bims-hypoxi Biomed News
on Hypoxia and HIF1-alpha
Issue of 2021‒08‒22
twenty-two papers selected by
Ashish Kaul
University of Tsukuba
  1. Serum hypoxia-inducible factor 1alpha emerges as a prognostic factor for severe traumatic brain injury.
  2. HIF1α is required for NK cell metabolic adaptation during virus infection.
  3. HIF-1α-Mediated miR-623 Regulates Apoptosis and Inflammatory Responses of Nucleus Pulposus Induced by Oxidative Stress via Targeting TXNIP.
  4. HIF-1α promotes SARS-CoV-2 infection and aggravates inflammatory responses to COVID-19.
  5. Hypoxia-Inducible Factor-1α in Macrophages, but Not in Neutrophils, Is Important for Host Defense during Klebsiella pneumoniae-Induced Pneumosepsis.
  6. Nano-Curcumin Protects Against Sodium Nitrite-Induced Lung Hypoxia Through Modulation of Mitogen-Activated Protein Kinases/c-Jun NH2-Terminal Kinase Signaling Pathway.
  7. 15,16-dihydrotanshinone I inhibits EOMA cells proliferation by interfering in posttranscriptional processing of hypoxia-inducible factor 1.
  8. Hypoxia-Inducible Factor (HIF) in Ischemic Stroke and Neurodegenerative Disease.
  9. Nitric oxide-releasing micelles with intelligent targeting for enhanced anti-tumor effect of cisplatin in hypoxia.
  10. Apatinib Inhibits Angiogenesis in Intrahepatic Cholangiocarcinoma by Regulating the Vascular Endothelial Growth Factor Receptor-2/Signal Transducer and Activator of Transcription Factor 3/Hypoxia Inducible Factor 1 Subunit Alpha Signaling Axis.
  11. Neutrophil HIF-1α stabilisation is augmented by mitochondrial ROS produced via the glycerol 3-phosphate shuttle.
  12. Activation of the mTOR/HIF-1α/VEGF axis promotes M1 macrophage polarization in non-eosCRSwNP.
  13. Targeting Hypoxia: Hypoxia-Activated Prodrugs in Cancer Therapy.
  14. Targeting USP22 with miR‑30‑5p to inhibit the hypoxia‑induced expression of PD‑L1 in lung adenocarcinoma cells.
  15. Albendazole-loaded cubosomes interrupt the ERK1/2-HIF-1α-p300/CREB axis in mice intoxicated with diethylnitrosamine: A new paradigm in drug repurposing for the inhibition of hepatocellular carcinoma progression.
  16. Hypoxic preconditioning protects against ischemic kidney injury through the IDO1/kynurenine pathway.
  17. Hypoxia alters the expression of ACE2 and TMPRSS2 SARS-CoV-2 cell entry mediators in hCMEC/D3 cells.
  18. Mitochondrial KATP channels stabilize intracellular Ca2+ during hypoxia in retinal horizontal cells of goldfish (Carassius auratus).
  19. Autophagy prevents osteocyte cell death under hypoxic conditions.
  20. Breakthrough Science: Hypoxia-Inducible Factors, Oxygen Sensing, and Disorders of Hematopoiesis.
  21. Activation of ERK-Drp1 signaling promotes hypoxia-induced Aβ accumulation by upregulating mitochondrial fission and BACE1 activity.
  22. Hypoxia: A teratogen underlying a range of congenital disruptions, dysplasias, and malformations.
  1. Clin Chim Acta. 2021 Aug 16. pii: S0009-8981(21)00295-3. [Epub ahead of print]
    Serum hypoxia-inducible factor 1alpha emerges as a prognostic factor for severe traumatic brain injury.
    Qing-Wei Lv, Zi-Qiang Zheng, Han Zhang, Mi Guo, Liang-Jun Shen.
      BACKGROUND: Hypoxia-inducible factor 1alpha (HIF-1α) is implicated in the cell's response to hypoxia. We investigated whether serum HIF-1α concentrations are correlated with the severity and clinical outcome of severe traumatic brain injury (sTBI).METHODS: Serum HIF-1α concentrations were quantified in 104 sTBI patients and 80 healthy controls. Trauma severity was assessed using Glasgow coma scale (GCS). Glasgow outcome scale (GOS) score of 1-3 at post-trauma 90 days was defined as a poor outcome. Multivariate analyses were performed to discern the relationship between serum HIF-1α concentrations and outcome.
    RESULTS: Patients displayed significantly higher serum HIF-1α concentrations than controls (median, 294.9 versus 102.7 pg/ml). HIF-1α concentrations were intimately related to GCS scores (r=-0.62) and GOS scores (r=-0.64). 48 patients (46.2%) experienced a poor outcome. Serum HIF-1α concentrations > 280.2 pg/ml significantly distinguished patients with the development of poor outcome with 77.1% sensitivity and 69.6% specificity (AUC, 0.750; 95% CI: 0.655-0.829). Serum HIF-1α concentrations > 280.2 pg/ml emerged as an independent predictor for poor outcome (OR: 4.179; 95% CI: 1.024-17.052).
    CONCLUSIONS: Serum HIF-1α concentrations are tightly associated with trauma severity and poor 90-day outcome, substantializing serum HIF-1α as a promising prognostic biomarker for sTBI.
    Keywords:  Biomarker; Hypoxia-inducible factor 1alpha; Outcome; Prognosis; Severe traumatic brain injury; Severity
    DOI:  https://doi.org/10.1016/j.cca.2021.08.017
  2. Elife. 2021 Aug 16. pii: e68484. [Epub ahead of print]10
    HIF1α is required for NK cell metabolic adaptation during virus infection.
    Francisco Victorino, Tarin Bigley, Eugene Park, Cong-Hui Yao, Jeanne Benoit, Liping Yang, Sytse J Piersma, Elvin J Lauron, Rebecca M Davidson, Gary Patti, Wayne M Yokoyama.
      Natural killer (NK) cells are essential for early protection against virus infection, and must metabolically adapt to the energy demands of activation. Here, we found upregulation of the metabolic adaptor hypoxia inducible factor-1α (HIF-1α) is a feature of mouse NK cells during murine cytomegalovirus (MCMV) infection in vivo. HIF-1 α -deficient NK cells failed to control viral load, causing increased morbidity. No defects were found in effector functions of HIF-1α KO NK cells however, their numbers were significantly reduced. Loss of HIF-1 α did not affect NK cell proliferation during in vivo infection and in vitro cytokine stimulation. Instead, we found HIF-1α -deficient NK cells showed increased expression of the pro-apoptotic protein Bim and glucose metabolism was impaired during cytokine stimulation in vitro. Similarly, during MCMV infection HIF-1α -deficient NK cells upregulated Bim and had increased caspase activity. Thus, NK cells require HIF-1α-dependent metabolic functions to repress Bim expression and sustain cell numbers for an optimal virus response.
    Keywords:  immunology; inflammation; mouse
    DOI:  https://doi.org/10.7554/eLife.68484
  3. Oxid Med Cell Longev. 2021 ;2021 6389568
    HIF-1α-Mediated miR-623 Regulates Apoptosis and Inflammatory Responses of Nucleus Pulposus Induced by Oxidative Stress via Targeting TXNIP.
    Xiaogang Bao, Zhenhua Wang, Qi Jia, Sibo Shen, Likang Wu, Qi Jiang, Changwei Li, Guohua Xu.
      Excessive apoptosis and inflammatory responses of nucleus pulposus (NP) cells induced by oxidative stress contribute to intervertebral disc degeneration (IVDD). Though some microRNAs are associated with IVDD, the specific microRNA that can mediate apoptotic and inflammatory responses of NP cells induced by oxidative stress synchronously still needs further identification. Here, we find that microRNA-623 (miR-623) is downregulated in IVDD and its expression is regulated by hypoxia-inducible factor-1α (HIF-1α) under oxidative stress conditions. Mechanistically, HIF-1α is observed to promote miR-623 expression by directly binding to its promoter region (-1,994/-1,987 bp). Functionally, miR-623 is found to work as an intermediator in alleviating apoptosis and inflammatory responses of NP cells induced by oxidative stress via regulating thioredoxin-interacting protein (TXNIP) expression by directly targeting its 3'-untranslated region (3'-UTR). Thus, on elucidating the expression and functional mechanisms of miR-623, our study suggests that miR-623 can be a valuable therapeutic target for treating oxidative stress-induced IVDD.
    DOI:  https://doi.org/10.1155/2021/6389568
  4. Signal Transduct Target Ther. 2021 Aug 18. 6(1): 308
    HIF-1α promotes SARS-CoV-2 infection and aggravates inflammatory responses to COVID-19.
    Mingfu Tian, Weiyong Liu, Xiang Li, Peiyi Zhao, Muhammad Adnan Shereen, Chengliang Zhu, Shanyu Huang, Siyu Liu, Xiao Yu, Miaomiao Yue, Pan Pan, Wenbiao Wang, Yongkui Li, Xulin Chen, Kailang Wu, Zhen Luo, Qiwei Zhang, Jianguo Wu.
      Cytokine storm induced by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a major pathological feature of Coronavirus Disease 2019 (COVID-19) and a crucial determinant in COVID-19 prognosis. Understanding the mechanism underlying the SARS-CoV-2-induced cytokine storm is critical for COVID-19 control. Here, we identify that SARS-CoV-2 ORF3a and host hypoxia-inducible factor-1α (HIF-1α) play key roles in the virus infection and pro-inflammatory responses. RNA sequencing shows that HIF-1α signaling, immune response, and metabolism pathways are dysregulated in COVID-19 patients. Clinical analyses indicate that HIF-1α production, inflammatory responses, and high mortalities occurr in elderly patients. HIF-1α and pro-inflammatory cytokines are elicited in patients and infected cells. Interestingly, SARS-CoV-2 ORF3a induces mitochondrial damage and Mito-ROS production to promote HIF-1α expression, which subsequently facilitates SARS-CoV-2 infection and cytokines production. Notably, HIF-1α also broadly promotes the infection of other viruses. Collectively, during SARS-CoV-2 infection, ORF3a induces HIF-1α, which in turn aggravates viral infection and inflammatory responses. Therefore, HIF-1α plays an important role in promoting SARS-CoV-2 infection and inducing pro-inflammatory responses to COVID-19.
    DOI:  https://doi.org/10.1038/s41392-021-00726-w
  5. Mediators Inflamm. 2021 ;2021 9958281
    Hypoxia-Inducible Factor-1α in Macrophages, but Not in Neutrophils, Is Important for Host Defense during Klebsiella pneumoniae-Induced Pneumosepsis.
    Natasja A Otto, Liza Pereverzeva, Valentine Leopold, Ivan Ramirez-Moral, Joris J T H Roelofs, Jeroen W J van Heijst, Alex F de Vos, Tom van der Poll.
      Hypoxia-inducible factor- (HIF-) 1α has been implicated in the ability of cells to adapt to alterations in oxygen levels. Bacterial stimuli can induce HIF1α in immune cells, including those of myeloid origin. We here determined the role of myeloid cell HIF1α in the host response during pneumonia and sepsis caused by the common human pathogen Klebsiella pneumoniae. To this end, we generated mice deficient for HIF1α in myeloid cells (LysM-cre × Hif1α fl/fl) or neutrophils (Mrp8-cre × Hif1α fl/fl) and infected these with Klebsiella pneumoniae via the airways. Myeloid, but not neutrophil, HIF1α-deficient mice had increased bacterial loads in the lungs and distant organs after infection as compared to control mice, pointing at a role for HIF1α in macrophages. Myeloid HIF1α-deficient mice did not show increased bacterial growth after intravenous infection, suggesting that their phenotype during pneumonia was mediated by lung macrophages. Alveolar and lung interstitial macrophages from LysM-cre × Hif1α fl/fl mice produced lower amounts of the immune enhancing cytokine tumor necrosis factor upon stimulation with Klebsiella, while their capacity to phagocytose or to produce reactive oxygen species was unaltered. Alveolar macrophages did not upregulate glycolysis in response to lipopolysaccharide, irrespective of HIF1α presence. These data suggest a role for HIF1α expressed in lung macrophages in protective innate immunity during pneumonia caused by a common bacterial pathogen.
    DOI:  https://doi.org/10.1155/2021/9958281
  6. Dose Response. 2021 Jul-Sep;19(3):19(3): 15593258211033148
    Nano-Curcumin Protects Against Sodium Nitrite-Induced Lung Hypoxia Through Modulation of Mitogen-Activated Protein Kinases/c-Jun NH2-Terminal Kinase Signaling Pathway.
    Ahlam Alhusaini, Sara Alhumaidan, Renad Almogren, Shaikha Alsaif, Ebtesam Alsultan, Iman Hussein.
      Background and objective: This study was designed to compare the efficacy of curcumin (CRN) with that of nano-curcumin (N-CRN) in the mitigation of various biochemical indices in hypoxic lung induced by sodium nitrite (SN) in rats.Methods: Twenty-four adult male albino rats were divided into 4 groups. Group 1: control group received carboxy methyl cellulose; Group 2: hypoxic group injected with single dose of SN (60 mg/kg, s.c.); Group 3: SN-intoxicated rats pre-injected with CRN (100 mg/kg, i.p.); and Group 4: SN-intoxicated rats pre-injected with N-CRN (100 mg/kg, i.p.). Curcumin and N-CRN were administered intraperitoneally 2 hour prior to SN intoxication. Hemoglobin concentration, serum tumor necrosis factor-alpha (TNF-α), and caspase-3 were analyzed. Gene expression of hypoxia inducible factor-1 (HIF-1α), matrix metallo-proteinases (MMP)-2, and tissue inhibitors of metalloproteinases (TIMPs)-2, as well as the protein expression of mitogen-activated protein kinases (MAPKs) and c-Jun NH2-terminal kinase (JNK) were examined in lung tissues.
    Results: Hemoglobin level was markedly reduced, and serum TNF-α and caspase-3 were significantly elevated post SN intoxication. The lung MMP-2 and HIF-1α mRNA were overexpressed in the hypoxic group; while TIMP-2 mRNA was downregulated. Sodium nitrite administration increased proteins' expressions of MAPK and JNK. Pretreatment with CRN or N-CRN markedly mitigated those alterations. These results were supported by histopathological examinations of lung tissue.
    Conclusion: Interestingly, N-CRN exhibited a pronounced protective effect via suppression of inflammatory and apoptotic biomarkers and modulation of MAPK/JNK signaling pathway.
    Keywords:  c-Jun NH2-terminal kinase; hypoxia inducible factor-1α; hypoxic lung; mitogen-activated protein kinases; nano-curcumin; tissue inhibitors of metalloproteinases
    DOI:  https://doi.org/10.1177/15593258211033148
  7. Int J Med Sci. 2021 ;18(14): 3214-3223
    15,16-dihydrotanshinone I inhibits EOMA cells proliferation by interfering in posttranscriptional processing of hypoxia-inducible factor 1.
    Peiwen Duan, Yingying Huang, Kai Chen, Cheng Cheng, Zhixiang Wu, Yeming Wu.
      Infantile hemangioma (IH), which threatens the physical and mental health of patients, is the most common benign tumor in infants. Previously, we found that 15,16-dihydrotanshinone I (DHTS) was significantly more effective at inhibiting hemangioma proliferation in vitro and in vivo than the first-line treatment propranolol. To investigate the underlying mechanism of DHTS, we used EOMA cells as a model to study the effect of DHTS. We compared the transcriptomes of control and DHTS-treated EOMA cells. In total, 2462 differentially expressed genes were detected between the groups. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed downregulated activity of the hypoxia-inducible factor 1 alpha (HIF-1α) signaling pathway in EOMA cells following treatment with DHTS. Thus, we investigated HIF-1α expression at protein and mRNA levels. Our results revealed that DHTS downregulated HIF-1α expression by interfering in its posttranscriptional processing, and the RNA-binding protein HuR participated in this mechanism. Our findings provide a basis for clinical transformation of DHTS and insight into pathogenic mechanisms involved in IH.
    DOI:  https://doi.org/10.7150/ijms.60774
  8. Front Cell Dev Biol. 2021 ;9 703084
    Hypoxia-Inducible Factor (HIF) in Ischemic Stroke and Neurodegenerative Disease.
    Elena V Mitroshina, Maria O Savyuk, Evgeni Ponimaskin, Maria V Vedunova.
      Hypoxia is one of the most common pathological conditions, which can be induced by multiple events, including ischemic injury, trauma, inflammation, tumors, etc. The body's adaptation to hypoxia is a highly important phenomenon in both health and disease. Most cellular responses to hypoxia are associated with a family of transcription factors called hypoxia-inducible factors (HIFs), which induce the expression of a wide range of genes that help cells adapt to a hypoxic environment. Basic mechanisms of adaptation to hypoxia, and particularly HIF functions, have being extensively studied over recent decades, leading to the 2019 Nobel Prize in Physiology or Medicine. Based on their pivotal physiological importance, HIFs are attracting increasing attention as a new potential target for treating a large number of hypoxia-associated diseases. Most of the experimental work related to HIFs has focused on roles in the liver and kidney. However, increasing evidence clearly demonstrates that HIF-based responses represent an universal adaptation mechanism in all tissue types, including the central nervous system (CNS). In the CNS, HIFs are critically involved in the regulation of neurogenesis, nerve cell differentiation, and neuronal apoptosis. In this mini-review, we provide an overview of the complex role of HIF-1 in the adaptation of neurons and glia cells to hypoxia, with a focus on its potential involvement into various neuronal pathologies and on its possible role as a novel therapeutic target.
    Keywords:  Alzheimer’s disease; HIF; Parkinson’s disease; adaptation; hypoxia; hypoxia-inducible factor; ischemia; neurodegeneration
    DOI:  https://doi.org/10.3389/fcell.2021.703084
  9. J Nanobiotechnology. 2021 Aug 16. 19(1): 246
    Nitric oxide-releasing micelles with intelligent targeting for enhanced anti-tumor effect of cisplatin in hypoxia.
    Yan Chen, Lei Fang, Weixin Zhou, Jinghan Chang, Xiaojuan Zhang, Chuanchuan He, Chen Chen, Ruicong Yan, Yakai Yan, Yao Lu, Chuanrui Xu, Guangya Xiang.
      BACKGROUND: Hypoxic tumor microenvironment (TME) promotes tumor metastasis and drug resistance, leading to low efficiency of cancer chemotherapy. The development of targeted agents or multi-target therapies regulating hypoxic microenvironment is an important approach to overcome drug resistance and metastasis.METHODS: In this study, chitosan oligosaccharide (COS)-coated and sialic acid (SA) receptor-targeted nano-micelles were prepared using film dispersion method to co-deliver cisplatin (CDDP) and nitric oxide (NO) (denoted as CTP/CDDP). In addition, we explored the mechanisms by which NO reversed CDDP resistance as well as enhanced anti-metastatic efficacy in hypoxic cancer cells.
    RESULTS: Because of the different affinities of COS and SA to phenylboronic acid (PBA) under different pH regimes, CTP/CDDP micelles with intelligent targeting property increased cellular uptake of CDDP and enhanced cytotoxicity to tumors, but reduced systemic toxicity to normal organs or tissues. In addition, CTP/CDDP showed stimulus-responsive release in TME. In terms of anti-tumor mechanism, CTP/CDDP reduced CDDP efflux and inhibited epithelial-mesenchymal transition (EMT) process of tumor by down-regulating hypoxia-inducible factor-1α (HIF-1α), glutathione (GSH), multidrug resistance-associated protein 2 (MRP2) and matrix metalloproteinase 9 (MMP9) expression, thus reversing drug resistance and metastasis of hypoxic tumor cells.
    CONCLUSIONS: The designed micelles significantly enhanced anti-tumor effects both in vitro and in vivo. These results suggested that CTP/CDDP represented a promising strategy to treat resistance and metastatic tumors.
    Keywords:  Chitosan oligosaccharide; Cisplatin; Drug resistance; HIF-1α; Hypoxia; Metastasis; Nitric oxide
    DOI:  https://doi.org/10.1186/s12951-021-00989-z
  10. Pharmacology. 2021 Aug 19. 1-11
    Apatinib Inhibits Angiogenesis in Intrahepatic Cholangiocarcinoma by Regulating the Vascular Endothelial Growth Factor Receptor-2/Signal Transducer and Activator of Transcription Factor 3/Hypoxia Inducible Factor 1 Subunit Alpha Signaling Axis.
    Man-Ping Huang, Shan-Zhi Gu, Bin Huang, Guo-Wen Li, Zheng-Ping Xiong, Tian Tang, Sai-Nan Zeng.
      INTRODUCTION: Intrahepatic cholangiocarcinoma (ICC), which is difficult to diagnose and is usually fatal due to its late clinical presentation and a lack of effective treatment, has risen over the past decades but without much improvement in prognosis.OBJECTIVE: The study aimed to investigate the role of apatinib that targets vascular endothelial growth factor receptor-2 (VEGFR2) in ICC.
    METHODS: MTT assays, cell scratch assays, and tube formation assays were used to assess the effect of apatinib on human ICC cell line (HuCCT-1) and RBE cells proliferation, migration, and angiogenic capacity, respectively. Expression of vascular endothelial growth factor (VEGF), VEGFR2, signal transducer and activator of transcription factor 3 (STAT3), pSTAT3, and hypoxia inducible factor 1 subunit alpha (HIF-1α) pathway proteins was assessed using Western blotting and mRNA expression analysis in HuCCT-1 was performed using RT-qPCR assays. The pcDNA 3.1(-)-VEGFR2 and pcDNA 3.1(-)-HIF-1α were transfected into HuCCT-1 and RBE cells using Lipofectamine 2,000 to obtain overexpressed HuCCT-1 and RBE cells.
    RESULTS: We found that apatinib-inhibited proliferation, migration, and angiogenesis of HuCCT-1 and RBE cells in vitro in a dose-dependent manner. We also proved that apatinib effectively inhibits angiogenesis in tumor cells by blocking the expression of VEGF and VEGFR2 in these cells. In addition, we demonstrated that apatinib regulates the expression of STAT3 phosphorylation by inhibiting VEGFR2. Finally, we showed that apatinib regulates ICC angiogenesis and HIF-1α/VEGF expression via STAT3.
    CONCLUSIONS: Based on the above findings, we conclude that apatinib inhibits HuCCT-1 and RBE cell proliferation, migration, and tumor angiogenesis by inhibiting the VEGFR2/STAT3/HIF-1α axis signaling pathway. Apatinib can be a promising drug for ICC-targeted molecular therapy.
    Keywords:  Angiogenesis; Apatinib; Hypoxia inducible factor 1 subunit alpha; Intrahepatic cholangiocarcinoma; Signal transducer and activator of transcription factor 3; Vascular endothelial growth factor receptor-2
    DOI:  https://doi.org/10.1159/000514410
  11. Blood. 2021 Aug 19. pii: blood.2021011010. [Epub ahead of print]
    Neutrophil HIF-1α stabilisation is augmented by mitochondrial ROS produced via the glycerol 3-phosphate shuttle.
    Joseph Alexander Willson, Simone Arienti, Pranvera Sadiku, Leila Reyes, Patricia Coelho, Tyler Morrison, Giulia Rinaldi, David H Dockrell, Moira K B Whyte, Sarah R Walmsley.
      Neutrophils are predominantly glycolytic cells that derive little ATP from oxidative phosphorylation; however, they possess an extensive mitochondrial network and maintain a mitochondrial membrane potential. Although studies have shown neutrophils need their mitochondria to undergo apoptosis and regulate NETosis, the metabolic role of the respiratory chain in these highly glycolytic cells is still unclear. Recent studies have expanded on the role of reactive oxygen species (ROS) released from the mitochondria as intracellular signalling molecules. Our study shows that neutrophils can use their mitochondria to generate ROS and that mitochondrial ROS release is increased in hypoxic conditions. This is needed for the stabilisation of a high level of the critical hypoxic response factor and pro-survival protein HIF-1α in hypoxia. Further, we demonstrate that neutrophils use the glycerol 3-phosphate pathway as a way of directly regulating mitochondrial function through glycolysis, specifically to maintain polarised mitochondria and produce ROS. This illustrates an additional pathway by which neutrophils can regulate HIF-1α stability and will therefore be of important consideration when looking for treatments of chronic inflammatory conditions where HIF-1α activation and neutrophil persistence at the site of inflammation are linked to disease severity.
    DOI:  https://doi.org/10.1182/blood.2021011010
  12. Allergy. 2021 Aug 14.
    Activation of the mTOR/HIF-1α/VEGF axis promotes M1 macrophage polarization in non-eosCRSwNP.
    Bing Zhong, Jintao Du, Feng Liu, Yafeng Liu, Shixi Liu, Lifeng Xie, Deyun Wang, Luo Ba.
      
    Keywords:  Hypoxia-induced factor-1α; chronic rhinosinusitis with nasal polyps; macrophage; mammalian target of rapamycin; vascular endothelial growth factor
    DOI:  https://doi.org/10.1111/all.15050
  13. Front Oncol. 2021 ;11 700407
    Targeting Hypoxia: Hypoxia-Activated Prodrugs in Cancer Therapy.
    Yue Li, Long Zhao, Xiao-Feng Li.
      Hypoxia is an important characteristic of most solid malignancies, and is closely related to tumor prognosis and therapeutic resistance. Hypoxia is one of the most important factors associated with resistance to conventional radiotherapy and chemotherapy. Therapies targeting tumor hypoxia have attracted considerable attention. Hypoxia-activated prodrugs (HAPs) are bioreductive drugs that are selectively activated under hypoxic conditions and that can accurately target the hypoxic regions of solid tumors. Both single-agent and combined use with other drugs have shown promising antitumor effects. In this review, we discuss the mechanism of action and the current preclinical and clinical progress of several of the most widely used HAPs, summarize their existing problems and shortcomings, and discuss future research prospects.
    Keywords:  AQ4N; EO9; PR-104; SN30000; TH-302; hypoxia; hypoxia-activated prodrugs; tirapazamine
    DOI:  https://doi.org/10.3389/fonc.2021.700407
  14. Oncol Rep. 2021 Oct;pii: 215. [Epub ahead of print]46(4):
    Targeting USP22 with miR‑30‑5p to inhibit the hypoxia‑induced expression of PD‑L1 in lung adenocarcinoma cells.
    Xiaoyang Hua, Heng Chu, Chuanxiao Wang, Xuexin Shi, Ailin Wang, Zhe Zhang.
      Lung cancer is one of the most common forms of cancer and accounts for a significant proportion of all cancer‑related deaths. Lung adenocarcinoma (LUAD) accounts for approximately 40% of all cases of lung cancer. In recent years, new developments in both the diagnosis and treatment of LUAD have been achieved. Unfortunately, the prognosis remains poor for patients with malignant LUAD. Hypoxia is a common characteristic of solid tumors and induce the immune evasion by increasing the expression of programmed cell death‑ligand‑1 (PD‑L1) in the tumor. In this study, it was predicted that ubiquitin‑specific peptidase 22 (USP22) is the direct target of the microRNA (miR)‑30‑5p family, including miR‑30a‑5p, miR‑30b‑5p, miR‑30c‑5p, miR‑30d‑5p and miR‑30e‑5p. Furthermore, the binding of USP22 with the miR‑30‑5p family was confirmed by luciferase assay. In addition, it was demonstrated that targeting USP22 via the miR‑30‑5p family inhibited the induction of PD‑L1 expression in hypoxic conditions, thus preventing activated T cells from killing LUAD cells. Our results indicated that miR‑30a‑5p, miR‑30b‑5p, miR‑30c‑5p, miR‑30d‑5p and miR‑30e‑5p represent new targets for the treatment of LUAD.
    Keywords:  hypoxia; immune escape; lung adenocarcinoma; microRNA‑30‑5p; programmed cell death‑ligand 1; ubiquitin-specific peptidase 22
    DOI:  https://doi.org/10.3892/or.2021.8166
  15. Biomed Pharmacother. 2021 Aug 17. pii: S0753-3322(21)00812-X. [Epub ahead of print]142 112029
    Albendazole-loaded cubosomes interrupt the ERK1/2-HIF-1α-p300/CREB axis in mice intoxicated with diethylnitrosamine: A new paradigm in drug repurposing for the inhibition of hepatocellular carcinoma progression.
    Sameh Saber, Mohamed Nasr, Ahmed S Saad, Ahmed A E Mourad, Naglaa A Gobba, Ahmed Shata, Abdel-Moneim Hafez, Ramy N Elsergany, Heba I Elagamy, Eman El-Ahwany, Noha A Amin, Samuel Girgis, Yaser H A Elewa, Mohamed H Mahmoud, Gaber El-Saber Batiha, Magdy Abou El-Rous, Islam Kamal, Mohamed M Y Kaddah, Ahmed E Khodir.
      Hepatocellular carcinoma (HCC) is a leading cause of cancer related deaths worldwide. It was suggested that albendazole (ABZ) is a powerful inhibitor of several carcinoma types. However, the bioavailability of ABZ is very poor. Additionally, the mechanisms underlying the antitumor effects of ABZ may go beyond its tubulin-inhibiting activity. Therefore, we aimed to examine the effects of ABZ suspension (i.p. and p.o.) and ABZ-loaded cubosomes (LC) on the diethylnitrosamine-induced HCC in mice. ABZ-loaded nanoparticles exhibited a mean particle size of 48.17 ± 0.65 nm and entrapped 93.26 ± 2.48% of ABZ. The in vivo absorption study confirmed a two-fold improvement in the relative bioavailability compared with aqueous ABZ suspension. Furthermore, the oral administration of ABZ cubosomal dispersion demonstrated regression of tumor production rates that was comparable with ABZ (i.p.). ABZ relieved oxidative stress, improved liver function, and decreased necroinflammation score. The antiangiogenic activity was evident as ABZ effectively downregulated tissue expression of CD34, mRNA expression of CD309 and VEGF at the protein expression level. Besides, lower levels of MMP-9 and CXCR4 indicated antimetastatic activity. ABZ showed a considerable level of apoptotic activity as indicated by increased mRNA expression level of p53 and the increased Bax/BCL-2 ratio and active caspase-3. Additionally, Ki-67 expression levels were downregulated showing an antiproliferative potential. These protective effects contributed to increasing survival rate of diethylnitrosamine-treated mice. These effects found to be mediated via interrupting ERK1/2-HIF-1α-p300/CREB interactions. Therefore, our findings revealed that disrupting ERK1/2-HIF-1α-p300/CREB interplay might create a novel therapeutic target for the management of HCC.
    Keywords:  Albendazole; Angiogenesis; Cubosomes; Drug Repurposing in Cancer Therapy; ERK1/2-HIF-1α-p300/CREB; Hepatocellular carcinoma
    DOI:  https://doi.org/10.1016/j.biopha.2021.112029
  16. Cell Rep. 2021 Aug 17. pii: S2211-1247(21)00981-5. [Epub ahead of print]36(7): 109547
    Hypoxic preconditioning protects against ischemic kidney injury through the IDO1/kynurenine pathway.
    Rafael Torosyan, Shengping Huang, Prashant V Bommi, Ratnakar Tiwari, Si Young An, Michael Schonfeld, Ganeshkumar Rajendran, Matthew A Kavanaugh, Benjamin Gibbs, Agnieszka D Truax, Samuel Bohney, M Wade Calcutt, Evan W Kerr, Roberta Leonardi, Peng Gao, Navdeep S Chandel, Pinelopi P Kapitsinou.
      Prolonged cellular hypoxia leads to energetic failure and death. However, sublethal hypoxia can trigger an adaptive response called hypoxic preconditioning. While prolyl-hydroxylase (PHD) enzymes and hypoxia-inducible factors (HIFs) have been identified as key elements of oxygen-sensing machinery, the mechanisms by which hypoxic preconditioning protects against insults remain unclear. Here, we perform serum metabolomic profiling to assess alterations induced by two potent cytoprotective approaches, hypoxic preconditioning and pharmacologic PHD inhibition. We discover that both approaches increase serum kynurenine levels and enhance kynurenine biotransformation, leading to preservation of NAD+ in the post-ischemic kidney. Furthermore, we show that indoleamine 2,3-dioxygenase 1 (Ido1) deficiency abolishes the systemic increase of kynurenine and the subsequent renoprotection generated by hypoxic preconditioning and PHD inhibition. Importantly, exogenous administration of kynurenine restores the hypoxic preconditioning in the context of Ido1 deficiency. Collectively, our findings demonstrate a critical role of the IDO1-kynurenine axis in mediating hypoxic preconditioning.
    Keywords:  IDO1; NAD(+); PHDs; hypoxia; ischemia-reperfusion; kidney; kynurenic acid; kynurenine; preconditioning
    DOI:  https://doi.org/10.1016/j.celrep.2021.109547
  17. Microvasc Res. 2021 Aug 17. pii: S0026-2862(21)00102-3. [Epub ahead of print] 104232
    Hypoxia alters the expression of ACE2 and TMPRSS2 SARS-CoV-2 cell entry mediators in hCMEC/D3 cells.
    Guinever E Imperio, Phetcharawan Lye, Hafsah Mughis, Hirotaka Hamada, Enrrico Bloise, Stephen J Lye, Stephen G Matthews.
      The mechanisms by which the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) induces neurological complications remain to be elucidated. We aimed to identify possible effects of hypoxia on the expression of SARS-CoV-2 cell entry mediators, angiotensin-converting enzyme 2 (ACE2) receptor and transmembrane protease serine 2 (TMPRSS2) protein, in human brain endothelial cells, in vitro. hCMEC/D3 cells were exposed to different oxygen tensions: 20% (Control group), 8% or 2% O2 (Hypoxia groups). Cells were harvested 6-, 24- and 48 h following hypoxic challenge for assessment of mRNA and protein, using qPCR and Western Blot. The response of the brain endothelial cells to hypoxia was replicated using modular incubator chambers. We observed an acute increase (6 h, p < 0.05), followed by a longer-term decrease (48 h, p < 0.05) in ACE2 mRNA and protein expression, accompanied by reduced expression of TMPRSS2 protein levels (48 h, p < 0.05) under the more severe hypoxic condition (2% O2). No changes in levels of von Willebrand Factor (vWF - an endothelial cell damage marker) or interleukin 6 (IL-6 - a pro-inflammatory cytokine) mRNA were observed. We conclude that hypoxia regulates brain endothelial cell ACE2 and TMPRSS2 expression in vitro, which may indicate human brain endothelial susceptibility to SARS-CoV-2 infection and subsequent brain sequelae.
    Keywords:  Angiotensin-converting enzyme 2 (ACE2); Blood-brain barrier (BBB); Covid19; Human cerebral microvascular endothelial cells (hCMEC/D3); Hypoxia; SARS-CoV-2; Transmembrane protease serine 2 (TMPRSS2)
    DOI:  https://doi.org/10.1016/j.mvr.2021.104232
  18. J Exp Biol. 2021 Aug 17. pii: jeb.242634. [Epub ahead of print]
    Mitochondrial KATP channels stabilize intracellular Ca2+ during hypoxia in retinal horizontal cells of goldfish (Carassius auratus).
    Michael W Country, Michael G Jonz.
      Neurons of the retina require oxygen to survive. In hypoxia, neuronal ATP production is impaired, ATP-dependent ion pumping is reduced, transmembrane ion gradients are dysregulated, and [Ca2+]i increases enough to trigger excitotoxic cell death. Central neurons of the common goldfish (Carassius auratus) are hypoxia-tolerant, but little is known about how goldfish retinas withstand hypoxia. To study the cellular mechanisms of hypoxia tolerance, we isolated retinal interneurons (horizontal cells; HCs), and measured intracellular Ca2+ concentration ([Ca2+]i) with Fura-2. Goldfish HCs maintained [Ca2+]i throughout 1 h of hypoxia, whereas [Ca2+]i increased irreversibly in HCs of the hypoxia-sensitive rainbow trout (Oncorhynchus mykiss) with just 20 min of hypoxia. Our results suggest mitochondrial ATP-dependent K+ channels (mKATP) are necessary to stabilize [Ca2+]i throughout hypoxia. In goldfish HCs, [Ca2+]i increased when mKATP was blocked with glibenclamide or 5-HD, whereas an mKATP agonist (diazoxide) prevented [Ca2+]i from increasing in hypoxia in trout HCs. We showed that hypoxia protects goldfish HCs via mKATP channels. Glycolytic inhibition with 2-deoxyglucose increased [Ca2+]i, which was rescued by hypoxia in an mKATP-dependent manner. We found no evidence of plasmalemmal KATP channels in patch-clamp experiments. Instead, we confirmed the involvement of KATP in mitochondria with TMRE imaging, as hypoxia rapidly (<5 min) depolarized mitochondria in an mKATP-sensitive manner. We conclude that mKATP channels initiate a neuroprotective pathway in goldfish HCs to maintain [Ca2+]i and avoid excitotoxicity in hypoxia. This model provides novel insight into the cellular mechanisms of hypoxia tolerance in the retina.
    Keywords:  Calcium; Goldfish; Hypoxia; Mitochondria; Retina; mKATP
    DOI:  https://doi.org/10.1242/jeb.242634
  19. Cells Tissues Organs. 2021 Aug 19.
    Autophagy prevents osteocyte cell death under hypoxic conditions.
    Mai Kurihara, Yoshiki Mukudai, Hitoshi Watanabe, Mariko Asakura, Yuzo Abe, Asami Houri, Junichiro Chikuda, Toshikazu Shimane, Tatsuo Shirota.
      
    DOI:  https://doi.org/10.1159/000519086
  20. Blood. 2021 Aug 19. pii: blood.2021011043. [Epub ahead of print]
    Breakthrough Science: Hypoxia-Inducible Factors, Oxygen Sensing, and Disorders of Hematopoiesis.
    Gregg L Semenza.
      Hypoxia-inducible factors (HIF) were discovered as activators of erythropoietin gene transcription in response to reduced O2 availability. O2-dependent hydroxylation of HIFs on proline and asparagine residues regulates protein stability and transcription activity, respectively. Mutations in genes encoding components of the oxygen sensing pathway cause familial erythrocytosis. Several small molecule inhibitors of HIF prolyl hydroxylases are currently in clinical trials as erythropoiesis stimulating agents. HIFs are overexpressed in bone marrow neoplasms, and the development of HIF inhibitors may improve outcome in these disorders.
    DOI:  https://doi.org/10.1182/blood.2021011043
  21. FEBS Open Bio. 2021 Aug 17.
    Activation of ERK-Drp1 signaling promotes hypoxia-induced Aβ accumulation by upregulating mitochondrial fission and BACE1 activity.
    Yuan Yuan, Jingjiong Chen, Xuhua Ge, Jiangshan Deng, Xiaofeng Xu, Yuwu Zhao, Hongmei Wang.
      Hypoxia is a risk factor for Alzheimer's disease (AD). Besides, mitochondrial fission is increased in response to hypoxia. In this study, we sought to investigate whether hypoxia-induced mitochondrial fission plays a critical role in regulating amyloid-β (Aβ) production. Hypoxia significantly activated extracellular signal-regulated kinase (ERK), increased phosphorylation of dynamin-related protein 1 (Drp1) at serine 616 and decreased phosphorylation of Drp1 at serine 637. Importantly, hypoxia triggered mitochondrial dysfunction, elevated β-secretase 1 (BACE1) and γ-secretase activities, and promoted Aβ accumulation in HEK293 cells transfected with β-amyloid precursor protein (APP) plasmid harboring the Swedish and Indiana familial Alzheimers disease (FAD) mutations (APPSwe/Ind HEK293 cells). Then, we investigated whether the extracellular signal-regulated kinase (ERK) inhibitor PD325901 and Drp1 inhibitor mitochondrial division inhibitor 1 (Mdivi-1) would attenuate hypoxia-induced mitochondrial fission and Aβ generation in APPSwe/Ind HEK293 cells. PD325901 and Mdivi-1 inhibited phosphorylation of Drp1 at serine 616, resulting in reduced mitochondrial fission under hypoxia. Furthermore, hypoxia-induced mitochondrial dysfunction, BACE1 activation and Aβ accumulation were downregulated by PD325901 and Mdivi-1. Our data demonstrate that hypoxia induces mitochondrial fission, impairs mitochondrial function and facilitates Aβ generation. The ERK-Drp1 signaling pathway is partly involved in the hypoxia-induced Aβ generation by regulating mitochondrial fission and BACE1 activity. Therefore, inhibition of hypoxia-induced mitochondrial fission may prevent or slow the progression of AD.
    Keywords:  Alzheimer’s disease; BACE1; ERK; Hypoxia; Mitochondrial fission
    DOI:  https://doi.org/10.1002/2211-5463.13273
  22. Am J Med Genet A. 2021 Sep;185(9): 2801-2808
    Hypoxia: A teratogen underlying a range of congenital disruptions, dysplasias, and malformations.
    Aaron P Adam, Kurlen S E Payton, Pedro A Sanchez-Lara, Margaret P Adam, Ghayda M Mirzaa.
      In this review, we explore evidence that hypoxia in the developing human fetus can lead not only to the more commonly accepted disruptive-type defects, but also patterns of anomalies that suggest that hypoxia can exert a more classic teratogenic effect, using the brain as one example. We review neuropathology in the context of intrauterine hypoxia, particularly as it relates to carbon monoxide poisoning, in utero strokes, and homozygous alpha-thalassemia. In general, the associated brain injuries resemble those seen with other causes of hypoxic-ischemic injury. Fetal strokes during development usually lead to loss of brain tissue in areas that do not follow a typical embryologic pattern, and therefore are considered disruptions. However, there is also evidence that fetal brain ischemia can cause more classically recognized patterns of abnormal embryonic neuronal migration and organization such as polymicrogyria, cortical dysplasia, or dysgenesis, including select types of focal cortical dysplasia. This study summarizes available literature and evidence to raise clinicians' awareness regarding the association between hypoxia and congenital anomalies, including brain malformations.
    Keywords:  brain malformation; carbon monoxide poisoning; hypoxia; stroke; teratogen
    DOI:  https://doi.org/10.1002/ajmg.a.62235
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