• 한국해양바이오학회지
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• 제7권2호
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• pp.35-41
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• 2015

Whales are marine mammals that are fully adapted to aquatic environment. Whales breathe by lungs so they require adaptive system to low oxygen concentration (hypoxia) while deep and prolonged diving. However, the study for the molecular mechanism underlying cetacean adaptation to hypoxia has been limited. Hypoxia-inducible factor (HIF) is the central transcription factor that regulates hypoxia-related gene expression. Here we identified HIF-binding sites in whale genome by phylogenetic footprinting and analyzed HIF-target genes to understand how whales cope with hypoxia. By comparison with the HIF-target genes of terrestrial mammals, it was suggested that whales may retain unique adaptation mechanisms to hypoxia.

• International Journal of Oral Biology
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• 제40권1호
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• pp.19-25
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• 2015

Osteocytes may function as mechanotransducers by regulating local osteoclastogenesis. Reduced availability of oxygen, i.e. hypoxia, could occur during disuse, bone development, and fracture. Receptor activator of nuclear factor-${\kappa}B$ ligand (RANKL) is an osteoblast/stromal cell derived essential factor for osteoclastogenesis. The hypoxia induced osteoclastogenesis via increased RANKL expression in osteoblasts was demonstrated. Hypoxic regulation of gene expression generally involves activation of the hypoxia-inducible factor (HIF) transcription pathway. In the present study, we investigated whether hypoxia regulates RANKL expression in murine osteocytes and HIF-$1{\alpha}$ mediates hypoxia-induced RANKL expression by transactivating RANKL promoter, to elucidate the role of osteocyte in osteoclastogenesis in the context of hypoxic condition. The expression levels of RANKL mRNA and protein, as well as hypoxia inducible factor-$1{\alpha}$ (HIF-$1{\alpha}$) protein, were significantly increased in hypoxic condition in MLO-Y4s. Constitutively active HIF-$1{\alpha}$ alone significantly increased the levels of RANKL expression in MLO-Y4s under normoxic conditions, whereas dominant negative HIF-$1{\alpha}$ blocked hypoxia-induced RANKL expression. To further explore to find if HIF-$1{\alpha}$ directly regulates RANKL transcription, a luciferase reporter assay was conducted. Hypoxia significantly increased RANKL promoter activity, whereas mutations of putative HIF-$1{\alpha}$ binding elements in RANKL promoter prevented this hypoxia-induced RANKL promoter activity in MLO-Y4s. These results suggest that HIF-$1{\alpha}$ mediates hypoxia-induced up-regulation of RANKL expression, and that in osteocytes of mechanically unloaded bone, hypoxia enhances osteoclastogenesis, at least in part, via an increased RANKL expression in osteocytes.

• 한국수산과학회지
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• 제46권1호
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• pp.70-76
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• 2013

Some fish live in aquatic environments with low or temporally changing $O_2$ availability. Variation in dissolved oxygen (DO) levels requires behavioral, physiological, and biochemical adaptations to ensure the uptake of sufficient $O_2$. Several species are relatively well adapted to tolerate low $O_2$ partial pressures (hypoxia). The medaka (Oryzias dancena ) is an important model organism for biomedical research that shows remarkable tolerance to hypoxia. We investigated the regulation and role of hypoxia-inducible factor-1 (HIF-$1{\alpha}$) as a general hypoxia-response gene and stanniocalcin-2 (STC2), which is one of the genes regulated by HIF-$1{\alpha}$ in mammals under hypoxia. We subjected adult male medaka to the following three acute hypoxia regimes: 1, 24, and 72 h at DO = $1.8{\pm}0.5$ ppm. The changes in STC2 and HIF-$1{\alpha}$ mRNA were monitored using quantitative real-time reverse-transcription PCR. We found strong upregulation of HIF-$1{\alpha}$ mRNA in the livers of fish exposed to hypoxia. Hypoxia rapidly upregulated STC-2 mRNA expression in muscle, but not in the brain, gills, liver, or intestine. Therefore, unlike in mammals, hypoxia might regulate O. dancena STC-2 expression in an HIF-$1{\alpha}$-independent manner.

• 약학회지
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• 제54권2호
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• pp.102-105
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• 2010

Our previous results showed that hypoxia inducible factor-1 (HIF-1) activated estrogen receptor (ER) in the absence of ligand. In this study, we have studied the effect ER overexpression on the activation of HIF-1. ER overexpression induced transcription activation of hypoxia response element driven luciferase and vascular endothelial growth factor. As a negative control, the effect of ER on androgen receptor response element was used. Our result indicate that the two ER$\alpha$ and HIF-1 signaling pathways shares part of the activation pathway.

• Molecules and Cells
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• 제37권9호
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• pp.637-643
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• 2014

Wound healing is a complex multi-step process that requires spatial and temporal orchestration of cellular and non-cellular components. Hypoxia is one of the prominent microenvironmental factors in tissue injury and wound healing. Hypoxic responses, mainly mediated by a master transcription factor of oxygen homeostasis, hypoxia-inducible factor-1 (HIF-1), have been shown to be critically involved in virtually all processes of wound healing and remodeling. Yet, mechanisms underlying hypoxic regulation of wound healing are still poorly understood. Better understanding of how the wound healing process is regulated by the hypoxic microenvironment and HIF-1 signaling pathway will provide insight into the development of a novel therapeutic strategy for impaired wound healing conditions such as diabetic wound and fibrosis. In this review, we will discuss recent studies illuminating the roles of HIF-1 in physiologic and pathologic wound repair and further, the therapeutic potentials of HIF-1 stabilization or inhibition.

• Biomolecules & Therapeutics
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• 제28권1호
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• pp.45-57
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• 2020

In the neurovascular unit, the neuronal and vascular systems communicate with each other. O₂ and nutrients, reaching endothelial cells (ECs) through the blood stream, spread into neighboring cells, such as neural stem cells, and neurons. The proper function of neural circuits in adults requires sufficient O₂ and glucose for their metabolic demands through angiogenesis. In a central nervous system (CNS) injury, such as glioma, Parkinson's disease, and Alzheimer's disease, damaged ECs can contribute to tissue hypoxia and to the consequent disruption of neuronal functions and accelerated neurodegeneration. This review discusses the current evidence regarding the contribution of oxygen deprivation to CNS injury, with an emphasis on hypoxia-inducible factor (HIF)-mediated pathways and Notch signaling. Additionally, it focuses on adult neurological functions and angiogenesis, as well as pathological conditions in the CNS. Furthermore, the functional interplay between HIFs and Notch is demonstrated in pathophysiological conditions.

• Bulletin of the Korean Chemical Society
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• 제31권7호
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• pp.2039-2042
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• 2010

• Bulletin of the Korean Chemical Society
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• 제31권11호
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• pp.3441-3444
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• 2010

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 2001년도 추계학술대회 및 정기총회
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• pp.100-100
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• 2001

Hypoxia is a pathophysiological condition that occurs during injury, ischemia, and stroke. Hypoxic stress induces the expression of genes associated with increased energy flux, including the glucose transporters Glutl and Glut3, several glycolytic enzymes, nitric oxide synthase, erythropoietin and vascular endothelial growth factor. Induction of these genes is mediated by a common basic helix-loop-helix PAS transcription complex, the hypoxia-inducible factor-l${\alpha}$ (HIF-1${\alpha}$)/ aryl hydrocarbon receptor nuclear translocator (ARNT). Insulin plays a central role in regulating metabolic pathways associated with energy storage and utilization. It triggers the conversion of glucose into glycogen and triglycerides and inhibits gluconeogenesis. Insulin also induced hypoxia-induced genes. However the underlying mechanism is unestablished. Here, we study the possibility that transcription factor HIF-1${\alpha}$ is involved in insulin-induced gene expression. We investigate the mechanism that regulates hypoxia-inducible gene expression In response to insulin We demonstrate that insulin increases the transcription of hypoxia- inducible gene. Insulin-induced transcription is not detected in Arnt defective cell lines. Under hypoxic condition, HIF- l${\alpha}$ stabilizes but does not under insulin treatment. Insulin-induced gene expression is inhibited by presence of PI-3 kinase inhibitor and Akt dominant negative mutant, whereas hypoxia-induced gene expression is not. ROS inhibitor differently affects insulin-induced gene expressions and hypoxia-induced gene expressions. Our results demonstrate that insulin also regulates hypoxia-inducible gene expression and this process is dependent on Arnt. However we suggest HIF-l${\alpha}$ is not involved insulin-induced gene expression and insulin- and hypoxia- induces same target genes via different signaling pathway.

• Asian Pacific Journal of Cancer Prevention
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• 제14권8호
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• pp.4853-4858
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• 2013

Objectives: To investigate whether hypoxia has an effect on regulation of multidrug resistance (MDR) to chemotherapeutic drugs in laryngeal carcinoma cells and explore the role of hypoxia-inducible factor-$1{\alpha}$ (HIF-$1{\alpha}$). Methods: Laryngeal cancer cells were cultured under normoxic and hypoxic conditions. The sensitivity of the cells to multiple drugs and levels of apoptosis induced by paclitaxel were determined by MTT assay and annexin-V/propidium iodide staining analysis, respectively. HIF-$1{\alpha}$ expression was blocked by RNA interference. The expression of HIF-$1{\alpha}$ gene was detected by real-time quantitative RT-PCR and Western blotting. The value of fluorescence intensity of intracellular adriamycin accumulation and retention in cells was evaluated by flow cytometry. Results: The sensitivity to multiple chemotherapy agents and induction of apoptosis by paclitaxel could be reduced by hypoxia (P<0.05). A the same time, the adriamycin releasing index of cells was increased (P<0.05). However, resistance acquisition subject to hypoxia in vitro was suppressed by down-regulating HIF-$1{\alpha}$ expression. Conclusion: HIF-$1{\alpha}$ could be considered as a key regulator for mediating hypoxia-induced MDR in laryngeal cancer cells via inhibition of drug-induced apoptosis and decrease in intracellular drug accumulation.