bims-oxygme 2025-02-23 papers

bims-oxygme

Biomed News

on Oxygen metabolism

Issue of 2025–02–23
eleven papers selected by
Onurkan Karabulut, Berkeley City College

Hypoxia modulates human pulmonary arterial adventitial fibroblast phenotype through HIF-1α activation.
Sevoflurane Preconditioning Rescues PKMζ Gene Expression from Broad Hypoxia-Induced mRNA Downregulation Correlating with Improved Neuronal Recovery.
Effects of acute intermittent hypoxia on muscle strength in individuals with spinal cord injury: A systematic review of randomized trials.
HypoxyStat, a small-molecule form of hypoxia therapy that increases oxygen-hemoglobin affinity.
Hypoxia inducible factor 3-alpha promotes a malignant phenotype in colorectal cancer cells.
Alpha-lipoic acid alleviated intermittent hypoxia-induced myocardial injury in mice by promoting autophagy through Nrf2 signaling pathway.
Aerobic exercise training improves learning and memory performance in hypoxic-exposed rats by activating the hippocampal PKA-CREB-BDNF signaling pathway.
Acute oxygen sensing by arterial chemoreceptors with a mutant mitochondrial complex I ND6 subunit lacking reverse electron transport.
Additive Effect of EPO and Altitude on Hemoglobin Mass but not Peak Oxygen Uptake.
The role of hyperbaric oxygen therapy in the treatment of diabetic foot ulcers - A literature review.
The Role of Hypoxia in Longevity.

bioRxiv. 2025 Jan 29. pii: 2025.01.27.635152. [Epub ahead of print]

Hypoxia modulates human pulmonary arterial adventitial fibroblast phenotype through HIF-1α activation.

Jennifer L Philip, Christine A Caneba, Laura R Caggiano, Nandhini Prakash, Tik-Chee Cheng, Katherine A Barlow, Tasneem Mustafa, Diana M Tabima, Timothy A Hacker, Kristyn S Masters, Naomi C Chesler.

Hypoxic pulmonary hypertension (HPH) develops in association with diseases characterized by low oxygen levels leading to pulmonary artery (PA) narrowing and death. Hypoxia has been linked to increased PA collagen and changes in PA adventitial fibroblast (PAAF) metabolism. However, the mechanisms by which hypoxia regulates PAAF function are unknown. Hypoxia-inducible factor-1α (HIF-1α) is a subunit of a transcription factor that is degraded in normoxia but stabilized in hypoxia and is involved in extracellular matrix remodeling by fibroblasts. We examined the role of hypoxia and HIF-1α in regulating PAAF function. Human PAAF (HPAAF) were cultured in normoxic and hypoxic conditions. Cells were further treated with HIF1-α inhibitor or no drug. Protein expression, mRNA expression, enzyme activity, and metabolite concentration were examined. Male C57BL6/J mice were exposed to 0 or 10 days of hypoxia after which right ventricular hemodynamics and tissue metabolism were assessed. Hypoxia led to an increase in collagen content and decrease in matrix metalloproteinase-2 (MMP2) activity. HIF-1α inhibition limited collagen accumulation and restored MMP2 activity. HPAAF demonstrated elevated lactic acid concentration and decreased ATP in hypoxia. HIF-1α inhibition blunted these effects. Mice exposed to hypoxia developed significant elevation in right ventricle systolic pressures and had decreased ATP levels in pulmonary tissue. This study investigated the mechanisms by which hypoxia drives HPAAF-mediated collagen accumulation and metabolic changes. We identify the key role of HIF-1α in regulating changes. These findings provide important insights into understanding HPAAF-mediated PA remodeling and help identify possible novel therapeutic targets.

DOI: https://doi.org/10.1101/2025.01.27.635152
NeuroSci. 2025 Jan 28. pii: 9. [Epub ahead of print]6(1):

Sevoflurane Preconditioning Rescues PKMζ Gene Expression from Broad Hypoxia-Induced mRNA Downregulation Correlating with Improved Neuronal Recovery.

Joan Y Hou, Kim D Allen, A Iván Hernandez, James E Cottrell, Ira S Kass.

  Hypoxia due to stroke is a major cause of neuronal damage, leading to loss of cognition and other brain functions. Sevoflurane preconditioning improves recovery after hypoxia. Hypoxia interferes with protein expression at the translational level; however, its effect on mRNA levels for neuronal protein kinase and anti-apoptotic genes is unclear. To investigate the link between sevoflurane preconditioning and gene expression, hippocampal slices were treated with 4% sevoflurane for 15 min, a 5 min washout, 10 min of hypoxia, and 60 min of recovery. We used quantitative PCR to measure mRNA levels in the CA1 region of rat hippocampi. The mRNA levels for specific critical proteins were examined, as follows: Protein kinases, PKCγ (0.22), PKCε (0.38), and PKMζ (0.55) mRNAs, and anti-apoptotic, bcl-2 (0.44) and bcl-xl (0.41), were reduced 60 min after hypoxia relative to their expression in tissue not subjected to hypoxia (set to 1.0). Sevoflurane preconditioning prevented the reduction in PKMζ (0.88 vs. 1.0) mRNA levels after hypoxia. Pro-apoptotic BAD mRNA was not significantly changed after hypoxia, even with sevoflurane preconditioning (hypoxia 0.81, sevo hypoxia 0.84 vs. normoxia 1.0). However, BAD mRNA was increased by sevoflurane in non-hypoxic conditions (1.48 vs. 1.0), which may partially explain the deleterious effects of volatile anesthetics under certain conditions. The DNA repair enzyme poly ADP-ribose polymerase 1 (PARP-1) was increased by sevoflurane in tissue not subjected to hypoxia (1.23). PARP-1 mRNA was reduced in untreated tissue after hypoxia (0.21 vs. 1.0); sevoflurane did not improve PARP-1 after hypoxia (0.27). Interestingly, the mRNA level of the cognitive kinase PKMζ, a kinase essential for learning and memory, was the only one protected against hypoxic downregulation by sevoflurane preconditioning. These findings correlate with previous studies that found that sevoflurane-induced improvement of neuronal survival after hypoxia was dependent on PKMζ. Maintaining mRNA levels for critical proteins may provide an important mechanism for preserving neuronal function after stroke.

Keywords:  anesthesia; anti-apoptotic mRNA; hypoxia; protein kinase mRNA; sevoflurane; transcriptional downregulation

DOI:  https://doi.org/10.3390/neurosci6010009
Injury. 2025 Feb 09. pii: S0020-1383(25)00071-3. [Epub ahead of print]56(3): 112211

Effects of acute intermittent hypoxia on muscle strength in individuals with spinal cord injury: A systematic review of randomized trials.

Anas R Alashram.

   INTRODUCTION: Muscle weakness is among the most common motor deficits in individuals with spinal cord injury (SCI). Acute intermittent hypoxia (AIH) has been used to improve motor function by facilitating neuroplasticity. The purpose of this systematic review is to explore the impacts of AIH on muscle strength in individuals with SCI, identify who would most likely respond well to the intervention, and determine the optimal therapeutic protocol.
METHODS: Relevant literature was explored in "PubMed, MEDLINE, The Cochrane Library, Scopus, PEDro, and Web of Science" databases until October 2024. Randomized trials that involved SCI patients who underwent AIH, compared with controls, and assessed muscle strength were included in this review. The methodological quality was assessed using the "Physiotherapy Evidence Database (PEDro)" scale. The effect sizes were calculated using Cohen's d.
RESULTS: Of 502 studies, seven studies met the eligibility criteria, and the sample sizes ranged from 12 to 28 participants across the included studies. In total, 146 SCI patients (mean age 46.76 years; 88 % male) were included in this systematic review. The PEDro scores of the studies included varied between 5 and 8, with a median score of 8.
CONCLUSIONS: AIH is a promising therapeutic modality for enhancing muscle strength post-SCI, specifically in patients with motor-incomplete injuries. Based on good quality studies, delivering AIH independently or in combination with other treatments for 15 short (60-90 s) episodes of hypoxic exposure (Oxygen = 9 %) alternating with 15 (60-90 s) normoxic episodes (Oxygen = 21 %), across one or more sessions, could yield meaningful outcomes. Nevertheless, the evidence is limited by treatment protocol variations, small sample sizes, and a lack of standardization in combining AIH with other treatments. Therefore, further studies with larger sample sizes, more diverse populations, and standardized treatment protocols are strongly needed to verify our findings. Future studies should also address the potential bias, examine the long-term effects, and investigate underlying mechanisms to provide more generalized evidence.

Keywords:  Acute intermittent hypoxia; Muscle strength; Rehabilitation; Spinal cord injury; Therapy

DOI:  https://doi.org/10.1016/j.injury.2025.112211
Cell. 2025 Feb 12. pii: S0092-8674(25)00098-4. [Epub ahead of print]

HypoxyStat, a small-molecule form of hypoxia therapy that increases oxygen-hemoglobin affinity.

Skyler Y Blume, Ankur Garg, Yolanda Martí-Mateos, Ayush D Midha, Brandon T L Chew, Baiwei Lin, Cecile Yu, Ryan Dick, Patrick S Lee, Eva Situ, Richa Sarwaikar, Eric Green, Vyas Ramanan, Gijsbert Grotenbreg, Maarten Hoek, Christopher Sinz, Isha H Jain.

  We have previously demonstrated that chronic inhaled hypoxia is remarkably therapeutic in the premier animal model of mitochondrial Leigh syndrome, the Ndufs4 knockout (KO) mouse. Subsequent work has extended this finding to additional mitochondrial diseases and more common conditions. However, challenges inherent to gas-based therapies have hindered the rapid translation of our findings to the clinic. Here, we tested a small molecule (hereafter termed HypoxyStat) that increases the binding affinity of hemoglobin for oxygen, thereby decreasing oxygen offloading to tissues. Daily oral dosing of HypoxyStat caused systemic hypoxia in mice breathing normoxic (21% O2) air. When administered prior to disease onset, this treatment dramatically extended the lifespan of Ndufs4 KO mice and rescued additional aspects of disease, including behavior, body weight, neuropathology, and body temperature. HypoxyStat was also able to reverse disease at a very late stage, thereby serving as a clinically tractable form of hypoxia therapy.

Keywords:  Leigh syndrome; hemoglobin; hyperoxia; hypoxia; mitochondrial disease; oxygen; red blood cells; therapy

DOI:  https://doi.org/10.1016/j.cell.2025.01.029
IUBMB Life. 2025 Feb;77(2): e70007

Hypoxia inducible factor 3-alpha promotes a malignant phenotype in colorectal cancer cells.

Alejandro Lopez-Mejia, Angela Patricia Moreno-Londoño, Gabriela Fonseca Camarillo, Jesús Kazuo Yamamoto-Furusho, Juan Antonio Villanueva-Herrero, Jorge Luis de Leon-Rendón, Maria Cristina Castañeda Patlán, Martha Robles-Flores.

  Colorectal cancer (CRC) is the third most common cancer worldwide. Hypoxia is a hallmark of the tumor microenvironment, and cellular adaptation to it is primarily mediated by the family of Hypoxia-inducible factors (HIFs) HIF-1α, HIF-2α, and HIF-3α. However, in contrast to HIF-1α and HIF-2α, a specific role for HIF-3α in cancer biology has not yet been clearly established. This research was aimed to elucidate the role of HIF-3α in colon cancer. As reported previously for HIF-1α and HIF-2α, we found that HIF-3α is also overexpressed under normoxic conditions in all cancer cell lines examined and in patient-derived tumor tissue samples compared with non-malignant cells and normal tissue, but remarkably, pulse-chase experiments demonstrated that HIF-3α displays high stability in cells compared with HIF-1α and HIF-2α. Progno Scan data analysis showed that overexpression of HIF-3α correlated with a patient's lower survival rate and a poor prognosis in colon adenocarcinoma patients. Knockdown of HIF-3α expression was carried out to investigate the effects derived from its silencing on malignant phenotype. We found a significative decrease in the Hypoxia Response Element (HRE) reporter transcriptional activity mediated by HIF-3α and a reduction in cell viability under oxidative stress in colon cancer cells with HIF-3α knockdown compared with control HIF-3α expressing cells. In addition, HIF-3α silencing also produced an increase in apoptotic rate, decreased clonogenic capacity, altered autophagy flux, and modulated the canonical Wnt/β pathway in an isoform-dependent and cell context-dependent manner in colon cancer cells. Overall, these data show that transcriptional activity mediated by HI3-3α plays an essential role in promoting the malignant phenotype, cell survival, and resistance to cell death in CRC cells.

Keywords:  HIF‐3α; colorectal cancer; hypoxia; hypoxia inducible factors

DOI:  https://doi.org/10.1002/iub.70007
Eur J Pharmacol. 2025 Feb 13. pii: S0014-2999(25)00133-5. [Epub ahead of print] 177380

Alpha-lipoic acid alleviated intermittent hypoxia-induced myocardial injury in mice by promoting autophagy through Nrf2 signaling pathway.

Xiao Wang, Shao-Ming Song, Wen-Qiang Lu, Yan Zhao, Ren-Jun Lv, Yao He, Na Dong, Qin Yu, Hong-Mei Yue.

  Obstructive sleep apnea syndrome (OSAS) is a prevalent sleep-related breathing disorder characterized by intermittent hypoxia (IH). Myocardial injury is a common complication associated with OSAS. Alpha-lipoic acid (LA), a potent antioxidant, has been utilized in various disease contexts and has demonstrated significant protective effects in myocardial infarction models. Given the limited treatment options available for OSAS-related myocardial injury, this study aimed to demonstrate the potential therapeutic effects of LA and to investigate the underlying mechanisms. IH is a widely employed method to simulate the pathophysiological conditions associated with OSAS. In vivo experiments were conducted using mice placed in a specialized hypoxic chamber to replicate IH conditions. Echocardiography indicated that exposure to IH severely impaired cardiac function. Treatment with LA activated the Nrf2 pathway and autophagy, which contributed to the improvement of cardiac function in mice with OSAS. Additionally, in vitro studies demonstrated that IH induced apoptosis and decreased cell viability in H9C2 cardiomyocytes. LA enhanced Nrf2 nuclear translocation and its downstream signaling pathways, thereby promoting autophagy, inhibiting apoptosis, and alleviating injury in H9C2 cardiomyocytes. Furthermore, in vitro inhibition of Nrf2 using ML385 reduced autophagy levels and attenuated the protective effects of LA against apoptosis in H9C2 cardiomyocytes. These findings suggest that LA may provide a promising therapeutic strategy for myocardial injury associated with OSAS. By elucidating these findings, new insights into the protective mechanisms of LA against IH-induced myocardial injury are provided, highlighting its potential as a therapeutic agent for diseases associated with OSAS.

Keywords:  alpha-lipoic acid; autophagy; intermittent hypoxia; myocardial injury; nrf2

DOI:  https://doi.org/10.1016/j.ejphar.2025.177380
BMC Neurosci. 2025 Feb 21. 26(1): 13

Aerobic exercise training improves learning and memory performance in hypoxic-exposed rats by activating the hippocampal PKA-CREB-BDNF signaling pathway.

Shichen Luo, Lei Shi, Tong Liu, Qiguan Jin.

   BACKGROUND: This study aims to investigate the effects of aerobic exercise training on learning and memory (L&M) performance in rats exposed to altitude hypoxia and its relationship with hippocampal plasticity and the PKA-CREB-BDNF signaling pathway.
METHODS: Male Sprague-Dawley rats were exposed to 14.2% hypoxia with or without 60 min of non-weight-bearing swimming training for 8 weeks. The L&M performance was evaluated using the Morris water maze, and the mRNA expression of PSD95, SYP, PKA, CREB, CBP, and BDNF in the hippocampus was detected.
RESULTS: Chronic hypoxia exposure significantly impaired L&M performance and reduced the mRNA expression of hippocampal PSD95, SYP, PKA, CREB, CBP, and BDNF. Aerobic exercise training effectively reversed these changes by enhancing hippocampal synaptic plasticity through the activation of the PKA-CREB-BDNF signaling pathway.
CONCLUSION: Aerobic exercise training can alleviate the decline in L&M performance caused by altitude hypoxia exposure, possibly through the activation of the hippocampal PKA-CREB-BDNF signaling pathway.

Keywords:  Aerobic exercise training; Altitude hypoxia; Hippocampus; Learning and memory; PKA–CREB–BDNF; Synaptic plasticity

DOI:  https://doi.org/10.1186/s12868-025-00935-x
FEBS Lett. 2025 Feb 21.

Acute oxygen sensing by arterial chemoreceptors with a mutant mitochondrial complex I ND6 subunit lacking reverse electron transport.

María Torres-López, Pedro F Spiller, Lin Gao, Paula García-Flores, Michael P Murphy, Patricia Ortega-Sáenz, José López-Barneo.

  Carotid body glomus cells are essential for stimulating breathing in response to hypoxia. They contain specialized mitochondria in which hypoxia induces the accumulation of NADH and H2O2 that modulate membrane ion channel activity. We investigated whether hypoxia induces reverse electron transport (RET) at mitochondrial complex I (MCI). We studied glomus cells from mice with a mutation in ND6, a core protein of MCI, which maintain normal MCI NADH dehydrogenase activity but cannot catalyze RET. The ND6 mutation increases the propensity of MCI to deactivate, and glomus cells with deactivated MCI are insensitive to acute hypoxia. These findings further indicate that MCI function is necessary for glomus cell responsiveness to hypoxia, although MCI RET does not seem to be required for this process.

Keywords:  ND6 mutation; acute oxygen sensing; carotid body glomus cells; hypoxia; mitochondrial complex I deactivation; reverse electron transport

DOI:  https://doi.org/10.1002/1873-3468.70017
Med Sci Sports Exerc. 2025 Feb 17.

Additive Effect of EPO and Altitude on Hemoglobin Mass but not Peak Oxygen Uptake.

Thomas Christian Bonne, Andreas Breenfeldt Andersen, Jacob Bejder, Joao Paulo Loures, Christine Dam, Jesús Rodríguez Huertas, Nikolai Baastrup Nordsborg.

PURPOSE: This study evaluated whether recombinant human erythropoietin (rhEpo) treatment combined with hypoxia provided an additive effect on hemoglobin mass (Hbmass) and V̇O2peak compared to altitude or rhEpo alone.
METHODS: 39 participants underwent two interventions, each containing 4 weeks baseline (PRE 1-4), 4 weeks exposure at sea level or 2,320 m of altitude (INT 1-4), and 4 weeks follow-up (POST 1-4). Participants were randomly assigned to 20 IU·kg-1 rhEpo or placebo injections every second day for 3 weeks during the exposure period at sea level (SL-EPO n = 25, SL-PLA n = 9) or at altitude (ALT-EPO n = 12, ALT-PLA n = 27).
RESULTS: Hbmass displayed a significant time×treatment effect (P < 0.001) when comparing ALT-EPO and ALT-PLA. Specifically, the increase in Hbmass was higher (P < 0.05 to P < 0.001) for ALT-EPO from INT 2 to POST 3 except for POST 2. Similarly, a significant time×treatment effect (P < 0.001) existed for changes in Hbmass when comparing ALT-EPO with SL-EPO, with the increase in Hbmass being higher (P < 0.01 to P < 0.001) for ALT-EPO from INT 2 to POST 4. A significant time×treatment effect was present when SL-PLA was compared with ALT-PLA (P < 0.05) and SL-EPO (P < 0.05). For V̇O2peak the time×treatment interaction was not significant when comparing ALT-EPO to ALT-PLA. However, when ALT-EPO was compared with SL-EPO, a significant time×treatment interaction existed (P < 0.001) due to a decrease in V̇O2peak during altitude.
CONCLUSIONS: The combined treatment of micro-doses of rhEpo and altitude exposure results in an additive increase in Hbmass but does not significantly enhance V̇O2peak compared to each treatment alone.

DOI: https://doi.org/10.1249/MSS.0000000000003680
J Diabetes Complications. 2025 Feb 13. pii: S1056-8727(25)00026-1. [Epub ahead of print]39(3): 108973

The role of hyperbaric oxygen therapy in the treatment of diabetic foot ulcers - A literature review.

Ken Mackay, Rhiannon Thompson, Matthew Parker, James Pedersen, Hayden Kelly, Mairi Loynd, Emily Giffen, Angus Baker.

  Diabetic Foot Ulcers (DFUs) are chronic foot wounds, in a person with diabetes, which are associated with peripheral arterial insufficiency and/or peripheral neuropathy of the lower limb. Recent UK audit figures report that approximately 50-60 % of DFUs remain unhealed after 12 weeks. Previous research has suggested that ischaemia plays a key role in the pathophysiology of many chronic wounds, including DFUs. For this reason, hyperbaric oxygen therapy (HOT) has been investigated. The study aimed to investigate 1) Current understanding of the physiology of normal wound healing and the pathological mechanisms that occur in DFUs to interrupt these processes; 2) Effectiveness of current DFU treatment approaches; 3) Effectiveness from clinical trials and meta-analyses for any demonstrated therapeutic benefits of HOT in the treatment of DFUs, 4) Patient selection criteria for HOT, and patients who stand to benefit most from treatment. The review found that wound healing is a complex process, involving many cells and signalling molecules, and it remains incompletely understood. However, current evidence suggests that hyperglycaemia, hypoxia, chronic inflammation (due to infection, immune-cell dysfunction or other causes), peripheral neuropathy, and macro- and micro-vascular dysfunction may all adversely affect DFU healing. The review found that current NICE guidelines do not approve HOT therapy in the UK for DFU's, despite encouraging clinical research findings. HOT shows theoretical promise and has been successfully used in the treatment of individual DFUs for several decades. Despite this, there remains a lack of strong clinical evidence of benefits to encourage HOT's wider use. The review found that there were four important patient selection criteria for HOT treatment, including glycaemic control, possible contraindications and complications associated with treatment, ulcer severity and resistance to first and second line treatments. The review concluded that further high-quality clinical research is needed to improve the evidence base.

Keywords:  DFU; Diabetes mellitus; Diabetic Management; HOT; Hyperbaric Oxygen Therapy; diabetes

DOI:  https://doi.org/10.1016/j.jdiacomp.2025.108973
Aging Dis. 2025 Feb 17.

The Role of Hypoxia in Longevity.

Ayesha Nisar, Sawar Khan, Yongzhang Pan, Li Hu, Pengyun Yang, Naheemat Modupeola Gold, Zhen Zhou, Shengjie Yuan, Meiting Zi, Sardar Azhar Mehmood, Yonghan He.

Aging is marked by a progressive decrease in physiological function and reserve capacity, which results in increased susceptibility to diseases. Understanding the mechanisms of driving aging is crucial for extending health span and promoting human longevity. Hypoxia, marked by reduced oxygen availability, has emerged as a promising area of study within aging research. This review explores recent findings on the potential of oxygen restriction to promote healthy aging and extend lifespan. While the role of hypoxia-inducible factor 1 (HIF-1) in cellular responses to hypoxia is well-established, its impact on lifespan remains complex and context-dependent. Investigations in invertebrate models suggest a role for HIF-1 in longevity, while evidence in mammalian models is limited. Hypoxia extends the lifespan independent of dietary restriction (DR), a known intervention underlying longevity. However, both hypoxia and DR converge on common downstream effectors, such as forkhead box O (FOXO) and flavin-containing monooxygenase (FMOs) to modulate the lifespan. Further work is required to elucidate the molecular mechanisms underlying hypoxia-induced longevity and optimize clinical applications. Understanding the crosstalk between HIF-1 and other longevity-associated pathways is crucial for developing interventions to enhance lifespan and healthspan. Future studies may uncover novel therapeutic strategies to promote healthy aging and longevity in human populations.

DOI: https://doi.org/10.14336/AD.2024.1630