bims-oxygme 2025-09-21 papers

bims-oxygme

Biomed News

on Oxygen metabolism

Issue of 2025–09–21
nine papers selected by
Onurkan Karabulut, Berkeley City College

Neuroprotective effects of estradiol and progesterone against hypoxia-induced apoptosis in mouse primary cortical neurons.
Hypoxia, Psychedelics, and Terminal Lucidity: A Perspective on Neuroplasticity and Neuropsychiatric Disorders.
Engineering microalgae-based oxygenators for hypoxia relief and enhanced photodynamic therapy against biofilms in diabetic wounds healing.
The Nuclear-Encoded Cytochrome c Oxidase Subunit COX4-1 Enhances Hypoxia Tolerance in Glioblastoma Cells.
Angiogenesis and Hypoxia Biomarkers Are Dysregulated in Progressive Multiple Sclerosis.
Endothelial αvβ3 integrin induction during hypoxia protects blood-brain barrier integrity.
Mapping neutrophil fate and function in ischemic stroke: A single-cell roadmap for translational insights.
Metformin nanoparticles mitigate cerebral ischemia reperfusion injury by improving mitochondrial dysfunction and inhibiting NLRP3 activation.
A novel holder and microfluidic system for spatially controlled hypoxia induction, mechanical stimulation and cardiac regeneration research.

J Neuropathol Exp Neurol. 2025 Sep 18. pii: nlaf035. [Epub ahead of print]

Neuroprotective effects of estradiol and progesterone against hypoxia-induced apoptosis in mouse primary cortical neurons.

Abolfazl Azami Tameh, Javad Amini Mahabadi, Mohammad Ali Atlasi, Cordian Beyer, Zeinab Vahidinia.

  Hypoxia leads to neuronal damage and 17β-estradiol (E2) and progesterone (P4) exhibit neuroprotective properties in such conditions. However, the precise mechanisms behind these effects remain unexplored. This study evaluates the neuroprotective effects and underlying mechanisms of E2, P4, and their combination (EP) against hypoxic injury. We created a cerebral hypoxia injury model using the hypoxia/reoxygenation (H/R) technique. Primary cortical neurons from 15-day-old mouse embryos were cultured for 7 days. They were then treated with E2, P4, or EP and subsequently subjected to hypoxia. Neurons were identified using MAP2; and neurites and cell bodies were immunolabeled with SMI-311 and SMI-312. Cell viability and damage were assessed by MTS and lactate dehydrogenase assays, apoptosis by PI/Hoechst staining, and cleaved caspase-3 expression by Western blotting. The results showed that most cultured cells were neurons with well-developed neurites. Hypoxia significantly reduced cell viability and increased neuronal death, with elevated caspase-3 expression. Hormone treatments enhanced cell viability and reduced neuronal death. To investigate the potential mechanism, we analyzed the cleaved caspase 3 expression but no significant differences in caspase-3 expression were observed between groups. Overall, hormone therapy alleviated hypoxic injury but did not affect caspase activity. This study provides insights into the neuroprotective mechanisms of hormone therapy.

Keywords:  17β-estradiol; caspase 3; cell apoptosis; hypoxia; progesterone

DOI:  https://doi.org/10.1093/jnen/nlaf035
ACS Pharmacol Transl Sci. 2025 Sep 12. 8(9): 2848-2854

Hypoxia, Psychedelics, and Terminal Lucidity: A Perspective on Neuroplasticity and Neuropsychiatric Disorders.

Junjie Zhang, Xiubo Du, Xinying Li, Xinyou Lv, Xiaohui Wang.

  Hypoxia and psychedelics, despite their distinct origins, both induce altered states of consciousness and promote neuroplasticity, suggesting a shared underlying mechanism relevant to neuropsychiatric treatment and neurological recovery. Terminal lucidity, the transient resurgence of cognitive function in late-stage dementia, highlights the brain's latent capacity for rapid reorganization, a phenomenon that may be driven by transient hypoxia. Similarly, acute intermittent hypoxia and pharmacological agents like HypoxyStat, which modulate oxygen availability, have emerged as potential strategies for enhancing neural adaptability. This perspective explores the hypothesis that controlled reductions in oxygen availabilitywhether through psychedelics, near-death experiences, meditation, holotropic breathwork, or hypoxia therapiestrigger calcium signaling pathways that promote synaptogenesis and the formation of new neural circuits. Rather than restoring damaged connections, this process may enable functional rerouting, thereby supporting cognitive resilience and behavioral compensation in conditions such as stroke, Alzheimer's disease, and psychiatric disorders. By integrating insights from psychedelic research, hypoxia-based therapies, and neuroplasticity studies, we propose a unifying framework that leverages altered oxygen homeostasis as a novel therapeutic strategy for neuropsychiatric and neurodegenerative diseases.

Keywords:  acute intermittent hypoxia; hypoxia therapy; neuroplasticity; neuropsychiatric disorders; psychedelics; terminal lucidity

DOI:  https://doi.org/10.1021/acsptsci.5c00440
J Colloid Interface Sci. 2025 Sep 12. pii: S0021-9797(25)02399-9. [Epub ahead of print]702(Pt 2): 139007

Engineering microalgae-based oxygenators for hypoxia relief and enhanced photodynamic therapy against biofilms in diabetic wounds healing.

Yu Zheng, Yanxin Wu, Ruping Li, Ruotong Yang, Ke Liu, Zhanlin Zhang, Ya Liu, Yao He.

  Diabetic wounds present complex therapeutic challenges due to bacterial infection, persistent inflammation, microvascular hypoxia, and biofilm formation. Although photodynamic therapy (PDT) enables antibacterial activity in deep tissues, its efficacy is limited under hypoxic conditions and within biofilms. To address this, we developed an engineered microalgae-based oxygen-generating system capable of sustained in situ oxygen production to alleviate hypoxia, enhance PDT effectiveness, and disrupt biofilms. Specifically, these oxygenators comprise Chlorella vulgaris (Cv) was encapsulated within a bioactive metal-phenolic network formed by epigallocatechin gallate (EGCG) and Fe3+ ions via layer-by-layer assembly, followed by loading with the photosensitizer tetra-(4-carboxyphenyl) porphyrin (TCPP), resulting in a multifunctional system designated as Cv@EFe-TCPP. The embedded Cv continuously produces oxygen through photosynthesis, a process modulated by the thickness of the coating. Meanwhile, the metal-phenolic coating and TCPP generate reactive oxygen species upon light irradiation. The endogenous oxygen supply significantly improves PDT efficiency by mitigating hypoxia, thereby enhancing antibacterial and anti-inflammatory outcomes. In addition, under light exposure, Cv@EFe-TCPP promotes cell migration, reduces inflammatory responses, and stimulates angiogenesis and tissue regeneration, without inducing detectable side effects in normal tissues. This study extends the scope of PDT-based antibacterial strategies by integrating photosynthetic oxygen production, offering a promising therapeutic platform for diabetic wound healing.

Keywords:  Chlorella vulgaris; Diabetic wound; Engineering oxygenators; Oxygen production; Photodynamic therapy

DOI:  https://doi.org/10.1016/j.jcis.2025.139007
J Oncol Res Ther. 2025 ;pii: 10299. [Epub ahead of print]10(3):

The Nuclear-Encoded Cytochrome c Oxidase Subunit COX4-1 Enhances Hypoxia Tolerance in Glioblastoma Cells.

Claudia R Oliva, Susanne Flor, Md Yousuf Ali, Corinne E Griguer.

  Glioblastoma (GBM) is the most common and aggressive primary brain cancer in adults. While chemo- and radiotherapy are often effective in treating newly diagnosed GBM, increasing evidence suggests that treatment-induced metabolic alterations promote tumor recurrence and further resistance. In addition, GBM tumors are typically hypoxic, which further contributes to treatment resistance. Recent studies have shown that changes in glioma cell metabolism driven by a shift in the isoform expression of mitochondrial cytochrome c oxidase (CcO) subunit 4 (COX4), a key regulatory subunit of mammalian CcO, may underlie the treatment-induced metabolic alterations in GBM cells. However, the impact of hypoxia on GBM energetics is not fully understood. Using isogenic GBM cell lines expressing either COX4-1 or the alternative COX4 isoform, COX4-2, we found that COX4-1 expressing cells maintained a more oxidative metabolism under hypoxia, characterized by increased CcO activity and ATP production, enhanced assembly of CcO-containing mitochondrial supercomplexes, and reduced superoxide production. Furthermore, COX4-1 expression was sufficient to increase radioresistance under hypoxic conditions. Untargeted metabolomic analysis revealed that the most significantly upregulated pathways in COX4-1-expressing cells under hypoxia were purine and methionine metabolism. In contrast, COX4-2-expressing cells showed increased activation of glycolysis and the Warburg effect. Our study provides new insights into how CcO regulatory subunits influence cellular metabolic networks and radioresistance in GBM under hypoxia, identifying potential therapeutic targets for improved treatment strategies.

Keywords:  COX4–1; Cytochrome c oxidase; Glioma; Hypoxia; Mitochondrial supercomplexes; Radioresistance

DOI:  https://doi.org/10.29011/2574-710x.10299
Neurol Neuroimmunol Neuroinflamm. 2025 Nov;12(6): e200477

Angiogenesis and Hypoxia Biomarkers Are Dysregulated in Progressive Multiple Sclerosis.

Heather Y F Yong, Rajiv W Jain, Maria Goiko, Nicholas J Batty, Serena Phillips, Mankarman Ghuman, Marcus Werner Koch, Carlos Camara-Lemarroy.

BACKGROUND AND OBJECTIVES: Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative CNS disorder characterized by a state of "virtual hypoxia." Angiogenesis, one of the main homeostatic responses to hypoxia, has been implicated in the pathophysiology of MS. The study objective was to determine whether angiogenic and hypoxia-related molecules are dysregulated in the serum and CNS of patients with progressive multiple sclerosis (PMS).
METHODS: Baseline serum samples were obtained from a phase II trial of Ibudilast in PMS (n = 203 analyzed) and matched to healthy controls (n = 53). Participants on previous therapeutics (interferons or glatiramer acetate) were excluded from analysis (n = 131). Angiogenic factors were measured using a commercially available bead-based multiplex assay, and hypoxia biomarkers were measured using a custom bead-based multiplex assay. To interrogate the expression of selected hypoxia and angiogenic markers in the CNS, we analyzed publicly available transcriptomic databases and in-house generated data from normal appearing white matter of 2 SPMS donors and 2 nonneurologic disease controls.
RESULTS: Circulating markers of hypoxia (such as hypoxia inducible factor-1-a, heme oxygenase-1, and heat shock protein-90) were increased in serum. Conversely, markers of angiogenesis (such as vascular endothelial growth factor-A [VEGF-A], heparin-binding epidermal growth factor, and hepatocyte growth factor) were reduced suggesting a blunting of the angiogenic response. Several of these changes were confirmed in the PMS CNS transcriptome. Lower levels of VEGF-A were associated with disability worsening on the timed-25 foot-walk test at 24 (p = 0.02) and 48 (p = 0.02) weeks and predicted disability worsening (hazard ratio 0.31, 95% CI 0.14-0.69, p = 0.034). Conversely, higher leptin levels trended to predict cognitive worsening on the symbol digit modalities test.
DISCUSSION: Hypoxia-angiogenesis signals are dysregulated in PMS. Increased hypoxia and an insufficient angiogenic adaptive response may play a role in PMS pathophysiology and be a relevant pathway, both in understanding disease mechanisms and as a possible therapeutic target.

DOI: https://doi.org/10.1212/NXI.0000000000200477
Proc Natl Acad Sci U S A. 2025 Sep 23. 122(38): e2510931122

Endothelial αvβ3 integrin induction during hypoxia protects blood-brain barrier integrity.

Sebok K Halder, Violaine D Delorme-Walker, Richard Milner.

  The blood-brain barrier (BBB) is critical for maintaining cerebral homeostasis, and its deterioration with age is an important pathogenic factor in the etiology of vascular dementia. Extracellular matrix-integrin interactions play a central role in regulating vascular stability. The αvβ3 integrin is not expressed by brain endothelial cells under stable conditions but is strongly induced by hypoxia. However, it is currently unclear whether αvβ3 integrin exerts a destructive or protective influence on BBB integrity. In young (8 to 10 wk) and aged (20 mo) mice, we examined the impact of a function-blocking β3 integrin antibody as well as the inhibitory peptide cilengitide on BBB disruption during exposure to CMH (8% O2). Hypoxic induction of brain endothelial β3 integrin was much stronger in aged mice. In both young and aged mice, β3 integrin inhibition greatly amplified hypoxia-induced BBB disruption, correlating with loss of tight junction proteins and induction of the leaky BBB marker mouse endothelial cell antigen (MECA)-32. Consistent with this, β3 integrin null mice showed increased levels of hypoxia-induced BBB disruption and MECA-32 expression. Cilengitide also reduced the integrity of a brain endothelial monolayer in vitro, prevented β3 integrin localization to focal adhesions, and reduced expression of vascular endothelial (VE)-cadherin and tight junction proteins. These observations suggest that hypoxic induction of endothelial αvβ3 integrin enhances BBB integrity by stabilizing endothelial adhesion. This raises the interesting possibility that pharmacological upregulation of endothelial αvβ3 integrin in the aged brain might hold therapeutic promise for vascular dementia.

Keywords:  aging; blood vessels; brain; chronic mild hypoxia; β3 integrin

DOI:  https://doi.org/10.1073/pnas.2510931122
Biochem Biophys Res Commun. 2025 Sep 15. pii: S0006-291X(25)01375-0. [Epub ahead of print]784 152659

Mapping neutrophil fate and function in ischemic stroke: A single-cell roadmap for translational insights.

Junbo Zhang, Zhuohui Chen, Yanyi Peng, Lingyue Zhang, Bo Xiao, Mengqi Zhang.

   BACKGROUND: Ischemic stroke (IS) accounts for 71 % of all strokes, whose diagnosis and prognosis require further exploration. Neutrophil extracellular traps (NETs) are produced by neutrophils, and there is already evidence that NETs play a role in IS, but further studies about crosstalk between immune cells, pathways and NETs are still needed.
MATERIALS AND METHODS: To assess the expression of neutrophil extracellular traps (NETs), we utilized single sample Gene Set Enrichment Analysis. Stroke-associated NETs genes (SN genes) were identified through differential expression analysis combined with Weighted Correlation Network Analysis. Based on these SN genes, we developed a sophisticated diagnostic model incorporating machine learning techniques. Furthermore, we constructed a single-cell atlas of neutrophil transitions in post-stroke mice. Validation of our findings was conducted both in vitro and in vivo. In vitro, we employed oxygen-glucose deprivation (OGD) experiments to simulate ischemic conditions, facilitating the assessment of NETs formation and monitoring alterations in SN genes expression within neutrophils. In vivo, validation involved tracking changes in peripheral blood levels of these genes in a mouse model of transient middle cerebral artery occlusion (tMCAO) post-cerebral ischemia.
RESULTS: A detailed single-cell landscape depicting the dynamic transitions of neutrophils within the cerebral microenvironment post-stroke has been elaborately constructed. NETs displayed significant differential expression between IS and control groups in peripheral blood, correlating strongly with the activities of neutrophils and macrophages. Pathways pertinent to IS and NETs were delineated. A diagnostic model incorporating two SN genes was developed, demonstrating an AUC greater than 0.98, effectively pinpointing the hyperacute phase of IS. Additionally, the ceRNA networks concerning IS and NETs were mapped out. In vitro validation with oxygen-glucose deprivation (OGD) experiments revealed marked changes in NET formation and SN genes expression in neutrophils, corroborating our computational predictions. In vivo validation using a mouse transient middle cerebral artery occlusion (tMCAO) model confirmed significant changes in peripheral blood levels of F12 and PLXDC2 after cerebral ischemia, proving the excellent predictive value of these markers for IS.
CONCLUSION: This study elucidates the complex roles and dynamic changes of neutrophils within the cerebral microenvironment of mice from 3 h to 3 days following stroke onset. We have identified key genes, immune cells, signaling pathways, and ceRNA networks implicated in the formation of NETs in IS. Our study constructed a robust diagnostic model capable of detecting the hyperacute phase of IS, with an AUC value greater than 0.98. The inclusion of experimental validation for the SN genes F12 and PLXDC2 not only corroborates our model's predictive accuracy but also underscores its potential utility in clinical settings. These findings offer promising avenues for improving early diagnosis and potentially guiding therapeutic strategies in IS.

Keywords:  Diagnosis model; Gene signature; Ischemic stroke; Neutrophil extracellular traps; PPI; WGCNA; ceRNA

DOI:  https://doi.org/10.1016/j.bbrc.2025.152659
Biomater Adv. 2025 Sep 11. pii: S2772-9508(25)00334-6. [Epub ahead of print]179 214507

Metformin nanoparticles mitigate cerebral ischemia reperfusion injury by improving mitochondrial dysfunction and inhibiting NLRP3 activation.

Lin Deng, Ting Cai, Jiayu Li, Yinfei Song, Sheng Guo, Tao Tao.

   BACKGROUND: Cerebral ischemia reperfusion injury (CIRI) is a serious condition that lacks highly effective treatment methods. After CIRI, microglia in the cortex of mice show high expression of CD44, which offers a potential target for the development of targeted drug-delivery systems to treat ischemic brain injury.
OBJECTIVE: This study aimed to design a targeted drug-delivery system for ischemic brain injury, and explore the underlying molecular mechanisms on CIRI.
METHODOLOGY: Hyaluronic acid-PEG-DSPE@metformin (HA@MET) nanoparticles were designed to specifically target the CD44 receptor on microglia. HA@MET was used to intervene in a CIRI mouse model, and then the infarct size and neurological scores were measured. Moreover, experiments on the expression of autophagy-related proteins (Beclin-1, Atg5, Sirt3), the production of reactive oxygen species (ROS), the activation of the NLRP3 inflammasome and the release of associated inflammatory factors (Caspase-1, IL-6, IL-1β) were performed.
RESULTS: In the CIRI mouse model, HA@MET treatment led to a significant reduction in infarct size and an improvement in neurological scores, indicating a strong therapeutic effect on ischemic brain injury. Mechanistically, HA@MET inhibited the expression of key autophagy proteins Beclin-1 and Atg5, while increasing the expression of Sirt3 protein. This action alleviated excessive mitochondrial autophagy and promoted the clearance of damaged mitochondria. After entering microglia, HA@MET released metformin, which decreased ROS production and inhibited the activation of the NLRP3 inflammasome, resulting in reduced concentrations of inflammatory factors (Caspase-1, IL-6, IL-1β) and alleviating the inflammatory responses associated with CIRI.
CONCLUSIONS: This study provides new perspectives and potential therapeutic targets for the treatment of ischemic brain injury. HA@MET, as a targeted drug-delivery system, shows promise in treating CIRI through multiple mechanisms, including regulating mitochondrial autophagy and inhibiting inflammation.

Keywords:  Cerebral ischemia reperfusion injury; Hyaluronic acid; Metformin nanoparticles; Microglia; Mitochondrial autophagy; NLRP3 inflammasome; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.bioadv.2025.214507
Lab Chip. 2025 Sep 18.

A novel holder and microfluidic system for spatially controlled hypoxia induction, mechanical stimulation and cardiac regeneration research.

Kołodziejek Dominik, Szlachetka Aleksandra, Iwoń-Szczawińska Zuzanna, Drozd Marcin, Wojasiński Michał, Jastrzębska Elżbieta.

Over the years, cardiovascular diseases have remained a leading cause of mortality worldwide, necessitating advanced experimental models to mimic the natural environment of the heart as closely as possible. New microfluidic heart models would enable precise modelling of the healthy heart as well as pathological mechanisms occurring during cardiac ischemia and testing new therapies would become more accessible than it is currently. In this study, we developed a two layer holder for creating hypoxic conditions in a dedicated microfluidic system for modelling cardiac infarction. By integrating the holder with a microsystem utilizing nanofibrous mats with iron(II, III) oxide (Fe3O4) magnetic nanoparticles we were able to create a tool for using (potentially patient specific) induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) in cardiac research. In the microsystem we induced hypoxia and conducted preliminary observations of cardiac regeneration using induced pluripotent stem cells (iPSCs). We found that iPSCs express cTnT when co-cultured with hypoxia-damaged iPSC-CMs indicating that the holder with an integrated microsystem can be used for hypoxia and cardiac regeneration studies.

DOI: https://doi.org/10.1039/d5lc00460h