• Journal of Ginseng Research
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• 제41권3호
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• pp.240-246
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• 2017

Background: Korean Red Ginseng (KRG) is a traditional herbal medicine made by steaming and drying fresh ginseng. It strengthens the endocrine and immune systems to ameliorate various inflammatory responses. The cyclooxygenase-2 (COX-2)/prostaglandin E2 pathway has important implications for inflammation responses and tumorigenesis. Peroxisome proliferator-activated receptor gamma ($PPAR{\gamma}$) is a transcription factor that regulates not only adipogenesis and lipid homeostasis, but also angiogenesis and inflammatory responses. Methods: The effects of the KRG on inhibition of hypoxia-induced COX-2 via $PPAR{\gamma}$ in A549 cells were determined by luciferase assay, Western blot, and/or quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The antimigration and invasive effects of KRG were evaluated on A549 cells using migration and matrigel invasion assays. Results and conclusion: We previously reported that hypoxia-induced COX-2 protein and mRNA levels were suppressed by KRG. This study examines the possibility of $PPAR{\gamma}$ as a cellular target of KRG for the suppression of hypoxia-induced COX-2. $PPAR{\gamma}$ protein levels and $PPAR{\gamma}$-responsive element (PPRE)-driven reporter activities were increased by KRG. Reduction of hypoxia-induced COX-2 by KRG was abolished by the $PPAR{\gamma}$ inhibitor GW9662. In addition, the inhibition of $PPAR{\gamma}$ abolished the effect of KRG on hypoxia-induced cell migration and invasion. Discussion: Our results show that KRG inhibition of hypoxia-induced COX-2 expression and cell invasion is dependent on $PPAR{\gamma}$ activation, supporting the therapeutic potential for suppression of inflammation under hypoxia. Further studies are required to demonstrate whether KRG activates directly $PPAR{\gamma}$ and to identify the constituents responsible for this activity.

• 대한방사성의약품학회지
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• 제1권2호
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• pp.137-144
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• 2015

Hypoxia is an important adverse prognostic factor for tumor progression and is a major cause of failure of radiation therapy. In case of short-term hypoxia, the metabolism can recover to normal, but if hypoxia persists, it causes irreversible cell damage and finally leads to death. So a hypoxia marker would be very useful in oncology. In particular, 2-nitroimidazole can be reduced to form a reactive chemical species, which can bind irreversibly to cell components in the absence of sufficient oxygen, thus, the development of radiolabeled nitroimidazole derivatives for the imaging of hypoxia remains an active field of research to improve cancer therapy result. 2-nitroimidazole based hypoxia marker, [$^{18}F$]FMISO holds promise for the evaluation of tumor hypoxia by Positron emission tomography (PET), at both global and local levels. In the present study, [$^{18}F$]FMISO was synthesized using an automatic synthesis module with high radiochemical purity (>99%) in 60 min. Immunohistochemical analysis using pimonidazole confirmed the presence of hypoxia in xenografted CT-26 tumor tissue. A biodistribution study in CT-26 xenografted mice showed that the increased tumor-to-muscle ratio and tumor-to-blood ratios from 10 to 120 min post-injection. In the PET study, [$^{18}F$]FMISO also showed increased tumor-to-muscle ratios from 10 to 120 min post-injection. In conclusion, this study demonstrates the feasibility and utility of [$^{18}F$]FMISO for imaging hypoxiain mouse colon cancer model using small animal PET.

• Parasites, Hosts and Diseases
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• 제57권2호
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• pp.117-125
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• 2019

Malarial infection induces tissue hypoxia in the host through destruction of red blood cells. Tissue hypoxia in malarial infection may increase the activity of $HIF1{\alpha}$ through an intracellular oxygen-sensing pathway. Activation of $HIF1{\alpha}$ may also induce vascular endothelial growth factor (VEGF) to trigger angiogenesis. To investigate whether malarial infection actually generates hypoxia-induced angiogenesis, we analyzed severity of hypoxia, the expression of hypoxia-related angiogenic factors, and numbers of blood vessels in various tissues infected with Plasmodium berghei. Infection in mice was performed by intraperitoneal injection of $2{\times}10^6$ parasitized red blood cells. After infection, we studied parasitemia and survival. We analyzed hypoxia, numbers of blood vessels, and expression of hypoxia-related angiogenic factors including VEGF and $HIF1{\alpha}$. We used Western blot, immunofluorescence, and immunohistochemistry to analyze various tissues from Plasmodium berghei-infected mice. In malaria-infected mice, parasitemia was increased over the duration of infection and directly associated with mortality rate. Expression of VEGF and $HIF1{\alpha}$ increased with the parasitemia in various tissues. Additionally, numbers of blood vessels significantly increased in each tissue type of the malaria-infected group compared to the uninfected control group. These results suggest that malarial infection in mice activates hypoxiainduced angiogenesis by stimulation of $HIF1{\alpha}$ and VEGF in various tissues.

• 대한의생명과학회지
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• 제19권3호
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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.

• BMB Reports
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• 제51권2호
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• pp.59-64
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• 2018

The airway epithelium is the first place, where a defense mechanism is initiated against environmental stimuli. Mucociliary transport (MCT), which is the defense mechanism of the airway and the role of airway epithelium as mechanical barriers are essential in innate immunity. To maintain normal physiologic function, normal oxygenation is critical for the production of energy for optimal cellular functions. Several pathologic conditions are associated with a decrease in oxygen tension in airway epithelium and chronic sinusitis is one of the airway diseases, which is associated with the hypoxic condition, a potent inflammatory stimulant. We have observed the overexpression of the hypoxia-inducible factor 1 (HIF-1), an essential factor for oxygen homeostasis, in the epithelium of sinus mucosa in sinusitis patients. In a series of previous reports, we have found hypoxia-induced mucus hyperproduction, especially by MUC5AC hyperproduction, disruption of epithelial barrier function by the production of VEGF, and down-regulation of junctional proteins such as ZO-1 and E-cadherin. Furthermore, hypoxia-induced inflammation by HMGB1 translocation into the cytoplasm results in the release of IL-8 through a ROS-dependent mechanism in upper airway epithelium. In this mini-review, we briefly introduce and summarize current progress in the pathogenesis of sinusitis related to hypoxia. The investigation of hypoxia-related pathophysiology in airway epithelium will suggest new insights on airway inflammatory diseases, such as rhinosinusitis for clinical application and drug development.

• 동의신경정신과학회지
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• 제17권2호
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• pp.15-36
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• 2006

Objective : This study was designed to assess effect of and Chenwangbosim-Dan(CWBSD) 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 CWBSD and herbs. Result : 1. In MTT assay of hypoxia CWBSD and BJI, SJH, IS, CHR, HS among all of herbs were effective. Especially CWBSD and IS were highly effective. 2. In MTT assay of reoxygenation SJI, SJH, VJ, IS, BJI were effective. Especially SJI, SJH, YJ were highly effective. 3. In LDH assay of hypoxia CWBSD, DS, DG, SJH, OMZ were effective. Especially CWBSD, DG were highly effective. 4. In LDH assay of reoxygenation all of herbs except CWBSD and BJI were generally effective. Especially CHR, SJH, YJ, OMZ, HS were highly effective. Conclusion : The results suggest that CWBSD, and it's ingradient(especially SJH, CHR and SJI) may have protective effect on condition of oxidative stress.

• 약학회지
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• 제44권3호
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• pp.237-244
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• 2000

Liver isolated from 18 hours fasted rats was subjected to $N_2$hypoxia (for 45 min) followed by reoxygenation (for 30 min). The perfusion medium used was Krebs-Henseleit bicarbonate buffer (pH 7.4, $37^{\circ}C$). Vitamin C (0.5 mM) and trolox C (0.5 mM), soluble vitamin E analog, were added to perfusate. Lactate dehydrogenase (LDH), total glutathione, oxidized glutathione, lipid peroxide and drug-metabolizing enzymes were measured. After hypoxia LDH significantly increased but this increase was attenuated by vitamin C and combination of vitamin C and E. Total glutathione and oxidized glutathione in perfusate markedly increased during hypoxia and this increase was inhibited by vitamins C, E and its combination. Similarly; oxidized glutathione and lipid peroxide in liver tissue increased after hypoxia and reoxygenation and this increase was inhibited by vitamin I and combination of vitamin C and E. Hepatic drug metabolizing function (phase I, II) were suppressed during hypoxia but improved during reoxygenation. While vitamins C and E only increased glucuronidation, the combination of vitamin C and E increased the oxidation, glucuronidation and sulfation. Our findings suggest that vitamins C and E synergistically ameliorates hepatocellular damage as indicated by abnormalities in drug metabolizing function during hypoxia/reoxygenation and that this protection is in major part, caused by decreased oxidative stress.

• 대한약리학회지
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• 제29권2호
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• pp.203-212
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• 1993

돼지의 적출뇌동맥에서 저산소 유발 수축반응을 관찰하고 그 기전을 구명하며 저산소가 혈관수축제의 수축반응과 acetylcholine (ACh)의 내피세포 의존성 이완반응에 미치는 영향을 검토코자하여 본 실험을 시행하였다. 내피세포가 존재하는 표본에서는 저산소는 일과성 혈관수축을 일으켰고 산소 재공급시에 일과성 이완 후 수축이 나타나는 이상성 (biphasic) 반응이 관찰되었다. KCI 및 $PGF_{2\alpha}$전처치로 수축된 표본에서 저산소 유발은 추가적 수축반응을 일으켰고, 산소재공급으로 이완반응이 관찰되었다. 내피세포 제거 후 및 nimodipine 또는 indomethacin처리 후 저산소와 산소 재공급에 의한 수축반응은 현저히 감약되었다. 저산소하에서 KCl의 수축반응은 영향받지 않았으나, $PGF_{2\alpha}$와 endothelin (ET)의 수축반응은 현저히 억제되었고 ET수축반응이 저산소에 가장 예민하였다. $PGF_{2\alpha}$와 ET로 수축된 내피세포 존재표본에서 ACh은 용량의존성 이완반응을 일으켰고 이 이완반응은 저산소 하에서 소실되었으며 내피세포 제거표본에서는 ACh의 이완반응이 관찰되지 않았다. $PGF_{2\alpha}$로 처리한 내피세포 존재표본에서 ACh은 cyclic GMP농도를 증가시켰고 이 증가는 저산소하에서 소실되었다. 이상의 성적으로 저산소와 산소 재공급 수축반응은 내피세포 및 calcium의존성이고, prostaglandin계 물질의 유리에 기인한다고 추론하였다.

• The Korean Journal of Physiology and Pharmacology
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• 제17권1호
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• pp.57-64
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• 2013

Cells can resist and even recover from stress induced by acute hypoxia, whereas chronic hypoxia often leads to irreversible damage and eventually death. Although little is known about the response(s) to acute hypoxia in neuronal cells, alterations in ion channel activity could be preferential. This study aimed to elucidate which channel type is involved in the response to acute hypoxia in rat pheochromocytomal (PC12) cells as a neuronal cell model. Using perfusing solution saturated with 95% $N_2$ and 5% $CO_2$, induction of cell hypoxia was confirmed based on increased intracellular $Ca^{2+}$ with diminished oxygen content in the perfusate. During acute hypoxia, one channel type with a conductance of about 30 pS (2.5 pA at -80 mV) was activated within the first 2~3 min following onset of hypoxia and was long-lived for more than 300 ms with high open probability ($P_o$, up to 0.8). This channel was permeable to $Na^+$ ions, but not to $K^+$, $Ca^+$, and $Cl^-$ ions, and was sensitively blocked by amiloride (200 nM). These characteristics and behaviors were quite similar to those of epithelial sodium channel (ENaC). RT-PCR and Western blot analyses confirmed that ENaC channel was endogenously expressed in PC12 cells. Taken together, a 30-pS ENaC-like channel was activated in response to acute hypoxia in PC12 cells. This is the first evidence of an acute hypoxia-activated $Na^+$ channel that can contribute to depolarization of the cell.

• 한국작물학회지
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• 제50권6호
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• pp.400-405
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• 2005

본 연구에서는 맥류 습해의 원인인 과습에 의한 근권의 산소부족이 맥류 뿌리의 생장 및 혐기 발효대사 효소(alcohol dehydrogenase, ADH; lactate dehydrogenase, LDH)에 미치는 영향을 조사하였다. 양액재배를 이용하여 1.5엽기 맥류 유묘에 용존산소 1.5-2 ppm 정도의 혐기처리를 1, 3, 5, 7일간 실시하였다. 혐기조건에서 뿌리의 생장은 모든 맥종에서 감소하였으며, 감소정도는 내습성이 낮은 보리가 내습성이 높은 밀과 호밀보다 낮았다. 정상조건에서 ADH 활성은 보리가 LDH 활성은 호밀이 가장 높았으나 두 효소 모두 맥종 간의 차이는 크지 않았다. 혐기처리에 의해 ADH와 LDH 활성은 모든 맥종에서 공통적으로 증가하였으며 증가 정도는 호밀과 밀에서 가장 높았고 보리에서 가장 낮았다. 혐기조건에서 이들 효소의 활성증가는 모든 맥종에서 유사하게 항시발현 동위효소의 증가 및 새로운 동위효소의 발현유도에 의해 나타났다. 혐기조건에서 ADH와 LDH 활성 증가 정도는 맥종의 재해저항성과 정의 상관관계가 인정되었다. 이러한 결과는 맥류의 내습성에 혐기 발효계 효소가 관여하고 있음을 의미하는 것으로 판단된다.