• Toxicological Research
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• v.35 no.1
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• pp.83-91
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• 2019

Nanoparticles (NPs) have been recognized as both useful tools and potentially toxic materials in various industrial and medicinal fields. Previously, we found that zinc oxide (ZnO) NPs that are neurotoxic to human dopaminergic neuroblastoma SH-SY5Y cells are mediated by lipoxygenase (LOX), not cyclooxygenase-2 (COX-2). Here, we examined whether human bone marrow-derived mesenchymal stem cells (MSCs), which are different from neuroblastoma cells, might exhibit COX-2- and/or LOX-dependent cytotoxicity of ZnO NPs. Additionally, changes in annexin V expression, caspase-3/7 activity, and mitochondrial membrane potential (MMP) induced by ZnO NPs and ZnO were compared at 12 hr and 24 hr after exposure using flow cytometry. Cytotoxicity was measured based on lactate dehydrogenase activity and confirmed by trypan blue staining. Rescue studies were executed using zinc or iron chelators. ZnO NPs and ZnO showed similar dose-dependent and significant cytotoxic effects at concentrations ${\geq}15{\mu}g/mL$, in accordance with annexin V expression, caspase-3/7 activity, and MMP results. Human MSCs exhibited both COX-2 and LOX-mediated cytotoxicity after exposure to ZnO NPs, which was different from human neuroblastoma cells. Zinc and iron chelators significantly attenuated ZnO NPs-induced toxicity. Conclusively, these results suggest that ZnO NPs exhibit both COX-2- and LOX-mediated apoptosis by the participation of mitochondrial dysfunction in human MSC cultures.

• Biomolecules & Therapeutics
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• v.32 no.1
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• pp.65-76
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• 2024

Bortezomib (BTZ) is a proteasome inhibitor used to treat multiple myeloma (MM). However, the induction of peripheral neuropathy is one of the major concerns in using BTZ to treat MM. In the current study, we have explored the effects of BTZ (0.01-5 nM) on rat neural stem cells (NSCs). BTZ (5 nM) induced cell death; however, the percentage of neurons was increased in the presence of mitogens. BTZ reduced the B-cell lymphoma 2 (Bcl-2)/Bcl-2 associated X protein ratio in proliferating NSCs and differentiated cells. Inhibition of βIII-tubulin (TUBB3) degradation was observed, but not inhibition of glial fibrillary acidic protein degradation, and a potential PEST sequence was solely found in TUBB3. In the presence of growth factors, BTZ increased cAMP response element-binding protein (CREB) phosphorylation, brain-derived neurotrophic factor (Bdnf) transcription, BDNF expression, and Tubb3 transcription in NSCs. However, in the neuroblastoma cell line, SH-SY5Y, BTZ (1-20 nM) only increased cell death without increasing CREB phosphorylation, Bdnf transcription, or TUBB3 induction. These results suggest that although BTZ induces cell death, it activates neurogenic signals and induces neurogenesis in NSCs.

• The Korean Journal of Physiology and Pharmacology
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• v.2 no.5
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• pp.565-572
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• 1998

The present study was to evaluate the protective effects of bromocriptine, which is known as $D_2$ dopamine receptor agonist and used for the treatment of patients with Parkinson's disease (PD), on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in vitro and in vivo. Lipid peroxidation product (malondialdehyde; MDA) produced by the administration of 6-OHDA was profoundly reduced following the treatment of bromocriptine in a dose-dependent manner in rabbit brain homogenate. Quinone formation by 6-OHDA autoxidation was also attenuated, and its effect was as potent as other antioxidants. Pretreatment of bromocriptine reduced the cytotoxicity of 6-OHDA on SH-SY5Y neuroblastoma cell lines dose-dependently. The loss of striatal dopamine and its metabolite, DOPAC (dihydroxyphenylacetic acid) as well as increase of MDA production caused by intrastriatal injection of 6-OHDA was significantly recovered following the treatment of bromocriptine. The present study clearly showed that bromocriptine had a protective action against 6-OHDA-induced neurotoxicity. These results suggest that bromocriptine has the antioxidant properties, which could be another advantage for delaying the progress of Parkinson's disease.

• The Korean Journal of Physiology and Pharmacology
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• v.11 no.5
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• pp.171-174
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• 2007

Neuronal death is a common characteristic hallmark of a variety of neurodegenerative disorders including Alzheimer's disease and Parkinson's disease. However, there have been no effective drugs to successfully prevent neuronal death in those diseases, whereas oriental medicinal plants have to possess valuable therapeutic potentials to treat neurodegenerative diseases. In the present study, in an attempt to provide neuroprotective agents from natural plants, 80% methanol extracts of a wide range of medicinal plants, which are native to Jeju Island in Korea, were prepared and their protective effects on hydrogen peroxide-induced apoptotic cell death were examined. Among those tested, extracts from Smilax china and Saururus chinesis significantly decreased hydrogen peroxide-induced apoptotic cell death. The extracts attenuated hydrogen peroxide($H_2O_2$)-induced caspase-3 activation in a dose-dependent manner. Further, plant extracts restored $H_2O_2$-induced depletion of intracellular glutathione, a major endogenous antioxidant. The data suggest that Jeju native medicinal plants could potentially be used as therapeutic agents for treating or preventing neurodegenerative diseases in which oxidative stress is implicated.

• Korean Journal of Pharmacognosy
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• v.39 no.4
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• pp.290-294
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• 2008

The objective of this study is screening the anti-oxidative effects of several plant MeOH extracts against oxidative stress in Neuroblastoma cell. Oxidative stress has been implicated in the pathogenesis of many neurotoxicity, neurodegenerative disorders and cell death. This oxidative stress is generated by ROS (Reactive Oxygen Species) such as nitric oxide, nitrogen dioxide, peroxyl, superoxide ($O_2^-$), hydroxyl, alkoxyl. So, in the present study, we induced oxidative stress by treatment of sodium nitroprusside (2.5 mM) in human neuroblastoma SH-SY5Y cell which was treated samples before 24hr, and cell viability was measured by MTT reduction assay. Of those tested, the extracts of Paeonia japonica (roots), Eucommia ulmoides (炒)(barks), Paeonia japonica (曝乾)(roots), Phyllostachys bambusoides (stems), Polygala tenuifolia (去心, 炒)(roots), Paeonia japonica (roots), Polygala tenuifolia (roots), Machilus thunbergii (barks), Mallotus japonicus (leaves), Poria cocos (whole), Sophora flavescens (roots), Angelica tenuissima (roots), Angelica gigas (當歸尾)(roots) showed anti-oxidative effects[$EC_{50}$<15.20 ${\mu}g$/ml(Carnosine:Positive control)]in dose dependent manner.

• Biomedical Science Letters
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• v.17 no.2
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• pp.167-171
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• 2011

[ ${\alpha}$ ]synuclein (${\alpha}$-syn) is implicated in the pathogenesis of Parkinson's disease (PD) and other related diseases. We have previously reported that ${\alpha}$-syn binds to the cell membranes in a transient and reversible manner. However, little is known about the physiologic function and/or consequence of this association. Here, we examined whether chemically induced perturbations to the cellular membranes enhance the binding of ${\alpha}$-syn, based on hypothesis that ${\alpha}$-syn may play a role in maintenance of membrane integrity or repair. We induced membrane perturbations or alterations in ${\alpha}$-syn-overexpressing human neuroblastoma cells (SH-SY5Y) by treating the cells with hydrogen peroxide ($H_2O_2$) or oleic acid. In addition, membranes fractionated from these cells were perturbed by treating them with proteinase K or chloroform. Dynamic interaction of ${\alpha}$-syn to the membranes was analyzed by the chemical cross-linking assay that we developed in the previous study. We found that membrane interaction of ${\alpha}$-syn was increased upon treatment with membrane-perturbing reagents in a dose and time dependent manner. These results suggest that perturbations in the cellular membranes cause increased binding of ${\alpha}$-syn, and this may have significant implication in the physiological function of ${\alpha}$-syn in cells.

• Proceedings of the Korea Society of Environmental Toocicology Conference
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• 2003.10a
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• pp.177-177
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• 2003

Methylmercury (MeHg) is a well-known neurotoxicant that causes severe damage to the central nervous system in humans. Many reports have shown that MeHg is poisonous to human body through contaminated foods and has released into the environment. Despite many studies on the pathogenesis of MeHg-induced central neuropathy, no useful mechanism of toxicity has been established so far. In this study, suppressive subtractive hybridization (SSH) was performed to identify differentially expressed genes on human neuroblastoma cell line, SH-SY5Y treated with DMSO and MeHg (6.25 uM) for 6 hr. Differentially expressed cDNA clones were sequenced and were screened by dot blot to eliminate false positive clones. 13 of 35 screened genes were confirmed using real time RT-PCR. These genes include EB1,90-kDa heat-shock protein, chromosome condensation-related SMC-associated protein and brain peptide Al, etc. Analysis of these genes may provide an insight into the neurotoxic effects of MeHg in human neuronal cells and a possibility to develop more efficient and exact monitoring system of heavy metals as ubiquitous environmental pollutants.

• Korean Journal of Pharmacognosy
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• v.40 no.1
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• pp.41-45
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• 2009

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzhemier's disease. Neuropathologically, PD is characterized by the selective loss of dopaminergic neurons. The neuronal toxicity of cytosolic excess dopamine (DA) has been described in many studies using several cell lines. In dopaminergic neurons, cytosolic excess DA is easily oxidized via monoamine oxidase (MAO)-B, tyrosinase or by auto-oxidation to produce neurotoxic metabolites such as DA quinone. So, in the present study, we induced cell death by treatment of DA ($600{\mu}M$) in human neuroblastoma SH-SY5Y cell which was treated samples before 24 hr, and cell viability was measured by fluorescence activated cell sorter (FACs) analysis. Of those tested, the extracts of Poria cocos (赤茯笭)(whole), Gastrodia elata (rhizomes), Eucommia ulmoides (炒)(barks), Syneilesis palmata (whole), Acorus gramineus (rhizomes), Ligustrum japonicum (leaves) showed neuroprotective effects in dose dependent manner.

• YAKHAK HOEJI
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• v.55 no.3
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• pp.213-218
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• 2011

The aim of this study is to evaluate the sedative effects of ethanol extract and the three major constituents of Cimicifugae Rhizoma. They decreased locomotor activity significantly, and enhanced sleeping duration induced by thiopental sodium. The ethanol extract of Cimicifugae rhizoma and 24-epi-7,8-didehydrocimigenol-3-xyloside (24-epi.) increased the $Cl^-$ influx into the intracellular area of SH-SY5Y neuroblastoma cells significantly. The present results demonstrate that the sedative effects of Cimicifugae rhizoma are mediated via the GABA-gated $Cl^-$ channel, partly by 24-epi.

• Korean Journal of Medicinal Crop Science
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• v.23 no.2
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• pp.144-149
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• 2015

The peel of Citrus sunki exhibits multiple biological activities such as anti-oxidant, anti-inflammation and anti-obesity, but little is known about neurodegeneration-related activities. In this study, we investigated the protective effect of ethanolic extract from both immature and mature Citrus sunki peel on neuronal cell death. Treatment of the neuroblastoma cell line SH-SY5Y with $MPP^+$, an inducer of Parkinson disease model, increased cell death in a dose dependent manner. Increased levels of active caspase-3 and cleaved PARP were detected. Treatment with immature Citrus sunki peel extract significantly reduced $MPP^+$-induced neurotoxicity. Cytoprotection with immature Citrus sunki peel extract was associated with a decrease in caspase-3 activation and PARP cleavage. In contrast, mature Citrus sunki peel extract had no significant effects. These data suggest that immature Citrus sunki peel extract may exert anti-apoptotic effect through the inhibition of caspase-3 signaling pathway on $MPP^+$-induced neuronal cell death.