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Biomolecules
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State-of-the-Art Targeting Hypoxia Signaling Pathway to Treat Human Diseases
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State-of-the-Art Targeting Hypoxia Signaling Pathway to Treat Human Diseases

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (1 October 2023) | Viewed by 4006

Special Issue Editors

Dr. Ruoli Chen

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Guest Editor
School of Pharmacy and Bioengineering, Keele University, Keele ST5 5BJ, UK
Interests: hypoxia inducible factors; stroke; neuroprotection; blood brain barrier; Vascular dementia; neuroinflammation; cerebrospinal fluid
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Nicholas R. Forsyth

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Guest Editor
Guy Hilton Research Centre, Keele University, Thornburrow Drive, Hartshill, Stoke-on-Trent ST4 7QB, UK
Interests: regenerative medicine; tissue engineering; hypoxia; adult stem cells; pluripotent stem cells; tendon; cartilage; respiratory system
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Christopher J. Schofield

E-Mail Website
Guest Editor
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK
Interests: synthetic chemistry; 2-oxoglutarate oxygenase; oxygen sensing; hypoxia; epigenetics; demethylases; DNA repair; obesity; antibiotic biosynthesis; flavonoid and ethylene biosynthesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Hypoxia is a state in which oxygen is not available in sufficient amounts at the tissue level to maintain adequate homeostasis. Hypoxia is mainly related to pathological situations, but it can also be a part of normal physiology, and it occurs in extreme environments, e.g., high altitude. Hypoxia activates the hypoxia signaling pathway, which is predominately governed by hypoxia-inducible factors (HIFs). HIFs are transcription factors and are stabilized at low O2 tension (hypoxia). HIF stabilization upregulates hundreds of human genes, which are related to metabolism, erythropoietin, angiogenesis, and cell proliferation and survival. Paradoxically, HIFs also upregulate several apoptotic genes. The HIF signaling pathway seems to be one of the body compensatory mechanisms, but excessive HIF stabilization may damage the tissue function, e.g., disrupt blood–brain barrier integrity. The proper modulation of the HIF signaling pathway altering gene expression in diseases can thus be used to treat diseases, e.g., anemia, ischemic diseases, and cancer. In this Special Issue, several of these aspects in hypoxia signaling modulation will be highlighted. We invite the submission of research papers that will consolidate our understanding in this area. Contributions to this Special Issue are invited in the format of reviews, research articles, communications, and concept papers.

Areas to be covered in this Special Issue may include, but are not limited to:

  • Hypoxia signaling in normal function;
  • Hypoxia signaling in diseases;
  • Hypoxia signaling in therapeutic targets;
  • The development of hypoxia mimetic agents for clinical uses;
  • The development of HIF inhibitors for clinical uses.

Dr. Ruoli Chen
Prof. Dr. Nicholas R. Forsyth
Prof. Dr. Christopher J. Schofield
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • hypoxia
  • hypoxia inducible factor
  • stabilizer
  • inhibitor

Published Papers (3 papers)

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Research

18 pages, 3292 KiB  
Article
TERT Promoter Methylation Is Oxygen-Sensitive and Regulates Telomerase Activity
by Fatma Dogan and Nicholas R. Forsyth
Biomolecules 2024, 14(1), 131; https://doi.org/10.3390/biom14010131 - 19 Jan 2024
Viewed by 1142
Abstract
Telomere repeats protect linear chromosomes from degradation, and telomerase has a prominent role in their maintenance. Telomerase has telomere-independent effects on cell proliferation, DNA replication, differentiation, and tumorigenesis. TERT (telomerase reverse transcriptase enzyme), the catalytic subunit of telomerase, is required for enzyme activity. [...] Read more.
Telomere repeats protect linear chromosomes from degradation, and telomerase has a prominent role in their maintenance. Telomerase has telomere-independent effects on cell proliferation, DNA replication, differentiation, and tumorigenesis. TERT (telomerase reverse transcriptase enzyme), the catalytic subunit of telomerase, is required for enzyme activity. TERT promoter mutation and methylation are strongly associated with increased telomerase activation in cancer cells. TERT levels and telomerase activity are downregulated in stem cells during differentiation. The link between differentiation and telomerase can provide a valuable tool for the study of the epigenetic regulation of TERT. Oxygen levels can affect cellular behaviors including proliferation, metabolic activity, stemness, and differentiation. The role of oxygen in driving TERT promoter modifications in embryonic stem cells (ESCs) is poorly understood. We adopted a monolayer ESC differentiation model to explore the role of physiological oxygen (physoxia) in the epigenetic regulation of telomerase and TERT. We further hypothesized that DNMTs played a role in physoxia-driven epigenetic modification. ESCs were cultured in either air or a 2% O2 environment. Physoxia culture increased the proliferation rate and stemness of the ESCs and induced a slower onset of differentiation than in ambient air. As anticipated, downregulated TERT expression correlated with reduced telomerase activity during differentiation. Consistent with the slower onset of differentiation in physoxia, the TERT expression and telomerase activity were elevated in comparison to the air-oxygen-cultured ESCs. The TERT promoter methylation levels increased during differentiation in ambient air to a greater extent than in physoxia. The chemical inhibition of DNMT3B reduced TERT promoter methylation and was associated with increased TERT gene and telomerase activity during differentiation. DNMT3B ChIP (Chromatin immunoprecipitation) demonstrated that downregulated TERT expression and increased proximal promoter methylation were associated with DNMT3B promoter binding. In conclusion, we have demonstrated that DNMT3B directly associates with TERT promoter, is associated with differentiation-linked TERT downregulation, and displays oxygen sensitivity. Taken together, these findings help identify novel aspects of telomerase regulation that may play a role in better understanding developmental regulation and potential targets for therapeutic intervention. Full article
(This article belongs to the Special Issue State-of-the-Art Targeting Hypoxia Signaling Pathway to Treat Human Diseases)
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16 pages, 2021 KiB  
Article
NanoFIRE: A NanoLuciferase and Fluorescent Integrated Reporter Element for Robust and Sensitive Investigation of HIF and Other Signalling Pathways
by Alison E. Roennfeldt, Timothy P. Allen, Brooke N. Trowbridge, Michael R. Beard, Murray L. Whitelaw, Darryl L. Russell, David C. Bersten and Daniel J. Peet
Biomolecules 2023, 13(10), 1545; https://doi.org/10.3390/biom13101545 - 19 Oct 2023
Viewed by 1460
Abstract
The Hypoxia Inducible Factor (HIF) transcription factors are imperative for cell adaption to low oxygen conditions and development; however, they also contribute to ischaemic disease and cancer. To identify novel genetic regulators which target the HIF pathway or small molecules for therapeutic use, [...] Read more.
The Hypoxia Inducible Factor (HIF) transcription factors are imperative for cell adaption to low oxygen conditions and development; however, they also contribute to ischaemic disease and cancer. To identify novel genetic regulators which target the HIF pathway or small molecules for therapeutic use, cell-based reporter systems are commonly used. Here, we present a new, highly sensitive and versatile reporter system, NanoFIRE: a NanoLuciferase and Fluorescent Integrated Reporter Element. Under the control of a Hypoxic Response Element (HRE-NanoFIRE), this system is a robust sensor of HIF activity within cells and potently responds to both hypoxia and chemical inducers of the HIF pathway in a highly reproducible and sensitive manner, consistently achieving 20 to 150-fold induction across different cell types and a Z′ score > 0.5. We demonstrate that the NanoFIRE system is adaptable via substitution of the response element controlling NanoLuciferase and show that it can report on the activity of the transcriptional regulator Factor Inhibiting HIF, and an unrelated transcription factor, the Progesterone Receptor. Furthermore, the lentivirus-mediated stable integration of NanoFIRE highlights the versatility of this system across a wide range of cell types, including primary cells. Together, these findings demonstrate that NanoFIRE is a robust reporter system for the investigation of HIF and other transcription factor-mediated signalling pathways in cells, with applications in high throughput screening for the identification of novel small molecule and genetic regulators. Full article
(This article belongs to the Special Issue State-of-the-Art Targeting Hypoxia Signaling Pathway to Treat Human Diseases)
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20 pages, 25287 KiB  
Article
5′-tRF-19-Q1Q89PJZ Suppresses the Proliferation and Metastasis of Pancreatic Cancer Cells via Regulating Hexokinase 1-Mediated Glycolysis
by Wenpeng Cao, Zhirui Zeng and Shan Lei
Biomolecules 2023, 13(10), 1513; https://doi.org/10.3390/biom13101513 - 12 Oct 2023
Viewed by 1056
Abstract
tRNA-derived small RNAs (tDRs) are dysregulated in several diseases, including pancreatic cancer (PC). However, only a limited number of tDRs involved in PC progression are known. Herein, a novel tDR, 5′-tRF-19-Q1Q89PJZ (tRF-19-Q1Q89PJZ), was verified in PC plasma using RNA and Sanger sequencing. tRF-19-Q1Q89PJZ [...] Read more.
tRNA-derived small RNAs (tDRs) are dysregulated in several diseases, including pancreatic cancer (PC). However, only a limited number of tDRs involved in PC progression are known. Herein, a novel tDR, 5′-tRF-19-Q1Q89PJZ (tRF-19-Q1Q89PJZ), was verified in PC plasma using RNA and Sanger sequencing. tRF-19-Q1Q89PJZ was downregulated in PC tissues and plasma, which was related to advanced clinical characteristics and poor prognosis. tRF-19-Q1Q89PJZ overexpression inhibited the malignant activity of PC cells in vitro, while tRF-19-Q1Q89PJZ inhibition produced an opposite effect. The differentially expressed genes induced by tRF-19-Q1Q89PJZ overexpression were enriched in “pathways in cancer” and “glycolysis”. Mechanistically, tRF-19-Q1Q89PJZ directly sponged hexokinase 1 (HK1) mRNA and inhibited its expression, thereby suppressing glycolysis in PC cells. HK1 restoration relieved the inhibitory effect of tRF-19-Q1Q89PJZ on glycolysis in PC cells and on their proliferation and mobility in vitro. tRF-19-Q1Q89PJZ upregulation inhibited PC cell proliferation and metastasis in vivo and suppressed HK1 expression in tumor tissues. Furthermore, tRF-19-Q1Q89PJZ expression was attenuated under hypoxia. Collectively, these findings indicate that tRF-19-Q1Q89PJZ suppresses the malignant activity of PC cells by regulating HK1-mediated glycolysis. Thus, tRF-19-Q1Q89PJZ may serve as a key target for PC therapy. Full article
(This article belongs to the Special Issue State-of-the-Art Targeting Hypoxia Signaling Pathway to Treat Human Diseases)
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