bims-oxygme 2025-06-29 papers

bims-oxygme

Biomed News

on Oxygen metabolism

Issue of 2025–06–29
fourteen papers selected by
Onurkan Karabulut, Berkeley City College

Hyperbaric Oxygen Attenuates Cerebral Ischemia-Reperfusion Injury in Rats by Modulating Sodium Channels.
Acidosis attenuates the hypoxic stabilization of HIF-1α by activating lysosomal degradation.
Hypoxia upregulates the expression of PD-L1 via NPM1 in breast cancer.
Aerobic Intermittent Hypoxic Training Is Not Beneficial for Maximal Oxygen Uptake and Performance: A Systematic Review and Meta-Analysis.
Hypoxia-induced metabolic reprogramming in mesenchymal stem cells: unlocking the regenerative potential of secreted factors.
Hyperbaric Oxygen Therapy Has the Potential to Extend Cold Ischemia Time by Reducing Inflammation and Apoptosis in Rat Livers.
Exploring a new direction in targeted cancer therapy through hyperbaric oxygen therapy combined with biomedical engineering techniques.
Comparison of early postnatal hemodynamics in neonates born at high-altitude or low-altitude using USCOM: a pilot study.
Thermophiles, Thick-Walled Bacteria, and Pseudomonads in High-Altitude Gut Microbiota.
Neuroprotective Proteins in Hypoxia-stressed Astrocyte-Derived Extracellular Vesicles.
Tibetan PHD2D4E;C127S variant protects from viral diseases in hypoxia, but predispose to infections in normoxia via HIFα:IFN axis.
Hypoxia Signaling in the Cell Type-Specific Regulation of Erythropoietin Production Throughout Mammalian Development.
Brain-derived exosomal hemoglobin transfer contributes to neuronal mitochondrial homeostasis under hypoxia.
Metabolomics Signatures of a Respiratory Tract Infection During an Altitude Training Camp in Elite Rowers.

Dev Neurobiol. 2025 Jul;85(3): e22974

Hyperbaric Oxygen Attenuates Cerebral Ischemia-Reperfusion Injury in Rats by Modulating Sodium Channels.

Binli Gao, Mei Peng, Fulan Chen, Xiaoling Peng, Ke Huang, Qiang Li, Yuee Dai, Xianrong Zeng.

  Ischemic stroke accounts for the majority of stroke cases. Hyperbaric oxygen therapy (HBOT) is being increasingly used as a treatment for this condition, but its precise mechanisms of action remain incompletely elucidated. This study examined hyperbaric oxygen (HBO) effects on sodium channels in hippocampal CA1 pyramidal neurons in rats with cerebral ischemia-reperfusion injury (CIRI). Using the middle cerebral artery occlusion (MCAO) model and whole-cell patch-clamp technology, voltage-gated sodium channel (VGSC) currents were measured at varying HBOT time points and treatment durations. Results showed that with a longer CIRI duration, the maximum current density (MCD) of sodium current (INa) decreased, while more HBOT sessions increased the MCD of INa. Notably, in the MCAO 6H group, 12 treatments of HBOT induced a leftward shift in the INa activation curve. Early HBOT intervention provided greater neuroprotection for sodium channels, and increased treatment sessions enhanced functional recovery. These findings suggest HBO's therapeutic potential in mitigating CIRI-related neuronal damage.

Keywords:  cerebral ischemia‐reperfusion injury; hippocampus; hyperbaric oxygen; pyramidal cell; sodium channel

DOI:  https://doi.org/10.1002/dneu.22974
J Cell Biol. 2025 Aug 04. pii: e202409103. [Epub ahead of print]224(8):

Acidosis attenuates the hypoxic stabilization of HIF-1α by activating lysosomal degradation.

Bobby White, Zhenyi Wang, Matthew Dean, Johanna Michl, Natalia Nieora, Sarah Flannery, Iolanda Vendrell, Roman Fischer, Alzbeta Hulikova, Pawel Swietach.

Hypoxia-inducible factors (HIFs) mediate cellular responses to low oxygen, notably enhanced fermentation that acidifies poorly perfused tissues and may eventually become more damaging than adaptive. How pH feeds back on hypoxic signaling is unclear but critical to investigate because acidosis and hypoxia are mechanistically coupled in diffusion-limited settings, such as tumors. Here, we examined the pH sensitivity of hypoxic signaling in colorectal cancer cells that can survive acidosis. HIF-1α stabilization under acidotic hypoxia was transient, declining over 48 h. Proteomic analyses identified responses that followed HIF-1α, including canonical HIF targets (e.g., CA9, PDK1), but these did not reflect a proteome-wide downregulation. Enrichment analyses suggested a role for lysosomal degradation. Indeed, HIF-1α destabilization was blocked by inactivating lysosomes, but not proteasome inhibitors. Acidotic hypoxia stimulated lysosomal activity and autophagy via mammalian target of rapamycin complex I (mTORC1), resulting in HIF-1α degradation. This response protects cells from excessive acidification by unchecked fermentation. Thus, alkaline conditions are permissive for at least some aspects of HIF-1α signaling.

DOI: https://doi.org/10.1083/jcb.202409103
J Immunother Cancer. 2025 Jun 23. pii: e010151. [Epub ahead of print]13(6):

Hypoxia upregulates the expression of PD-L1 via NPM1 in breast cancer.

Yihui Yu, Ran Sun, Feiyun Hu, Zite Ding, Xin Li, Jiyuan Han, Leiting Liang, Tian Wang, Guifu Xi, Xueyi Dong, Yanlei Li, Xiulan Zhao, Danfang Zhang.

   BACKGROUND: A hypoxic microenvironment is the most frequent characteristic in tumor microenvironment. Programmed death-ligand 1 (PD-L1) is an important molecule and therapeutic target that mediates the immune response of tumor cells. Previous studies have shown that hypoxia can lead to increased expression of Nucleophosmin 1 (NPM1) and PD-L1. However, the exact regulatory mechanisms of NPM1 and PD-L1 expression under hypoxic conditions are still poorly understood.
METHODS: The relationships among hypoxia, NPM1 and PD-L1 were explored by western blotting, immunofluorescence staining, flow cytometry and chromatin immunoprecipitation-quantitativePCR(ChIP-qPCR). Animal tumor models were established to explore the effect of NPM1 expression on tumor growth. The relationships between NPM1 and breast cancer (BC) clinical features and immune infiltration were revealed by bioinformatics analysis.
RESULTS: NPM1 mediates increased PD-L1 expression in the hypoxic microenvironment of BC. HIF-1α can increase the expression of NPM1 by activating the p-AKT pathway and binding to the NPM1 promoter. Increased expression of NPM1 can promote tumor growth and inhibit T cell infiltration. Bioinformatics analysis showed that the high expression of NPM1 was associated with poorer survival and immunosuppression in patients with BC.
CONCLUSIONS: The hypoxic microenvironment promotes PD-L1 expression via NPM1 in BC, which may be further associated with the inhibition of tumor immunity. NPM1 may serve as a potential target for modulating PD-L1 immunotherapy.

Keywords:  Breast cancer; Hypoxia; Immunotherapy; NPM1; PD-L1

DOI:  https://doi.org/10.1136/jitc-2024-010151
Scand J Med Sci Sports. 2025 Jun;35(6): e70088

Aerobic Intermittent Hypoxic Training Is Not Beneficial for Maximal Oxygen Uptake and Performance: A Systematic Review and Meta-Analysis.

Gianluigi Dorelli, Gaia Giuriato, Giovanni Zamboni, Michael Daini, Mattia Cominacini, Luca Giuseppe Dalle Carbonare, Eivind Wang, Ernesto Crisafulli, Federico Schena, Massimo Venturelli.

  Although many studies have investigated whether aerobic training in hypoxia (IHT) could bring advantages to maximal oxygen uptake (V̇O2max) and sea-level performance when compared to analogous normoxic training (NT), the literature results are inconsistent. This variability may come from differences in population, training protocols, hypoxic methods, and potential bias. Therefore, a comprehensive meta-analysis with strict inclusion criteria is needed to assess the effects of aerobic IHT on V̇O2max and performance. This study aims to review previous meta-analyses and analyze all parallel-design studies examining the effect of aerobic IHT compared to NT on V̇O2max and sea-level aerobic performance. Systematic research was conducted following PRISMA guidelines regarding the effects of aerobic IHT on sea-level V̇O2max and performance outcomes. The analysis accounted for characteristics of the population, training protocol, hypoxic environment, and publication details. A total of 35 studies involving 524 participants were included. The analysis showed that IHT, compared to NT, did not significantly improve V̇O2max (p = 0.333), peak power output (p = 0.159), and time to exhaustion (p = 0.410). Subgroup analyses identified no significant differences based on fitness level (p = 0.690) and exercise modality (p = 0.900); however, a publication bias was found (p = 0.004). These results suggest that, despite some enthusiastic findings in the literature, possibly influenced by publication-related biases, aerobic IHT does not offer superior improvement in V̇O2max and performance compared with NT. Therefore, adding hypoxia to aerobic exercise does not enhance training adaptations.

Keywords:  VO2max; aerobic performance; hemoglobin; hypoxic training; intermittent hypoxic training; mitochondria density; muscle capillarization; oxygen cascade

DOI:  https://doi.org/10.1111/sms.70088
Front Cell Dev Biol. 2025 ;13 1609082

Hypoxia-induced metabolic reprogramming in mesenchymal stem cells: unlocking the regenerative potential of secreted factors.

Wendy V Jaraba-Álvarez, Ashanti C Uscanga-Palomeque, Vanesa Sanchez-Giraldo, Claudia Madrid, Hector Ortega-Arellano, Karolynn Halpert, Carolina Quintero-Gil.

  Mesenchymal stem cells (MSCs) are a cornerstone of regenerative medicine, primarily due to their ability to secrete bioactive factors that modulate inflammation, promote tissue repair, and support regeneration. Recent research highlights the importance of preserving the native cellular microenvironment to optimize MSC function and survival post-transplantation. Preconditioning strategies, such as hypoxia exposure, have emerged as powerful tools to enhance MSC therapeutic potential by mimicking physiological conditions in their natural niche. This perspective article explores the metabolic adaptations induced by hypoxia in MSCs, focusing on shifts in mitochondrial function, glycolysis, oxidative phosphorylation, and metabolic intermediates that enhance cellular survival and bioactivity. We also discuss how these metabolic changes influence the composition and function of MSC-derived secreted factors, particularly exosomes and other extracellular vesicles, in modulating tissue repair. Furthermore, we provide an overview of preclinical and clinical studies that have evaluated hypoxia-preconditioned MSCs and their byproducts, assessing their efficacy in various therapeutic contexts. Special attention is given to the role of hypoxia-induced mitochondrial adaptations in improving MSC function and the emerging potential of metabolic inhibitors or respiration modulators as strategies to further refine MSC-based therapies. By integrating metabolic insights with clinical evidence, we aim to offer a comprehensive perspective on optimizing MSC culture conditions to enhance their regenerative properties, acknowledging that this remains a theoretical standpoint, as conventional culture methods are generally not conducted under hypoxic conditions. This approach holds promise for the development of more effective therapeutic strategies that leverage metabolic modulation to improve MSC-based interventions for a range of diseases.

Keywords:  cellular microenvironment; extracellular vesicles (EV); hypoxia preconditioning; mesenchymal stem cells (MSC); mitochondria; regenerative medicine

DOI:  https://doi.org/10.3389/fcell.2025.1609082
Exp Clin Transplant. 2025 May;23(5): 371-378

Hyperbaric Oxygen Therapy Has the Potential to Extend Cold Ischemia Time by Reducing Inflammation and Apoptosis in Rat Livers.

Başak Büyük, Özlem Öztopuz, Neslihan Düzenli.

OBJECTIVES: Preserving allograft function is crucial for the success of organ transplantation. Although static cold storage helps reduce organ damage, its effectiveness is limited. This study aimed to investigate the effects of early and short-term hyperbaric oxygen therapy applied to cold-stored rat liver tissues on inflammation and apoptosis and the potential to extend the tolerable cold ischemia time.
MATERIALS AND METHODS: We collected Wistar rat livers after perfusion and placed them in static cold storage alone or treated them with hyperbaric oxygen for 60 or 120 minutes immediately after placing them in cold storage. Samples were kept in cold storage for 24 hours. We evaluated histological changes by hematoxylin and eosin staining, expression levels of tumor necrosis factor-alpha and interleukin 10 by immunohistochemistry, interleukin 6 gene by reverse transcriptase-polymerase chain reaction, and apoptotic index by terminal deoxynucleotidyl transferase dUTP nick end-labeling methods.
RESULTS: Hyperbaric oxygen therapy reduced development of sinusoidal dilatation but not hydropic degeneration. This treatment also reduced the apoptotic index and expression levels of tumor necrosis factor-alpha, interleukin 10, and interleukin 6 gene (interleukin 6 mRNA). Exceptforinterleukin 6 gene expression, the decreases were more pronounced with hyperbaric oxygen therapy applied for 120 versus 60 minutes. Hyperbaric oxygen therapy partially mitigated histopathological changes in cold-stored livers and exhibited antiapoptotic and cytokine-mediated antiinflammatory effects proportional to the duration of administration.
CONCLUSIONS: Hyperbaric oxygen therapy in addition to static cold storage, even for a limited period, may contribute to an expanded cold ischemia time and increased allograft survival.

DOI: https://doi.org/10.6002/ect.2024.0080
Front Oncol. 2025 ;15 1580515

Exploring a new direction in targeted cancer therapy through hyperbaric oxygen therapy combined with biomedical engineering techniques.

Shuhao Mei, Yuyin Han, Hailian Yi, Yuling Gao, Yong Liu, Xiaoyang Gong.

  The hypoxic tumor microenvironment and dense extracellular matrix (ECM) are key factors limiting the effectiveness of cancer treatments. Hyperbaric oxygen therapy (HBOT) effectively alleviates hypoxia by increasing the oxygen partial pressure (pO2) in tumor tissues, enhancing the sensitivity of chemotherapy, radiotherapy, and immunotherapy. In recent years, the rapid development of biomedical engineering technologies such as nanodrug delivery, engineered bacteria, and immunocellular therapy has provided new strategies to address issues like poor drug penetration and immunosuppressive microenvironments. Studies have shown that the combined application of HBOT and biomedical engineering technologies can synergize: on one hand, HBOT induces reactive oxygen species (ROS) generation and regulates matrix metalloproteinase (MMPs) expression, degrading collagen and fibronectin in the ECM, reducing tumor stiffness, increasing nanodrug penetration depth by 1.8 times and immune cell infiltration rate by 2.3 times. On the other hand, biomedical engineering technologies target delivery of chemotherapy drugs (such as temozolomide/porous silicon nanoparticles), photosensitizers, or gene editing tools (such as CRISPR-Cas9) in conjunction with the improved oxygenation microenvironment by HBOT, significantly enhancing the anti-tumor effects. This article provides a systematic review of the mechanisms, clinical translation outcomes, and safety issues of HBOT combined with biomedical engineering technologies, and highlights the future focus on optimizing individualized treatment plans, long-term efficacy evaluation, and molecular mechanism analysis to promote the clinical application of this interdisciplinary treatment model.

Keywords:  biomedical engineering technology; cancer treatment; extracellular matrix; hyperbaric oxygen therapy; nanodrug delivery

DOI:  https://doi.org/10.3389/fonc.2025.1580515
Eur J Pediatr. 2025 Jun 21. 184(7): 433

Comparison of early postnatal hemodynamics in neonates born at high-altitude or low-altitude using USCOM: a pilot study.

Yue Yang, Gong Ga Zhuo Ma, Wenchao Hong, Jiaming Wang, Aili Xu, Chongbing Yan.

  This study's purpose is to compare early postnatal hemodynamics between neonates from high- and low-altitude regions using Ultrasound Cardiac Output Monitor (USCOM) measurements. We prospectively enrolled hemodynamically stable neonates from Shanghai Children's Hospital (low-altitude group, sea level) and People's Hospital of Shigatse City (high-altitude group, 3850 m) between January and June 2024. Hemodynamic parameters derived from USCOM and clinical data (including oxygen saturation, heart rate, blood pressure, and hemoglobin levels) were obtained on postnatal day 7. The Mann-Whitney U test was employed to compare the differences between groups. The analysis included 80 neonates (40 per group) with comparable baseline characteristics, including gender, gestational age, weight, length, hemoglobin, oxygen carrying capacity, heart rate, and diastolic and mean blood pressure (p > 0.05). Compared to low-altitude group, high-altitude group demonstrated significantly higher stroke volume index (SVI), cardiac output (CO), cardiac index (CI), Smith-Madigan inotropy index (SMII), and systolic blood pressure (p < 0.05). Subgroup analysis indicated that preterm infants in the high-altitude group showed increased SVI, CO, CI, and SMII with lower systemic vascular resistance index (SVRI) (p < 0.05), whereas term infants in the group exhibited elevated CI, SMII, and systolic and mean blood pressure, compared to infants in the low-altitude group, respectively (p < 0.05).
CONCLUSION: Neonates born at high altitude may maintain circulatory adaptation through enhanced myocardial contractility and cardiac performance, while the compensatory responses seem to differ between preterm infants (Frank-Starling mechanism) and term infants (sympathetic-driven regulation).
WHAT IS KNOWN: • Neonates born at high altitude demonstrate lower SpO2 and cardiovascular adaptations to hypobaric hypoxia. • While USCOM enables non-invasive hemodynamic monitoring in neonates, physiological differences at different altitude levels may affect the interpretation of USCOM measurements.
WHAT IS NEW: • First USCOM-derived comparison reveals elevated cardiac efficiency (higher SVI, CI, and SMII) in neonates born at high-altitude. • The compensatory mechanisms for hypobaric hypoxia differed according to cardiovascular maturity: preterm infants relied on the Frank-Starling mechanism, whereas term infants exhibited sympathetic activation.

Keywords:  Hemodynamic parameters; High-altitude; Neonate; Oxygen saturation; Ultrasound Cardiac Output Monitor

DOI:  https://doi.org/10.1007/s00431-025-06272-9
J Gastroenterol Hepatol. 2025 Jun 23.

Thermophiles, Thick-Walled Bacteria, and Pseudomonads in High-Altitude Gut Microbiota.

Fang Yan, Shi-Min Wu, Wen-Qiang Yuan, Yun-Han Yang, Hao Zhu, De-Jun Cui.

   BACKGROUND AND AIM: High-altitude environments are characterized by low oxygen and reduced low pressure, which impose significant physiological challenges on organisms. Among various adaptive systems, the intestinal flora plays a crucial role in maintaining gut health and barrier integrity function under such conditions. This study aimed to elucidate the regulatory mechanisms of intestinal flora in high-altitude environments, focusing on downregulating intracellular Bone Morphogenetic Protein 4 (BMP4) to influence glycolysis metabolism, thereby affecting intercellular communication of the intestinal mucosal barrier and matrix remodeling.
METHODS: High-altitude mouse intestinal flora composition and function were analyzed using 16S rRNA and metagenomic sequencing. Additionally, single-cell sequencing was employed to examine cell population communication and gene expression differences between normal and high-altitude mouse intestinal tissues.
RESULTS: Single-cell sequencing showed significantly reduced interactions between intestinal fibroblasts and epithelial cells in high-altitude mice, accompanied by a marked increase in BMP4 expression. Overexpression of BMP4 was found to activate the glycolysis pathway. Gut microbiota metabolites, including secondary bile acids, lactic acid, and butyrate, exhibited protective effects on hypoxia-induced intestinal mucosal barrier injury, with butyrate showing the most prominent effect. Under hypoxic conditions, butyrate suppressed the BMP4/glycolysis pathway, thereby alleviating hypoxia-induced intestinal mucosal barrier damage.
CONCLUSION: This study uncovered a novel mechanism by which the gut microbiota in high-altitude environments modulate glycolysis metabolism through BMP4 downregulation, thereby affecting intercellular communication and matrix remodeling within the intestinal mucosal barrier.

Keywords:  butyrate mitigation; glycolysis metabolism; high‐altitude environments; hypoxia adaptation; intestinal flora; intestinal mucosal barrier

DOI:  https://doi.org/10.1111/jgh.17032
Curr Neuropharmacol. 2025 Jun 19.

Neuroprotective Proteins in Hypoxia-stressed Astrocyte-Derived Extracellular Vesicles.

Berenice N Bernal Vicente, Isaac Ponce, Manuel Santos Gutiérrez, Emmanuel Ríos Castro, Luis B Tovar-Y-Romo.

   BACKGROUND: Mass spectrometry-based proteomic analysis advancements have generated extensive protein data from cells involved in neurodegenerative diseases. The field of neuroproteomics is expanding to include the study of extracellular vesicles (EVs) to identify potential biomarkers for disease prevention and endogenous factors involved in neuroprotection.
METHODS: In this study, the cortical astrocytes in normoxia were cultured and subjected to hypoxic conditions and obtained astrocyte-derived EVs released in supernatant separately then performed label- free mass spectrometry-based proteomics of these EVs to determine which is the effect of the hypoxic event on the cargo proteins. A meta-analysis of the results compared with previously published databases was conducted. Data was deposited in the ProteomeXchange Consortium with the identified PXD050160.
RESULTS: This study revealed a differential expression of 83 upregulated proteins under hypoxic conditions and 61 downregulated proteins under normoxic conditions, highlighting the protective protein signatures elicited by astrocytes.
CONCLUSION: The present study makes a novel contribution by employing proteomic techniques to characterize the protein cargo of EVs isolated from primary rat astrocytes. This approach allows for a more refined analysis of astrocyte-specific intercellular signaling under hypoxic conditions. It offers valuable insights into the roles of astrocytes in maintaining brain homeostasis and contributing to pathological processes.

Keywords:  Astrocyte; EV cargo; extracellular vesicles; hypoxia; meta-analysis; neuroprotection; proteomics; stroke.

DOI:  https://doi.org/10.2174/011570159X359837250611052037
PLoS Pathog. 2025 Jun 26. 21(6): e1013296

Tibetan PHD2D4E;C127S variant protects from viral diseases in hypoxia, but predispose to infections in normoxia via HIFα:IFN axis.

Riya Ghosh, Garima Joshi, Nishith M Shrimali, Kanchan Bhardwaj, Tsewang Chorol, Tashi Thinlas, Parvaiz A Koul, Josef T Prchal, Prasenjit Guchhait.

We previously reported that Tibetan-specific variant of prolyl-hydroxylase-2 (PHD2)D4E;C127S protects highlanders from hypoxia-triggered pathologies by destabilizing hypoxia-inducible factor (HIF)-1α. Others have reported that stabilized HIF1α negatively regulates interferon (IFN)-regulating factor (IRF)-3 under hypoxia. We examined the role of PHD2D4E;C127S variant in IFN synthesis in immune cells during viral infections. Primary monocytes and cells engineered to express the PHD2D4E;C127S variant displayed protection against dengue virus (DENV)-2 infection by suppressing HIF1α, in turn promoting IRF-3 and IFNα/β synthesis in hypoxia (3% O2) in vitro. However, under normoxia (21% O2), these mutant cells increased reactive oxygen species (ROS) generation following DENV2 infection. Increased ROS then suppressed PHD2D4E;C127S activity, reflected by reduced hydroxylation and concomitant stabilization of HIF1α, resulting in suppressed IFN synthesis and higher DENV2 replication. The PHD2WT cells demonstrated the opposite trend. Our data further confirmed the inverse correlation between HIF1α and IFN pathways. CAY10585, an HIF1α-inhibitor, decreased the DENV2 infection by increasing IFN-A/B and IRF-3/7/9 expression. HIF1α-depleted monocytes also showed a similar response to the infection. We extended our findings to COVID-19 infection. The CD4/CD8 T-cells collected from Tibetans with PHD2D4E;C127S variant and exposed to SARS-CoV-2 infection showed elevated expression of IFN-γ in response to exposure to SARS-CoV-2 receptor-binding domain (RBD) peptide under hypoxia, and a lesser expression under normoxia. The study thus highlights a unique crosstalk of PHD2D4E;C127S variant with HIF1α-IFN axis under environmental pO2 in protecting or predisposing Tibetans to viral infections.

DOI: https://doi.org/10.1371/journal.ppat.1013296
Mol Cell Biol. 2025 Jun 27. 1-9

Hypoxia Signaling in the Cell Type-Specific Regulation of Erythropoietin Production Throughout Mammalian Development.

Norio Suzuki, Taku Nakai, Yuma Iwamura, Koichiro Kato.

  To maintain the oxygen supply to peripheral organs, the production of erythropoietin (EPO), an essential growth factor for red blood cells, is controlled in a hypoxia-inducible manner in mammals. The developmentally earliest site of EPO production, which is necessary for primitive erythropoiesis in the yolk sac and bloodstream, is found in a subset of neural crest and neuroepithelial cells during mid-stage embryonic development. These neural EPO-producing (NEP) cells maintain their immaturity and EPO-producing ability in their hypoxic microenvironment, which is inherent in developing embryos. After oxygenation of the fetus by the establishment of the circulatory system and EPO-driven erythropoiesis, the site of EPO production shifts to hepatocytes of the fetal liver, where erythropoiesis also occurs. In adult mammals, a specific fibroblastic cell fraction in the renal interstitium, known as renal EPO-producing (REP) cells, secretes the majority of EPO to support bone marrow erythropoiesis. Hypoxia-inducible transcription factors (HIFs) are involved in EPO production across NEP cells, hepatocytes, and REP cells, whereas the regulatory mechanisms are distinct for each cell type. This review summarizes the molecular mechanisms of EPO gene regulation throughout all life stages and discusses the associations of HIF signaling in EPO production with other stimuli, including inflammation and metabolism.

Keywords:  HIF; PHD; erythropoiesis; transcriptional regulation

DOI:  https://doi.org/10.1080/10985549.2025.2522720
Elife. 2025 Jun 23. pii: RP99986. [Epub ahead of print]13

Brain-derived exosomal hemoglobin transfer contributes to neuronal mitochondrial homeostasis under hypoxia.

Zhengming Tian, Yuning Li, Feiyang Jin, Zirui Xu, Yakun Gu, Mengyuan Guo, Qianqian Shao, Yingxia Liu, Hanjiang Luo, Yue Wang, Suyu Zhang, Chenlu Yang, Xin Liu, Xunming Ji, Jia Liu.

  Hypoxia is an important physiological stress causing nerve injuries and several brain diseases. However, the mechanism of brain response to hypoxia remains unclear, thus limiting the development of interventional strategies. This study conducted combined analyses of single-nucleus transcriptome sequencing and extracellular vesicle transcriptome sequencing on hypoxic mouse brains, described cell-cell communication in the brain under hypoxia from intercellular and extracellular dimensions, confirmed that hemoglobin mRNA was transferred from non-neuronal cells to neurons, and eventually expressed. Then we further explored the role of exosomal hemoglobin transfer in vitro, using human-derived cell lines, and clarified that hypoxia promoted the transfer and expression of exosomal hemoglobin between endothelial cells and neurons. We found the vital function of exosomal hemoglobin to protect against neurological injury by maintaining mitochondrial homeostasis in neurons. In conclusion, this study identified a novel mechanism of 'mutual aid' in hypoxia responses in the brain, involving exosomal hemoglobin transfer, clarified the important role of exosomal communication in the process of brain stress response, and provided a novel interventional perspective for hypoxia-related brain diseases.

Keywords:  brain-derived extracellular vesicles; hemoglobin; hypoxia; mitochondrial homeostasis; mouse; nerve injury; neuroscience

DOI:  https://doi.org/10.7554/eLife.99986
Metabolites. 2025 Jun 17. pii: 408. [Epub ahead of print]15(6):

Metabolomics Signatures of a Respiratory Tract Infection During an Altitude Training Camp in Elite Rowers.

Félix Boudry, Fabienne Durand, Corentine Goossens.

  Background: Respiratory pathologies, such as COVID-19 and bronchitis, pose significant challenges for high-level athletes, particularly during demanding altitude training camps. Metabolomics offers a promising approach for early detection of such pathologies, potentially minimizing their impact on performance. This study investigates the metabolic differences between athletes with and without respiratory illnesses during an altitude training camp using urine samples and multivariate analysis. Methods: Twenty-seven elite rowers (15 males, 12 females) participated in a 12-day altitude training camp at 1850 m. Urine samples were collected daily, with nine athletes developing respiratory pathologies (8 COVID-19, 1 bronchitis). Nuclear Magnetic Resonance spectroscopy was used to analyze the samples, followed by data processing with Principal Component Analysis (PCA) and Partial Least Squares Discriminant Analysis (PLS-DA), allowing to use Variable Importance in Projection (VIP) scores to identify key metabolites contributing to group separation. Results: The PLS-DA model for respiratory illness showed good performance (R2 = 0.89, Q2 = 0.35, p < 0.05). Models for altitude training achieved higher predictive power (Q2 = 0.51 and 0.72, respectively). Metabolites kynurenine, N-methylnicotinamide, pyroglutamate, propionate, N-formyltryptophan, tryptophan and glucose were significantly highlighted in case of respiratory illness while trigonelline, 3-hydroxyphenylacetate, glutamate, creatine, citrate, urea, o-hydroxyhippurate, creatinine, hippurate and alanine were correlated to effort in altitude. This distinction confirms that respiratory illness induces a unique metabolic profile, clearly separable from hypoxia and training-induced adaptations. Conclusions: This study highlights the utility of metabolomics in identifying biomarkers of respiratory pathologies in athletes during altitude training, offering the potential for improved monitoring and intervention strategies. These findings could enhance athlete health management, reducing the impact of illness on performance during critical training periods. Further research with larger cohorts is warranted to confirm these results and explore targeted interventions.

Keywords:  NMR; PLS-DA; altitude training; athlete health; metabolomics; respiratory pathology

DOI:  https://doi.org/10.3390/metabo15060408