bims-oxygme 2025-04-27 papers

bims-oxygme

Biomed News

on Oxygen metabolism

Issue of 2025–04–27
eight papers selected by
Onurkan Karabulut, Berkeley City College

Metabolic Adaptations and Therapies in Cardiac Hypoxia: Mechanisms and Clinical Implications/ Potential Strategies.
Transient Single Cell Hypoxia Induced by Localized Galvanostatic Oxygen Challenge.
Primary Cilia, Hypoxia, and Liver Dysfunction: A New Perspective on Biliary Atresia.
GCH1 contributes to high-altitude adaptation in Tibetans by regulating blood nitric oxide.
Non-canonical Wnt co-receptors ROR1/ROR2 are differentially regulated by hypoxia in colon cancer cells.
Targeting hypoxia-related pathobiology in Alzheimer's disease: strategies for prevention and treatment.
Human gut microbiota adaptation to high-altitude exposure: longitudinal analysis over acute and prolonged periods.
Chronic Intermittent Hypoxia-Induced Neural Injury: Pathophysiology, Neurodegenerative Implications, and Therapeutic Insights.

JACC Basic Transl Sci. 2025 Apr 02. pii: S2452-302X(24)00458-3. [Epub ahead of print]

Metabolic Adaptations and Therapies in Cardiac Hypoxia: Mechanisms and Clinical Implications/ Potential Strategies.

Huili Li, Fei Xiao, Chenghui Zhou, Tao Zhu, Sheng Wang.

  Cardiac hypoxia triggers a cascade of responses and functional changes in myocardial and non-myocardial cells, profoundly affecting cellular metabolism, oxygen-sensing mechanisms, and immune responses. Myocardial cells, being the primary cell type in cardiac tissue, undergo significant alterations in energy metabolism, including glycolysis, fatty acid metabolism, ketone body utilization, and branched-chain amino acid metabolism, to maintain cardiac function under hypoxic conditions. Non-myocardial cells, such as fibroblasts, endothelial cells, and immune cells, although fewer in number, play crucial roles in regulating cardiac homeostasis, maintaining structural integrity, and responding to injury. This review discusses the metabolic reprogramming of immune cells, particularly macrophages, during ischemia-reperfusion injury and explores various therapeutic strategies that modulate these metabolic pathways to protect the heart during hypoxia. Understanding these interactions provides valuable insights and potential therapeutic targets for heart disease treatment.

Keywords:  cardiac; cell interaction; hypoxia; metabolism; therapy

DOI:  https://doi.org/10.1016/j.jacbts.2024.12.008
ACS Meas Sci Au. 2025 Apr 16. 5(2): 234-241

Transient Single Cell Hypoxia Induced by Localized Galvanostatic Oxygen Challenge.

Marlene H Hill, Gabriel N Meloni, Bruno G Frenguelli, Patrick R Unwin.

Studying cells exposed to low and controllable oxygen levels is key to investigating various fundamental aspects of pathological states, such as stroke and cancer. At present, available methodologies applied in vitro focus on large groups of cells exposed to low oxygen conditions through slow-time approaches, such as environmental incubators or microfluidic devices. Here, we demonstrate a novel approach for titrating the local oxygen concentration around individual adhered PC12 cells, enabling single cells within a population to be exposed to hypoxic-like conditions. A 25 μm diameter platinum disk microelectrode performing the oxygen reduction reaction (ORR) at constant current (galvanostatic control) is used as a microscale oxygen scavenger that can be positioned precisely over individual cells. By coupling the galvanostatic oxygen challenge with confocal laser scanning microscopy (CLSM) and a commercially available hypoxia dye (Image-iT Green hypoxia reagent), we monitor the response of single cells when exposed to depleted oxygen concentrations over time. Numerical simulations are used to characterize the oxygen and pH gradient imposed by the microelectrode at different cathodic currents, revealing that within seconds, the oxygen depletion zone reaches a steady-state condition, extending a few microelectrode radii into solution, while the corresponding pH gradient is strongly compressed by the buffer solution. Cells under the microelectrode show a marked increase in average fluorescence rate relative to control, reporting their hypoxic conditions and demonstrating the effectiveness of the proposed method. Heterogenous cell response in a challenged group is also observed, highlighting the ability of this approach to investigate the natural heterogeneity in cell populations. This work provides a platform and roadmap for future studies of cellular systems where the ability to control and vary oxygen concentration on a rapid time scale would be beneficial.

DOI: https://doi.org/10.1021/acsmeasuresciau.4c00100
Cells. 2025 Apr 15. pii: 596. [Epub ahead of print]14(8):

Primary Cilia, Hypoxia, and Liver Dysfunction: A New Perspective on Biliary Atresia.

Patrícia Quelhas, Diogo Morgado, Jorge Dos Santos.

  Ciliopathies are disorders that affect primary or secondary cellular cilia or structures associated with ciliary function. Primary cilia (PC) are essential for metabolic regulation and embryonic development, and pathogenic variants in cilia-related genes are linked to several pediatric conditions, including renal-hepatic diseases and congenital defects. Biliary atresia (BA) is a progressive infantile cholangiopathy and the leading cause of pediatric liver transplantation. Although the exact etiology of BA remains unclear, evidence suggests a multifactorial pathogenesis influenced by both genetic and environmental factors. Patients with BA and laterality defects exhibit genetic variants associated with ciliopathies. Interestingly, even isolated BA without extrahepatic anomalies presents morphological and functional ciliary abnormalities, suggesting that environmental triggers may disrupt the ciliary function. Among these factors, hypoxia has emerged as a potential modulator of this dysfunction. Hypoxia-inducible factor 1-alpha (HIF-1α) plays a central role in hepatic responses to oxygen deprivation, influencing bile duct remodeling and fibrosis, which are key processes in BA progression. This review explores the crosstalk between hypoxia and hepatic ciliopathies, with a focus on BA. It discusses the molecular mechanisms through which hypoxia may drive disease progression and examines the therapeutic potential of targeting hypoxia-related pathways. Understanding how oxygen deprivation influences ciliary function may open new avenues for treating biliary ciliopathies and improving patient outcomes.

Keywords:  HIF1alpha; biliary atresia; ciliopathies; ischemic cholangiopathy; liver; therapeutic interventions

DOI:  https://doi.org/10.3390/cells14080596
J Genet Genomics. 2025 Apr 18. pii: S1673-8527(25)00114-6. [Epub ahead of print]

GCH1 contributes to high-altitude adaptation in Tibetans by regulating blood nitric oxide.

Yongbo Guo, Wangshan Zheng, Tian Yue, Baimakangzhuo, Xuebin Qi, Kai Liu, Liya Li, Yaoxi He, Bing Su.

  Nitric oxide (NO) is a key vasodilator that regulates vascular pressure and blood flow. Tibetans have developed a "blunted" mechanism for regulating NO levels at high altitude, with GTP cyclohydrolase 1 (GCH1) identified as a key candidate gene. Here, we present comprehensive genetic and functional analyses of GCH1, which exhibits strong Darwinian positive selection in Tibetans. We show that Tibetan-enriched GCH1 variants down-regulate its expression in the blood of Tibetans. Based on this observation, we generate the heterozygous Gch1 knockout (Gch1+/-) mouse model to simulate its downregulation in Tibetans. We find that under prolonged hypoxia, the Gch1+/- mice have relatively higher blood NO and blood oxygen saturation levels compared to the wild-type (WT) controls, providing better oxygen supplies to the cardiovascular and pulmonary systems. Markedly, hypoxia-induced cardiac hypertrophy and pulmonary remodeling are significantly attenuated in the Gch1+/- mice compared with the WT controls, likely due to the adaptive changes in molecular regulations related to metabolism, inflammation, circadian rhythm, extracellular matrix, and oxidative stress. This study sheds light on the role of GCH1 in regulating blood NO, contributing to the physiological adaptation of the cardiovascular and pulmonary systems in Tibetans at high altitude.

Keywords:  Adaptation; GCH1; High altitude; Hypoxia; Nitric oxide; Tibetans

DOI:  https://doi.org/10.1016/j.jgg.2025.04.005
Biochim Biophys Acta Mol Cell Res. 2025 Apr 21. pii: S0167-4889(25)00073-4. [Epub ahead of print]1872(5): 119968

Non-canonical Wnt co-receptors ROR1/ROR2 are differentially regulated by hypoxia in colon cancer cells.

Eduardo Alvarado-Ortiz, María Cristina Castañeda-Patlán, Angela Patricia Moreno-Londoño, José Manuel Tinajero-Rodríguez, Paola Briseño-Díaz, Miguel Angel Sarabia-Sánchez, Miguel Vargas, Elizabeth Ortiz-Sánchez, Martha Robles-Flores.

  ROR1 and ROR2 co-receptors are transducers of non-canonical Wnt responses that promote an aggressive phenotype in several cancer types, including colon cancer. It has been demonstrated that hypoxia promotes tumor progression through the action of Hypoxia Inducible Factors (HIFs). An in silico analysis revealed that ROR2 is overexpressed in the advanced clinical stages of colon cancer. In line with this, ROR1 and ROR2 were found to be only expressed in malignant colon cells compared to non-malignant ones. The blockade of either ROR1 or ROR2 impaired colon cancer cells' colony formation abilities and the migration capacity of them. Additionally, the silencing of the ROR2 co-receptor blocked the metastatic ability of colon cancer cells in a xenografted mice model. We found that while silencing HIF-1α did not significantly reduce ROR1 or ROR2 expression, inhibiting HIF-2α and HIF-3α expression greatly decreased the protein levels of both co-receptors in colon cancer cells. The HIF-1α subunit expression is induced in acute hypoxia, whereas HIF-2α and HIF-3α show higher activity in chronic hypoxia, which may be functionally relevant since hypoxia induced a decrease in the constitutive active β-catenin transcriptional activity in SW480 cells. While both ROR1 and ROR2 stimulate proliferation and migration under normoxic conditions, the exposure of cells to hypoxia increased the expression of ROR1 or ROR2, depending on the Wnt cellular context, Thus, our results indicate that hypoxia partially represses β-catenin transcriptional activity and activates non-canonical Wnt signaling by regulating ROR1/ROR2 expression to induce an aggressive migrating and metastatic phenotype in colon cancer cells.

Keywords:  Hypoxia; Hypoxia inducible factors; Metastasis; Non-canonical Wnt signaling; ROR1/ROR2 co-receptors

DOI:  https://doi.org/10.1016/j.bbamcr.2025.119968
Mol Biol Rep. 2025 Apr 23. 52(1): 416

Targeting hypoxia-related pathobiology in Alzheimer's disease: strategies for prevention and treatment.

Veerta Sharma, Reet Verma, Thakur Gurjeet Singh.

   INTRODUCTION: Alzheimer's Disease (AD) is a neurodegenerative condition characterised by cognitive decline and memory impairment. Recent research highlights the important role of hypoxia, a state of insufficient oxygen availability, in exacerbating AD pathogenesis.
MATERIALS AND METHODS: Through the use of a number of different search engines like Scopus, PubMed, Bentham, and Elsevier databases, a literature review was carried out for investigating the role of hypoxia mediated pathobiology in AD. Only peerreviewed articles published in reputable journals in English language were included. Conversely, non-peer-reviewed articles, conference abstracts, and editorials were excluded, along with studies lacking experimental or clinical relevance or those unavailable in full text.
CONCLUSION: Hypoxia exacerbates core pathological features such as oxidative stress, neuroinflammation, mitochondrial dysfunction, amyloid-beta (Aβ) dysregulation, and hyperphosphorylation of tau protein. These interlinked mechanisms establish a self-perpetuating cycle of neuronal damage, accelerating disease progression. Addressing hypoxia as a modifiable risk factor offers potential for both prevention and treatment of AD. Exploring hypoxia and the HIF signalling pathway may help counteract the neuropathological and symptomatic effects of neurodegeneration.

Keywords:  Alzheimer’s disease; HIF-1; Hypoxia; Mitochondrial dysfunction; Neuroinflammation; Oxidative stress

DOI:  https://doi.org/10.1007/s11033-025-10520-4
Microbiol Spectr. 2025 Apr 21. e0291624

Human gut microbiota adaptation to high-altitude exposure: longitudinal analysis over acute and prolonged periods.

Xianzong Ma, Changwei Duan, Xiaoying Wang, Yurong Tao, Lang Yang, Yongsheng Teng, Yuanming Pan, Mingjie Zhang, Junfeng Xu, Jianqiu Sheng, Xin Wang, Peng Jin.

  This study investigated the longitudinal effects of acute (7-day) and prolonged (3-month) high-altitude exposure on gut microbiota in healthy adult males, addressing the limited data available in human populations. A cohort of 406 healthy adult males was followed, and fecal samples were collected at three time points: baseline at 800 m (406 samples), 7 days after ascending to 4,500 m (406 samples), and 2 weeks post-return to 800 m following 3 months at high altitude (186 samples). High-throughput 16S ribosomal DNA sequencing was employed to analyze microbiota composition and diversity. Results revealed significant changes in alpha- and beta-diversity, with acute high-altitude exposure inducing more pronounced effects compared to prolonged exposure. Specifically, acute exposure increased opportunistic pathogens (Ruminococcus and Oscillibacter) but decreased beneficial short-chain fatty acid producers (Faecalibacterium and Bifidobacterium). Notably, these changes in microbiota persisted even after returning to low altitude, indicating long-term remodeling. Functional analyses revealed substantial changes in metabolic pathways, suggesting microbiota-driven adaptations to energy utilization under high-altitude hypoxic conditions. In summary, acute high-altitude exposure caused dramatic changes in gut microbiota, while prolonged exposure led to structural and functional reshaping. These findings enhance our understanding of how high-altitude environments reshape gut microbiota.
IMPORTANCE: This study is the first to investigate the impact of high-altitude exposure on gut microbiota adaptation in a large-scale longitudinal cohort. It seeks to enhance understanding of how high-altitude environments reshape gut microbiota. Acute exposure to high altitude significantly affected both α-diversity and β-diversity of gut microbiota, with acute exposure causing more pronounced changes than prolonged adaptation, indicating temporary disruptions in microbial communities. Notable shifts in microbial abundance were observed, including increased levels of genera linked to hypoxic stress (e.g., Gemmiger, Ruminococcus, and Parabacteroides) and decreased levels of beneficial bacteria (e.g., Faecalibacterium, Roseburia, and Bifidobacterium), suggesting possible adverse health effects. Functional analysis indicated changes in metabolism-related pathways post-exposure, supporting the idea that high-altitude adaptations involve metabolic adjustments for energy management. These findings enhance understanding of high-altitude physiology, illustrating the role of gut microbiota in hypoxic health.

Keywords:  16S rDNA; dysbacteriosis; gut microbiota; high altitude; longitudinal effects

DOI:  https://doi.org/10.1128/spectrum.02916-24
CNS Neurosci Ther. 2025 Apr;31(4): e70384

Chronic Intermittent Hypoxia-Induced Neural Injury: Pathophysiology, Neurodegenerative Implications, and Therapeutic Insights.

Nan-Nan Jia, Meng-Fan Yao, Chun-Xue Zhu, Mei-Juan He, Hai-Feng Zhu, Zun-Yu Chen, Han-Peng Huang, Chen Qiao.

  Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a sleep-related respiratory disorder that poses a global threat to human health. Chronic intermittent hypoxia (CIH) is its main pathological feature. With the advancements in medical research, the study of CIH-induced neural injury has gained increasing attention. Studies have shown that CIH can lead to or aggravate neuroinflammation and apoptosis by increasing blood-brain barrier (BBB) permeability, promoting oxidative stress, activating glial cells, and triggering multiple signaling pathways, ultimately resulting in neural injury. These processes contribute to the development of Alzheimer's disease, Parkinson's disease, and stroke. This review aims to summarize the progress in CIH-induced neural injury and explore various underlying mechanisms, with the goal of providing new insights for the development of therapeutic interventions targeting CIH-related neural damage.

Keywords:  chronic intermittent hypoxia; glial cells; neural injury; neuroinflammation; obstructive sleep apnea‐hypopnea syndrome

DOI:  https://doi.org/10.1111/cns.70384