bims-oxygme 2024-12-29 papers

bims-oxygme

Biomed News

on Oxygen metabolism

Issue of 2024–12–29
ten papers selected by
Onurkan Karabulut, Berkeley City College

The interplay of NAD and hypoxic stress and its relevance for ageing.
Myocardial mRNA expression of interleukin-6 and hypoxia inducible factor-1α in neonates with congenital cardiac defects.
Cluster Headache and Hypoxia: Breathing New Life into an Old Theory, with Novel Implications.
Where are we in targeting hypoxia-induced pathways in inflammatory arthritis? Current understanding, insights, and future directions.
Exploring the pharmacological mechanisms for alleviating OSA: Adenosine A2A receptor downregulation of the PI3K/Akt/HIF‑1 pathway (Review).
The gut microbiota mediates memory impairment under high-altitude hypoxia via the gut-brain axis in mice.
Chronic intermittent hypobaric hypoxia alleviates early-stage posttraumatic osteoarthritis via NF-κB/Nrf2 pathway in mice.
Primary cilia as antennas for oxygen.
Ubiquitin-specific protease 7 maintains c-Myc stability to support pancreatic cancer glycolysis and tumor growth.
The impact of chronic intermittent hypoxia on enzymatic activity in memory-associated brain regions of male and female rats.

Ageing Res Rev. 2024 Dec 20. pii: S1568-1637(24)00464-1. [Epub ahead of print]104 102646

The interplay of NAD and hypoxic stress and its relevance for ageing.

Johannes Burtscher, Vanna Denti, Johanna M Gostner, Alexander Kh Weiss, Barbara Strasser, Katharina Hüfner, Martin Burtscher, Giuseppe Paglia, Martin Kopp, Tobias Dünnwald.

  Nicotinamide adenine dinucleotide (NAD) is an essential regulator of cellular metabolism and redox processes. NAD levels and the dynamics of NAD metabolism change with increasing age but can be modulated via the diet or medication. Because NAD metabolism is complex and its regulation still insufficiently understood, achieving specific outcomes without perturbing delicate balances through targeted pharmacological interventions remains challenging. NAD metabolism is also highly sensitive to environmental conditions and can be influenced behaviorally, e.g., by exercise. Changes in oxygen availability directly and indirectly affect NAD levels and may result from exposure to ambient hypoxia, increased oxygen demand during exercise, ageing or disease. Cellular responses to hypoxic stress involve rapid alterations in NAD metabolism and depend on many factors, including age, glucose status, the dose of the hypoxic stress and occurrence of reoxygenation phases, and exhibit complex time-courses. Here we summarize the known determinants of NAD-regulation by hypoxia and evaluate the role of NAD in hypoxic stress. We define the specific NAD responses to hypoxia and identify a great potential of the modulation of NAD metabolism regarding hypoxic injuries. In conclusion, NAD metabolism and cellular hypoxia responses are strongly intertwined and together mediate protective processes against hypoxic insults. Their interactions likely contribute to age-related changes and vulnerabilities. Targeting NAD homeostasis presents a promising avenue to prevent/treat hypoxic insults and - conversely - controlled hypoxia is a potential tool to regulate NAD homeostasis.

Keywords:  ageing; hypoxia inducible factor; hypoxic injury; nicotinamide adenine dinucleotide; oxygen; sirtuins

DOI:  https://doi.org/10.1016/j.arr.2024.102646
Mol Cell Pediatr. 2024 Dec 21. 11(1): 14

Myocardial mRNA expression of interleukin-6 and hypoxia inducible factor-1α in neonates with congenital cardiac defects.

Nesrine Farhat, Jaime Vazquez-Jimenez, Ruth Heying, Marie-Christine Seghaye.

   BACKGROUND: In neonates with congenital heart disease (CHD), myocardial remodelling involves activation of inflammatory pathways. The role of hypoxemia related pathways is however unknown. This study was therefore designed to investigate myocardial mRNA expression of interleukin (IL)-6 and hypoxia-inducible factor (HIF)-1α in neonates with CHD and analyse its influence on post-operative outcome.
RESULTS: 14 neonates with CHD scheduled for open cardiac surgery were studied. In group 1 (n = 5), pre-operative transcutaneous arterial oxygen saturation (SaO2) was ≤ 85% and in group 2 (n = 9) > 85%. Expression of IL-6- and HIF-1α-mRNA was studied on right atrial biopsy by RT-PCR and corelated to post-operative (po) outcome. Group 1 patients showed higher mean arterial blood pressure (MAP) and lower glycaemia 4 h po (p = 0.047 and p = 0.021, respectively). In the whole cohort, SaO2 correlated negatively with MAP (Pearson R: -0.662, p = 0.010). mRNA coding for IL-6 and HIF-1α was detected in the myocardium of all neonates independently of age, gender, or type of CHD. IL6-mRNA expression was not influenced by pre-operative hypoxemia but was associated with higher lactate levels in early po period (Pearson R: 0,611, p = 0,020). HIF-1α-mRNA expression correlated negatively with pre-operative SaO2 (Pearson R: -0.551, p = 0.04) and with aspartate aminotransferase levels 4 h po (Pearson R: 0.625, p = 0.017).
CONCLUSION: Our study shows that besides inflammatory pathways, hypoxemia related pathways are activated in the myocardium of neonates with CHD. Myocardial expression of both IL-6-mRNA and HIF-1α-mRNA relates to biological markers of a worse po outcome.

Keywords:  Congenital heart disease; Gene expression; HIF-1α; IL-6; Myocardium; Neonates; Post-operative outcome

DOI:  https://doi.org/10.1186/s40348-024-00187-5
Neurol Int. 2024 Dec 04. 16(6): 1691-1716

Cluster Headache and Hypoxia: Breathing New Life into an Old Theory, with Novel Implications.

Jonathan M Borkum.

  Cluster headache is a severe, poorly understood disorder for which there are as yet virtually no rationally derived treatments. Here, Lee Kudrow's 1983 theory, that cluster headache is an overly zealous response to hypoxia, is updated according to current understandings of hypoxia detection, signaling, and sensitization. It is shown that the distinctive clinical characteristics of cluster headache (circadian timing of attacks and circannual patterning of bouts, autonomic symptoms, and agitation), risk factors (cigarette smoking; male gender), triggers (alcohol; nitroglycerin), genetic findings (GWAS studies), anatomical substrate (paraventricular nucleus of the hypothalamus, solitary tract nucleus/NTS, and trigeminal nucleus caudalis), neurochemical features (elevated levels of galectin-3, nitric oxide, tyramine, and tryptamine), and responsiveness to treatments (verapamil, lithium, melatonin, prednisone, oxygen, and histamine desensitization) can all be understood in terms of hypoxic signaling. Novel treatment directions are hypothesized, including repurposing pharmacological antagonists of hypoxic signaling molecules (HIF-2; P2X3) for cluster headache, breath training, physical exercise, high-dose thiamine, carnosine, and the flavonoid kaempferol. The limits of current knowledge are described, and a program of basic and translational research is proposed.

Keywords:  cluster headache; genes; hypoxia inducible factor; neurochemistry; pharmacology; prevention; trigeminovascular

DOI:  https://doi.org/10.3390/neurolint16060123
Int Immunopharmacol. 2024 Dec 22. pii: S1567-5769(24)02405-6. [Epub ahead of print]146 113883

Where are we in targeting hypoxia-induced pathways in inflammatory arthritis? Current understanding, insights, and future directions.

Lisa Wang, Akihiro Nakamura.

   INTRODUCTION: Joint tissues affected by inflammatory arthritis (IA) create hypoxic microenvironments that sustain the inflammatory response. Although targeting molecules in hypoxia-induced pathways has provided valuable insights into potential novel therapies for various types of IA, progress remains preclinical, and no clinical trials have been conducted for IA.
METHODS: A literature search was conducted to create a narrative review exploring the role of hypoxia and its signaling pathways in IA pathogenesis, as well as the potential and future directions for IA therapies that target hypoxia-induced molecules before moving forward to clinical applications.
RESULTS: Hypoxia is a prevalent feature of the IA synovial microenvironment and contributes to disease progression. Various studies and preclinical models demonstrate how hypoxia-inducible factors, vascular endothelial growth factors, and matrix metalloproteinases, among other molecules, influence rheumatoid arthritis, axial spondyloarthritis, psoriatic arthritis, and juvenile idiopathic arthritis. Despite these findings, drug development targeting these molecules in IA has been limited due to challenges in delineating the mechanistic pathways of hypoxia, the distinct roles of hypoxia-induced molecules depending on anatomical sites, and concerns regarding pharmacokinetics and patient safety. However, given that hypoxia-induced molecule-targeting therapies have been successfully approved for treating cancers and cardiovascular diseases, further research is needed to advance the application of similar medications in IA.
CONCLUSIONS: Given the pathogenic effects of hypoxic microenvironments in IA, it is imperative to continue gathering compelling evidence to advance hypoxia-induced therapies. Furthermore, elucidating the safety and efficacy of such drugs in various preclinical models, in collaboration with chemists and the pharmaceutical industry, is crucial for accelerating the development of novel, optimized treatment methods.

Keywords:  Axial spondyloarthritis (AxSpA); Hypoxia inducible factor (HIF); Inflammatory arthritis (IA); Juvenile idiopathic arthritis (JIA); Matrix metalloproteinase (MMP); Psoriatic arthritis (PsA); Rheumatoid arthritis (RA); Vascular endothelial growth factor (VEGF)

DOI:  https://doi.org/10.1016/j.intimp.2024.113883
Biomed Rep. 2025 Feb;22(2): 21

Exploring the pharmacological mechanisms for alleviating OSA: Adenosine A2A receptor downregulation of the PI3K/Akt/HIF‑1 pathway (Review).

Nini Ma, Peijie Liu, Ning Li, Yushi Hu, Liang Kang.

  Obstructive sleep apnea (OSA) is the most common type of sleep apnea, which leads to episodes of intermittent hypoxia due to obstruction of the upper airway. A key feature of OSA is the upregulation and stabilization of hypoxia-inducible factor 1 (HIF-1), a crucial metabolic regulator that facilitates rapid adaptation to changes in oxygen availability. Adenosine A2A receptor (A2AR), a major adenosine receptor, regulates HIF-1 under hypoxic conditions, exerting anti-inflammatory properties and affecting lipid metabolism. The present study explored the roles of A2AR in OSA regulation, specifically focusing on its effects via the PI3K/Akt/HIF-1 pathway. The findings enhance our understanding the pharmacological potential of A2AR in OSA management and suggest future research directions in exploring its clinical applications.

Keywords:  PI3K/Akt; adenosine; adenosine A2A receptor; hypoxia-inducible factor 1; obstructive sleep apnea

DOI:  https://doi.org/10.3892/br.2024.1899
FEBS J. 2024 Dec 23.

The gut microbiota mediates memory impairment under high-altitude hypoxia via the gut-brain axis in mice.

Wenhao Li, Yuhao Wang, Yi Shi, Fenfen He, Zaihua Zhao, Jingchun Liu, Zhenbo Gao, Jianbin Zhang, Xuefeng Shen.

  Hypoxia is a predominant risk factor at high altitudes, and evidence suggests that high-altitude hypoxia alters the gut microbiota, which plays an essential regulatory role in memory function. However, the causal relationship between the gut microbiota and memory impairment under hypoxic conditions remains unclear. In this study, we employed a high-altitude hypoxia model combined with fecal microbiota transplantation (FMT) approach in mice to explore the effects of the gut microbiota on memory impairment in a hypoxic environment. We observed that high-altitude hypoxia exposure reduced short- and long-term memory and hippocampus-dependent fear memory abilities, along with decreased relative abundance of Ligilactobacillus and Muribaculum. Moreover, hypoxic conditions increased intestinal and blood-brain barrier permeability. FMT from hypoxia-exposed mice into naïve antibiotic-treated mice resulted in similar memory impairments, Ligilactobacillus and Muribaculum abundance changes, and increased intestinal/blood-brain barrier permeability. Correlation analysis showed a robust positive association between Ligilactobacillus and Muribaculum with hippocampus-dependent contextual fear memory. Likewise, Ligilactobacillus was positively correlated with short-term memory. Therefore, Ligilactobacillus and Muribaculum may be key microbes in reducing memory ability in hypoxia, with the intestinal and blood-brain barriers as primary pathways. Our findings provide further evidence for the potential regulatory mechanism by which gut microbiota dysbiosis may contribute to memory impairment in a high-altitude environment.

Keywords:  fecal microbiota transplantation; gut microbiota; gut–brain axis; hypoxia; memory

DOI:  https://doi.org/10.1111/febs.17365
J Orthop Surg Res. 2024 Dec 26. 19(1): 878

Chronic intermittent hypobaric hypoxia alleviates early-stage posttraumatic osteoarthritis via NF-κB/Nrf2 pathway in mice.

Guowei Ren, Lindan Geng, Dong Ren, Haowei Hou, Shuangquan Yao, Zhenhua Shi, Pengcheng Wang.

   BACKGROUND: Posttraumatic osteoarthritis (PTOA) is directly associated with early acute articular cartilage injury. Inhibition of cartilage destruction immediately following joint damage can effectively slow or prevent PTOA progression. Therefore, we sought to determine intervention targets and therapeutic strategies in the acute stage of cartilage injury. The benefits of chronic intermittent hypobaric hypoxia (CIHH) extend to various body tissues, but its impact on acute cartilage injury remains unclear. We selected PTOA initiation as the therapeutic window and administered CIHH treatment immediately following cartilage injury initiation to investigate its protective effect on cartilage and molecular mechanism changing with time-varying.
METHODS: The non-invasive PTOA mouse model was established by applying a single rapid specific impact force to the right knee's tibial plateau, initiating load-induced PTOA development, closely resembling the pathological changes in human diseases. Following loading, we inhibited cartilage destruction by treating mice immediately in a hypobaric chamber with a hypobaric hypoxia mimic at 5000 m altitude. Cohorts of mice subjected to distinct experimental conditions were monitored for 3, 7, 14 or 28 days. Safranin O-Fast Green staining, Immunohistochemistry, immunofluorescence, ELISA, and western blotting were performed to evaluate the therapeutic effects of CIHH on cartilage in vivo. The nuclear translocation of NF-κB p65 and Nrf2 were detected by immunofluorescence.
RESULTS: The results showed that inhibiting cartilage destruction using CIHH immediately following acute articular cartilage injury initiation delayed the progression of PTOA, decreased the Mankin score and suppressed the expression of proinflammatory factors, including iNOS, NO, TNF-α, and IL-1β. Meanwhile, immediate CIHH treatment reduced levels of the catabolic enzymes ADAMTS5 and MMP13 in the cartilage matrix, reversed degradation of Collagen II and COMP, and inhibited oxidative stress by decreasing ROS levels. Moreover, CIHH suppressed NF-κB signaling by activating the Nrf2 in vivo studies.
CONCLUSION: Our study demonstrated that immediate CIHH treatment following cartilage injury initiation can attenuate load-induced cartilage damage by activating Nrf2/HO-1 and inhibiting the NF-κB p65 signalling pathways to counteract oxidative stress and inflammatory reactions, enhance the metabolic balance of the cartilage matrix and delay cartilage degeneration. This treatment may represent a potential therapeutic strategy for limiting PTOA progression.

Keywords:  Acute cartilage injury; Chronic intermittent hypobaric hypoxia; NF-κB/Nrf2; Oxidative stress; Posttraumatic osteoarthritis; ROS

DOI:  https://doi.org/10.1186/s13018-024-05376-6
Am J Physiol Cell Physiol. 2024 Dec 23.

Primary cilia as antennas for oxygen.

Pascal Schneider, Joachim Fandrey, Tristan Leu.

  Over the last few decades, the primary cilium, an inconspicuous cell organelle, has increasingly become the focus of current research. The primary cilium is a microtubule-based, non-motile, antenna-like structure that is present on almost all mammalian cells. The ciliary membrane incorporates a large number of receptor molecules, which further characterize this cellular organelle. These include receptors of the Sonic hedgehog (Shh)-, Wnt- or Platelet-derived growth factor (PDGF)-signaling pathways. For this reason, as well as due to the fact that extracellular signaling molecules can bind to the ciliary membrane, primary cilia have been named "the antenna of the cell". In addition to their signaling function, the association of ciliary dysfunctions with a variety of diseases, so-called ciliopathies, underscores the importance of this functional cellular structure. Recent studies have also implicated primary cilia in the adaptation to low‑oxygen conditions, which are characteristic for ischemia, such as in stroke or myocardial infarction, or tumor entities. The aim of this review is to provide an overview of these multiple facets and to take a closer look at the evolution of an inconspicuous cell organelle to a major player in hypoxia.

Keywords:  HIF; cilia; hypoxia; oxygen sensing

DOI:  https://doi.org/10.1152/ajpcell.00298.2024
J Transl Med. 2024 Dec 20. 22(1): 1135

Ubiquitin-specific protease 7 maintains c-Myc stability to support pancreatic cancer glycolysis and tumor growth.

Jichun Gu, Xi Xiao, Caifeng Zou, Yishen Mao, Chen Jin, Deliang Fu, Rongkun Li, Hengchao Li.

   BACKGROUND: The typical pathological feature of pancreatic ductal adenocarcinoma (PDAC) is a significant increase in stromal reaction, leading to a hypoxic and poorly vascularized tumor microenvironment. Tumor cells undergo metabolic reprogramming, such as the Warburg effect, yet the underlying mechanisms are not fully understood.
METHODS: Interference and overexpression experiments were conducted to analyze the in vivo and in vitro effects of USP7 on the growth and glycolysis of tumor cells. Small-molecule inhibitors of USP7 and transgenic mouse models of PDAC were employed to assess the consequences of targeting USP7 in PDAC. The molecular mechanism underlying USP7-induced c-Myc stabilization was determined by RNA sequencing, co-IP and western blot analyses.
RESULTS: USP7 is abnormally overexpressed in PDAC and predicts a poor prognosis. Hypoxia and extracellular matrix stiffness can induce USP7 expression in PDAC cells. Genetic silencing of USP7 inhibits the glycolytic phenotypes in PDAC cells, while its overexpression has the opposite effect, as demonstrated by glucose uptake, lactate production, and extracellular acidification rate. Importantly, USP7 promotes PDAC tumor growth in a glycolysis-dependent manner. The small-molecule inhibitor P5091 targeting USP7 effectively suppresses the Warburg effect and cell growth in PDAC. In a transgenic mouse model of PDAC, named KPC, P5091 effectively blocks tumor progression. Mechanistically, USP7 interacts with c-Myc, enhancing its stability and expression, which in turn upregulates expression of glycolysis-related genes.
CONCLUSIONS: This study sheds light on the molecular mechanisms underlying the Warburg effect in PDAC and unveils USP7 as a potential therapeutic target for improving PDAC treatment.

Keywords:  Aerobic glycolysis; Deubiquitinating enzymes; Glucose metabolism; HAUSP

DOI:  https://doi.org/10.1186/s12967-024-05962-6
Res Sq. 2024 Dec 13. pii: rs.3.rs-5449794. [Epub ahead of print]

The impact of chronic intermittent hypoxia on enzymatic activity in memory-associated brain regions of male and female rats.

Steve Mabry, Jessica L Bradshaw, Jennifer J Gardner, E Nicole Wilson, Janak Sunuwar, Hannah Yeung, Sharad Shrestha, J Thomas Cunningham, Rebecca L Cunningham.

Background Obstructive sleep apnea (OSA) is an intermittent hypoxia disorder associated with cognitive dysfunction, including learning and memory impairments. There is evidence that alterations in protease activity and neuronal activation as associated with cognitive dysfunction, are dependent on sex, and may be brain region-specific. However, the mechanisms mediating OSA-induced cognitive impairments are unclear. Therefore, we used a rat model of OSA, chronic intermittent hypoxia (CIH), to investigate protease activity (e.g., calpain and caspase-3) and neuronal activation (early growth response protein 1, EGR-1) in brain regions associated with learning and memory. We used a rat model of OSA known as chronic intermittent hypoxia (CIH) to investigate protease activity (calpain and caspase-3) and neuronal activation (early growth response protein 1, EGR-1) in brain regions associated with learning and memory. Methods Male and female Sprague Dawley rats were exposed to CIH or room air (normoxic) for 14 days. We quantified protease activity and cleaved spectrin products, along with EGR-1 protein expression in hippocampal subregions (CA1, CA3), cortical regions [entorhinal cortex (ETC), retrosplenial cortex (RSC), cerebellar cortex (CC)], and subcortical regions [raphe nucleus (RN), locus coeruleus (LC)] associated with learning and memory. Within each group, Pearson correlations of calpain activity, caspase-3 activity, and EGR-1 expression were performed between brain regions. Sex differences within normoxic and CIH correlations were examined. Results CIH dysregulated calpain activity in male ETC and female CA1 and RSC. CIH dysregulated caspase-3 activity in male RN and female CA1 and RSC. CIH decreased calpain and caspase-3 cleavage products in male ETC. CIH decreased calpain-cleaved spectrin in male RSC but increased these products in female RSC. EGR-1 expression was decreased in male and female RN. Correlational analysis revealed CIH increased excitatory connections in males and increased inhibitory connections in females. EGR-1 expression in males shifted from negative to positive correlations. Conclusions Overall, these data show that CIH dysregulates protease activity and impairs neuronal function in a brain region- and sex-dependent manner. This indicates that males and females exhibit sex-specific vulnerabilities to mild OSA. These findings concur with our previous behavioral studies that demonstrated memory impairment in CIH-exposed rats.

DOI: https://doi.org/10.21203/rs.3.rs-5449794/v1