bims-oxygme Biomed News
on Oxygen metabolism
Issue of 2025–03–02
ten papers selected by
Onurkan Karabulut, Berkeley City College
  1. Hypoxia Promotes Gluconeogenesis Through PGC-1α in the Liver of Lasiopodomys brandtii.
  2. Placental Adaptation to Hypoxia: The Case of High-Altitude Pregnancies.
  3. Hypoxia Regulates the Proliferation and Apoptosis of Coronary Artery Smooth Muscle Cells Through HIF-1α Mediated Autophagy in Yak.
  4. The impact of high altitude (hypobaric hypoxia) on insulin resistance in humans.
  5. [Research Advances in the Roles of High-Altitude Hypoxic Stress in Hepatocellular Carcinoma].
  6. Proteomics and Expression of HIF2α/BNIP3L Signaling in Yak Brains at Different Altitudes.
  7. Cardiomyocytes in Hypoxia: Cellular Responses and Implications for Cell-Based Cardiac Regenerative Therapies.
  8. RETRACTION: Effect of Hyperbaric Oxygen Treatment on Diabetic Foot Ulcers: A Meta-Analysis.
  9. Short bouts of hypoxia improve insulin sensitivity in adults with type 2 diabetes.
  10. Semaglutide enhances PINK1/Parkin‑dependent mitophagy in hypoxia/reoxygenation‑induced cardiomyocyte injury.
  1. Integr Zool. 2025 Feb 28.
    Hypoxia Promotes Gluconeogenesis Through PGC-1α in the Liver of Lasiopodomys brandtii.
    Mengke Li, Maolin Huang, Jun Wan, Yunfei Gao, Jiahui Song, Xiujuan Li, Qinghua Li, Han Cheng, Tian Shao, Zhenlong Wang.
      Oxygen is a critical factor for the survival of most lifeforms, as inadequate availability disrupts internal metabolic balance. Hypoxia-induced disruptions in glucose metabolism can be fatal to many animals. However, there is currently limited research on the energy metabolism of species that inhabit environments with intermittently low oxygen levels. In this study, we investigated the gluconeogenic metabolic response patterns of adult Lasiopodomys brandtii (Brandt's vole) and Mus musculus (Kunming mice) under hypoxia (10% O2, 12 h), followed by 1 h reoxygenation period. Our results indicated that, unlike M. musculus, L. brandtii did not accumulate lactate after hypoxia treatment. This suggests that L. brandtii may deal with lactate accumulation caused by oxygen deficiency during hypoxia through the PGC-1α regulated gluconeogenesis pathway of the liver, which can restore the level of anaerobic glycolytic products in the liver and blood caused by hypoxia relatively quickly and ensure the stable survival of the organism in a hypoxic environment. Intriguingly, L. brandtii also did not exhibit O2 debt repayment after short-time reoxygenation. Our study revealed that liver PGC-1α regulating gluconeogenic metabolism in L. brandtii plays an important role in the maintenance of internal homeostasis of body acid-base balance under hypoxic environments, presenting a potential mechanism for the improvement of hypoxia tolerance in L. brandtii.
    Keywords:  Lasiopodomys brandtii; PGC‐1α; gluconeogenesis; hypoxia; liver
    DOI:  https://doi.org/10.1111/1749-4877.12961
  2. Int J Environ Res Public Health. 2025 Feb 04. pii: 214. [Epub ahead of print]22(2):
    Placental Adaptation to Hypoxia: The Case of High-Altitude Pregnancies.
    Sofia Ahrens, Dominique Singer.
      Even in the highest inhabited regions of the world, well above 2500 m altitude, women become pregnant and give birth to healthy children. The underlying adaptation to hypobaric hypoxia provides interesting insights into the physio(patho)logy of the human placenta. Although increasing altitude is regularly associated with fetal growth restriction (FGR), oxygen deficiency does not appear to be a direct cause. Rather, placental oxygen consumption is reduced to maintain the oxygen supply to the fetus. This comes at the expense of placental synthesis and transport functions, resulting in inappropriate nutrient supply. The hypoxia-inducible factor (HIF-1α), which modulates the mitochondrial electron transport chain to protect placental tissue from reactive oxygen species, plays a key role here. Reduced oxygen consumption also reflects decreased placental vascularization and perfusion, which is accompanied by an increased risk of maternal pre-eclampsia at high altitude. In native highlanders, the latter seems to be attenuated, partly due to a lower release of HIF-1α. In addition, metabolic peculiarities have been described in indigenous people that enhance glucose availability and thus reduce the extent of FGR. This review attempts to revisit the (albeit incomplete) knowledge in this area to draw the clinical reader's attention to the crucial role of the placenta in defending the fetus against hypoxia.
    Keywords:  fetal growth restriction; high altitude; highland ancestry; hypobaric hypoxia; metabolic adaptation; placenta; pre-eclampsia; pregnancy
    DOI:  https://doi.org/10.3390/ijerph22020214
  3. Biomolecules. 2025 Feb 10. pii: 256. [Epub ahead of print]15(2):
    Hypoxia Regulates the Proliferation and Apoptosis of Coronary Artery Smooth Muscle Cells Through HIF-1α Mediated Autophagy in Yak.
    Shanshan Yang, Yan Cui, Rui Ma, Sijiu Yu, Hui Zhang, Pengfei Zhao, Junfeng He.
      Cell proliferation and migration mediated by hypoxia-inducible factor-1α (HIF-1α) are important processes of hypoxic cardiac vascular remodeling. HIF-1α also regulates the physiological hypoxic adaptation of the coronary artery in the yak heart, but the potential mechanism remains to be completely elucidated. In this study, coronary artery proliferation increased with age and hypoxia adaptation time. In vitro analysis showed that hypoxia can promote the proliferation of coronary vascular smooth muscle cells (CASMCs). Meanwhile, HIF-1α plays an important role in the regulation of proliferation and migration under hypoxia. Autophagy regulates cell proliferation and migration to participate in hypoxia adaptation in plateau animals. Here, the level of autophagy increased significantly in yak coronary arteries with age and was regulated by HIF-1α-mediated hypoxia. In addition, autophagy could also mediate the hypoxic effect on the proliferation and migration of CASMCs. In summary, the results revealed that the increase in yak heart coronary artery thickening with age increases vascular smooth muscle cell proliferation and migration, mainly achieved through hypoxia-mediated HIF-1α-regulated autophagy. These results contribute to understanding how the heart adapts to life in a hypoxic environment.
    Keywords:  autophagy; heart coronary smooth muscle cells; hypoxia; migration; proliferation; yak
    DOI:  https://doi.org/10.3390/biom15020256
  4. J Physiol Biochem. 2025 Feb 28.
    The impact of high altitude (hypobaric hypoxia) on insulin resistance in humans.
    María M Adeva-Andany, Lucia Adeva-Contreras, Natalia Carneiro-Freire, Eva Ameneiros-Rodríguez, Matilde Vila-Altesor, Isabel Calvo-Castro.
      Exposure to hypobaric hypoxia (high altitude) diminishes systemic tissue oxygenation. Tissue hypoxia induces insulin resistance and a metabolic switch that reduces oxidative phosphorylation and glucose storage while enhancing glycolysis. Similarly to hypobaric hypoxia, insulin resistance develops in normal humans undergoing normobaric hypoxia and in patients with obstructive sleep apnea. Following acute exposure to high altitude, insulin resistance returns to baseline values upon returning to sea level or when compensatory mechanisms restore tissue oxygenation. However, insulin resistance persists in subjects unable to achieve sufficient oxygen delivery to tissues. Likewise, long-term residents at high altitude develop persistent insulin resistance when compensatory mechanisms do not attain adequate tissue oxygenation. Among these subjects, insulin resistance may cause clinical complications, such as hypertriglyceridemia, reduced HDL-c, visceral obesity, metabolic dysfunction-associated steatotic liver disease, essential hypertension, type 2 diabetes, subclinical vascular injury, cardiovascular disease, and kidney disease. Impaired tissue oxygenation allows the stabilization of hypoxia-inducible factor-1 (HIF-1), a transcription factor that modulates the transcriptional activity of a number of genes to coordinate the physiological responses to tissue hypoxia. Among them, HIF-1 downregulates PPARG, that codes peroxisome proliferator-activated receptor-gamma (PPAR-γ) and PPARGCA, that codes PPAR-γ coactivator-1α, in order to enable insulin resistance and the metabolic switch from oxidative phosphorylation toward glycolysis.
    Keywords:  Cardiovascular disease; Hypoxia-inducible factors; Insulin resistance; Kidney disease; Peroxisome proliferator-activated receptor-γ; Peroxisome proliferator-activated receptor-γ coactivator-1α
    DOI:  https://doi.org/10.1007/s13105-025-01069-8
  5. Sichuan Da Xue Xue Bao Yi Xue Ban. 2024 Nov 20. 55(6): 1436-1445
    [Research Advances in the Roles of High-Altitude Hypoxic Stress in Hepatocellular Carcinoma].
    Yubo Liang, Lingjuan Li, Baiyang Liu, Jie Gao, Xingming Chen, Jin Li, Yang Ke, Yongbin Chen.
      Hepatocellular carcinoma (HCC), one of the most prevalent malignant tumors causing the highest mortality globally, imposes an especially heavy burden of disease in China. Individuals living in high-altitude areas have a lower incidence of and mortality resulting from HCC compared with those in low-altitude regions do, potentially due to adaptive evolution in responses to hypoxic stress. Notably, high-altitude hypoxic stress is associated with the development and progression of HCC. Hypoxic stress may be involved in the development and progression of HCC by modulating the senescence, apoptosis, metabolism, tumor microenvironment, and tumor immunity of HCC cells. Additionally, the latest clinical findings indicate that high-altitude hypoxic environment has a significant impact on liver regeneration after HCC resection surgery. However, there is still a debate going on regarding whether high-altitude hypoxic stress promotes or inhibits the progression of HCC. This review covers three main aspects, the impact of adaptive evolution to high-altitude hypoxic stress on the development and progression of HCC in long-term residents of high-altitude areas, the effects of high-altitude hypoxic stress on the senescence, apoptosis, metabolism, tumor microenvironment, tumor metabolism, and tumor immunity of HCC cells, and the effect of high-altitude hypoxic stress on liver regeneration after HCC resection. We discussed the effect of changes in oxygen concentrations, cellular context, and tissue microenvironment on HCC development and progression. Moreover, we highlighted the potential for using research findings on mechanisms underlying high-altitude hypoxic stress to optimize HCC treatment strategies.
    Keywords:  Development and progression; Hepatocellular carcinoma; High altitude; Hypoxic stress; Liver regeneration; Review
    DOI:  https://doi.org/10.12182/20241160605
  6. Int J Mol Sci. 2025 Feb 16. pii: 1675. [Epub ahead of print]26(4):
    Proteomics and Expression of HIF2α/BNIP3L Signaling in Yak Brains at Different Altitudes.
    Qian Zhang, Yan Cui, Sijiu Yu, Junfeng He, Yangyang Pan, Meng Wang, Jialing Che.
      The yak, a unique inhabitant of low-oxygen environments, exhibits brain adaptability to hypoxic conditions. However, the impact of hypoxia on yak brain proteomics and the expression of the HIF2α/BNIP3L signaling pathway remains unexplored. This study utilized TMT-based proteomics analysis to identify differentially expressed proteins (DEPs) in the cerebral cortexes of 9-month-old yaks at high (n = 3) and low (n = 3) altitudes. Additionally, qRT-PCR, Western blot, immunohistochemistry, and immunofluorescence were used to analyze HIF2α, BNIP3L, Beclin1, LC3-II, and cleaved caspase-3 expression in various brain regions from both altitude groups. KEGG analysis revealed that the DEPs were mainly concentrated in the synthesis and metabolism, DNA replication, and repair pathways. Specifically, the autophagy in KEGG attracted our attention due to its absence in other animals. HIF2α, BNIP3L, Beclin1, and LC3-II in the autophagy pathway increased significantly. Furthermore, the results of qRT-PCR and Western blot analysis showed that, at the same altitude, the mRNA and protein levels of HIF2α, BNIP3L, LC3-II, and Beclin1 in the cerebral cortexes and hippocampi of yaks were significantly higher than those in the thalami, medulla oblongatae, and cerebella (p < 0.05), while the expression of cleaved caspase-3 was not significantly different among the regions (p > 0.05). Additionally, within the same brain region, the expression levels of HIF2α, BNIP3L, Beclin1, and LC3-II in high-altitude yaks were higher than those in low-altitude yaks. Moreover, there was no difference in the cleaved caspase-3 mRNA and protein expression between the high-altitude and low-altitude yaks. Immunohistochemistry revealed that HIF2α-positive signaling was expressed in the nucleus and cytoplasm of neurons, while BNIP3L, LC3-II, Beclin1, and cleaved caspase-3 were concentrated in the cytoplasm. The immunofluorescence results showed that HIF2α, BNIP3L, LC3-II, Beclin1, cleaved caspase-3, and NeuN were co-located in the neurons of the cerebral cortex, hippocampus, thalamus, medulla oblongata, and cerebellum, respectively. This study offers a complete characterization of the yak cerebral cortex proteome at different altitudes. The higher expression of HIF2α, BNIP3L, Beclin1, and LC3-II in the cerebral cortexes and hippocampi of yaks indicates that these brain regions are more resistant to hypoxia. In addition, the increased HIF2α/BNIP3L signaling in the high-altitude yaks may enhance brain tissue adaptation to hypoxic conditions.
    Keywords:  BNIP3L; Beclin1; HIF2α; LC3-II; brain; cleaved caspase-3; yak
    DOI:  https://doi.org/10.3390/ijms26041675
  7. Bioengineering (Basel). 2025 Feb 06. pii: 154. [Epub ahead of print]12(2):
    Cardiomyocytes in Hypoxia: Cellular Responses and Implications for Cell-Based Cardiac Regenerative Therapies.
    Kiera D Dwyer, Caroline A Snyder, Kareen L K Coulombe.
      Myocardial infarction (MI) is a severe hypoxic event, resulting in the loss of up to one billion cardiomyocytes (CMs). Due to the limited intrinsic regenerative capacity of the heart, cell-based regenerative therapies, which feature the implantation of stem cell-derived cardiomyocytes (SC-CMs) into the infarcted myocardium, are being developed with the goal of restoring lost muscle mass, re-engineering cardiac contractility, and preventing the progression of MI into heart failure (HF). However, such cell-based therapies are challenged by their susceptibility to oxidative stress in the ischemic environment of the infarcted heart. To maximize the therapeutic benefits of cell-based approaches, a better understanding of the heart environment at the cellular, tissue, and organ level throughout MI is imperative. This review provides a comprehensive summary of the cardiac pathophysiology occurring during and after MI, as well as how these changes define the cardiac environment to which cell-based cardiac regenerative therapies are delivered. This understanding is then leveraged to frame how cell culture treatments may be employed to enhance SC-CMs' hypoxia resistance. In this way, we synthesize both the complex experience of SC-CMs upon implantation and the engineering techniques that can be utilized to develop robust SC-CMs for the clinical translation of cell-based cardiac therapies.
    Keywords:  heart regenerative; hypoxia; ischemia; myocardial infarction (MI); pro-survival; stem cell derived cardiomyocytes (SC-CMs); stem cell therapies
    DOI:  https://doi.org/10.3390/bioengineering12020154
  8. Int Wound J. 2025 Mar;22(3): e70267
    RETRACTION: Effect of Hyperbaric Oxygen Treatment on Diabetic Foot Ulcers: A Meta-Analysis.
       RETRACTION: M. S. Imam, A. K. Almutairi, A. M. Alhajri, M. M. Alharby, M. H. Alanazi, A. G. Alotaibi, and M. E. A. Abdelrahim, "Effect of Hyperbaric Oxygen Treatment on Diabetic Foot Ulcers: A Meta-Analysis," International Wound Journal 21, no. 2 (2024): e14427, https://doi.org/10.1111/iwj.14427. The above article, published online on 05 October 2023, in Wiley Online Library (http://onlinelibrary.wiley.com/), has been retracted by agreement between the journal Editor in Chief, Professor Keith Harding; and John Wiley & Sons Ltd. Following an investigation by the publisher, all parties have concluded that this article was accepted solely on the basis of a compromised peer review process. The editors have therefore decided to retract the article. The authors did not respond to our notice regarding the retraction.
    DOI:  https://doi.org/10.1111/iwj.70267
  9. J Appl Physiol (1985). 2025 Feb 27.
    Short bouts of hypoxia improve insulin sensitivity in adults with type 2 diabetes.
    Jiahui Zhao, Sahar D Massoudian, Sten Stray-Gundersen, Frank Wojan, Sophie Lalande.
      Hypoxia stimulates glucose uptake independently from the action of insulin. The purpose of this study was to determine the effect of intermittent hypoxia, consisting of alternating short bouts of breathing hypoxic and room air, on glucose concentration, insulin concentration, and insulin sensitivity during an oral glucose tolerance test in adults with type 2 diabetes and adults with normal glycemic control. Nine adults with type 2 diabetes (two women, HbA1c: 7.3±1.5%, age: 52±13 years) and nine adults with normal glycemic control (four women, HbA1c: 5.4±0.1%, age: 24±4 years) performed a 2-hour oral glucose tolerance test on two separate visits to the laboratory. Following ingestion of the glucose drink, participants were exposed to either an intermittent hypoxia protocol, consisting of eight 4-min hypoxic cycles at a targeted oxygen saturation of 80% interspersed with breathing room air to resaturation, or a sham protocol consisting of eight 4-min normoxic cycles interspersed with breathing room air. Intermittent hypoxia did not attenuate the increase in glucose concentration but attenuated the increase in insulin concentration in response to an oral glucose tolerance test in comparison with the sham protocol in adults with type 2 diabetes. Insulin sensitivity was greater during intermittent hypoxia in comparison with the sham protocol in adults with type 2 diabetes (0.043±0.036 vs. 0.032±0.046 μmol/kg/min/pmol, p=0.01), but did not change in the control group (0.122±0.015 vs. 0.128±0.008 μmol/kg/min/pmol, p=0.12). In conclusion, intermittent hypoxia improved insulin sensitivity in adults with type 2 diabetes.
    Keywords:  insulin sensitivity; intermittent hypoxia; type 2 diabetes
    DOI:  https://doi.org/10.1152/japplphysiol.00932.2024
  10. Mol Med Rep. 2025 May;pii: 111. [Epub ahead of print]31(5):
    Semaglutide enhances PINK1/Parkin‑dependent mitophagy in hypoxia/reoxygenation‑induced cardiomyocyte injury.
    Liqin Li, Lili Jin, Yaping Tian, Jun Wang.
      The present study aimed to explore how semaglutide can help protect the heart from injury caused by hypoxia/reoxygenation (H/R) and to reveal the underlying mechanism. Briefly, AC16 cardiomyocytes were subjected to 8 h of hypoxia followed by 12 h of reoxygenation to simulate H/R. The cells were divided into the following five groups: Normoxia, H/R, H/R + semaglutide, H/R + semaglutide + rapamycin (autophagy inducer), and H/R + semaglutide + 3‑methyladenine (3‑MA; autophagy inhibitor) groups. Cell viability was examined using a Cell Counting Kit‑8 assay, ATP levels were examined using a bioluminescent detection kit, reactive oxygen species (ROS) production was detected using a ROS Assay Kit, and monomeric red fluorescent protein (mRFP)‑green fluorescent protein (GFP)‑LC3 was assessed using tandem mRFP‑GFP fluorescence microscopy, while autophagosomes were observed using transmission electron microscopy. Furthermore, the protein expression levels of autophagy markers (LC3, p62 and Beclin1) and regulators of mitochondrial autophagy [PTEN‑induced putative kinase protein‑1 (PINK1) and Parkin] were examined using western blot analysis. In AC16 cells, exposure to hypoxia followed by reoxygenation led to an increase in oxidative stress. This condition also induced an increase in autophagy activity, as evidenced by an increase in the number of autophagosomes, elevated LC3‑II/LC3‑I ratio, and upregulation of p62, Beclin1, PINK1 and Parkin expression compared with those in cells cultured under normoxia. Notably, treatment with semaglutide or rapamycin effectively reversed the H/R‑induced oxidative stress, enhanced the changes in autophagy activity, autophagosome levels and elevated LC3BII/LC3BI ratio, and increased the expression levels of Beclin1, PINK1, Parkin and p62 expression. Notably, the use of 3‑MA exhibited distinct effects under the same conditions; it exacerbated oxidative stress, decreased autophagy activity and reduced the LC3BII/LC3BI ratio. In conclusion, semaglutide was found to reduce oxidative stress caused by H/R and to increase autophagy via the ROS/PINK1/Parkin/p62 pathway. The present study offers a novel understanding of how semaglutide may protect the heart, and suggests its potential use in the treatment of myocardial ischemia/reperfusion injury.
    Keywords:  PTEN‑induced putative kinase protein‑1/Parkin pathway; autophagy; cardioprotection; hypoxia/reoxygenation; semaglutide
    DOI:  https://doi.org/10.3892/mmr.2025.13476
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