• Asian Pacific Journal of Cancer Prevention
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• v.15 no.7
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• pp.3219-3226
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• 2014

Chemotherapy continues to be a mainstay of cancer treatment, although drug resistance is a major obstacle. Lipid metabolism plays a critical role in cancer pathology, with elevated ether lipid levels. Recently, alkylglyceronephosphate synthase (AGPS), an enzyme that catalyzes the critical step in ether lipid synthesis, was shown to be up-regulated in multiple types of cancer cells and primary tumors. Here, we demonstrated that silencing of AGPS in chemotherapy resistance glioma U87MG/DDP and hepatic carcinoma HepG2/ADM cell lines resulted in reduced cell proliferation, increased drug sensitivity, cell cycle arrest and cell apoptosis through reducing the intracellular concentration of lysophosphatidic acid (LPA), lysophosphatidic acid-ether (LPAe) and prostaglandin E2 (PGE2), resulting in reduction of LPA receptor and EP receptors mediated PI3K/AKT signaling pathways and the expression of several multi-drug resistance genes, like MDR1, MRP1 and ABCG2. ${\beta}$-catenin, caspase-3/8, Bcl-2 and survivin were also found to be involved. In summary, our studies indicate that AGPS plays a role in cancer chemotherapy resistance by mediating signaling lipid metabolism in cancer cells.

• Biomolecules & Therapeutics
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• v.26 no.2
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• pp.175-181
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• 2018

Carbon monoxide (CO) is well-known as toxic gas and intrinsic signaling molecule such as neurotransmitter and blood vessel relaxant. Recently, it has been reported that low concentration of CO exerts therapeutic actions under various pathological conditions including liver failure, heart failure, gastric cancer, and cardiac arrest. However, little has been known about the effect of CO in neurodegenerative diseases like Parkinson's disease (PD). To test whether CO could exert a beneficial action during oxidative cell death in PD, we examined the effects of CO on 6-hydroxydopamine (6-OHDA)-induced cell death in C6 glioma cells. Treatment of CO-releasing molecule-2 (CORM-2) significantly attenuated 6-OHDA-induced apoptotic cell death in a dose-dependent manner. CORM-2 treatment decreased Bax/Bcl2 ratio and caspase-3 activity, which had been increased by 6-OHDA. CORM-2 increased phosphorylation of NF-E2-related factor 2 (Nrf2) which is a transcription factor regulating antioxidant proteins. Subsequently, CORM-2 also increased the expression of heme oxygenase-1 and superoxide dismutases (CuZnSOD and MnSOD), which were antioxidant enzymes regulated by Nrf2. These results suggest that CO released by CORM-2 treatment may have protective effects against oxidative cell death in PD through the potentiation of cellular adaptive survival responses via activation of Nrf2 and upregulation of heme oxygenase-1, leading to increasing antioxidant defense capacity.

• YAKHAK HOEJI
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• v.60 no.2
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• pp.92-99
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• 2016

Parkinson's disease (PD) is one of the representative neurodegenerative movement disorders with the selective loss of dopaminergic neurons in the substantia nigra. 6-Hydroxydopamine (6-OHDA) is widely used as an experimental model system to mimic PD and has been reported to cause neuronal cell death via oxidative and/or nitrosative stress. Therefore, daily intake of dietary or medicinal plants which fortifies cellular antioxidant capacity can exert neuroprotective effects in PD. In the present study, we have investigated the protective effect of Korean red ginseng (KRG) against 6-OHDA-induced nitrosative death in C6 glioma cells. Treatment of C6 cells with 6-OHDA decreased cell viability and increased expression of inducible nitric oxide synthase, production of nitric oxide as well as peroxynitrite, and formation of nitrotyrosine. 6-OHDA led to apoptotic cell death as determined by decreased Bcl-2/Bax, phosphorylation of JNK, activation of caspase-3, and cleavage of PARP. Conversely, pretreatment of C6 cells with KRG attenuated 6-ODHA-induced cytotoxicity, apoptosis, and nitrosative damages. To further elucidate the molecular mechanism of KRG protection against 6-OHDA-induced nitrosative cell death, we have focused on the cellular self-defense molecules against exogenous noxious stimuli. KRG treatment up-regulated heme oxygenase-1 (HO-1), a key antioxidant enzyme essential for cellular defense against oxidative and/or nitrosative stress via activation of Nrf2. Taken together, these findings suggest KRG may have preventive and/or therapeutic potentials for the management of PD.

• Korean Journal of Clinical Laboratory Science
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• v.52 no.4
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• pp.408-416
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• 2020

This study examined the neuronal cytotoxicity of aluminum chloride (AlCl3), a dementia inducer, and the protective effects of Aster yomena (Kitam.)(AY) extract on AlCl3-induced cytotoxicity in cultured C6 glioma cells. The antioxidative effects, such as the inhibitory ability of xanthine oxidase (XO) and superoxide anion-radical (SAR) scavenging ability, on cell viability were examined. AlCl3 decreased the cell viability significantly in a dose-dependent manner, and the XTT50 value was 130.0 μM in these cultures. The cytotoxicity of AlCl3 was determined to be mid-toxic according to the Borenfreund and Puerner' toxic criteria. Quercetin (QU), an antioxidant, increased the cell viability reduced by AlCl3-induced cytotoxicity. The protective effect of the AY extract on AlCl3-induced cytotoxicity was analyzed. The AY extract increased the cell viability remarkably compared to the AlCl3-treated group and showed the inhibitory ability of XO and SAR-scavenging ability. The cytotoxicity of AlCl3 was correlated with oxidative stress, and the AY extract effectively prevented AlCl3-induced cytotoxicity through its antioxidative effects. In conclusion, natural resources, such as the AY extract, may be a putative agent for improving the cytotoxicity of heavy metallic compounds correlated with oxidative stress, such as AlCl3, a morbid agent.

• Korean Journal of Clinical Laboratory Science
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• v.54 no.4
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• pp.298-306
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• 2022

This study sought to evaluate the mechanism of cellular injury caused by ferrous sulfate (FeSO₄) and the protective effects of Parnassia palustris L. (PP) extract against FeSO₄-induced cytotoxicity of cultured C6 glioma cells. FeSO₄ is known to cause neurotoxicity and induce Parkinson's disease. The antioxidative effects of PP, such as superoxide dismutase (SOD)-like and superoxide anion-radical (SAR)-scavenging activities, as well as effects on cell viability, were studied. FeSO₄ significantly decreased cell viability in a dose-dependent manner and the XTT₅₀ value, the concentration of FeSO₄ which reduced the cell viability by half, was measured at 63.3 μM in these cultures. FeSO₄ was estimated to be highly cytotoxic by the Borenfreund and Puerner toxicity criteria. Quercetin, an antioxidant, significantly improved cell viability, damaged by FeSO₄-induced cytotoxicity. While evaluating the protective effects of the PP extract on FeSO₄-induced cytotoxicity, it was observed that the extract significantly increased cell viability compared to the FeSO₄-treated group. Also, the PP extract showed superoxide dismutase (SOD)-like and superoxide anion radical (SAR)-scavenging activities. Based on these findings, it can be concluded that FeSO₄ induced oxidative stress-related cytotoxicity, and the PP extract effectively protected against this cytotoxicity via its antioxidative effects. In conclusion, natural antioxidant sources such as PP may be agents useful for preventing oxidative stress-related cytotoxicity induced by heavy metal compounds such as the FeSO₄, a known Parkinsonism inducer.

• Journal of Korean Neurosurgical Society
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• v.30 no.5
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• pp.553-560
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• 2001

Objective : The objective of this study was to determine the photodynamic therapeutic response of U-87 human glioma cell in vitro as well as in the nude rat xenograft model using photofrin as photosensitizer. Material and Method : U-87 cells were cultured on 96-well culture plates, photofrin(Quadralogic Technologies Inc., Vancouver, Canada) was added into the cell culture medium at concentration of $1{\mu}g/ml$, $2.5{\mu}g/ml$, $5{\mu}g/ml$, $10{\mu}g/ml$ and $20{\mu}g/ml$. 24 hour after drug treatment, cells were treated with optical(632nm) irradiation of $100mJ/cm^2$, $200mJ/cm^2$ and $400mJ/cm^2$. Photofrin(12.5mg/kg, i.p.) was administered to 28 nude rats containing intracerebral U-87 human glioma as well as 26 normal nude rats. 48 hours after administration, animals were treated with optical irradiation(632nm) of $35J/cm^2$, $140J/cm^2$ and $280J/cm^2$ to exposed tumor and normal brain. The photofrin concentration was measured in tumor and normal brain in a separate population of animals. Results : By MTT assay, there was 100% cytotoxicity at any dose of photofrin with optical irradiation of $200mJ/cm^2$ and $400mJ/cm^2$. But at the optical irradiation of $100mJ/cm^2$ cells were killed in dose dependent manner 28.5%, 49.1%, 54.4%, 78.2%, and 84.6% at concentration of $1{\mu}g/ml$, $2.5{\mu}g/ml$, $5{\mu}g/ml$, $10{\mu}g/ml$ and $20{\mu}g/ml$, respectively. Dose dependent PDT lesions in both tumor and normal brain were observed. In the tumor lesion, only superficial tissue damage was found with optical irradiation of $35J/cm^2$. However, in the optical irradiation group of $140J/cm^2$ and $280J/cm^2$ the volume of lesions was measured of $7.2mm^3$ and $14.0mm^3$ for treatment at $140J/cm^2$ and $280J/cm^2$, respectively. The U-87 bearing rats showed a photofrin concentration in tumor tissue of $6.53{\pm}2.16{\mu}g/g$, 23 times higher than that found in the contralateral hemisphere of $0.28{\pm}0.15{\mu}g/g$. Conclusion : Our data indicate that the U-87 human glioma in vitro and in the xenografted rats is responsive to PDT. At these doses, a reproducible injury can be delivered to human glioma in this model. Strategies to spare the normal brain collateral damage are being studied.

• Journal of Korean Society of Occupational and Environmental Hygiene
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• v.27 no.3
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• pp.193-200
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• 2017

Objectives: This study was performed to evaluate the neurototoxicity of the environmental pollutant lead acetate(LA) and the protective effect of the D-2-amino-5-phosphonovaleric acid(APV), N-methyl-D-aspartate(NMDA) receptor antagonist on LA-induced cytotoxicity in cultured C6 glioma cells. Materials and Methods: For this study, cell viability in cultured C6 glioma cells was assessed by XTT assay and antioxidative effect, such as lactate dehydrogenase(LDH) activity, by LDH detection kit. Results: LA significantly decreased cell viability in a dose-dependent manner, and the XTT50 value was determined to be 33.3 uM of LA. The cytotoxicity of LA was deemed highly toxic according to Borenfreund and Puerner's toxic criteria. The vitamin E antioxidant significantly increased cell viability damaged by LA-induced cytotoxicity in these cultures. For the protective effect of APV on LA-induced cytotoxicity, APV significantly increased not only cell viability, but also inhibition of LDH activity. From these results, it is suggested that oxidative stress is involved in the neurotoxicity of LA, and APV effectively protected against LA-induced cytotoxicity via an antioxidative effect as an inhibotory activity of LDH. Conclusions: Natural resources like APV may be putative therapeutic agents for the toxic diminution of environmental pollutants such as LA correlated with oxidative stress.

• The Journal of Internal Korean Medicine
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• v.28 no.3
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• pp.409-420
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• 2007

Objectives : The purpose of this study was to identify the anti-tumor effects of realgar on various cancer cells through molecular biologic and cellular biologic methods. Materials & Methods : We used 5 kinds of cancer cell lines:stomach cancer cell (AGS), glioma cells (T98G, A172, SNU-489) and prostate cancer cells (LNCaP). We injected the boiled extract of realgar. $50{\mu}$g/ml and $100{\mu}$g/ml to culture media (ml) for 24 hours. We examined the morphological changes under an inverted microscope and a fluorescence microscope. We measured the suppressive effect on viability of 5 kinds of cancer cells via XTT assay. We examined the effect on the revelation of PARP cleavage, Bcl-2 protein and Bax protein by western blot analysis. Results : The extract of realgar caused markedly morphological changes on AGS, T98G, SNU-489, and LNCaP. All of them showed withdrawn and floating appearance. The suppressive effect on viability of AGS, T98G, A172, SNU-489, and LNCaP showed that each test group had more suppressive effect on viability of AGS, T98G, A172, SNU-489, and LNCaP than the control group, which was statistically significantly (p<0.01). The extract of realgar did not induce PARP cleavage in AGS, T98G, A 172, SNU-489, or LNCaP. In the revelation of protein related to apoptosis, the protein levels of Bcl-2 decreased and the protein levels of Bax increased in AGS, T98G, SNU-489, and LNCaP treated with realgar. The protein levels of Bcl-2 decreased and the protein levels of Bax did not change in A172 treated with realgar. Conclusions : This experiment showed that realgar has anti-tumor effect on stomach cancer cells (AGS), glioma cells (T98G, SNU-489L and prostate cancer cells (LNCaP)

• Korean Journal of Clinical Laboratory Science
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• v.49 no.1
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• pp.8-14
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• 2017

To examine the protective effect of rosmarinic acid on the aluminum of dementia inducer, cultured C6 glioma cells were treated with various concentrations of aluminum chloride ($AlCl_3$) or rosmarinic acid. The cell viability, electron donating ability (EDA), superoxide dismutase (SOD)-like activity, and inhibitory activity of lipid peroxidation were evaluated for the antioxidant effect of rosmarinic acid. In these cultures, $AlCl_3$ sowed a cytotoxic effect by decreasing the cell viability in a dose-dependent manner; then, the $XTT_{50}$ value was measured at $142.2{\mu}M$ of $AlCl_3$ after treating the cultured C6 glioma cells with media containing $120{\sim}160{\mu}M\;AlCl_3$. Therefore, its toxicity was determined as mid-cytotoxic by Borenfreund and Puerner's toxic criteria; while, vitamin E of antioxidant markedly increased the cell viability on $AlCl_3$-induced cytotoxicity in these cultures. This study showed the antioxidant effect of rosmarinic acid via several assays, such as electron donating activity (EDA), superoxide dismutase (SOD)-like activity, and inhibitory activity of lipid peroxidation. From these findings, it is suggested that the oxidative stress is involved in $AlCl_3$-induced cytotoxicity, and rosmarinic acid was effective in the protection of $AlCl_3$-induced cytotoxicity by antioxidant activity. In conclusion, natural resources, like rosmarinic acid, may be a putative antioxidant agent for the treatment of reactive oxygen species (ROS)-mediated disease, such as dementia.

• Molecules and Cells
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• v.43 no.6
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• pp.539-550
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• 2020

Glioblastoma multiforme (GBM) is a fatal malignant tumor that is characterized by diffusive growth of tumor cells into the surrounding brain parenchyma. However, the diffusive nature of GBM and its relationship with the tumor microenvironment (TME) is still unknown. Here, we investigated the interactions of GBM with the surrounding microenvironment in orthotopic xenograft animal models using two human glioma cell lines, U87 and LN229. The GBM cells in our model showed different features on the aspects of cell growth rate during their development, dispersive nature of glioma tumor cells along blood vessels, and invasion into the brain parenchyma. Our results indicated that these differences in the two models are in part due to differences in the expression of CXCR4 and STAT3, both of which play an important role in tumor progression. In addition, the GBM shows considerable accumulation of resident microglia and peripheral macrophages, but polarizes differently into tumor-supporting cells. These results suggest that the intrinsic factors of GBM and their interaction with the TME determine the diffusive nature and probably the responsiveness to non-cancer cells in the TME.