bims-oxygme 2025-05-04 papers

bims-oxygme

Biomed News

on Oxygen metabolism

Issue of 2025–05–04
ten papers selected by
Onurkan Karabulut, Berkeley City College

Under (Genetic Selection) Pressure: Human Tumors and Human Populations in Hypoxia.
Study on the Protective Effect of Methyl Rosmarinate on Hypoxic Mice and Their Erythrocytes.
Mechanism of Mitophagy to Protect Yak Kidney from Hypoxia-Induced Fibrosis Damage by Regulating Ferroptosis Pathway.
Harnessing Hypoxia: Bacterial Adaptation and Chronic Infection in Cystic Fibrosis.
Faecalibacterium duncaniae Mitigates Intestinal Barrier Damage in Mice Induced by High-Altitude Exposure by Increasing Levels of 2-Ketoglutaric Acid.
Role of miRNAs in the regulation of the triploid rainbow trout (Oncorhynchus mykiss) liver transcriptome in hypoxic environments.
Hypoxia Induces Extensive Protein and Proteolytic Remodeling of the Cell Surface in Pancreatic Adenocarcinoma (PDAC) Cell Lines.
Engineered Feedback Employing Natural Hypoxia-Responsive Factors Enhances Synthetic Hypoxia Biosensors.
Gut microbiota and hyperbaric oxygen therapy.
Long-term exposure to high-altitude hypoxic environments reduces blood pressure by inhibiting the renin-angiotensin system in rats.

Cancer Discov. 2025 May 02. 15(5): 875-877

Under (Genetic Selection) Pressure: Human Tumors and Human Populations in Hypoxia.

Frank S Lee.

Arenillas and colleagues report that pheochromocytomas and paragangliomas in the setting of chronic hypoxia due to cyanotic congenital heart disease harbor, at high frequency, somatic gain-of-function mutations in the EPAS1 gene, which encodes for one of the oxygen-labile subunits of the hypoxia-inducible factor complex. Interestingly, germline loss-of-function EPAS1 alleles are under natural selection in human populations subjected to a different chronic hypoxia condition, namely, high altitude. See related article by Arenillas et al., p. 1037.

DOI: https://doi.org/10.1158/2159-8290.CD-25-0175
Drug Des Devel Ther. 2025 ;19 3179-3192

Study on the Protective Effect of Methyl Rosmarinate on Hypoxic Mice and Their Erythrocytes.

Qianwen Guo, Ziyue Yin, Rong Wang, Yuemei Sun, Anpeng Zhao, Wanteng Yao, Wenbin Li.

   Objective: We have previously identified methyl rosmarinic (MR) acid as a 2.3-bisphosphoglycerate mutase (BPGM) activator. The present study aimed to verify the protective effect of MR on plateau field hypoxia mice and the mechanism of increased oxygen release capacity of erythrocytes in vivo.
Methods: The anti-hypoxic effect of MR was investigated in a plateau field environment in Specific Pathogen Free -grade healthy BALB/c mice, male and female, and the effect of different doses of MR on the survival time of mice in confined space was investigated in an atmospheric pressure confinement hypoxia experiment, plasma inflammatory markers, oxidative stress indices of myocardial, brain, lung and liver tissues, as well as the histopathological damage and hypoxia in each experimental group were measured by HE staining and hypoxia probe method. Finally, the effects of MR administration to mice on the energy metabolic pathways and metabolites of erythrocytes in vivo were investigated.
Results: After acute plateau entry in mice, the energy metabolic pathway of erythrocytes shifted to the glycolytic pathway as the duration of hypoxia increased. The administration of MR to hypoxic mice further activated Bisphosphoglycerate mutase (BPGM) and increased the levels of glyceraldehyde-3-phosphate and 2.3-bisphosphoglycerate (2,3-BPG), as well as further shifted glucose to the glycolytic pathway and further enhanced the activity of rate-limiting enzymes in the glycolytic pathway.
Conclusions: MR activates BPGM in erythrocytes to produce more 2, 3-BPG from the glycolytic branch, thus exerting a protective effect against injury in hypoxic mice in the highland field.

Keywords:  2,3-biphosphoglyceric acid; erythrocytes; glycolysis; hypoxia; methyl rosmarinate

DOI:  https://doi.org/10.2147/DDDT.S493866
Biomolecules. 2025 Apr 09. pii: 556. [Epub ahead of print]15(4):

Mechanism of Mitophagy to Protect Yak Kidney from Hypoxia-Induced Fibrosis Damage by Regulating Ferroptosis Pathway.

Xuefeng Bai, Hongqin Lu, Rui Ma, Sijiu Yu, Shanshan Yang, Junfeng He, Yan Cui.

  Renal fibrosis is a critical pathological feature of various chronic kidney diseases, with hypoxia being recognized as an important factor in inducing fibrosis. Yaks have long inhabited high-altitude hypoxic environments and do not exhibit fibrotic damage under chronic hypoxia. However, the underlying protective mechanisms remain unclear. This study compared the renal tissue structure and collagen volume between low-altitude cattle and high-altitude yaks, revealing that yaks possess a significantly higher number of renal tubules than cattle, though collagen volume showed no significant difference. Under hypoxic treatment, we observed that chronic hypoxia induced renal fibrosis in cattle, but did not show a significant effect in yaks, suggesting that the hypoxia adaptation mechanisms in yaks may have an anti-fibrotic effect. Further investigation demonstrated a significant upregulation of P-AMPK/AMPK, Parkin, PINK1, LC3Ⅱ/Ⅰ, and BECN1, alongside a downregulation of P-mTOR/mTOR in yak kidneys. Additionally, hypoxia-induced renal tubular epithelial cells (RTECs) showed increased expression of mitophagy-related proteins, mitochondrial membrane depolarization, and an increased number of lysosomes, indicating that hypoxia induces mitophagy. By regulating the mitophagy pathway through drugs, we found that under chronic hypoxia, activation of mitophagy upregulated E-cadherin protein expression while downregulating the expression of Vimentin, α-SMA, Collagen I, and Fibronectin. Simultaneously, there was an increase in SLC7A11, GPX4, and GSH levels, and a decrease in ROS, MDA, and Fe2⁺ accumulation. Inhibition of mitophagy produced opposite effects on protein expression and cellular markers. Further studies identified ferroptosis as a key mechanism promoting renal fibrosis. Moreover, in renal fibrosis models, mitophagy reduced the accumulation of ROS, MDA, and Fe2⁺, thereby alleviating ferroptosis-induced renal fibrosis. These findings suggest that chronic hypoxia protects yaks from hypoxia-induced renal fibrosis by activating mitophagy to inhibit the ferroptosis pathway.

Keywords:  ferroptosis; hypoxia adaptation; mitophagy; renal fibrosis; yak

DOI:  https://doi.org/10.3390/biom15040556
FEMS Microbiol Rev. 2025 May 01. pii: fuaf018. [Epub ahead of print]

Harnessing Hypoxia: Bacterial Adaptation and Chronic Infection in Cystic Fibrosis.

Ciarán J Carey, Niamh Duggan, Joanna Drabinska, Siobhán McClean.

  The exquisite ability of bacteria to adapt to their environment is essential for their capacity to colonise hostile niches. In the cystic fibrosis (CF) lung, hypoxia is among several environmental stresses that opportunistic pathogens must overcome to persist and chronically colonise. Although the role of hypoxia in the host has been widely reviewed, the impact of hypoxia on bacterial pathogens has not yet been studied extensively. This review considers the bacterial oxygen-sensing mechanisms in three species that effectively colonise the lungs of people with CF, namely Pseudomonas aeruginosa, Burkholderia cepacia complex and Mycobacterium abscessus and draws parallels between their three proposed oxygen-sensing two-component systems: BfiSR, FixLJ, and DosRS, respectively. Moreover, each species expresses regulons that respond to hypoxia: Anr, Lxa, and DosR, and encode multiple proteins that share similar homologies and function. Many adaptations that these pathogens undergo during chronic infection, including antibiotic resistance, protease expression, or changes in motility, have parallels in the responses of the respective species to hypoxia. It is likely that exposure to hypoxia in their environmental habitats predispose these pathogens to colonisation of hypoxic niches, arming them with mechanisms than enable their evasion of the immune system and establish chronic infections. Overcoming hypoxia presents a new target for therapeutic options against chronic lung infections.

Keywords:   Burkholderia cepacia complex; Mycobacterium abscessus ; Pseudomonas aeruginosa ; Hypoxia; adaptation; chronic infection; lung disease

DOI:  https://doi.org/10.1093/femsre/fuaf018
Nutrients. 2025 Apr 19. pii: 1380. [Epub ahead of print]17(8):

Faecalibacterium duncaniae Mitigates Intestinal Barrier Damage in Mice Induced by High-Altitude Exposure by Increasing Levels of 2-Ketoglutaric Acid.

Xianduo Sun, Wenjing Li, Guangming Chen, Gaosheng Hu, Jingming Jia.

  Background/Objectives: Exposure to high altitudes often results in gastrointestinal disorders. This study aimed to identify probiotic strains that can alleviate such disorders. Methods: We conducted a microbiome analysis to investigate the differences in gut microbiota among volunteers during the acute response and acclimatization phases at high altitudes. Subsequently, we established a mouse model of intestinal barrier damage induced by high-altitude exposure to further investigate the roles of probiotic strains and 2-ketoglutaric acid. Additionally, we performed untargeted metabolomics and transcriptomic analyses to elucidate the underlying mechanisms. Results: The microbiome analysis revealed a significant increase in the abundance of Faecalibacterium prausnitzii during the acclimatization phase. Faecalibacterium duncaniae (F. duncaniae) significantly mitigated damage to the intestinal barrier and the reduction of 2-ketoglutaric acid levels in the cecal contents induced by high-altitude exposure in mice. Immunohistochemistry and TUNEL staining demonstrated that high-altitude exposure significantly decreased the expression of ZO-1 and occludin while increasing apoptosis in ileal tissues. In contrast, treatment with F. duncaniae alleviated the loss of ZO-1 and occludin, as well as the apoptosis induced by high-altitude exposure. Furthermore, 2-ketoglutaric acid also mitigated this damage, reducing the loss of occludin and apoptosis in mice. Transcriptomic analysis indicated that high-altitude exposure significantly affects the calcium signaling pathway; conversely, the administration of F. duncaniae significantly influenced the PPAR signaling pathway, mineral absorption, and the regulation of lipolysis in adipocytes. Additionally, the expression of the FBJ osteosarcoma oncogene (Fos) was markedly reduced following the administration of F. duncaniae. Conclusions:F. duncaniae mitigates hypoxia-induced intestinal barrier damage by increasing levels of 2-ketoglutaric acid and shows promise as a probiotic, ultimately aiding travelers in adapting to high-altitude environments.

Keywords:  2-ketoglutaric acid; gastrointestinal issues; gut microbiota; hypoxia exposure; probiotics

DOI:  https://doi.org/10.3390/nu17081380
Comp Biochem Physiol Part D Genomics Proteomics. 2025 Apr 18. pii: S1744-117X(25)00104-2. [Epub ahead of print]55 101515

Role of miRNAs in the regulation of the triploid rainbow trout (Oncorhynchus mykiss) liver transcriptome in hypoxic environments.

Jun Sun, Yan Han, Jiao Li, Huizhen Li, Yuqiong Meng, Guoliang Sun, Changzhong Li, Rui Ma.

  To investigate the effects of hypoxia on the liver of triploid rainbow trout (Oncorhynchus mykiss), we integrated transcriptomic and bioinformatics analyses to decipher the regulatory roles of miRNAs and their target genes under hypoxic conditions. Comparative analyses identified 45 differentially expressed miRNAs (DEmiRNAs) between the hypoxic (group D) and normoxic (group E) groups, as well as 117 hypoxia-associated miRNA-mRNA pairs that exhibited negative regulatory interactions. A systematic miRNA-mRNA interaction network was subsequently constructed to visualise these relationships. Gene Ontology (GO) enrichment analyses showed that target genes of DEmiRNAs were mainly enriched in immune system processes and stimulus-response biological functions. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis further showed that vascular endothelial growth factor (VEGF) and ErbB co-activate the downstream MAPK cascade, which plays a crucial role in regulating hepatocyte metabolism, survival, and hypoxia tolerance. The coordinated action of these three pathways together mediates hypoxic stress adaptation in rainbow trout. These findings deepen our understanding of the molecular mechanisms of hypoxic stress in rainbow trout.

Keywords:  Hypoxia; MiRNA-mRNA negative regulation; Transcriptome; Triploid rainbow trout; VEGF signaling pathway

DOI:  https://doi.org/10.1016/j.cbd.2025.101515
J Proteome Res. 2025 May 01.

Hypoxia Induces Extensive Protein and Proteolytic Remodeling of the Cell Surface in Pancreatic Adenocarcinoma (PDAC) Cell Lines.

Irene Lui, Kaitlin Schaefer, Lisa L Kirkemo, Jie Zhou, Rushika M Perera, Kevin K Leung, James A Wells.

  The tumor microenvironment (TME) plays a crucial role in cancer progression. Hypoxia is a hallmark of the TME and induces a cascade of molecular events that affect cellular processes involved in metabolism, metastasis, and proteolysis. In pancreatic ductal adenocarcinoma (PDAC), tumor tissues are extremely hypoxic. Here, we leveraged mass spectrometry technologies to examine hypoxia-induced alterations in the abundance and proteolytic modifications to cell surface and secreted proteins. Across four PDAC cell lines, we discovered extensive proteolytic remodeling of cell surface proteins involved in cellular adhesion and motility. Looking outward at the surrounding secreted space, we identified hypoxia-regulated secreted and proteolytically shed proteins involved in regulating the humoral immune and inflammatory response, and an upregulation of proteins involved in metabolic processing and tissue development. Combining cell surface N-terminomics and secretomics to evaluate the cellular response to hypoxia enabled us to identify significantly altered candidate proteins which may serve as potential biomarkers and therapeutic targets in PDAC. Furthermore, this approach provides a blueprint for studying dysregulated extracellular proteolysis in other cancers and inflammatory diseases.

Keywords:  Cancer-regulated proteolysis; Cell surface N-terminomics; Hypoxia; Protein shedding; Secretomics; Tumor microenvironment

DOI:  https://doi.org/10.1021/acs.jproteome.4c01037
ACS Synth Biol. 2025 May 02.

Engineered Feedback Employing Natural Hypoxia-Responsive Factors Enhances Synthetic Hypoxia Biosensors.

Kathleen S Dreyer, Patrick S Donahue, Jonathan D Boucher, Katherine M Chambers, Marya Y Ornelas, Hailey I Edelstein, Benjamin D Leibowitz, Katherine J Zhu, Kate E Dray, Joseph J Muldoon, Joshua N Leonard.

  Inadequate oxygen supply is a feature of multiple acute and chronic diseases, and hypoxia biosensors can be deployed in engineered cells to study or treat disease. Although mediators of hypoxia-responsiveness have been characterized, dynamics of this response are less understood, and there is no general approach for tuning biosensor performance to meet application-specific needs. To address these gaps, we investigated the use of genetic circuits to enhance biosensor performance through feedback, ultimately achieving both low background and amplified hypoxia-induced gene expression. To build insight into the mechanisms by which our circuits modulate performance, we developed an explanatory mathematical model. Our analysis suggests a previously unreported dual regulatory mechanism in the natural hypoxia response, providing new insights into regulatory dynamics in chronic hypoxia. This study exemplifies the potential of using synthetic gene circuits to perturb natural systems in a manner that uniquely enables the elucidation of novel facets of natural regulation.

Keywords:  ODE models; biosensor; gene circuit; hypoxia; synthetic biology

DOI:  https://doi.org/10.1021/acssynbio.4c00714
Med Gas Res. 2025 Dec 01. 15(4): 548-549

Gut microbiota and hyperbaric oxygen therapy.

Daisuke Muroya, Shinya Nadayoshi, Yutaro Kai, Shin Sasaki, Yuichi Goto, Kohji Okamoto.

DOI: https://doi.org/10.4103/mgr.MEDGASRES-D-25-00018
Front Physiol. 2025 ;16 1565147

Long-term exposure to high-altitude hypoxic environments reduces blood pressure by inhibiting the renin-angiotensin system in rats.

Delong Duo, Junbo Zhu, Mengyue Wang, Xuejun Wang, Ning Qu, Xiangyang Li.

   Introduction: This study assesses the effects of chronic high-altitude hypoxia on blood pressure regulation in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats, focusing on cardiovascular remodelling, hemodynamic alterations, and renin-angiotensin system (RAS) modulation.
Methods: Eight-week-old male SHR and WKY rats were divided into four groups: the SHR high-altitude hypoxia group (SHR-H), WKY high-altitude hypoxia group (WKY-H), SHR control group (SHR-C), and WKY control group (WKY-C). The hypoxia groups were exposed to 4,300 m (PaO2: 12.5 kPa) for 10 weeks. Blood pressure was measured via non-invasive tail-cuff method, cardiac function via echocardiography, and right heart pressures via catheterization. Histopathological analysis included haematoxylin and eosin and Masson/Weigert staining for organ damage and vascular remodelling, whereas RAS components were assessed using immunohistochemistry.
Results: The results showed that chronic hypoxia significantly reduced systolic blood pressure, diastolic blood pressure, and mean arterial pressure in SHR-H rats, but not in WKY-H rats. SHR-H rats showed a reduced ejection fraction, fractional shortening, systolic left ventricular anterior wall thickness, and diastolic left ventricular anterior wall thickness, increased left ventricular diastolic diameter, and left ventricular systolic diameter, whereas WKY-H showed only ejection fraction and fractional shortening decline. Both groups developed elevated mean pulmonary arterial pressure, right ventricular systolic pressure, and right ventricular end-diastolic pressure. SHR-H rats displayed aortic medial thinning, elastic fibre degradation, increased blood viscosity, and multi-organ damage (myocardial necrosis, pulmonary fibrosis), whereas WKY-H rats showed medial thinning and erythrocyte hyperplasia without fibrosis. Immunohistochemistry revealed suppression of the angiotensin-converting enzyme (ACE)-angiotensin II (Ang II)-angiotensin II type I (AT1) axis in SHR-H, whereas WKY-H exhibited reduced Ang I/II without ACE2 and Mas receptor (MasR) changes.
Conclusion: Long-term hypoxic exposure at high-altitude reduces blood pressure in SHR rats, which may be attributed to a combination of cardiac functional compensation failure, vascular remodelling, and simultaneous inhibition of the ACE-Ang II-AT1R and ACE2-Ang1-7-MasR axes.

Keywords:  blood pressure; high-altitude hypoxia; renin-angiotensin system; spontaneously hypertensive rats; wistar kyoto rats

DOI:  https://doi.org/10.3389/fphys.2025.1565147