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Eun-Mi Park

Publications and source records attributed to Eun-Mi Park.

At least 19 recordsLinked to original sources
PubMed2006

High superoxide dismutase and low glutathione peroxidase activities in red blood cells predict susceptibility of lung cancer patients to radiation pneumonitis.

Radiation pneumonitis is an unpredictable complication of radiotherapy for lung cancer and a condition which can cause significant morbidity. The ability to identify patients at a high risk of developing pneumonitis is critical, since it will enable the individualization of the treatment plan. Because the cytotoxic effect of radiation is propagated through reactive oxygen species (ROS) and ROS-driven oxidative stress, the role of antioxidant defense systems in radiation pneumonitis was investigated. Using the pneumonitis-sensitive C3H/HeN mice as a model, we demonstrated that the antioxidant response of the lung correlated well with that of red blood cells (RBC). We then proceeded to test whether differences of RBC antioxidant response would predict the pneumonitis development in patients. Superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT) activities and glutathione in RBC were measured at baseline and then weekly for 6 weeks of treatment in 15 eligible patients receiving concurrent chemo-radiotherapy for unresectable stage III NSCLC. Striking differences were found in the antioxidant activities of RBC with respect to the pneumonitis development. Those who developed pneumonitis showed higher SOD and lower GPX activities at baseline compared to those who did not (3.7 vs 6.8 units/mg for median SOD, 16.5 vs 10.7 nmol/min/mg for median GPX). The functional imbalance of SOD and GPX was displayed consistently throughout the treatment period. The sensitivity and specificity of pneumonitis prediction were further increased when the GPX/SOD ratio was analyzed (pretreatment P = 0.0046). Our results provide a strong rationale to monitor SOD and GPX activities of RBC to identify patients who are at risk of developing pneumonitis, and to implement a strategy of increasing the GPX/SOD ratio in order to lower the risk.

Adult↗
PubMed2006

Prx1 suppresses radiation-induced c-Jun NH2-terminal kinase signaling in lung cancer cells through interaction with the glutathione S-transferase Pi/c-Jun NH2-terminal kinase complex.

Radiotherapy is one of the major treatment modalities for lung cancer. Cell killing by ionizing radiation is mediated primarily through the reactive oxygen species (ROS) and ROS-driven oxidative stress. Prx1, a peroxiredoxin family member, was shown to be frequently elevated in lung cancer cells and tissues. Although the antioxidant function of Prx1 is expected to affect the radiotherapy response of lung cancer, the physiologic significance of its peroxidase activity in irradiated cells is unclear because the catalytic Cys52 is easily inactivated by ROS due to its overoxidation to sulfinic or sulfonic acid. In this study, we investigated the role of Prx1 in radiation sensitivity of human lung cancer cells, with special emphasis on the redox status of the catalytic Cys52. We found that overexpression of Prx1 enhances the clonogenic survival of irradiated cells and suppresses ionizing radiation-induced c-Jun NH2-terminal kinase (JNK) activation and apoptosis. The peroxidase activity of Prx1, however, is not essential for inhibiting JNK activation. The latter effect is mediated through its association with the glutathione S-transferase pi (GSTpi)-JNK complex, thereby preventing JNK release from the complex. Reduced JNK activation is observed when the peroxidase activity of Prx1 is compromised by Cys52 overoxidation or in the presence of the Cys52 to Ser52 mutant (Prx1C52S) lacking peroxidase activity. We show that both Prx1 and Prx1C52S interact with the GSTpi-JNK complex and suppress the release of JNK from the complex. Our study provides new insight into the antiapoptotic function of Prx1 in modulating radiosensitivity and provides the impetus to monitor the influence of Prx1 levels in the management of lung cancer.

Antioxidants↗
PubMed2006

Hypoxia increases androgen receptor activity in prostate cancer cells.

Recent studies show that prostate cancer cells are able to survive in a hypoxic tumor environment, and the extent of tumor hypoxia correlates with poor clinical outcome. Androgen deprivation, the most common form of prostate cancer therapy, was itself shown to induce a state of transient hypoxia at the microenvironmental level. Because androgen receptor (AR) signaling plays a critical role in prostate cancer, we investigated the effect of hypoxia in regulating AR function. We found that in LNCaP prostate cancer cells, AR binding to the androgen-responsive element (ARE), prostate-specific antigen accumulation, and ARE-reporter gene activity were increased after hypoxia treatment. Hypoxia-enhanced AR function was also observed when AR was exogenously introduced into AR-null DU145 cells. Confocal microscopy and chromatin immunoprecipitation assays showed that AR translocation to the nucleus and AR recruitment to the prostate-specific antigen promoter were facilitated after hypoxia treatment. The AR stimulatory effect seemed to be ligand-dependent because it was abrogated when cells were cultured in an androgen-depleted medium, but was restored with the addition of R1881, a synthetic androgen. The sensitivity of AR activation to R1881 was also increased after hypoxia treatment. Although concentrations of <1 nmol/L R1881 did not induce ARE reporter activity under normoxic conditions, exposure to hypoxia greatly potentiated the AR response to low levels of R1881. Collectively, our results provide compelling evidence that changes in hypoxia/reoxygenation stimulate AR trans-activation and sensitization. The AR-stimulatory effect of an unstable tissue oxygenation milieu of a tumor is likely to contribute to treatment resistance and the emergence of recurrent prostate cancer.

Cell Hypoxia↗
PubMed2006

Enhanced ERK dependent CREB activation reduces apoptosis in staurosporine-treated human neuroblastoma SK-N-BE(2)C cells.

Activation of cAMP response element binding protein (CREB) is implicated in neuronal survival. The mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) activates a transcription factor CREB. Previously, we reported that N-acetyl-O-methyldopamine (NAMDA) protects neurons from ischemia via enhancing ERK dependent CREB phosphorylation. To investigate whether NAMDA induces endogenous survival pathways in apoptotic conditions and whether the neuroprotectant enhances a preexisting survival pathway, we determined the degree of ERK-CREB activation and resistance to apoptosis in staurosporine-treated SK-N-BE(2)C neurons. Compared to forskolin-treated apoptotic cultures, NAMDA-treated cultures induced a minimum activation on ERK (pERK) or CREB (pCREB). However, NAMDA enhanced the activation of ERK and CREB in the presence of forskolin (1.7-fold increase for pCREB, 2.1-fold increase for pERK2, p<0.05 from forskolin). The effect was completely blocked by a specific MEK inhibitor U0126, suggesting the involvement of ERK dependent CREB signaling. Cleavage of caspase-3 and poly-(ADP-ribose)-polymerase was additively reduced in cultures treated with NAMDA and forskolin simultaneously, but not in the presence of U0126. The data showed that NAMDA enhances forskolin-induced ERK-CREB activation and potentiates forskolin-induced resistance to apoptosis. The study indicates that enhancing endogenous survival pathways by NAMDA combined with other neuroprotective measure(s) might be a useful strategy to reduce apoptosis.

Analysis of Variance↗
PubMed2006

Inducible nitric oxide synthase contributes to gender differences in ischemic brain injury.

Estrogens have antiinflammatory actions and protect the brain from ischemic injury. Cerebral ischemia is accompanied by an inflammatory reaction that contributes to the tissue damage, an effect mediated in part by toxic amounts of nitric oxide (NO) produced by the inducible isoform of NO synthase (iNOS). Therefore, estrogens may protect the female brain by modulating postischemic iNOS expression. To test this hypothesis, we studied whether iNOS plays a role in the mechanisms of the reduced susceptibility to ischemic injury observed in female mice. The middle cerebral artery was occluded for 20 mins using an intraluminal filament in C57Bl/6 mice, and infarct volume was assessed 3 days later in cresyl violet-stained sections. Infarcts were 53% smaller in female mice than in males (P < 0.05), a reduction abolished by ovariectomy (OVX) and reinstated by estrogen replacement. In normal female mice, postischemic iNOS mRNA was lower than in males (P < 0.05). Ovariectomy increased iNOS mRNA after ischemia and estrogen replacement blocked this effect. Furthermore, the iNOS inhibitor aminoguanidine reduced infarct volume in male, but not in female, mice. Similarly, male iNOS-null mice had smaller infarcts than wild-type mice, but female iNOS nulls were not protected. Ovariectomy and OVX with estrogen replacement did not affect infarct volume in iNOS-null female mice. The findings suggest that the neuroprotection conferred by estrogens is, in part, related to attenuation of iNOS expression. Such attenuation could result from the potent antiinflammatory effects of estrogens that downregulate iNOS expression via transcriptional or posttranscriptional mechanisms.

Animals↗
PubMed2006

Analysis of human plasma proteome by 2DE- and 2D nanoLC-based mass spectrometry.

We compared the 2DE coupled to MALDI-TOF-MS and ESI-MS/MS analysis (2DE-MS) and the on-line 2D nanoLC, followed by nanoESI-MS/MS analysis (2DLC-MS), for the separation and identification of proteins in high abundance protein-depleted human plasma. Identification of proteins in the plasma by the two methods demonstrated that the majority of the identified protein set was unique to each method. Therefore, if a comprehensive coverage of the proteome identification is desired, it is ideal to apply both methods. The 2DE-MS method is amenable to protein spot-based quantitation, whereas the 2DLC-MS method may provide an advantage of the high throughput application.

Adult↗
PubMed2006

Effect of ionizing radiation on rat tissue: proteomic and biochemical analysis.

Reactive oxygen species (ROS), generated by ionizing radiation, has been implicated in its effect on living tissues. We confirmed the changes in the oxidative stress markers upon irradiation. We characterized the changes in the proteome profile in rat liver after administering irradiation, and the affected proteins were identified by MALDI-TOF-MS and ESI-MS/MS. The identified proteins represent diverse sets of proteins participating in the cellular metabolism. Our results demonstrated that proteomics analysis is a useful method for characterization of a global proteome change caused by ionizing radiation to unravel the molecular mechanisms involved in the cellular responses to ionizing radiation.

Animals↗
PubMed2006

Neural network-based analysis of thiol proteomics data in identifying potential selenium targets.

Generation of a monomethylated selenium metabolite is critical for the anticancer activity of selenium. Because of its strong nucleophilicity, the metabolite can react directly with protein thiols to cause redox modification. Here, we report a neural network-based analysis to identify potential selenium targets. A reactive thiol specific reagent, BIAM, was used to monitor thiol proteome changes on 2D gel. We constructed a dynamic model and evaluated the relative importance of proteins mediating the cellular responses to selenium. Information from this study will provide new clues to unravel mechanisms of anticancer action of selenium. High impact selenium targets could also serve as biomarkers to gauge the efficacy of selenium chemoprevention.

Antineoplastic Agents↗
PubMed2006

Analysis of protein redox modification by hypoxia.

We examined hypoxia-induced changes in global thiol proteome profile in human prostate cancer cells using a BIAM-based display method. We analyzed the kinetics of protein thiol modification by using a pattern recognition algorithm, self-organizing maps (SOM) clustering, and identified the BIAM-labeled proteins by MALDI-TOF and ESI-tandem mass spectrometry. We found 99 out of 215 of total BIAM-labeled proteins were affected by hypoxia treatment and, yet, with diverse patterns and kinetics of redox modification. Our study proved that proteomics analysis employing the BIAM-labeling method can provide valuable information pertaining to global changes in the redox status of proteins in response to hypoxia.

Apoptosis↗
PubMed2005

The class B scavenger receptor CD36 mediates free radical production and tissue injury in cerebral ischemia.

The class B scavenger receptor CD36 is involved in the cytotoxicity associated with inflammation, but its role in the inflammatory reaction that accompanies cerebral ischemia has not been examined. In this study, we investigated whether CD36 contributes to the brain damage produced by cerebral ischemia. The middle cerebral artery was transiently occluded in wild-type mice and in mice deficient in CD36. In wild-type mice, CD36 protein expression was increased in the ischemic brain, such that it was located predominantly in cells expressing the microglia/macrophage marker CD11b. The infarct produced by middle cerebral artery occlusion was 49% smaller in CD36-null mice than in wild-type controls, an effect associated with improved neurological function. The attenuation in brain injury in CD36 nulls could not be attributed to differences in cerebral blood flow during ischemia-reperfusion. However, the increase in reactive oxygen species (ROS) produced by cerebral ischemia was markedly attenuated in CD36-null mice in the early stage after reperfusion. The data unveil a previously unrecognized role of CD36 in ischemia-induced ROS production and brain injury. Modulation of CD36 signaling may provide a new strategy for the treatment of ischemic stroke.

Animals↗
PubMed2005

Obligatory role of inducible nitric oxide synthase in ischemic preconditioning.

Sublethal insults can induce a transient tolerance toward subsequent lethal ischemia, a phenomenon termed ischemic preconditioning (IPC). In the myocardium, nitric oxide derived from 'inducible' nitric oxide synthase (iNOS or NOS II) plays a critical role in the expression of IPC produced by sublethal ischemia. Here, we investigated whether iNOS is involved in IPC in brain. Ischemic preconditioning was produced in mice by three episodes of 1-min bilateral common carotid artery (BCCA) occlusion, each followed by 5 mins of reperfusion. After 24 h, mice underwent middle cerebral artery (MCA) occlusion for 20 mins. Intraischemic cerebral blood flow was monitored during both in BCCA and MCA occlusion (MCAO) by laser-Doppler flowmetry. Mice were killed 3 days after MCAO, and infarct volume was determined in thionine-stained sections. Infarct volume was significantly reduced 24 h after IPC (70%; P<0.05). Treatment with the iNOS inhibitor aminoguanidine (400 mg/kg), abolished the IPC-induced protection. Furthermore, IPC failed to induce ischemic tolerance in iNOS-null mice. In wild-type mice, IPC increased the resistance to Ca(2+)-mediated depolarization in isolated brain mitochondria. However, in iNOS-null mice IPC failed to induce such resistance. We conclude that iNOS is required for the full expression of IPC and that such effect is coupled to an increased resistance of mitochondria to injury. Thus, iNOS-derived nitric oxide, in addition to its deleterious effects on the late stages of ischemic brain damage, can also be beneficial by promoting ischemic tolerance through signaling, ultimately resulting in mitochondrial protection.

Animals↗
PubMed2005

Du-zhong (Eucommia ulmoides Oliv.) cortex water extract alters heme biosynthesis and erythrocyte antioxidant defense system in lead-administered rats.

This study examined the ameliorative effect of a Du-zhong (Eucommia ulmoides Oliv.) cortex water extract (DzCw) on heme biosynthesis and erythrocyte antioxidant enzyme activities in lead (Pb)-administered rats. Male rats were divided into three groups: normal control group, Pb control group (Pb), and DzCw-administered Pb group (Pb + DzCw). The Pb (25 mg/kg of body weight) was administered orally once a week for 4 weeks, while the DzCw was administered orally at a dosage of 0.139 g of DzCw/kg of body weight/day. DzCw administration significantly lowered plasma Pb concentration compared with the Pb group. Furthermore, the blood hematocrit and hemoglobin levels were significantly higher in the Pb + DzCw group than in the Pb group. Although the blood and hepatic delta-aminolevulinic acid dehydratase (ALAD) activities were significantly lower in the Pb group compared with the normal control group, both ALAD activities was normalized with the administration of DzCw. The erythrocyte superoxide dismutase and catalase activities were significantly higher in the Pb group than in the normal control group, whereas the glutathione peroxidase activity and glutathione level were lowered by Pb administration compared with the normal group. However, the administration of DzCw was found to enhance the antioxidant defense system and significantly lower lipid peroxidation levels in erythrocytes compared with the Pb group. These results indicate that the DzCw administration alleviated the Pb-induced oxidative stress in the erythrocytes through elevating the blood and hepatic ALAD activity and enhancing the antioxidant enzyme activities.

Administration, Oral↗
PubMed2004

Interaction between inducible nitric oxide synthase and poly(ADP-ribose) polymerase in focal ischemic brain injury.

BACKGROUND AND PURPOSE: Overactivation of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) contributes to ischemic brain injury. Because PARP upregulates proinflammatory genes, we investigated whether inducible nitric oxide synthase (iNOS), a gene involved in the deleterious effects of postischemic inflammation, participates in the mechanisms by which PARP activation contributes to cerebral ischemic injury. METHODS: The middle cerebral artery (MCA) was occluded in mice for 20 minutes using an intravascular filament, and injury volume was measured 72 hours later in Nissl-stained brain sections. mRNA expression was assessed in the postischemic brain by the quantitative "real-time" polymerase chain reaction. RESULTS: The PARP inhibitor PJ34 reduced infarct volume and attenuated postischemic iNOS mRNA upregulation by 72%. To determine whether iNOS contributes to the toxicity of PARP, the iNOS inhibitor aminoguanidine was co-administered with PARP inhibitors. Unexpectedly, co-administration of PARP and iNOS inhibitors, or treatment of iNOS-null mice with PARP inhibitors, abrogated the protective effect afforded by iNOS or PARP inhibition alone. The loss of neuroprotection was associated with upregulation of the inflammatory genes iNOS, intercellular adhesion molecule-1, and gp91(phox). CONCLUSIONS: The results suggest that iNOS expression contributes to the deleterious effects exerted by PARP activation in cerebral ischemia. However, iNOS activity is required for the protective effect of PARP inhibition and, conversely, PARP activity must be present for iNOS inhibition to be effective. The findings unveil a previously unrecognized deleterious interaction between iNOS and PARP that is relevant to the development of combination therapies for ischemic stroke.

Animals↗
PubMed2004

Simultaneous identification of rifampin-resistant Mycobacterium tuberculosis and nontuberculous mycobacteria by polymerase chain reaction-single strand conformation polymorphism and sequence analysis of the RNA polymerase gene (rpoB).

Interspecies variations and mutations associated with rifampin resistance in rpoB of Mycobacterium allow for the simultaneous identification of rifampin-resistant Mycobacterium tuberculosis and nontuberculous mycobacteria by PCR-SSCP analysis and PCR- sequencing. One hundred and ten strains of rifampin-susceptible M. tuberculosis, 14 strains of rifampin-resistant M. tuberculosis, and four strains of the M. avium complex were easily identified by PCR-SSCP. Of another seven strains, which showed unique SSCP patterns, three were identified as rifampin-resistant M. tuberculosis and four as M. terrae complex by subsequent sequence analysis of their rpoB DNAs (306 bp). These results were concordant with those obtained by susceptibility testing, biochemical identification, and 16S rDNA sequencing.

Antitubercular Agents↗
PubMed2004

Identification of Mycobacterium tuberculosis by PCR-linked reverse hybridization using specific rpoB oligonucleotide probes.

A reverse probe hybridization method using two different Mycobacterium tuberculosis-specific rpoB DNA probes in combination was evaluated for the identification of M. tuberculosis culture isolates. Among the 384 isolates tested, 354 strains were identified as M. tuberculosis, which included 37 rifampin-resistant strains, and 30 were nontuberculous mycobacteria (NTM). This result was in accord with partial rpoB sequence analysis and IS6110 polymerase chain reaction (PCR) results, but not with the results of biochemical testing, which produced two false negative results. Because of its high level of sensitivity and specificity, we suggest that M. tuberculosis-specific rpoB probes immobilized on micro-titer well plates or on other solid matrixes can be used efficiently for the rapid and convenient identification of M. tuberculosis.

DNA Probes↗
PubMed2003

Two cinnamate derivatives produce similar alteration in mRNA expression and activity of antioxidant enzymes in rats.

Cinnamate is a widespread secondary metabolite of phenolic compound synthesized by plants for defensive purposes. The current study was designed to investigate the effect of two structurally related cinnamate derivatives, 4-hydroxycinnamate and 3-(4-hydroxyphenyl)propionic acid (HPP), on the mRNA expression and activity of antioxidant enzymes in high-cholesterol-fed rats. Male rats were fed a 1 g/100 g high-cholesterol diet with supplements of either 4-hydroxycinnamate or HPP (0.135 mmol/100 g diet) for 6 weeks. The plasma paraoxonase activity was found to be higher in the cinnamate-derivative-supplemented groups than in the control group. The erythrocyte superoxide dismutase (SOD) and catalase (CAT) activities, plus glutathione (GSH) level, were all significantly higher in the 4-hydroxycinnamate- and HPP-supplemented groups than in the control group. However, both 4-hydroxycinnamate and HPP supplementation significantly lowered the hepatic activities and mRNA expression of CAT and glutathione peroxidase (GSH-Px) compared to the control group. The hepatic mRNA expression and activity of SOD did not differ between the groups. The hepatic thiobarbituric acid reactive substances (TBARS) level was significantly lowered by the 4-hydroxycinnamate and HPP supplementation. Accordingly, these results indicate that supplementation by 4-hydroxycinnamate and HPP would seem to enhance the antioxidative defense of erythrocyte. Both HPP and 4-hydroxycinnamate would appear to be beneficial in improving the function of antioxidative enzymes on a molecular level in high-cholesterol-fed rats.

Animals↗
PubMed2003

Cinnamate supplementation enhances hepatic lipid metabolism and antioxidant defense systems in high cholesterol-fed rats.

This study investigated the effect of cinnamate, a phenolic compound found in cinnamon bark and other plant materials, on lipid metabolism and antioxidant enzyme activities in rats fed a high cholesterol diet. Three groups of rats were given a diet containing 1 g of cholesterol/kg for 6 weeks. The control group only received the high cholesterol diet, whereas the other two groups received a diet supplemented with lovastatin or cinnamate (0.1 g/100 g of diet). The plasma high-density lipoprotein-cholesterol levels were significantly higher in the cinnamate group than in either the control or lovastatin groups, and the atherogenic index was significantly lower in rats with cinnamate supplementation. Supplementation with cinnamate resulted in significantly lower hepatic cholesterol and triglyceride levels. Accumulation of hepatic lipid droplets was higher in the control group than in the rats supplemented with either cinnamate or lovastatin. Hepatic 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase activity was significantly lower in the cinnamate group compared with the other groups, whereas only acyl-CoA:cholesterol acyltransferase activity was significantly lower in the lovastatin group compared with the control group. Cinnamate supplementation resulted in higher catalase and glutathione peroxidase activities, while hepatic thiobarbituric acid-reactive substances were significantly lower in both the cinnamate and lovastatin groups. The fecal acidic sterol was higher in the lovastatin group than in the control or cinnamate groups. These results suggest that dietary cinnamate inhibits hepatic HMG-CoA reductase activity, resulting in lower hepatic cholesterol content, and suppresses lipid peroxidation via enhancement of hepatic antioxidant enzyme activities.

Animals↗