bims-oxygme Biomed News
on Oxygen metabolism
Issue of 2025–01–26
fourteen papers selected by
Onurkan Karabulut, Berkeley City College
  1. Exploring the Molecular Interplay Between Oxygen Transport, Cellular Oxygen Sensing, and Mitochondrial Respiration.
  2. HIF-1 and HIF-2 in cancer: structure, regulation, and therapeutic prospects.
  3. Genomic and physiological mechanisms of high-altitude adaptation in Ethiopian highlanders: a comparative perspective.
  4. Hypoxia as a medicine.
  5. MiRNA-223-5p inhibits hypoxia-induced apoptosis of BMSCs and promotes repair in Legg-Calvé-Perthes disease by targeting CHAC2 and activating the Wnt/β-catenin signaling pathway.
  6. Identification of robust RT-qPCR reference genes for studying changes in gene expression in response to hypoxia in breast cancer cell lines.
  7. CaMKIIγ advances chronic intermittent hypoxia-induced cardiomyocyte apoptosis via HIF-1 signaling pathway.
  8. Therapeutic delivery of oxygen using artificial oxygen carriers demonstrates the possibility of treating a wide range of diseases.
  9. Nitroaromatic-based triazene prodrugs to target the hypoxic microenvironment in glioblastoma.
  10. The role of alternative oxidase in the maintenance of cellular redox balance under hypoxia via participation in nitric oxide turnover.
  11. Effect of β-catenin on hypoxia induced epithelial mesenchymal transition in HK-2 cells by regulating Brachyury.
  12. The Link between Oxygen and Basement Membranes.
  13. The oxygen level in air directs airway epithelial cell differentiation by controlling mitochondrial citrate export.
  14. A Study of Volatile Organic Compounds in Patients with Obstructive Sleep Apnea.
  1. Antioxid Redox Signal. 2025 Jan 23.
    Exploring the Molecular Interplay Between Oxygen Transport, Cellular Oxygen Sensing, and Mitochondrial Respiration.
    Sirsendu Jana, Abdu I Alayash.
      Significance: The mitochondria play a key role in maintaining oxygen homeostasis under normal oxygen tension (normoxia) and during oxygen deprivation (hypoxia). This is a critical balancing act between the oxygen content of the blood, the tissue oxygen sensing mechanisms, and the mitochondria, which ultimately consume most oxygen for energy production. Recent Advances: We describe the well-defined role of the mitochondria in oxygen metabolism with a special focus on the impact on blood physiology and pathophysiology. Critical Issues: Fundamental questions remain regarding the impact of mitochondrial responses to changes in overall blood oxygen content under normoxic and hypoxic states and in the case of impaired oxygen sensing in various cardiovascular and pulmonary complications including blood disorders involving hemolysis and hemoglobin toxicity, ischemia reperfusion, and even in COVID-19 disease. Future Directions: Understanding the nature of the crosstalk among normal homeostatic pathways, oxygen carrying by hemoglobin, utilization of oxygen by the mitochondrial respiratory chain machinery, and oxygen sensing by hypoxia-inducible factor proteins, may provide a target for future therapeutic interventions. Antioxid. Redox Signal. 00, 000-000.
    Keywords:  blood; hemoglobin; hypoxia; mitochondria; oxygen homeostasis
    DOI:  https://doi.org/10.1089/ars.2023.0428
  2. Cell Mol Life Sci. 2025 Jan 18. 82(1): 44
    HIF-1 and HIF-2 in cancer: structure, regulation, and therapeutic prospects.
    Yi Shi, Daniele M Gilkes.
      Hypoxia, or a state of low tissue oxygenation, has been characterized as an important feature of solid tumors that is related to aggressive phenotypes. The cellular response to hypoxia is controlled by Hypoxia-inducible factors (HIFs), a family of transcription factors. HIFs promote the transcription of gene products that play a role in tumor progression including proliferation, angiogenesis, metastasis, and drug resistance. HIF-1 and HIF-2 are well known and widely described. Although these proteins share a high degree of homology, HIF-1 and HIF-2 have non-redundant roles in cancer. In this review, we summarize the similarities and differences between HIF-1α and HIF-2α in their structure, expression, and DNA binding. We also discuss the canonical and non-canonical regulation of HIF-1α and HIF-2α under hypoxic and normal conditions. Finally, we outline recent strategies aimed at targeting HIF-1α and/or HIF-2α.
    Keywords:  Cancer; HIF-1; HIF-2; Hypoxia; Tumor
    DOI:  https://doi.org/10.1007/s00018-024-05537-0
  3. Front Genet. 2024 ;15 1510932
    Genomic and physiological mechanisms of high-altitude adaptation in Ethiopian highlanders: a comparative perspective.
    Wubalem Desta Seifu, Abreham Bekele-Alemu, Changqing Zeng.
      High-altitude adaptation is a remarkable example of natural selection, yet the genomic and physiological adaptation mechanisms of Ethiopian highlanders remain poorly understood compared to their Andean and Tibetan counterparts. Ethiopian populations, such as the Amhara and Oromo, exhibit unique adaptive strategies characterized by moderate hemoglobin levels and enhanced arterial oxygen saturation, indicating distinct mechanisms of coping with chronic hypoxia. This review synthesizes current genomic insights into Ethiopian high-altitude adaptation, identifying key candidate genes involved in hypoxia tolerance and examining the influence of genetic diversity and historical admixture on adaptive responses. Furthermore, the review highlights significant research gaps, particularly the underrepresentation of Ethiopian populations in global genomic studies, the lack of comprehensive genotype-phenotype analyses, and inconsistencies in research methodologies. Addressing these gaps is crucial for advancing our understanding of the genetic basis of human adaptation to extreme environments and for developing a more complete picture of human physiological resilience. This review offers a comparative perspective with Tibetan and Andean highlanders, emphasizing the need for expanding genomic representation and refining methodologies to uncover the genetic mechanisms underlying high-altitude adaptation in Ethiopian populations.
    Keywords:  Ethiopian highlanders; comparative analysis; genetic diversity; genomics; high-altitude adaptation; hypoxia tolerance; physiological mechanisms
    DOI:  https://doi.org/10.3389/fgene.2024.1510932
  4. Sci Transl Med. 2025 Jan 22. 17(782): eadr4049
    Hypoxia as a medicine.
    Robert S Rogers, Vamsi K Mootha.
      Oxygen is essential for human life, yet a growing body of preclinical research is demonstrating that chronic continuous hypoxia can be beneficial in models of mitochondrial disease, autoimmunity, ischemia, and aging. This research is revealing exciting new and unexpected facets of oxygen biology, but translating these findings to patients poses major challenges, because hypoxia can be dangerous. Overcoming these barriers will require integrating insights from basic science, high-altitude physiology, clinical medicine, and sports technology. Here, we explore the foundations of this nascent field and outline a path to determine how chronic continuous hypoxia can be safely, effectively, and practically delivered to patients.
    DOI:  https://doi.org/10.1126/scitranslmed.adr4049
  5. PLoS One. 2025 ;20(1): e0315230
    MiRNA-223-5p inhibits hypoxia-induced apoptosis of BMSCs and promotes repair in Legg-Calvé-Perthes disease by targeting CHAC2 and activating the Wnt/β-catenin signaling pathway.
    Jiafei Yang, Tianjiu Zhang, Xingtao Zhu, Zhexi He, Xu Jiang, Song Yu, Huajian Gu.
      Legg-Calvé-Perthes disease (LCPD) involves femoral head osteonecrosis caused by disrupted blood supply, leading to joint deformity and early osteoarthritis. This study investigates the role of miRNA-223-5p in regulating hypoxia-induced apoptosis and enhancing osteogenesis in bone marrow mesenchymal stem cells (BMSCs). Utilizing a juvenile New Zealand white rabbit model of LCPD established through femoral neck ligation, we transfected BMSCs with miR-223-5p mimics, inhibitors, and controls, followed by hypoxic exposure. The impact of miR-223-5p on BMSC apoptosis was assessed using qPCR, Western blotting, and dual-luciferase reporter assays, focusing on the Wnt/β-catenin signaling pathway. In vivo, we evaluated the effects of transplanting miR-223-5p-overexpressing BMSCs into the LCPD model. Our results indicate that miR-223-5p is downregulated under hypoxic conditions. Overexpression of miR-223-5p in BMSCs inhibited hypoxia-induced apoptosis and activated the Wnt/β-catenin pathway by directly targeting CHAC2. In vivo, miR-223-5p-overexpressing BMSCs enhanced femoral head osteogenesis and reduced necrosis in the LCPD model. These findings suggest that miR-223-5p inhibits hypoxia-induced apoptosis in BMSCs by targeting CHAC2 and activating the Wnt/β-catenin pathway, proposing miR-223-5p as a promising target for improving bone repair in ischemic conditions.
    DOI:  https://doi.org/10.1371/journal.pone.0315230
  6. BMC Genomics. 2025 Jan 21. 26(1): 59
    Identification of robust RT-qPCR reference genes for studying changes in gene expression in response to hypoxia in breast cancer cell lines.
    Jodie R Malcolm, Katherine S Bridge, Andrew N Holding, William J Brackenbury.
      Hypoxia is common in breast tumours and is linked to therapy resistance and advanced disease. To understand hypoxia-driven breast cancer progression, RT-qPCR is a widely used technique to quantify transcriptional changes that occur during malignant transformation. Reference genes (RGs) are endogenous RT-qPCR controls used to normalise mRNA levels, allowing accurate assessment of transcriptional changes. However, hypoxia reprograms transcription and post-transcriptional processing of RNA such that favoured RGs including GAPDH or PGK1 are unsuitable for this purpose. To address the need for robust RGs to study hypoxic breast cancer cell lines, we identified 10 RG candidates by analysing public RNA-seq data of MCF-7 and T-47D (Luminal A), and, MDA-MB-231 and MDA-MB-468 (triple negative breast cancer (TNBC)) cells cultured in normoxia or hypoxia. We used RT-qPCR to determine RG candidate levels in normoxic breast cancer cells, removing TBP and EPAS1 from downstream analysis due to insufficient transcript abundance. Assessing primer efficiency further removed ACTB, CCSER2 and GUSB from consideration. Following culture in normoxia, acute, or chronic hypoxia, we ascertained robust non-variable RGs using RefFinder. Here we present RPLP1 and RPL27 as optimal RGs for our panel of two Luminal A and two TNBC cell lines cultured in normoxia or hypoxia. Our result enables accurate evaluation of gene expression in selected hypoxic breast cancer cell lines and provides an essential resource for assessing the impact of hypoxia on breast cancer progression.
    DOI:  https://doi.org/10.1186/s12864-025-11216-6
  7. Sleep Breath. 2025 Jan 21. 29(1): 85
    CaMKIIγ advances chronic intermittent hypoxia-induced cardiomyocyte apoptosis via HIF-1 signaling pathway.
    Xuechao Yang, Xinyu Sha, Gang Wang, Duo Xu, Jingji Zhang, Ming Tang, Jiahai Shi.
       BACKGROUND: Our previous study have demonstrated chronic intermittent hypoxia (CIH) induced cardiomyocyte apoptosis and cardiac dysfunction. However, the molecular mechanisms are complicated and varied. In this study, we first investigated the CaMKIIγ expression and signaling pathway in the pathogenesis of cardiomyocyte apoptosis after CIH.
    METHODS: Rats were separated into CIH and Normoxia groups, and H9c2 cells were divided into Control and CIH + 8 h groups. Rat body weight (BW) was markedly gained from two to six weeks. Furthermore, CIH decreased cardiac dysfunction, damaged cellular structure, induced myocardial fibrosis, and promoted cardiomyocyte apoptosis by HE, masson, sirius-red, and TUNEL staining. Western blot, immunohistochemical, immunofluorescence, double immunofluorescence staining were performed to investigate CaMKIIγ, Bcl-2, Bax, Caspase 3, HIF-1 protein expression.
    RESULTS: Heart weight (HW) and HW/BW ratio in CIH group was markedly gained compared with the Normoxia group. CaMKIIγ expression was notably increased after CIH, and mainly expressed in the cytoplasm in vivo and vitro. The results of HIF-1 expression have the same trend of CaMKIIγ expression and cardiomyocyte apoptosis. In addition, the co-localizations of CaMKIIγ with Caspase 3, and CaMKIIγ with HIF-1 were observed by double immunofluorescence staining.
    CONCLUSIONS: These results indicated increased CaMKIIγ expression advances CIH-induced cardiomyocyte apoptosis via HIF-1 signaling pathway, which afford a new insight and provide a potential therapy for OSA patients.
    Keywords:  Apoptosis; CaMKIIγ; Cardiomyocyte; Chronic intermittent hypoxia; H9c2 cells; HIF-1
    DOI:  https://doi.org/10.1007/s11325-024-03225-8
  8. J Nanobiotechnology. 2025 Jan 18. 23(1): 25
    Therapeutic delivery of oxygen using artificial oxygen carriers demonstrates the possibility of treating a wide range of diseases.
    Nijaya Mohanto, Himangsu Mondal, Young-Joon Park, Jun-Pil Jee.
      Artificial oxygen carriers have emerged as potential substitutes for red blood cells in situations of major blood loss, including accidents, surgical procedures, trauma, childbirth, stomach ulcers, hemorrhagic shock, and blood vessel ruptures which can lead to sudden reduction in blood volume. The therapeutic delivery of oxygen utilizing artificial oxygen carriers as red blood cell substitutes presents a promising avenue for treating a spectrum of disease models. Apart from that, the recent advancement of artificial oxygen carriers intended to supplant conventional blood transfusions draws significant attention due to the exigencies of warfare and the ongoing challenges posed by the COVID-19 pandemic. However, there is a pressing need to formulate stable, non-toxic, and immunologically inert oxygen carriers. Even though numerous challenges are encountered in the development of artificial oxygen carriers, their applicability extends to various medical treatments, encompassing elective and cardiovascular surgeries, hemorrhagic shock, decompression illness, acute stroke, myocardial infarction, sickle cell crisis, and proficient addressing conditions such as cerebral hypoxia. Therefore, this paper provides an overview of therapeutic oxygen delivery using assorted types of artificial oxygen carriers, including hemoglobin-based, perfluorocarbon-based, stem cell-derived, and oxygen micro/nanobubbles, in the treatment of diverse disease models. Additionally, it discusses the potential side effects and limitations associated with these interventions, while incorporating completed and ongoing research and recent clinical developments. Finally, the prospective solutions and general demands of the perfect artificial oxygen carriers were anticipated to be a reference for subsequent research endeavors.
    Keywords:  Artificial oxygen carriers; Disease models; Hemoglobin; Perfluorocarbon; Red blood cell substitutes; Stem cell; Therapeutic oxygen delivery
    DOI:  https://doi.org/10.1186/s12951-024-03060-9
  9. RSC Med Chem. 2025 Jan 20.
    Nitroaromatic-based triazene prodrugs to target the hypoxic microenvironment in glioblastoma.
    Cláudia Braga, Margarida Ferreira-Silva, M Luísa Corvo, Rui Moreira, Alexandra R Fernandes, João Vaz, Maria J Perry.
      Hypoxia is a hallmark of the glioblastoma multiforme microenvironment and represents a promising therapeutic target for cancer treatment. Herein, we report nitroaromatic-based triazene prodrugs designed for selective activation by tumoral endogenous reductases and release of the cytotoxic methyldiazonium ion via a self-immolative mechanism. While compounds bearing a 2-nitrofuran bioreductive group were more efficiently activated by nitroreductases, 4-nitrobenzyl prodrugs 1b, 1d and 1e elicited a more pronounced cytotoxic effect against LN-229 and U-87 MG glioblastoma cell lines under hypoxic conditions when compared to temozolomide (TMZ), the golden standard for glioblastoma treatment. This cytotoxic response aligns with the increased apoptosis levels in LN-229 cells and senescence induction in U-87 MG cells, promoted by prodrugs 1d and 1e, under hypoxic conditions. These results highlight the potential of these hypoxia-activated nitroaromatic-based triazene prodrugs for selective delivery of the cytotoxic methyldiazonium ion and support further optimization to provide a safer alternative for glioblastoma treatment.
    DOI:  https://doi.org/10.1039/d4md00876f
  10. J Exp Bot. 2025 Jan 22. pii: eraf021. [Epub ahead of print]
    The role of alternative oxidase in the maintenance of cellular redox balance under hypoxia via participation in nitric oxide turnover.
    Abir U Igamberdiev, Natalia V Bykova.
      Alternative oxidase (AOX) regulates the level of reactive oxygen species and nitric oxide (NO) in plants. While under normoxic conditions it alleviates NO formation, there are several indications that in the conditions of low oxygen such as during seed germination before radicle protrusion, in meristematic stem cells, and in flooded roots AOX can be involved in the production of NO from nitrite. Whereas the first reports considered this role as indirect, more evidence is accumulated that AOX can act as a nitrite: NO reductase. Such activity of the structurally similar di-iron proteins in bacteria has been demonstrated. We review the literature on this topic and show that AOX can be induced under hypoxic conditions and participate in NO turnover via the phytoglobin-NO cycle. This results in the facilitation of glycolytic reactions by reoxidation of the glycolytically formed NADH and diverting the glycolytic carbon toward the formation of alanine and other amino acids. Pyruvate formed in glycolysis can activate AOX and facilitate its operation under these conditions. It is concluded that AOX is an important player in the hypoxic response in plants that regulates the redox level by participating in NO turnover as a nitrite: NO reductase in cooperation with nitrate reductase and phytoglobin.
    Keywords:  alternative oxidase; hypoxia; mitochondria; nitric oxide; phytoglobin; redox regulation; seed germination
    DOI:  https://doi.org/10.1093/jxb/eraf021
  11. Biochem Biophys Rep. 2025 Mar;41 101907
    Effect of β-catenin on hypoxia induced epithelial mesenchymal transition in HK-2 cells by regulating Brachyury.
    Ping Sun, Haihui Yang, Binying Min, Yongfu Li, Jun Wang, Mo Chen, Diping Yu, Wenjuan Sun.
       Background: Chronic kidney disease (CKD) has become a worldwide health problem and the incidence rate and mortality of CKD have been rising. Renal fibrosis (RF) is the final common pathological feature of almost all kinds of CKD and Epithelial-mesenchymal transition (EMT) is the predominant stage of RF. β-catenin is a key component of the Wnt signaling pathway, which has been fully proven to promote EMT. However, the underlying mechanism of β-catenin in EMT during the pathogenesis of RF is yet to be determined.
    Objective: This study was designed to investigate the effects of β-catenin on RF-related EMT and further investigate its underlying mechanism.
    Methods: Human proximal tubular epithelial cell (HK-2) was treated with hypoxia to construct RF injury cell model. The viability of cells was determined by CCK-8 assay. Immunofluorescence was used to detect α-SMA content. Expressions of β-catenin, Brachyury and RF-related proteins were measured by Western blot. The correlation between β-catenin and Brachyury was detected by ChIP-qPCR and dual luciferase reporter assay.
    Results: We found β-catenin was overexpressed in hypoxia-induced HK-2 cells. In the RF cell model, silencing of β-catenin weakened the EMT and fibrogenesis activity of HK-2 cells. Mechanistically, we found β-catenin binds to T-cell factor (TCF) to activate Brachyury, which is a positive player in EMT. Further studies clarified that Brachyury was responsible for β-catenin-promoted the EMT and HK-2 cell injury under hypoxia condition.
    Conclusions: Herein, we demonstrated that β-catenin is overexpressed in hypoxia-induced HK-2 cells and promotes EMT and cell injury via activating Brachyury. These findings suggest that targeting β-catenin/Brachyury may be an effective new approach for treating RF.
    Keywords:  Brachyury; Chronic kidney disease; EMT; Renal fibrosis; β-catenin
    DOI:  https://doi.org/10.1016/j.bbrep.2024.101907
  12. Rev Physiol Biochem Pharmacol. 2025 ;187 61-87
    The Link between Oxygen and Basement Membranes.
    Colin D McCaig.
      Epithelial tissues and the basement membranes they sit on did not appear for billions of years. Their appearance was delayed most likely by a lack of oxygen, which is required for collagen synthesis, and which only began to build up following the Great Oxygenation Event ~ 2.4 billion years ago. Both the oxygenation of Earth and the multiple roles of collagen require regulation by electrical forces.
    Keywords:  Basement membranes; CLASPs; Collagen; Cyanobacteria; Earth oxygenation; Electron transport collagen remodelling; Phosphosynthesis; TOGs
    DOI:  https://doi.org/10.1007/978-3-031-68827-0_8
  13. Sci Adv. 2025 Jan 24. 11(4): eadr2282
    The oxygen level in air directs airway epithelial cell differentiation by controlling mitochondrial citrate export.
    Bo Ram Kim, Adam J Rauckhorst, Michael S Chimenti, Tayyab Rehman, Henry L Keen, Philip H Karp, Eric B Taylor, Michael J Welsh.
      Oxygen controls most metazoan metabolism, yet in mammals, tissue O2 levels vary widely. While extensive research has explored cellular responses to hypoxia, understanding how cells respond to physiologically high O2 levels remains uncertain. To address this problem, we investigated respiratory epithelia as their contact with air exposes them to some of the highest O2 levels in the body. We asked how the O2 level in air controls differentiation of airway basal stem cells into the ciliated epithelial cells essential for clearing airborne pathogens from the lung. Through a metabolomics screen and 13C tracing on primary cultures of human airway basal cells, we found that the O2 level in air directs ciliated cell differentiation by increasing mitochondrial citrate export. Unexpectedly, disrupting mitochondrial citrate export elicited hypoxia transcriptional responses independently of HIF1α stabilization and at O2 levels that would be hyperoxic for most tissues. These findings identify mitochondrial citrate export as a cellular mechanism for responding to physiologically high O2 levels.
    DOI:  https://doi.org/10.1126/sciadv.adr2282
  14. Metabolites. 2025 Jan 11. pii: 42. [Epub ahead of print]15(1):
    A Study of Volatile Organic Compounds in Patients with Obstructive Sleep Apnea.
    Chuan Hao Gui, Zhunan Jia, Zihao Xing, Fuchang Zhang, Fang Du, Alex Chengyao Tham, Ming Yann Lim, Yaw Khian Chong, Agnes Si Qi Chew, Khai Beng Chong.
      Background: Obstructive Sleep Apnea (OSA) is a prevalent sleep disorder characterized by intermittent upper airway obstruction, leading to significant health consequences. Traditional diagnostic methods, such as polysomnography, are time-consuming and resource-intensive. Objectives: This study explores the potential of proton-transfer-reaction mass spectrometry (PTR-MS) in identifying volatile organic compound (VOC) biomarkers for the non-invasive detection of OSA. Methods: Breath samples from 89 participants, including 49 OSA patients and 40 controls, were analyzed using PTR-MS. Significance analysis was performed between OSA patients and controls to identify potential biomarkers for OSA. To as-sess the differences in VOC concentrations between OSA patients and control subjects, the Wilcoxon rank-sum test was employed. partial least squares discriminant analysis (PLS-DA) analysis and heatmap plot was conducted to visualize the differentiation between OSA patients and control subjects based on their VOC profiles.In order to further investigate the correlation between identified biomarkers and the severity of OSA measured by Apnea-Hypopnea Index (AHI), regression analysis was conducted between biomarkers and AHI Index. Results: The results identified specific VOCs, including m045 (acetaldehyde), m095.950, and m097.071, which showed significant differences between OSA patients and controls. Advanced statistical analyses, including PLS-DA and correlation mapping, highlighted the robustness of these biomarkers, with m045 (acetaldehyde) specifically emerging as a potential biomarker associated with the AHI Index. Conclusions: This study underscores the potential of VOCs as biomarkers for identifying patients with severe AHI levels. The analysis of VOCs using PTR-MS presents a rapid, non-invasive, and cost-effective method that could be seamlessly integrated into clinical practice, allowing clinicians to better stratify patients based on their need for polysomnography and prioritize those requiring earlier testing. Future studies are necessary to validate these findings in larger cohorts and to explore the integration of PTR-MS with other diagnostic modalities for improved accuracy and clinical utility.
    Keywords:  PTR-MS; biomarkers; breath analysis; clinical diagnostics; obstructive sleep apnea
    DOI:  https://doi.org/10.3390/metabo15010042
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