Increased Abnormal Erythrocytes Caused by Spleen Filtration Deficiency Provide a Hypoxic Environment for the Occurrence of Psoriasis.

Psoriasis is a chronic autoimmune disease with a long disease course and frequent relapse characteristics. It is now recognised to be associated with epidermal environments of inflammatory cytokines. However, its pathogenesis is still not completely clear. We found the haemorheology of psoriatic patients to be abnormal, and ageing and deformed erythrocytes increased in the blood. The abnormal erythrocytes were more likely to induce psoriasis, which was confirmed in a mouse model induced by different blood components of psoriatic patients/healthy volunteers. Spleen filtration dysfunction, which caused abnormal erythrocytes, was also more likely to induce psoriasis, which was confirmed in a mouse model induced by splenectomy. The mechanism was the weakening of the 'eat me' function of spleen macrophages phagocytizing ageing and deformed erythrocytes, resulting in the dysfunction of spleen filtration and the increase of ageing and deformed erythrocytes in the body. Additionally, the decreased oxygen-carrying capacity and the declined antioxidant capacity of those erythrocytes led to the hypoxia environment, making psoriasis more likely to be induced. These findings demonstrate that spleen filtration dysfunction contributes to the pathogenesis of psoriasis and suggest that improving it may be an effective therapy for psoriasis and control its relapse.

Acute psycho-physiological responses to submaximal constant-load cycling under intermittent hypoxia-hyperoxia vs. hypoxia-normoxia in young males.

Background: Hypoxia and hyperoxia can affect the acute psycho-physiological response to exercise. Recording various perceptual responses to exercise is of particular importance for investigating behavioral changes to physical activity, given that the perception of exercise-induced pain, discomfort or unpleasure, and a low level of exercise enjoyment are commonly associated with a low adherence to physical activity. Therefore, this study aimed to compare the acute perceptual and physiological responses to aerobic exercise under intermittent hypoxia-hyperoxia (IHHT), hypoxia-normoxia (IHT), and sustained normoxia (NOR) in young, recreational active, healthy males. Methods: Using a randomized, single-blinded, crossover design, 15 males (age: 24.5 ± 4.2 yrs) performed 40 min of submaximal constant-load cycling (at 60% peak oxygen uptake, 80 rpm) under IHHT (5 × 4 min hypoxia and hyperoxia), IHT (5 × 4 min hypoxia and normoxia), and NOR. Inspiratory fraction of oxygen during hypoxia and hyperoxia was set to 14% and 30%, respectively. Heart rate (HR), total hemoglobin (tHb) and muscle oxygen saturation (SmO2) of the right vastus lateralis muscle were continuously recorded during cycling. Participants' peripheral oxygen saturation (SpO2) and perceptual responses (i.e., perceived motor fatigue, effort perception, perceived physical strain, affective valence, arousal, motivation to exercise, and conflict to continue exercise) were surveyed prior, during (every 4 min), and after cycling. Prior to and after exercise, peripheral blood lactate concentration (BLC) was determined. Exercise enjoyment was ascertained after cycling. For statistical analysis, repeated measures analyses of variance were conducted. Results: No differences in the acute perceptual responses were found between conditions (p ≥ 0.059, ηp 2 ≤ 0.18), while the physiological responses differed. Accordingly, SpO2 was higher during the hyperoxic periods during the IHHT compared to the normoxic periods during the IHT (p < 0.001, ηp 2 = 0.91). Moreover, HR (p = 0.005, ηp 2 = 0.33) and BLC (p = 0.033, ηp 2 = 0.28) were higher during IHT compared to NOR. No differences between conditions were found for changes in tHb (p = 0.684, ηp 2 = 0.03) and SmO2 (p = 0.093, ηp 2 = 0.16). Conclusion: IHT was associated with a higher physiological response and metabolic stress, while IHHT did not lead to an increase in HR and BLC compared to NOR. In addition, compared to IHT, IHHT seems to improve reoxygenation indicated by a higher SpO2 during the hyperoxic periods. However, there were no differences in perceptual responses and ratings of exercise enjoyment between conditions. These results suggest that replacing normoxic by hyperoxic reoxygenation-periods during submaximal constant-load cycling under intermittent hypoxia reduced the exercise-related physiological stress but had no effect on perceptual responses and perceived exercise enjoyment in young recreational active healthy males.

Convergent evolution in high-altitude and marine mammals: Molecular adaptations to pulmonary fibrosis and hypoxia.

High-altitude and marine mammals inhabit distinct ecosystems but share a common challenge: hypoxia. To survive in low-oxygen environments, these species have evolved similar phenotypic pulmonary adaptations, characterized by a high density of elastic fibers. In this study, we explored the molecular mechanisms underlying these adaptations, focusing on pulmonary fibrosis and hypoxia tolerance through comparative genomics and convergent evolution analyses. We observed significant expansions and contractions in certain gene families across both high-altitude and marine mammals, closely associated with processes involved in pulmonary fibrosis. Notably, members of the keratin gene family, such as KRT17 and KRT14, appear to be associated with the development of the dense elastic fiber phenotype observed in the lungs of hypoxia-tolerant mammals. Through selection pressure and amino acid substitution analyses, we identified multiple genes exhibiting convergent accelerated evolution, positive selection, and amino acid substitution in these species, associated with adaptation to hypoxic environments. Specifically, the convergent evolution of ZFP36L1, FN1, and NEDD9 was found to contribute to the high density of elastic fibers in the lungs of both high-altitude and marine mammals, facilitating their hypoxia tolerance. Additionally, we identified convergent amino acid substitutions and gene loss events associated with sperm development, differentiation, and spermatogenesis, such as amino acid substitutions in SLC26A3 and pseudogenization of CFAP47, as confirmed by PCR. These genetic alterations may be linked to changes in the reproductive capabilities of these animals. Overall, this study offers novel perspectives on the genetic and molecular adaptations of high-altitude and marine mammals to hypoxic environments, with a particular emphasis on pulmonary fibrosis.

A 63-Year-Old Presents With Acute Fatigue, Dyspnea, and Hypoxia.

CASE PRESENTATION: A 63-year-old woman without significant medical history presented to an urgent care center with a 3-day history of fatigue and dyspnea on exertion. She was found to have an oxygen saturation in the low 80s on room air and was transferred to the closest hospital for further evaluation. Initial chest radiographs showed extensive bilateral interstitial opacities favoring the mid to lower lungs. A general infectious workup was unrevealing. The cause of her symptoms was thought to be an atypical bacterial or viral infection. She was discharged home on supplemental oxygen, 2 L/min via nasal cannula; instructed to finish a 7-day course of antibiotics; and given strict return precautions. Six days later she returned to the ED with worsening dyspnea despite finishing the prescribed course of antibiotics; she was admitted for further evaluation. She had emigrated from Northern India in the early 2000s. While in India, cooking was performed over an open fire. Their home was situated on a poultry farm. She has never smoked. She was up to date on typical cancer screening. She had no pets and denied further exposure to birds since moving to the United States. Her occupational history included manufacturing, but she denied significant exposure to dusts or metal shavings.

Multi-omics analysis reveals phenylalanine enhance mitochondrial function and hypoxic endurance via LKB1/AMPK activation.

Many studies have focused on the effects of small molecules, such as amino acids, on metabolism under hypoxia. Recent findings have indicated that phenylalanine levels were markedly elevated in adaptation to chronic hypoxia. This raises the possibility that phenylalanine treatment could markedly improve the hypoxic endurance. However, the importance of hypoxia-regulated phenylalanine is still unclear. This study investigates the role of phenylalanine in hypoxia adaptation using a hypoxic zebrafish model and multi-omics analysis. We found that phenylalanine-related metabolic pathways are significantly up-regulated under hypoxia, contributing to enhanced hypoxic endurance. Phenylalanine treatment reduced ROS levels, improved mitochondrial oxygen consumption rate (OCR), and extracellular acidification rate (ECAR) in hypoxic cells. Western blotting revealed increased phenylalanine uptake via L-type amino transporters (LAT1), activating the LKB1/AMPK signaling pathway. This activation up-regulated peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) and the Bcl-2/Bax ratio, while down-regulating uncoupling protein 2 (UCP2), thereby improving mitochondrial function under hypoxia. This is the first comprehensive multi-omics analysis to demonstrate phenylalanine's crucial role in hypoxia adaptation, providing insights for the development of anti-hypoxic drugs.

Sodium Hydrosulfide Protects Rats from Hypobaric-Hypoxia-Induced Acute Lung Injury.

Hydrogen sulfide (H2S), as a key gas signaling molecule, plays an important role in regulating various diseases, with appropriate concentrations providing antioxidative, anti-inflammatory, and anti-apoptotic effects. The specific role of H2S in acute hypoxic injury remains to be clarified. This study focuses on the H2S donor sodium hydrosulfide (NaHS) and explores its protective effects and mechanisms against acute hypoxic lung injury. First, various mouse hypoxia models were established to evaluate H2S's protection in hypoxia tolerance. Next, a rat model of acute lung injury (ALI) induced by hypoxia at 6500 m above sea level for 72 h was created to assess H2S's protective effects and mechanisms. Evaluation metrics included blood gas analysis, blood routine indicators, lung water content, and lung tissue pathology. Additionally, LC-MS/MS and bioinformatic analyses were combined in performing quantitative proteomics on lung tissues from the normoxic control group, the hypoxia model group, and the hypoxia model group with NaHS treatment to preliminarily explore the protective mechanisms of H2S. Further, enzyme-linked immunosorbent assays (ELISA) were used to measure oxidative stress markers and inflammatory factors in rat lung tissues. Lastly, Western blot analysis was performed to detect Nrf2, HO-1, P-NF-κB, NF-κB, HIF-1α, Bcl-2, and Bax proteins in lung tissues. Results showed that H2S exhibited significant anti-hypoxic effects in various hypoxia models, effectively modulating blood gas and blood routine indicators in ALI rats, reducing pulmonary edema, improving lung tissue pathology, and alleviating oxidative stress, inflammatory responses, and apoptosis levels.

Hypoxia-mediated rescue of retinal ganglion cells deficient in mitochondrial complex I is independent of the hypoxia-inducible factor pathway.

Continuous exposure to environmental hypoxia (11% O2) has been shown to markedly slow the progressive degeneration of retinal ganglion cells (RGCs) in a mouse model of mitochondrial optic neuropathy with RGC-specific deletion of the key mitochondrial complex I accessory subunit ndufs4. As a first step toward identifying the therapeutic mechanism of hypoxia in this model, we conducted a series of experiments to investigate the role of the hypoxia-inducible factor (HIF) regulatory pathway in RGC neuroprotection. Vglut2-Cre; ndufs4loxP/loxP mice were crossed with strains bearing floxed alleles of the negative HIF regulatory vhl or of the two major HIF α-subunit isoforms, Hif1α and Hif2α. Deletion of vhl within ndufs4-deficient RGCs failed to prevent RGC degeneration under normoxia, indicating that HIF activation is not sufficient to achieve RGC rescue. Furthermore, the rescue of ndufs4-deficient RGCs by hypoxia remained robust despite genetic inactivation of Hif1α and Hif2α. Our findings demonstrate that the HIF pathway is entirely dispensable to the rescue of RGCs by hypoxia. Future efforts to uncover key HIF-independent molecular pathways induced by hypoxia in this mouse model may be of therapeutic relevance to mitochondrial optic neuropathies such as Leber hereditary optic neuropathy.

Profiling hypoxia signaling reveals a lncRNA signature contributing to immunosuppression in high-grade glioma.

Background: Hypoxic conditions in glioma are linked to tumor aggressiveness, poor prognosis, and treatment resistance. Long non-coding RNAs (lncRNAs) play key roles in the hypoxic and immune microenvironment of cancers, but their link to hypoxia-induced immunosuppression in high-grade glioma (HGG) is not well-studied. Methods: Gene expression profiles from TCGA and CGGA, along with clinical and genomic data, were analyzed. Bioinformatics methods including Consensus Clustering, Pearson correlation, and Cox regression analyses were used. Cell proliferation was assessed using cell counting kit-8 and colony formation assays. Glioma-macrophage interactions were evaluated using a co-culture model. Results: Hypoxia subtype clustering showed hypoxic stress correlates with worse HGG prognosis. Eight hypoxia-related lncRNAs (AP000695.4, OSMR-AS1, AC078883.3, RP11-545E17.3, LINC01057, LINC01503, TP73-AS1, and LINC00672) with prognostic value were identified, forming a risk signature that separated patients into distinct prognostic groups. Multivariate Cox regression confirmed the signature as an independent prognostic factor. High-risk patients had greater hypoxia, leading to an immunosuppressive environment and immunotherapy resistance via tumor-associated macrophages (TAMs). TP73-AS1 significantly influenced hypoxia-induced TAM infiltration and M2 polarization. Conclusions: We profiled hypoxic stress in HGG and developed an 8-lncRNA hypoxia-related signature predicting patient survival and immunotherapy response, emphasizing its role in hypoxia-induced immunosuppression.

Mitochondrial Stress as a Central Player in the Pathogenesis of Hypoxia-Related Myocardial Dysfunction: New Insights.

Hypoxic injury is a critical pathological factor in the development of various cardiovascular diseases, such as congenital heart disease, myocardial infarction, and heart failure. Mitochondrial quality control is essential for protecting cardiomyocytes from hypoxic damage. Under hypoxic conditions, disruptions in mitochondrial homeostasis result in excessive reactive oxygen species (ROS) production, imbalances in mitochondrial dynamics, and initiate pathological processes including oxidative stress, inflammatory responses, and apoptosis. Targeted interventions to enhance mitochondrial quality control, such as coenzyme Q10 and statins, have shown promise in mitigating hypoxia-induced mitochondrial dysfunction. These treatments offer potential therapeutic strategies for hypoxia-related cardiovascular diseases by regulating mitochondrial fission and fusion, restoring mitochondrial biogenesis, reducing ROS production, and promoting mitophagy.

Chronic hypoxia drives the occurrence of ferroptosis in liver of fat greening (Hexagrammos otakii) by activating HIF-1α and promoting iron production.

BACKGROUND: Hypoxia caused by global climate change and human activities has become a growing concern eliciting serious effect and damages to aquatic animals. Hexagrammos otakii is usually a victim of hypoxia which caused by high density aquaculture and high nutrient input. The mechanism underlying ferroptosis regulation after hypoxia-stress in liver of H. otakii, however, remains elusive. METHODS: For a duration of 15 days, expose the H. otakii to low concentrations of dissolved oxygen (3.4 ± 0.2 mg/L). Detecting alterations in the H. otakii liver tissue by chemical staining, immunohistochemistry, and electron microscopy. The expression variations of relevant genes in the liver of the H. otakii were simultaneously detected using Western blot and qPCR. A correlation analysis was performed between HIF-1α and iron ion expression in the liver of H. otakii following hypoxic stress. RESULTS: In this study, we conducted the whole ferroptosis integrated analysis of H. otakii under chronic hypoxic condition. Reactive oxygen species (ROS) are highly accumulated under the hypoxia treatment (Superoxide Dismutase, SOD; Catalase, CAT), and which results in a significantly enhanced of lipid peroxidation (Lipid Peroxidation, LPO; Malondialdehyde, MDA; Aminotransferase, AST; Alanine aminotransferase, ALT) in liver tissue. The HIF-1α signaling is activated to cope with the hypoxia stress through strategies including changing iron ion concentration (Fe3+ and TFR1) to breaking the oxidation balance (GSH and GSH-Px), and enhancing ferroptosis gene expression (GPX4). The expression of genes related to ferroptosis pathway (DMT1, FTH1, STEAP3, ACSL4, γ-GCS, SLC7A11) is significantly upregulated and associated to the expression of iron and HIF-1α. CONCLUSIONS: It is demonstrated that the HIF-1α/Fe3+/ROS/GPX4 axis is involved in promoting ferroptosis in fat greening hepatocytes following hypoxia-stress. Ultimately, our findings unveil a process by which hypoxic stress strongly encourages ferroptosis by triggering HIF-1α and boosting iron synthesis.

Inhibition of the FOXO1-ROCK1 axis mitigates cardiomyocyte injury under chronic hypoxia in Tetralogy of Fallot by maintaining mitochondrial quality control.

INTRODUCTION: Persistent chronic myocardial hypoxia causes disturbances in mitochondrial quality control (MQC), ultimately leading to increased cardiomyocyte injury in patients with Tetralogy of Fallot (TOF). The present study aimed to identify the key effector molecules of cardiomyocyte injury under chronic hypoxia in TOF. METHODS: Clinical data from TOF patients were collected and whole transcriptome sequencing was performed on myocardial samples. Chronic hypoxia models were established in cardiac-specific knockout mice and cardiomyocytes, and a series of molecular experiments were used to determine the specific mechanisms involved. RESULTS: Clinical cohort data and whole-transcriptome sequencing analysis of myocardial samples from TOF patients revealed that forkhead box O1 (FOXO1) plays an important role in chronic hypoxic cardiomyocyte injury. In a model of chronic hypoxia established in FOXO1 cardiac-specific knockout mice and FOXO1 gene-deficient cardiomyocytes, the AMPK signaling pathway regulates the expression of FOXO1, which in turn disrupts MQC by regulating the transcriptional activation of Rho-associated protein kinase 1 (ROCK1), and increasing the production of mitochondrial ROS, thereby exacerbating damage to cardiomyocytes. Excessive reactive oxygen species (ROS) production during MQC dysfunction further activates Cox7a2L to increase the assembly of the respiratory chain supercomplex. In addition, we found that miR-27b-3p partially binds to the 3' untranslated region of FOXO1 to exert a protective effect. CONCLUSIONS: Maintenance of MQC under chronic hypoxia is achieved through a series of injury-protection mechanisms, suggesting that FOXO1 inhibition may be crucial for future mitigation of chronic hypoxic cardiomyocyte injury in TOF.

Common tenrecs (Tenrec ecaudatus) reduce oxygen consumption in hypoxia and in hypercapnia without concordant changes to body temperature or heart rate.

Common tenrecs (Tenrec ecaudatus) are fossorial mammals that use burrows during both active and hibernating seasons in Madagascar and its neighboring islands. Prevailing thought was that tenrecs hibernate for 8-9 months individually, but 13 tenrecs were removed from the same sealed burrow 1 m deep from the surface. Such group hibernation in sealed burrows presumably creates a hypoxic and/or hypercapnic environment and suggests that this placental mammal may have an increased tolerance to hypoxia and hypercapnia. Higher tolerances to hypoxia and hypercapnia have been documented for other mammals capable of hibernation and to determine if this is the case for tenrecs, we exposed them to acute hypoxia (4 h of 16 or 7% O2), progressive hypoxia (2 h of 16, 10 and 4% O2), or progressive hypercapnia (2 h of 2, 5 and 10% CO2) at cold (16 °C) or warm (28 °C) ambient temperatures (Ta). Oxygen equilibrium curves were also constructed on the whole blood of tenrecs at 10, 25, and 37 °C to determine if hemoglobin (Hb)-O2 affinity contributes to hypoxia tolerance. In animals held at 16 °C, normoxic and normocapnic levels of oxygen consumption rate ( V ˙ O 2 ), body temperature (Tb), and heart rate (HR) were highly variable between individuals. This inter-individual variation was greatly reduced in animals held at 28 °C for oxygen consumption rate and body temperature. Both hypoxia (acute and progressive) and progressive hypercapnia led to decreases in V ˙ O 2 as well as the variation in V ˙ O 2 between animals held at 16 °C. The fall in oxygen consumption rate in 7% O2 independent of changes in body temperature in tenrecs held at 16 °C is unique and not consistent with the typical hypoxic metabolic response seen in other hibernating species that depends on concomitant falls in Tb. In animals held at 28 °C, exposure to O2 levels as low as 4% and CO2 levels as high as 10% had no significant effect on V ˙ O 2 , HR, or Tb, indicative of high tolerance to both hypoxia and hypercapnia. High variation in heart rate remained between individuals in all gas compositions and at all temperatures. Tenrec Hb-O2 affinity was similar to other homeothermic placental mammals and likely does not contribute to the increased hypoxia tolerance. Ultimately, our results suggest changes in Ta dictate physiological responses to hypoxia or hypercapnia in tenrecs, responses more characteristic of reptiles than of most placental mammals. Given that numerous anatomical and physiological characteristics of tenrecs suggest that they may be representative of an ancestral placental mammal, our findings suggest the typical hypoxic metabolic response evolved later in mammalian evolution.

Oral antioxidant edaravone protects against cognitive deficits induced by chronic hypobaric hypoxia at high altitudes.

Chronic hypobaric hypoxia at high altitudes can impair cognitive functions, especially causing deficits in learning and memory, which require therapeutic intervention. Here, we showed that mice subjected to hypobaric hypoxia (simulating an altitude of 5000 m) for one month experienced significant cognitive impairment, accompanied by increased biomarker levels of oxidative stress in the brain and blood. Oral administration of a novel formulation of edaravone, a free radical scavenger approved for the treatment of ischaemic stroke and amyotrophic lateral sclerosis, significantly alleviated oxidative stress and cognitive impairments caused by chronic hypobaric hypoxia. Furthermore, oral edaravone treatment also mitigated neuroinflammation and restored hippocampal neural stem cell exhaustion. Additionally, periostin (Postn) is vital in the cognitive deficits caused by chronic hypobaric hypoxia and may be a molecular target of edaravone. In conclusion, our results suggest that oxidative stress plays a crucial role in the cognitive deficits caused by chronic hypobaric hypoxia and that oral edaravone is a potential medicine for protecting against cognitive deficits caused by chronic hypobaric hypoxia in high-altitude areas.

Effects of cognitive training under hypoxia on cognitive proficiency and neuroplasticity in remitted patients with mood disorders and healthy individuals: ALTIBRAIN study protocol for a randomized controlled trial.

BACKGROUND: Cognitive impairment is prevalent across neuropsychiatric disorders but there is a lack of treatment strategies with robust, enduring effects. Emerging evidence indicates that altitude-like hypoxia cognition training may induce long-lasting neuroplasticity and improve cognition. We will investigate whether repeated cognition training under normobaric hypoxia can improve cognitive functions in healthy individuals and patients with affective disorders and the neurobiological underpinnings of such effects. METHODS: In sub-study 1, 120 healthy participants are randomized to one of four treatment arms in a double-blind manner, allowing for examination of separate and combined effects of three-week repeated moderate hypoxia and cognitive training, respectively. In sub-study 2, 60 remitted patients with major depressive disorder or bipolar disorder are randomized to hypoxia with cognition training or treatment as usual. Assessments of cognition, psychosocial functioning, and quality of life are performed at baseline, end-of-treatment, and at 1-month follow-up. Functional magnetic resonance imaging (fMRI) scans are conducted at baseline and 1-month follow-up, and [11C]UCB-J positron emission tomography (PET) scans are performed at end-of-treatment to quantify the synaptic vesicle glycoprotein 2A (SV2A). The primary outcome is a cognitive composite score of attention, verbal memory, and executive functions. Statistical power of ≥ 80% is reached to detect a clinically relevant between-group difference with minimum n = 26 per treatment arm. Behavioral data are analyzed with an intention-to-treat approach using mixed models. fMRI data is analyzed with the FMRIB Software Library, while PET data is quantified using the simplified reference tissue model (SRTM) with centrum semiovale as reference region. DISCUSSION: The results will provide novel insights into whether repeated hypoxia cognition training increases cognition and brain plasticity, which can aid future treatment development strategies. TRIAL REGISTRATION: ClinicalTrials.gov, NCT06121206 . Registered on 31 October 2023.

Inherited anoxia tolerance and growth performance can result in enhanced invasiveness in hybrid fish.

Northern hemisphere freshwater ecosystems are projected to experience significant warming and shortening of winter duration in this century. This change coupled with depletion of oxygen (hypoxia) will result in a shift toward fish species with higher optimal temperatures for growth and reproduction that can mitigate hypoxic stress. Here, we tested the assumption that reproduction between two distant species, i.e. anoxic-intolerant common carp (Cyprinus carpio) and anoxic-tolerant goldfish (Carassius auratus), results in the expression of genes responsible for ethanol synthesis (alcohol dehydrogenase and pyruvate dehydrogenase subunit E1ß2). The expression of this ethanol-producing pyruvate decarboxylase pathway may transform the biochemical characteristics of progeny into anoxic-tolerant hybrids, expanding their suitable environmental range and potentially increasing invasiveness. Concurrently, a genetic strategy for improving fish tolerance to oxygen-depleted environments will be a valuable physiological trait in fish culture. Differential quantification of gene expression by analyzing mRNA revealed that, compared with koi×koi, koi female×goldfish male (F1 hybrid) possessed the pyruvate dehydrogenase subunit E1ß2 gene construct, which was expressed at significantly greater levels in red muscle. The potential of this hybrid to both survive in extreme anoxic conditions and grow at elevated water temperatures would likely contribute to their ecological success.

[Clinical, laboratory and morphological comparisons in cellular alteration under conditions of hypoxia]. / Kliniko-laboratorno-morfologicheskie sopostavleniya pri kletochnoi al'teratsii v usloviyakh gipoksii.

OBJECTIVE: To compare structural changes in tissues with clinical and laboratory parameters and immunohistochemical determination of proteins HIF1α, HIF2α, caspase-3 during cellular alteration under conditions of hypoxia in the liver and kidneys in an experiment on pigs. MATERIAL AND METHODS: Laboratory parameters related to the state of gas exchange (decrease in partial pressure of arterial blood oxygen (PaO2), arterial blood saturation, lactate level, kidney function (creatinine, urea) and liver (ALT, AST, bilirubin) in 18 animals were analyzed in comparison with the results of a morphological study. Histological examination evaluated alterative and inflammatory tissue changes of varying severity, and also determined the expression of transcription factors HIF1α and HIF2α and a marker of apoptosis - caspase-3. The ratio between laboratory parameters and structural changes was assessed individually for each animal. RESULTS: In the liver, a statistically significant dependence of the content of HIF2α protein in cells on the severity of dystrophic changes and serum lactate levels was revealed. A statistically significant correlation was shown between an increase in transaminase and bilirubin levels and the severity of alterative changes in liver tissue. However, there was no significant relationship between the number of caspase-3 positive cells and the severity of dystrophic changes. A statistically significant correlation was found between creatinine and urea levels and the severity of alterative changes in kidney tissues. With significant dystrophic changes, a statistically significant dependence of the expression of HIF2α and caspase-3 proteins and a very high correlation of caspase-3 - lactate indicators were revealed. CONCLUSION: A significant correlation was shown between histological changes in tissues and clinical and laboratory parameters. Severe hypoxia with lactate accumulation directly affects the integrity and function of cells, which manifests itself in structural changes. Based on the results of a comparative study, it can be concluded that the assessment of alterative changes in liver and kidney tissues is important.

Normobaric Hypoxia Symptom Recognition in Three Training Sessions.

INTRODUCTION: Hypoxia training is mandatory for military pilots, but variability in hypoxia symptoms challenges the training. In a previous study we showed that 64% of pilots recognized hypoxia faster in their second normobaric hypoxia session conducted 2.4 yr after the first. Our aim here was to evaluate whether a third session conducted 5.0 yr after the first would provide further benefit. METHODS: This study was conducted under normobaric conditions in a tactical F/A-18C Hornet simulator in three sessions in which the pilots performed visual identification missions and breathed 21% oxygen in nitrogen. The breathing gas was changed to a hypoxic mixture containing either 8%, 7%, or 6% oxygen in nitrogen without the pilot's knowledge. Data were collected from 102 military pilots. The primary outcome was the time taken for initial identification of hypoxia symptoms. RESULTS: Hypoxia symptoms were recognized on average in the first session in 8% oxygen in 100 s, 7% oxygen in 90 s, and 6% oxygen in 78 s; in the second in 87 s, 80 s, and 71 s, respectively; and in the third in 79 s, 67 s, and 64 s, respectively. In 2 sessions 20 pilots and in each 3 training sessions 3 pilots had slow recognition times. DISCUSSION: Hypoxia symptom recognition improved the further the repeated normobaric hypoxia training went. More emphasis should be put on the 23% group of slow hypoxia symptom recognizers and more customized hypoxia training for them should be offered. Leinonen AM, Varis NO, Kokki HJ, Leino TK. Normobaric hypoxia symptom recognition in three training sessions. Aerosp Med Hum Perform. 2024; 95(10):758-764.

Maternal NO2 exposure and fetal growth restriction: Hypoxia transmission and lncRNAs-proinflammation-mediated abnormal hematopoiesis.

Epidemiological studies show a strong correlation between air pollution and fetal growth restriction (FGR), but existing results are controversial due to inherent limitations, such as causality of specific pollutants, developmental origin, and maternal-fetal transmission. To address this controversy, we first conducted a retrospective analysis of 28,796 newborns and revealed that maternal nitrogen dioxide (NO2) exposure during the second trimester was positively associated with FGR, with an adjusted odds ratio of 1.075 (95% confidence interval: 1.020-1.133) per 10 µg/m3 NO2 increase for small for gestational age. Then, by establishing an animal model of prenatal NO2 exposure, we confirmed its adverse effects on embryonic growth and hematopoiesis in the yolk sac and fetal liver, primarily affecting the differentiation of hematopoietic stem and progenitor cells and erythroid maturation. By applying internal exposure analyses coupled with 15N isotope tracing, we found that maternal NO2 inhalation induced acquired methemoglobinemia through its byproducts and placental hypoxia in pregnant mice. Importantly, by combining transcriptional profiling, bioinformatics analysis, and RNA binding protein immunoprecipitation (RIP)/chromatin immunoprecipitation (CHIP), we clarified that placental-fetal hypoxia transmission activated hypoxia-inducible factors, disturbed hematopoiesis through the hypoxia-inducible factor 1ß-long noncoding RNAs-CCAAT/enhancer binding protein alpha-proinflammatory signaling pathway, ultimately contributing to FGR progression. These findings provide insights for risk prevention and clinical intervention to promote child well-being in NO2-polluted areas.

Study on the mechanism of echinacoside in preventing and treating hypoxic pulmonary hypertension based on proteomic analyses.

Hypoxic pulmonary hypertension (HPH), a chronic condition affecting the cardiopulmonary system, has high mortality. Echinacoside (ECH) is a phenylethanoid glycoside, which is used to ameliorate pulmonary vascular remodeling and pulmonary vasoconstriction in rats. Accordingly, we aimed to explore the mechanism of ECH in preventing and treating HPH. Sprague Dawley rats were housed in a hypobaric hypoxia chamber for 28 days to obtain the HPH model. The experimental rats were randomly allocated into the following several groups: normoxia group, chronic hypoxia group, and ECH group. The therapeutic results of ECH (10, 20, and 40 mg/kg) showed that ECH reduced mPAP, Hb, Hct, and RVHI in HPH rats. Then this work employed label-free quantitative proteomic analysis, western blotting, and RT-PCR to investigate the mechanism by which ECH prevents HPH. The results found that in the chronic hypoxia group, the levels of ACSL1, COL6A1, COL4A2, COL1A1, and PC increased compared to the normoxia group. However, the opposite effect was observed in the chronic hypoxia group treated with ECH. The study indicates that the administration of ECH may slow the pathological progression of HPH by suppressing the inflammatory response, inhibiting smooth muscle cell proliferation, and minimizing the deposition of extracellular matrix.

Targeting hypoxia and thrombospondin-2 in diabetic wound healing.

Impaired wound healing in diabetic patients is the leading cause of diabetes-associated hospitalizations and approximately 50% of lower limb amputations. This is due to multiple factors, including elevated glucose, sustained hypoxia, and cell dysfunction. Previously, diabetic wounds were found to contain excessive levels of the matricellular protein thrombospondin-2 (TSP2) and genetic ablation of TSP2 in diabetic mice or treatment of wounds with a hydrogel derived from TSP2-null mouse skin improved healing. Previously, TSP2 has been shown to be repressed by hypoxia, but in the present study we observed sustained hypoxia and overlapping TSP2 deposition in diabetic wounds. We determined this observation was due to the insufficient HIF-1α activation verified by western blot and immunofluorescent analysis of wound tissues and in vitro hypoxia experiments. Application of Dimethyloxalylglycine (DMOG), which can stabilize HIF-1α, inhibited TSP2 expression in diabetic fibroblasts in hypoxic conditions. Therefore, we prepared DMOG-containing TSP2KO hydrogel and applied it to the wounds of diabetic mice. In comparison to empty TSP2KO hydrogel or DMOG treatment, we observed improved wound healing associated with a reduction of TSP2, reduced hypoxia, and increased neovascularization. Overall, our findings shed light on the intricate interplay between hyperglycemia, hypoxia, and TSP2 in the complex environment of diabetic wounds.