scholarly journals Regeneration in Spinal Disease: Therapeutic Role of Hypoxia-Inducible Factor-1 Alpha in Regeneration of Degenerative Intervertebral Disc

2021 ◽  
Vol 22 (10) ◽  
pp. 5281
Author(s):  
Jin-Woo Kim ◽  
Neunghan Jeon ◽  
Dong-Eun Shin ◽  
So-Young Lee ◽  
Myongwhan Kim ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Structural Changes ◽  
Hypoxia Inducible Factor ◽  
Low Oxygen ◽  
Hypoxia Inducible Factor 1 ◽  
Metabolic Activities ◽  
Cartilaginous Endplate ◽  
Ivd Degeneration ◽  
Complex Joint

The intervertebral disc (IVD) is a complex joint structure comprising three primary components—namely, nucleus pulposus (NP), annulus fibrosus (AF), and cartilaginous endplate (CEP). The IVD retrieves oxygen from the surrounding vertebral body through CEP by diffusion and likely generates ATP via anaerobic glycolysis. IVD degeneration is characterized by a cascade of cellular, compositional, structural changes. With advanced age, pronounced changes occur in the composition of the disc extracellular matrix (ECM). NP and AF cells in the IVD possess poor regenerative capacity compared with that of other tissues. Hypoxia-inducible factor (HIF) is a master transcription factor that initiates a coordinated cellular cascade in response to a low oxygen tension environment, including the regulation of numerous enzymes in response to hypoxia. HIF-1α is essential for NP development and homeostasis and is involved in various processes of IVD degeneration process, promotes ECM in NP, maintains the metabolic activities of NP, and regulates dystrophic mineralization of NP, as well as angiogenesis, autophagy, and apoptosis during IVD degeneration. HIF-1α may, therefore, represent a diagnostic tool for early IVD degeneration and a therapeutic target for inhibiting IVD degeneration.

scholarly journals Inhibition of aberrant Hif1α activation delays intervertebral disc degeneration in adult mice

Bone Research ◽  
2022 ◽  
Vol 10 (1) ◽  
Author(s):  
Zuqiang Wang ◽  
Hangang Chen ◽  
Qiaoyan Tan ◽  
Junlan Huang ◽  
Siru Zhou ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Genetic Ablation ◽  
Adult Mice ◽  
Conditional Deletion ◽  
Current Therapies ◽  
Cartilaginous Endplate ◽  
Ivd Degeneration ◽  
Deficient Mice

AbstractThe intervertebral disc (IVD) is the largest avascular tissue. Hypoxia-inducible factors (HIFs) play essential roles in regulating cellular adaptation in the IVD under physiological conditions. Disc degeneration disease (DDD) is one of the leading causes of disability, and current therapies are ineffective. This study sought to explore the role of HIFs in DDD pathogenesis in mice. The findings of this study showed that among HIF family members, Hif1α was significantly upregulated in cartilaginous endplate (EP) and annulus fibrosus (AF) tissues from human DDD patients and two mouse models of DDD compared with controls. Conditional deletion of the E3 ubiquitin ligase Vhl in EP and AF tissues of adult mice resulted in upregulated Hif1α expression and age-dependent IVD degeneration. Aberrant Hif1α activation enhanced glycolytic metabolism and suppressed mitochondrial function. On the other hand, genetic ablation of the Hif1α gene delayed DDD pathogenesis in Vhl-deficient mice. Administration of 2-methoxyestradiol (2ME2), a selective Hif1α inhibitor, attenuated experimental IVD degeneration in mice. The findings of this study show that aberrant Hif1α activation in EP and AF tissues induces pathological changes in DDD, implying that inhibition of aberrant Hif1α activity is a potential therapeutic strategy for DDD.

scholarly journals The Role of Hypoxia-Inducible Factor 1 in Mild Cognitive Impairment

2016 ◽  
Vol 37 (6) ◽  
pp. 969-977 ◽  
Author(s):  
Osigbemhe Iyalomhe ◽  
Sabina Swierczek ◽  
Ngozi Enwerem ◽  
Yuanxiu Chen ◽  
Monica O. Adedeji ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1

scholarly journals Hypoxia-inducible factor–1 and associated upstream and downstream proteins in the pathophysiology and management of glioblastoma

2014 ◽  
Vol 37 (6) ◽  
pp. E8 ◽  
Author(s):  
Matthew Womeldorff ◽  
David Gillespie ◽  
Randy L. Jensen
Keyword(s):  
Cellular Response ◽  
Treatment Options ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1 ◽  
Poor Patient ◽  
Growth Development ◽  
The Relationship ◽  
Insight Into ◽  
Upstream Regulators

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with an exceptionally poor patient outcome despite aggressive therapy including surgery, radiation, and chemotherapy. This aggressive phenotype may be associated with intratumoral hypoxia, which probably plays a key role in GBM tumor growth, development, and angiogenesis. A key regulator of cellular response to hypoxia is the protein hypoxia-inducible factor–1 (HIF-1). An examination of upstream hypoxic and nonhypoxic regulation of HIF-1 as well as a review of the downstream HIF-1–regulated proteins may provide further insight into the role of this transcription factor in GBM pathophysiology. Recent insights into upstream regulators that intimately interact with HIF-1 could provide potential therapeutic targets for treatment of this tumor. The same is potentially true for HIF-1–mediated pathways of glycolysis-, angiogenesis-, and invasion-promoting proteins. Thus, an understanding of the relationship between HIF-1, its upstream protein regulators, and its downstream transcribed genes in GBM pathogenesis could provide future treatment options for the care of patients with these tumors.

scholarly journals Normoxic Tumour Extracellular Vesicles Modulate the Response of Hypoxic Cancer and Stromal Cells to Doxorubicin In Vitro

2020 ◽  
Vol 21 (17) ◽  
pp. 5951
Author(s):  
Laura Patras ◽  
Marcel H. A. M. Fens ◽  
Pieter Vader ◽  
Arjan Barendrecht ◽  
Alina Sesarman ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Extracellular Vesicles ◽  
Hypoxia Inducible Factor ◽  
B Cell Lymphoma ◽  
Tumour Microenvironment ◽  
Hypoxia Inducible Factor 1 ◽  
Apoptotic Protein ◽  
Donor Cells

Extracellular vesicles (EV) secreted in the tumour microenvironment (TME) are emerging as major antagonists of anticancer therapies by orchestrating the therapeutic outcome through altering the behaviour of recipient cells. Recent evidence suggested that chemotherapeutic drugs could be responsible for the EV-mediated tumour–stroma crosstalk associated with cancer cell drug resistance. Here, we investigated the capacity of tumour EV (TEV) secreted by normoxic and hypoxic (1% oxygen) C26 cancer cells after doxorubicin (DOX) treatment to alter the response of naïve C26 cells and RAW 264.7 macrophages to DOX. We observed that C26 cells were less responsive to DOX treatment under normoxia compared to hypoxia, and a minimally cytotoxic DOX concentration that mounted distinct effects on cell viability was selected for TEV harvesting. Homotypic and heterotypic pretreatment of naïve hypoxic cancer and macrophage-like cells with normoxic DOX-elicited TEV rendered these cells slightly less responsive to DOX treatment. The observed effects were associated with strong hypoxia-inducible factor 1-alpha (HIF-1α) induction and B-cell lymphoma–extra-large anti-apoptotic protein (Bcl-xL)-mediated anti-apoptotic response in normoxic DOX-treated TEV donor cells, being also tightly connected to the DOX-TEV-mediated HIF-1α induction, as well as Bcl-xL levels increasing in recipient cells. Altogether, our results could open new perspectives for investigating the role of chemotherapy-elicited TEV in the colorectal cancer TME and their modulatory actions on promoting drug resistance.

The role of hypoxia inducible factor-1 in cell metabolism – a possible target in cancer therapy

2006 ◽  
Vol 10 (4) ◽  
pp. 583-599 ◽  
Author(s):  
Rachida S Bel Aiba ◽  
Elitsa Y Dimova ◽  
Agnes Görlach ◽  
Thomas Kietzmann
Keyword(s):  
Cancer Therapy ◽  
Cell Metabolism ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1

scholarly journals 55th Bowditch Lecture: Effects of chronic hypoxia on the pulmonary circulation: Role of HIF-1

2012 ◽  
Vol 113 (9) ◽  
pp. 1343-1352 ◽  
Author(s):  
Larissa A. Shimoda
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Circulation ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1 ◽  
Pulmonary Arterial ◽  
Expression And Activity

When exposed to chronic hypoxia (CH), the pulmonary circulation responds with enhanced contraction and vascular remodeling, resulting in elevated pulmonary arterial pressures. Our work has identified CH-induced alterations in the expression and activity of several ion channels and transporters in pulmonary vascular smooth muscle that contribute to the development of hypoxic pulmonary hypertension and uncovered a critical role for the transcription factor hypoxia-inducible factor-1 (HIF-1) in mediating these responses. Current work is focused on the regulation of HIF in the chronically hypoxic lung and evaluation of the potential for pharmacological inhibitors of HIF to prevent, reverse, or slow the progression of pulmonary hypertension.

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