bims-oxygme 2025-09-07 papers

bims-oxygme

Biomed News

on Oxygen metabolism

Issue of 2025–09–07
eleven papers selected by
Onurkan Karabulut, Berkeley City College

The role of hypoxic microenvironment in rheumatoid arthritis.
Exploring the role of HIF-1α in pathogenesis of parkinson's disease and its potential as a therapeutic target.
STAT3/Snail Signaling and Progression of Hypoxia Tolerance in Breast Cancer Cells.
Hypoxia Disrupted Serotonin Levels in the Prefrontal Cortex and Striatum, Leading to Depression-like Behavior.
PHPT1 acts as an inhibitor in high-altitude pulmonary hypertension via negative TRPV5 signaling regulation.
DNA methylation in adaptation to high-altitude environments and pathogenesis of related diseases.
Patient-derived organoids reveal hypoxia-driven plasticity and therapeutic vulnerabilities in pheochromocytomas and paragangliomas.
Hypoxia-inducible factors in breast cancer: prognostic indicators and emerging biomarkers: narrative review.
Genome-wide selection signal analysis reveals the adaptability of Tibetan sheep to high altitudes.
Hypoxia, Inflammation, and Cytokine Crosstalk in Sickle Cell Disease: From Mechanisms to Modulation- A Narrative Review.
Nanomedicine Targeting the Warburg Effect: Advanced Strategies for Cancer Therapy.

Front Immunol. 2025 ;16 1633406

The role of hypoxic microenvironment in rheumatoid arthritis.

Qiu-Han Zheng, Ye Zhai, Ying-Hang Wang, Zhi Pan.

  Rheumatoid Arthritis (RA) is an autoimmune disease caused by many factors, with a high disability rate, unsatisfactory clinical treatment effect, and unclear pathogenesis. The oxygen level in the joint cavity is significantly reduced, and the hypoxic microenvironment has become a key factor in the pathogenesis and progression of RA. Based on the latest research developments, this review delves into the structure and main functions of the key factor HIF in the hypoxic microenvironment, and expounds the main regulatory mechanisms of HIF. The effect of the hypoxic microenvironment on the pathological changes of RA was analyzed, especially how hypoxia affects the signal transduction of related molecules and cells, thus aggravating the occurrence and development of RA. In addition, the review also discusses emerging therapeutic strategies aimed at targeting the hypoxic pathways, including HIF-1α inhibitors, Hyperbaric oxygen therapy, and the application of traditional Chinese medicine. By providing a comprehensive overview of the interplay between RA and the hypoxic microenvironment, this review aims to provide new perspectives on the underlying mechanisms of RA and provide a theoretical basis for the development of therapeutic drugs to improve the hypoxic microenvironment of RA.

Keywords:  hypoxia inducible factor; hypoxic microenvironment; molecular mechanism; rheumatoid arthritis; treatment strategy

DOI:  https://doi.org/10.3389/fimmu.2025.1633406
Mol Biol Rep. 2025 Sep 02. 52(1): 858

Exploring the role of HIF-1α in pathogenesis of parkinson's disease and its potential as a therapeutic target.

Navpreet Kaur, Khadga Raj Aran.

  Hypoxia is an inadequate oxygen supply to the tissues, which hinders the brain's ability to produce energy and causes unconsciousness, followed by death in a matter of minutes. Upon detecting oxygen deprivation, the body initiates a cardiorespiratory response that includes increased lung ventilation, vasoconstriction, and an increased heart rate to improve oxygen supply. Moreover, during hypoxia, there is stabilization of hypoxia inducible factor (HIF), including HIF-1α and HIF-2α, where HIF-1α predominantly regulates genes involved in metabolic reprogramming and immediate stress response, and HIF-2α is engaged in sustaining vascular endothelial growth factor (VEGF) and erythropoietin (EPO) gene expression. The brain is an extremely oxygen-dependent organ, as it uses one-fifth of the body's oxygen at rest, making it particularly vulnerable during hypoxia. According to the literature, it results in metabolic changes in neurons via impacting various enzymatic activities, which further trigger inflammatory responses and oxidative stress, resulting in Parkinson's disease (PD). PD is a progressive neurodegenerative disease, characterised by α-synuclein aggregation, Lewy body formation, and dopaminergic neuronal loss in the substantia nigra. HIF-1α is involved in various pathological mechanisms underlying PD, including α-synuclein aggregation, neuroinflammation, mitochondrial dysfunction, and proteasomal degradation. Emerging evidence from several preclinical studies demonstrates that HIF-1α could be a promising therapeutic target due to its active involvement in PD pathology. This review aims to elucidate the interconnection between hypoxia and the development of PD by evaluating the role of HIF-1α in the pathogenesis of PD and summarizing possible therapeutic strategies based on modifying the activity of the HIF-1α signaling.

Keywords:  HIF-1α; Hypoxia; Neuroinflammation; Parkinson's disease; Targeted therapy; Α-Synuclein

DOI:  https://doi.org/10.1007/s11033-025-10944-y
Biochemistry (Mosc). 2025 Aug;90(8): 1064-1076

STAT3/Snail Signaling and Progression of Hypoxia Tolerance in Breast Cancer Cells.

Olga E Andreeva, Danila V Sorokin, Alexander M Scherbakov, Svetlana V Vinokurova, Pavel B Kopnin, Nadezhda V Elkina, Maria D Fedorova, Alexey N Katargin, Danila S Elkin, Mikhail A Krasil'nikov.

  One of the hallmarks of malignant neoplasms is their ability to sustain growth under hypoxic conditions resulting from insufficient oxygenation of tumor tissues. Prolonged hypoxia is associated with the gradual adaptation of tumor cells to low oxygen levels, leading to the enhanced survival, increased metastatic potential, and development of resistance to anticancer therapies. The aim of this study was to investigate the mechanisms underlying adaptation of breast cancer cell to prolonged hypoxia and maintenance of the hypoxia-tolerant phenotype. Using long-term culturing under low oxygen conditions (1% O2), we established hypoxia-adapted sublines of luminal (MCF-7) and triple-negative (MDA-MB-231) breast cancer cells, characterized by a stable growth in a hypoxic environment. The acquisition of hypoxia tolerance was accompanied by the activation of the HIF-1α-dependent transcription factor STAT3 and persistent overexpression of Snail, a key downstream effector of STAT3. The maintenance and stabilization of hypoxia-tolerant phenotype are mediated by miR-181a-2, which targets the STAT3/Snail signaling axis in the resistant cells. Analysis of DNA methylation status revealed no significant changes in the expression or activity of DNA methyltransferases (DNMTs) in the hypoxia-adapted cells. However, pharmacological inhibition of DNMTs using decitabine, as well as DNMT knockdown, increased cell sensitivity to hypoxia and partially reversed the hypoxia-resistant phenotype, which was accompanied by the activation of pro-apoptotic p53 signaling. In conclusion, our findings suggest that the acquired hypoxia tolerance in breast cancer cells is mediated, at least in part, by the activation of the miR-181a-2/STAT3/Snail signaling pathway. Furthermore, the use of demethylating agents may represent a promising therapeutic approach to targeting hypoxia-tolerant cancer cell populations.

Keywords:  STAT3; Snail; breast cancer; hypoxia; methylation; miR-181a-2

DOI:  https://doi.org/10.1134/S0006297925601315
Biology (Basel). 2025 Jul 24. pii: 931. [Epub ahead of print]14(8):

Hypoxia Disrupted Serotonin Levels in the Prefrontal Cortex and Striatum, Leading to Depression-like Behavior.

Hasan Çalışkan, Koray Hamza Cihan, Seda Koçak, Gözde Karabulut, Erhan Nalçacı.

  Hypoxia can adversely affect multiple organ systems. This study investigated the impact of intermittent hypoxia on serotonin levels and depression-like behaviors across distinct neuroanatomical regions. Sixteen adult female Wistar albino rats were divided into two groups: control (n = 8) and hypoxia (n = 8). The hypoxia group was exposed to a simulated altitude of 3000 for 5 h daily over 14 days. Behavioral assessments included locomotor activity (open field test) and depression-like behaviors (forced swimming test). Serotonin levels were quantified via ELISA in the prefrontal cortex, striatum, thalamus, hypothalamus, hippocampus, and serum. Intermittent hypoxia did not alter locomotor activity (p > 0.05) but significantly increased depression-like behavior (p < 0.05), accompanied by a pronounced reduction in swimming behavior (p < 0.0001), a marker associated with serotonergic function. Serotonin levels were significantly reduced in the prefrontal cortex (p < 0.005) and striatum (p < 0.05), while no changes were observed in other regions or serum (p > 0.05). These findings demonstrate that intermittent hypoxia induces depression-like behaviors and region-specific serotonin depletion, particularly in the prefrontal cortex and striatum. This underscores the need to evaluate hypoxia-related brain health implications in conditions such as sleep apnea and acute mountain sickness.

Keywords:  depression-like behaviors; forced swimming test; hypoxia; prefrontal cortex; serotonin; striatum

DOI:  https://doi.org/10.3390/biology14080931
J Transl Med. 2025 Aug 28. 23(1): 968

PHPT1 acts as an inhibitor in high-altitude pulmonary hypertension via negative TRPV5 signaling regulation.

Ge Guo, Ming-Xiang Zhu, Xiang Xu, Xin Li, Yi-Bing Chen, Yan-Ying Shen, Han-Lu Li, Li-Ting Cheng, Kun-Lun He, Yong-Ming Yao, Chun-Lei Liu.

   BACKGROUND: Low barometric pressure hypoxia at high altitudes triggers vascular remodeling, resulting in high-altitude pulmonary hypertension (HAPH). The key step is the transformation of pulmonary artery smooth muscle cells (PASMCs) from a contractile to synthetic phenotype. Protein kinases and phosphatases contribute to phenotype transformation by altering phosphorylated protein expression.
OBJECTIVES: In this study, we aimed to investigate the role of phosphohistidine phosphatase 1 (PHPT1) in PASMC transformation and its regulatory pathway in HAPH.
METHODS: An HAPH model was constructed in wild-type, PHPT1-/-, and PHPT1+/+ rats by placing them in a hypobaric chamber. Evaluations included hemodynamic measurements, echocardiography, histopathological analysis, and various cellular assays. RNA-seq and western blotting were used to identify intervention targets, and co-immunoprecipitation was used to determine the interaction between PHPT1 and TRPV5.
RESULTS: PHPT1 protein expression was downregulated in HAPH, and its knockdown impaired cardiopulmonary functions, including elevated mean pulmonary artery pressure (mPAP), right ventricular systolic pressure (RVSP), and increased right ventricular thickness, and enhanced PASMC proliferation and migration. PHPT1 directly interacted with TRPV5 phosphorylation sites, whereas Asp30Ala/Arg157Ala functioned to prevent this interaction. PHPT1 overexpression protected against cardiopulmonary damage, reducing mPAP, RVSP, the D/W ratio, and MWT%. Additionally, PHPT1 overexpression mitigated PASMC proliferation and migration, resulting in restored TRPV5, p-Akt, p-SMAD2/3, and p-TGF-β expression under hypoxic conditions.
CONCLUSIONS: These findings underscore that PHPT1 inhibits PASMC proliferation and migration through TRPV5 signaling, thereby reducing mPAP and improving right ventricular function in HAPH. Therefore, PHPT1 targeting could potentially contribute to the development of novel therapeutic approaches for treating HAPH.

Keywords:  Ca2+ signaling; High-altitude pulmonary hypertension; PHPT1; TRPV5 signaling

DOI:  https://doi.org/10.1186/s12967-025-06980-8
Hum Genomics. 2025 Aug 30. 19(1): 100

DNA methylation in adaptation to high-altitude environments and pathogenesis of related diseases.

Xingkai Zhang, Yuxi Yang, Qinghai Shi.

  High-altitude environments, characterized by hypoxia, low temperatures, and intense ultraviolet radiation, pose significant challenges to human physiology and health. DNA methylation, as a key epigenetic regulatory mechanism, plays a central role in human adaptation to high-altitude environments and in disease pathogenesis. Current research indicates that high-altitude native populations (such as Tibetans and Andeans) modulate the methylation of hypoxia-responsive genes like EPAS1 and EGLN1 to enhance oxygen transport efficiency and energy metabolism patterns, while simultaneously suppressing excessive erythropoiesis and oxidative stress damage. This epigenetic regulation not only compensates for the lag in genetic adaptation over time but also forms synergistic networks with genetic variations. For instance, the functional SNPs of the EPAS1 gene are co-localized with its differentially methylated regions, revealing a delicate balance between genetic and epigenetic interactions under environmental stress. On the other hand, aberrant methylation patterns may disrupt the homeostasis of the HIF pathway, leading to acute and chronic high-altitude illnesses. This article provides a review of the recent research progress in plateau medicine and DNA methylation (up to 2025), including human clinical studies and animal model research. This includes research on high-altitude adaptation/acclimatization, as well as studies on inadequate adaptation to high altitude in relation to acute and chronic high-altitude-related diseases, cognitive decline, and pregnancy risks. By elucidating the core mechanisms underlying the "environmen - epigenetics - phenotype" axis, this work aims to provide a theoretical foundation for precision health interventions in high-altitude regions.

Keywords:  Adaptation; DNA methylation; Diseases; Epigenetic; High-altitude; Hypoxia

DOI:  https://doi.org/10.1186/s40246-025-00794-x
bioRxiv. 2025 Aug 23. pii: 2025.08.22.671868. [Epub ahead of print]

Patient-derived organoids reveal hypoxia-driven plasticity and therapeutic vulnerabilities in pheochromocytomas and paragangliomas.

Xiaojing Wang, Maite Calucho, Cynthia M Estrada-Zuniga, Mehwish Noureen, Hector Gonzalez-Cantu, Samantha Mossuto, Jonathan N Levi, Bethany Landry, Qianjin Guo, Kailee A Rutherford, Zi-Ming Cheng, Andreanne Sannajust, Sapna Raghunathan, Sanskriti Balaji, Viviane Nascimento da Conceicao, Summer Norris, S Yusra Munawar, Huyen Thi-Lam Nguyen, Jacob De Rosa, Gail Tomlinson, James X Wu, Michael W Yeh, Masha J Livhits, Anand Vaidya, James Powers, Ron Lechan, Art Tischler, Miao Zhang, Paul Graham, Camilo Jimenez, Mirko Peitzsch, Nicole Bechmann, Graeme Eisenhofer, Yanli Ding, Mio Kitano, Alice Soragni, Patricia L M Dahia.

Pheochromocytomas and paragangliomas (PPGLs) are rare chromaffin cell-derived neuroendocrine tumors of sympathetic (catecholamine-producing) or parasympathetic (nonsecretory) origin, frequently driven by dysregulation of hypoxia-inducible factor (HIF) signaling, particularly HIF-2α. Although often benign, PPGLs can metastasize unpredictably, with limited therapeutic options once disseminated. Progress has been hindered by the lack of robust preclinical models, especially those that capture their molecular complexity and microenvironmental influences. To address this gap, we established patient-derived tumor organoids (PDOs) from 35 PPGLs, encompassing a broad spectrum of clinical and molecular phenotypes. The organoids retained key immunohistochemical, genomic, transcriptomic, and catecholamine-secretory features of their parental tumors. PPGL organoids cultured under hypoxic conditions generally exhibited enhanced viability, supporting hypoxia as a driver of cell survival. Hypoxia activated HIF-1α and expanded ASCL1 + cell populations, suggesting a lineage shift toward an immature chromaffin state. In contrast, long-term normoxic cultures activated hypoxia inducible factor 2α (HIF-2α) and acquired a hybrid sympathoblast-mesenchymal identity in subpopulations with upregulation of extracellular matrix and cell cycle markers, independent of genotype. These features resemble high-risk neuroblastoma subtypes and establish a molecular parallel suggestive of shared lineage plasticity and pathogenic programs, detectable in primary PPGLs. Drug screening across a library of up to 51 drugs and combinations revealed both shared and unique vulnerabilities, with response rates to approved therapies matching clinical observations. The CDK4/6 inhibitor abemaciclib, previously unexplored in PPGLs, elicited the strongest activity. Abemaciclib-responsive PDOs and their matched tumors, including a metastatic sample, exhibited epithelial mesenchyme transition enrichment, nominating potential biomarkers for patient stratification. Our results establish PDOs as a novel platform for modeling neuroendocrine tumor biology, reveal microenvironment-driven plasticity in PPGLs, with potential translational relevance, and identify actionable vulnerabilities in a disease with few effective systemic therapies.
Main findings: PDOs can be successfully generated from PPGLs of various genetic backgrounds and reflect parental tumor propertiesPDO cultures grown in hypoxia retain main molecular features of parental tumors, have increased viability and a more immature developmental/biosynthetic profileLong term PDOs grown for 4 weeks in normoxia activate HIF2α, drift toward a hybrid sympathoblast-mesenchymal-like identity resembling relapsed/therapy resistant neuroblastomas, features that can be detected in primary tumorsA subset of PDOs respond to Abemaciclib, a drug class not previously used therapeutically in PPGLs.

DOI: https://doi.org/10.1101/2025.08.22.671868
Ann Med Surg (Lond). 2025 Sep;87(9): 5614-5623

Hypoxia-inducible factors in breast cancer: prognostic indicators and emerging biomarkers: narrative review.

Emmanuel Ifeanyi Obeagu.

  The hypoxia-inducible factor (HIF) pathway is a critical regulator of cellular responses to low oxygen conditions, which are prevalent in solid tumors like breast cancer. Under hypoxic conditions, HIF transcription factors, particularly HIF-1α and HIF-2α, orchestrate various tumor-promoting processes, including angiogenesis, metabolic reprogramming, and metastasis. These adaptive responses contribute significantly to tumor progression and resistance to conventional therapies. As such, understanding the molecular mechanisms underlying the HIF pathway offers valuable insights into breast cancer biology and provides a foundation for the development of novel therapeutic strategies. Recent advancements in the identification of biomarkers associated with the HIF pathway have shown potential for improving prognosis and guiding therapeutic decisions. Biomarkers such as HIF-1α, vascular endothelial growth factor, glucose transporter 1, and carbonic anhydrase IX are linked to hypoxia-driven tumor behaviors and may serve as indicators of disease aggressiveness and patient outcomes. Their integration into clinical practice could enable more precise stratification of patients for HIF-targeted interventions, facilitating the move toward personalized treatment regimens in breast cancer care.

Keywords:  angiogenesis; biomarkers; breast cancer; hypoxia-inducible factor (HIF); therapeutic targeting

DOI:  https://doi.org/10.1097/MS9.0000000000003500
Front Vet Sci. 2025 ;12 1632017

Genome-wide selection signal analysis reveals the adaptability of Tibetan sheep to high altitudes.

Yufang Song, Chao Yuan, Tingting Guo, Bowen Chen, Fan Wang, Zengkui Lu, Jianbin Liu.

  Altitude adaptation is a complex process involving multiple physiological and biochemical responses to hypoxia and other environmental stresses. In-depth genetic analysis of Tibetan sheep, which exhibit significant adaptations to high-altitude hypoxia, promises to elucidate hypoxia-tolerance mechanisms in plateau animals. Here, we conducted a genome-wide selection scan on three Tibetan sheep populations: low-altitude Tao (TS; 2887 m), medium-altitude Tianjun white (WT; 3331 m), and high-altitude Huoerba (HB; 4614 m). Using the population differentiation index (Fst) and nucleotide diversity (θπ) ratio, we analyzed selection signals associated with hypoxia at high-altitudes. We screened 865, 941, and 876 candidate genes in the TS vs. WT, TS vs. HB, and WT vs. HB group comparisons, respectively, 55 of which were jointly screened. Integrated analysis further identified several key pathways and genes under positive selection in Tibetan sheep populations, including metabolic pathways (GSTA1, ALAS1, HMOX2, SCD, ME1, ACSL6, PIK3C2G), melanogenesis (MITF, EP300), and the HIF-1 signaling pathway (ERBB2, HIF1A, RELA). Among these, the metabolic pathways may enhance energy production under hypoxic conditions, while melanogenesis and the HIF-1 signaling pathway are likely associated with ultraviolet radiation protection and hypoxia tolerance, respectively. This study provides valuable insights into the genetic mechanism of high-altitude adaptation in Tibetan sheep, and also provides important theoretical basis for the conservation and breeding of Tibetan sheep and the sustainable development of plateau animal husbandry.

Keywords:  Fst; Tibetan sheep; high-altitude adaptation; selection signal; whole-genome resequencing; θπ ratio

DOI:  https://doi.org/10.3389/fvets.2025.1632017
Pediatric Health Med Ther. 2025 ;16 217-225

Hypoxia, Inflammation, and Cytokine Crosstalk in Sickle Cell Disease: From Mechanisms to Modulation- A Narrative Review.

Emmanuel Ifeanyi Obeagu.

  Sickle cell disease (SCD) is a genetically inherited group of hemoglobinopathies characterized by the polymerization of hemoglobin S, chronic hemolytic anemia, and vaso-occlusion. The interplay between inflammation and hypoxia is central to the pathophysiologic manifestations of SCD and drives many of its complications. In this narrative review, we explore the bidirectional relationship between inflammatory pathways and hypoxic stress, with a focus on immune dysregulation, endothelial activation, and redox imbalance. The paper also highlights how mitochondrial dysfunction, reactive oxygen species (ROS) generation, glycolytic shifts affecting 2,3-diphosphoglycerate (2,3-DPG), and complement activation contribute to disease exacerbation. The review critically examines limitations of in vitro and animal models in mimicking the complex human pathophysiology, underscoring the need for translational research and clinical studies, especially in low- and middle-income countries (LMICs). Additionally, the paper evaluates emerging therapeutic interventions targeting inflammatory and hypoxia-related pathways, including small molecules, biologics, and gene-modifying strategies. Recognizing the heterogeneity in disease severity, this narrative review emphasizes the importance of personalized treatment approaches, integration of non-invasive biomarkers, and enhanced infrastructure for clinical trials in resource-limited settings.

Keywords:  cytokines; hypoxia; immune modulation; inflammation; sickle cell disease

DOI:  https://doi.org/10.2147/PHMT.S544217
Crit Rev Oncol Hematol. 2025 Sep 03. pii: S1040-8428(25)00310-5. [Epub ahead of print] 104922

Nanomedicine Targeting the Warburg Effect: Advanced Strategies for Cancer Therapy.

Xin Wang, Wenyuan Yang, Bingyan Shen, Beier Jiang, Zhenzhen Zhang, Haigang Wu.

  Cancer remains the foremost cause of mortality globally, characterized by un-controlled cellular proliferation driven by oncogenic mutations and other factors. These mutations disrupt cellular homeostasis, leading to a spectrum of adverse physiological responses. A key feature of cellular metabolism in cancer is the Warburg effect, in which cancer cells preferentially rely on glycolysis for ATP production, even in the presence of oxygen, to meet their elevated metabolic demands. Traditional interventions have often failed to block this metabolism due to limitations in drug design and administration. The advent of nanomedicine has ushered in new possibilities for cancer treatment, offering precise control over drug release and targeted delivery. By leveraging nanocarriers, it is possible to specifically target the altered metabolic pathways in cancer cells, thereby presenting a promising therapeutic strategy. This review provides a comprehensive examination of the Warburg effect and the cutting-edge advancements in nanomedicine aimed at reprogramming cancer cell metabolism. Particular attention is given to the potential applications of these nanotechnological interventions in treating cancer, highlighting the promising synergy between nanomedicine and metabolic reprogramming as a viable approach to counteract cancer progression.

Keywords:  Cancer management; Combination therapy; Hypoxia; Lactate; Metabolic reprogramming; Nanomedicine; Warburg Effect

DOI:  https://doi.org/10.1016/j.critrevonc.2025.104922