bims-oxygme Biomed News
on Oxygen metabolism
Issue of 2025–03–09
seven papers selected by
Onurkan Karabulut, Berkeley City College
  1. Exploring cytochrome P450 under hypoxia: potential pharmacological significance in drug metabolism and protection against high-altitude diseases.
  2. Survival mechanisms of plants under hypoxic stress: Physiological acclimation and molecular regulation.
  3. Blue plaque series: Mabel Purefoy FitzGerald (1872-1973).
  4. Metabolomic analysis of rat arterial serum under hypobaric hypoxia: Adaptive regulation of physiological systems by metabolic reprogramming.
  5. p75NTR modulation prevents cellular, cortical activity and cognitive dysfunctions caused by perinatal hypoxia.
  6. Two tales of therapeutic innovations for Leigh syndrome spectrum.
  7. Oxidative stress and nitric oxide metabolism responses during prolonged high-altitude exposure in preterm born adults.
  1. Drug Metab Dispos. 2025 Feb;pii: S0090-9556(24)15876-X. [Epub ahead of print]53(2): 100026
    Exploring cytochrome P450 under hypoxia: potential pharmacological significance in drug metabolism and protection against high-altitude diseases.
    Qian Wang, Guiqin Liu, Yabin Duan, Delong Duo, Junbo Zhu, Xiangyang Li.
      High-altitude hypoxia affects the human respiratory, central nervous, cardiovascular, and endocrine systems. These outcomes affect the expression of cytochrome P450 (CYP), the most important family of metabolic enzymes in the body that is involved in the metabolism of both exogenous and endogenous substances (such as arachidonic acid, vitamins, and steroids). Hypoxia influences CYP expression and activity, mediating changes in drug and endogenous substance metabolism, with endogenous metabolites playing a significant role in controlling high-altitude diseases. However, the mechanisms regulating CYP changes under hypoxic conditions and the effects of CYP changes on drug and endogenous metabolism remain unclear. We explored how changes in CYP expression and activity during hypoxia affect the metabolism of drugs and endogenous substances, such as arachidonic acid, vitamins, and steroid hormones, and how CYPs are controlled by nuclear receptors, epigenetic modifications, cytokines, and gut microbiota during hypoxia. Special attention will also be given to the complex role of CYP and its metabolites in the pathophysiology of high-altitude diseases to provide valuable insights for plateau medicine research. SIGNIFICANCE STATEMENT: Cytochrome P450 is a class of monooxygenases that metabolize xenobiotics and endogenous substances. Hypoxia affects the expression and activity of cytochrome P450, and this in turn affects the metabolism of drugs and endogenous substances, leading to altered clinical efficacy and the development of hypoxia-associated diseases. A comprehensive understanding of the changes and regulatory mechanisms of cytochrome P450 under hypoxic conditions can improve therapeutic protocols in hypoxic environments and provide new ideas for the targeted treatment of hypoxic diseases.
    Keywords:  Cytochrome P450; Drug metabolism; Endogenous; High-altitude diseases; High-altitude hypoxia
    DOI:  https://doi.org/10.1016/j.dmd.2024.100026
  2. J Integr Plant Biol. 2025 Mar 07.
    Survival mechanisms of plants under hypoxic stress: Physiological acclimation and molecular regulation.
    Lin-Na Wang, Wei-Cheng Wang, Ke Liao, Ling-Jing Xu, Dao-Xin Xie, Ruo-Han Xie, Shi Xiao.
      Hypoxia (low-oxygen tension) caused by complete submergence or waterlogging is an abiotic stress factor that severely affects the yield and distribution of plants. To adapt to and survive under hypoxic conditions, plants employ several physiological and molecular strategies that integrate morphological acclimation, metabolic shifts, and signaling networks. Group VII ETHYLENE RESPONSE FACTORS (ERF-VIIs), master transcription factors, have emerged as a molecular hub for regulating plant hypoxia sensing and signaling. Several mitogen-activated protein kinases and calcium-dependent protein kinases have recently been reported to be involved in potentiating hypoxia signaling via interaction with and phosphorylation of ERF-VIIs. Here, we provide an overview of the current knowledge on the regulatory network of ERF-VIIs and their post-translational regulation in determining plant responses to hypoxia and reoxygenation, with a primary focus on recent advancements in understanding how signaling molecules, including ethylene, long-chain acyl-CoA, phosphatidic acid, and nitric oxide, are involved in the regulation of ERV-VII activities. Furthermore, we propose future directions for investigating the intricate crosstalk between plant growth and hypoxic resilience, which is central to guiding breeding and agricultural management strategies for promoting flooding and submergence stress tolerance in plants.
    Keywords:  ERF‐VIIs; hypoxia; protein kinases; reoxygenation; submergence
    DOI:  https://doi.org/10.1111/jipb.13880
  3. Exp Physiol. 2025 Mar 07.
    Blue plaque series: Mabel Purefoy FitzGerald (1872-1973).
    Martha Tissot van Patot.
      Mabel Purefoy FitzGerald (1872-1973) was the first centenarian to receive an honorary degree from the University of Oxford. She received an honorary bachelor of the arts 68 years after being the first woman to complete the Honour School of Physiology. Her work from a solo trip through the wild and unruly mining communities high in the Colorado Rocky Mountains in 1911 revealed that to compensate for the hypoxia of high altitude, residents had lowered CO2 and elevated haemoglobin. These data are some of the first to suggest a hypoxia-sensing mechanism. Until recently, her other numerous achievements and astonishing experiences struggling to become a physician at the turn of the 20th century have remained lost to history. FitzGerald's numerous accomplishments are a testament to her passion for medical science and unparalleled courage in the face of innumerable setbacks.
    Keywords:  altitude; digestion; history of medicine; hypoxia; physiology; respiration; women
    DOI:  https://doi.org/10.1113/EP092275
  4. Biochem Biophys Rep. 2025 Mar;41 101943
    Metabolomic analysis of rat arterial serum under hypobaric hypoxia: Adaptive regulation of physiological systems by metabolic reprogramming.
    Dengqin Ma, Bing Li, Bang Xin, Bingfang Xie, Enpen Zhu, Zihao Zhang, Xiaoqin Ha.
       Objective: To investigate the associations between metabolic changes and functions, including energy metabolism, immune response, and redox balance, under short-term hypobaric hypoxia exposure. Non-targeted metabolomics and bioinformatics analysis were applied to explore the adaptive mechanisms of organisms in hypobaric hypoxia.
    Methods: Healthy adult male Sprague-Dawley rats were placed in environments simulating altitudes of 6500 m (HC group) and 1588 m (Control group). After 14 days, arterial serum samples were analyzed using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). Significant metabolites (P < 0.05, VIP >1) were identified, and KEGG enrichment analysis was conducted. Differential metabolites were globally analyzed with MetaboAnalyst 5.0.
    Results: A total of 117 significantly altered metabolites were identified. In the HC group, 84 metabolites significantly increased, while 33 metabolites significantly decreased compared to the Control group. KEGG enrichment analysis revealed significant metabolic pathways, including the PPAR signaling pathway, bile secretion, arginine biosynthesis, alcoholism, and cholesterol metabolism (P < 0.05). Global analysis indicated that these differential metabolites were involved in various pathways, such as energy metabolism, amino acid metabolism, nucleotide metabolism, lipid metabolism, vitamin and cofactor metabolism, steroid metabolism, neurotransmitter metabolism, and heme metabolism, all of which play crucial roles in multiple biological processes.
    Conclusion: Short-term hypobaric hypoxia exposure significantly altered the metabolite profiles in the arterial serum samples of rats, revealing adaptive metabolic reprogramming in energy metabolism, redox balance, immune function, endocrine regulation, and neurological systems.
    Keywords:  Energy metabolism; Hypobaric hypoxia; Immune regulation; Metabolic reprogramming; Metabolomics; Redox homeostasis
    DOI:  https://doi.org/10.1016/j.bbrep.2025.101943
  5. Brain. 2025 Mar 04. pii: awaf084. [Epub ahead of print]
    p75NTR modulation prevents cellular, cortical activity and cognitive dysfunctions caused by perinatal hypoxia.
    Bidisha Chattopadhyaya, Karen K Y Lee, Maria Isabel Carreño-Muñoz, Andrea Paris-Rubianes, Marisol Lavertu-Jolin, Martin Berryer, Frank M Longo, Graziella Di Cristo.
      Children who experienced moderate perinatal hypoxia are at risk of developing long-lasting subtle cognitive and behavioural deficits, including learning disabilities and emotional problems. Understanding the underlying mechanisms is an essential step for designing targeted therapy. Fast-spiking, parvalbumin-positive (PV) GABAergic interneurons modulate the generation of gamma oscillations, which in turn regulate many cognitive functions including goal-directed attentional processing and cognitive flexibility. Due to their fast-firing rate, PV cell function requires high levels of energy, which may render them highly vulnerable to conditions of metabolic and oxidative stress caused by perinatal hypoxia. Here, we show that adult mice that experienced moderate perinatal hypoxia (MPH) have decreased cortical PV expression levels in addition to specific impairments in social behaviour, recognition memory and cognitive flexibility. We further found that the expression level of the neurotrophin receptor p75NTR, which limits PV cell maturation during the first postnatal weeks, is increased in MPH mice. Genetic deletion of p75NTR in GABAergic neurons expressing the transcription factor Nkx2.1, which include PV cells, protects mice from PV expression loss and the long-term cognitive effects of MPH. Finally, treatment with a p75NTR inhibitor starting after MPH and lasting for a week, prevented PV expression loss and the occurrence of cognitive and cortical activity deficits in adult mice. Altogether our data reveals p75NTR-mediated signaling, as a potential molecular target, for the treatment of the cognitive alterations caused by MPH.
    Keywords:  GABAergic interneurons; cognition; electroencephalogram (EEG); p75NTR; parvalbumin; perinatal hypoxia
    DOI:  https://doi.org/10.1093/brain/awaf084
  6. J Neurogenet. 2025 Mar 06. 1-3
    Two tales of therapeutic innovations for Leigh syndrome spectrum.
    Wei-Sheng Lin.
      Leigh syndrome spectrum is the most common form of childhood-onset mitochondrial encephalopathy and is characterized by progressive neurodegeneration. Treatment options for this condition remain limited to date. Nonetheless, two lines of research endeavor in the past decade have shown encouraging results worthy of further investigations. First, therapeutic hypoxia appears to improve neurological outcomes, which is somewhat counterintuitive but supported by preclinical evidence. Furthermore, nicotinic acid or nicotinamide riboside could be an adjunctive therapy that enhances the neuroprotective effect of hypoxia. Second, preclinical studies and preliminary clinical experience suggest that sildenafil is potentially disease-modifying for Leigh syndrome. Sildenafil has already been used to treat pulmonary hypertension, and its repurposing for Leigh syndrome has been endorsed by European Medicines Agency. This perspective aims to raise awareness about these progresses, as well as to call for more clinical studies to ensure safe and effective implementation of these treatment approaches in clinical practice.
    Keywords:  Leigh syndrome; hypoxia; mitochondrial encephalopathy; sildenafil
    DOI:  https://doi.org/10.1080/01677063.2025.2473087
  7. J Sport Health Sci. 2025 Feb 26. pii: S2095-2546(25)00012-2. [Epub ahead of print] 101034
    Oxidative stress and nitric oxide metabolism responses during prolonged high-altitude exposure in preterm born adults.
    Marie Chambion-Diaz, Giorgio Manferdelli, Benjamin J Narang, Guido Giardini, Tadej Debevec, Vincent Pialoux, Grégoire P Millet.
       BACKGROUND: Prematurely-born individuals tend to exhibit higher resting oxidative stress, although evidence suggests they may be more resistant to acute hypoxia-induced redox balance alterations. We aimed to investigate the redox balance changes across a 3-day hypobaric hypoxic exposure at 3375 m in healthy adults born preterm (gestational age ≤32 weeks) and their term-born (gestational age ≥38 weeks) counterparts.
    METHODS: Resting venous blood was obtained in normoxia (prior to altitude exposure), immediately upon arrival to altitude, and the following 3 mornings. Antioxidant (superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), and ferric reducing antioxidant power (FRAP)), pro-oxidant (xanthine oxidase (XO) and myeloperoxidase (MPO)) enzyme activity, oxidative stress markers (advanced oxidation protein product (AOPP) and malondialdehyde (MDA)), nitric oxide (NO) metabolites (nitrites, nitrates, and total nitrite and nitrate (NOx)), and nitrotyrosine were measured in plasma.
    RESULTS: SOD increased only in the preterm group (p < 0.05). Catalase increased at arrival in preterm group (p < 0.05). XO activity increased at Day 3 for the preterm group, while it increased acutely (arrival and Day 1) in control group. MPO increased in both groups throughout the 3 days (p < 0.05). AOPP only increased at arrival in the preterm (p < 0.05) whereas it decreased at arrival up to Day 3 (p < 0.05) for control. MDA decreased in control group from arrival onward. Nitrotyrosine decreased in both groups (p < 0.05). Nitrites increased on Day 3 (p < 0.05) in control group and decreased on Day 1 (p < 0.05) in preterm group.
    CONCLUSION: These data indicate that antioxidant enzymes seem to increase immediately upon hypoxic exposure in preterm adults. Conversely, the blunted pro-oxidant enzyme response to prolonged hypoxia exposure suggests that these enzymes may be less sensitive in preterm individuals. These findings lend further support to the potential hypoxic preconditioning effect of preterm birth.
    Keywords:  Altitude; Antioxidant; Hypoxia; Nitrosative stress; Oxidative stress; Premature birth; Prematurity
    DOI:  https://doi.org/10.1016/j.jshs.2025.101034
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