bims-oxygme Biomed News
on Oxygen metabolism
Issue of 2025–01–19
nine papers selected by
Onurkan Karabulut, Berkeley City College
  1. Hypoxia Regulates Brown Adipocyte Differentiation and Stimulates miR-210 by HIF-1α.
  2. Integrated Network Pharmacology and Metabolomics to Investigate the Effects and Possible Mechanisms of Ginsenoside Rg2 Glycine Ester Derivative Against Hypoxia.
  3. Hypoxia Compromises the Differentiation of Human Osteosarcoma Cells to CAR-R, a Hydroxylated Derivative of Lithocholic Acid and Potent Agonist of the Vitamin D Receptor.
  4. STAT6 deficiency mitigates the severity of pulmonary arterial hypertension caused by chronic intermittent hypoxia by suppressing Th2-inducing cytokines.
  5. Hypoxia-responsive nanoparticles for fluorescence diagnosis and therapy of cancer.
  6. Resetting of the Human Circadian Melatonin Rhythm by Ambient Hypoxia.
  7. Aldose Reductase: A Promising Therapeutic Target for High-Altitude Pulmonary Edema.
  8. Effects of melatonin on the mitogen-activated protein kinase signaling genes in hypoxic Leydig cells.
  9. miRNA-541-5p regulates myocardial ischemia-reperfusion injury by targeting ferroptosis.
  1. Int J Mol Sci. 2024 Dec 26. pii: 117. [Epub ahead of print]26(1):
    Hypoxia Regulates Brown Adipocyte Differentiation and Stimulates miR-210 by HIF-1α.
    Jan Caca, Alexander Bartelt, Virginia Egea.
      MicroRNAs (miRNAs) are short sequences of single-stranded non-coding RNAs that target messenger RNAs, leading to their repression or decay. Interestingly, miRNAs play a role in the cellular response to low oxygen levels, known as hypoxia, which is associated with reactive oxygen species and oxidative stress. However, the physiological implications of hypoxia-induced miRNAs ("hypoxamiRs") remain largely unclear. Here, we investigate the role of miR-210 in brown adipocyte differentiation and thermogenesis. We treated the cells under sympathetic stimulation with hypoxia, CoCl2, or IOX2. To manipulate miR-210, we performed reverse transfection with antagomiRs. Adipocyte markers expression, lipid accumulation, lipolysis, and oxygen consumption were measured. Hypoxia hindered BAT differentiation and suppressed sympathetic stimulation. Hypoxia-induced HIF-1α stabilization increased miR-210 in brown adipocytes. Interestingly, miR-210-5p enhanced differentiation under normoxic conditions but was insufficient to rescue the inhibition of brown adipocyte differentiation under hypoxic conditions. Although adrenergic stimulation activated HIF-1α signaling and upregulated miR-210 expression, inhibition of miR-210-5p did not significantly influence UCP1 expression or oxygen consumption. In summary, hypoxia and adrenergic stimulation upregulated miR-210, which impacted brown adipocyte differentiation and thermogenesis. These findings offer new insights for the physiological role of hypoxamiRs in brown adipose tissue, which could aid in understanding oxidative stress and treatment of metabolic disorders.
    Keywords:  brown adipocytes; hypoxamiRs; hypoxia; miR-210; miRNAs; thermogenesis
    DOI:  https://doi.org/10.3390/ijms26010117
  2. Biomed Chromatogr. 2025 Feb;39(2): e6074
    Integrated Network Pharmacology and Metabolomics to Investigate the Effects and Possible Mechanisms of Ginsenoside Rg2 Glycine Ester Derivative Against Hypoxia.
    Qinghai Dong, Fei Shi, Fang Lin, Yaqi Wang, Yang An, Hongliu Xie, Jihua Liu.
      Previous studies have suggested that ginsenoside Rg2 glycine ester derivative (RG) exhibits therapeutic potential in mitigating hypoxia. This study aimed to elucidate the potential mechanism of RG in hypoxia injury through a combined approach of metabolomics and network pharmacology. Initially, a CoCl2-induced cell hypoxia model was established, and the therapeutic impact of RG on biochemical indices was evaluated. Subsequently, metabolomics analysis of cell samples was conducted to identify biomarkers, and network pharmacology was employed to identify potential targets of RG for hypoxia treatment. Finally, the key target and pathway were verified. The study revealed that RG could reverse CoCl2-induced abnormalities in biochemical indicators. Metabolomics analysis identified 13 biomarkers and seven metabolic pathways associated with RG treatment. Utilizing network pharmacology, five key targets and five metabolic pathways were identified, partially aligning with the metabolomics results. Molecular docking results demonstrated the effective binding of RG to the key targets. Enzyme linked immunosorbent assay verified that RG could exert antihypoxia effect by activated PI3K/Akt pathway. In conclusion, this integrated strategy, combining metabolomics with network pharmacology, sheds light on the protective mechanism of RG against hypoxia-induced cellular damage. The findings offer valuable insights for future research and potential applications of RG in the field.
    Keywords:  antihypoxia activity; ginsenoside Rg2 glycine ester derivative; metabolomics; network pharmacology
    DOI:  https://doi.org/10.1002/bmc.6074
  3. Int J Mol Sci. 2025 Jan 03. pii: 365. [Epub ahead of print]26(1):
    Hypoxia Compromises the Differentiation of Human Osteosarcoma Cells to CAR-R, a Hydroxylated Derivative of Lithocholic Acid and Potent Agonist of the Vitamin D Receptor.
    Haley Evans, Alexander Greenhough, Laura Perry, Gonzalo Lasanta, Carmen M Gonzalez, Antonio Mourino, Jason P Mansell.
      The active metabolite of vitamin D3, calcitriol (1,25D), is widely recognised for its direct anti-proliferative and pro-differentiation effects. However, 1,25D is calcaemic, which restricts its clinical use for cancer treatment. Non-calcaemic agonists of the vitamin D receptor (VDR) could be better candidates for cancer treatment. In this study, we examined the influence of the hydroxylated lithocholic acid derivative CAR-R on osteosarcoma (OS) cell (MG63) growth and differentiation. Treatment of MG63 cells with CAR-R inhibited growth under conventional and hypoxic conditions. Co-treating cells with CAR-R and a lysophosphatidic acid (LPA) analogue resulted in their differentiation, as supported by synergistic increases in alkaline phosphatase (ALP) activity. Under hypoxic conditions, however, this differentiation response was attenuated. The importance of observed increases in hypoxia inducible factors (HIFs) were investigated through targeted disruption using pharmacological and genetic approaches. Disruption elicited a reduction in ALP activity, suggesting an important role for HIFs in OS differentiation. Finally, we examined the expression of the VDR protein. Hypoxic MG63s expressed less VDR, with the levels increasing with CAR-R exposure. Whilst these findings are encouraging, future studies aimed at bolstering the pro-differentiating effect of CAR-R under hypoxic conditions are warranted if this agent is to gain traction in the treatment of OS.
    Keywords:  alkaline phosphatase; differentiation; hypoxia; lithocholic acid; osteosarcoma; vitamin D receptor
    DOI:  https://doi.org/10.3390/ijms26010365
  4. Respir Res. 2025 Jan 13. 26(1): 13
    STAT6 deficiency mitigates the severity of pulmonary arterial hypertension caused by chronic intermittent hypoxia by suppressing Th2-inducing cytokines.
    Pan Jiang, Huai Huang, Zilong Liu, Guiling Xiang, Xiaodan Wu, Shengyu Hao, Shanqun Li.
       BACKGROUND: Obstructive sleep apnea (OSA) is frequently associated with increased incidence and mortality of pulmonary hypertension (PH). The immune response contributes to pulmonary artery remodeling and OSA-related diseases. The immunologic factors linked to OSA-induced PH are not well understood. STAT6 is crucial in the signaling pathway that modulates immune response. However, the status of phosphorylated STAT6 (p-STAT6) in an OSA-induced PH mouse model remains largely unexplored.
    METHODS: Chronic intermittent hypoxia (CIH) plays a crucial role in the progression of OSA. This study utilized a in vivo CIH model to examine the role of STAT6 in CIH-induced PH.
    RESULTS: CIH mice exhibited pulmonary artery remodeling and pulmonary hypertension, indicated by increased right ventricular systolic pressure (RVSP), higher right ventricular to left ventricular plus septum (RV/LV + S) ratios, and significant morphological alterations compared to normoxic (Nor) mice. Increased p-STAT6 in the lungs and elevated p-STAT6 + IL-4 + producing T cells in CIH mice. STAT6 deficiency (STAT6-/-) improved PH and PA remodeling in CIH-induced PH mouse models.STAT6 deficiency impaired the T helper 2 (Th2) immune response, affecting IL-4 and IL-13 secretion. IL-4, rather than IL-13, activated STAT6 in human pulmonary artery smooth muscle cells (hPASMCs). STAT6 knockdown decreased the proliferation in IL-4 treated hPASMCs.
    CONCLUSION: These findings exhibit the critical role of STAT6 in the pathogenesis of CIH induced PH by regulating Th2 immune response.STAT6 could be a significant therapeutic target for OSA-related PH.
    Keywords:  Chronic intermittent hypoxia; Pulmonary hypertension; STAT6; Th2 immune response
    DOI:  https://doi.org/10.1186/s12931-024-03062-z
  5. Theranostics. 2025 ;15(4): 1353-1375
    Hypoxia-responsive nanoparticles for fluorescence diagnosis and therapy of cancer.
    Yubing Zhang, Jiaqi Xing, Juan Jiang, Maoliang Liao, Guojun Pan, Yanfeng Wang.
      Hypoxia, caused by rapid tumor growth and insufficient oxygen supply, is a defining characteristic of numerous solid tumors and exerts a significant influence on tumor growth, metastasis, and invasion. Early diagnosis and effective killing of tumor cells are crucial for cancer treatment. In recent years, the emergence of nanomaterials has overcome the difficulties in the delivery of chemotherapeutic drugs and contrast agents to tumor area. In this review, we summarize the development of hypoxia-responsive nanoparticles for fluorescence imaging and tumor therapy in the last five years, and further discuss their design strategies and applications in bioimaging. In addition, we discuss the therapeutic strategies of hypoxia-responsive prodrugs on different nanoplatforms and the future prospects of hypoxia-responsive nanomedicine in tumor therapy.
    Keywords:  fluorescence imaging; hypoxia; nanoparticles; prodrugs; tumor therapy
    DOI:  https://doi.org/10.7150/thno.104190
  6. J Pineal Res. 2025 Jan;77(1): e70029
    Resetting of the Human Circadian Melatonin Rhythm by Ambient Hypoxia.
    Titiaan E Post, Riccardo De Gioannis, Jan Schmitz, Martin Wittkowski, Tina Martin Schäper, Anna Wrobeln, Joachim Fandrey, Marie-Therese Schmitz, Joseph S Takahashi, Jens Jordan, Eva-Maria Elmenhorst, Daniel Aeschbach.
      Circadian clocks in the body drive daily cycles in physiology and behavior. A master clock in the brain maintains synchrony with the environmental day-night cycle and uses internal signals to keep clocks in other tissues aligned. Work in cell cultures uncovered cyclic changes in tissue oxygenation that may serve to reset and synchronize circadian clocks. Here we show in healthy humans, following a randomized controlled single-blind counterbalanced crossover study design, that one-time exposure to moderate ambient hypoxia (FiO2 ~15%, normobaric) for ~6.5 h during the early night advances the dim-light onset of melatonin secretion by 9 min (95% CI: 1-16 min). Exposure to moderate hypoxia may thus be strong enough to entrain circadian clocks to a 24-h cycle in the absence of other entraining cues. Together, the results provide direct evidence for an interaction between the body's hypoxia-sensing pathway and circadian clocks. The finding offers a mechanism through which behaviors that change tissue oxygenation (e.g., exercise and fasting/eating) can affect circadian timing and through which hypoxia-related diseases (e.g., obstructive sleep apnea and chronic obstructive pulmonary disease) can result in circadian misalignment and associated pathologies. Trial Registration: Registration number: DRKS00023387; German Clinical Trials Register: http://www.drks.de.
    Keywords:  circadian clocks; humans; hypoxia; hypoxia‐inducible factors; melatonin; oxygen; phase shifting
    DOI:  https://doi.org/10.1111/jpi.70029
  7. Int J Mol Sci. 2025 Jan 02. pii: 341. [Epub ahead of print]26(1):
    Aldose Reductase: A Promising Therapeutic Target for High-Altitude Pulmonary Edema.
    Dan Song, Mengjie Wang, Xinjie Zhao, Yanru Zhang, Yiyi Zhang, Xiaohua Hao, Jialu Yuan, Haojie Tang.
      The Qinghai-Tibet Plateau, famously known as the "Roof of the World", has witnessed a surge in individuals traveling or working there. However, a considerable percentage of these individuals may suffer from acute mountain sickness (AMS), with high-altitude pulmonary edema (HAPE) being a severe and potentially life-threatening manifestation. HAPE disrupts the balance of intrapulmonary tissue fluid, resulting in severe lung function impairment. Current therapeutic interventions for HAPE have limitations and are accompanied by significant side effects. Aldose reductase (AR), a crucial enzyme in the polyol metabolic pathway, has been implicated in various diseases. In this study, we sought to explore the role of AR in HAPE. Utilizing both in vivo and in vitro models, we investigated the impact of AR on hypoxia-induced pulmonary edema, vascular pressure, inflammatory factors, and oxidative stress. Our findings revealed that AR knockdown mitigated hypoxia-induced pulmonary edema, decreased the expression of vascular pressure and inflammatory factors, and enhanced the expression related to oxidative stress. These results indicate that AR may serve as a potential therapeutic target for HAPE, offering a plausible pathological basis and novel drug targets for the prevention and treatment of this condition.
    Keywords:  aldose reductase; high-altitude pulmonary edema; inflammatory factors; oxidative stress; vascular pressure
    DOI:  https://doi.org/10.3390/ijms26010341
  8. Vet Res Forum. 2024 ;15(12): 673-680
    Effects of melatonin on the mitogen-activated protein kinase signaling genes in hypoxic Leydig cells.
    Mona Ghasemi, Adel Saberivand, Mohammadreza Gholami, Vahideh Assadollahi, Masoud Alasvand.
      Leydig cells play a crucial role in male reproductive physiology, and their dysfunction is often associated with male infertility. Hypoxia negatively affects the structure and function of Leydig cells. This study aimed to investigate the impact of melatonin on the c-Jun N-terminal kinase (Jnk), P38, and extra-cellular signal-regulated kinases 1 and 2 (Erk1/2) mitogen-activated protein kinase (MAPK) signaling pathways in TM3 mouse Leydig cells under hypoxia induced by cobalt (II) chloride (CoCl2). The TM3 cell line was utilized as a subject of research, and 100 μM CoCl2 was employed to induce hypoxia. Following the addition of 10.00 ng mL-1 melatonin, quantitative reverse transcription-polymerase chain reaction and western blot analyses were conducted to assess the gene expression and protein level of Jnk, p38, and Erk1/2, while enzyme-linked immunosorbent assay was used to measure testosterone secretion. The results showed that melatonin significantly increased testosterone production in the CoCl2 + melatonin group compared to the CoCl2-treated group. Furthermore, melatonin elevated both the protein level and mRNA expression of Erk1/2, Jnk, and p38 genes in the CoCl2 + melatonin group compared to the CoCl2 group. In conclusion, melatonin activated the Jnk, p38, and Erk1/2 MAPK signaling pathways and enhanced testosterone production in the presence of CoCl2 in TM3 cells.
    Keywords:  Hypoxia; Leydig cells; Melatonin; Mitogen-activated protein kinase; Signal transduction
    DOI:  https://doi.org/10.30466/vrf.2024.2026202.4231
  9. J Cardiothorac Surg. 2025 Jan 15. 20(1): 63
    miRNA-541-5p regulates myocardial ischemia-reperfusion injury by targeting ferroptosis.
    ZhiYu Zhao, BoXia Li, DianWei Cheng, YuFang Leng.
       BACKGROUND: This article aims to use high-throughput sequencing to identify miRNAs associated with ferroptosis in myocardial ischemia-reperfusion injury, select a target miRNA, and investigate its role in H9C2 cells hypoxia-reoxygenation injury.
    METHODS: SD rats and H9C2 cells were used as subjects. ELISA kits quantified MDA, SOD, GSH, LDH, and ferritin levels. TTC staining evaluated infarction size. HE staining observed histopathological changes. DCFH-DA fluorescent probe detected ROS. CCK-8 kit measured cell viability. HiSeq 2000 sequencing performed differential expression analysis of miRNAs. qRT-PCR and Western blots assessed the expression levels of GPX-4, ACSL-4, HO-1, TFR-1 and TFR-2. SPSS 21.0 software conducted statistical analysis.
    RESULTS: Myocardial ischemia-reperfusion injury resulted in decreased levels of SOD and GSH, increased levels of LDH and MDA, up-regulation of ferritin, ACSL-4, HO-1, and TFR-2, down-regulation of GPX-4, increased tissue damage, and accumulation of ROS. However, DFO treatment reversed these changes. Subsequently, the target gene miRNA-541-5p was obtained by miRNA sequencing screening, and further validation revealed that miRNA-541-5p expression was increased in the myocardial tissues of rats in the I/R injury model group compared with those of rats in the NC group, P < 0.05. Subsequently, by constructing H9C2 cell lines with miRNA-541-5p overexpression and miRNA-541-5p expression inhibition, miRNA-541-5p expression was inversely correlated with the survival of H9C2 cells after hypoxia-reoxygenation injury. miRNA-541-5p up-regulation led to a decrease in SOD and GSH, an increase in ferritin and MDA, and an accumulation of ROS. wb and qRT-PCT demonstrated that high miRNA-541-5p expression up-regulated the expression of protein/mRNA expression of ACSL-4, HO-1, ferritin, and TFR-1, but down-regulated protein/mRNA expression of GPX-4. In addition, ADAM 7, FNIP 2, HOXD 10, HCCS and STK 3 were preliminarily identified as potential candidate target genes for miRNA-541-5p by bioinformatics analysis. Among them, ADAM7 emerges as the most suitable potential target gene based on the selection criteria.
    CONCLUSION: In summary, miRNA-541-5p may be a biomarker of myocardial I/R damage diseases and can regulate oxidative stress and iron death by inhibiting the expression of miRNA-541-5p, thereby reducing mechanisms of I/R injury.
    Keywords:  Ferroptosis; MiRNA sequencing; MiRNA-541-5p; Myocardial ischemia–reperfusion injury
    DOI:  https://doi.org/10.1186/s13019-024-03260-2
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