bims-oxygme Biomed News
on Oxygen metabolism
Issue of 2025–04–13
thirteen papers selected by
Onurkan Karabulut, Berkeley City College
  1. Decoding Proteomic cross-talk between hypobaric and normobaric hypoxia: Integrative analysis of oxidative stress, cytoskeleton remodeling, and inflammatory pathways.
  2. Effect of hypoxia on extracellular vesicles in malignant and non-malignant conditions.
  3. Current Landscape of Hypoxia in Thyroid Cancer Pathogenesis and Treatment.
  4. Integrative Proteomic and Phosphoproteomic Profiling Reveals Molecular Mechanisms of Hypoxic Adaptation in Brandt's Voles (Lasiopodomys brandtii) Brain Tissue.
  5. Differential influence of 1,8-Cineol on distinct hypoxia-related immune alterations in human monocytes.
  6. The landscape of research on ferroptosis under hypoxic conditions: a bibliometric analysis.
  7. The hypoxia signaling pathway in the development of acute myeloid leukemia.
  8. Umbilical cord blood pTau217 and BD-tau are associated with markers of neonatal hypoxia: a prospective cohort study.
  9. Activation of notch signaling pathway is a potential mechanism for mucin2 reduction and intestinal mucosal barrier dysfunction in high-altitude hypoxia.
  10. Resveratrol attenuates the CoCl2-induced hypoxia damage by regulation of lysine β-hydroxybutyrylation in PC12 cells.
  11. Neurological Manifestations Associated with Exercise at Altitude.
  12. A hypoxia research-driven path led to identifying neuroprotection mediators: an interview with Dr. Nicolas G. Bazan.
  13. A comprehensive analysis of microRNA alteration in an ApoE(-/-) mice model of white adipose tissue injury induced by chronic intermittent hypoxia.
  1. Life Sci. 2025 Apr 03. pii: S0024-3205(25)00245-0. [Epub ahead of print]371 123611
    Decoding Proteomic cross-talk between hypobaric and normobaric hypoxia: Integrative analysis of oxidative stress, cytoskeleton remodeling, and inflammatory pathways.
    Poornima Sharma, Swaraj Mohanty, Yasmin Ahmad.
       AIMS: To investigate the differential regulation of proteomic landscapes elicited by hypobaric hypoxia (HH) and normobaric hypoxia (NH) and to shed light on the molecular cross-talk underlying pre-acclimatization strategies.
    MATERIALS AND METHODS: Label-free LCMS-MS quantitative proteomics was employed to evaluate the lung tissues of SD rats (n = 6) subjected to 6 h of acute HH at 25,000 ft associated with reduced barometric pressure, 282 mmHg, and NH at 8 % FiO2.
    KEY FINDINGS: Our findings indicate that NH facilitated the minimal downregulation of proteins involved in maintaining pulmonary cytoskeleton integrity, including calpain 2, vitronectin, and beta-arrestin 1, whereas HH leads to severe downregulation of these proteins, causing a greater cytoskeleton disruption. Proteins contributing to redox homeostasis such as iNOS and SOD, were upregulated in both hypoxic conditions. However, SIRT1-mediated ROS-triggered proteins, including FOXO1 and FOXO4, exhibited upregulation in HH and downregulation in NH. Other proteins, HIF-1α and IDH, were upregulated in HH compared to NH. Additionally, Hemopexin was severely downregulated in HH relative to NH.
    SIGNIFICANCE: For the first time, this study uncovers the comparative proteomic analysis of two distinct pre-acclimatization interventions by employing varied hypoxia modeling strategies highlighting the key molecular mechanism involved in HH acclimatization induced by differential hypoxia simulating technique.
    Keywords:  Cytoskeleton; Hypobaric hypoxia; Inflammation; Normobaric hypoxia; Redox homeostasis
    DOI:  https://doi.org/10.1016/j.lfs.2025.123611
  2. Cancer Treat Res Commun. 2025 Apr 07. pii: S2468-2942(25)00061-9. [Epub ahead of print]43 100924
    Effect of hypoxia on extracellular vesicles in malignant and non-malignant conditions.
    Vahid Niazi, Soudeh Ghafouri-Fard.
      Extracellular vesicles (EVs) are produced by virtually all types of cells and can be detected in nearly all extracellular places. These particles mediate intercellular communication and transfer their cargo to the recipient cells, inducing a variety of processes in these cells through transmission of several biomolecules such as miRNAs, lncRNAs, other transcripts and a variety of proteins. It has been documented that size, quantity, and expression of biomolecules in the EVs are influenced by the level of oxygen. In fact, hypoxia can affect several cellular processes through modulation of the cargo of these vesicles. Hypoxic exosomes derived from tumor cells have several protumoral effects on the recipient cells, including enhancement of proliferation, migration, and invasion in other tumoral cells, induction of metastasis in distant organs, stimulation of angiogenesis in the endothelial cells, and modulation of macrophage polarization. Hypoxic EVs also contribute to several non-malignant diseases. This review summarizes the effect of hypoxia on EVs cargo in malignant and nonmalignant diseases of different organs.
    Keywords:  Cancer; Exosome; Extracellular vesicle; Hypoxia
    DOI:  https://doi.org/10.1016/j.ctarc.2025.100924
  3. Crit Rev Oncol Hematol. 2025 Apr 08. pii: S1040-8428(25)00107-6. [Epub ahead of print] 104719
    Current Landscape of Hypoxia in Thyroid Cancer Pathogenesis and Treatment.
    Jianhong Ye, Liang Chen.
      Thyroid cancer, the most prevalent endocrine malignancy, exhibits diverse clinical behaviors ranging from indolent to highly aggressive forms. A critical factor influencing the progression and treatment resistance of thyroid cancer is hypoxia-a condition characterized by inadequate oxygen supply to the tumor microenvironment. Hypoxia induces the stabilization of hypoxia-inducible factors (HIFs), particularly HIF-1α and HIF-2α, drive various oncogenic processes such as epithelial-mesenchymal transition (EMT), angiogenesis, metabolic reprogramming, and immune evasion. These processes contribute to the aggressive phenotypes observed in poorly differentiated and anaplastic thyroid cancers. This review explores the molecular mechanisms by which hypoxia and HIFs influence thyroid cancer pathogenesis, focusing on key signaling pathways, including NF-κB, Wnt/β-catenin, Hedgehog, and others. Furthermore, we discuss potential therapeutic strategies targeting the hypoxic microenvironment, such as HIF inhibitors and natural compounds, which have shown promise in preclinical studies. Understanding the role of hypoxia in thyroid cancer not only offers insights into the disease's progression but also highlights new avenues for therapeutic intervention aimed at improving patient outcomes.
    Keywords:  Hypoxia; Thyroid cancer; hypoxia-inducible factors; signaling pathways; therapeutic strategy
    DOI:  https://doi.org/10.1016/j.critrevonc.2025.104719
  4. Cells. 2025 Apr 01. pii: 527. [Epub ahead of print]14(7):
    Integrative Proteomic and Phosphoproteomic Profiling Reveals Molecular Mechanisms of Hypoxic Adaptation in Brandt's Voles (Lasiopodomys brandtii) Brain Tissue.
    Panqin Wang, Yongyan Liu, Yimeng Du, Yiwen Gao, Tian Shao, Weifeng Guo, Zhenlong Wang, Han Cheng.
      Rapid ascent to high altitudes by unacclimatized individuals significantly increases the risk of brain damage, given the brain's heightened sensitivity to hypoxic conditions. Investigating hypoxia-tolerant animals can provide insights into adaptive mechanisms and guide prevention and treatment of hypoxic-ischemic brain injury. In this study, we exposed Brandt's voles to simulated altitudes (100 m, 3000 m, 5000 m, and 7000 m) for 24 h and performed quantitative proteomic and phosphoproteomic analyses of brain tissue. A total of 3990 proteins and 9125 phosphorylation sites (phospho-sites) were quantified. Differentially expressed (DE) analysis revealed that while protein abundance changes were relatively modest, phosphorylation levels exhibited substantial alterations, suggesting that Brandt's voles rapidly regulate protein structure and function through phosphorylation to maintain cellular homeostasis under acute hypoxia. Clustering analysis showed that most co-expressed proteins exhibited non-monotonic responses with increasing altitude, which were enriched in pathways related to cytokine secretion regulation and glutathione metabolism, contributing to reduced inflammation and oxidative stress. In contrast, most co-expressed phospho-sites showed monotonic changes, with phospho-proteins enriched in glycolysis and vascular smooth muscle contraction regulation. Kinase activity prediction identified nine hypoxia-responsive kinases, four of which belonging to the CAMK family. Immunoblot validated that the changes in CAMK2A activity were consistent with predictions, suggesting that CAMK may play a crucial role in hypoxic response. In conclusion, this work discovered that Brandt's voles may cope with hypoxia through three key strategies: (1) vascular regulation to enhance cerebral blood flow, (2) glycolytic activation to increase energy production, and (3) activation of neuroprotective mechanisms.
    Keywords:  Brandt’s voles; brain; hypoxia; phosphoproteomic; proteomic
    DOI:  https://doi.org/10.3390/cells14070527
  5. Sci Rep. 2025 Apr 09. 15(1): 12126
    Differential influence of 1,8-Cineol on distinct hypoxia-related immune alterations in human monocytes.
    Nele Jagodzinski, Anke Leichtle, Reinhard Depping, Kirstin Plötze-Martin, Samer G Hakim, Karl-Ludwig Bruchhage, Ralph Pries.
      1,8-Cineol is a natural plant-based therapeutic agent and is commonly used to treat a broad range of acute and chronic airway inflammatory diseases. 1,8-Cineol has recently been shown to attenuate the checkpoint molecule PDL-1 in circulating monocytes in patients with chronic Otitis media (OM) and was associated with an improved clinical outcome. Hypoxia-inducible factor (HIF) is thought to play an essential role in the middle ear inflammatory process, mainly due to dysfunctions of the eustachian tube. However, the unambiguous impact of 1,8-Cineol on hypoxia-driven immune alterations of human monocytes and the related inflammatory microenvironment have not been investigated thus far. Therefore, we used the human monocytes to investigate the impact of 1,8-Cineol on the cellular hypoxia response with regards to expression levels of different adhesion molecules, chemokine receptors, and different cell stress-related proteins. Furthermore, the secretion patterns of a variety of chemokines and cytokines were evaluated. The study aimed to better understand the influence of the monoterpene 1,8-Cineol on hypoxia and normoxia-associated monocyte characteristics and related inflammatory processes, all of which are crucial for the development of various human diseases.
    Keywords:  1,8-Cineol; Adhesion molecules; Cytokines; FGF-7; Hypoxia; Monocytes
    DOI:  https://doi.org/10.1038/s41598-025-97314-7
  6. Front Pharmacol. 2025 ;16 1519000
    The landscape of research on ferroptosis under hypoxic conditions: a bibliometric analysis.
    Di Yu, Yibo Hu, Meijuan Ma, Wenjia Li, Xiaohui Zhao.
       Background: Ferroptosis is a newly identified type of iron-dependent cell death that characterized by an increase in intracellular iron ions, which disrupt the balance of the cellular lipid peroxidation system, causing lipid peroxidation and ultimately resulting in cell death. Interestingly, ferroptosis is modulated by hypoxia and plays a role in hypoxia-related diseases. Therefore, we performed a bibliometric review of the Web of Science Core Collection (WoSCC) database to investigate the link between ferroptosis and hypoxia from January 2013 to December 2023.
    Method: The core collection within the Web of Science bibliographic index was consulted to extract relevant articles and reviews. Data on publications, countries, institutions, authors, journals, citations, and keywords in the included studies were systematically analyzed using Microsoft Excel 2019 and CiteSpace 6.3.R1 software.
    Result: A comprehensive analysis and visualization of 472 research papers on ferroptosis under hypoxic conditions published between 2013 and 2023 revealed emerging research hotspots and trends. Initially, a scarcity of studies existed in this field. However, this was succeeded by a significant increase in research interest in subsequent years, culminating in a peak of 204 publications in 2023. Research in this field focused primarily on the Asian region. Notably, research hotspots include diseases related to hypoxia, treatment therapy and pathogenesis. Among the researchers in this field, Supuran emerged as the most prolific author. Wuhan University was the leading institution in terms of research output, and China was the most prolific country in this area of study. Among the top ten journals ranked by the number of publications, nine were classified as Q1, indicating the high level of credibility of these studies. The research conducted by Stockwell et al., featured in the journal "Cell," currently has the most citations. Present scholarly pursuits are primarily focused on comprehending the mechanisms through which interventions affect hypoxia-related diseases through the ferroptosis pathway, as well as on probing and pinpointing prospective treatment targets.
    Conclusion: This study highlights key areas of interest and emerging trends in ferroptosis research in the presence of hypoxic conditions, thus providing valuable insights for future directions of exploration for the diagnosis and treatment of hypoxia-related diseases.
    Keywords:  bibliometric analysis; citespace; ferroptosis; hotspot; hypoxia
    DOI:  https://doi.org/10.3389/fphar.2025.1519000
  7. Biomed Pharmacother. 2025 Apr 05. pii: S0753-3322(25)00193-3. [Epub ahead of print]186 117999
    The hypoxia signaling pathway in the development of acute myeloid leukemia.
    Liqing Yang, Yuanzhong Chen, Yong Wu.
      Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Although advances in targeted agents have greatly improved the prognosis of patients with AML in recent years, those who fail to achieve remission or relapse after remission are still in urgent need of novel therapeutic strategies. The hypoxia signaling pathway is involved in various biological processes, and hypoxia-inducible factor alpha (HIF-α) is considered a potential therapeutic target in AML. The bone marrow microenvironment is known to be in a state of chronic hypoxia, which is important for hematopoietic stem cells to maintain quiescence, and provides leukemic stem cells with a refuge from immune defenses and chemotherapeutic agents. Therefore, this review aims to explore the role of the HIF-α signaling pathway in the development of AML.
    Keywords:  Acute myeloid leukemia; Bone marrow microenvironment; Hypoxia-inducible factor alpha; Targeted therapy
    DOI:  https://doi.org/10.1016/j.biopha.2025.117999
  8. medRxiv. 2025 Mar 24. pii: 2024.12.20.24319360. [Epub ahead of print]
    Umbilical cord blood pTau217 and BD-tau are associated with markers of neonatal hypoxia: a prospective cohort study.
    Emma Payne, Fernando Gonzalez-Ortiz, Kaitlin Kramer, Thomas Payne, Shreeya Marathe, Neha Mahajan, Ashly Liu, Jessica Barry, Andrew Duckworth, Mitchell Brookes, Bradley de Vries, Benjamin Moran, Helen Manning, Adrienne Gordon, Kaj Blennow, Henrik Zetterberg, David Zalcberg, Robert D Sanders.
       Objective: Current methods for early detection of hypoxic-ischemic encephalopathy (HIE) are limited by lack of specificity, cost, and time constraints. Blood tau protein concentrations reflect neuropathology in adults. This study examines tau as a potential HIE biomarker in neonates by relating cord blood levels to short-term fetomaternal outcomes. We aimed to examine 1) association of BD-tau with non-reassuring fetal status; 2) correlations between cord blood tau and other hypoxia biomarkers; 3) associations between tau levels and risk factors for fetomaternal morbidity; 4) associations between tau levels and short-term fetomaternal outcome.
    Methods: 107 maternal participants were prospectively recruited at Royal Prince Alfred Hospital-a large Australian tertiary referral centre. Simoa analysis detected umbilical cord blood pTau217 and brain-derived (BD)-tau levels.
    Results: Of 509 deliveries, cord blood was analysed in 107/110 recruited maternal participants. BD-tau correlated with non-reassuring fetal status (OR=3.0;95%CI=1.6- 5.7;p=0.001), though not when adjusting for mode of delivery and gestational age. BD-tau was higher in vaginal deliveries, and positively associated with pTau217, NfL, and lactate (p<0.001), and negatively associated with pH and base excess. pTau217 was higher in preterm neonates and was associated with neurofilament light chain (Spearman's rho=0.44,p<0.001). BD-tau and pTau217 were associated with maternal hypertension and placental abnormalities.
    Conclusions: Cord blood BD-tau correlates with surrogate markers of fetal hypoxia, whilst pTau217 may represent a marker of neurodevelopment. Further studies could explore whether these findings translate to clinical use of tau as an HIE biomarker.
    Funding: US National Institutes of Health (grant:R01AG063849-01).
    DOI:  https://doi.org/10.1101/2024.12.20.24319360
  9. Sci Rep. 2025 Apr 09. 15(1): 12154
    Activation of notch signaling pathway is a potential mechanism for mucin2 reduction and intestinal mucosal barrier dysfunction in high-altitude hypoxia.
    Ruhan Jia, Ying Han, Qinfang Zhu, Jingxuan Zhang, Huan Zhang, Maojia Ka, Yi Ma, Mohammed Gamah, Wei Zhang.
      High-altitude hypoxia can cause gastrointestinal issues and damage the intestinal mucosal barrier, which is crucial for digestion and nutrient absorption. The Notch signaling pathway affects this barrier's integrity. This study explores the Notch pathway's role in hypoxia-induced intestinal injury. C57BL/6 mice were used to model intestinal mucosal barrier injury through dextran sodium sulfate (DSS) and hypobaric hypoxia (simulating 5000 m altitude for 7 days). Mice were treated with Notch inhibitor Dibenzazepine (DBZ) and Mucin2 (MUC2) activator Prostaglandin E2 (PGE2). We evaluated weight, colon length, histology, Zonula occludens 1 (ZO-1) and Claudin-1 levels, MUC2 and Notch1 staining, serum diamine oxidase (DAO) and D-lactate (D-La), inflammatory markers, and Notch pathway proteins. DSS and hypoxia caused weight loss, colon shortening, ulcers, and inflammation, with fewer goblet cells and lower MUC2 levels. Elevated serum DAO, D-La, and inflammatory markers indicated severe intestinal damage. DBZ treatment post-DSS and hypoxia significantly reduced these symptoms. PGE2 activation of MUC2 also alleviated symptoms and mitigated intestinal damage. Hypoxia worsens DSS-induced mucosal barrier disruption by activating the Notch pathway, shifting stem cell differentiation towards absorptive cells instead of goblet cells, reducing MUC2 secretion, and intensifying damage. Targeting the Notch pathway and enhancing MUC2 expression could effectively treat hypoxia-induced intestinal injury.
    Keywords:  High-altitude hypoxia; Intestinal mucosa barrier; MUC2; Notch signaling pathway
    DOI:  https://doi.org/10.1038/s41598-025-96176-3
  10. BMC Neurol. 2025 Apr 10. 25(1): 153
    Resveratrol attenuates the CoCl2-induced hypoxia damage by regulation of lysine β-hydroxybutyrylation in PC12 cells.
    Yamei Wang, Jian Zhao, Liang Sun, Dingding Xu, Xiaoming Wei, Jia Li, Zihan Mo, Nian Xia, Junge Zhou, Yuan Yao, Qiao Hu, Qingqing Zhou.
       BACKGROUND: Stroke is a cerebrovascular disease that is the main cause of death and disability worldwide. Hypoxia is a major factor that causes neuronal damage and even cellular death. However, the mechanism and therapeutic drugs for hypoxia are not completely understood.
    METHODS: In this study, PC12 cells (a rat adrenal pheochromocytoma cell line) were exposed to Cobalt chloride (CoCl2) to induce hypoxia. Using this cell model, the impacts of hypoxia on cell viability, proliferation, reactive oxygen species (ROS), and the levels of lysine β-hydroxybutyrylation (Kbhb) and the inflammatory signaling factor P65 were examined. In addition, we explored the ability of resveratrol (RES) to alleviate CoCl2-induced hypoxia damage.
    RESULTS: RES attenuated CoCl2-induced decreases of cell viability and cell proliferation and increase of ROS production in PC12 cells. CoCl2 downregulated Kbhb in PC12 cells, but RES alleviated this effect. In addition, upregulated Kbhb by 3-hydroxybutyric acid sodium could partially recover the CoCl2-induced hypoxia damage to PC12 cells, including cell viability, cell proliferation, oxidative stress, and the protein level of the inflammatory signaling factor P65.
    CONCLUSION: Our results indicate that RES protects against CoCl2-induced hypoxia damage in PC12 cells by modulating Kbhb, a novel post-translational modification.
    Keywords:  CoCl2 ; Hypoxia; Lysine β-hydroxybutyrylation; PC12 cells; Reactive oxygen species; Resveratrol
    DOI:  https://doi.org/10.1186/s12883-025-04171-y
  11. Curr Neurol Neurosci Rep. 2025 Apr 09. 25(1): 29
    Neurological Manifestations Associated with Exercise at Altitude.
    A Marengo, M Tejada, I Hancco Zirena, S Molina.
       PURPOSE OF REVIEW: The effects that exercise at altitude has on the neurological system are diverse and still not well studied, and range from metabolic adaptations to modification of cerebral blood flow and neurotransmitters. In this review we summarise changes with exercise intensity, the implications of ascent, cognitive impairment, psychosis-like symptoms, the role of exercise in the development and prevention of AMS, and use of free radical scavengers to enhance sports performance and acclimatization.
    RECENT FINDINGS: We discuss the impact of oxidative stress in hypobaric hypoxia and reactive oxygen species (ROS) production and its consequences, with special focus on exercise at altitude. Finally we consider how moderate intensity exercise could help prevent AMS, and the necessity of research on high intensity exercise with elevated rate of ascent, the development of specific tools of cognitive assessment, and the role of free-radical scavengers in the prevention of AMS and neurological symptoms.
    Keywords:  Cognitive; Exercise; High-altitude illness; Hypoxia; Neurological; Oxidative stress
    DOI:  https://doi.org/10.1007/s11910-025-01418-6
  12. Cell Death Discov. 2025 Apr 04. 11(1): 141
    A hypoxia research-driven path led to identifying neuroprotection mediators: an interview with Dr. Nicolas G. Bazan.
    Nicolas G Bazan.
      
    DOI:  https://doi.org/10.1038/s41420-025-02436-6
  13. Front Genet. 2025 ;16 1474223
    A comprehensive analysis of microRNA alteration in an ApoE(-/-) mice model of white adipose tissue injury induced by chronic intermittent hypoxia.
    Jinjie Zhang, Yaopeng Guo, Meilin Ji, Shu Lin, Dexin Liu, Qingshi Chen.
       Background: MicroRNAs (miRNAs) represent a class of noncoding small RNAs and are implicated in many diseases. However, the role of miRNA in obstructive sleep apnea (OSA)-induced white adipose tissue (WAT) dysfunction remains to be fully elucidated. Using miRNA sequencing (miRNA-seq), we uncovered the miRNA expression profiles in chronic intermittent hypoxia (CIH)-induced WAT dysfunction mice.
    Methods: We established an apolipoprotein-deficient (ApoE-/-) CIH mouse model and identified differentially expressed miRNAs (DEmiRs) using miRNA-seq technology. With the help of Gene Ontology (GO) functional enrichment and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, we determined the biological functions of these DEmiRs. In addition, RT-qPCR was performed for further evaluation of the sequencing data. Finally, we constructed a conserved negative correlation (CNC) network to expound the relationship between miRNA and target genes.
    Results: Overall, 13 miRNAs were found to be upregulated and 18 miRNAs downregulated in the CIH-induced mouse model of WAT dysfunction. KEGG pathway analysis results indicated that the lysosome pathway participated in CIH-induced WAT dysfunction. Then, eight miRNAs were shortlisted for RT-qPCR validation. Based on the data, we chose these DEmiRs to construct a miRNA-mRNA regulatory network.
    Conclusion: Overall, we identified 31 DEmiRs in the ApoE-/- CIH mouse model. Our findings may play a major role in explaining the pathophysiological mechanisms of WAT dysfunction induced by obstructive sleep apnea.
    Keywords:  bioinformatics analysis; chronic intermittent hypoxia; miRNA sequencing; microRNA; white adipose tissue dysfunction
    DOI:  https://doi.org/10.3389/fgene.2025.1474223
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