bims-oxygme 2025-07-06 papers

bims-oxygme

Biomed News

on Oxygen metabolism

Issue of 2025–07–06
eight papers selected by
Onurkan Karabulut, Berkeley City College

[2-oxoglutarate-dependent dioxygenase family as a molecular sensor for cellular oxygen and metabolic sensing].
Research on the correlation between gut microbiota and brain cognitive function under chronic hypoxia at high altitude.
Severe acute hypoxia upregulates anaerobic metabolism in non-reproductive but not queen naked mole-rats.
Protective mechanism of polysaccharides from Phellinus linteus on H9c2 cardiomyocyte injury induced by hypoxia/reoxygenation.
Exploring Hypoxia-Induced Neuroprotection Mechanisms in Post-Stroke Recovery.
Metabolic response to an acute bout of mild dynamic exercise performed under normobaric moderate hypoxia: A NMR-based metabolomics study.
Single-cell transcriptomics of vascularized human brain organoids decipher lineage-specific stress adaptation in fetal hypoxia-reoxygenation injury.
MiR-125a-5p in extracellular vesicles of neural stem cells acts as a crosstalk signal modulating neuroinflammatory microenvironment to alleviate cerebral ischemia-reperfusion injury.

Nihon Yakurigaku Zasshi. 2025 ;160(4): 251-255

[2-oxoglutarate-dependent dioxygenase family as a molecular sensor for cellular oxygen and metabolic sensing].

Koh Nakayama, Yoji Andrew Minamishima.

Hypoxic condition is formed in our body when the oxygen demand exceeds the supply. Hypoxic response is triggered under such condition to maintain homeostasis. However, it had been unclear for a long time how cells sense changes of surrounding oxygen environment and activate hypoxic response. Studies of molecular machinery responding to hypoxia largely progressed in the mid 90's after the identification of Hypoxia-Inducible Factor, HIF. Then, the prolyl hydroxylase domain-containing protein (PHD)-HIF pathway was characterized as a central pathway for cells to monitor the decrease in oxygen concentration and maintain cellular function in hypoxia. PHD is recognized as one of the cellular oxygen sensors because it requires oxygen molecule for its enzymatic activity. Importantly, there is a large enzyme family named 2-oxoglutarate-dependent dioxygenase (2OGDD), which require O2, Fe2+, 2-oxoglutarate as co-factors like PHD. In this review, we will overview how 2OGDDs operate, and what are their roles in pathological situation. We also discuss possible direction of how we can establish drugs to target 2OGDDs.

DOI: https://doi.org/10.1254/fpj.25021
Front Neurosci. 2025 ;19 1600069

Research on the correlation between gut microbiota and brain cognitive function under chronic hypoxia at high altitude.

Feng Zeng, Hanxue Li, Yan Ma, Shuang Ma.

   Background: Long-term exposure to high-altitude hypoxia can lead to cognitive impairment, yet the role of the gut microbiota in this process remains unclear. This study investigated the contribution of gut microbiota to cognitive dysfunction induced by chronic hypoxia.
Methods: C57BL/6 J mice were assigned to four groups: control group (NC), control pseudo-germ-free group (CA), hypoxic group (HC), and hypoxic pseudo-germ-free group (HA). HC and HA groups were exposed to a hypobaric oxygen chamber simulating an altitude of 5,000 m (11% O₂) for 28 days. Control mice were housed Xining, 2,200 m altitude (16% O₂). All groups had free access to water; CA and HA groups received oral administration of a four-antibiotic cocktail in drinking water to deplete gut microbiota and establish pseudo-germ-free mouse models. Cognitive function was assessed by the Morris water maze, Expression levels of hippocampal BDNF, SYP, and PSD-95 were determined using Western blotting. H&E staining was used to observe morphological changes in colonic tissues. Gut microbiota composition and metabolic profiles were analyzed through 16S rRNA gene sequencing and metabolomics, respectively, followed by multi-omics correlation analyses.
Results: Chronic hypoxia impaired learning and memory in mice, which was further exacerbated by gut microbiota depletion. This was evidenced by prolonged escape latency, and reduced expression of synaptic plasticity-related proteins. Although hypoxia induced colonic injury, pseudo-germ-free status did not aggravate colonic pathology. Hypoxia and microbiota depletion significantly altered gut microbial diversity, with cognitive impairment negatively correlated with Morganella and Klebsiella abundance and positively correlated with Prevotella, Bifidobacterium and Lactobacillus. Additionally, tryptophan metabolism and urea cycle were identified as critical pathways regulating chronic hypobaric hypoxia-induced cognitive dysfunction. S-adenosylhomocysteine and 2-isopropylmalic acid were pinpointed as potential biomarkers for hypoxia-induced cognitive impairment.
Conclusion: These findings highlight the regulatory role of the gut microbiota in cognitive dysfunction under chronic hypoxic conditions and suggest potential microbiota-targeted strategies for preventing hypoxia-related brain injury.

Keywords:  cognitive impairment; gut microbiota; high altitude hypoxia; metabolome; microbiota-gut-brain axis

DOI:  https://doi.org/10.3389/fnins.2025.1600069
J Exp Biol. 2025 Jun 30. pii: jeb.250397. [Epub ahead of print]

Severe acute hypoxia upregulates anaerobic metabolism in non-reproductive but not queen naked mole-rats.

Mohammad Ojaghi, Matthew E Pamenter.

  Most vertebrates upregulate anaerobic metabolism in severe hypoxia, which results in metabolic acidosis that must be resolved during reoxygenation. Naked mole-rats (NMRs) are hypoxia-tolerant mammals and drastically reduce their metabolic rate while maintaining systemic pH homeostasis during acute hypoxia. Whether or not NMRs employ anaerobic metabolism in hypoxia is currently debated. Given the robust systemic hypoxic hypometabolism of this species we hypothesized that anaerobic metabolism is recruited on a tissue-specific basis that varies between developmental stages and colony caste position. To test this, we treated subordinate juvenile and adult, and breeding (queen) NMRs in normoxia (21% O2) or hypoxia (3% O2) for 1 h, and then measured blood lactate, glycolytic enzyme activity, and the expression of genes that encode for enzymes involved in glycogen and glucose metabolism, and lactate transport. We found that (1) blood lactate levels increase similarly during hypoxia across developmental stages and castes; but that (2) glycolytic activity increased or remained stable in subordinates and juveniles but was unchanged or reduced in queens; (3) MCT4 gene expression decreased markedly in subordinate and juvenile brain and increased in muscle and kidney, but was unchanged in queens; and (4) the expression of genes associated with glycogenolysis and gluconeogenesis varied across tissues in subordinates/juveniles with some markers being down or upregulated or unchanged, but were always unchanged or downregulated queens. Taken together, our results suggest that hypoxia upregulates glycolysis and glycogen mobilization in subordinates and juveniles, but not in queens.

Keywords:  Breeder; Development; Glycolysis; Hypoxic metabolic response; Juvenile

DOI:  https://doi.org/10.1242/jeb.250397
BMC Res Notes. 2025 Jul 01. 18(1): 263

Protective mechanism of polysaccharides from Phellinus linteus on H9c2 cardiomyocyte injury induced by hypoxia/reoxygenation.

Xiaoyu Ren, Qingxian Mei, Yuan Zhou, Lili Jiang, Fei Liu, Jinfeng Wang.

   OBJECTIVE: This study aimed to explore the protective mechanism of Phellinus linteus polysaccharides (Phps) against hypoxia/reoxygenation (H/R)-induced injury in H9c2 cardiomyocytes, focusing on oxidative stress, apoptosis, and PI3K-AKT pathway regulation.
RESULTS: H9c2 cardiomyocytes were divided into control, H/R model, and Phps-treated groups (low/medium/high doses). The H/R model (established by exposing cells to hypoxia for 10 h followed by 4 h of reoxygenation.) induced significant injury: cell viability decreased, SOD activity reduced by 45%, and Bcl-2 expression declined at both mRNA and protein levels, while LDH activity increased by 66%, MDA content surged by 99%, and Bax expression (mRNA/protein) and p-PI3K and p-AKT levels were upregulated, with statistical significance (P < 0.05 vs. control). Compared to the H/R model group, the Phps treatment (low, medium, high) groups showed a significant increase in H9c2 cardiomyocytes viability, SOD activity, and mRNA and protein expression levels of Bcl-2. The LDH activity, MDA content, mRNA levels of Bax, and protein expression levels of Bax, p-PI3K and p-AKT significantly decreased, with statistical significance (P < 0.05). These results suggest that Phps may improve H/R induced damage in H9c2 cardiomyocytes by downregulating the ratio of Bax/Bcl-2 through the PI3K-AKT pathway.

Keywords:   Phellinus Linteus polysaccharides ; Apoptosis related proteins; H9c2 cardiomyocytes; Hypoxia/reoxygenation (H/R)

DOI:  https://doi.org/10.1186/s13104-025-07308-x
Transl Stroke Res. 2025 Jul 05.

Exploring Hypoxia-Induced Neuroprotection Mechanisms in Post-Stroke Recovery.

Malachi Nyamukondiwa, Elizaveta S Koneva, Eugeny E Achkasov, Zhang Xinliang, Padmanabha Reddy Y, Narasimha M Beeraka, Oleg S Glazachev.

  Stroke recovery is a multifaceted process influenced by various neuroprotective mechanisms that support long-term rehabilitation. Recent studies on hypoxia-induced neuroprotection have shown promising potential in enhancing stroke recovery through adaptive cellular responses. Hypoxic conditioning in techniques of passive intermittent hypoxic exposures (IHE) or intermittent hypoxic-hyperoxic exposures (IHHE), which alternates between low and normal/high oxygen levels, is emerging as a novel complementary therapy that may improve post-stroke outcomes by promoting neuroprotection, neurogenesis, and vascular remodeling. This review aims to explore the therapeutic implications of IHE/IHHE as a novel complementary therapy to mitigate post-stroke exacerbations and enhance recovery through various physiological and molecular mechanisms. A comprehensive literature search was conducted using public databases such as PubMed, Scopus, Relemed, the National Library of Medicine, and Google Scholar. The search focused on studies related to hypoxia training, neuroprotection, stroke recovery, and IHE/IHHE. The review synthesizes current findings on the pathophysiological insights and therapeutic potential of intermittent hypoxic conditioning in stroke rehabilitation. The review highlights several key areas where IHE/IHHE shows adaptive responses involving hypoxia-inducible factor (HIF) signaling, reactive oxygen species (ROS) regulation, and mitochondrial energetics, contributing to enhanced neuroprotection and tissue recovery. Angiogenesis and vascular remodeling: IHE/IHHE promotes angiogenesis and improves cerebral blood flow, facilitating vascular remodeling and improved perfusion in damaged brain areas. Neurogenesis: IHE/IHHE enhances neurogenesis, aiding in brain repair and functional recovery by promoting neuronal survival and regeneration. Cognitive and motor function: IHE/IHHE has been shown to improve cognitive performance and motor function in post-stroke patients, as well as in elderly individuals with mild cognitive impairment. Cardioprotection: IHE/IHHE reduces cardiovascular risk factors, such as hypertension and inflammation, and has been shown to enhance cardiac function in patients with ischemic heart disease. Integrative rehabilitation: Incorporating IHE/IHHE into post-stroke rehabilitation programs may enhance physical and cognitive outcomes, supporting a holistic approach to recovery. Hypoxic conditioning in modes of IHE/IHHE represents a promising complementary therapy for stroke recovery, leveraging adaptive responses to hypoxia and hyperoxia to promote neuroprotection, neurogenesis, and vascular remodeling. Further research is needed to optimize IHHE protocols, understand their long-term effects, and integrate them effectively into clinical practice. This review benefits physicians, molecular biologists, and neurologists and describes the potential of IHE/IHHE in enhancing stroke rehabilitation outcomes, and highlights the need for well-controlled clinical trials to validate its efficacy and safety.

Keywords:  Angiogenesis; Cardioprotection; Cognitive enhancement; Intermittent hypoxic–hyperoxic exposure; Neurogenesis; Neuroprotection; Rehabilitation; Stroke recovery

DOI:  https://doi.org/10.1007/s12975-025-01364-y
PLoS One. 2025 ;20(7): e0325447

Metabolic response to an acute bout of mild dynamic exercise performed under normobaric moderate hypoxia: A NMR-based metabolomics study.

Flaminia Cesare Marincola, Daniela Masu, Veronica Libonati, Michela Tozzi, Raffaella Isola, Romina Vargiu, Elisabetta Marini, Silvana Roberto, Sara Magnani, Giovanna Ghiani, Gabriele Mulliri, Antonio Crisafulli, Andrea C Rinaldi.

The combination of hypoxia and exercise offers significant potential benefits for non-athletic individuals, particularly in clinical and rehabilitation settings. Personalized hypoxic exercise programs can be tailored to improve cardiovascular and metabolic health, enhance recovery, and promote adaptation to low-oxygen environments. However, finding the optimal balance between exercise variables (intensity, duration, frequency, type of exercise), and hypoxic exposure parameters (altitude level, duration, session frequency), remains challenging. Further research is needed to understand how these variables interact to optimize hypoxic exercise protocols. In the present study, we explored the effects of a single session of mild dynamic exercise conducted in normobaric hypoxia (FiO2 = 13.5%) on the plasma and urine metabolome of thirteen healthy young adults (age 29.7 ± 4.5 y, body mass index 23.5 ± 1.4 kg/m2). For comparative purposes, participants performed the same exercise under normoxia (FiO2 = 21%). During both exercise sessions, subjects wore a mask connected to a hypoxic gas generator while seated on a cycle ergometer. After a 4 minute rest, they pedaled for 3 minutes at 30% of their Wmax, followed by 6 minutes of recovery. Hemodynamic parameters were measured at four time points, and biological samples (blood and urine) were collected before the test and within 5 minutes of exercise completion. Samples were analyzed by 1H NMR spectroscopy. Univariate and multivariate statistical analysis of NMR datasets revealed noteworthy changes in the levels of certain metabolites following the hypoxic session: 3-hydroxybutyrate, branched-chain amino acids, citrate, lactate, phenylalanine, succinate, and tyrosine in plasma; 3-hydroxyisobutyrate, 3-hydroxyisovalerate, alanine, acetone, dimethylamine, glycine, lactate, succinate, and taurine in urine. These metabolic shifts, along with their statistically significant correlations with hemodynamic parameters, suggest an adaptive modulation of energy metabolism pathways in response to mild hypoxic stress.

DOI: https://doi.org/10.1371/journal.pone.0325447
Theranostics. 2025 ;15(14): 7001-7024

Single-cell transcriptomics of vascularized human brain organoids decipher lineage-specific stress adaptation in fetal hypoxia-reoxygenation injury.

Simeng Yi, Min Huang, Chunmei Xian, Xi Kong, Shigang Yin, Jianhua Peng, Yong Zhang, Xiuju Du, Yong Jiang, Bingqing Xie, Huangfan Xie.

  Rationale: Fetal hypoxia, a major contributor to neonatal mortality, induces complex neurovascular disruptions in developing brains, yet human-specific cellular mechanisms remain poorly understood due to limitations in existing models. This study establishes an advanced vascularized human cortical organoid (vhCO) model to decode cell type-specific injury mechanisms and therapeutic targets during hypoxia-reoxygenation. Methods: We developed vhCOs by integrating cortical and vascular organoids, recapitulating mid-to-late gestational neurodevelopment with diverse lineages-neural progenitors, neurons, microglia, and functional vasculature with blood-brain barrier properties. Hypoxia-reoxygenation experiments were conducted on vhCOs, followed by single-cell transcriptomic profiling to dissect cellular responses. Results: Key findings include: (1) Lineage-specific vulnerabilities: astrocyte precursors exhibited developmental arrest, while immature GABAergic neurons (Subtype I) underwent neurogenic collapse. Microglia displayed a biphasic inflammatory response-initially suppressed, then hyperactivated post-reoxygenation, diverging from animal models; (2) Hypoxia memory persisted in non-neural cells (pericytes, fibroblasts), driving compartment-specific vascular remodeling via Notch signaling and collagen deposition; (3) Rewired neural-non-neural crosstalk networks (e.g., IGF2-IGF2R, LGALS3-MERTK, Wnts-SFRP2) revealed novel repair targets inaccessible to conventional models. Conclusions: By prioritizing single-cell resolution, this study delineates human-specific neurovascular pathophysiology and stress adaptation networks in hypoxic brain injury. The vhCO platform bridges translational gaps, offering a paradigm for precision therapeutics and advancing research on developmental brain disorders.

Keywords:  GABAergic neuron; blood-brain barrier; fetal hypoxia; single-cell RNA-sequencing; vascularized brain organoid

DOI:  https://doi.org/10.7150/thno.117001
Theranostics. 2025 ;15(14): 7064-7089

MiR-125a-5p in extracellular vesicles of neural stem cells acts as a crosstalk signal modulating neuroinflammatory microenvironment to alleviate cerebral ischemia-reperfusion injury.

Qingyue Liu, Heran Ma, Jing Liao, Zihan Zhu, Hongyuan Chen, Dong Sun, Longkun Wang, Lu Lu, Xiaowei Chen, Xinke Zhang, Fengshan Wang.

  Rationale: Ischemic stroke is the second leading cause of death worldwide. Ischemia-reperfusion injury plays a major role in brain function damage and leads to disability. Currently, there are no ideal therapeutic methods for preventing and treating ischemia-reperfusion injury. Extracellular vesicles (EVs) are a promising therapy for cerebral ischemia-reperfusion injury (CIRI). The main purpose of this study was to identify the pivotal miRNAs in EVs that affect functional recovery following CIRI, develop engineered EVs encapsulating key miRNAs, and identify the underlying mechanisms. Methods: Next-generation sequencing was used to identify the crucial differentiating ingredients between EVs from normoxia- and hypoxia-conditioned human neural stem cells (hNSCs). HNSC EVs were electroporated with miR-125a-5p mimics and characterized using nanoparticle tracking analysis and electron microscopy. The role and mechanism by which EV-packaged miR-125a-5p mediates CIRI were investigated in vitro and in vivo. Results: In the present study, miR-125a-5p derived from the EVs of hNSCs was found to signal the crosstalk between different cells, such as microglia and neurons, under ischemic conditions. Furthermore, hNSC-EVs loaded with miR-125a-5p (EVsmiR) promoted the polarization of anti-inflammatory M2 microglia, resulting in altered inflammatory responses and decreased inflammatory cytokine secretion. Additionally, EVs-miR-125a-5p exerts a significant impact on microglia, subsequently translocating to neurons and inhibiting neuronal death. Moreover, increased miR-125a-5p levels in hNSC-EVs effectively inhibited neuronal apoptosis and improved the axonal ultrastructure and neurological function in vivo. Mechanistically, EVsmiR regulate the TLR4/NF-κB signaling pathway by targeting IKBKG to alleviate neuroinflammation induced by CIRI. Conclusions: Our findings demonstrate that miR-125a-5p mechanisms contribute to modulating the neuroinflammatory microenvironment and miR-125a-5p-enriched EVs may be a promising therapeutic strategy for CIRI.

Keywords:  IKBKG; cerebral ischemia-reperfusion injury; extracellular vesicles; miR-125a-5p; neuroinflammation

DOI:  https://doi.org/10.7150/thno.115993