bims-oxygme Biomed News
on Oxygen metabolism
Issue of 2024–12–22
ten papers selected by
Onurkan Karabulut, Berkeley City College
  1. 2-oxoglutarate-dependent Dioxygenases (2-OGDDs) as Oxygen Sensors: Their Importance in Health and Disease.
  2. DNA Damage and Inflammatory Response of p53 Null H358 Non-Small Cell Lung Cancer Cells to X-Ray Exposure Under Chronic Hypoxia.
  3. Temporal Effects of Hypoxia Exposure at High Altitudes on Compensatory Brain Function: Evidence from Functional Connectivity of Resting-State EEG Brain Networks.
  4. Hypoxia Activated Nitric Oxide Donor Compounds for the Prevention and Treatment of Myocardial Hypoxia-Induced Injury.
  5. Implementation of the Oxygen Saturation Index as a Predictor of Outcome in Prenatally Diagnosed CDH Neonates in the First 24 Hours of Life.
  6. Development of myopia in scuba diving and hyperbaric oxygen treatment: a case report and systematic review.
  7. Cerebral oxidative stress, inflammation and apoptosis induced by intermittent hypoxia: a systematic review and meta-analysis of rodent data.
  8. Decoding the enigmatic estrogen paradox in pulmonary hypertension: delving into estrogen metabolites and metabolic enzymes.
  9. Gut microbiota's role in high-altitude cognitive impairment: the therapeutic potential of Clostridium sp. supplementation.
  10. Acclimatized Lowlanders Exhibit a Hypocoagulable Profile after a Passive Ascent at High Altitude.
  1. J Biochem. 2024 Dec 16. pii: mvae087. [Epub ahead of print]
    2-oxoglutarate-dependent Dioxygenases (2-OGDDs) as Oxygen Sensors: Their Importance in Health and Disease.
    Peter W T Lee, Minoru Kobayashi, Takakuni Dohkai, Itsuki Takahashi, Takumi Yoshida, Hiroshi Harada.
      Since low oxygen conditions below physiological levels, hypoxia, is associated with various diseases, it is crucial to understand the molecular basis behind cellular response to hypoxia. Hypoxia-inducible factors (HIFs) have been revealed to primarily orchestrate the hypoxia response at the transcription level and have continuously attracted great attention over the past three decades. In addition to these hypoxia-responsive effector proteins, 2-oxoglutarate-dependent dioxygenase (2-OGDD) superfamily including prolyl-4-hydroxylase domain-containing proteins (PHDs) and factor inhibiting HIF-1 (FIH-1) have attracted even greater attention in recent years as factors that act as direct oxygen sensors due to their necessity of oxygen for the regulation of the expression and activity of the regulatory subunit of HIFs (HIF-α). Herein, we present a detailed classification of 2-OGDD superfamily proteins, such as Jumonji C-domain-containing histone demethylases (JmjC-KDMs), Ten-Eleven translocation (TET) enzymes, AlkB family of DNA/RNA demethylases, and Lysyl hydroxylases, and discusses their specific functions and associations with various diseases. By introducing the multifaceted roles of 2-OGDD superfamily proteins in the hypoxic response, this review aims to summarize the accumulated knowledge about the complex mechanisms governing cellular adaptation to hypoxia in various physiological and pathophysiological contexts.
    Keywords:  2-oxoglutarate-dependent dioxygenase (2-OGDD); epigenetics; gene regulation; hypoxia; metabolism
    DOI:  https://doi.org/10.1093/jb/mvae087
  2. Int J Mol Sci. 2024 Nov 23. pii: 12590. [Epub ahead of print]25(23):
    DNA Damage and Inflammatory Response of p53 Null H358 Non-Small Cell Lung Cancer Cells to X-Ray Exposure Under Chronic Hypoxia.
    Hasan Nisar, Melanie Brauny, Frederik M Labonté, Claudia Schmitz, Bikash Konda, Christine E Hellweg.
      Hypoxia-induced radioresistance limits therapeutic success in cancer. In addition, p53 mutations are widespread in tumors including non-small cell lung carcinomas (NSCLCs), and they might modify the radiation response of hypoxic tumor cells. We therefore analyzed the DNA damage and inflammatory response in chronically hypoxic (1% O2, 48 h) p53 null H358 NSCLC cells after X-ray exposure. We used the colony-forming ability assay to determine cell survival, γH2AX immunofluorescence microscopy to quantify DNA double-strand breaks (DSBs), flow cytometry of DAPI-stained cells to measure cell cycle distribution, ELISAs to quantify IL-6 and IL-8 secretion in cell culture supernatants, and RNA sequencing to determine gene expression. Chronic hypoxia increased the colony-forming ability and radioresistance of H358 cells. It did not affect the formation or resolution of X-ray-induced DSBs. It reduced the fraction of cells undergoing G2 arrest after X-ray exposure and delayed the onset of G2 arrest. Hypoxia led to an earlier enhancement in cytokines secretion rate after X-irradiation compared to normoxic controls. Gene expression changes were most pronounced after the combined exposure to hypoxia and X-rays and pertained to senescence and different cell death pathways. In conclusion, hypoxia-induced radioresistance is present despite the absence of functional p53. This resistance is related to differences in clonogenicity, cell cycle regulation, cytokine secretion, and gene expression under chronic hypoxia, but not to differences in DNA DSB repair kinetics.
    Keywords:  DNA double-strand breaks; DNA repair; cell cycle; hypoxia; interleukin expression; ionizing radiation; lung cancer; non-small cell lung cancer cells; radioresistance; survival
    DOI:  https://doi.org/10.3390/ijms252312590
  3. High Alt Med Biol. 2024 Dec 17.
    Temporal Effects of Hypoxia Exposure at High Altitudes on Compensatory Brain Function: Evidence from Functional Connectivity of Resting-State EEG Brain Networks.
    Hong Ren, Xi-Yue Yang, Rui Su, HaiLin Ma, Hao Li.
      Ren, Hong, Xi-Yue Yang, Rui Su, HaiLin Ma, and Hao Li. Temporal Effects of Hypoxia Exposure at High Altitudes on Compensatory Brain Function: Evidence from Functional Connectivity of Resting-State EEG Brain Networks. High Alt Med Biol. 00:00-00, 2024. Background: The aim of this study was to investigate the effects of prolonged exposure to hypobaric hypoxia at high altitude on changes in brain function measured by electroencephalography (EEG), focusing specifically on the resting-state brain network functional connectivity and compensatory adaptations in brain function among individuals with varying durations of high altitude residency. Methods: In study I, 64 participants were divided into high-altitude group (HG) and low-altitude group (LG). Ninety-six long-term migrants residing at an altitude of 3,650 m were recruited for studyII and categorized into three groups based on their duration of stay at high altitude: group A (1-2 years), group B (8-10 years), and group C (18-20 years). Resting-state EEG data were collected from each participant, and functional connectivity analysis was conducted using Phase Locking Value. Results: Study I showed that participants with HG had stronger functional connectivity in the occipital lobe than those with LG (p < 0.05). The study II findings indicate that there were significant differences in functional connectivity strength among the frontal and occipital lobes in groups A, B, and C across the α, β, δ, and θ frequency bands. Specifically, the functional connectivity strength of the frontal lobe was significantly higher in group A compared with group B, and in group B compared with group C (p < 0.05). Additionally, the functional connectivity of the occipital lobe was significantly higher in group C compared with group B, and in group B compared with group A (p < 0.05). Conclusions: The consistent results of the whole frequency band suggest that the individual's occipital lobe function is enhanced to compensate for the damage of frontal lobe function, so as to better adapt to the extreme environment at high altitude.
    Keywords:  brain networks; functional connectivity; high-altitude exposure; resting-state EEG
    DOI:  https://doi.org/10.1089/ham.2024.0063
  4. J Med Chem. 2024 Dec 18.
    Hypoxia Activated Nitric Oxide Donor Compounds for the Prevention and Treatment of Myocardial Hypoxia-Induced Injury.
    Wanxiang Yang, Wen Zhou, Shaohua Gou.
      A series of hypoxia-targeted nitric oxide donor compounds were designed and synthesized by using an ether linker to connect N-methyl-N-nitroso-p-phenol and nitrobenzyl alcohols, respectively. Among them, N6, with acceptable pharmacokinetic parameters in mice, exhibited a high selective NO release in H9c2 cells under hypoxia and in the dissected heart tissue of the tested mice as desired. Mechanistic investigations revealed that N6 could regulate vascular dilation and modulate proteins associated with myocardial injury both in vitro and in vivo. Animal tests demonstrated that N6 showed better therapeutic and preventive effects against myocardial hypoxia injury than the commercial drug isosorbide mononitrate. Our research evidence that N6 has a potent therapeutic potential in treating myocardial hypoxic injury, which can be further investigated as a promising drug candidate for coronary heart disease.
    DOI:  https://doi.org/10.1021/acs.jmedchem.4c02132
  5. Pediatr Pulmonol. 2024 Dec 17. e27447
    Implementation of the Oxygen Saturation Index as a Predictor of Outcome in Prenatally Diagnosed CDH Neonates in the First 24 Hours of Life.
    Lennart Hale, Judith Leyens, Bartolomeo Bo, Clara Engel, Christoph Berg, Lukas Schroeder, Andreas Mueller, Florian Kipfmueller.
       AIMS: This study aimed to evaluate the Oxygen Saturation Index (OSI) as a noninvasive measure for early postnatal management and outcome prediction in neonates with congenital diaphragmatic hernia (CDH). Additionally, the study analyzed the correlation and predictive ability of OSI, Oxygenation Index (OI), Horovitz Index (HI), and partial pressure of arterial oxygen (PaO2) regarding mortality and the need for extracorporeal membrane oxygenation (ECMO).
    METHODS: A retrospective, single-center study using data from 2013 to 2020. Parameters for calculating indices were extracted from patient charts every hour during the first 24 h of life. Statistical analyses included ROC analysis for predictive cut-off values and Spearman's rank for correlation assessments.
    RESULTS: The study included 138 neonates. Postductal OSI demonstrated high sensitivity (80%-85%) and negative predictive value (NPV) for predicting mortality and ECMO need, with cut-off values between 11.5 and 13. Optimal cut-off values for predicting ECMO need were 10 at 12 and 24 h (sensitivity 96.7%). OSI, OI, HI, and PaO2 showed comparable predictive capabilities with strong correlations. The lowest OI of 18 predicted mortality with a sensitivity of 75% and specificity of 90.9%. Strong correlations were found between the lowest PaO2 and lowest HI (0.963-0.974), and between highest OI and lowest PaO2 (-0.922 to -0.945).
    CONCLUSION: OSI is a promising index for predicting outcomes in CDH neonates, showing strong correlation with indices like OI and HI. Despite limitations, OSI provides continuous, bedside monitoring without invasive blood sampling. Further prospective studies are needed to validate these findings and establish new cut-off values.
    Keywords:  Oxygen Saturation Index; Oxygenation Index; congenital diaphragmatic hernia; extracorporeal membrane oxygenation; outcome prediction
    DOI:  https://doi.org/10.1002/ppul.27447
  6. Diving Hyperb Med. 2024 Dec 20. 54(4): 328-337
    Development of myopia in scuba diving and hyperbaric oxygen treatment: a case report and systematic review.
    Sofia A Sokolowski, Anne K Räisänen-Sokolowski, Richard V Lundell.
       Introduction: A 54-year-old, previously healthy Caucasian male diver was on a 22-day liveaboard diving holiday. During this time, he performed 75 open-circuit dives, of which 72 were with enriched air nitrox. All dives were within recreational length and depth. After the trip he noticed a worsening of vision and his refraction had changed from the previous -3.75/-5.75 to -5.5/-7.75 dioptres. Hyperoxic myopia is a well-known phenomenon after hyperbaric oxygen treatment (HBOT), but related literature in recreational divers is scarce.
    Methods: A systematic literature review on the effect of a hyperoxic environment on the development of myopia was done according to the PRISMA guidelines. Three databases were searched: Ovid MEDLINE, Scopus, and the Cochrane Library. A risk of bias analysis was done on all articles, and the GRADE approach was used to evaluate the quality of evidence. Articles that had sufficient data were used to synthesise a visualisation of oxygen exposure and changes in refraction.
    Results: Twenty-two articles were included in this review. These included five case reports, two case series, nine cohort studies, one randomised controlled trial and five reviews, of which one was systematic. Most articles described HBOT patients' ocular complications, although four articles were diver centric. The synthesis of results suggests that divers tend to get a greater myopic shift with a smaller exposure. However, the data were too heterogeneous to perform meaningful statistical analyses. This review is the first to focus on divers instead of HBOT patients.
    Conclusions: The case presented led to a systematic literature review on the effects of hyperbaric oxygen on refractive changes in both HBOT patients and divers. The data were too heterogeneous to make meaningful suggestions on a safety limit to prevent myopisation in diving.
    Keywords:  Myopization; Ophthalmology; Oxygen toxicity; Recreational divers; Repetitive diving; Safety; Side effects
    DOI:  https://doi.org/10.28920/dhm54.4.328-337
  7. Eur Respir Rev. 2024 Oct;pii: 240162. [Epub ahead of print]33(174):
    Cerebral oxidative stress, inflammation and apoptosis induced by intermittent hypoxia: a systematic review and meta-analysis of rodent data.
    Bayan El Amine, Joey Fournier, Mélanie Minoves, Sébastien Baillieul, Frédéric Roche, Nathalie Perek, Jean-Louis Pépin, Renaud Tamisier, Charles Khouri, Claire Rome, Anne Briançon-Marjollet.
      Obstructive sleep apnoea (OSA) contributes to cerebrovascular diseases and cognitive decline. Preclinical studies support the deleterious impact on the brain of intermittent hypoxia (IH), one of the main components of OSA, but heterogeneity in rodent species and brain regions studied, or induced by IH paradigms, can challenge interpretation of the studies. Hence, we conducted a systematic review and meta-analysis to evaluate the impact of IH on rodent brain oxidative stress, inflammation, apoptosis and the expression of brain-derived neurotrophic factor (BDNF) and hypoxia-inducible factor 1 (HIF-1). PubMed and Web of Science searches identified 663 articles related to IH exposure, of which 60 were included. The examined outcomes were oxidative stress, inflammation, apoptosis, HIF-1 or BDNF in brains. Standardised mean difference was used to compare studies. Metaregressions were performed to clarify the impact of IH exposure parameters, rodent characteristics or cerebral localisation on these outcomes. IH-induced oxidative stress (increased malondialdehyde (MDA) and NADPH oxidase (NOX) and decreased superoxide dismutase), increased inflammation (tumour necrosis factor-α, NF-κB and inducible nitric oxide synthase), HIF-1 and apoptosis evaluated by terminal deoxynucleotidyl transferase dUTP nick-end labelling and cleaved caspase-3. In contrast, B-cell lymphoma 2 (BCL2) and BDNF expression were not significantly modified. Metaregressions showed that MDA, NOX and BDNF were associated with determinants of IH cycles (inspired oxygen fraction and duration of hypoxia) and some parameters depended on localisation. Rodent characteristics had little impact on the outcomes. Our meta-analysis robustly establishes that IH, independently of other confounders, has a strong effect on the brain by inducing oxidative stress, inflammation and apoptosis in rodent models. Our findings support the interest of considering and treating cerebral consequences of OSA in clinical practice.
    DOI:  https://doi.org/10.1183/16000617.0162-2024
  8. Cell Mol Biol Lett. 2024 Dec 18. 29(1): 155
    Decoding the enigmatic estrogen paradox in pulmonary hypertension: delving into estrogen metabolites and metabolic enzymes.
    Qiang You, Hequn Song, Ziming Zhu, Jinzheng Wang, Ruixin Wang, Mingjia Du, Yingjie Fu, Jinxiang Yuan, Rubin Tan.
      Pulmonary hypertension (PH) presents a puzzling sex bias, being more prevalent in women yet often less severe than in men, and the underlying reasons remain unclear. Studies using animal models, and limited clinical data have revealed a protective influence of exogenous estrogens, known as the estrogen paradox. Research suggests that beyond its receptor-mediated effects, estrogen acts through metabolites such as 2-ME2, 4-OHE2, and 16-OHE2, which are capable of exhibiting protective or detrimental effects in PH, prompting the need to explore their roles in PH to untangle sex differences and the estrogen paradox. Hypoxia disrupts the balance of estrogen metabolites by affecting the enzymes responsible for estrogen metabolism. Delving into the role of these metabolic enzymes not only illuminates the sex difference in PH but also provides a potential rationale for the estrogen paradox. This review delves into the intricate interplay between estrogen metabolites, metabolic enzymes, and PH, offering a deeper understanding of sex-specific differences and the perplexing estrogen paradox in the context of this condition.
    Keywords:  CYPs; Estrogen; Estrogen metabolites; HSD17B; Hypoxia; Pulmonary hypertension
    DOI:  https://doi.org/10.1186/s11658-024-00671-w
  9. Sci China Life Sci. 2024 Dec 18.
    Gut microbiota's role in high-altitude cognitive impairment: the therapeutic potential of Clostridium sp. supplementation.
    Wei Zhou, Yongqiang Zhou, Shikun Zhang, Bin Li, Zhong Li, Zhijie Bai, Dezhi Sun, Chaoji Huangfu, Ningning Wang, Tiantian Xia, Congshu Huang, Lina Guan, Xi Yang, Yangyi Hu, Pengfei Zhang, Pan Shen, Rui Wang, Zhexin Ni, Yue Gao.
      Prolonged exposure to high-altitude environments may increase the risk of cognitive decline in young migrants. Recent studies suggest that hypobaric hypoxia-induced alterations in gut microbial composition could partly contribute to this risk. However, the absence of direct evidence from cohort studies and an unclear mechanism hinder intervention development based on this hypothesis. This study recruited 109 young male migrants living in Xizang to investigate the microbial mechanisms underlying cognitive impairment associated with high-altitude migration. Multi-omic analysis revealed distinct microbiome and metabolome features in migrants with cognitive decline, notably a reduced abundance of Clostridium species and disrupted fecal absorption of L-valine. Mechanistic studies showed that hypobaric hypoxia significantly damaged the intestinal barrier, leading to lipopolysaccharide (LPS) leakage and an influx of inflammatory factors into the peripheral blood, which activated microglia and caused neuronal injury in the hippocampus of mice. Additionally, compromised L-valine absorption due to intestinal barrier damage correlated with lower hippocampal glutamate levels and neurotrophic factors. Intervention with Clostridium sp. effectively restored the intestinal barrier and enhanced L-valine absorption, which mitigated hypobaric hypoxia-induced inflammation and hippocampal neural damage in mice. In conclusion, cognitive impairment among young migrants at high altitude may be attributed to hypobaric hypoxia-induced gut microbiota disruption and subsequent intestinal barrier dysfunction. This study may provide a promising approach for preventing and treating high-altitude-associated cognitive impairment.
    Keywords:   Clostridium sp.; L-valine; cognition impairment; high-altitude; microbial mechanisms
    DOI:  https://doi.org/10.1007/s11427-024-2779-9
  10. High Alt Med Biol. 2024 Dec 18.
    Acclimatized Lowlanders Exhibit a Hypocoagulable Profile after a Passive Ascent at High Altitude.
    Emeric Stauffer, François Caton, Raphael Marlu, Aurélien Pichon, Landry Seyve, Michael Furian, Aymeric Paillisser, Florence Berquet, Jeremy De Abreu, Blandine Deschamps, Benoit Polack, Philippe Connes, Paul Robach, Stéphane Doutreleau, Julien V Brugniaux, Samuel Verges, Benoit Champigneulle.
      Stauffer, Emeric, François Caton, Raphael Marlu, Aurélien Pichon, Landry Seyve, Michael Furian, Aymeric Paillisser, Florence Berquet, Jeremy De Abreu, Blandine Deschamps, Benoit Polack, Philippe Connes, Paul Robach, Stéphane Doutreleau, Julien V Brugniaux, Samuel Verges, and Benoit Champigneulle.Acclimatized lowlanders exhibit a hypocoagulable profile after a passive ascent at high altitude. High Alt Med Biol. 00:00-00, 2024. Background: Discordant results have been previously reported regarding the impact of high-altitude (HA) exposure on coagulation. We aimed to investigate changes in coagulation parameters in lowlanders exposed to HA for 14 days using a combination of dynamic coagulation assays and conventional in vitro tests. Material and Methods: We assessed coagulation in 10 lowlanders using whole-blood rotational thromboelastometry (ROTEM), thrombin generation assay (TGA) on poor-platelet plasma, and conventional coagulation tests. Tests were performed at low altitude (LA, 210 m) and at the end of a 14-day sojourn at HA, including passive ascents to 3,800 m for 6 days and then to 5,100 m for 8 days. Results: Conventional tests revealed significant changes in coagulation factors and inhibitors after HA exposure, although these changes remained within normal ranges. ROTEM assays demonstrated a delayed clot initiation in EXTEM/FIBTEM, without any alteration in clot firmness, in HA versus LA (p < 0.01). TGA changes showed an increase in time to peak (p < 0.01), a decrease in endogenous thrombin potential (p < 0.05), and a decrease in thrombin peak (p < 0.001). Conclusions: We found no evidence of hypercoagulability in lowlanders after a 14-day sojourn at HA. In contrast, dynamic coagulation assays (ROTEM and TGA) revealed a hypocoagulable pattern.
    Keywords:  blood coagulation; high altitude; hypoxia; thrombin generation; thromboelastometry
    DOI:  https://doi.org/10.1089/ham.2024.0128
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