bims-oxygme 2025-10-05 papers

bims-oxygme

Biomed News

on Oxygen metabolism

Issue of 2025–10–05
seven papers selected by
Onurkan Karabulut, Berkeley City College

Hypoxia Increases Sarcolemmal Na+/HCO3 - Cotransport Activity via an ERK1/2-Dependent Pathway in Cardiac HL-1 Cell Line.
Hypoxia-Driven Histone Modifications Govern Gene Regulation for Mature Eye Lens Formation.
6-Hydroxygenistein Ameliorates High Altitude Brain Injury via Activating PI3K/AKT Signaling Pathway Based on Transcriptomic Analysis and Experimental Validation.
Caffeine, MitoQ, and GABA Prophylaxis of Mitochondrial Dysfunction Induced in Human Pulmonary Cells by Normobaric-Hyperoxia and Hyperbaric-Hyperoxia.
Hedgehog signaling activation rescues hypoxia-induced ferroptosis in human brain organoids.
Exploring the genetic footprints of high altitude adapted humans and livestock.
HIF-1α regulates the progression of metabolic dysfunction-associated steatotic liver disease.

J Cell Physiol. 2025 Oct;240(10): e70097

Hypoxia Increases Sarcolemmal Na+/HCO3 - Cotransport Activity via an ERK1/2-Dependent Pathway in Cardiac HL-1 Cell Line.

Gül Şimşek, Pawel Swietach, Hilmi Burak Kandilci.

  As a major modulator of cardiac function, intracellular pH (pHi) is tightly controlled by sarcolemmal acid-base transporters to within narrow limits (7.1-7.3). Na+/H+ exchanger (NHE1) and Na+/HCO3 - cotransporter (NBC) are the main acid-extruding membrane proteins; the latter is further subdivided into electrogenic (NBCe1/NBCe2) and electroneutral (NBCn1) isoforms. In the underperfused heart, acid disturbances are often accompanied by hypoxia, but their interplay on cardiac NBC activity is unknown. Here, we studied the effect of acute (1 mM dithionite and 100% N2, 10 min) and long-term hypoxia (1% O2, 48 h) on sarcolemmal NBC activity using fluorimetric assays in mouse atrial-derived HL-1 cells and primary rat cardiomyocytes. NBCe1 and NBCn1 transcripts were detected in HL-1 cells. Ensemble NBC activity, defined as the HCO3 --dependent acid-extrusion flux, was promptly inhibited under acute anoxia. In contrast, pHi-sensitivity of NBC flux was increased after long-term hypoxia, likely an adaptive response. This increase was not due to buffering capacity changes but was mimicked by dimethyloxalylglycine (1 mM, DMOG), which stabilizes hypoxia inducible factor under normoxic conditions. Hypoxia affected neither NBCn1 nor NBCe1 protein levels, indicating a modulatory effect on transporter activity. The contribution of electrogenic (NBCe1) and electroneutral (NBCn1) isoforms, dissected from fluxes generated under hyperkalemia, showed that long-term hypoxia selectively raised NBCn1 activity. This effect was blocked by U0126, an inhibitor of extracellular signal-regulated kinase 1/2, implicating phosphorylation. Our results show that acute anoxia and prolonged hypoxia regulate NBC-dependent flux by distinct mechanisms ostensibly to retain pH control under the combination of acidosis and hypoxia.

Keywords:  ERK 1/2 signaling; HIF; bicarbonate transport; hypoxia; intracellular pH

DOI:  https://doi.org/10.1002/jcp.70097
Invest Ophthalmol Vis Sci. 2025 Oct 01. 66(13): 2

Hypoxia-Driven Histone Modifications Govern Gene Regulation for Mature Eye Lens Formation.

Lisa Brennan, Joshua Disatham, Marc Kantorow.

Purpose: Evidence suggests that the hypoxic environment of the lens regulates the expression of genes required for lens formation and function. Here, we tested the hypothesis that hypoxia regulates these genes through the induction of specific histone modifications.
Methods: Global levels of hypoxia-induced histone modifications were determined in cultured day 13 chick lenses exposed to 1% oxygen. The genome-wide localizations of H3K27ac and H3K4me3 were identified by cleavage under target and release using nuclease analysis and mapped to within 5 kb of the transcriptional start sites of genes activated or repressed by hypoxia identified by RNA sequencing. The requirement for these histone modifications for hypoxia-induced gene expression was determined using inhibitors of histone writers and erasers.
Results: The levels of activating modifications H3K4me3, H3K9ac, H3K14ac, and H3K27ac in hypoxia-treated lenses increased, whereas levels of repressive modifications H3K9me3 and H3K27me3 remained unchanged. Hypoxia-specific H3K4me3 and/or H3K27ac regions were detected within 5 kb of the transcriptional start sites of more than 900 fiber cell genes with increased expression upon hypoxia exposure and 350 genes with decreased expression. The inhibition of histone writers and erasers resulted in altered levels of key fiber cell genes upon hypoxia exposure.
Conclusions: These results provide evidence that hypoxia-induced histone modifications regulate the genes required for mature lens formation and provide a framework for understanding the role of hypoxia-specific histone modifications in the regulation of genes in more complex tissues.

DOI: https://doi.org/10.1167/iovs.66.13.2
Drug Des Devel Ther. 2025 ;19 8641-8656

6-Hydroxygenistein Ameliorates High Altitude Brain Injury via Activating PI3K/AKT Signaling Pathway Based on Transcriptomic Analysis and Experimental Validation.

Yu Xin, Gege Wang, Chenyu Yang, Huiping Ma, Linlin Jing.

   Purpose: Our Prior research has shown that 6-hydroxygenistein (6-OHG) alleviates hypobaric hypoxia induced brain injury (HHBI) achieved by its powerful antioxidant, anti-inflammatory, and anti-apoptotic capabilities, but its mechanism still requires additional investigation. The objective of this study was to uncover the protective mechanism of 6-OHG against HHBI based on transcriptomics analysis and experimental validation.
Methods: The gene levels in brain tissue obtained from previous study were accessed via the RNA-Seq technique. DESeq2 R package was used to identify the differentially expressed genes (DEGs). Functional enrichment analysis and molecular docking were investigated utilizing the clusterProfiler R package and Autodock Vina software, respectively. In experimental validation stage, histological analysis was performed using Hematoxylin-Eosin (HE) staining. Oxidative stress, inflammatory, and apoptotic indexes in brain tissue were measured using commercial kits. Western blot was applied for detecting related protein expression.
Results: The RNA-Seq analysis revealed 905 differentially expressed genes (DEGs) between the Con and Mod groups, with 239 upregulated and 666 downregulated. Between the 6-OHG and Mod groups, there were 192 DEGs, including 98 upregulated and 94 downregulated genes. Go and KEGG function analyses highlighted the PI3K/AKT signaling pathway as a crucial regulatory mechanism. Western blot analysis showed that HH exposure caused a decrease in the ratios of p-PI3K/PI3K and p-AKT/AKT in the mouse brain, but this effect was reversed by 6-OHG treatment, indicating that 6-OHG activates the PI3K/AKT signaling pathway. Furthermore, LY294002, a selective PI3K inhibitor, effectively blocked this activation and also abolished the protective effects of 6-OHG on histopathological damage, as well as its antioxidant, anti-inflammatory, and anti-apoptotic activities in HHBI mice.
Conclusion: 6-OHG mitigates HHBI by activating the PI3K/AKT signaling pathway, suggesting its potential therapeutic application for HHBI treatment.

Keywords:  6-hydroxygenistein; PI3K/AKT signaling pathway; hypobaric hypoxia induced brain damage; therapeutic target; transcriptomics

DOI:  https://doi.org/10.2147/DDDT.S526988
Oxid Med Cell Longev. 2025 ;2025 5589475

Caffeine, MitoQ, and GABA Prophylaxis of Mitochondrial Dysfunction Induced in Human Pulmonary Cells by Normobaric-Hyperoxia and Hyperbaric-Hyperoxia.

Tanvir Hossain, Jackson T Secor, David M Eckmann.

  Exposure to hyperoxia lasting either a few days at normobaria or a few hours at hyperbaria induces pulmonary oxygen toxicity. Cellular functional changes resulting from oxygen toxicity include alterations in both mitochondrial dynamics and bioenergetics. The primary goal of this study was to quantify the prophylactic effects of three compounds, caffeine, MitoQ, and γ-aminobutyric acid (GABA), to protect human pulmonary cells in vitro from mitochondrial alterations induced by normobaric- and hyperbaric-hyperoxic conditions. Using cultured lung microvascular and pulmonary artery endothelial cells as well as A549 cells, we examined mitochondrial dynamic and bioenergetics function following exposure to normobaric-hyperoxic (5% CO2 and 95% O2 for 72 h) and hyperbaric-hyperoxic (~5% CO2 equivalent and remainder O2 at pressure of 4.8 atmosphere absolute (ATA) for 4 h) conditions in the presence of the drugs. Mitochondrial respiration parameters, inner membrane potential, motility, intracellular distribution, and size were measured, along with quantitation of respiration complex levels. Redistribution of intracellular ATP-linked respiration was determined. Comparisons of results were made to controls under normobaric-normoxic conditions. Effects of the drugs under control conditions were also measured. Presence of the drugs resulted in differential effects on hyperoxia-induced alterations in cellular respiration function, stability of mitochondrial potential, and distribution of ATP-linked respiration within the cell. Inclusion of these drugs also produced unique signatures for respiration complex protein levels. Moreso for caffeine than for MitoQ and GABA, its inclusion in the face of hyperoxic exposure served to preserve mitochondrial bioenergetics function, primarily by promoting intracellular redistribution of mitochondrial volume to the perinuclear space. These results indicate a potential role for pharmacologic prophylaxis via therapeutics targeted to support mitochondrial function as a means of protecting the lung from hyperoxia-induced pulmonary cellular oxygen toxicity.

Keywords:  hyperbaric; mitochondria; oxygen; pulmonary; toxicity

DOI:  https://doi.org/10.1155/omcl/5589475
Neural Regen Res. 2025 Sep 29.

Hedgehog signaling activation rescues hypoxia-induced ferroptosis in human brain organoids.

Simeng Yi, Min Huang, Chunmei Xian, Xi Kong, Shigang Yin, Jianhua Peng, Hongda Li, Yong Jiang, Bingqing Xie, Huangfan Xie.

   ABSTRACT: Fetal hypoxia disrupts neurodevelopment. In particular, the developing brain is extremely vulnerable to hypoxia injury; however, the specific vulnerable cell types and their underlying molecular mechanisms remain underexplored. In the present study, we established a human brain organoid model that reproduced the pathophysiological process of fetal hypoxia during early to mid-gestation. Through single-cell transcriptomic technology, we identified seven neural lineages in these organoids, including cortical progenitors and neurons. Further analysis revealed the specific responses to hypoxia among different types of cells regarding the mechanistic target of rapamycin complex 1 signaling pathway, fatty acid synthesis, the unfolded protein response, and the innate immune response. In terms of development, the maturation of glutamatergic and γ-aminobutyric acid-ergic neurons was significantly delayed after hypoxia exposure, whereas progenitor cells were less affected. In terms of function, we identified two subtypes of γ-aminobutyric acid-ergic neurons with different sensitivities to hypoxia. The more mature type 2 neurons were the most sensitive to hypoxia, which manifested as ferroptosis activation and impaired expression of neurite proteins (e.g., microtubule-associated protein 2). By contrast, the less mature type 1 neurons showed some tolerance to hypoxia. A mechanistic study revealed that pharmacological activation of the hedgehog pathway can inhibit ferroptosis and restore expression of the neurite protein microtubule-associated protein 2 in type 2 γ-aminobutyric acid-ergic neurons under hypoxia. Collectively, these findings delineate the lineage-specific patterns of hypoxia vulnerability and establish hedgehog pathway regulation as a potential target for neuroprotective strategies in fetal brain hypoxic injury.

Keywords:  GABAergic neurons; brain organoids; ferroptosis; fetal brain injury; hedgehog signaling; human; hypoxia; nerve regeneration; neurodevelopment; neuroprotective strategies; single-cell RNA-sequencing

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00338
Mamm Genome. 2025 Sep 30.

Exploring the genetic footprints of high altitude adapted humans and livestock.

Manish Tiwari, Gayatri Gujar, Siriluck Ponsuksili, C G Shashank, Shweta Sharma, Monika Sodhi, Manishi Mukesh.

  High-altitude environments such as the Himalayas, Andes, and Ethiopian regions pose extreme environmental challenges like hypobaric hypoxia, cold stress, and extreme UV radiation. This prompts both short-term physiological and long-term genetic adaptations in resident human and livestock populations. Various genetic studies suggest that candidate genes, such as HIF1A, EPAS1, EGLN1, MITF, ITPR2, VEGFA etc. are involved in hypoxia response, erythropoiesis, angiogenesis and metabolic regulation that results in high altitude adaptation. Phylogenetic comparisons of HIF family genes, suggest evolutionary divergence between humans and livestock, however, closer relationships exist among the ruminants suggesting shared adaptive pressures. The present study revealed that despite of the different evolutionary history, both humans and livestock across the different geographical regions show similar type of traits, driven by certain genes (either the same genes or different genes working in similar ways). These genes have been naturally selected over the time and helped the humans and livestock to survive at extreme environments. Furthermore, enrichment analysis suggests convergent evolution at the gene and pathway levels, supporting the genetic adaption in humans and livestock across the different geographical regions. This review will serve as a valuable information source for researchers working in the fields of high-altitude environments, evolutionary biology and environmental genomics.

Keywords:  Adaptation; Candidate genes; EPAS1; HIF1A; High altitude; Human; Livestock

DOI:  https://doi.org/10.1007/s00335-025-10161-9
Digestion. 2025 Oct 01. 1-16

HIF-1α regulates the progression of metabolic dysfunction-associated steatotic liver disease.

Qi Liu, Hao Liu, Yi Zheng, Zhengyi Yang, Sha Wen.

BACKGROUND: With the improvement in living standards, metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common chronic liver disease worldwide, garnering increasing concern due to its significant health risks. MASLD encompasses a spectrum of pathological processes ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC), and it has become a leading cause of liver-related mortality. Due to the lack of specific therapeutic targets, current diagnostic, treatment, and management strategies for MASLD remain inadequate.
SUMMARY: This review aims to explore the pathophysiological manifestations of MASLD, the mechanisms through which HIF-1α contributes to disease progression, and the potential therapeutic approaches targeting HIF-1α, offering feasible strategies for treating advanced MASLD.
KEY MESSAGE: Studies suggest that hepatocytes in MASLD are often in a hypoxic state, which activates hypoxia-inducible factor-1α (HIF-1α), playing a crucial role in disease progression. During hypoxia, the expression of HIF-1α increases throughout the different stages of MASLD, interacting with various genes and pathways, influencing lipid metabolism, steatosis, and fibrosis progression.

DOI: https://doi.org/10.1159/000548503