bims-oxygme Biomed News
on Oxygen metabolism
Issue of 2024–12–15
ten papers selected by
Onurkan Karabulut, Berkeley City College
  1. Zinc Homeostasis Plays Important Roles in Hypoxia Tolerance: A Study Conducted Clinically and In Vitro.
  2. In vitro effect of vitaminB12 on embyro growth by induction of hypoxia in culture.
  3. Effects of 5-Wk Repeated Sprint Training in Hypoxia on Global Inspiratory and Core Muscle Functions.
  4. A Novel Hypoxia-Featured Genes Prognostic Model for Identification of Hypoxia Subtypes in Diffuse Large B-Cell Lymphoma.
  5. Autophagy inhibition induces AML cell death and enhances the efficacy of chemotherapy under hypoxia.
  6. Profiling paracrine interactions between hypoxic and normoxic skeletal muscle tissue in a microphysiological system fabricated from 3D printed components.
  7. Statement of Retraction: F-box and WD repeat domain-containing 7 (FBXW7) mediates the hypoxia inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) signaling pathway to affect hypoxic-ischemic brain damage in neonatal rats.
  8. Early Restrictive vs Liberal Oxygen for Trauma Patients: The TRAUMOX2 Randomized Clinical Trial.
  9. Caffeine's Neuroprotective Effect on Memory Impairment: Suppression of Adenosine A2A Receptor and Enhancement of Tyrosine Hydroxylase in Dopaminergic Neurons Under Hypobaric Hypoxia Conditions.
  10. Effects of allosteric effectors on oxygen binding to crystals of hemoglobin in the R-quaternary structure.
  1. High Alt Med Biol. 2024 Dec 10.
    Zinc Homeostasis Plays Important Roles in Hypoxia Tolerance: A Study Conducted Clinically and In Vitro.
    Yan Guo, Chao Yu, Zhongsheng Lu, Menglan Zhang, Qiang Zhang, Xiao Liu.
      Guo, Yan, Chao Yu, Zhongsheng Lu, Menglan Zhang, Qiang Zhang, and Xiao Liu. Zinc homeostasis plays important roles in hypoxia tolerance: A study conducted clinically and in vitro. High Alt Med Biol. 00:00-00, 2024. Objective: High-altitude environments pose significant challenges to human physiology due to reduced oxygen availability, often resulting in altitude-related illnesses such as high-altitude cerebral edema (HACE). This study focuses on understanding the role of zinc homeostasis in enhancing hypoxia tolerance, which may be pivotal in mitigating the adverse effects of such illnesses. Methods: The study involved healthy individuals from high-altitude (4,500-5,000 m) and low-altitude areas (0-200 m), as well as patients with HACE. Blood samples were collected and analyzed. Additionally, a hypoxic model was developed using human brain microvascular endothelial cells (HBMECs), and zinc intervention was implemented. Results: In the blood samples of patients with HACE and those of healthy individuals, there were over 4,000 differentially expressed genes (DEGs), with more than 300 of them linked to zinc. Among these zinc-associated genes, only carbonic anhydrase I (CA1) exhibited a substantial upregulation in expression, while the expression of others was notably downregulated. Compared with the high-altitude group, hemoglobin (Hb) (14.7 vs. 19.5 g/dl) and plasma zinc (37.0 vs. 94.0 mmol/dl) were lower in HACE, while CA1 (55.4 vs. 8.6 g/l) was elevated (p < 0.01). In vitro studies confirmed that exposure to hypoxia (O2 8%-8.5%, 24 hours) inhibited HBMECs proliferation and migration, increased apoptosis and necrosis, and led to abnormal expression of CA1 and various zinc transport proteins. However, zinc intervention (6 μM, 24 hours) significantly mitigated these adverse effects and improved the cell's ability to tolerate hypoxia. Conclusion: Zinc homeostasis was crucial for hypoxia tolerance. Proper zinc supplementation could potentially alleviate symptoms associated with hypoxia intolerance, such as altitude sickness, but further confirmation was needed.
    Keywords:  altitude sickness; carbonic anhydrase I; high-altitude cerebral edema; human brain microvascular endothelial cells; zinc; zinc transporter proteins
    DOI:  https://doi.org/10.1089/ham.2024.0036
  2. Toxicol Res (Camb). 2024 Dec;13(6): tfae207
    In vitro effect of vitaminB12 on embyro growth by induction of hypoxia in culture.
    Dilara Patat, Mehtap Nisari, Harun Ulger, Tolga Ertekin, Ertugrul Dagli, Dicle Cayan, Ozge Al, Hatice Guler, Goksemin Fatma Sengul, Mustafa Tastan.
      In this study, effects of vitaminB12 on embryonic development have been investigated by supplying vitaminB12 on a hypoxia-induced embryo culture. 9.5-day-old embryos from Wistar albino adult pregnant rats were used in our experimental set up.10 μM and 100 μM vitaminB12 were added to culture medium which is then exposed to in vitro hypoxia. Additionally, 11.5-day-old embryos and yolksacs were examined morphologically. Different vitaminB12 doses are compared within experimental groups. It was found that both control and experimental groups in 11.5-day-old embryos are at same developmental stage. It was also determined that oxygen deficiency influenced embryonic development and yolk sac vascularity in hypoxia group, are lagging behind in all experimental groups (P < 0.05). However, the development of vitaminB12 embryos were similar to control group under normoxic conditions (P > 0.05). It was also observed that development was compensated through supplement of vitaminB12 to hypoxia group (P < 0.05). It was indicated that the development in H + 100 μM vitB12 groups was quite close to control group. However, development of H + 10 μM vitB12 embryos were in parallel with hypoxic group. Furthermore, H + 100 μM vitB12 group showed higher embryonic development than H + 10 μM vitB12 group (P < 0.05).VitaminB12 treatment has been used to prevent intrauterine growth restriction which can be caused by many different pharmacological agents. However, nobody has investigated effects of vitaminB12 on hypoxia-induced early embryo growth retardation. In the light of our findings, administration of 100 μM vitaminB12 restores damage of embryonic development due to hypoxia and this application also increases embryonic vascularity and circulation. Thus, supplementation of vitaminB12 can be offered as a therapeutic approach towards cell death and diseases such as neurovascular and cardiovascular diseases and in the near future.
    Keywords:  embryonic development; embryonic growth retardation; hypoxia; therapeutic approaches; vitaminB12rat; whole embryo culture
    DOI:  https://doi.org/10.1093/toxres/tfae207
  3. J Sports Sci Med. 2024 Dec;23(4): 767-777
    Effects of 5-Wk Repeated Sprint Training in Hypoxia on Global Inspiratory and Core Muscle Functions.
    Qingde Shi, Jinlei Nie, Tomas K Tong, Haifeng Zhang, Zhaowei Kong.
      Repeated-sprint training in hypoxia (RSH) has been shown to boost team-sport players' repeated-sprint ability (RSA). Whether players' global inspiratory muscle (IM) and core muscle (CM) functions would be altered concomitantly with RSH was not reported. This study was designed to compare the concomitant alternations in players' RSA and their IM and CM functions during a team-sport-specific intermittent exercise protocol (IEP) before and after the intervention. Twenty players were assigned into either RSH or control (CON) groups (n = 10 for each). RSH players participated in 5-wk RSH (15 sessions, 3 sets 5x5-s all-out treadmill sprints interspersed with 25-s passive recovery under the hypoxia of 13.5%) while CON players had no corresponding training. The changes in RSA between pre- and post-intervention, and the alterations in IM and CM functions that were revealed by maximum inspiratory mouth pressure (PImax) and sport-specific endurance plank test (SEPT) performance, respectively, between pre- and post-IEP and across pre- and post-intervention in the RSH group were compared with that of CON. Following the 5-wk RSH, players' RSA improved significantly (>6%, p < 0.05) while PImax and SEPT performance did not alter (P > 0.05). Nevertheless, PImax which declined markedly in pre-intervention IEP (pre-IEP 155.4 ± 22.7 vs post-IEP 140.6 ± 22.8 cmH2O, p < 0.05) was alleviated significantly in post-intervention IEP (152.2 ± 27.4 vs 152.6 ± 31.8, p > 0.05), while the concomitant declined SEPT performance in the pre-intervention IEP (155 ± 24.6 vs 98.1 ± 21.7 s, p < 0.05) was retained post intervention (170.7 ± 38.1 vs 100.5 ± 33.4, p < 0.05). For the CON, all variables were unchanged (p > 0.05). Such findings suggest that 5-wk RSH could enhance players' RSA but not global IM and CM functions. Nonetheless, the decline in PImax in pre-intervention IEP alleviated significantly post intervention led to a postulation that players' IM endurance, rather than strength, might improve with the 5-wk RSH regimen, while the possible improved IM endurance did not advance the fatigue resistance of CM.
    Keywords:  Intermittent hypoxic training; inspiratory muscle strength; maximum inspiratory mouth pressure; respiratory muscle training; sport-specific endurance plank test
    DOI:  https://doi.org/10.52082/jssm.2024.767
  4. Cell Biochem Biophys. 2024 Dec 11.
    A Novel Hypoxia-Featured Genes Prognostic Model for Identification of Hypoxia Subtypes in Diffuse Large B-Cell Lymphoma.
    Geng Lyu, Ruixin Sun, Xiaxin Liu, Zizhen Xu.
      Diffuse large B-cell lymphoma (DLBCL), known as the predominant type of aggressive B-cell lymphoma, is biologically and clinically heterogeneous. The prognosis of DLBCL is quite different among subtypes. Hypoxia is one of the key elements in tumor microenvironment, promoting tumor progression by means of various mechanisms, such as increased proliferation, altered metabolism, enhanced angiogenesis, and greater migratory capability, among others. The primary purpose of this research is to investigate the connection between hypoxia-featured genes (HFGs), prognosis in DLBCL, and their capacity association with the immune microenvironment. Various hypoxia-associated patterns for DLBCL patients from GEO and TCGA databases were identified by means of an unsupervised consensus clustering algorithm. CIBERSORT and IOBR package is used to identify different immune infiltration status. To develop a predictive model using hypoxia-related genes, we conducted univariate Cox regression, multivariate Cox regression, and LASSO regression assessment. Subsequently, we confirmed the predictive importance of these hypoxia-associated genes, highlighting hypoxia-associated characteristics, and explored the connection between the hypoxia model and the immune environment. Three hypoxia clusters were identified. We also observed that each pattern of hypoxia response was significantly related to different prognoses. It was found that the immune status among hypoxia clusters is different. After developing a prognostic risk model using 5 hypoxia-related genes, we discovered that the risk score is related to immune factors and how effective drugs are in treating DLBCL. In DLBCL patients, varying hypoxia patterns correlate with both prognostic outcomes and the immune microenvironment. Hypoxia-featured genes (HFGs) function as a standalone predictive element in these patients. It is also potentially a reliable indicator for predicting clinical responses to ICI therapy and traditional drugs.
    Keywords:  Diffuselarge B-cell lymphoma; Hypoxia signaling pathway; Immune checkpoint inhibitors; Prognostic prediction model; Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1007/s12013-024-01637-7
  5. bioRxiv. 2024 Nov 26. pii: 2024.11.24.625107. [Epub ahead of print]
    Autophagy inhibition induces AML cell death and enhances the efficacy of chemotherapy under hypoxia.
    Eunice S Wang, Hannah R S Fay, Kaitlyn M Dykstra, Michael N Phelps, Matthew Johnson, Annemarie Harrigan, Marianna C Giorgi.
      Outcomes of relapsed/refractory acute myeloid leukemia (AML) are poor, and strategies to improve outcomes are urgently needed. One important factor promoting relapse and chemoresistance is the ability of AML cells to thrive in vivo within an intrinsically hypoxic bone marrow microenvironment. Here we show that human AML cells exhibit enhanced autophagy, specifically mitophagy (i.e., increased accumulation of mitochondria and decreased mitochondrial membrane potential) under hypoxia. To target this pathway, we investigated the activity of the potent chloroquine-derived autophagy inhibitor, Lys05, on human AML cells, patient samples, and patient derived xenograft models. Inhibition of autophagy by Lys05 in AML cells prevented removal of damaged mitochondria and preferentially enhanced cell death under hypoxia mirroring the marrow microenvironment. Lys05 eradicated human AML cells of all genotypes including p53 mutant cells. Lys05 treatment in primary AML xenografted mice decreased CD34+CD38- human cells and prolonged overall survival. Moreover, Lys05 overcame hypoxia-induced chemoresistance and improved the efficacy of cytarabine, venetoclax, and azacytidine in vitro and in vivo in AML models. Our results demonstrate the importance of autophagy, specifically mitophagy, as a critical survival and chemoresistance mechanism of AML cells under hypoxic marrow conditions. Therapeutic targeting of this pathway in future clinical studies for AML is warranted.
    DOI:  https://doi.org/10.1101/2024.11.24.625107
  6. Lab Chip. 2024 Dec 12.
    Profiling paracrine interactions between hypoxic and normoxic skeletal muscle tissue in a microphysiological system fabricated from 3D printed components.
    Megan L Rexius-Hall, Malinda D Madrigal, Cem Y Kilic, Keyue Shen, Megan L McCain.
      Disrupted blood flow in conditions such as peripheral artery disease and critical limb ischemia leads to variations in oxygen supply within skeletal muscle tissue, creating regions of poorly perfused, hypoxic skeletal muscle surrounded by regions of adequately perfused, normoxic muscle tissue. These oxygen gradients may have significant implications for muscle injury or disease, as mediated by the exchange of paracrine factors between differentially oxygenated tissue. However, creating and maintaining heterogeneous oxygen landscapes within a controlled experimental setup to ensure continuous paracrine signaling is a technological challenge. Here, we engineer oxygen-controlled microphysiological systems to investigate paracrine interactions between differentially oxygenated engineered muscle tissue. We fabricated microphysiological systems with dual oxygen landscapes that also had engineered control over paracrine interactions between hypoxic and normoxic skeletal muscle tissues, which were differentiated from C2C12 myoblasts cultured on micromolded gelatin hydrogels. The microphysiological systems interfaced with a new 3D-printed oxygen control well plate insert, which we designed to distribute flow to multiple microphysiological systems and minimize evaporation for longer timepoints. With our system, we demonstrated that amphiregulin, a myokine associated with skeletal muscle injury, exhibits unique upregulation in both gene expression and secretion after 24 hours due to paracrine interactions between hypoxic and normoxic skeletal muscle tissue. Our platform can be extended to investigate other impacts of paracrine interactions between hypoxic and normoxic skeletal muscle and can more broadly be used to elucidate many forms of oxygen-dependent crosstalk in other organ systems.
    DOI:  https://doi.org/10.1039/d4lc00603h
  7. Bioengineered. 2024 Dec;15(1): 2299599
    Statement of Retraction: F-box and WD repeat domain-containing 7 (FBXW7) mediates the hypoxia inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) signaling pathway to affect hypoxic-ischemic brain damage in neonatal rats.
      
    DOI:  https://doi.org/10.1080/21655979.2024.2299599
  8. JAMA. 2024 12 10.
    Early Restrictive vs Liberal Oxygen for Trauma Patients: The TRAUMOX2 Randomized Clinical Trial.
    TRAUMOX2 Trial Group
       Importance: Early administration of supplemental oxygen for all severely injured trauma patients is recommended, but liberal oxygen treatment has been associated with increased risk of death and respiratory complications.
    Objective: To determine whether an early 8-hour restrictive oxygen strategy compared with a liberal oxygen strategy in adult trauma patients would reduce death and/or major respiratory complications.
    Design, Setting, and Participants: This randomized controlled trial enrolled adult trauma patients transferred directly to hospitals, triggering a full trauma team activation with an anticipated hospital stay of a minimum of 24 hours from December 7, 2021, to September 12, 2023. This multicenter trial was conducted at 15 prehospital bases and 5 major trauma centers in Denmark, the Netherlands, and Switzerland. The 30-day follow-up period ended on October 12, 2023. The primary outcome was assessed by medical specialists in anesthesia and intensive care medicine blinded to the randomization.
    Interventions: In the prehospital setting or on trauma center admission, patients were randomly assigned 1:1 to a restrictive oxygen strategy (arterial oxygen saturation target of 94%) (n = 733) or liberal oxygen strategy (12-15 L of oxygen per minute or fraction of inspired oxygen of 0.6-1.0) (n = 724) for 8 hours.
    Main Outcomes and Measures: The primary outcome was a composite of death and/or major respiratory complications within 30 days. The 2 key secondary outcomes, death and major respiratory complications within 30 days, were assessed individually.
    Results: Among 1979 randomized patients, 1508 completed the trial (median [IQR] age, 50 [31-65] years; 73% male; and median Injury Severity Score was 14 [9-22]). Death and/or major respiratory complications within 30 days occurred in 118 of 733 patients (16.1%) in the restrictive oxygen group and 121 of 724 patients (16.7%) in the liberal oxygen group (odds ratio, 1.01 [95% CI, 0.75 to 1.37]; P = .94; absolute difference, 0.56 percentage points [95% CI, -2.70 to 3.82]). No significant differences were found between groups for each component of the composite outcome. Adverse and serious adverse events were similar across groups, with the exception of atelectasis, which was less common in the restrictive oxygen group compared with the liberal oxygen group (27.6% vs 34.7%, respectively).
    Conclusions and Relevance: In adult trauma patients, an early restrictive oxygen strategy compared with a liberal oxygen strategy initiated in the prehospital setting or on trauma center admission for 8 hours did not significantly reduce death and/or major respiratory complications within 30 days.
    Trial Registration: ClinicalTrials.gov Identifier: NCT05146700.
    DOI:  https://doi.org/10.1001/jama.2024.25786
  9. CNS Neurosci Ther. 2024 Dec;30(12): e70134
    Caffeine's Neuroprotective Effect on Memory Impairment: Suppression of Adenosine A2A Receptor and Enhancement of Tyrosine Hydroxylase in Dopaminergic Neurons Under Hypobaric Hypoxia Conditions.
    Zhifeng Zhong, Huaping Dong, Simin Zhou, Chaoqun Lin, Pei Huang, Xiaoxu Li, Jijian Zhang, Jiaxin Xie, Yu Wu, Peng Li.
       AIMS: Chronic hypobaric hypoxia frequently results in memory deficits, with severe cases showing marked alterations in dopamine levels and its metabolites. This research explores caffeine's modulation of the adenosine A2A receptor (A2AR) and its regulatory effects on tyrosine hydroxylase (TH), aiming to restore dopamine homeostasis and mitigate memory impairments associated with hypoxia. The goal is to identify novel preventive strategies against cognitive decline induced by hypoxia.
    METHODS: Network pharmacological analysis was employed to predict the interactions between caffeine, cognitive function, and hypobaric hypoxia-related disorders. The novel object recognition and Y-maze tests were utilized to assess caffeine's impact on memory deficits under hypobaric hypoxia conditions in male mice. LC-MS/MS analysis was subsequently conducted to examine the variations in dopamine and its metabolites within the midbrain. Molecular docking further confirmed the binding affinities between A2AR and caffeine, as well as TH and caffeine. Additionally, immunofluorescence and protein-protein docking were employed to elucidate the interaction between A2AR and TH.
    RESULTS: The findings highlight the pivotal role of adenosine receptors and dopamine-related pathways in the interplay between caffeine, cognition, and hypobaric hypoxia-related disorders. Behavioral tests demonstrated that caffeine effectively alleviated memory impairments caused by chronic hypobaric hypoxia. LC-MS/MS results revealed significant differences in dopamine, metanephrine, and 3-hydroxyanthranilic acid levels following caffeine treatment for hypoxia-induced cognitive deficits. Molecular docking confirmed the high affinity between A2AR and caffeine, as well as TH and caffeine, while immunofluorescence and protein-protein docking provided insights into the A2AR-TH interaction and its modulation during hypobaric hypoxia.
    CONCLUSIONS: Caffeine exhibits potent neuroprotective effects against chronic high-altitude-induced cognitive impairments, potentially through its action on A2AR, leading to enhanced TH expression and subsequent release of dopamine and its related neurotransmitters.
    Keywords:  adenosine A2A receptor; caffeine; dopaminergic neurons; hypobaric hypoxia; memory impairment; tyrosine hydroxylase
    DOI:  https://doi.org/10.1111/cns.70134
  10. Protein Sci. 2025 Jan;34(1): e5232
    Effects of allosteric effectors on oxygen binding to crystals of hemoglobin in the R-quaternary structure.
    Naoya Shibayama.
      Much is known about how allosteric effectors influence the equilibrium between the relaxed (R) and tense (T) states of hemoglobin (Hb), but little is known about how and to what extent the effectors lower the intrinsic O2 affinity of each allosteric state, especially the R-state. Here, we provide a thorough characterization of the O2 equilibria of effector-bound and unbound R-quaternary form crystals of horse Hb without a quaternary structural switching. In the absence of effectors, R crystals of horse Hb were shown to bind O2 noncooperatively with a very high affinity virtually identical to that of R crystals of human Hb. We found that the effector bezafibrate (BZF) and its derivative L35 lower the overall O2 affinity of R crystals by approximately a factor of 3 and 2, respectively, while both maintaining noncooperative oxygenation. These effects are observed regardless of whether the effectors are co-crystallized or soaked into the effector-free protein crystals with a different lattice, confirming that the observed affinity reduction is induced by the BZF derivatives and not by crystal packing forces. Our findings, combined with available co-crystal structural data, suggest that the BZF derivatives lower the O2 affinity of the R-quaternary structure of Hb through structural constraints imposed by a quaternary shift slightly toward T. Additionally, since no co-crystal of R-state Hb with the effector inositol hexakisphosphate (IHP) is available, we only present an IHP-soaking experiment showing little change in O2 affinity, and poor IHP binding to the R crystal structure of horse Hb is suggested.
    Keywords:  allosteric effector; hemoglobin; hemoglobin crystals; microspectrophotometry; oxygen affinity; two‐state model
    DOI:  https://doi.org/10.1002/pro.5232
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