bims-oxygme 2025-08-10 papers

bims-oxygme

Biomed News

on Oxygen metabolism

Issue of 2025–08–10
eight papers selected by
Onurkan Karabulut, Berkeley City College

USP3 stabilizes MIC19 by deubiquitination under hypoxic stress and promotes the progression of non-small cell lung cancer.
Distinct immune cell profiles associated with high-altitude hypoxia and severe acute mountain sickness.
Hypoxia ameliorates neurodegeneration and movement disorder in a mouse model of Parkinson's disease.
The key role of hyaluronic acid molecular weight in HIF-1α pathway-mediated hypoxic microenvironment reprogramming.
Lactylation modification of HIF-1α enhances its stability by blocking VHL recognition.
Biomimetic lipid nanocarriers overcome hypoxia barriers in lung cancer therapy.
Effect of Hyperbaric Oxygen Treatment on Lipid Metabolism and Neurovascular Microenvironment in an Apolipoprotein E Knockout Mouse Model.
Photosynthetic Solutions for Organ Perfusion Based on Microalgae and Cyanobacteria Display Differential In Vitro and In Vivo Features for Intravascular Oxygenation.

Acta Pharmacol Sin. 2025 Aug 06.

USP3 stabilizes MIC19 by deubiquitination under hypoxic stress and promotes the progression of non-small cell lung cancer.

Wen-Hao Zhao, Hua Huang, Chen Ding, Ze-Xia Zhao, Chao-Yi Jia, Ying-Jie Wang, Zi-Xuan Hu, Guan-Nan Wang, Yong-Wen Li, Jing-Hao Liu, Hong-Yu Liu, Jun Chen.

  Hypoxia is a common phenomenon in the microenvironment of solid tumors; mitochondria, as the site of cellular oxidative respiration, are among the first organelles to be affected under hypoxic conditions. Mitochondrial cristae organizing protein 19 (MIC19), a core component of the mitochondrial contact site and cristae organizing system (MICOS), is essential for preserving mitochondrial activity. In this study, we investigated the effects of hypoxia on MIC19 and its regulatory mechanisms in non-small cell lung cancer (NSCLC). We showed that the expression levels of MIC19 were significantly increased in NSCLC, which were associated with advanced stages and a poor prognosis in patients with NSCLC. We demonstrated that MIC19 promoted the proliferation and invasion of A549 and PC9 cells in vitro, and MIC19 played a crucial role in maintaining mitochondrial function. We revealed that USP3 mediated the hypoxia-induced upregulation of MIC19 expression in A549 and PC9 cells. In the hypoxic microenvironment, HIF-1α bound to the USP3 promoter region and promoted USP3 expression, which in turn stabilized MIC19 through K48-linked deubiquitination, thereby driving NSCLC progression. The role of MIC19 in NSCLC growth and progression was confirmed in nude mice bearing A549 xenograft tumors in vivo. In conclusion, under hypoxic conditions, USP3 stabilizes MIC19 through deubiquitination, thereby promoting NSCLC progression. This study reveals the HIF1α-USP3-MIC19 axis in NSCLC progression, providing a theoretical basis for future therapeutic strategies.

Keywords:  MIC19; NSCLC; USP3; hypoxia; ubiquitination

DOI:  https://doi.org/10.1038/s41401-025-01625-4
J Physiol. 2025 Aug 06.

Distinct immune cell profiles associated with high-altitude hypoxia and severe acute mountain sickness.

Jingxuan Han, Jian Gao, Yanyun Ma, Yi Li, Chenyuan Wu, Shiguan Le, Yiran Zhao, Helian Li, Yali Luo, Xuling Han, Yuan Guo, Yuanfeng Li, Gangqiao Zhou, Li Jin, Jiucun Wang, Feng Qian.

  High-altitude hypobaric hypoxia is associated with immune dysregulation, potentially linked to the progression of altitude illnesses such as acute mountain sickness (AMS) in unacclimatized individuals. However, the immune signatures associated with AMS severity remain poorly understood. This study investigated immune dynamics under high-altitude exposure and identified immune signatures associated with AMS severity. In this longitudinal study, 205 lowlanders travelled from Chongqing (∼200 m) to Xizang (∼3600 m) by air. Immune status was comprehensively assessed using multi-parametric flow cytometry, alongside monitoring of clinical features at baseline, 1 day after arrival (acute phase) and after 90 days at high altitude (chronic phase). Results demonstrated that high-altitude exposure induced systemic, sustained immune cell perturbations. Using the high-altitude immune score (HI score), derived from immune cell composition, we revealed immune status was associated with hypoxic conditions and changed concurrently with haematopoietic and liver function. Cross-sectional analysis revealed immune cell alterations associated with AMS severity, including reduced frequencies of eosinophils, basophils, plasmacytoid dendritic cells and CD4+ T cells, which was more evident in severe AMS patients. Among these immune alterations, the reduction in eosinophils mediates the relationship between hypoxia and AMS severity. In vitro experiments further suggested hypoxia-induced eosinophil apoptosis may account for the eosinophil reduction. Through network analysis, we identified two immune features as potential biomarkers for predicting and classifying severe AMS cases. This study provides detailed immune dynamics under high-altitude hypoxia exposure and unveils key immune features associated with AMS severity, offering valuable insights for disease prediction and stratification. KEY POINTS: High-altitude exposure induces systemic perturbations in the immune system. Immune status correlates with haematopoietic and liver function under hypoxia. Immune cell alterations are associated with the severity of acute mountain sickness (AMS). The reduction in eosinophils is likely driven by hypoxia-induced apoptosis. Immune biomarkers can predict and diagnose severe AMS cases.

Keywords:  acute mountain sickness; eosinophils; high‐altitude exposure; hypoxia; immune cell alterations; network analysis

DOI:  https://doi.org/10.1113/JP288584
Nat Neurosci. 2025 Aug 06.

Hypoxia ameliorates neurodegeneration and movement disorder in a mouse model of Parkinson's disease.

Eizo Marutani, Maria Miranda, Timothy J Durham, Sharon H Kim, Dreson L Russell, Presli P Wiesenthal, Paul Lichtenegger, Marissa A Menard, Charlotte F Brzozowski, Haobo Li, Gary Ruvkun, Joshua D Meisel, Laura Volpicelli-Daley, Vamsi K Mootha, Fumito Ichinose.

Parkinson's disease (PD) is characterized by inclusions of α-synuclein (α-syn) and mitochondrial dysfunction in dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc). Patients with PD anecdotally experience symptom improvement at high altitude; chronic hypoxia prevents the development of Leigh-like brain disease in mice with mitochondrial complex I deficiency. Here we report that intrastriatal injection of α-syn preformed fibrils (PFFs) in mice resulted in neurodegeneration and movement disorder, which were prevented by continuous exposure to 11% oxygen. Specifically, PFF-induced α-syn aggregation resulted in brain tissue hyperoxia, lipid peroxidation and DA neurodegeneration in the SNpc of mice breathing 21% oxygen, but not in those breathing 11% oxygen. This neuroprotective effect of hypoxia was also observed in Caenorhabditis elegans. Moreover, initiating hypoxia 6 weeks after PFF injection reversed motor dysfunction and halted further DA neurodegeneration. These results suggest that hypoxia may have neuroprotective effects downstream of α-syn aggregation in PD, even after symptom onset and neuropathological changes.

DOI: https://doi.org/10.1038/s41593-025-02010-4
Int J Biol Macromol. 2025 Aug 03. pii: S0141-8130(25)07063-1. [Epub ahead of print] 146506

The key role of hyaluronic acid molecular weight in HIF-1α pathway-mediated hypoxic microenvironment reprogramming.

Jing Liu, Meishan Piao, Yunxing Li, Cheng Yang, Bingtian Zhao.

  Hypoxia is a key factor in delaying chronic wound healing, so therapeutic strategies to alleviate tissue hypoxia are urgently needed. While oxygen-delivering materials have been studied, their long-term biosafety and stability remain unclear. Hyaluronic acid (HA) has shown tissue repair properties, but its role in alleviating hypoxic injury remains unknown. In this study, HA samples with different molecular weights (HA I, HA II, and HA III) were prepared through enzymatic hydrolysis. Structural characterization revealed that HA I exhibited a spherical conformation, while HA II and HA III possessed a flexible chain and semi-flexible chain conformations, respectively. Moreover, HA alleviated oxidative and inflammatory damage in hypoxic environments, with HA II (Mw ≈ 30.8 kDa) showing superior activity. Mechanistically, HIF-1α regulation is central to the anti-hypoxia activity of HA. The in vivo experiments demonstrated that HA II could promote angiogenesis and epidermal regeneration of hypoxic tissues. This study systematically revealed the structure-activity relationship between the molecular weight, chain conformation, and anti-hypoxia activity of HA, suggesting enzymatic hydrolysis as a promising strategy to enhance therapeutic potential of HA for hypoxic diseases.

Keywords:  Anti-hypoxia; Chronic wound; Hyaluronic acid; Mechanism; Molecular weight

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.146506
Cell Commun Signal. 2025 Aug 04. 23(1): 364

Lactylation modification of HIF-1α enhances its stability by blocking VHL recognition.

Chengyu Li, Chen Fu, Wenhan Zhou, Hongmin Li, Zhaojun Liu, Gang Wu, Tong He, Ming Shen, Honglin Liu.

  Hypoxia-inducible factor 1α (HIF-1α) is a master regulator of cellular adaptation to hypoxia. Although prolyl hydroxylation-mediated degradation via the von Hippel-Lindau (VHL) ubiquitination complex is a well-established regulatory mechanism, the role of lactate-induced posttranslational modifications in HIF-1α stabilization remains incompletely understood. Here, we demonstrate that lactate induces lysine lactylation of HIF-1α at distinct residues across species-specifically, K644 in mice and K12 in humans and pigs-to increase protein stability by impairing VHL recognition. Mass spectrometry and mutagenesis analyses revealed that lactylation at these sites reduces K48-linked ubiquitination and proteasomal degradation, even when HIF-1α is hydroxylated. Structural modeling and functional assays revealed that lactylation sterically hinders VHL binding without affecting hydroxylation. Notably, lactylated HIF-1α exhibited increased transcriptional activity, as evidenced by increased promoter occupancy and upregulation of hypoxia-responsive genes (Vegfa, Glut1). Cross-species comparisons highlighted evolutionary divergence in lactylation sites while preserving the functional conservation of this modification. Our findings reveal that lactylation is a universal regulatory mechanism that overrides classical hydroxylation-dependent degradation, expanding our understanding of metabolic control over hypoxic signaling.

Keywords:  Degradation; HIF-1α; Hydroxylation; Lactate; Lactylation; Ubiquitination; VHL

DOI:  https://doi.org/10.1186/s12964-025-02366-x
J Control Release. 2025 Aug 05. pii: S0168-3659(25)00710-2. [Epub ahead of print]386 114099

Biomimetic lipid nanocarriers overcome hypoxia barriers in lung cancer therapy.

Chenghao Qu, Xi-Zhi Kang, Jiacheng Li, Xin-Yan Kan, Yuxia Luan, Di Ning.

  Lung cancer, a major cause of cancer-related deaths, poses significant therapeutic challenges due to tumor hypoxia. Various drug delivery systems are designed to alleviate tumor hypoxia. However, their effectiveness is limited by complex physiological barriers, as well as issues like biocompatibility and colloidal stability. Natural lipids play key roles in physiological processes, including cellular interactions and immunomodulation, and are highly biocompatible. Herein, following the biomimetic concept of lung cancer cell membranes and the modulation of natural lipid nanostructures, we custom-designed lung cancer cell membrane-mimicking nanocarriers (LCCMNs) for efficient oxygen-generating drug delivery to hypoxic regions of lung tumors. The optimized nanocarriers effectively overcame various physiological barriers and possessed good biocompatibility and structural stability, thereby ensuring efficient drug delivery. Meanwhile, these nanocarriers, which carried lung cancer-associated glycolipid antigens and immune adjuvants, were more effective at alleviating the immunosuppression caused by hypoxia. As a proof-of-concept, we developed a self‑oxygenating nanosystem based on LCCMNs to enhance the efficacy of lung cancer treatment combining radiotherapy and immunotherapy, and this nanosystem efficiently improved therapeutic outcomes. Our development of LCCMNs aims to address the problem of hypoxia in lung tumors during treatment.

Keywords:  Lung cancer; Lung cancer cell membrane-mimicking nanocarriers; Natural lipid; Radiotherapy and immunotherapy; Tumor hypoxia

DOI:  https://doi.org/10.1016/j.jconrel.2025.114099
J Integr Neurosci. 2025 Jul 28. 24(7): 39656

Effect of Hyperbaric Oxygen Treatment on Lipid Metabolism and Neurovascular Microenvironment in an Apolipoprotein E Knockout Mouse Model.

Guoying Dong, Yuxiao Liu, Huijun Liu, Chen Qiao, Xia Chen, Linxiao Wang.

   BACKGROUND: Dyslipidemia during midlife represents a significant risk factor for neuropathological alterations associated with cognitive decline. Given the currently incurable nature of dementia, implementation of preventive strategies and early therapeutic interventions prior to disease progression are paramount. Emerging evidence suggests that hyperbaric oxygen (HBO) therapy exhibits neuroprotective properties in various neurological conditions. However, whether HBO treatment modulates lipid metabolism dysregulation and subsequent neurodegeneration remains unanswered. This investigation aimed to elucidate the therapeutic potential of HBO treatment in ameliorating cerebral dysfunction and metabolic perturbations using apolipoprotein E (ApoE)-deficient (ApoE-/-) mice.
METHODS: ApoE-/- mice received HBO treatment for 10 consecutive days, and then behavioral assessment tests were performed. Serum and brain tissue were collected to measure oxidative stress levels and inflammatory factors.
RESULTS: Compared with ApoE-/- group, cognitive declines was significantly reversed in mice of the ApoE-/-+HBO mice. The blood lipid profiles of ApoE-/- mice were also improved after HBO treatment, accompanied by a reduction in body weight. Moreover, HBO treatment was found to ameliorates neuronal injury and amyloid-β deposition in the hippocampus of ApoE-/- mice. Further studies have revealed that the benefits of HBO treatment occurred through the reduction of inflammatory factors and attenuation of oxidative stress.
CONCLUSIONS: These findings indicate that HBO treatment effectively improves the intracerebral microenvironment of ApoE-/- mice, providing a novel regulatory mechanism of protection against dyslipidemia-associated brain deficits by HBO treatment.

Keywords:  apolipoprotein E; cognitive dysfunction; dyslipidemias; hyperbaric oxygenation; inflammation

DOI:  https://doi.org/10.31083/JIN39656
ACS Appl Bio Mater. 2025 Aug 07.

Photosynthetic Solutions for Organ Perfusion Based on Microalgae and Cyanobacteria Display Differential In Vitro and In Vivo Features for Intravascular Oxygenation.

Daniela Becerra, Valentina Vargas-Torres, Valentina Veloso-Giménez, Daniela Gallardo-Agüero, Miguel Miranda, Valentina Hernández-Pavez, Nicolás González-Quezada, Sebastián San Martín, Mauricio P Boric, José Tomás Egaña.

  The delivery of photosynthetic microorganisms has emerged as a strategy for tissue oxygenation, offering a promising approach to treat several hypoxic conditions. Among these, intravascular photosynthesis has been proposed for ex vivo organ preservation; however, the most suitable photosynthetic microorganisms and their behavior during intravascular perfusion remain to be fully elucidated. Therefore, this study evaluates key properties of photosynthetic solutions for organ perfusion, based on the microalgaeChlamydomonas reinhardtii and the cyanobacterium Synechococcus elongatus. In vitro characterization showed that both microorganisms maintained viability, morphology, and oxygen production capacity in a Ringer's lactate-based medium for at least 24 h, with both photosynthetic solutions exhibiting rheological properties compatible with organ perfusion. In vivo perfusion of rat kidneys demonstrates sustained hemodynamic stability, with S. elongatus showing lower variability in vascular resistance. Histological analysis revealed significant retention of both microorganisms within renal structures, with S. elongatus inducing less tubular damage. Additionally, biocompatibility assays with human endothelial cells and zebrafish larvae showed no significant cytotoxic effects of the photosynthetic solutions. These findings support the feasibility of using photosynthetic microorganisms for intravascular photosynthesis, highlighting S. elongatus as particularly promising due to its lower oxygen consumption in darkness and reduced tissue damage after perfusion. This work provides significant insights toward the development of biologically active perfusion systems for innovative preservation strategies for organ transplantation.

Keywords:  Chlamydomonas reinhardtii; Synechococcus elongatus; biological oxygen carriers; microbial biocompatibility; organ perfusion; photosynthetic microorganisms; photosynthetic therapies; renal preservation

DOI:  https://doi.org/10.1021/acsabm.5c01137