peter M. Glazer. Hypoxia induces down-regulation of stimulator of interferon genes (STING) that is synergized with oncometabolites [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1263.

Physiological responses to hypoxia are constrained by environmental temperature in heterothermic tenrecs.

Malagasy tenrecs are placental hibernating mammals that seal the entrances to their burrows and hibernate either singly or in groups for 8-9 months, which is likely to create a hypoxic and hypercapnic burrow environment. Therefore, we hypothesized that tenrecs are tolerant to environmental hypoxia and hypercapnia. Many hypoxia- and hypercapnia-tolerant fossorial mammals respond to hypoxia by decreasing metabolic rate and thermogenesis, and have blunted ventilatory responses to both environmental hypoxia and hypercapnia. However, tenrecs exhibit extreme metabolic and thermoregulatory plasticity, which exceeds that of most heterothermic mammals and approaches that of ectothermic reptiles. Thus, we predicted that tenrecs would have abnormal physiological responses to hypoxia and hypercapnia relative to other fossorial mammals. To test this, we exposed common tenrecs (Tenrec ecaudatus) to moderate and severe hypoxia (9 and 4% O2) or hypercapnia (5 and 10% CO2) in either 28 or 16°C while non-invasively measuring metabolic rate, thermogenesis and ventilation. We found that tenrecs exhibit robust metabolic decreases in both hypoxia and hypercapnia. Furthermore, tenrecs have blunted ventilatory responses to both hypoxia and hypercapnia, and these responses are highly temperature sensitive such that they are reduced or absent in 16°C. Thermoregulation was highly variable in 16°C but constrained in 28°C across all treatment conditions and was not impacted by hypoxia or hypercapnia, unlike in other heterothermic mammals. Taken together, our results indicate that physiological responses to hypoxia and hypercapnia in tenrecs are highly dependent on environmental temperature and differ from those of other mammalian heterotherms.