bims-oxygme Biomed News
on Oxygen metabolism
Issue of 2025–09–14
twelve papers selected by
Onurkan Karabulut, Berkeley City College
  1. The gut-kidney axis in high-altitude hypoxia: pathophysiological mechanisms and the central role of hypoxia inducible factor.
  2. Gestational hypoxia increases brain-blood barrier permeability in the neonatal cerebral cortex of Guinea pigs.
  3. Hypoxia promotes pancreatic adenocarcinoma progression by stabilizing ID1 via TRIM21 suppression.
  4. Latest Nanoparticles to Modulate Hypoxic Microenvironment in Photodynamic Therapy of Cervical Cancer: A Review of In Vivo Studies.
  5. Hypoxia Induces Immunosuppression by Silencing STING in Cancer.
  6. Peptidylarginine deiminase 4 deficiency alleviates hypoxia/reoxygenation-induced cardiomyocyte injury.
  7. Bridging Inflammation and Repair: The Promise of MFG-E8 in Ischemic Stroke Therapy.
  8. Ciprofol Regulates the Activity of Mitochondrial Respiratory Chain Complex I During Cerebral Ischemia-Reperfusion by Targeting Flavin Mononucleotide: A Metabolomic Study.
  9. Optimized dose of hydrogen-enriched water with minocycline combination therapy in experimental ischemic stroke.
  10. Alpinetin protects against myocardial ischemia-reperfusion injury by inhibiting ferroptosis and apoptosis via mitochondrial ferritin.
  11. Effects of High Intensity Interval Training in Normobaric Hypoxia on Aerobic Performance and Exercise-Induced Motor Performance Fatigue in Young Biathletes.
  12. Inherent single-cell heterogeneity of the transcriptional response to hypoxia in cancer cells.
  1. Ann Med. 2025 Dec;57(1): 2557514
    The gut-kidney axis in high-altitude hypoxia: pathophysiological mechanisms and the central role of hypoxia inducible factor.
    Peiwen Wu, Xun Li, Wenjie Long, Yu Ma, Bo Xue, Wen Xie, Xin Ma.
       BACKGROUND: The high-altitude plateau environment, defined by hypobaric hypoxia, poses considerable health risks to human populations. Due to their substantial oxygen requirements, the kidneys are particularly susceptible, as are the intestines, with their intricate microbiota and essential barrier functions. This review examines the pathophysiological consequences of high-altitude hypoxia on renal and intestinal health, specifically highlighting the interorgan communication mediated by the gut-kidney axis.
    DISCUSSION: Prolonged hypobaric hypoxia causes notable functional and structural impairment in the kidneys, exacerbating pathologies such as acute kidney injury and chronic kidney disease, and is associated with altitude-induced disorders including polycythemia and hyperuricemia. Simultaneously, the hypoxic milieu disrupts gut microbiota composition, weakens intestinal barrier integrity and alters mucosal immune responses. These intestinal disturbances are increasingly acknowledged as pivotal factors in renal pathophysiology via the gut-kidney axis. Microbial metabolites and compromised barrier function may enter systemic circulation, triggering inflammation and fibrotic processes. The hypoxia-inducible factor pathway emerges as a central molecular mechanism activated in both organs, modulating critical processes such as renal fibrosis and intestinal permeability. Furthermore, dietary habits common among high-altitude populations can influence gut microbiota, introducing additional complexity to this axis and presenting both risks and potential therapeutic opportunities.
    CONCLUSIONS: The gut-kidney axis is critically involved in mediating the adverse health effects of high-altitude hypoxia. A thorough understanding of the HIF pathway, microbial metabolites and barrier dysfunction offers an integrative framework for elucidating the underlying pathogenic mechanisms. Targeting this axis through interventions such as dietary modification and probiotic supplementation represents a promising strategy for preventing and treating high-altitude-related renal and intestinal disorders, thereby improving health outcomes for high-altitude residents.
    Keywords:  Plateau; diet; gut–kidney axis; hypoxia; intestinal tract; kidney disease
    DOI:  https://doi.org/10.1080/07853890.2025.2557514
  2. Pediatr Res. 2025 Sep 09.
    Gestational hypoxia increases brain-blood barrier permeability in the neonatal cerebral cortex of Guinea pigs.
    Esteban G Figueroa, Adolfo A Paz, Tamara A Jiménez, Osvaldo Meza-Vilches, Daniel Palma C, Fernanda Muños-Guzman, Felipe Beñaldo, Emilio A Herrera, Alejandro González-Candia.
       BACKGROUND: Fetal growth restriction (FGR) causes an adaptive redistribution of the cardiac output towards sustained cerebral vasodilation. However, the consequences of FGR and cerebral vasodilatation due to fetal hypoxia on the blood-brain barrier (BBB) are still poorly studied. This study assesses BBB permeability in the neonatal cortex of pups gestated under intrauterine hypobaric hypoxia.
    METHODS: 15 Guinea pig (Cavia porcellus) newborns were used in this study; 8 were gestated in normoxia (Nx), and 7 were gestated under chronic hypobaric hypoxia (Hx). Fetal examinations by ultrasound were assessed. At birth, pups were euthanized, and the cerebral cortex was collected to determine gene and protein expression. The permeability was quantified by immunolocalization of perivascular albumin in the prefrontal cortex BBB.
    RESULT: The brain-sparing phenotype was associated with increased medial cerebral artery vasodilation during gestation and carotid endothelial vasodilation at birth. Additionally, gestational hypoxia decreased the protein levels of claudin-5 and claudin-12 in the neonatal cortex. Finally, albumin-immunopositive areas significantly increased in the brain parenchyma in the Hx neonatal cortex.
    CONCLUSION: Our findings demonstrate that gestational hypoxia is associated with changes in the expression of genes and proteins related to the paracellular permeability of the BBB, which appears relevant to normal neurodevelopmental processes in perinatal life.
    IMPACT: Gestational hypoxia generated a redistribution of flow (brain-sparing effects) associated with an increase in the cerebroplacental index and a growth restriction at birth using guinea pigs as an FGR model. The brain-sparing phenotype is associated with a decrease in the expression of claudins in the cerebral vasculature and increased BBB permeability in newborns gestated in hypobaric hypoxia. The observed permeability of the BBB in the neonatal cortex resembles the permeability phenotypes of postnatal hypoxia models, such as those of cerebral infarction or neonatal ischemic encephalopathy.
    DOI:  https://doi.org/10.1038/s41390-025-04345-x
  3. Front Oncol. 2025 ;15 1616968
    Hypoxia promotes pancreatic adenocarcinoma progression by stabilizing ID1 via TRIM21 suppression.
    Rui Cheng, Yuanjun Tang, Xuedi Cao, Zhanya Huang, Yunyun Guo, Renjing Jin, Yan Wang, Yang Liu, Lixiang Xue, Yuqing Wang.
       Introduction: Pancreatic adenocarcinoma (PAAD) is a highly aggressive malignancy characterized by a profoundly hypoxic tumor microenvironment, which fosters tumor progression and confers resistance to therapy The oncogenic regulator ID1has been implicated in PAAD malignancy, however, the mechanisms underlying hypoxia-induced stabilization of ID1 and the role of ubiquitin-mediated degradation remain poorly understood. Elucidating these pathways is essential for identifying novel therapeutic targets for PAAD.
    Methods: In this study, we examined ID1 expression in PAAD tissues and cell lines using publicly available databases and in vitro models. We simulated hypoxic conditions to assess their effects on ID1 expression and tumor cell behaviors, including proliferation, migration, and invasion. Protein stability was investigated via cycloheximide chase, proteasome and autophagy inhibition, and ubiquitination assays. Mass spectrometry identified TRIM21 as an E3 ubiquitin ligase interacting with ID1. To investigate its regulatory role, we generated stable TRIM21 knockdown and overexpression pancreatic cancer cell lines. Finally, in vivo xenograft experiments were conducted to evaluate the impact of ID1 and TRIM21 on tumor growth.
    Results: ID1 was markedly overexpressed in PAAD tissues and cell lines, correlating with advanced tumor stage, metastasis, and reduced patient survival. Hypoxia elevated ID1 protein levels without significantly affecting its mRNA, suggesting post-translational stabilization. Mechanistic studies revealed that hypoxia inhibits ubiquitin-proteasome-mediated degradation of ID1 by downregulating TRIM21, an E3 ubiquitin ligase responsible for ID1 ubiquitination. TRIM21 knockdown restored ID1 levels and promoted tumor cell function, whereas TRIM21 overexpression suppressed these malignant phenotypes and mitigated hypoxia-induced aggressiveness. In vivo, ID1 silencing impeded, while TRIM21 knockdown accelerated, pancreatic tumor growth, confirming their opposing roles in tumor progression.
    Discussion: Our findings demonstrate that hypoxia drives pancreatic tumor progression by downregulating TRIM21, leading to stabilization of the oncogenic protein ID1. The TRIM21-ID1 axis emerges as a promising therapeutic target for PAAD, suggesting that restoring TRIM21-mediated ID1 degradation could counteract hypoxia-induced malignancy.
    Keywords:  Id1; TRIM21; hypoxia; pancreatic adenocarcinoma; ubiquitination
    DOI:  https://doi.org/10.3389/fonc.2025.1616968
  4. Int J Mol Sci. 2025 Sep 01. pii: 8503. [Epub ahead of print]26(17):
    Latest Nanoparticles to Modulate Hypoxic Microenvironment in Photodynamic Therapy of Cervical Cancer: A Review of In Vivo Studies.
    Dorota Bartusik-Aebisher, Mohammad A Saad, Agnieszka Przygórzewska, Paweł Woźnicki, David Aebisher.
      Photodynamic therapy (PDT) is a promising, minimally invasive treatment for cervical cancer, but its efficacy is significantly limited by hypoxia-oxygen deficiency in the tumour microenvironment. The aim of this study was to present strategies to counteract hypoxia in PDT using the latest nanotechnologies. Based on a review of the literature available in PubMed/MEDLINE, Scopus, and Web of Science databases, covering the period from January 2024 to March 2025, nine original in vivo studies were identified that investigated the use of nanoparticle-based strategies to overcome hypoxia and enhance the efficacy of PDT in cervical cancer. A variety of approaches to improve tumour oxygenation are described, including the catalytic decomposition of hydrogen peroxide (H2O2) with manganese oxide (MnO2), the use of bimetallic nanozymes (e.g., Au2Pt), and FeOOH structures and oxygen storage and control systems (e.g., endoperoxides). Strategies to reduce oxygen consumption by cancer cells, such as nitric oxide (NO) release or inhibition of mitochondrial oxidative phosphorylation, are also discussed. The review shows that appropriately designed nanoparticles can effectively counteract hypoxia, enhancing the efficacy of PDT by intensifying reactive oxygen species (ROS) generation and modulating HIF-1α factor expression. The strategies presented here have the potential to significantly improve the efficacy of photodynamic therapy in the treatment of cervical cancer, especially under conditions of limited oxygen availability.
    Keywords:  PDT; cancer; cervical cancer; hypoxia
    DOI:  https://doi.org/10.3390/ijms26178503
  5. Cancer Res. 2025 Sep 12.
    Hypoxia Induces Immunosuppression by Silencing STING in Cancer.
    Yuhong Lu, Annali M Yurkevicz, Yanfeng Liu, Peter M Glazer.
      Stimulator of interferon genes (STING), a key component of the cGAS/STING pathway, is crucial for nucleic acid sensing and plays a significant role in tumor immune responses. However, STING is often silenced in various cancers, aiding tumor development. This study showed that tumor hypoxia downregulates STING in multiple cancer types, suppressing downstream pathways and inhibiting immunogenic cell death. Hypoxia-induced downregulation of STING occurred in a HIF-1α-dependent manner, and STING silencing was associated with epigenetic modifications mediated by lysine demethylases KDM1A and KDM5A and further exacerbated by oncometabolite dysregulation. In vivo, hypoxia affected the efficacy of STING agonists on tumor growth and immune responses. Inhibiting KDM1A reversed hypoxia-induced STING downregulation and reactivated STING in previously suppressed cancer cells. This study highlights the interaction between hypoxia, oncometabolites, and immune signaling in cancer and suggests that targeting KDM1A could restore the STING pathway and improve the efficacy of cancer therapy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-2038
  6. PLoS One. 2025 ;20(9): e0330864
    Peptidylarginine deiminase 4 deficiency alleviates hypoxia/reoxygenation-induced cardiomyocyte injury.
    Matthias Mand, Michelle Holthaus, Helmut R Lieder, Petra Kleinbongard, Lenard Conradi, Thorsten Wahlers, Adnana Paunel-Görgülü.
       BACKGROUND: Cardiac ischemia reperfusion (I/R) injury is a serious consequence of reperfusion therapy for myocardial infarction (MI). Peptidylarginine deiminase 4 (PAD4) is a calcium-dependent enzyme that catalyzes the citrullination of proteins. In previous studies, PAD4 inhibition protected distinct organs from I/R injury by preventing the formation of neutrophil extracellular traps (NETs) and attenuating inflammatory responses. Here, we hypothesized that cardiomyocyte PAD4 expression may play a role in acute I/R injury.
    METHODS: Infarct size was determined in isolated pressure constant-perfused hearts from WT and PAD4-deficient (PAD4-/-) mice. Additionally, extracellular reactive oxygen species (ROS) and cell viability were quantified in freshly isolated adult cardiomyocytes exposed to hypoxia followed by reoxygenation (H/R). Resistance to oxidative stress was proven in both genotypes by treatment of neonatal cardiomyocytes with hydrogen peroxide. Moreover, intracellular ROS formation, ATP production, mitochondrial membrane polarisation, caspase-3 activation, and cell viability were quantified after hypoxia followed by 4 h and 20 h of reoxygenation, respectively. The PAD4-specific inhibitor GSK484 was added before H/R or at reperfusion in certain experiments.
    RESULTS: Infarct size was smaller in PAD4-/- hearts following I/R when compared to the WT. Similarly, the viability of adult and neonatal PAD4-/- cardiomyocytes was better preserved after H/R, accompanied by reduced ROS formation. PAD4 deficiency maintained mitochondrial integrity and protected neonatal cardiomyocytes against apoptosis. However, these cells did not exhibit resistance to hydrogen peroxide-induced cell death, indicating an unaltered antioxidative state. Whereas pharmacological PAD4 inhibition by GSK484 before H/R sustained intracellular ATP levels in WT cardiomyocytes, administration of GSK484 at reoxygenation did not. However, GSK484 significantly improved cardiomyocyte metabolic activity, regardless of the time of administration.
    CONCLUSIONS: Our study is the first to demonstrate that PAD4 expression in cardiomyocytes contributes to H/R injury independent of systemic immune responses and NETs. Consequently, PAD4 may serve as a therapeutic target to alleviate I/R injury.
    DOI:  https://doi.org/10.1371/journal.pone.0330864
  7. Int J Mol Sci. 2025 Sep 06. pii: 8708. [Epub ahead of print]26(17):
    Bridging Inflammation and Repair: The Promise of MFG-E8 in Ischemic Stroke Therapy.
    Ye-Jin Han, Hye-Jin Lee, Dong-Ho Geum, Jong-Hoon Kim, Dong-Hyuk Park.
      Ischemic stroke is a neurological disorder resulting from localized brain injury due to focal cerebral ischemia, typically caused by the blockage of one or, in some cases, a few cerebral arteries. This arterial obstruction leads to hypoxia and energy failure, culminating in primary brain damage. Although reperfusion is critical to salvage viable tissue, it often intensifies injury through oxidative stress, inflammation, and cell death-a phenomenon called ischemia-reperfusion (I/R) injury. Milk fat globule-EGF factor 8 (MFG-E8), a multifunctional glycoprotein secreted by stem and immune cells, is a key regulator of inflammation and tissue repair. By modulating microglial activation, attenuating proinflammatory cytokine releases, and preserving neuronal integrity, MFG-E8 mitigates ischemia-reperfusion injury and emerges as a novel therapeutic target for ischemic stroke.
    Keywords:  MFG-E8; efferocytosis; ischemic stroke; lactadherin; neuroinflammation
    DOI:  https://doi.org/10.3390/ijms26178708
  8. J Integr Neurosci. 2025 Aug 26. 24(8): 40079
    Ciprofol Regulates the Activity of Mitochondrial Respiratory Chain Complex I During Cerebral Ischemia-Reperfusion by Targeting Flavin Mononucleotide: A Metabolomic Study.
    Jixin Chen, Guoyou Chen, Yueheng Wu, Shuai Liu, Yifan Ma, Maonan Liu, Wei Yu.
       BACKGROUND AND PURPOSE: Ciprofol, a novel intravenous anesthetic, has been shown to exert protective effects against ischemic stroke, a leading cause of death and disability; however, its molecular mechanisms remain unclear. This study aimed to explore the molecular mechanisms underlying the neuroprotective effects of ciprofol using metabolomics.
    METHODS: This study used a middle cerebral artery occlusion (MCAO) rat model to simulate cerebral ischemia-reperfusion injury (CIRI). The rats were divided into ciprofol, MCAO, and sham groups. Histological and neurobehavioral testing methods were used to investigate the therapeutic effects of ciprofol in rats. Ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry was used to screen for differential metabolites and related metabolic pathways in the serum and brain of the three groups. Spectrophotometry was used to detect in vitro mitochondrial respiratory chain complex I (MRCC-I) activity.
    RESULTS: Neurological behavioral scores and cerebral infarct volumes of rats in the ciprofol group were significantly lower than those of rats in the MCAO group. Metabolomic analysis revealed 19 differential metabolites in serum samples and 31 differential metabolites in brain samples, including flavin mononucleotide (FMN). These metabolites were mainly enriched in the tricarboxylic acid cycle, respiratory electron transport chain, and amino acid and lipid metabolism. In vitro experiments demonstrated that ciprofol promoted the activity of MRCC-I during CIRI by increasing FMN levels.
    CONCLUSION: The mechanisms of action of ciprofol during treatment of cerebral ischemia involve the tricarboxylic acid cycle, respiratory electron transport chain, and amino acid and lipid metabolism and may directly affect MRCC-I activity by regulating FMN.
    Keywords:  cerebral ischemia; flavin mononucleotide; metabolomics; mitochondrial complex I
    DOI:  https://doi.org/10.31083/JIN40079
  9. Brain Res. 2025 Sep 09. pii: S0006-8993(25)00503-7. [Epub ahead of print] 149940
    Optimized dose of hydrogen-enriched water with minocycline combination therapy in experimental ischemic stroke.
    Zhao Jiang, Tharun T Alamuri, Darren L Yang, Tyler Annarino, Eric R Muir, Tim Q Duong.
       BACKGROUND: Ischemic stroke remains a leading cause of death and disability worldwide, with limited effective treatments due to the complexity of its pathophysiology. Molecular hydrogen (H2) and minocycline (M), both possessing anti-inflammatory and antioxidant properties, have shown individual neuroprotective potential in preclinical models. However, the optimal therapeutic dosing of H2, particularly in combination with other agents, remains undefined.
    OBJECTIVE: This study aimed to (1) determine the dose-response relationship of hydrogen-enriched water in a rat model of transient middle cerebral artery occlusion (MCAO), and (2) evaluate whether optimized H2 dosing combined with minocycline provides superior neuroprotection compared to H2 monotherapy.
    METHODS: Sixty-six male and female Sprague-Dawley rats underwent 60-minute MCAO followed by treatment with varying doses (5-30 mL/kg) of hydrogen-enriched water (3.2 ppm), alone or in combination with minocycline (20 mg/kg). Treatments were administered post-reperfusion as well as on days 1 and 2. Behavioral outcomes (Garcia score) and infarct volumes (TTC staining) were assessed at 7 days post-stroke.
    RESULTS: The optimal H2 dose was 20 mL/kg, which produced the highest Garcia scores and lowest infarct volumes. A dose-dependent effect was observed with a quadratic fit (R2 = 0.751 for Garcia scores; R2 = 0.289 for lesion volume). Combination therapy with H2 and minocycline significantly outperformed H2 monotherapy in both neurological recovery and infarct reduction, with no sex differences observed.
    CONCLUSION: Hydrogen-enriched water shows a dose-dependent neuroprotective effect in experimental ischemic stroke, with 20 mL/kg identified as the optimal dose. Combined therapy with minocycline further enhances outcomes, supporting the potential of dual-agent strategies for improved stroke treatment. These findings provide a foundation for translational development of H2-based combination therapies in clinical settings.
    Keywords:  Ischemia; Minocycline; Molecular hydrogen; Neuroprotection; Rats; Stroke
    DOI:  https://doi.org/10.1016/j.brainres.2025.149940
  10. Eur J Pharmacol. 2025 Sep 05. pii: S0014-2999(25)00877-5. [Epub ahead of print]1005 178123
    Alpinetin protects against myocardial ischemia-reperfusion injury by inhibiting ferroptosis and apoptosis via mitochondrial ferritin.
    Chenchao Zou, Fajia Hu, Xiuqi Wang, Lanxiang Liu, Huaxi Zou, Jichun Liu, Songqing Lai, Huang Huang.
       PURPOSE: Ischemia-reperfusion injury remains a major problem following myocardial infarction. Alpinetin (ALPT) has been reported to exhibit cardioprotective effects as well as resistance to ischemia-reperfusion injury. However, its role and mechanism during myocardial ischemia-reperfusion injury are unknown.
    METHODS: The anoxia/reoxygenation (A/R) injury model of H9c2 cells and the ischemia reperfusion (I/R) injury model of Sprague-Dawley rats were used in this study. Multiple indicator evaluations, flow cytometry, western blot, and transmission electron microscopy were performed to assess the protective effect of alpinetin pretreatment and its mechanism of action. In addition, the role of mitochondrial ferritin (FTMT) in alpinetin-based protection was investigated using pAD/FTMT-shRNA. The experimental findings were ultimately validated in rat I/R injury models.
    RESULTS: Similar to ferrostatin-1, alpinetin decreased prostaglandin-endoperoxide synthase 2 (PTGS2), lactate dehydrogenase, malondialdehyde, ferrous iron, reactive oxygen species, and oxidized glutathione disulfide (GSSG) levels and increased cell viability, glutathione (GSH) levels, the GSH/GSSG ratio, and glutathione peroxidase 4 protein levels in the injury models. Alpinetin also reversed A/R injury-induced increased caspase-3 activity and apoptosis rate and decreased Bcl-2/Bax ratio and mitochondrial membrane potential level. Of note, alpinetin attenuated mitochondrial damage induced by A/R injury. These protective effects were blocked via FTMT silencing.
    CONCLUSION: Alpinetin protects against myocardial ischemia-reperfusion injury by inhibiting ferroptosis and apoptosis via FTMT.
    Keywords:  Alpinetin; Apoptosis; Ferroptosis; Ischemia–reperfusion injury; Mitochondrial ferritin
    DOI:  https://doi.org/10.1016/j.ejphar.2025.178123
  11. J Sports Sci Med. 2025 Sep;24(3): 613-625
    Effects of High Intensity Interval Training in Normobaric Hypoxia on Aerobic Performance and Exercise-Induced Motor Performance Fatigue in Young Biathletes.
    Aleksandra Żebrowska, Marcin Sikora, Rafał Mikołajczyk, Dagmara Gerasimuk, Mabliny Thuany, Katja Weiss, Beat Knechtle, Barbara Hall.
      This study investigated the effect of high-intensity interval training (HIIT) in normobaric hypoxia on aerobic performance in young biathlon athletes. In addition, the study aimed to assess the impact of training in hypoxia on the mechanisms of exercise-induced motor performance fatigue. In a randomized, controlled crossover study twelve athletes (age 15.7 ± 1.0 years) completed a HIIT in normobaric hypoxia (hypoxia training) (fraction of inspired oxygen, FiO2 = 15.2%) and normoxia (normoxia training) in a randomized order. The HIIT was performed 3 days/week for 6 weeks (3 weeks in hypoxia and 3 weeks in normoxia, with a 3 week wash-out period in between) and consisted of 5 x 4 minutes running (80% of peak oxygen uptake), separated by 3 minutes of active recovery and 4 x 1minute arm cranking (60% peak power), interspersed with a 2 minute rest. Peak oxygen uptake (V̇O2peak), hypoxia-inducible factor 1 alpha (HIF1α), vascular endothelial growth factor (VEGF), pro-inflammatory cytokines, muscle damage biomarkers and total antioxidant status were analyzed before and after both training protocols (HT and NT). A significant effect of hypoxia on V̇O2peak (ηp2 = 0.321, p = 0.044) and hypoxia and training on V̇O2LT and haemoglobin concentrations (ηp2 = 0.689 p = 0.001) were observed. The V̇O2peak was significantly higher post-HT compared to pre-HT (p < 0.01). A significant effect of oxygen conditions and training on the serum post-exercise VEGF (ηp2 = 0.352, p = 0.033) and myoglobin concentrations (ηp2 = 0.647 p = 0.001) was found. A significant effect of hypoxia was also observed for cytokines levels: interleukin-6 (ηp2 = 0.324 p = 0.042), tumour necrosis factor alpha (ηp2 = 0.474 p = 0.009) and transforming growth factor beta (ηp2= 0.410, p = 0.018) with a non-significant effect on antioxidant status. This study shows significant differences in the aerobic performance and biomarkers of muscle damage after exposure to hypoxia training. These findings highlight that HIIT in hypoxia is sufficient to enhance aerobic performance and may also reduce skeletal muscle susceptibility to fatigue in young biathletes.
    Keywords:  Hypoxia; biathlon; biomarkers of skeletal muscle damage; lactate threshold; oxygen uptake; training
    DOI:  https://doi.org/10.52082/jssm.2025.613
  12. NAR Cancer. 2025 Sep;7(3): zcaf021
    Inherent single-cell heterogeneity of the transcriptional response to hypoxia in cancer cells.
    Małgorzata Wilk, Thomas Knöpfel, Stana M Burger, Stellor Nlandu Khodo, Roland H Wenger.
      Hypoxia-inducible factor (HIF) is a master regulator of cancer cell adaptation to tumor hypoxia and is involved in cancer progression. Single-cell (sc) differences in the HIF response allow for tumor evolution and cause therapy resistance. These sc-differences are usually ascribed to tumor microenvironmental differences and/or clonal (epi)genetic variability. However, the sc-heterogeneity of the HIF response in otherwise identical cells cultured under defined in vitro conditions has not yet been addressed. Therefore, we analyzed the sc-response to hypoxia in nonclonal cell lines and multiple clonal derivatives, including HIF-1α or HIF-2α knockouts. While HIF-1α and HIF-1 target mRNA sc-heterogeneity was slightly higher than global transcription or specific housekeeping messenger RNAs (mRNAs), HIF-2α and especially HIF-2 target mRNA sc-heterogeneity was extraordinary, and remained in independent clones following HIFα knockouts. Unexpectedly, neither HIF-2α mRNA nor nuclear protein levels correlated with target mRNA levels. Unsupervised but not supervised HIF target gene dimensionality reduction revealed the initial sample composition after scRNA-seq, demonstrating that, owing to sc-heterogeneity, individual HIF target genes are not sufficient to unequivocally identify hypoxic cancer cells. In conclusion, the pronounced intrinsic sc-heterogeneity of the HIF response represents a hitherto unrecognized feature of cancer cells that impairs clinical HIF pathway-dependent cancer cell identification and targeting.
    DOI:  https://doi.org/10.1093/narcan/zcaf021
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