• Radiation Oncology Journal
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• v.12 no.1
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• pp.9-16
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• 1994

Hypothesis that hypoxic tumors should be more responsive to the addition of preferential hypoxic cell cytotoxin SR 4233 (tirapazamine) to fractionated irradiation was tested in the mouse SCCVll carcinoma and RIF-1 sarcoma, Model of hypoxic tumor was established using the tumor bed effect: tumors growing in the preirradiated tissue (preirradiated tumors) were more hypoxic than tumors growing in the unirradiated tissue (unirradiated tumors). When the tumors reached a mean volume of 100 $mm^{3}$, both unirradiated and preirradiated tumors were treated with a fractionated course of 6${\times}$2 Gy in 3 days or 8${\times}$2.5 Gy in 4 days with SR 4233 (0.08 mmol/kg/injection) given 30 minutes before each irradiation or without SR 4233. Compared to the unirradiated tumors, hypoxic preirradiated tumors were approximately 5 times more resistant to fractionated irradiation alone but were approximately 5 times more responsive to SR 4233. Addition of SR 4233 Potentiated the effect of fractionated irradiation in both unirradiated and preirradiated tumors. Potentiation in the preirradiated tumors was morequal to or greater than that in the unirradiated tumors and seemed to be higher for more fractionated treatment. We confirm the hypothesis in a transplantable mouse tumor. Present results suggest that radioresistance of some hypoxic tumors can be overcome with hypoxic cytotoxin.

• Journal of Life Science
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• v.26 no.10
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• pp.1137-1152
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• 2016

Cells sense, respond, and adapt to a low oxygen environment called hypoxia, which is widely involved in a variety of human diseases. Adaptation to low oxygen concentrations includes gene expression changes by inducing hypoxic genes and reducing aerobic genes. Recently, the mitochondrial respiratory chain has been implicated in the control of these oxygen-regulated genes when cells experience hypoxia. In order to obtain an insight into an effect of the mitochondrial respiratory chain on cellular response to hyxpoxia, we here examined whole genome transcript signatures of respiration-proficient and respiration-deficient budding yeasts exposed to hypoxia using DNA microarrays. By comparing whole transcriptomes to hypoxia in respiration-proficient and respiration-deficient yeasts, we found that there are several classes of oxygen-regulated genes. Some of them require the mitochondrial respiratory chain for their expression under hypoxia while others do not. We found that the majority of hypoxic genes and aerobic genes need the mitochondrial respiratory chain for their expression under hypoxia. However, we also found that there are some hypoxic and aerobic genes whose expression under hypoxia is independent of the mitochondrial respiratory chain. These results indicate a key involvement of the mitochondrial respiratory chain in oxygen-regulated gene expression and multiple mechanisms for controlling oxygen-regulated gene expression. In addition, we provided gene ontology analyses and computational promoter analyses for hypoxic genes identified in the study. Together with differentially regulated genes under hypoxia, these post-analysis data will be useful resources for understanding the biology of response to hypoxia.

• Journal of the Korean Society of Marine Environment & Safety
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• v.16 no.3
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• pp.241-248
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• 2010

Hypoxic(oxygen-deficient) water masses are a key threat to the ecosystem of shallow marine coastal areas worldwide. The phenomena of hypoxia occurred at Gamak Bay, on the southeast coast of Korea, in late June 2007. In this paper, the physicochemical characteristics of seawater were surveyed for a period of hypoxic water mass disappearance. The hypoxic water mass was located between Sunso and the northwestern area of the inner bay. The dissolved oxygen(DO) concentrations of surface and bottom water were $1.3mgL^{-1}$ and less than $2mgL^{-1}$, respectively, in the hypoxic water masses, and $4.5{\sim}6.8mgL^{-1}$ and $3.8{\sim}6.0mgL^{-1}$ at the other oxygen-rich sample sites, respectively. Chlorophyll a concentrations were $4.9{\sim}25.3{\mu}gL^{-1}$ at the surface, $2.3{\sim}23.1{\mu}gL^{-1}$ in the middle, and $1.9{\sim}9.0{\mu}gL^{-1}$ at the bottom of the hypoxic water masses. When the hypoxic water mass appeared in Gamak Bay, it formed three different vertical types. The first type occurred throughout the water depth around Sunso. The second type developed from the bottom. The third type of hypoxic water mass was formed in the middle water layer when the inversion of water temperature occurred. The third type of phenomena appeared at only St. 9, St. 14 and St. 21 sites near the Hodo coast. Aquatic surface respiration of bottom-dwelling fishes such as the oriental goby(Acanthogobius flavimanus) was observed and many crustaceans were seen along the adjacent shore of the hypoxic water mass area. About 3,000 oriental gobies as well as many crustaceans died due to this event in Gamak Bay. The results of this study could provide fundamental data for the mechanism of hypoxic water masses in Gamak Bay.

• Proceedings of the PSK Conference
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• 2003.10a
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• pp.104-105
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• 2003

Hypoxic-ischemic (H-I) encephalopathy in the prenatal and perinatal period is a major cause of morbidity and mortality and often results in cognitive impairment, seizures, and motor impairment (cerebral palsy). Many studies of neonatal H-I brain injury have utilized the well characterized Levine model in which unilateral carotid ligation is followed by exposure to hypoxia. (omitted)

• Journal of Life Science
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• v.24 no.12
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• pp.1330-1338
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• 2014

In Mycobacterium tuberculosis H37Rv 16 adenylyl cyclase (AC) genes have been identified, while 10 AC genes have been found in non-pathogenic Mycobacterium smegmatis. Expression of 6 AC genes (MSMEG_0218, MSMEG_3243, MSMEG_3780, MSMEG_4279, MSMEG_4477, and MSMEG_6154) among 10 AC genes in M. smegmatis was increased when M. smegmatis was subjected to hypoxic growth conditions. On the other hand, only MSMEG_3780 and MSMEG_4279 were slightly induced in the presence of NO. The cAMP levels in cells and culture media were 450- and 9.8-fold increased, respectively, when M. smegmatis was grown under hypoxic conditions relative to those grown aerobically. Intracellular levels of cAMP were increased 5.8-fold on the exposure to NO. The DevSR two-component system is known to be involved in the induction of many genes whose expression is induced under hypoxic conditions and in the presence of NO. Expression of 6 hypoxically induced AC genes was observed to be induced in a devR deletion mutant grown under hypoxic conditions, indicating that the induction of the 6 AC genes under hypoxic conditions is independent of the DevSR two-component system. In order to identify a trans-acting regulatory element that is pertinent in the hypoxic induction of MSMEG_3780, ligand-fishing analysis was performed using the upstream DNA of MSMEG_3780 and MSMEG_5136 protein was identified.

• Molecules and Cells
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• v.43 no.11
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• pp.945-952
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• 2020

Hypoxia induces the expression of several genes through the activation of a master transcription factor, hypoxia-inducible factor (HIF)-1α. This study shows that hypoxia strongly induced the expression of two carboxypeptidases (CP), CPA4 and CPE, in an HIF-1α-dependent manner. The hypoxic induction of CPA4 and CPE gene was accompanied by the recruitment of HIF-1α and upregulation in the active histone modification, H3K4me3, at their promoter regions. The hypoxic responsiveness of CPA4 and CPE genes was observed in human adipocytes, human adipose-derived stem cells, and human primary fibroblasts but not mouse primary adipocyte progenitor cells. CPA4 and CPE have been identified as secreted exopeptidases that degrade and process other secreted proteins and matrix proteins. This finding suggests that hypoxia changes the microenvironment of the obese hypoxic adipose tissue by inducing the expression of not only adipokines but also peptidases such as CPA4 and CPE.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.5
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• pp.2031-2035
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• 2015

Intra-tumoral hypoxia is an environment that promotes tumor cell migration, angiogenesis and epithelial-mesenchymal transition that accounts for a major mechanism of metastasis. Chloroquine potentially offers a new therapeutic approach with an 'old' drug for effective and safe cancer therapies, as it exerts anti-metastatic activity. We investigated the inhibitory effect of chloroquine on cholangiocarcinoma (CCA) cell migration under cobalt chloride ($CoCl_2$)-stimulated hypoxia. We showed that chloroquine suppressed CCA cell migration under hypoxic-mimicking conditions on exposure to $100{\mu}M$ $CoCl_2$. Moreover, chloroquine stabilized the protein level of prolyl hydroxylase domain proteins (PHD-2) but reduced the levels of hypoxic responsive proteins such as hypoxia-inducible factor (HIF-$1{\alpha}$) and vascular endothelial growth factor (VEGF). It also suppressed epithelial mesenchymal transition (EMT) by increasing the ratio of E-cadherin to N-cadherin under hypoxic conditions. In conclusion, chloroquine can inhibit hypoxia-stimulated metastasis via HIF-$1{\alpha}$/VEGF/EMT which may serve as a useful additional strategy for CCA therapy.

• BMB Reports
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• v.49 no.3
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• pp.173-178
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• 2016

Liver cells experience hypoxic stress when drug-metabolizing enzymes excessively consume O₂ for hydroxylation. Hypoxic stress changes the transcription of several genes by activating a heterodimeric transcription factor called hypoxia-inducible factor-1α/β (HIF-1α/β). We found that hypoxic stress (0.1% O₂) decreased the expression of cytochrome P450 7A1 (CYP7A1), a rate-limiting enzyme involved in bile acid biosynthesis. Chenodeoxycholic acid (CDCA), a major component of bile acids, represses CYP7A1 by activating a transcriptional repressor named small heterodimer partner (SHP). We observed that hypoxia decreased the levels of both CDCA and SHP, suggesting that hypoxia repressed CYP7A1 without inducing SHP. The finding that overexpression of HIF-1α increased the activity of the CYP7A1 promoter suggested that hypoxia decreased the expression of CYP7A1 in a HIF-1-independent manner. Thus, the results of this study suggested that hypoxia decreased the activity of CYP7A1 by limiting its substrate O₂, and by decreasing the transcription of CYP7A1.

• Journal of Korean Neurosurgical Society
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• v.50 no.4
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• pp.381-384
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• 2011

The authors report a case of atypical extraventricular neurocytoma (EVN) transformed from EVN which had been initially diagnosed as an oligodendroglioma 15 years ago. An 8-year-old boy underwent a surgical resection for a right frontal mass which was initially diagnosed as oligodendroglioma. When the tumor recurred 15 years later, a secondary operation was performed, followed by salvage gamma knife treatment. The recurrent tumor was diagnosed as an atypical EVN. The initial specimen was reviewed and immunohistochemistry revealed a strong positivity for synaptophysin. The diagnosis of the initial tumor was revised as an EVN. The patient maintained a stable disease state for 15 years after the first operation, and was followed up for one year without any complications or disease progression after the second operation. We diagnosed an atypical extraventricular neurocytoma transformed from EVN which had been initially diagnosed as an oligodendroglioma 15 years earlier. We emphasize that EVN should be included in the differential diagnosis of oligodendroglioma.

• Biomedical Science Letters
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• v.19 no.3
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• pp.180-187
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• 2013

Hypoxia is an integral part of the environment during luteolysis. In this study we examined whether hypoxia could directly stimulate endothelial cells to produce nitric oxide (NO). Endothelial cells were cultured in hypoxic (5% $O_2$) or normoxic (20% $O_2$) conditions and the levels of total NO, inducible NO and endothelial NO was measured. We found that hypoxia but not normoxia upregulated NO production. The increased NO levels correlated with increased inducible NO synthase (iNOS) expression whereas expression of endothelial NOS (eNOS) expression remained constant. Addition of the iNOS specific inhibitor 1400W to hypoxic cultures prevented NO production suggesting that hypoxia-induced NO production in endothelial cells was due mainly to upregulation of iNOS. We also found that prostaglandin $F_{2{\alpha}}$ (PGF) production was unaffected by hypoxia suggesting that upregulation of NO was not due to increased synthesis of PGF. In summary, we report that endothelial cells cultured under hypoxic conditions produce NO via the iNOS pathway. This study provides the importance of the relation between the hypoxic environment and the induction of NO by endothelial cells during regression of the corpus luteum in the ovary.