• The Korean Journal of Nuclear Medicine Technology
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• v.27 no.2
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• pp.83-93
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• 2023

Hypoxia indicates the condition of low oxygen levels in tissues. In oncology, hypoxia can induce cancer progression and metastasis, as well as cause resistance to cancer therapies. The detection of hypoxia by using molecular imaging, particularly, positron emission tomography (PET) has been extensively studied due to many advantages. Nitroimidazoles, the moieties that can be trapped in hypoxic tissues due to selective reduction, have been used to design and synthesize of hypoxia-targeting radiopharmaceuticals. This review provides a summary of synthetic routes towards ¹⁸F-labeled-nitroimidazole radiotracers for PET imaging of hypoxia.

• Proceedings of the Korean Society of Toxicology Conference
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• 2001.10a
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• pp.199-199
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• 2001

Both hypoxia and insulin induce same target genes including vascular endothelial growth factor (VEGF), glycolitic enzymes and glucose transporters. However these two signals eventually trigger quite different metabolic pathways. Hypoxia induces glycolysis for anaerobic ATP production, while insulin increase glycolysis for lipogenesis and energy storage. Hypoxia-induced gene expression is mediated by Hypoxia-inducible Factorl (HIF-1) that consists of HIF-1 $\alpha$ and $\beta$ subunit.(omitted)

• Proceedings of the Korean Society of Fisheries Technology Conference
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• 2001.10a
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• pp.265-266
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• 2001

Cardiovascular and respiratory responses of fish exposed to environmental hypoxia have on the subject of a number of investigations. Although relatively few species have been examined, generalized responses to ambient hypoxia include an elevation of blood pressure, increased systemic vascular resistance and bradycardia (Fritsche and Nilsson, 1990; Bushnell and Brill, 1991). The degree of bradycardia experienced by fish during hypoxia is highly variable and may depend upon the severity of the hypoxia and the rapidity with which it is imposed. (omitted)

• The Journal of Korean Medicine
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• v.23 no.1
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• pp.120-132
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• 2002

Objectives : The purpose of this investigation was to evaluate the effect of Goomicheongsim-won Extracts on E20 corticells and P7 cerebellar cells exposed to hypoxia, and the effect on neuronal protection by elimination of Rhinoceros unicornis L. and/or Orpiment $As_2S_3$. Methods : P7 cerebellar cells were grown in various concentrations of KM-A, KM-B, KM- C and KM-D. On 7 DIV (day in vitro), cells were exposed to hypoxia (98% $N_2/5%{;}CO_2,{\;}3{\;}hr,{\;}37^{\circ}C$) and normoxia, and then further incubated for 3 days. Neuronal viabilities were expressed as percentages of control. E20 cortical cells were grown in various concentrations of KM-A, KM-B, KM-C, and KM-D. On 7 DIV, cells were exposed to hypoxia and normoxia, and then further incubated for 3 and 7 days. Results : I. The effect of KM-A on neuronal protection was significantly increased P7 cerebellar granule cells and E20 cortical cells on normoxia and hypoxia. 2. The effect of KM-B on neuronal protection was increased P7 cerebellar granule cells on normoxia, but was significantly decreased P7 cerebellar granule cells on hypoxia. The effect of KM-B on neuronal protection was non-significantly increased E20 cortical cells on normoxia and hypoxia. 3. The effect of KM-C on neuronal protection was non-significantly increased P7 cerebellar granule cells on normoxia and hypoxia and was decreased (p=0.058) on hyperconcentration of the extracts in normoxia. The effect of KM-C on neuronal protection was significantly increased P7 cerebellar granule cells and E20 cortical cells on normoxia and hypoxia (10 DIV), and the effect was E20 cortical cells on normoxia (14 DIV), non-significantly increased E20 cortical cells on hypoxia (14DIV). 4. The effect of KM-D on neuronal protection was increased P7 cerebellar granule cells on normoxia but was not on hyperconcentration of the extracts, was significantly decreased on hyperconcentration of the extracts in hypoxia. The effect of KM-D on neuronal protection was significantly increased E20 cortical cells on normoxia and was significantly increased E20 cortical cells increased on hypoxia (10 DIV). Conclusions : Goomicheongsim-won extracts had applicable effect on E20 corticells and P7 cerebellar cells exposed to hypoxia. The effect on neuronal protection by elimination of Rhinoceros unicornis L. and/or Orpiment $As_2S_3$ was changed.

• Biomolecules & Therapeutics
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• v.16 no.3
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• pp.249-254
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• 2008

The present study was undertaken to determine whether hypoxia influences on the agonist-induced vascular smooth muscle contraction and, if so, to investigate the related mechanism. The measurement of isometric contractions using a computerized data acquisition system was combined with molecular experiments. Hypoxia significantly inhibited fluoride-induced contraction regardless of endothelial function, but there was no relaxation on thromboxane $A_2$ mimetic U-46619-induced contraction suggesting that other pathway such as $Ca^{2+}$ entry or thin filament regulation was not affected. In addition, hypoxia significantly decreased fluoride-induced increase of phospho-myosin-targeting subunit of myosin light chain phosphatase (pMYPT1). Interestingly, hypoxia didn't inhibit significantly phenylephrine-induced contraction suggesting that myosin light chain kinase (MLCK) activity or thin filament regulation is less important on the hypoxia-induced vasorelaxation in the denuded muscle than Rho-kinase activity. In conclusion, this study provides the evidence and possible related mechanism concerning the vasodilation effect of hypoxia on the agonist-specific contraction in rat aortic rings regardless of endothelial function.

• Journal of Oriental Neuropsychiatry
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• v.16 no.2
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• pp.73-88
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• 2005

Object : This study was designed to asses the effect of Kunnuetang and herbs on Mouse neuroblastoma 2a cells damaged by hypoxia-reoxygenation. Method : Mouse neuroblastoma 2a (N2a) cells were measured by MTT assay and LDH assay after 48h hypoxia and 6h reoxygenation. Mouse neuroblastoma 2a (N2a) cells were treated by Kunnuetang, Duchang and Daejo. Result : 1. Kunnuetang, was effective on LDH assay of hypoxia and reoxygenation. 2. Duchang and Daejo were generally effective on LDH assay of hypoxia and reoxygenation. 3. In MTT assay of hypoxia Kunnuetang was not effective. Duchung and Daejo were not generally effective on MTT assay, but in certain condition Herbs were effective. 4. In MTT assay of reoxygenation Kunnuetang and Daejo were not effective. But Duchung was effective in certain condition. Conclusion : The results suggest that Kunnuetang, Duchang and Daejo may have protective effect on vascular dementia and ad patient.

• Radiation Oncology Journal
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• v.34 no.4
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• pp.239-249
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• 2016

Tumor hypoxia, a common feature occurring in nearly all human solid tumors is a major contributing factor for failures of anticancer therapies. Because ionizing radiation depends heavily on the presence of molecular oxygen to produce cytotoxic effect, the negative impact of tumor hypoxia had long been recognized. In this review, we will highlight some of the past attempts to overcome tumor hypoxia including hypoxic radiosensitizers and hypoxia-selective cytotoxin. Although they were (still are) a very clever idea, they lacked clinical efficacy largely because of 'reoxygenation' phenomenon occurring in the conventional low dose hyperfractionation radiotherapy prevented proper activation of these compounds. Recent meta-analysis and imaging studies do however indicate that there may be a significant clinical benefit in lowering the locoregional failures by using these compounds. Latest technological advancement in radiotherapy has allowed to deliver high doses of radiation conformally to the tumor volume. Although this technology has brought superb clinical responses for many types of cancer, recent modeling studies have predicted that tumor hypoxia is even more serious because 'reoxygenation' is low thereby leaving a large portion of hypoxic tumor cells behind. Wouldn't it be then reasonable to combine hypoxic radiosensitizers and/or hypoxia-selective cytotoxin with the latest radiotherapy? We will provide some preclinical and clinical evidence to support this idea hoping to revamp an enthusiasm for hypoxic radiosensitizers or hypoxia-selective cytotoxins as an adjunct therapy for radiotherapy.

• Biomolecules & Therapeutics
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• v.20 no.3
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• pp.280-285
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• 2012

The developing embryo naturally experiences relatively low oxygen conditions in vivo. Under in vitro hypoxia, mouse embryonic stem cells (mESCs) lose their self-renewal activity and display an early differentiated morphology mediated by the hypoxia-inducible factor-$1{\alpha}$ (HIF-$1{\alpha}$). Previously, we demonstrated that histone deacetylase (HDAC) is activated by hypoxia and increases the protein stability and transcriptional activity of HIF-$1{\alpha}$ in many human cancer cells. Furthermore HDAC1 and 3 mediate the differentiation of mECSs and hematopoietic stem cells. However, the role of HDACs and their inhibitors in hypoxia-induced early differentiation of mESCs remains largely unknown. Here, we examined the effects of several histone deacetylase inhibitors (HDACIs) on the self-renewal properties of mESCs under hypoxia. Inhibition of HDAC under hypoxia effectively decreased the HIF-$1{\alpha}$ protein levels and substantially improved the expression of the LIF-specific receptor (LIFR) and phosphorylated-STAT3 in mESCs. In particular, valproic acid (VPA), a pan HDACI, showed dramatic changes in HIF-$1{\alpha}$ protein levels and LIFR protein expression levels compared to other HDACIs, including sodium butyrate (SB), trichostatin A (TSA), and apicidin (AP). Importantly, our RT-PCR data and alkaline phosphatase assays indicate that VPA helps to maintain the self-renewal activity of mESCs under hypoxia. Taken together, these results suggest that VPA may block the early differentiation of mESCs under hypoxia via the destabilization of HIF-$1{\alpha}$.

• Biomedical Science Letters
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• v.27 no.2
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• pp.69-76
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• 2021

The aim of this study was to evaluate gamma-aminobutyric acid (GABA)-induced erythropoietin (EPO) and EPO-receptor expression in human Hep3B cells and Sprague Dawley (SD) rats during hypoxia. Expression levels of EPO, EPO-R mRNA, Janus kinase-2 (JAK-2), vascular endothelial growth factor (VEGF), hypoxia inducible factor-1 (HIF-1), and HIF-2 in response to GABA treatment were evaluated in cell lines. SD rats were randomly divided into 5 groups of 8 rats each, and GABA was orally administered; the groups were the normal control (NC), hypoxia-exposed (G0), as well as the GABA 1 mg/100 g body weight (BW) GABA treated group (G1), 5 mg/100 g BW GABA treated group (G5), and 10 mg/100 g BW GABA treated group (G10) with hypoxia. We analyzed EPO levels and red blood cell counts in rat blood and EPO gene expression in kidney tissue. EPO and VEGF mRNA levels in Hep3B cells exposed to hypoxia were significantly increased and further increased after GABA treatment. However, the expression of EPO-R and JAK-2 mRNAs were not affected by GABA, but hypoxia-induced HIF-1 and HIF-2 mRNA expression was inhibited by GABA. In the kidney tissue of rats exposed to hypoxia, the expression level of EPO mRNA was greatly increased, but levels in the GABA treatment groups significantly decreased. EPO levels in the serum showed the same significant trend, but the red blood cell counts were not significantly different. These findings demonstrate that HIF-1 and HIF-2 activation increase EPO expression in Hep3B cells exposed to hypoxia. However HIF decreased by GABA addition and VEGF increased significantly.

• The Korean Journal of Physiology and Pharmacology
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• v.25 no.2
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• pp.159-166
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• 2021

Nicotinamide adenine dinucleotide phosphate oxidases (NOXs) are the major enzymatic source of reactive oxygen species (ROS). NOX2 and NOX4 are expressed in the heart but its role in hypoxia-induced atrial natriuretic peptide (ANP) secretion is unclear. This study investigated the effect of NOX on ANP secretion induced by hypoxia in isolated beating rat atria. The results showed that hypoxia significantly upregulated NOX4 but not NOX2 expression, which was completely abolished by endothelin-1 (ET-1) type A and B receptor antagonists BQ123 (0.3 μM) and BQ788 (0.3 μM). ET-1-upregulated NOX4 expression was also blocked by antagonists of secreted phospholipase A2 (sPLA2; varespladib, 5.0 μM) and cytosolic PLA2 (cPLA2; CAY10650, 120.0 nM), and ET-1-induced cPLA2 expression was inhibited by varespladib under normoxia. Moreover, hypoxia-increased ANP secretion was evidently attenuated by the NOX4 antagonist GLX351322 (35.0 μM) and inhibitor of ROS N-Acetyl-D-cysteine (NAC, 15.0 mM), and hypoxia-increased production of ROS was blocked by GLX351322. In addition, hypoxia markedly upregulated Src expression, which was blocked by ET receptors, NOX4, and ROS antagonists. ET-1-increased Src expression was also inhibited by NAC under normoxia. Furthermore, hypoxia-activated extracellular signal-regulated kinase 1/2 (ERK1/2) and protein kinase B (Akt) were completely abolished by Src inhibitor 1 (1.0 μM), and hypoxia-increased GATA4 was inhibited by the ERK1/2 and Akt antagonists PD98059 (10.0 μM) and LY294002 (10.0 μM), respectively. However, hypoxia-induced ANP secretion was substantially inhibited by Src inhibitor. These results indicate that NOX4/Src modulated by ET-1 regulates ANP secretion by activating ERK1/2 and Akt/GATA4 signaling in isolated beating rat hypoxic atria.